Volume 20, Number 1 January 2013

Volume 20, Number 1

January 2013

ISSN 1117-4153

THE TROPICAL JOURNALOF

HEALTH SCIENCES

PUBLISHED

BY

COLLEGE OF HEALTH SCIENCESUNIVERSITY OF ILORIN, ILORIN, NIGERIA

(A WHO Collaborating Centre for Research an Manpower Development)Also available on AFRICAN JOURNAL ONLINE (AJOL)

i

Volume 20, Number 1January 2013

THE TROPICAL JOURNAL OF HEALTH SCIENCES

Official Publication of the College of Health Sciences, University of Ilorin

EDITORIAL BOARD

EDITOR-IN-CHIEFA.B. Okesina

ASSOCIATE EDITORS

E.O. OlorundareT.O. OdebodeO.T. Adedoyin

BUSINESS/CIRCULATION MANAGERT.M. Akande

CONSULTING EDITORS

O.K. Alausa NIGERIA V. Neufeld CANADA

E.B. Attah NIGERIA E.H.O. Parry UNITED KINGDOM

J.D. Hamilton AUSTRALIA H.G. Schmidt GERMANY

D.R. Hopkins UNITED STATES O.Sofola NIGERIA

O.O. Kale NIGERIA J.Weisfeld EGYPT

ii

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The Tropical journal of Health Sciences

ISSN 1117-4153

AIMS AND SCOPE

iii

THE TROPICAL JOURNAL OF HEALTH SCIENCES

Volume 20 Number 1 January, 2013

CONTENTS

Research papers

Editorial comments v

iv

1

8

13

18

23

31

37

45

49

Occupational Hazards, Hazard Prevention And Health Problems Among Workers Of Local Sawmill Industries In A Fast Growing Peri-Urban Community Southwestern Nigeria

J.O. Bamidele, A.A.Adeomi, E.O.Okeyode

Strategies For Enhancing Competencies Among Clinical Officers In KenyaKaranja Lawrence Mwangi

An Open Comparative Antihypertensive Effects Of Amlodipine (“Norvasc®”), Lisinopril (“Zestril®”)

and BendrofluazideO.G. Opadijo, E.O. Sanya, P.M. Kolo, K.W. Wahab

Reference Values and Relationship between Cardio-Respiratory Fitness Index and Body Mass Index of Adolescent Students in a Southwestern Nigerian Community

A.O Akinpelu, O.O. Oyewole, A.C Odole, C.A Gbiri

Vitamin E Attenuates Toxic Effects Of Combined Administration Of Ivermectin And Albendazole In Selected Rat Tissues

R.O. Arise, S.O Malomo.

Bacterial Isolates Of Blood In Children With Suspected Septicaemia In A Nigerian Tertiary Hospital

O.T. Adedoyin, M Ibrahim, W.B.R. Johnson, A.I. Ojuawo, O.A. Mokuolu, S.K. Ernest, O.Adesiyun, AO. Adegboye, A.A. Akanbi II, S. Odimayo, O V.Adebara, A.O. Saka

Microarchitectural Changes in the Superior Colliculli of Male Wistar Rats after Cigarette and Cotton Wool Smoke ExposureG.O. Omotoso, B.U. Enaibe, E.A. Caxton-Martins

The Effect of Metformin on Serum Levels of FSH, LH, Oestrogen and Progesterone in Diabetic Rats3L.S. Ojulari, S.A. Biliaminu, T.T. Ahmed, F.I. Abdulazeez, O.S. Oyekunl , F.A. Niyi-Odumosu, O.A. Adegoke 41

Any Association Between ABO /Rh Blood Groups And Breast Cancer ?A.S. Oguntola, E.O. Akanni , M.L. Adeoti

Challenges Of Haematuria In Pregnancy In The TropicsA.A. Popoola, K. Adesina, S.A. Kuranga, A.L. Babata, I.Oseni, O. Abiola

EDITORIALCOMMENTS

Welcome to the volume 20 number 1 edition of Tropical Journal of Health Sciences. The articles in this edition cut across various aspects of medical practice and basic medical sciences. The first article addressed report of a research carried out on occupational hazard among workers in the wood industry. Majority of the respondents were aware of hazards in the work place, but their practice, with regard to use of protective devices, was poor. Workers therefore suffered different forms of work-related injuries, many of which would have been prevented. The need to deliver enlightenment campaigns to workers, in the local sawmill industry about hazard prevention was recommended.

The article from Kenya assessed competencies of clinical officers (COs). Most of the COs (63 percent) rated their competence at below best practice. Noted deficiencies were in generic skills such as information technology, management and finance. On-the-job training, publication and holding of administrative duties were statistically associated with superior ratings on competence. This study demonstrates that it is feasible to assess the competence of COs using a brief self-administered questionnaire. It also shows that in order to enhance the competencies of COs, interventions such as on-the-job training and mentorship programs are required.

Comparative study showed that bendrofluazide is potent, efficacious and tolerable as relatively newer antihypertensive agents and more economical. However, it may add more to the ischaemic burden in view of its unfriendly effects on serum metabolic parameters especially total cholesterol. Frequent checkups for these undesirable metabolic side effects and prompt intervention are needed in patients, when this drug is in use.

Research using rats showed that vitamin E may be able to ameliorate toxic effects of combined use of ivermectin and albendazole. Therefore, the use of vitamin E along with the two drugs was advocated.

Damaging effect of cigarette on the brain was demonstrated by research on rats exposed to both cotton wool smoke and cigarette smoke. The histological sections of the animals exposed to cigarette smoke showed reduced number of neurons, reduced density of neuronal bodies, many cytoplasmic vacuolations, and distorted cytoarchitecture, compared with the control animals. Animals exposed to cotton wool smoke alone, showed few vacuolated spaces only on day 21. Authours suggested that these histological changes were most likely due to the oxidative stress and ischaemia resulting from the cigarette smoke.

Professor AB OkesinaEditor –in – Chief

v

Correspondence to:

1

Occupational Hazards, Hazard Prevention And Health Problems Among Workers Of Local Sawmill Industries In

A Fast Growing Peri-Urban Community Southwestern Nigeria

1 2 3J.O. Bamidele; A.A.Adeomi; E.O.Okeyode 1Department of Community Medicine, Faculty of Clinical Sciences, College of Health Sciences,

Ladoke Akintola University of Technology (LAUTECH), Ogbomoso, Oyo State, Nigeria.2Department of Community Medicine, Ladoke Akintola University of Technology (LAUTECH) Teaching Hospital, Ogbomoso, Oyo State, Nigeria.

3Department of Community Medicine, Ladoke Akintola University of Technology (LAUTECH) Teaching Hospital, Osogbo, Osun State, Nigeria.

Dr. J.O. Bamidele Department of Community Medicine, Faculty of Clinical Sciences, LAUTECH College of Health Sciences, Ogbomoso, Oyo State, Nigeria.Tel: +234 803 394 3665e-mail: [email protected]@yahoo.co.uk

Abstract Majority of the respondents were aware of With urbanization, the timber and saw milling hazards in the work place, but their preventive

industries have assumed a significant part of practices, as it relates to use of protective devices, was occupation of the people, and no doubt these workers poor. Consequently, these workers have suffered are everyday exposed to various hazards in their different forms of work-related injuries, many of which workplaces. It is therefore important to carry out this would have been prevented. There is therefore need for study to determine the occupational hazards this more enlightenment of workers in the local sawmill specific group of workers are exposed to and also their industry about hazard prevention and the need of using awareness and prevention of these hazards in the protective devices.community under study.

Key words: Occupation hazards; prevention; saw A descriptive cross-sectional study was carried millers; plank dealers; personal protective equipmentout in Osogbo Local Government Area and data were

collected using pre-tested semi-structured Introduction questionnaires. Utilizing the multi-stage sampling

Generally, the major wood processing technique, 210 questionnaires were administered to the industries in Nigeria are typically large capacity workers who consented. One hundred and ninety six facilities industry such as large sawmills, plywood mill, questionnaires were fully completed and used for pulp and paper plants and quite large numbers of small analysis. scale wood products manufacturing companies such as The mean age of the respondents was 39.99 ±

1furniture industries, cabinet makers and carpentry. 5.62 years with 62.8% of the workers falling within the In Nigeria, majority of the sawmill industries are active working age group of 20-49 years old. One located in the wood producing rain forest areas of the hundred and forty-four (73.0%) were aware of hazards Country in which the western states are among. The in their work place, of which 87.5% knew wood dust to largest concentration of sawmills are in Lagos, Ekiti, be hazardous to their health. Of the injuries and illness Cross River, Ondo, Oyo, Imo, Edo, Delta, Ogun and suffered at the work place, minor cuts (68.4%); Osun States which account for over 90% of the saw accidental injuries (54.1%); visual impairment/eye

2irritation (51.5%); and respiratory problems due to milling activities in the Country. With urbanization, wood dust (46.9%) ranked highest in that order. the timber and sawmilling industries have assumed a Majority of the workers ranging from 67.9% to 89.9% significant part of occupation of the people, and no never used any protective devices. About two-thirds of doubt these workers are everyday exposed to various

3the respondents associated the injury and health hazards in their workplaces.problem they had with their work, and there were The nature of the work done by workers in this significant associations (p<0.05) between accidental occupation and the types of equipments and materials injuries, skin irritations and respiratory problems with they handle is associated with many on-the-job

4the work process. hazards. Hazards and injuries resulting from working in sawmills include: mechanical hazards such as being caught-in or struck by machinery, falling from a height, heavy lifting or repetitive movements, twisting or reaching; chemical hazards such as breathing in noxious or toxic chemicals like wood dust, while working for increase productivity, as well as the physical hazards such as unfavourable weather conditions which the workers are exposed to, and noise

5pollution that is injurious to human health. There are lots of human involvements (manual handling) in sawmilling operations which makes workers to be exposed to higher levels of risks associated with log handling and machine operation, environmental

J.O. Bamidele et al/ The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

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14hazards, work related body injuries, and in extreme the population of Osogbo LGA at 155,507. There 5,6cases, death. were three registered sawmilling industries in the

Hazards experienced in sawmill industries also community under study with an estimated work force include; environmental hazards as a result of poor of 350 as documented by the industries and respondents forestry practices and management, poor solid waste were recruited from all of them. management and toxic emissions to air, which all The sample size formula for population less

15constitute hazard to the public; while noise, hazards than ten thousand was used to get the desired number due to machinery use, and ergonomic hazards resulting of respondents recruited for the study. Systematic from lifting of heavy loads, reaching for objects, sampling technique was used to select the respondents

6repetitive work, and poor work posture, as well as in all the three sawmilling industries using the list of respiratory problems constitute hazard to the individual workers (sample frame) as given by the manager of

7-12 each factory. A semi-structured pretested worker. questionnaire was used to elicit information from They are also exposed to synthetic chemicals respondents by interviewer method. Information sort used in these woods. Most adverse effects caused by include: socio-demographic characteristics of the microorganism associated with wood dust have respondents; occupational history; awareness by immunological background and the best known effects respondents of hazards in their workplace and mode of are those caused by moulds which may abundantly prevention and the presence of any preventive develop in suitable conditions on stored wood (planks, measures and compliance with safety regulations. chips) as a secondary wood infection. The inhalation of

Data were analyzed using the statistical large amounts of spores and mycelia fragment of fungi package for social sciences (SPSS). Cross-tabulations may cause in exposed workers strong antibody of variables were constructed and p-value set at p<0.05. response and respiratory disorders or organic dust toxic

13 Ethical clearance was obtained from the Ethical syndrome.committee of the LAUTECH Teaching Hospital, A large number of workforce is engaged in the Osogbo. Permission to carry out the study was given by sawmill industries in Osun State and awareness of the Works department of the LGA and the Manager in hazards inherent to these workers will make them take charge of each of the sawmill industries. The necessary steps in protecting themselves from the respondents also gave verbal consent.adverse health effects of these hazards, thus making our

present and future work force healthy and productive. ResultsThis study therefore seeks to determine the

Out of the 210 questionnaires that were occupational hazards this specific group of workers are administered to the workers, 196 (93.3%) were found exposed to, their work related health problems and also to be adequately filled for analysis. As shown in table 1, their awareness and prevention of these hazards in the the mean age of the respondents was 39.99 ± 5.62 years community under study.with 123(62.8%) of the workers falling within the active working age group of 20-49 years. Majority of Materials And Methodsthe workers were males (166, 85.0%), had secondary This descriptive cross sectional study was school education and above (137, 70.0%), earned carried out in Osogbo Local Government Area (LGA) monthly income of less than ten thousand naira (80, of Osun State. Osogbo LGA is part of the popular 40.8%) and had received formal training for the job ancient town of Osogbo. This community under study (160, 82.0%). was a relatively quiet peri-urban and traditional Most of respondents, 144 (73.0%) were aware of community South West of Nigeria until very recently hazards in their work place, table 2. The commonly when some government policies attracted students and known types or sources of hazards by this group of workers alike to the city. Among these policies are the respondents include wood dust (87.5%), electricity sittings of tertiary institutions by the State Government (75.7%), manual lifting of objects (75.0%), fire and also the instruction of the Central Bank of Nigeria (73.0%), machine (69.5%), noise (61.1%), heat to all Commercial Banks to locate their branches in all (52.8%) and snake bite (38.9%).the State capitals in Nigeria of which Osogbo is one. Of the injuries and illnesses suffered at the work place, This brought some level of urbanization into the city minor cuts (134, 68.4%), accidental injuries (106, and the sprouting of numerous buildings both private 54.1%), visual impairment/eye irritation (101, 51.5%) abodes, tourist hotels, and work places. There was also and respiratory problems due to wood dust (92, 46.9%) a boom in social and economic activities including the ranked highest in that order. Most of the respondents sawmill industries. (126, 64.0%) associated the injury and health problem Osogbo LGA consists of 15 political wards and they had with their work. Table 3.7 health districts; residents are predominantly of In table 4, only 41 respondents (21.0%) and only 31 Yoruba tribe comprising of both indigenes and non-respondents (15.8%) had ever received health indigenes. The national population census of 2006 put


3

Table 1: Socio -demographic characteristics of the respondents (n=196)

Variables

Frequency (%)

Age in

years

< 20

20-29

30-39

40-49

50 +

Mean age

12 (6.1)

45 (23.0)

43 (21.9)

35 (17.9)

61 (31.1)

39.99 ± 5.62 years

Gender

Male

Female

166 (85.0)

30 (15.0)

Marital status

Married

Single

146 (74.0)

50 (26.0)

Level of Education

None

Primary

Secondary

Post Secondary

14 (7.0)

45 (23.0)

82 (42.0)

55 (28.0)

Income of respondents per month (Naira)

< 10,000

10,000-19,999

20,000-29,999

30,000-39,999

40,000 and above

80 (40.8)

74 (37.7)

24 (12.2)

4 (2.0)

14 (7.1)

Religion of respondents Christianity

Islam

90 (46.0)

106 (54.0)

Job description

of respondents

in the

sawmills

Administrators Saw-millers

Plank dealers

5 (2.1)

44 (22.9) 147 (75.0)

Received formal training for the job Yes

No

160 (82.0)

36 (18.0)

education on safety at work and had ever gone for routine medical examinations respectively. Usage of personal protective equipments (PPEs) was highest for protective wears/overall (21, 10.7%) and least for helmet (3, 1.5%). Only 4 (2.0%) and 8(4.1%) of the respondents always used earmuffs and face masks respectively. Concerning the reasons given by respondents for non-usage of PPE, 80 (40.8%) felt they were not necessary, 65 (33.2%) claimed they were not always available and 41 (20.9%) thought they were inconvenient to use. Thirty seven (18.9%) respondents and 46 (23.3%) respondents use the bathroom and the changing room at the w o r k p l a c e a f t e r w o r k respectively, while only 51 (26.0%) of the respondents were aware of a government policy concerning accident/injury compensation at work place.Selected socio-demographic characteristics of respondents were cross tabulated with their awareness about hazards in their work place, but there was no significant association between any of factors and their awareness about hazards in their workplace. Accidental injuries, skin irritation and respiratory problems were h o w e v e r , f o u n d t o b e significantly associated with the work process p<0.05).

Discussion The level of awareness was high among respondents with 7 out of 10 respondents aware of one hazard or the other in their work place, and about 90% of those that were aware of work place hazards knew wood dust to be hazardous to their health. This differs from

16the finding of Osagbemi et al where there was low level of awareness of hazards among the saw millers, with less than 30% knowing wood dust to be a form of hazard. This however, may be due to the high literacy level of the


4

Table 2: Awareness of hazards an d types of hazards at the work place (n=196)

Variables

Yes (%)

No (%)

Don’t know (%)

Awareness of hazards at the work place

144 (73.0)

52 (27.0)

-

Types/sources of hazards :

-

Noise

-

Heat

-

Chemical

-

Machine

-

Wood dust

-

Fire

-

Manual lifting of objects

-

Electricity

-

Snake bite

88

(61.1)

76 (52.8)

29 (20.1)

100 (69.5)

126 (87.5)

105 (73.0)

108 (75.0)

109 (75.7)

56 (38.9)

41 (28.5)

46 (31.9)

88 (61.1)

29 (20.1)

13 (9.0)

29 (20.1)

25 (17.4)

26 (18.1)

73 (50.7)

15 (10.4)

22 (15.3)

27 (18.8)

15 (10.4)

5 (3.5)

10 (6.9)

11 (7.6)

9 (6.2)

15 (10.4)

Table 3: Work place injuries and illness suffered as a result of workplace exposure by respondents. (n=196) Variables

Yes (%)

No (%)

Don’t know (%)

Injuries sustained at work:

-

Fall

-

Burns

-

Fracture

-

Accidental injuries

-

Minor cuts

-

Hearing problem

-

Visual impairment and eye irritation

-

Skin irritation

-

Respiratory problems due to wood dust

64 (32.7)

6 (3.1)

34 (17.4)

106 (54.1)

134 (68.4)

28 (14.3)

101 (51.5)

50 (25.5)

92 (46.9)

117 (59.7)

174 (88.8)

148 (75.5)

74 (37.8)

53 (27.0)

151 (77.7)

80 (40.8)

133 (67.9)

93 (47.4)

15 (7.7)

16 (8.2)

14 (7.1)

16 (8.2)

9 (4.6)

17 (8.7)

15 (7.7)

13 (6.6)

11 (5.6)

Is your injury or health problem a direct

result of your work process?

126 (64.0)

70 (36.0)

-

respondents in this study, with 70% having a minimum irritations and respiratory problems with the work of secondary school education. process.

Despite the high level of awareness of work This pattern of work-related injuries has been 1,4,17place hazards, there was a high prevalence of work- similarly documented by other researchers. Bello

1related injuries among the respondents. More than two- and Mijinyawa found that 83% of the mill workers thirds and more than half of the respondents had had investigated had sustained some form of work related minor cuts and visual impairment/eye irritation injuries. In another study carried out among sawmill respectively. About 15% of the respondents also workers in Ilorin, Kwara state, 4 out of 10 of the

16reported hearing problems; more than 3 out of 10 respondents reported minor injuries. Omokhodion reported work-related falls, a quarter reported skin and Kolude in their study of the health problems of mill irritation and nearly 2 out of 10 had had work related operators in a tropical African population also reported bone fractures. Furthermore, about two-thirds of the difficulty in hearing in about 30% of their respondents

17respondents associated the injury and health problem and tinnitus in another 2 out of 10 respondents. they had with their work, and there were significant High prevalence of respiratory problems

4,7-12associations between accidental injuries, skin among sawmill workers has been well documented,


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Table 4: Availability a nd usage of preventive measures at work place by respondents (n=196)

Variables

Yes (%)

No (%)

Don’t know (%)

Ever received health education on safety at the work place

41 (21.0)

155 (79.0)

-

Ever gone for routine medical examination

31 (15.8)

165 (84.2)

-

Awareness of accident/injury compensation plan at the work place

51 (26.0)

145 (74.0)

-

Usage of social/recreational of facilities available at the work place:

-

Toilet

-

Bathroom

-

Running tap

-

Canteen

-

Changing room

187 (95.4)

37 (18.9)

178 (90.8)

128 (65.3)

46 (23.5)

9 (4.6)

159 (81.1)

18 (9.1)

68 (34.7)

150(76.5)

Use of personal protective equipments (PPE):

-

Goggles

-

Boot

-

Helmet

-

Hand gloves

-

Protective wear/overall

-

Ear muffs

-

Face masks

Reasons for none usage of PPE:

-

Not necessary

80 (40.8%)

-

Not always available 65 (33.2%)

-

Not convenient to use 41 (20.9%)

-

Indifferent

10 (5.1%)

Always

17 (8.6)

13 (6.6))

3 (1.5)

10 (5.1)

21 (10.7)

4 (2.0)

8 (4.1)

Occasionally

35 (17.9)

25 (12.8)

19 (1.7)

37 (18.9)

42 (21.4)

16 (8.2)

23 (11.7)

Never

144 (73.5)

158 (80.6)

174 (88.8)

149 (76.1)

133 (67.9)

176 (89.9)

165 (84.2)

Table 5: Association of some selected Variables with Awareness of Hazards (n=196)

Variable Aw areness of Hazards df X2 p-value

Yes(%) No(%) Age (in years) Less than 20 20 - 29 30 – 39 40 – 49 50 and above

8(66.7) 27(60.0) 28(65.1) 27(77.1) 54(88.5)

4(33.3) 18(40.0) 15(34.9) 8(22.9) 7(11.5)

12

11.728

0.468 Not Significant

Educational level

None

Primary

Secondary Post-secondary

13(92.9)

33(73.3) 54(65.9) 44(80.0)

1(7.1)

12(26.7) 28(34.1) 11(20.0)

8

14.287

0.075 Not Significant

Formal training Yes

No

121(75.6)

23(63.9)

39(24.4)

13(36.1)

4

7.607

0.107

Not Significant


6

Table 6: Association of some selected Variables with the Work Process (n=196)

Variable Association with Work Process df X2 p-value

Yes (%) No (%)

Accidental Injuries

Yes No

79(62.7) 47(37.3)

27(38.6) 43(61.4)

1 10.55 <0.01 Significant

Skin irritation Yes No

40(31.7) 86(68.3)

10(14.3) 60(85.7)

1

7.22

<0.01 Significant

Respiratory problems Yes No

71(56.3) 55(43.7)

21(30.0) 49(70.0)

1

12.54

<0.001 Significant

and this was corroborated by the finding of this study wood dust to be hazardous to their health. with nearly half of the respondents reporting

Conclusion And Recommendationrespiratory problems due to wood dust. In a study Majority of the respondents were aware of carried out in Kaduna State, Nigeria, the Peak

hazards in the work place, but their preventive Expiratory Flow Rate (PEFR), Forced Vital Capacity practices, as it relates to use of protective devices, was (FVC), 1 sec Forced Expiratory Volume (FEV1) and poor. Consequently, these workers have suffered the FEV1/FVC ratio (FEV1%) were significantly

18 19 different forms of work-related injuries, many of which reduced among wood workers. Ihekwaba et al also would have been prevented. There is therefore need for worked on the lung function indices of sawmill workers more enlightenment of workers in the local sawmill and found that exposure to sawdust environment by industries about hazard prevention and the need of both primary and secondary sawmill workers reduces

7 using protective devices. There is also a need for their lung function indices. The study by Ugheoke et allegislations and enforcements to ensure workers' safety in Benin City, Nigeria where sawmill workers were and health in the workplace. compared with suitable controls also revealed that

sawmill workers had a clearly higher prevalence of Acknowledgment pulmonary symptoms when compared to the normal

The authors are grateful to the research population.assistants that assisted in data collection and the This pattern of work-related injuries and sawmill workers that participated in this study illnesses may not be unconnected with the fact that the especially for the time they spared to answer the preventive measures and practices were generally poor various questions put to them. among the respondents. More than 8 out of 10

respondents had never had routine medical Referencesexamination of any kind, 8 out of 10 respondents had

never received health education on safety at work and three-quarters were not aware of accident/injury compensation plan at the work place. More than 80% of the workers had never used such personal protective equipments as boots, helmets, ear muffs and face masks. This is almost similar to but slightly better than the findings of similar studies among sawmill workers

7in Benin City , where 95% of their respondents and none of the sawmill workers studied by Awoyemi in

12Ilorin wore no personal protective equipment such as 4

the face mask. In another study by Fatusi and Erhabor, less than 20% of sawmill workers used protective masks despite the fact that most of them recognized

References1. Bello SR, Mijinyawa Y. Assessment of Injuries in Small Scale Sawmill Industry of South Western Nigeria. Agricultural Engineering International: the CIGR Journal of Scientific Research and Development. 2010;12:1-11. 2. Raw Materials Research and Development Council (RMRDC). Multi-disciplinary committee report of a techno-economic survey on Wood and Wood Products Sector (4th update). 2003;3. Margaret B. Work and Health, an introduction to occupational health care. 1st ed. Chapman and Hall; 1995.

https://www.researchgate.net/publication/13675651_EURODIAB_IDDM_Complications_Study_Group_Parental_history_of_hypertension_and_parental_of_diabetes_and_microvascular_complications_in_insulin-dependent_diabetes_mellitus_EURODIAB_IDDM_Complications_Stu?el=1_x_8&enrichId=rgreq-18865aac9404a94dbb920c30fbe2e466-XXX&enrichSource=Y292ZXJQYWdlOzIzNTYxMTA0MjtBUzoxMjI3MTk4MDY5NTU1MjBAMTQwNjI3MDA5MDIxNg==


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4. Fatusi A, Erhabor G. Occupational health of sawmill workers in Ilorin, Nigeria. Bioscience status of sawmill workers in Nigeria. Journal of Research Communications. 1997; 19(2):139-141.reasearch and Social Health. 1996;116(4):232-236. 13. Alexsoon S, Ponten B. New Erogonomic 5. Judd HM, Janice KW. Safety in the wood problems in mechanised logging operations. products industry. Forest Products Journal. International Journal of Industrial Economics. 2004;54(10). 1990;5:267-273. 6. Aruofor RO. Review and improvement of data 14. Federal Republic of Nigeria Official Gazette. related to wood-products in Nigeria. EC-FAO Legal Notice on Publication of 2006 Census Final Partnership Programme (1998-2001). Tropical forestry Results. Abuja. 2009;96(2):B1-42. Budget line; 2000. 15. Olawuyi JF (ed). Biostatistics: A foundation 7. Ugheoke AJ, Wahab KW, Erhabor GE. course in health sciences: formulas for calculating Prevalence of Respiratory Symptoms among Sawmill sample size. 1st ed. Toyin Alabi Printing Co; 1996. Workers in Benin City, Nigeria. International Journal 16. Osagbemi GK, La-Kadri RT, Aderibigbe SA. of Tropical Medicine. 2009;4(1):1-3. Awareness of Occupational Hazards, Health Problems 8. Liou S, Cheng S, Lai F, Yang J. Respiratory and Safety Measures among Sawmill Workers in North symptoms and pulmonary function in mill workers Central Nigeria. TAF Preventive Medicine Bulletin. exposed to wood dust. American Journal of Industrial 2010;9(4):325-328. Medicine. 1996;30(3):293-299. 17. Omokhodion F, Kolude OO. Health problems 9. Massey. Dust harms sawmill workers. Massey of mill operators in a tropical African population. University. 2002;:5. WAJM. 2005;24(3):256-258. 10. Okwari O, Antai A, Owu D, Peters E, Osim E. 18. Tanko Y, Olakunle Y, Jimoh A, Mohammed A, Lung function status of workers exposed to wood dust Goji ADT, Musa KY. Effects of Wood Dust on in timber markets in Calabar, Nigeria. African Journal Cardiopulmonary Functions and Anthropometric of Medicine and Medical Sciences. 2005;34(2):141- Parameters of Carpenters and Non-Carpenters in 145. Sabon Gari Local Government Area, Kaduna State , 11. Mandryk J, Alwis KU, Hocking AD. Effects of Nigeria. 2011;3(1):43-46. Personal Exposures on Pulmonary Function and Work- 19. Ihekwaba AE, Nwafor A, Adienbo OM. Lung related Symptoms Among Sawmill workers. Annals of function indices in primary and secondary sawmill Occupational Hygiene. 2000;44(4):281-289. workers in PortHarcourt, Nigeria. Zoology. 12. Awoyemi AO. Occupational health problems 2009;11:101 - 105.

Correspondence to:

8

Strategies For Enhancing Competencies

Among Clinical Officers In Kenya

Karanja Lawrence Mwangi

Institute of Tropical Medicine and Infectious Diseases (ITROMID). Jomo Kenyatta University of Agriculture and Technology, P.O. Box 62000 Nairobi 00100 Kenya.

Karanja Lawrence Mwangi P. o. Box 9625, Nakuru 200100 KenyaTel: +254 0720 372 980Email:[email protected]

Abstract Key Words: Clinical Officers, Competencies, Questions have been raised about the Assessment , Strategies , Self-adminis tered

effectiveness of clinical officers' practice. Data that can questionnaire, KenyaIntroductioninform the design of appropriate policies on There has been an upsurge of interest in human development of the competence of clinical officers resources required to deliver health care in low-income (COs) in Kenya is limited. This study explored the settings as part of the drive to achieve the Millennium possibility of using a brief self-administered Development Goals. The Second National Health questionnaire to assess the levels of competence among Sector Strategic Plan of Kenya (NHSSP II COs in Kenya. A competence assessment tool was 2008–2012)recognizes the central role of managing

1developed following standard procedures. This tool and developing the health workforce . It further was then tested using a survey of 367 randomly appreciates that attention must be paid to performance selected COs working in selected public health of health workers through performance appraisal facilities in the country. Responses on COs systems. This indicates that the development of the competences were summarized using the top box competence of health workers is critical.method. Regression analysis was used to identify the Competence can be defined as cognitive, key levers of competence. interpersonal skills, moral and personality attributes

2The results illustrated that most of the surveyed which enable one to perform a specific job properly . COs were male, married and in their third decade of Regardless of training, competence grows through life. The typical clinical officer also had limited experience and the extent to which individuals' are able university education, had little on-the-job training, to learn, reflect and adapt. It is believed that the rarely publishes, undertakes administrative duties and development of competencies after basic training

3has limited networks. The competence assessment tool influences the performance of health professionals . showed some promise with a Cronbach's alpha (α) of However, this is contingent upon system and individual 0.65. The COs gave themselves an average score of related influences. A useful model divides competence 32.85 (SD = 3.60) on competence, with a range of 18- into four domains: cognition, integration, relations and

440. Most of the COs (63 percent) rated their affective . In clinical settings, cognition refers to competence at below best practice. Noted deficiencies acquiring and using knowledge to solve problems. were in generic skills particularly in information Integration is the use of biomedical and psychosocial technology, management and finance. On-the-job data in clinical reasoning. Relations refer to the art of training, publication and holding of administrative communicating effectively to patients, carers and duties were statistically associated with superior colleagues. The affective domain encompasses the ratings on competence. willingness, patience and emotional awareness to use

This study demonstrates that it is feasible to skills judiciously and humanely. It is now recognized assess the competence of COs using a brief self- that clinical competencies can be measured and

5administered questionnaire. It also shows that enhance improved . The challenge has been on the identification the competence of Cos, interventions such as on-the- of tool kits for assessing the competencies of health job training and mentorship programs were suggested. workers.

Clinical Officers (COs) are legally recognized 6

as qualified medical practitioners in Kenya . They are required to among others run health units, examine and treat patients, prepare legal documents such as medical certificates, death notification, P3 forms and present medical evidence in court. There are concerns about the

7effectiveness of the COs' practice . Need therefore exists to develop their competence. However, data that can inform the design of appropriate interventions on the development of the competence of COs in Kenya is limited. This deficiency compromises reforms that aim

K.L. Mwangi / The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

9

at attaining health equity in the country. This study voluntary organizations, held any administrative posts, explored the possibility of using a brief self- had any publications and whether they had taken any administered questionnaire to assess the levels of specialized courses in clinical medicine were also competence among COs in Kenya. posed. In addition the COs were asked to indicate an

estimate of the number of patients they attended to Methods daily.

This was a survey of COs in all public health Data was collected through a self-administered facilities in the country. COs in the two national referral questionnaire. The process took nine months from hospitals namely Kenyatta National Hospital and Moi September 2009 to May 2010 to complete and involved Referral Hospital were excluded primarily due to the 18 trained research assistants. Data was collected from complex nature of their functions. provincial hospitals, district and sub-district hospitals,

It is estimated that there are about 9,000 health centres and dispensaries in the sampled districts. registered COs in Kenya with approximately 2,167 The scale-size of the hospitals varies introducing

8 heterogeneity on the data.working in public health facilities . A random sample of Responses on the competences of COs were 18 larger districts (now counties) was selected from the

summarized using the top box method. This involved eight provinces of the country. A mapping of human reporting the percentage of COs whose responses resource was then conducted in the selected districts. A indicated the most favourable outcome for a given list of practicing COs in the sampled districts was then

9 measure. The results were interpreted in the light of prepared. Following formulas provided in literature it current theories of quality improvement which was calculated that a minimum of 326 COs were recommend comparisons to best practices rather than to sufficient for this evaluation. However, 365 COs were minimal standards. Stepwise regression analysis was eventually surveyed. The simple random sampling used to identify the key levers of COs competence. The technique was used to select the study sample. The sum of all the 10 competence items was used as the selected COs had to be registered to operate in Kenya dependent variable. Independent variables included and had to give informed consent to be eligible. Those socio-demographic variables and other characteristics off-duty for any reason during the data collection related to the COs practice. In the analysis, statistical period were excluded from the study. significance of the regression coefficients (betas) were A competence assessment tool was developed interpreted using their standard errors and a ρ value of based on literature with the help of a panel of experts. less than 5 percent. Data was analyzed using the The development of this tool followed standard

10 Statistical Package for Social Sciences (SPSS) Version procedure . Constructs were extracted from existing 3-5 13.0.literature . A panel of experts in social science

research and clinical practice and training then helped Clearance to conduct the study was provided to operationalize these constructs. The selected items

by The National Council for Science and Technology were then pre-tested with a sample of COs in Nakuru. through a letter referenced NCST/5/002/R/1002. Questions not performing as expected in the pre-test Permission was sought from Provincial Directors of were reworded for clarity. The reliability of the tool was Medical Services and/or Public Health and Sanitation tested using the internal consistency technique and the heads of each hospital. Oral assent was sought (Cronbach's alpha). Overall, ten questions on COs from the COs for administering the questionnaire. Data competencies were developed.management was done with confidentiality.The main questions involved COs ratings on

their frequency of undertaking community health activities, health education, following treatment

Resultsguidelines, mentoring junior staff, supervision of The results illustrate that the surveyed COs were students, surfing the internet, patient history taking and mainly males, married and in their third decade of life physical examinations. These were rated on a four (Table 1). The surveyed COs were most likely to have likert scale ranging from 'never' to 'always'. The COs limited university education, little on-the-job training, were also asked to judge their proficiency in limited networks, rarely publish and usually undertake managerial and financial skills on a four likert scale administrative duties. ranging from 'poor' to 'excellent'. The evaluative The overall competency scale showed satisfactory responses in this study were deemed attractive since internal consistency with a Cronbach's alpha literature on competence highlights the key role of self coffecicient (α) of 0.65 and there was no notable assessment, self accreditation and reflection. damage to the internal consistency even if any of the Other questions included social-demographic individual items were removed. The COs gave variables such as age, sex, marital status, highest level themselves an average score of 32.85 (SD = 3.60), with of education attained and years of experience in clinical a range of 18-40 (Table 2). Most of the COs (62.2 work. Questions on whether the COs belonged to any


10

Table 1: The Attributes of the Surveyed COs (n = 365)

Characteristic Frequency (%) Sex

Males

265 (72.6)

Females

100 (27.4) Marital status

Married

277 (75.8)

Not Married

88 (24.1)

Education

Degree and Above

15 (4.1)

Diploma

350 (95.9)

Specialization

Yes

179 (49.0)

No

156 (51.0)

Administrator

Yes

198 (54.2)

No

167 (45.8)

Publication

Yes

48 (13.2)

No

317 (86.8)

Networks

Yes

127 (34.8)

No

238 (65.2)

Age in years (Mean ± SD)

37.60 ± 9.48

Number of patients (Mean ± SD) 44.53 ± 32.33

Experience in years (Mean ± SD) 12.39 ± 8.73

Number of trainings attended (Mean ± SD) 3.72 ± 2.84

Table 2: Distribution of Competence Scores

Competence Score

Frequency (%)

=24

9 (2.7)

25-29

42 (12.8)

30-34

153 (46.6)

35-40

124 (37.8)

Total

328

(100)

Table 3: Regression Results on Factors Associated with COs Competence

Parameter β Std. Error t 95% Confidence Interval Eta Squared Lower

Bound Upper Bound

Intercept* 34.02 0.71 47.77 32.62 35.42 0.884 Trainings* 0.24 0.07 3.41 0.10 0.39 0.037 Administrator (No)* -3.26 1.15 -2.87 -5.54 -1.03 0.027 Publications (No)* -1.74 0.70 -2.49 -3.12 -0.36 0.020

*Associations statistically significant at ρ < 0.05

50%

68%

76%

67%

39%

55%

26%

21%

32%

29%

Physical examination

History taking

Follow laid down guidelines

Offer health education

Community health activities

Mentor junior staff

Supervise Students

Finance

Management

Surf internet

Figure 1: Proportions of C Os Indicating the Most Favourable Response to Measures of

Competence


11

percent) rated their competence at below best practice. difficult to assess except in relation to activities people Most of the COs indicated that they experience care about. The fundamental problem is that high level

problems in generic skills particularly in information competencies are difficult and demanding activities technology, management and finance (Figure 1). Other that no one will engage in unless they very much care problematic areas were supervision of students and about the activity or unless they find these activities

5conducting community health activities which were intrinsically satisfying . Such qualities will, therefore, undertaken by only 29 and 39 percent of the COs most often only be developed and displayed while respectively. people are undertaking activities they care about. The

Stepwise regression results showed that the key levers of COs competence were identified as socio-demographic characteristics of the COs were not number of on-the-job trainings, publication and associated with their ratings on competence. Further holding administrative duties. Success in undertaking the highest level of education attained, years of these activities depends on bringing to bear a range of experience in clinical work, belonging to voluntary cognitive, integrative, affective and relational skills organizations, taking specialized courses in clinical and calls for persistence over a long period of time. medicine and the number of patients they attended to What is not clear at the moment is the cost-daily were not associated with ratings on competence. effectiveness of these correlates of competence.

Statistically significant regression coefficients for the estimated generalized linear model are shown in ConclusionTable 3. On-the-job training, number of publications This study has demonstrated that it is feasible to and holding administrative duties were statistically assess the competence of COs using a brief self-associated with superior ratings on competence. The administered questionnaire. Most of the COs rated their results indicate that the number of on-the-job trainings overall competence at below best practice. To enhance was positively associated with higher ratings of the competence of COs interventions such as on-the-competence. Having no administrative duties was job training and mentorship programs are suggested.associated with lower ratings of competence. COs with no publications were less likely to rate their Acknowledgementcompetence favourably. No interaction effects among I sincerely wish to thank G. M. Wagema for his the independent variables were found to be statistically support in managing data in this study.significant. The last column of the table, Eta squared shows the practical significance of the variables. All the Referencesstatistically significant independent variables explain less than four percent of the variance each. 1. Ministry of Medical Services. The second national

health sector strategic plan of Kenya (NHSSP II Discussion 2008–2012). Nairobi: Ministry of Medical Services;

Most of the COs rated their competence at 2008.below best practice. This suggests that there is ample room for improvement. The overall results concur with 2. Southgate L. Professional competence in medicine. reports on concerns expressed regarding the Hosp Med. 1999; 60:203-5.

7, 11effectiveness of COs' practice . These results however, differ with the report that shows that 3. Rethans JJ, Norcini JJ, Baron-Maldonaldo M, et al. postoperative outcomes of caesarian sections The relationship between competence and performed by COs in Malawi were comparable with performance: implications for assessing practice

12 performance. Med Educ. 2002; 36 (10):901-09. [Cited those of medical doctors . The problem with such an 2 0 1 2 F e b 1 2 ] ; D O I : 1 0 . 1 0 4 6 / j . 1 3 6 5 -assessment is that it may be interpreted that post-2923.2002.01316.xoperative outcomes for medical doctors were just as

bad. The finding that most COs rate their competence at 4. Epstein RM, Hundert EM. Defining and assessing below excellent is a source of concern when compared professional competence. JAMA. 2002; 287:226-34.to the enormous tasks that they are charged with.

The results indicate that most COs experience 5. Carr SJ. Assessing clinical competency in medical problems in information technology, management and senior house officers: how and why should we do it? finance. Most also neglect community health activities. Postgrad Med J. 2004; 80: 63-66This is a concern since health service management and

community health are core components of the training 13 6. Government of Kenya. The clinical officers curriculum for COs . Efforts should be made to

(training, registration and licensing) Act chapter 260. identify the reasons behind this observation.Nairobi. Government Printer; 1990.The presented profile shows COs with limited avenues

for developing their competence. Competence is

12

7. Karanja LM, Kakai R, Onyango RO. Participation Teaching and Referral Hospital, Eldoret, Kenya. of clinical officers in preventive health care services Theses & Dessertations (Health Sciences).2009 [Cited at rural health facilities in Kenya Afr J Health Sci. A p r 1 0 t h 2 0 1 1 ] ; Av a i l a b l e i n t e r n e t : 2012; 21(3-4):107-112. http://hdl.handle.net/123456789/411. 8. Ministry of Public Health and Sanitation (Kenya). 12. Chilopora G, Pereira C, Kamwendo F, Chimbiri A, Annual health sector statistics report 2008. Division of Malunga E, Bergstrom S. Postoperative outcome of Health Management Information Systems. 2009 [Cited caesarean sections and other major emergency 2 0 1 2 F e b 1 2 ] ; A v a i l a b l e I n t e r n e t : obstetric surgery by clinical officers and medical http:/www.publichealth.go.ke/index.php. officers in Malawi. Hum Resour Health. 2007[Cited

thMar 12 2011]; 5:17. Medline: 17570847 doi: 9. Suresh K, Chandrashekara S. Sample size estimation 10 .1186 /1478-4491-5-17 Ava i l ab le f rom: and power analysis for clinical research studies. J Hum h t t p : / / w w w . h u m a n - r e s o u r c e s -Reprod Sci. 2012 Jan; 5(1):7-13. health.com/content/5/1/17.

10. Kothari CR. Research methodology. Methods and 13. Government of Kenya. The Kenya medical training nd

techniques. 2 revised ed. New Delhi. New Age college curriculum. Nairobi. Government Printers; International Press Limited; 2008. 2004.

11. Karanja CN. Improving the quality of interpersonal communication skills of clinical officers at Moi


13

Correspondence to:

An Open Comparative Antihypertensive Effects Of Amlodipine (“Norvasc®”), Lisinopril (“Zestril®”)

and Bendrofluazide

1 2 2 2O.G. Opadijo, E.O. Sanya, P.M. Kolo, K.W. Wahab1 Department of Medicine, College of Health Sciences, Ladoke Akintola

University of Technology, Osogbo,PMB 4400,Osogbo.2 Department of Medicine, University of Ilorin, PMB 1515, Ilorin, Nigeria

Dr Emmanuel O Sanya Neurology unit, Department of MedicineUniversity of Ilorin Teaching Hospital PO Box 5314 Ilorin.Email: [email protected]

Abstract Bendrofluazide is as potent, efficacious and Several antihypertensive drugs are available tolerable as relatively newer antihypertensive agents

for treating systemic hypertension (SH), prominent and more economical. However, it may add more to the among these are newer calcium channel blockers and ischaemic burden in view of its unfriendly effects on Angiotensin converting enzyme inhibitors. However, serum metabolic parameters especially total few studies have compared the antihypertensive cholesterol. Frequent checkups for these undesirable efficacy, potency, compliance and side effects of these metabolic side effects and prompt intervention may be agents against a traditional diuretic agent among adult needed in patients on diuretic agent such as Nigerian hypertensives. This study was carried out to bendrofluazide.address these issues.

This prospective open comparative study is on Key words: Hypertension, Bendrofluazide, dihydropyridine calcium channel blocker (DHP-CCB), Amlodipine, Lisinopril, Metabolic, side effects Angiotensin converting enzyme inhibitor (ACE-I) versus a diuretic agent in newly diagnosed adult hypertensive Nigerians. Three hundred and twenty- Introductionfour newly diagnosed adult hypertensives with blood Systemic hypertension (SH) is associated with

an increased risk of cardiovascular events such as pressure ≥140/90mmHg taken twice with mercury 1

strokes, ischaemic heart disease, renal and heart column sphygmomanometer (Accoson®) at 2 weeks 2failure. The cardiovascular risks are enhanced in the interval were recruited for the study. Patients were

3-4presence of other factors and uncontrolled SH. randomly selected into each of 3 groups A, B, and C Therefore, stable control of blood pressure (BP) over a sequentially with each group taking a particular long term with drugs with minimal side effects is antihypertensive agent in a titrating manner except for desirable in order to enhance drug compliance and to bendrofluazide for the study period. Baseline

5-6reduce morbidity and mortality. Of the long list of parameters such as the weight, height, body mass readily available anti-hypertensive drugs; thiazides and index, fasting blood sugar, lipid profiles and serum thiazide-like diuretic agents e.g. hydrochlorothiazide biochemistry as well as resting electrocardiogram were and bendrothiazide have been established to reduce done and compared on each patient pre and post study. blood pressure and mortality. Amlodipine besylate Reported side effects were also noted. Study period was (“Norvasc”), a third generation dihydropyridine for 15 months. calcium channel antagonist with a long half-life Of the 324 patients recruited, 280 cases (156 (t1/2=36-48hours) and prolonged duration of action is females and 124 males) completed the study with a

7attrition rate of 44(13.6%). The result of the study also in forefront of management of SH. Likewise, showed that blood pressure control was similar in the Lisinopril (“Zestril”), a long acting angiotensin three groups. However, Bendrofluazide appeared to be converting enzyme-inhibitor (ACE-I) has been proven

8 9more potent, less expensive and affordable than other to be useful in the therapy of SH and heart failure in two drugs. Bendrofluazide caused more significant adult Nigerians. These drugs, even though useful and elevation of serum metabolic parameters especially beneficial, their clinical, anti-hypertensive efficacy, blood sugar and total cholesterol than the other two tolerability and metabolic side effects have not been drugs in addition to the significant hypokalaemia and studied comparatively against a well established erectile dysfunction. thiazide-like diuretic agent (Bendrofluazide) in adult

Nigerians with hypertension. This therefore necessitated this study in our centre.

Material and MethodsThree hundred and twenty four newly

diagnosed adult Nigerians with mild to moderate hypertension corresponding to grade I and II in the World Health Organization and International

E.O. Sanya et al/ The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

14

Hypertension Society (WHO-ISH) classification of was added at each clinic visit until the BP was < 10 140/90mmHg or maximum does of 10mg daily was hypertension of 1999 were recruited consecutively

attained. Group C patients were equally placed on from the cardiovascular clinic of the medicine titrating dosage of Lisinopril (“Zestril”) starting at department of the Teaching Hospital and followed up 5mg. An upward 5mg daily titration was added until for 15months. Study subjects comprised of 144 maximum daily dose of 30mg was reached, or DBP < (44.4%) males and 180 (55.6%) females.90mmHg. During the upwards titration whenever They were randomly divided into 3 groups A. patient experience dizziness further increase is B and C after thorough explanation as regards the withheld and the previous dose is maintained. The cost purpose of the study was given and informed consent of the drugs on the counter was also compared.obtained from each participant. Ethical approval was Frequency table was generated and statistical analysis obtained from ethic committee of University of Ilorin was done using two-sample t-test for differences Teaching Hospital. Excluded from the study were between 2 groups and student t-test for paired pregnant and lactating women, patients with ischaemic observations. A P value of <0.05 was considered heart disease, stroke, kidney and heart failure. Group A statistically significant.comprised of 120 patients (68 females and 52 males),

group B 112 patients (60 females and 52 males) and Results group C 92 patients (48 females with 44 males). Blood

A total of 280 patients out of the initial 324 pressures were taken in sitting position after 15 minute recruited completed the study given attrition rate of rest in a quiet room using mercury (Accoson) 13.6% (44/324). The age range of study participants sphygmomanometer. Phases I & V korokoff's sounds varied from 28-80 years (mean 54.7+ 0.9 years). The were taken as the systolic and diastolic BP, numbers of patients in the three groups that completed respectively. Pulse rate and body mass indices (BMI) the study are as follows: group A 108 patients (38.6%) were also calculated. Blood samples were collected with male: female of 44:64; group B 92 patients from fasting blood glucose and lipid profiles which (32.9%) with male: female of 40:52; and group C 80 include: total cholesterol (TC), low density lipoprotein patients (28.6%) with male: female 40:40. Patient's cholesterol (LDL-C), high density lipoprotein clinical characteristics are as shown in Table 1. cholesterol (HDL-C) and triglyceride) (TG). Blood

A total of 44 patients dropped out before samples were also analyzed for serum biochemical + + completion of study and these consisted of: 12 (27.3%) indices such as sodium (Na ), potassium (K ), urea, uric

on bendrofluazide, 20 from amlodipine group (45.5%), acid and creatinine (Cr) as well as haematologic and 12 (27.3%) of lisinopril group. Eight out of the 12 profile. Twelve lead electrocardiogram (ECG) was on bendrofluazide developed diabetes mellitus (FBS recorded on each participant using a portable Seward >7.1) within 6 month of commencement of treatment 9953 ECG machine and interpreted by one of the out of the 15 months study period. This therefore authors (O.G.O). A rhythm strip using standard lead II necessitated change of medication and withdrawal was also recorded for QT interval determination which from study. Thus, 8/120 patients (6.6%) on was then corrected for heart rate with Bazette's formula bendrofluazide had diabetes mellitus while 4 patients which is from same group were lost to follow up. Four from among the 20 patients on amlodipine that withdrew, developed diabetes given a rate of 3.5% (4/112). The 12 where QTo is the measured/observed QT interval in patients (27.3%) from lisinopril group who dropped out seconds and R-R interval in seconds.did so due to severe and persistent cough. The drugs The patients were then placed on the

ndresponses were taken on the first month, 2 month and medication in a pre-packed container depending on the

thgroup they belonged. The clinic follow-up period was 4 month for all groups. Eighty-nine patients (82.7%) initially 4 weeks interval for 4 months and 2 monthly responded to 5mg bendrofluazide; while 70 (75.8%) intervals later on. Compliance with the medication was responded well to 5mg amlodipine and 54 (68.3%)

thchecked by counting the number of tablets remaining at patients to 20mg daily dose of lisinopril at the end of 4 clinic visits. Any side effects observed by the patients month and all effects were sustained. The mean FBS during the period of drug usage were noted and was significantly higher in patients on diuretics in recorded at each clinic visit. Response to therapy was comparison to those on amlodipine and lisinopril regarded as a sitting diastolic blood pressure (DBP) (p=0.0001). reduction to < 90mmHg and the target B.P < The haemogram profile remained stable in all 140/90mmHg. the groups. Nineteen patients (17.6%) in group A had a

Patients in group A were started on ß-blocker (atenolol) added to the bendrofluazide for bendrofluazide 5mg daily. Group B patents used good control of their blood pressures as against 17 titrating dosage of Amlodipine besylate (Norvasc) (18.5%) in group B and 25 (31.3%) in group C (P = 0.01 starting with 5mg daily. An upward titration of 2.5mg and 0.0001 respectively).

RR

QTo

-= QTc


15

Table 1: characteristics of the patients at the start of studyCharacteristics bendrofluazide amlodipine , lisinopril P value Population 108 92 80 A vs B A vs C Age(yr) 55.2+1.4 53.3+2.4 55.6+2.6 - - Heart Rate (b/min) 76.0+7.0 76.0+7.6 76.0+7.9 - - SBP (mmHg) 165.7+2.5 166.7+4.3 165.5+4.5 - - DBP (mmHg)

101.4+2.3

101.0+3.4

100.0+3.5

-

-

QTc

0.49+0.02

0.48+0.02 0.47+0..02

-

-

BMI(kgm-2

26.4+1.7

26.2+1.7

26.6+1.8

-

-

FBS(mmol/L)

5.3.+0.4

5.8+0.8

4.9+0.8

0

0.001

TC(mmol/L)

4.6+0.4

4.1+0.7

4.3+0.7

0.11

0.1 LDL-C(mmol/L)

1.32+0.36

2.69+0.55

2.93+0.6

-

- HDL-C(mmol/L)

1.32+0.36

1.21+0.37

1.12+0.37

-

- TG(mmol/L)

1.32+0.22

1.22+0.4

1.28+0.4

-

- Cr (µmol/l)

98.4+3.5 92.5+3.4

104.6+3.4 0.001 0

Na+(mmol/L)

135.2+3.9 135.3+3.8

135.3+4.1

-

-

K+(mmol/L)

3.7+1.3

3.7+1.4 3.7+1.3

-

-

Urea(mmol/L)

4.2+1.0 4.1+1.0 4.0+1.1

-

-

Uric Acid(mmol/L)

0.28+0.04 0.27+0.03 0.29+0.04

-

-

Atherogenic index

(HDL/TC) 0.28

0.30 0.26

-

-

Table 2: characteristics of the patients at the end of study

Characteristics

bendrofluazide

amlodipine

lisinopril

P value

Population 108 92 80

A vs B A vs C

Age(yr)

45.9+1.2

49.3+2.7

55+2.8

0 0

Heart Rate (b/min) 76.2+7.3

75

+7.2

75+7.6

0 0

SBP (mmHg)

125.5+3.7

127.4+4.2

130.3+3.5

-

0.01

DBP (mmHg) 77.9+3.3

80.7+3.4

81.6+3.7 -

0.1

QTc 0.45+0.03

0.4+0.02 0.39+0.02

-

-

FBS

(mmol/L

6.7.+1.4 4.2+0.8 4+0.8 0.001

0.001

TC

(mmol/L)

5.95+0.5

3.6+0.7 4+0.8

0.001

0.001

LDL-C(mmol/L)

2.38+0.59

2.36+0.58

2.68+0.62 -

-

HDL-C(mmol/L)

1.07+0.28

1.23+0.42

1.47+0.46 -

-

TG (mmol/L)

1.42+0.32 1.14+0.4 1.34+0.44

-

-

Cr (µmol/l) 98.5+3.7

92.2+3.6

100.6+3.8

0.001 -

Na+(mmol/L)

135.6+3.5

135.1+3.3

135.2+3.3 -

-

K+

(mmol/L)

2.6+1.2

3.8+1

3.9+1 0.01 0.01

Urea(mmol/L)

6.53+1.4

4+1.1

4+1.2 0.001 -

Uric Acid(mmol/L)

0.44+0.06

0.26+0.04

0.28+0.04

0.001 0.001

Atherogenic index (HDL/TC)

0.18 0.36 0.37

Table 3: Reported side effects

of antihypertensive drugs

Side effects

bendrofluazide amlodipine

lisinopril

p-value

n= 108

92 80

A vs B

A vs C

Cough 56

Headaches 5

44 29

-

0.001

Dizziness

-

21

8 0.0001

0.001

Skin rashes

-

-

5 -

0.5

Pruritus

-

4

5 0.5

0.5

Ankle Oedema

-

10

-

0.01

-

Gum hyperplasia

-

4

-

0.5

-

Diuresis

70

29

13 0.001

0.001

Precordial pain

-

16

4 0.00001

0.5

Erectile dysfunction 38

19 7

0.0001 0.001


16

On the average 5mg tablet and 10mg tablet of available in Nigeria is alternative in patients who might amlodipine cost N55.00 and N100.00 respectively (at need this drug in order to prevent this observed the time of the study). A 5mg, 10mg and 20mg tablet of hypokalaemia associated with thiazide diuretic agents. Iisinopril cost N35.00, N65.00 and N85.00 There was a noticeable elevation in mean urea and uric respectively as against 5mg tablet of bendrofluazide acid level in group A patients, however, none had gouty which cost N2.00. arthritis during the study period. Since hyperuricaemia

has been associated with development of coronary 17,18Discussion heart disease, it might be necessary for patients on

It is evident from this study that both thiazide diuretic to regularly check their serum uric amlodipine and lisinopril are effective and potent in acid level as a preventive measure. lowering BP as diuretic; in essence and possibly The use of bendrofluazide resulted in reducing morbidity and mortality associated with significant occurrence of erectile dysfunction (ED).

9,11,12hypertension in a similar manner to diuretic agent. The incidence was minimal in group C patients on

At the end of 15 months of medication, there lisinopril indicating the protection and possibly was no appreciable difference in the mean diastolic vascular remodelling by lisinopril. In groups B and C blood pressures (DBP) among the three groups of the reported ED occurred within first 8 months of patients. However, the mean systolic blood pressure therapy in comparison to ED associated with (SBP) in patients in group C was significantly higher bendrofluazide that occurred much earlier and this than that of patients in group A. This suggests a possible effect was sustained. The other side effects reported by superior effect of bendrofluazide in comparison to the patients are as shown in Table 3. The combination of lisinopril in lowering SBP at this dosage (Table 2). lisinopril with atenolol (a ß blocker with anti-rennin Amlodipine appears to have a better but non-significant activity) in group C patents whose blood pressures efficacy over lisinopril as far as DBP reduction is were not properly controlled was to maintain drug concerned (t=1.55 and p=0.2). However, there is a similarity with the other two groups.significant reduction of SBP by amlodipine than Part of the study limitation is its open label nature lisinopril (t=4.833 and P = 0.01) an effect similar to which could lead to bias, but we tried to overcome this bendrofluazide. This is compatible with previous by taking several blood pressures recordings to the reports which suggest greater effect of diuretic and nearest value. Nevertheless the finding of this study dihydropyridine calcium channel blocker, (DHP-CCB) corroborates earlier report and is relevant to clinical on BP reduction in Africans in comparison with ACE- practice in this environment.

13 In conclusion, bendrofluazide may not be I.inferior to amlodipine or lisinopril in terms of Use of bendrofluazide resulted in significantly compliance, tolerance, efficacy and anti-hypertensive elevated fasting blood sugar and total cholesterol when potency. Judging from its potent anti-hypertensive compared to amlodipine and lisinopril, an observation

14 effect in this study, it remains unsurpassed in keeping that had been earlier reported. The low density 19with ALLHAT study. However, periodic evaluation of cholesterol was significantly reduced at the end of the

serum metabolic parameters and potassium level is study period in all groups, however, the differences important when thiazide diuretic is used. Combination between the groups was not significant. Translation of of low dose thiazide diuretic with either DHP-CCB and this to coronary heart disease remains unclear. or ACE-I, which tends to blunt some of the metabolic However, the development of diabetes in few patients

20that withdrew from bendrofluazide coupled with the effects of thiazide diuretic, may be more beneficial elevation of atherogenic index from moderate risk and especially in terms of regression of left ventricular

21(0.28) as baseline to high risk level (0.18) at the end of hypertrophy which has been related to higher the study may predispose individuals on mortality than even coronary artery disease.bendrofluazide to disease states especially vascular

15,16,17occlusion. ReferencesFinding of this study corroborates earlier view 1. MacMahon S, Peto R, Cutler J. Blood

15 pressures, stroke and coronary heart disease. Part I, that use of lisinopril might be reno-protective as prolonged difference in blood pressure. Prospective suggested by significant reduction in serum creatinine observational studies corrected for the regression level at completion of period (104.6+3.4 compared to dilution bias. Lancet 1990; 335: 785-794.100.6+3.8; t=4.938 and P=0.001). Bendrofluazide use 2. Araoye MA, Olowoyeye JO. The clinical was associated with significant reduction in serum spectrum of hypertensive heart failure: A point-score potassium level; although no case of cardiac system for solving an old problem. E Afr JM 1984; 61: arrhythmia was recorded. It is possible that few cases of 306-315.cardiac arrhythmia could have missed since none had a 3. Opadijo OG. Risk Factors associated with 24 hours Holter monitoring. Consumption of fruits rich cardiovascular disease and death in adult Nigerians in potassium especially banana which is widely


17

with essential hypertension. NJIM 2000; 3: 41-45. 13. Malacco E, Manda G, Rappelli A, Menotti A, 4. Donnelly R, Meredith PA, Miller SHK, Howie Zuccaro M.S, Copponi A, et al. Treatment of isolated CA, Elliot HL. Pharmacodynamic modeling of the systolic hypertension: the SHELL Study results. Blood antihypertensive response to amlodipine. Clin Press 2003; 12:160- 167.Pharmacol Ther. 1993; 54:303-310. 14. Opadijo OG, Omotoso ABO. Blood sugar 5. Multiple Risk Factor Intervention Trial profile in mild to moderate systemic hypertensive on Research Group. Multiple risk factor intervention trial thiazide diuretics whose blood pressure are well in mild hypertension. Risk factor changes and controlled. NJM 1996 ;5: 48-50.mortality. JAMA 1982; 248:1465-1477. 15. Raij L, Chiou Xue-Chiou, Owens R, Wrigley 6. Materson BJ, Reda DJ, Cushman WC, Massie B. Therapeutic Implications of hypertension-induced BM, Freis ED, Kocher MS, et al. Single drug therapy glomerular injury. Am. J. Med 1985; 79 (Suppl 3c): 37-for hypertension in men: a comparison of six 41.antihypertensive agents with placebo. The Department 16. Siscovick DS, Raghunathan TE, Psaty BM, of Veterans Affairs cooperative study group on Koepsell TD, Wickklund TG, Linx et al. Diuretic Antihypertensive Agents. N Engl J Med 1993;328: therapy for hypertension and the risk of primary cardiac 914-921. arrest. N Engl J. Med 1994; 330 1852- 1857.7. Isah AO, Obasohan AO, Okpako LO. Open 17. Franceasca V, Denise P, Giovanna L. Serum evaluation of amlodipine in the monotherapeutic uric and target organ damage in primary hypertension. treatment of mild of moderate hypertension in Nigeria Hypertension 2005; 45: 991.patients. Curr Therap Res 1992; 52:812-818. 18. Alderman MH, Cohen H, Madhaven S. 8. Abengowe, CU, Ezedinachi EMU, Balogun Kivilghn S. Does treatment mediated increase in uric MO. An Open trail of lisinopril (Zestril) in mild to acid reduce the cardio protective effect of diuretics in moderate hypertension in Nigeria, WAJM 1977; 164 hypertensive patients? Am J, Hypertens 1998; 2:16.9. Opadijo O.G. Effect of lisinopril on QTc and 19. Furberg CD, Wright JT, Jr, Dans BR, Cutler arrhythmias in patients with chronic heart failure. JA. Alderman M, Black H. et al. Major outcomes in NJIM 2000; 3:50-53. high-risk hypertension patients randomized to 10. World Health Organization-International angiotensin converting enzyme inhibitor or calcium Society of hypertension guidelines for the ch an ne l bl oc ker Vs diuretic (ALLHAT) study. JAMA management of hyper tens ion: Guidel ines 2002;2981- 2997.subcommittee: J Hypert 1999; 17: 151-183. 20. Weinbergber MH. Influence of an angiotensin 11. Pasty BM, Lumley T, Furberg CD, converting enzyme inhibitor on diuretic – induced Schellenbaum G, Pabor M, Alderman MH, et al. metabolic effects in hypertension. Hypertension 1983; Health outcomes associated with various 5(Suppl 3): 132-138.antihypertensive therapies used as first-line agents: a 21. Schmieder RE, Schlaich MP, Klingbeil AU, network meta-analysis JAMA 2003;289:2534-2544 . Martus P. Update on reversal of left ventricular 12. Opadijo OG. Biochemical and Metabolic hypertrophy in essential hypertension (a meta-analysis effects of short term thiazide diuretic therapy in mild to of all randomized double-blind studies until December moderate hypertension. Nig Med Pract 1997; 33: 58- 1996). Nephrol Dial transplant 1998; 13:564-569.61.

Correspondence to:

18

Reference Values and Relationship between Cardio-Respiratory

Fitness Index and Body Mass Index of Adolescent Students in

a Southwestern Nigerian Community

1 2 1 3A.O Akinpelu, O.O. Oyewole, A.C Odole and C.A Gbiri 1.Department of Physiotherapy, College of Medicine, University of Ibadan, Ibadan, Nigeria

2;Department of physiotherapy, Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria 3.Department of Physiotherapy, College of Medicine, University of Lagos, Lagos, Nigeria

Oyewole O.O,Department of Physiotherapy,Olabisi Onabanjo University Teaching Hospital,PMB 2001, Sagamu, Nigeria+234 803 397 [email protected]

Abstract IntroductionCardio-respiratory Fitness Index (CRFI) and Cardio-Respiratory Fitness (CRF) and body

Body Mass Index (BMI) are related to health, and their adiposity are both related to health, and their interrelationship has been documented but with little interrelation to each other has been documented but information on Nigeria population. This study derived with little information on Nigeria population. Findings

reference values for CRFI and BMI and investigated from the Aerobics Center Longitudinal Study presentthe relationship between the two variables among convincing evidence that fitness is a more potent risk

adolescent students in a Southwestern Nigerian factor for mortality than is fatness and that high fitness

community. level attenuates theeffect of obesity on mortality in this 1.A random sample of 1638 adolescent students cohort of men High cardio-respiratory fitness have

(12-18 years) in Sagamu Local Government Area been shown to lower the risk of all-cause and participated in the cross-sectional survey. CRFI was cardiovascular disease mortality among both assessed using the 3-minute Harvard step test and BMI hypertensive and normotensive people with metabolic

2 3was computed from weight and height. Data were syndrome , it protects against cancer mortality in men , analysed using percentiles, t-test and Pearson's and reduced the risk factor for functional decline

4 moment correlation at p < 0.05. independent of disease processes . Promotion ofParticipants' age was 14.99±1.84 years; their physical fitness and activity early in children has been

2 BMI and CRFI were 19.06±2.69kg/m and considered an optimal strategy for preventing these 65.65±.10.77 respectively. Male participants' CRFI lifelong diseases. was higher and their BMI was lower (p<0.05) than Evaluating obesity in children and adolescents those of female participants. Reference values for is important because obesity poses a serious health

burden as it is associated with an increased risk of CRFI ranged from <57 as poor to ≥93 as excellent; for 2 chronic diseases such as cardiovascular disease, BMI ranged from >15.5kg/m as desirable to

52 diabetes mellitus and some cancers . It is important to >26.6kg/m as very obese. Participants' CRFI develop appropriate anthropometric measures for correlated inversely (p<0.05) with their BMI. It was obesity in order to identify and prevent the concluded that CRFI decreases as BMI increases

6development of obesity-related disorders . Among the among adolescent students in this Nigerian several criteria available in the literature, those community. Reference CRFI and BMI values derived

7proposed by the International Obesity Task Force , here-in may serve as useful guide in categorizing 8World Health Organization (WHO) and the Centers adolescent students in Southwestern Nigeria.

9for Disease Control and Prevention (CDC) are the

Key word: Cardio-respiratory fitness index, Body most widely used. However, it has been suggested that mass index, reference values, relationship, adolescent a correct assessment of a growth pattern requires the students, Southwestern Nigeria. comparison of an individual's data with standards

obtained from a representative sample of the 10population the individual belongs to . Hence, the need

for population based reference values. Previous studies have reported the relationship

11-13between CRF and indices of adiposity . These studies reported inverse association between CRF and indices of adiposity. Using specific tests, reference values of Cardio-Respiratory Fitness Index (CRFI)

14 have been generated in many populations and based on these values, adolescents have been categorized into different levels of cardio-respiratory fitness. Population based reference values for BMI have also

15-17been reported for many nations . Reference CRFI

O.O. Oyewole et al/ The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

19

values are not readily available for Nigerian adolescent inexpensive and widely used field method of assessing students. Although reference BMI values for each age cardio-respiratory fitness. It requires little or no skill. within the adolescent brackets (12-18 years) have been The test was conducted in a well ventilated classroom

18 in each school. The procedure was explained and earlier generated , reference BMI values for demonstrated to each participant. Dressed in their adolescents as a group in South-western Nigeria seem school sports uniform, each participant was asked to unavailable. Therefore, the aims of this study were to step up and down a step bench (40cm for males and derive reference CRFI (assessed using the 3-minute 33cm for females) for a maximum period of three Harvard step test) and BMI values for adolescent minutes (180 seconds), unless he/she was tired or could students in a Southwestern Nigerian community and to not keep up with the required pace of 30 steps per investigate the relationship between their CRFI and minute. A metronome, set at 120 beats per minute was BMI. used to maintain the stepping pace of 30 steps per minute. Participants were encouraged to put in best Methodseffort during the test. The duration for which a The study was approved by the Research participant could perform the step test was recorded in E th i c s Commi t t ee o f t he Un ive r s i t y o f seconds. Immediately after completing the step test, the Ibadan/University College Hospital, Ibadan, Nigeria. participant sat quietly on a chair. The heart rate was Participants for this study were apparently healthy counted 1 to 1 ½, 2 to 2 ½ and 3 to 3 ½ minutes after secondary school students (12-18 years), selected by a stepping ceases. The CRFI was computed with the probability proportional to size from stratified 8 public following formula: and 3 private secondary schools from Sagamu local

government area of Ogun state, Nigeria. Permission to conduct the study was obtained from the Local Education Authority and the principals of the selected secondary schools. Selected adolescent students were

Data analysisscreened for neurological and musculoskeletal The mean and standard deviation of problems, such as paralysis and deformities that could

participants' age, weight, height, BMI and CRFI were limit their performance at the physical fitness test by calculated. The percentiles for BMI and CRFI were one of the authors. Their blood pressure was also computed and used to determine reference values. measured to detect any one with high blood pressure. Independent t-test was used to compare CRFI of male Students with physical disabilities were excluded from and female students. Pearson's moment correlation was the study and were counseled. Those with blood used to determine relationship between BMI and CRFI pressure ?140/90 mmHg were referred to nearest at p<0.05. government hospital for follow-up.

Informed consent was obtained from the Resultsparticipants and their parents. The nature, purpose and

The participants comprised 1638 (760 males procedure of the study were explained to the and 848 females) adolescent students and their mean participants in detail. The sex and age (as at last age was 14.99±1.84 years. Their mean weight was birthday) of each participant were recorded. Thereafter, 46.2±10.0 kg and their mean height was 1.55±0.10 weight and height were measured using a portable

2 weighing scale (Camry model BR9012, China) and a meters. Participants' mean BMI was 19.06±2.69 kg/mheight meter (Wunder, China) respectively as and their mean CRFI was 65.65 ± 10.77. Female

18 participants (14.8±1.8 years) had significantly (p = described in an earlier report . The BMI was then 0.039) higher BMI than their male counterparts. On the computed using a standard formula [BMI= weight

2 other hand, male participants (15.1±1.9 years) scored (kg)/height (m) ]. significantly (p = 0.000) higher mean CRFI than female Cardio- Respiratory Fitness Index (CRFI) was

th thparticipants (table 1). The 25 and 99 percentiles of measured using the 3-minute Harvard Step Test, an

CRFI = Duration of exercise in second X 100 2 X sum of pulse counts in recovery .

Table 1: Comparison of Male and Female Participants’ CRFI and BMI ____________________________________________________________ Variable Male Female t p-value Mean SD Mean SD BMI 18.92 2.83 19.19 2.54 -2.068 0.039 CRFI 67.80 9.26 63.65 11.66 7.947 0.000 ____________________________________________________________


20

Table 2: Percentiles of Participants’ Body Mass Index and Cardio-respiratory Fitness Index

Variables Percentile 5th 25th 50th 75th 85th 95th 99th

_________________________________________________________________________________________________________________ Male 15.31 16.88 18.51 20.53 21.62 23.90 27.12 BMI(kg/m2) Female 15.56 17.40 18.77 20.79 21.92 23.77 26.32 All 15.48 17.22 18.65 20.65 21.74 23.83 26.62 Male 52.80 64.40 69.77 73.77 75.00 82.57 93.75 CRFI Female 49.45 52.33 64.29 72.00 52.33 83.33 91.34 All 50.00 56.60 66.67 73.17 75.00 82.10 91.84

BMI = Body Mass Index CRFI = Cardio-Respiratory Fitness Index

Table 3: Reference Values of Cardio-respiratory Fitness Index and Body Mass Index Variables Category All Male Female CRFI Poor (<25th) <57 <64 <52 Average (25th – 50th) 57-67 64-70 52-64 Good (>50th – 75th) 68-73 71-74 65-72 Very good (>75th -99th) 74-92 75-94 73-91 Excellent (>99th) =93 =95 =92 BMI Underweight (<5

th) <15.5 <15.3 <15.6

(kg/m2) Desirable (=5th - <85th) 15.5-21.7 15.3-21.6 15.6-21.9 Overweight (=85

th – 95

th) 21.8-23.8 21.7-23.8 22.0-23.8

Obese (=95th - 99

th) 23.9-26.6 23.9-27.1 23.9-26.3

Very obese(>99 th) >26.6 >27.1 >26.3

Key: CRFI = Cardio respiratory fitness index BMI = Body mass index Figure in parentheses are Percentiles

Table 4: Pearson’s Correlation coefficient between Participants’ CRFI and BMI ________________________________________________ r p-value ________________________________________________ All -0.108 0.05 Male -0.083 0.02 Females -0.116 0.001 _________________________________________________

2 2 There was low, but significant inverse correlation BMI for participants were 17.22 kg/m and 26.62 kg/m th between participants' CRFI and BMI. This correlation respectively. For CRFI, the 5 percentile was 50.00 and

th remained significant when data was analysed 99 percentile was 91.84 for all participants (Table 2). separately for male and female participants (table 4). The table also shows the percentiles of BMI and CRFI .for male and female participants. Discussion Table 3 shows the reference values of CRFI

The mean CRFI score of participants in this and BMI. The categories were based on percentiles study (65.65 ± 10.77) is similar to the value (65.66 ± generated in this study. CRFI >57.0 was categorized as 13.24) reported in a previous study for 87 adolescent poor, 68-73 as good and ≥ 93.0 as excellent for all

19students in Ibadan, Southwestern Nigeria . The participants. For BMI, desirable weight was 15.5-21.7,

2 average CRFI scores for male and female students in obese was 23.9-26.67kg/m . The table also shows the the present study are also fairly comparable to the reference values for male and female participants.


21

19 2values reported in the previous study . The two studies comparison with WHO 2007 and ~2 - 4kg/m in boys 2 used the same test, the 3-minute Harvard Step Test to and ~6 - 7kg/m in girls in comparison with CDC 2000

assess participants' CRFI. In another study that used the reference values for overweight and obesity. In the 20

3-minute Harvard Step Test , the mean CRFI score in lower limit, present reference values are higher by 1-2 2the present study also compares well with the value kg/m for overweight and obesity compared with WHO

(60.56 ± 13.49) reported for non residential secondary 2007 BMI values. From the present study range BMI 20 2school students in India . However, the mean CRFI values for overweight are 21.7 – 23.8 kg/m for males

2score for male students (67.80±9.26) in the present and 22.0 – 23.8 kg/m for females and for obese are 23.9 2 2study is lower than that (90 ± 7.07) reported for male – 27.1 kg/m for males and 23.9- 26.3 kg/m for

21India students . This difference could be due to the females. It is clear that the reference values for BMI wider age range of participants in that study or better generated in this study for Nigerian adolescents is cardio-respiratory fitness level of the Indian students in different from that generated by WHO 2007 and CDC the previous study. The finding that male students 2000. These findings support the need for generation of demonstrated higher value than the female students reference values for different populations. However,

19, 22-23corroborates the findings of other authors who the present BMI cut off points are fairly comparable to reported that gender had influence on cardio- the values adapted by the IOTF, despite the fact that the respiratory fitness with males greater than females. sample in that study excluded adolescents from tropical

th 7The 25 percentile score (57) of participants' Africa . For age 12-18 years, the IOTF cut off points 2 CRFI indicates the score of the quarter of the students range from 21.22 – 25 kg/m for overweight males

thwith the lowest CRFI. The 99 percentile score while for overweight females range from 21.68 – 25 2indicates the CRFI topmost 1% of students that is those kg/m , and for obese, the range vary between 26.02 and

2with the highest CRFI. It is difficult to compare the 30 kg/m for males and females between 26.67 and 30 2 reference values for CRFI generated in the present kg/m . Therefore, the percentile scores for the different

study with those generated for other populations BMI categories generated in this study may be used to because of methodological differences. In the study by classify secondary school students in Sagamu local

14Nagle , reference values generated for American government area and possibly southwestern part of adolescents were based on the 4-minute Harvard Step Nigeria with different body types. More so, a correct Test, rather than the 3-minute Harvard Step Test used in assessment of a growth pattern requires the comparison the present study. As one would expect, the reference of the subject's data with standards obtained from a values for American adolescents were higher than those representative sample of the population the subject

10generated in this study possibly due to methodological belongs to . differences or difference in the exercise habits of This study shows low significant inverse American and Nigerian adolescents. Generally, it correlation between cardio-respiratory fitness and

1, appears that exercise and sports facilities as well as BMI. This observation is consistent with other studies24-25motivation to develop good exercise habit are more . These authors reported inverse relationship

readily available to children and adolescents in the between cardio-respiratory fitness and BMI. The United State of America than in Nigeria. This suggests significant inverse correlation between CRFI and BMI the need for all stakeholders in Nigeria to make implies that to some extent, a cardio-respiratory fitness available more exercise and sports facilities in order to level of a person is determined by the degree of promote good exercise habit among adolescent adiposity in him/her. This finding buttresses the need students in Nigeria. It appears that reference values of for school children to engage in healthy life style such CRFI for Nigerian adolescents, based on nationwide as regular participation in exercise which will keep not surveys are not readily available for referencing. In the only their BMI within normal range, but will also absence of such nationwide surveys, it is our belief that improve their cardio-respiratory fitness level. reference values generated in this study (for 3-minutes Harvard step test) may serve as a useful guide to Conclusion and Recommendation: exercise physiologists and healthcare providers in Our findings indicate that the higher the BMI Southwestern Nigeria in categorizing adolescents. of these adolescents, the lower their CRFI. Hence, the

The mean BMI of participants in this study need to encourage adolescent students in Southwestern 2(19.06 kg/m ) is less than mean values reported in Nigeria to participate in regular exercises so as to

10, 15, 16previous studies . The BMI cut off points for improve their cardio-respiratory fitness level and keep overweight and obesity generated in this study are their BMI within normal range. The CRFI categories lower compared with CDC 2000 and WHO 2007 BMI and BMI reference values derived in this study may be reference values for overweight and obesity. In the used as standard for Southwestern Nigerian male and upper limit, the present reference values are lower by female adolescent students.

2~4kg/m for overweight and obese adolescents in


22

References 41.1. Stevens J, Cai J, Evenson K.R and Thomas R: 14. Nagle F.J, Bruno B and John P.N: Graduational Fitness and fatness as predictors of mortality from all steps test for assessing work capacity. Journal of causes and from cardiovascular disease in men and Applied Physiology 1965; 20(4): 740-755.women in the lipid research clinic study. American 15. Moreno LA, Mesana MI, Gonza´lez-Gross M, Journal of Epidemiology 2002; 156: 832-841 Gil CM, Fleta J, Wa¨rnberg J, Ruiz JR, Sarrı´a A, 2. LaMonte M.J, Barlow C.E, Jurca R, Kampert Marcos A, Bueno M and the AVENA Study Group. J.B, Church T.S and Blair S.N: Cardiorespiratory Anthropometric body fat composition reference values fitness is inversely associated with the incidence of in Spanish adolescents. The AVENA Study. European metabolic syndrome: a prospective study of men and Journal of Clinical Nutrition advance online women. Circulation 2005; 112(4): 505-12. p u b l i c a t i o n , 1 9 O c t o b e r 2 0 0 5 ; 3. Lee C.D and Blair S.N: Cardiorespiratory doi:10.1038/sj.ejcn.1602285fitness and smoking-related and total cancer mortality 16. Gharib NM, Rasheed P. Anthropometry and in men. Medicine and Science in Sports and Exercise body composition of school children in Bahrain. Ann 2002; 34(5): 735-9. Saudi Med 2009; 29:258-694. Morey M.C, Pieper C.F and Carnoni-Huntley 17. Kulaga Z, Litwin M, Tkaczyk M, Różdżyńska J: Physical fitness and functional limitation in A, Barwicka K, Grajda A, Świąder A, Gurzkowska B, community-dwelling older adults. Medicine and Napieralska E and Pan H. The height-, weight-, and Science in Sports and Exercise 1998; 30(5): 715-23. BMI-for-age of Polish school-aged children and 5. Low S, Chin MC, Ma S, Heng D, Deurenberg- adolescents relative to international and local growth Yap M. Rationale for Redefining Obesity in Asians. references. BMC Public Health 2010, 10:109. Doi: Ann Acad Med Singapore 2009; 38:66-74 10.1186/1471-2458-10-1096. Yang JJ, Shiwaku K, Nabika T, Masuda J, 18. Akinpelu A.O, Oyewole O.O and Oritogun Kobayashi S. High frequency of cardiovascular risk K.S: Reference growth values for adolescents aged 12-factors in overweight adult Japanese subjects. Arch 18 years in a Nigerian community. Journal of Med Res 2007; 38:337-44. Biomedical Research 2009; 12:7-13. 7. Cole TJ, Bellizzi MC, Flegal KM, Dietz WD. 19. Ajayi B.F: Comparison of physical fitness Establishing a standard definition for child overweight profile of paramilitary and non-paramilitary subjects. and obesity worldwide: international survey. BMJ An M.Sc dissertation in the department of 2000; 320(7244):1240-3. physiotherapy, University of Ibadan, Nigeria. 20028. de Onis M, Onyango AW, Borghi E, Siyam A, 20. Choudhuri D, Choudhuri S, Kulkarni V.A: Nishida C, Siekmann J: Development of a WHO Physical fitness: a comparative study between students growth reference for school-aged children and of residential (Sainik) and non-residential schools adolescents. Bull World Health Organ 2007, 85:660- (aged 12-14 years). Indian Journal of Physiology and 667. Pharmacology 2002; 46(3): 328-32 9. Kuczmarski RJ, Ogden CL, Guo SS, 21. Mahanta S, Chandra A.M and Sadhu N: Grummer-Strawn LM, Flegal KM, Mei Z, et al. 2000 Interrelation of one mile running time and HST score CDC growth charts for the United States: methods and among rural school boys. Journal of Human Ergology development. Vital Health Stat 11. 2002 ;( 246):1-190. (Tokyo) 1994; 23(1):51-710. López-Siguero JP, García JMF, Castillo JDL, 22. Kelley GA, Lowing L and Kelley K: Gender

. differences in the aerobic fitness levels of young Molina JAM, Cosano CR and Ortiz AJ Cross-sectional African-American adults. Journal of National Medical study of height and weight in the population of Association. 1999; 91(7): 384-8.Andalusia from age 3 to adulthood. BMC Endocrine 23. Guerra S, Ribeiro J.C, Costa R, Duarte J and Disorders 2008, 8(Suppl 1):S1Mota J: Relationship between cardiorespiratory 11. Janssen I, Katzmarzyk P.T, Ross R, Leon A.S, fitness, body composition and blood pressure in school Skinner J.S, Rao D.C, Wilmore J.H, Rankinen T and children. Journal of Sports Medicine and Physical Bouchard C: Fitness alters the association of body mass Fitness 2002; 42(2): 207-13index and waist circumference with total and 24. Kim J, Must A, Fitzmaurice G.M, Gillman abdominal fat. Obesity Research 2004; 12:525-537.M.W, Chomitz V, Kramer E, McGowan R and Peterson 12. Jette M, Sidney K, Quenneville J and Landry K.E: Relationship of physical fitness to prevalence and F: Relation between cardiorespiratory fitness and incidence of overweight among school children. selected risk factors for coronary heart disease in a Obesity Research 2005; 13(7): 1246-54population of Canadian men and women. Canadian 25. Mota J, Flores L, Flores L, Ribeiro J.C and Medical Association Journal 1992; 146(3):1353-1360.Santos M.P: Relationship of single measures of 13. Nassis G.P, Pasarra G and Sidossis L.S: cardiorespiratory fitness and obesity in young Central and total adiposity are lower in overweight and schoolchildren. American Journal of Human Biology obese children with high cardiorespiratory fitness. 2006; 18(3): 335-41. European Journal of Clinical Nutrition 2005; 59:137-

Correspondence to:

23

Vitamin E Attenuates Toxic Effects Of Combined Administration

Of Ivermectin And Albendazole In Selected Rat Tissues

R.O. Arise and S.O Malomo.

Department of Biochemistry, University of Ilorin, Ilorin, Kwara State, Nigeria.

R.O. ArinseDepartment of Biochemistry, University of Ilorin, Ilorin, Kwara State, Nigeria.E-mail: [email protected]

Abstract IntroductionThis study was carried out to investigate Vitamin E is one of the fat soluble vitamins

whether vitamin E as an antioxidant can reduce or found in many foods, fats and oils. It is widely known nullify the toxic potential of ivermectin and for its antioxidant property and has been found in albendazole combination therapy. appreciable amount in spinach, turnip greens, and

Ivermectin (0.4mg/kg body weight) and/or chard. In conjunction with superoxide dismutase, albendazole (15mg/kg body weight) were daily and vitamin E forms the first line antioxidative defence in

1orally administered to albino rats for 14 days. The humans at the cellular level .This vitamin protects effect of oral administration of 30 mg/kg body weight unsaturated lipids in biological membranes from

2of vitamin E along with combined administration of the peroxidative degeneration and it stabilizes the two drugs was investigated. The rats were sacrificed 24 structure of the biomembranes. Apart from these

thh after the 14 day administration and the activities of activities, vitamin E has been implicated in other

+ + 2+ 2+Na -K ATPase and Ca -Mg - ATPase were assayed in physiological roles. It has been established that vitamin the liver, kidney, brain, and small intestine. Catalase E plays important roles in cell signal transduction and

3(CAT) activity was assayed in the liver and brain, while stimulation of immune response . It regulates platelet malondialdehyde level was determined in the serum, aggregation by inhibiting platelet cyclooxygenase

4liver and brain. activity, thus reducing prostaglandin production . There were a significant increases (p<0.05) in Vitamin E has been implicated in the regulation of

all parameters investigated in the tissues except for protein kinase C activation, protein and nucleic acid observed significant (p<0.05) decrease in brain metabolism, hormonal production, mitochondrial

5ATPases activities and liver malondialdehyde level function and protection of LDL from oxidation . The following 14 days co-administration of the two drugs protective role of vitamin E against free-radical when compared with the controls. However, mediated cardiovascular diseases, cancer, cataracts, administration of vitamin E along with the combined immune malfunctions and Alzheimer's disease has also

5administration of the two drugs resulted in significant been reported . decreases (p<0.05) in all the parameters except for a Ivermectin is a white or slightly yellow

6significant increase in the brain ATPase activity and crystalline powder used for the treatment of filariasis liver malondialdehyde level. and onchocerciasis. Both diseases are major public

7The results suggested that vitamin E may health problems in several tropical countries . Report of revert or prevent the toxic effects of combined resistance to ivermectin in nematodes is becoming

8administration of ivermectin and albendazole. increasingly common . In view of this and the co-Therefore, the use of vitamin E along with the two endemic nature of the two diseases, clinical trials of drugs may be encouraged. ivermectin and albendazole combination have

9commenced in some African countries like Ghana . Keywords: Ivermectin, albendazole, combination However, there is paucity of information regarding the therapy, vitamin E, anti-oxidants, ATPase toxic effect of this therapy. Separate administration of

the two drugs has been reported to interfere with normal functioning of the heart as seen in a few cases of tachycardia and deaths recorded in animals repeatedly

10treated with ivermectin and albendazole separately . Amounts approaching the therapeutic doses of ivercmetin in animals (100 to 200µg/kg bodyweight)

11are hazardous to humans . A clinical trial of ivermectin as a single oral dose produced haematoma in two patients and prolongation of prothrombin time in all patients. Studies involving 400g/kg ivermectin in a 14-day course revealed a minimal transient increase in

12serum and liver aminotransferases . Albendazole and

R.O. Arinse et al/ The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

24

other members of benzimidazole class such as rats, appropriate volumes were administered to give the 19carbendazole, oxfendazole, and perbendazole have required dose . The administrations of the drugs were

11shown tetratogenic effects e.g. birth defects . Hence done at 24 h. interval (usually at 9.00 a.m.) and the rats pregnant women or animals are advised not to use these fed with rat pellets and water ad libitum. The animals

13 were housed in wooden cages. Animal husbandry and drugs. Rawden et al . reported elevated liver enzymes experimentation were consistent with the Guiding in rats administered albendazole. Albendazole may

201 4 Principles in the Use of Animals in Toxicology . The potentiate kidney dysfunction and l iver 15 16 rats were sacrificed 24 h after the last dose.derangement . Arise and Malomo reported that

Preparation of Serum and Tissues Homogenatederangement in membrane integrity and function of The rats were made unconscious in a jar containing cells occurred in rats co-administered with ivecmetin cotton wool soaked with chloroform. They were then and albendazole. They also proposed free radicals removed and neck area cleared of fur and the jugular mediated mechanism as the mode by which the co-

16 - vein was cut with sterile scalpel blade. The blood was administration of the two drugs elicits its toxic effect18 collected and centrifuged at 3000 rpm for 5 min to . Thus, the objective of this study was to investigate

obtain the serum. Immediately after the collection of the potential of vitamin E at reverting the toxic effects blood, the brain, liver, kidney (decapsulated) and small of the combined administration of the two drugs in rats. intestine (cleared of waste) were removed and immediately transferred into a well labelled container Materials And Methodscontaining ice-cold 0.25M sucrose solution and later Materialshomogenized.Experimental AnimalsBiochemical analysisA total of 25 male albino rats (Rattus novergicus) of ATPase activities were assayed using the method average weight 157.50 g +2.50 g were obtained from

21 22of Ronner et al. and catalase by the method of Sinha . the Animal Holding Unit of the Department of Determination of lipid peroxidation was done by Biochemistry, University of Ilorin, Ilorin, Kwara State, evaluating malondialdehyde level of the brain using the Nigeria.

23method of Varshney and Kale . DrugsStatistical AnalysisIvermectin and albendazole were products of Merck

All data are presented as means ± standard and Co. England and Glaxo Smithkline Beecham, deviation (SD). Statistical analyses were carried out Netherlands respectively.

24using Duncan Multiple-Range test . In all cases, Reagentsprobability level of 95% confidence interval was taken All reagents used were of analytical grade and were as significant.prepared in all-glass distilled water. The reagents were

stored in clean, airtight reagent bottles.Results

+ + 2+ 2+Methods Na -K - and Ca -Mg -ATPase activities Animal Grouping increased significantly (p<0.05) following the

The rats were randomly grouped into five combined administration of ivermectin and consisting of five rats each and received oral treatment albendazole for 14 days in the kidney and small for fourteen days. Group 1 was administered intestine but was reduced in the brain (Figures 1 and 2). appropriate volume of distilled water and served as the Separate administration of the two drugs did not result

+ + control. Group 2 and Group 3 were administered in any significant change (p>0.05) in Na -K ATPase 2+0.4mg/kg body weight (b.w) ivermectin and 15mg/kg activity in kidney, brain and small intestine; and Ca -

2+ b.w albendazole respectively. Rats in group 4 were Mg ATPase activity in the brain. Also separate administered combined dose of ivermectin and administration of the two drugs for 14 days reduced

2+ 2+ albendazole while rats in group 5 were administered Ca -Mg ATPase activity significantly in the kidney 30mg/kg b.w vitamin E in addition to the co- and small intestine (p<0.05; Figure 2). The addition of administration of the two drugs daily. vitamin E to the combination resulted in significant

2+ 2+ Preparation and Administration of Drugs decrease in Ca -Mg - ATPase activity (p<0.05) of all The drugs were prepared using distilled water the tissues investigated except the brain which showed

throughout the duration of the experiment. A stock significantly elevated (p<0.05) activity. There was + + - solution of 15mg/ml albendazole and 0.4mg/ml significant decrease in Na -K ATPase activity in the

ivermectin were prepared. For maximal absorption, kidney and small intestine but significant increase taking into consideration that the drugs were in tablet (p<0.05) in the activity in the brain following 14 days forms and that their respective solubility in water was oral administration of vitamin E in addition to the low, the drug solutions were administered orally with combined administration of the two drugs. the aid of a canula according to their average body Effects of ivermectin and/or albendazole in the weight since there were variations in the body weight of


25

0

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(nM/ml)

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Figure 1: Effects of ivermectin and/or albendazole in the presence and absence of vitamin E on the specific

1activities of selected rat tissue + +

Na -K ATPase after 14 days of drug administration.

1Values are means (n=5) + S.D (bars with different superscripts are significantly different at P<0.05). Key: Iver= Ivermectin; Alb= Albendazole; VitE = Vitamin E.

F i g u r e 2 : E f f e c t s o f ivermectin and/or albendazole in the presence and absence of vitamin E on the specific

1activities of selected rat tissue

2+ 2+Ca -Mg ATPase after 14 days of drug administration.


F i g u re 3 : E f f e c t s o f i v e r m e c t i n a n d / o r albendazole in the presence and absence of vitamin E on malondialdehyde (MDA)

1concentration in rat liver and brain after 14 days of drug administration.

Values are means (n=5) + S.D (bars with different superscripts are significantly different at P<0.05). Key: Iver= Ivermectin; Alb= Albendazole; VitE = Vitamin E.


26

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(Katf

)

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F i g u re 4 : E f f e c t s o f i v e r m e c t i n a n d / o r albendazole in the presence and absence of vitamin E on

1rat liver catalase activity after 1 4 d a y s o f d r u g administration.


F i g u re 5 : E ff e c t s o f i v e r m e c t i n a n d / o r albendazole in the presence and absence of vitamin E on

1rat brain catalase activity after 14 days of drug administration.


presence and absence of vitamin E on malondialdehyde Administration of ivermectin and/or albendazole for 14 (MDA) concentration in rat liver and brain after 14 days caused a significant elevation (p<0.05) in the liver days of drug administration was represented in Figure catalase activity in comparison to controls. Inclusion of 3. Neither of the drugs caused any significant change vitamin E in the combined administration, restored (p>0.05) in the concentration of MDA in the serum and catalase activity to the range of the control values brain when compared with controls (Figure 3). The (Figure 4). co–administration of ivermectin with albendazole for Administration of ivermectin or albendazole 14 days caused a significant elevation (p<0.05) in did not affect (p>0.05) brain catalase activity (Figure concentration of MDA formed in the serum. However, 5). However their co – administration led to a inclusion of vitamin E with the combined significant increase (p<0.05) in the enzyme activity of administration of both drugs significantly reduced brain when compared with control. The co – (p<0.05) the concentration of MDA formed. The administration of vitamin E with the two drugs reduced separate administration of ivermectin; and albendazole catalase activities significantly (P<0.05).caused significant increase in the concentration of MDA formed in the liver while the co- administration Discussion

+ +of the two drugs with or without vitamin E caused a Na -K ATPase is found in the plasma + +significant reduction (p<0.05) in the MDA membrane of all higher eukaryotic cells. Na -K

concentration of the liver when compared with the ATPase plays important physiological roles such as control (Figure 3). maintenance of the resting potential in excitable cells,

+Catalase activity was assayed in the liver and and ensuring Na and fluid reabsorption by the tubules. + +brain of the experimental animals and the result The significant increase in Na -K ATPase in all the

obtained is shown in figure 4 and 5 respectively. treatment groups revealed that ivermectin, albendazole

27

2+ or their combination may have imposed some form of kidney may lead to an increase in intracellular Ca + stress on liver cells, thus the increased synthesis of the concentration which may in turn, lead to leakage of K

25 32enzyme molecule to offset the stress .The significant out of the cells with corresponding loss of cell water . + +increase in the renal enzyme activity following the The consequent effect of this is inhibition of Na -K -

33administration of the combined ivermectin and ATPase activity . Also these may affect the albendazole may be attributed to induction of the osmoregulatory role of the kidney. However, the enzyme to offset the stress imposed by the drug combination therapy displayed negative synergism by regimen. The administration of vitamin E with the significantly increasing the enzyme activity. This may combination may have also helped to reduce some of be due to increased enzyme synthesis in order to the stress, as evidenced by its reversal of the effects counteract this effect. Addition of Vitamin E however produced by administration of the drug combination. led to normal activity thus implying free radical

+ +The brain Na -K - ATPase activity was significantly formation as the mechanism of toxicity. In the brain, the reduced in the combination group. This may be combined ivermectin and albendazole administration ascribed to the modulatory effect of albendazole in led to reduction in the enzyme activity. It may therefore potentiating the neurotoxic effect of ivermectin by mean that the presence of albendazole mediates the competitively preventing its efflux by p-glycoprotein accumulation of ivermectin in the brain cells with the while albendazole gets pumped out of the brain. The neurotoxic effect exhibited by deranging the brain cell reversal of this effect in the presence of vitamin E membrane. Hence the consequent loss of enzyme

26suggests free radical generation or formation of activity which was reversed by the administration of reactive oxygen species as possible mechanism of vitamin E.ivermectin neurotoxicity. Thus the binding of the drug This role of vitamin E may be due to the fact to various subunits essential for the activity of the that the vitamin is a physiological antioxidant and

34enzyme possibly via cysteine residues, as reported in protects cell membranes against oxidative damage . the interaction of ivermectin with cytochrome P Vitamin E has been reported to inhibit protein 450

27 35CY3A , may reduce the enzyme activity. For instance, phosphorylation . It may inhibit the formation of + +

ATPase are phosphatidic acid from phospholipids and this has been all the known functions of Na -Kassociated with the α-subunit of the heterodimer of the reported to take place via a phosphorylating kinase

28 reaction associated with increased intracellular enzyme . The binding of the drug to such a subunit may 33calcium ion concentration . Thus vitamin E may modulate the activity of the enzyme. This may be, in

+ + maintain membrane integrity by preventing protein part, the reason, for the inhibition of Na -K - ATPase oxidation and lipid peroxidation through its free radical activity in mouse small intestine in vitro reported by

29 scavenging properties. Vitamin E may also prevent the Wang et al. . This may also be the reason for the + + protein-kinase dependent phosphorylation of the reduction in the activities of rat brain Na -K ATPase as

various segments of the enzyme subunits.observed in this study.2+ Oxidation of membrane lipids results in The concentration of Ca in extra-cellular

30 formation of MDA which causes loss of cellular space is four times higher than that of cytosol . This 2+ integrity and has been associated with the etiology of gradient is maintained by the active transport of Ca

several chronic diseases. Lipid peroxidation is assessed across the plasma membrane. The significant increase 36

2+ 2+ by maximal rate of malondialdehyde formation . In the in the hepatic activity of Ca -Mg - ATPase in all the liver, malondialdehyde levels have been associated treatment groups may be due to increased production of

37with early liver oxidative stress as well as oxidative the enzyme to conteract the stress imposed by these damage of proteins and lipid peroxidation of membrane drug regimen. Vitamin E however helped to reduce the phospholipids which is a possible pathogenic effect imposed by the combined therapy. The

3 8mechanism of liver injury . In the brain, significant reduction in the kidney and small intestine malondialdehyde levels can be used to measure various enzyme activity following ivermectin, and albendazole

39diseased conditions. Weigand et al. investigated administration may be attributed to membrane cerebral formation of malondialdehyde as an index of derangement or inhibition of the enzyme by the drugs.

31 2+ lipid peroxidation in relation to different sources of Ahern et al. reported that ivermectin increased Careactive oxygen species in patients undergoing carotid release from sarcosplasmic reticulum vesicles and

2+ endarterectomy. It has been proposed to be one of the from endosplasmic reticulum by inhibiting Ca uptake 2+ 2+ major mechanisms of secondary damage in traumatic by Ca -Mg ATPase. This inhibition may account for

2+ brain injury. The brain is particularly prone to oxidative the elevated Ca levels in the serum as observed in the injury because the membrane lipids are essentially rich present study. This may also be the reason for the

40-412+ 2+ in polyunsaturated fatty acid .reduced activity of Ca -Mg - ATPase in the kidney

The significant increase in serum MDA levels and small intestine as observed in the present study. 2+ 2+ following combined administration of ivermectin and This reduction in Ca -Mg - ATPase activity in the



28

albendazole to rats, vis-a-vis the significant reduction The significant increase in the brain catalase activity in in the hepatic MDA levels of the hepatic cells may be the co-administration of ivermectin with albendazole due to some form of hepatic plasma membrane damage may be due to the possibility of albendazole being a causing the leakage of MDA to extracellular space. It substrate of p-gylcoprotein of blood brain barrier with may also be that the increased MDA levels caused higher affinity than ivermectin, thereby making it induction of antioxidant enzymes which was high possible for increased efflux out of the brain. This enough to counter and reduce the MDA concentration therefore may have led to the accumulation of or that the level of antioxidant here was high enough to ivermectin in the brain. This may possibly trigger cope and reduce the level of this oxidant. The production of reactive oxygen species and significant increase in hepatic MDA levels in the concomittant increased catalase activity to cope with ivermectin or albendazole administered rats and brain these. The reduction in activity in the presence of MDA concentration in the combination group is vitamin E may be ascribed to the antioxidant status of suggestive of alteration in the cellular redox status of vitamin E which may have prevented excessive the animals as a result of increased lipid peroxidation. production of free radicals or that this enhancement of The level of antioxidant enzymes might also not be the antioxidant defence in experimental animals is the

42 response of the brain to increase the detoxification of sufficient to cope with the level of oxidant influx . ivermectin.This increase in MDA formation suggests that the

antifilarials are capable of inducing oxidative stress Conclusionwhich may overload the endogenous detoxification

The toxicity potentiated by the co-mechanism of the cells. Albendazole has been reported administration of ivermectin and albendazole may be to cause increased formation of MDA in the blood of

43 nullified by co-administration of vitamin E with the healthy mice . However, addition of vitamin E brought two drugs. Therefore, possible inclusion of vitamin E down the level of MDA in all the tissues. This may be into ivermectin and albendazole combination therapy due to its antioxidant and scavenging properties.may be encouraged.It has been reported that membrane lipid

peroxidation results in the loss of polyunsaturated fatty Referencesacids, decreased membrane fluidity and severe 1. Sklodowska, M., Gromadzinska, J., Biernacka, structural changes leading to loss of enzymes and in

44 M., Wasowicz, W., Wolkanin, P., Marszalek, A., other cases receptor activity . Direct free radical Brozik, H. and Pokuszynska, K. (1996). Vitamin E, damage to membrane proteins may also occur as a

45 thiobarbituric acid active substance concentrations and result of lipid peroxidation leading to their activation . superoxide dismutase activity in the blood of children Thus, the loss of enzyme activities from tissues and with juvenile rheumatoid arthritis. Clin. Exp. sometimes the elevated activities of tissue enzymes as Rheumatol. 14:433-440.observed with different enzymes studied may be 2. Ball, G.F.M. (1988). Fat-soluble vitamin assays attributed to membrane lipid peroxidation and direct in food analysis. Elsevier Science Publishers Ltd., free radical damage to membrane proteins. London pp35-50.The body responds on exposure to xenobiotics 3. De-la-Fuente, M., Carazo, M., Correa, R. and by induction of antioxidant enzymes which acts to Del-Rio, M. (2000). Changes in macrophage and convert harmful metabolites of the xenobiotics lymphocyte functions in guinea-pigs after different pathways to harmless molecules and maintain the amounts of vitamin E ingestion. Br. J. Nutri. 84:25-33.cellular integrity of tissues by scavenging free radicals 4. Machlin. L.J (1991). Vitamin E. In: Handbook generated in the xenobiotics reactions. However,

nddifferent responses of catalase have been described in of Vitamins, 2 ed. Marcel Dekker, New York. pp 99-animals exposed to different xenobiotics. Some studies 144.observed increased catalase activity and were 5. Traber, M.G (1998). Synthetic as compared correlated to the reduced absorption of iron or with natural vitamin E is preferentially excreted as a – inhibition of haem biosynthesis caused by drug

CEHC in human urine: studies using deuterated alpha-46, 47exposure . Differently, other studies pointed to

tocopheryl acetates. FEBS. Letts. 437: 145-148.elevated enzyme activities which suggested a 48 6. Chabala, J.C., Mrozik, H., Tolma, R.L. Eskola, significant role in protecting cells . In this study

P.L.A. and Fisher, G.H. (1980). Ivermectin : A new however, administration of ivermectin and/or broad spectrum antiparasitic agent. J. Med. Chem. 23: albendazole for 14 days resulted in a marked increase in

liver catalase activity, whereas, in the presence of 1136-1934.vitamine E, catalase activity was reversed. Therefore it 7. Ottesen, E.A. and Ramachandran, C.P. (1995). could be suggested that the enhancement of the Lymphatic filariasis in tropical countries. Parasitol. antioxidant defence in experimental animals is a

Today 11: 129 – 131.hepatic response to increase the detoxification process.


29

biochemical study of the interaction of some 8. Sangster, N.C. (1996). Managing parasiticide trypanocides with rat tissue cellular system. Ph. D

resistance. Vet. Parasitol. 98:89-109.Thesis, University of Ife, Ile-Ife.

9. Awadzi, K., Addy, E.T., Opoku, N.O, Plenge- 20. Derenlanko, M.J. (2000). Guiding Principles Borig, A. and Burtner, D.W. (2003). O. volvulus in the use of Animals in Toxicology In: resistance to ivermectin: evidence for resistance and Toxicologist's Pocket Handbook. CRC Press Boca

Raton, London pp. 1-7.resistance monitoring in the field. Final report of the 21. Ronner, P., Gazzotti, P. and Carafoli, E. (1977). conference on the eradicatibility of onchocerciasis.

2+ 2+A lipid requirement for the Ca , Mg - ATPase Filarial J. 2:2-17.of erthrocyte membranes. Arch. Biochem. Biophys. 10. Gardon, J., Gardon-Wendel, N., Demanaga- 179: 578-583.

Ngamgue, N., Kamgno, J., Chippaux, J.P. and 22. Sinha, K.A (1971). Colorimetric assay of

Boussineq, M. (1997). Serious reactions after mass catalase Anal. Biochem. 47: 389-394.treatment of onchocerciasis with ivermectin in an area 23. Varshney, R and Kale, R.K. (1990). Effect of endemic for Loa Loa infection. Lancet 350:18-22. calmodulin antagonist on radiation induced lipid 11. Horton, J., Witt. C., Ottesen, e.A., Lazdins, J.K., peroxidation in microsome. Int. J. Rad. Biol. 58: 733-

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Correspondence to:

31

Bacterial Isolates Of Blood In Children With Suspected

Septicaemia In A Nigerian Tertiary Hospital1 2 1 1 1 1 O.T. Adedoyin, M Ibrahim, W.B.R. Johnson, A.I. Ojuawo, O.A. Mokuolu, S.K. Ernest,

1 1 1 1 3 1 O.Adesiyun, AO. Adegboye, A.A. Akanbi II, S. Odimayo, O V.Adebara, A.O. Saka

1.Department of Paediatrics and child Health, University of Ilorin Teaching Hospital, P.M.B. 1459, Ilorin, Nigeria. 2. Aminu Kano Teaching Hospital, Kano, Nigeria.

3.Federal Medical Center, Ido-Ekiti, Nigeria.

Prof OT AdedoyinDepartment of Paediatrics and Child HealthUniversity of Ilorin Teaching Hospital,P.M.B.1459Ilorin, NigeriaE-mail: [email protected]

Abstract Introduction The prevailing aetiology of septicemia varies The under-five mortality rate in most

1over time form region to region and it determines the developing countries is still unacceptably high. Most antibiotic choice for both presumptive and definitive of these developing countries are in Africa. Though a management at any given period. The study aimed to vast majority of these deaths are poorly investigated, determine the current aetiology of septicaemia in they are probably the resultant effects of poverty and

1febrile children </=13 years. Children admitted to the malnutrition which are prevalent in Africa. However, Emergency Paediatric Unit (EPU) having fever had except for a few works, the exact contribution of their blood taken for aerobic bacteria,culture and septicaemia to high under-five mortality rate is yet to be

1sensitivity. Those that have received or taken fully elucidated.antibiotics within 24 hours of admission were Septicaemia is an underestimated health excluded. Out of a total of 288 specimens successfully problem for most African countries largely because analyzed, 110 were positive for growth. Excluding the most health facilities lack the resources for doing 5 contaminated ones, there was 38.2% prevalence of microbiologic studies. Where the facilities are also septicemia among the febrile patients studied. The available, they have limited capacities as they may not leading organism recovered include Staphylococcus be able to culture anaerobes or even type the strains of aureus which accounted for a prevalence of 63(57.3%). bacteria isolated. The few health facilities that can do This was followed by Salmonella typhi, 14 (12.7%). microbiologic studies are concentrated in the tertiary Furthermore, 82(74.5%) of the isolates were gram health institutions located mainly in the urban areas positive, while 28 (25.5%) were gram negative with few in the rural areas. organisms. The gram positive organisms were more However, reports from some African countries, sensitive to Ofloxacin (100%), Ciprofloxacin (95%), notably Kenya and Gambia, have indicated bacterial Cefuroxime (84%) and gentamicin (82%). The gram infections as a major cause of mortality and morbidity

2-3negative organisms were more sensitive to among children in Africa. Berkley et al in Kenya Ciprofloxacin (100%), Ceftazidime (92%), Ofloxacin found an overall risk of any bacteraemic disease for (88%) and gentamicin (77%). The quinolones children under the age of five to be 505 per 100,000. In adequately covered both the gram positive and negative their study, 28.0% of all hospital deaths were associated

4organisms. We recommend the use of a combination of with septicaemia. This compares with 22.0% death ciprofloxacin and gentamicin or cefuroxime and associated with malaria suggesting that bacterial gentamicin for empiric treatment of suspected infection may be responsible for more deaths in septicaemia in our setting. children than malaria in an area of endemic malaria

among febrile children. Key words: Septicaemia; Children; Nigeria. Furthermore, the etiology of septicaemia

varies from region to region. It also changes over time within a locality in terms of isolates and resistance pattern hence the need for continuous surveillance.

Methodology This cross sectional study was carried out at the University of Ilorin Teaching Hospital, Ilorin, Nigeria from August 2006-December 2007. The Hospital is located in the North Central Zone of Nigeria. It receives referrals from about four adjoining States in Nigeria which include Oyo, Osun, Kogi and Niger. It has an Emergency Paediatric Unit (EPU) where the patients were recruited. An average of 2,400 children per annum (200/month) was admitted into the EPU in the last three years before the study. The sample size was

O.T. Adedoyin et al/ The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

32

5 A major limitation of this study is that though 300 determined using the standard formula. with tolerable patients were recruited for the study, some of the margin of error set at 5% and estimated prevalence of patients were found to have incomplete data during the bacteraemia set at 25.0% and allowing for an attrition process of data analysis. Unfortunately, we were unable rate of 5.0%, a sample size of 300 patients was obtained to retrieve some of the data. This accounted for and hence recruited. However at the end of the study variation and therefore inconsistent number of patients period, only 288 blood specimens were successfully analyzed for some variables.analyzed.

Febrile children between the ages of 1 month and 13 o Resultsyears (rectal temperature > 37.2 C) were recruited for

Socio-demographic characteristics, temperature the study, while those who have been on antibiotics in pattern and duration of admission in the study the last 72 hours before admission or denied consent populationwere excluded. Temperatures were recorded using a A total of 300 patients were recruited for the study. This mercury thermometer inserted into the rectum for 3 comprise of 185 males and 115 females giving a male: minutes. Written consents were sought from the female ratio of 1.6.1. Most of the children parents/caregivers after detailed information was 192/297(64.6%) were in the 13-60 months age group given. Ethical clearance was obtained from the followed by 56/297(18.9%) in the 61-168 months age Hospital Ethics Committee. group and 49/297(16.5%) children in the 1-12months Five milliliters of blood was collected age group. The temperature of the 123/272(45.2%) aseptically via venepuncture and dispensed using a

o o ochildren ranged between 37.4 C and 38.5 C, 38.6 C-new needle into a blood culture bottle containing o othioglycollate broth and transfered immediately to the 40 C in 137/272 (50.37%) and >40 C in 12 (4.41%)

Research Laboratory of the Department of children. Most of the children 130/286 (45.5%) Microbiology , University of Ilorin Teaching hospital, required admission for 1-3 days, 82/286 (28.7%) for >8 Ilorin for culture and antibiotic sensitivity testing. days, 66/286 (23.1%) for 4-7 days while 8/286 (2.7%) Subcultures were done after the first 24 hours and then were not admitted.daily for up to 2 weeks on Blood, chocolate and Bacteria isolates in the study populationMacConkey agar. Blood and MacConkey plates were Out of a total of 288 blood culture specimen incubated aerobically (while chocolate plates were successfully analyzed, there were bacteria isolates in

o 110 specimen excluding the 5 mixed growths that were incubated inside candle extinction jar) at 37 C for contaminated giving a 38.2% prevalence of 24hours.septicaemia among the febrile patients recruited for the Colonies were characterized using a study. The most common bacteria isolate was combination of colonial morphology, standard Staphylococcus aureus 63 (57.3%) . This was followed biochemical tests and serological tests where

6 by Salmonella typhi 14 (12.7%), Staphylococcus appropriate. Antibiotic sensitivity testing was epidermidis 9 (8.2%), Staphylococcus saprophyticus 7 performed using the modified Kirby Bauer disc

7 (6.4%) and Enterobacter 7 (6.4%) (Table 2). The Diffusion method. Pure colonies of isolated organism distribution of the bacteria isolates according to gender were suspended in sterile normal saline inside Bijou of the patients is as shown on Tables 2&3. Out of the bottles and the turbidity of the suspension adjusted to 110 bacteria isolates, 82(74.5%) were gram positive, 0.5 McFarland's standard. A sterile cotton swab was while 28 (25.5%) were gram negative. The gram dipped into the suspension and squeezed against the positive isolates occurred in 39 males and 43 females side of the bottle. The swab was then used to inoculate a M: F ratio 1:1.1, while the gram negative isolates Mueller Hinton agar before the application of single

o occurred in 15 males and 13 females M:F ratio 1.2:1 antibiotic discs and subsequent incubation at 37 C (Table 3).aerobically for 18-24hours.Antibiotic sensitivity of the bacteria isolatesZone diameters of inhibition around each disc The sensitivity of staphylococcus aureus to ofloxacin, were measured using a calibrated ruler and interpreted ciprofloxacin, gentamycin and cefuroxime was 100%, according to National Committee for Clinical 94%, 77.4% and 62.5% respectively (Table 4). Its Laboratory Standard (NCCLS). Escherichia coli resistance to augmentin and cloxacillin was 55.9%and (ATCC 25922), Staphylococcus aureus (ATCC 68.8% respectively. The sensitivity of Salmonella typhi (25923) and Pseudomonas aeruginosa (ATCC 2785) to ciprofloxacin, ofloxacin, ceftazidime and augmentin were used as control for gram positive, gram negative is 100.0%, 81.8%, 75.0% and 71.4% respectively and Pseudomonas isolates respectively.(Table 4). The gram positive organisms were more The antibiotics discs used were Ofloxacin (5µg), sensitive to ofloxacin (100%), ciprofloxacin (95.0%) Augmentin (10ug), Cefuroxime (30 µg), Ceftazidime and cefuroxime (84.0%). The gram negative organisms (30µg), Gentamycin (30µ), Ciprofloxacin (10 µg), on the other hand were more sensitive to ciprofloxacin Amoxycill in (30 µg), Cloxacill in (20µg), (100.0%), ceftazidime (92.0%) and ofloxacin (88.0%). nitrofurantoin (300 µg), Tetracycline (30 µg).


33

Table 1: Blood culture resul ts in the study population Organism Number Percentage No growth

173

60.1

Staphylococcus aureus

63

21.9 Salmonella typhi

14

4.9

Staphylococcus epidermidis

9

3.1

Staphylococcus saprophyticus

7

2.4

Enterobacter Spp

7

2.4

Pseudomonas aeruginosa

3

1.0

Klebsiella Spp

3

1.0

Citrobacter Spp

3

1.0

Escherichia coli

1

0.4

Mixed growth

5

1.8

Total

288

100

Table 2: Prevalence and distribution of

bacterial isolates

according to gender

Bacteria isolate

Number

Male

Female

Percentage

Staphylococcus aureus

63

28

35

57.3

Salmonella typhi

14

8

6

12.7

Staphylococcus epidermidis

9

6

3

8.2

Staphylococcus saprophyticus

7

3

4

6.4

Enterobacter Spp

7

3

4

6.4


3

2

1

2.7


3

2

1

2.7

Klebsiella Spp

3

2

1

2.7

Citrobacter Spp

3

2

1

2.7

Escherichia coli

1

0

1

0.9

Total

110

54

56

100

Table 3: Case fatality according to Gram

reaction of

bacterial isolates

and gender of the patients

Gram stain

Number

Males

Females

No. of deaths

Case Fatality (%)

Gram +ve

82

39

43

1

1.2

Gram -ve

28

15

13

2

7.1

Total

110

54

56

3

Gram +ve-

Gram positive, Gram-ve-Gram negative

Table 4: Antibiotic sensitivity pattern of the bac teria isolates

Org.

No.

Aug

n(%)

Am

n(%)

Tetr

n(%)

Gent

n(%)

Oflo

n(%)

Cipr

n(%)

Cef

n(%)

Cefta

n(%)

Nitr

n(%)

Clox

n(%)

StapA

63

28(44.)

21(33.)

19(29.)

51(80.6)

63(10)

59(94)

53(84.)

37(58.1)

20(31.2)

Sal

14

12(85.)

7(50)

4(28.6)

12(84.6)

11(81.)

14(10)

13(90)

14(100)

8(58.3)

StapE

9

9(100)

6(67)

6(67)

9(100)

9(100)

9(100)

6(66.6)

6(67)

StapS

7

7(100)

7(100)

7(100)

Enter

7

2(33)

1(11.1)

4(50)

5(66.7)

7(100)

7(100)

2(28.6)

6(87.5)

5(73)

Pseud 3 2(67) 1(33) 2(67) 3(100)

3(100)

1(33.3)

3(100)

Citro 3 2(67) 1(33) 1(33) 3(100)

3(100)

1(33) 1(67)

E.coli 1 1(100) 1(100)

1(100)

1(100)

Aug -Augmentin, Amo -amoxycillin, Tet - tetracycline, Gent -gentamicin, Oflo -ofloxacin, Cipro -Ciprofloxacin, Cef- cefuroxime, Ceft-Ceftazidime, Nitr –Nitrofurantoin, Clox-cloxacillinStapA-staphylococus aureus, Stap E, Staph ylococcus epidermidis, Stap S, Staphylococcus saprophyticus, Enter -Enterobacter, Pseud -Pseudomonas Aeruginosa, Citro -citrobacter, E.Coli -Escherichia coli.

34

The two antibiotics that cover both gram positive and accounting for 57.3% of all the bacterial isolates. This negative organisms satisfactorily are ciprofloxacin and was followed by Salmonella typhi and other ofloxacin. Staphylococcal organisms. This was not in agreement

4, 18-23 Outcome and Case fatality among the various with the finding of other workers. Some of these bacteria isolates workers particularly in the East African region obtained A total of 8 deaths were recorded amongst the 288 Streptococcus pneumoniae and Salmonella typhi as the patient whose blood culture specimens were analyzed predominant isolates. The different settings may accounting for 2.8% mortality. Out of this 8 deaths, 5 account for this. occurred amongst the 173 patients in which there was It is interesting to note that the outcome in no aerobic bacteria growth giving a case fatality of these children managed for septicaemia was 2.9%, 3 occurred amongst 110 patients with positive impressive as the case fatality was low indicating that bacteria isolates giving a case fatality of 2.7%. Two septicaemia was treatable particularly when deaths were recorded amongst children with growth of interventional measures are introduced early. This was Salmonella typhi giving a case fatality of 14.3% and not the case in similar studies where high mortality was

4 one occurred amongst the 63 patients with growth of obtained. It is thought that the empirical use of

Staphylococcus aureus giving a case fatality of 1.6%. antibiotics which is common in most hospitals in

No death was recorded amongst the patients with other Nigeria may be contributory to the low mortality. It is

isolates. Similarly one death was recorded among the also the practice in our center to commence children

82 children with gram positive isolates giving a case suspected to have septicaemia on broad spectrum

fatality of 1.2% while two deaths occurred among the antibiotics while awaiting the blood culture and

28 children with gram negative isolates giving a case sensitivity result which take 3-7 days before they are

fatality of 7.1%.obtained. The antibiotics are later changed based on the sensitivity result if it is different from the empirical

Discussionantibiotics being used. The outcome of this study is

Bacterial infections are significant causes of expected to further guide us in the choice of empirical

morbidity and mortality in the developing countries. antibiotics before laboratory results are obtained.

Monitoring of the susceptibility pattern of the The outcome of this study indicate that

pathogens on a regular basis and surveillance for septicaemia is of public health significance and

resistance is imperative. This is because the problem of therefore should attract the attention and positive

bacteria resistance to antibiotics is increasing in intervention of World Health Organization (WHO) in 8-12 13

tropical countries and worldwide. Aetiology of addition to the traditional areas where they have paid 24-25septicaemia varies from region to region. It also

attention. For a start, a pro-active introduction of changes over time within a locality. Furthermore, the

bacteria vaccines such as Hib and pneumovax would Nigerian picture of the pattern of organism causing

not be a bad idea since they have been found to reduce septicaemia has not been adequately studied in all the

the severity of such infections. In countries in which H. regions, hence this study is expected to fill this gap.

influenzae type b and pneumococcal conjugate Fever remains a common feature of many

vaccines have been introduced in infancy, there hasillnesses among children worldwide. Malaria has

been a dramatic reduction in severe illness caused by 14 26-28remained a leading cause of fever in Nigeria.

theseorganisms.However this study has shown that 38.2% of fever in

The antibiotic sensitivity of most of the children may be due to septicaemia hence it is likely

organisms took a different turn with surprisingly that some of the children diagnosed to have malaria

increasing and remarkable sensitivity to quinolones may also have been co-infected with bacteria, a view

while they were resistant to routine antibiotics. For which has been corroborated by the work of Ayoola et

instance, the Staphylococcus aureus in this study were 15al in Ibadan. Our finding of 38.2 % prevalence of resistant to augmentin, amoxycillin and ceftazidime. septicaemia is similar to the findings of other The finding of augmentin resistant Staphylococcus 16-17workers. This prevalence figure is however aureus may suggest over-use of augmentin in treating exclusive of the contribution of anaerobes which could many infections in Nigeria despite its enormous cost. be part of this study as there was no facility for its The same goes for amoxycillin and cloxacillin which culture in our Centre. The burden of septicaemia are still largely prescribed by medical practitioners among febrile children may therefore be more than because they are cheaper. what we obtained in our study. Furthermore, in our Quinolones are largely contraindicated in setting ,some febrile children would have been tried on children because of the result of trials carried out in antibiotics which are easily obtained across the counter juvenile animal which indicated that it causes cartilage

29before presenting in hospital thereby affecting damage. Histological examination of the joint surface bacteriological culture yield. of affected animal revealed loss of cartilaginous matrix Staphylococcus aureus was the leading organism



35

and chondrocytes and cavitation within the immediate Bauni E, Mwarumba S, Ngetsa C, Slack MPE, Njenga zone of cartilage accompanied by cartilage fibrillation

S, Hart A, Maitland K, English M, Marsh K, Scott JAG. or chondrocyte clustering or loss of the surface layer

Bacteraemia among Children admitted to a rural which covers the cavitation (loss of the outer wall of the 29 Hospital in Kenya. N Eng1 J Med. 2005; 352:39-47cavity). This conception is however fast changing as

5. Araoye MO. Sample size determination. In: the drug is been increasingly used in children even in 29 Research methodology with Statisitics for Health and developed countries.

Furthermore, Salmonella typhi was surprisingly more Social Sciences. Nathadex Publishers, Ilorin: 2003; sensitive to the quinolones, augmentin, cefuroxime and 115-129.ceftazidime. While the quinolones are fast gaining 6. Cheesbrough M. Collection, transport and ground in the treatment of septicaemia, caution should examination of blood and bone marrow. In: Medical 30still be exercised because resistance is being reported.

Laboratory Manual for Tropical Countries. Vol II. In order to stem the tide of increasing drug resistance

Medical Microbiology Cheesbrough M (ed.). which has been the bane of other equally potent Butterworth-Heineman, Oxford 1994; 175-180.antibiotic, antibiotic combination therapy is suggested. 7. Bauer A W, Kirby QM, Sherrns JC, Turik M. This will produce synergistic bactericidal effect which Antibiotic susceptibility testing by standardized single has proven effective in the treatment of bacteria

31 32 disk method. Am J. Clin. Path. 1966; 45: 493 – 496.endocarditis and pyelonephritis.8. Berkley JA, Maitland K, Mwangi I, Ngetsa C, In conclusion, the leading causes of

septicaemia among febrile children in our setting are Mwarumba S, Lowe BS, Newton CR, Marsh K, Scott Staphylococcus aureus and Salmonella typhi. A JA, English M. Use of clinical syndromes to target combination of quinolones and gentamicin is adviced antibiotic prescribing in seriously ill Children in for the empiric treatment of suspected Staphylococcus malaria endemic areas: observational study. Brit Med J. aureus septicaemia while ciprofloxacin or ceftazidime

2005; 330(7498):995-1002.would be most useful for that of Salmonella typhi.

9. Montefiore D, Okubadejo OA. Organisms and Furthermore, there should be a high index of suspicion their sensitivities among hospital patients.1.Ecology. of septicaemia in any child with a febrile illness. When Afr J Med Sci 1970:1:49-56in doubt, it will be advantageous to commence empiric

antibiotics before blood culture result comes out. A 10. Montefiore D, Rotowa NA, Adeyemi-Doro combination of ciprofloxacin and gentamicin is highly FAB, Nwafor MB. An in-vitro comparison of antibiotic recommended under such circumstance. activity against commonly isolated bacteria from

hospital patients. Nig Med J 1982: 12:71-79Supported by First Bank Nigeria Limited

11. Eke PI, Rotimi VO. In-vitro anti-microbial susceptibility of clinical isolates of pathogenic bacteria

We are indebted to the resident doctors in the to 10 antibiotics including phospomycin.Afr J Med Sci

Departments of Microbiology and Parasitology and 1987:16:1-8Paediatrics and Child Health and all the nursing staff in 12. Montefiore D, Rotimi VO, Adeyemi-Doro the Emergency Paediatric Unit of the University of

FAB. The problem of bacterial resistance to antibiotics Ilorin Teaching Hospital, Ilorin, Nigeria.among strains isolated from hospital patients in Lagos

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1989:23:641-6511. Ibeziako NS. In: Paediatrics and child health in 13. O'Brien TF. Resistance to antibiotics at a tropical region,Azubuike JC, Nkangineme KEO medical centers in different parts of the world. J (eds.), African Educational Services, Owerri, Antimicro chemother 1986: 18 Suppl.C: 243-253.Nigeria,1999;5-7. 14. Training manual for management of malaria in 2. Barkley J, Mwarumba S, Bramham K, Lowe Nigeria (Participant's manual). Produced by the B, Marsh K, Bacteraemia complicating severe malaria Federal Ministry of Health, Abuja, Nigeria, February in Children. Trans Roy Soc Trop Med Hyg. 2005; 19-27.1999;93:283-286 15. Ayoola OO, Adeyemo AA, Osinusi K. 3. Enwere G, Van henssbroek MB, Adegbola R, Concurrent bactaeremia and malaria in febrile Nigerian Palmer A, Onyiora E, Weber M, Greenwood B. infant. Trop Doct 2005; 35(1):34-36.Bacteraemia in Cerebral Malaria. Ann Trop Med 16. Okwara FN, Obimbo EM, Wafula EM, Murila 1998;18(4):275-278. FV. Bactaeremia, urinary tract infection and malaria in 4. Berkley JA, Lowe BS, Mwangi I, Williams T, hospitalized febrile children in Nairobi: is there an

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November 29, 2004, at http://www.who.int/child-association? E Afr Med J 2004; 8(1): 47-51.adolescent-health/overview/child_health/map_01_

17. Evans JA, Adusei A, Timmann C, May J, world.jpg

Mack D, Agbenyega T, Horstmann RD, Frimpong E. 25. Klugman KP, Mahdi SA, Heubner RE, Kohberger High mortality of infant bactaremia clinically R, Mbelle N, Pierce N. A trial of a 9-valent

indistinguishable from severe malaria. QJM 2004; pneumococcal conjugate vaccine in children with and

97(9):591-597. those without HIV infection. N Engl J Med 2003;349:1341-1348. 18. Ghiorghis B, Geyid A, Haile M. Bacteremia in

febrile out-patient children. East Afr Med J 1992; 26. Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, Lynfield R, Reingold A, Cieslak PR, 69:74-77. Pilshvili T,Jackson D, Facklam RR,Jorgensen JH,

19. Lepage P, Bogaerts J, Van Goethem C, Shuchat A. Decline in invasive pneumococcal disease Ntahorutaba M, Nsengumuremyi F, Hitimana DG, after the introduction of protein-polysaccharide Vandepitte J, Butzler JP, Levy J. Community-acquired conjugate vaccine. N Engl J Med 2003;348: 1737-

1746. bacteremia in African children. Lancet 1987; 1:1458-

1461. 27. Mulholland K, Hilton S, Adegbola R, Usen S, Oparaugo A, Omosigho C, Weber M, Palmer A, 20. Cotton MF, Burger PJ, Bodenstein WJ. Schneider G, Jobe K, Lahai G, Jaffar S, Secka O,Lin K, Bacteremia in children in the south-western Cape: a Ethevenaux c, Greenwood B. Randomised trial of hospital-based survey. S Afr Med J 1992; 81:87-90. Haemophilus influenzae type-b tetanus protein

20. Walsh AL, Pire AJ, Graham SM, Molyneux conjugate vaccine for prevention of pneumonia and

EM, Molyneux ME. Bactaeremia in febrile Malawian meningitis in Gambian infants. Lancet 1997;

children: clinical and microbiologic features. Pediatr 349:1191-1197. [Erratum, Lancet 1997; 350:524.]

Infect Dis J 2000; 19:312-318. 28. Takizawa T, Hashimoto K, Minami T,

21. Bahwere P, Levy J, Hennart P, Donnen P, Lomoyo Yamashita S, Owen K. The comparative arthropathy of W, Dramaix-Wilmet M, Butzler JP, De-Moi P.

fluoroquinolone in dogs. Hum Exp Toxicol 1999: 392-Community-acquired bacteremia among hospitalized

399.children in rural central Africa. Int J Infect Dis 2001; 29. Daini OA, Ogbolu OA, Ogunledun AA. 5:180-188. Quinolones resistance and R-plasmids of some gram

22.O'Dempsey TJ, McArdle TF, Lloyd-Evans N, negative enteric bacilli. Afr J Clin Exp Microbiol Baldeh I, Laurence BE, Secka O, greenwood BM. 2005:6(1):14-20. Importance of enteric bacteria as a cause of pneumonia, 30. Working Party of the British Society for meningitis and septicemia among children in a rural

community in The Gambia, West Africa. Pediatr Infect Antimicrobial Chemotherapy. The antibiotic Dis J 1994; 13:122-128. prophylaxis of infective endocarditis. Lancet

1982:11:1323-1326. 23. UNICEF. The state of the world's children 2004. ( A c c e s s e d N o v e m b e r 1 8 , 2 0 0 4 , a t 31. McCabe WR, Jackson GG. The treatment of http://www.unicef.org/publications/2004_OfficialSu pyelonephritis: Bacterial, drug and host factors in mm_ENG.pdf.) success or failure among 252 patients. N Eng J Med 24. World Health Organization. Proportional mortality 1965: 272:1037-1044.among under-fives, worldwide 2001. (Accessed

Correspondence to:

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Dr .G.O. Omotoso,Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, P.M.B. 1515, Ilorin, Nigeria.Email: [email protected] Tel: +234 703 050 5707.

Microarchitectural Changes in the Superior Colliculli of Male

Wistar Rats after Cigarette and Cotton Wool Smoke Exposure

G.O. Omotoso, B.U. Enaibe, E.A. Caxton-MartinsDepartment of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences,

University of Ilorin, Ilorin, P.M.B. 1515, Ilorin, Nigeria.

Abstract IntroductionTobacco is a preventable risk factor to many Tobacco smoking is a known risk factor of

clinical conditions. The effects of cigarette smoke was many clinical conditions in the body. It has been studied on the superior colliculus of male Wistar rats. associated with diseases of the lungs, heart, brain, liver,

1, 2Twenty (20) adult rats were grouped into a control and a and other organs . Tobacco has thousands of treatment group. While the control group was exposed components, many of which are volatilised during to cotton wool smoke, the treatment group was allowed burning, while others, such as the aromatic to inhale smoke from completely burnt cigarette, a stick hydrocarbons, are formed during combustion of the

3per rat, for a period of 21 days. At the end of days 7, 14 leaf components .and 21, animals from the two groups were sacrificed by By virtue of its short-term actions on the cervical dislocation and the superior colliculus excised, cholinergic system, nicotine has positive effects on

3fixed in formol calcium, and some of the tissues certain cognitive domains . Nicotine is responsible for (superior colliculi) were homogenised for enzyme the acute effects of tobacco, while tar is responsible for

4studies. Blood samples were also collected its chronic effects . The components of a cigarette stick intracardially for enzyme studies. Tissue sections were differ depending on the manufacturer, and a completely prepared for histological studies using H&E stains, and burned cigarette stick usually contains between 1-6 mg

5a quantitative study was done on the activity of lactate of nicotine . The carbon monoxide produced during dehydrogenase (LDH) enzyme. burning of cigarette also has additional adverse effects,

5While serum LDH decreased in the treatment as a component of the smoke . Vascular injury resulting group, the tissue LDH increased, compared with the from ischaemic process leads to reduction in the supply control group that received the cotton wool smoke. The of oxygen and nutrients to the brain, thereby causing histological sections of the treatment group exposed to various forms of degenerative changes in the tissue.

6cigarette smoke showed reduced number of neurons, The superior colliculus (SC) is a visual relay centre , reduced density of neuronal bodies, many cytoplasmic transforming both visual and non-visual sensory vacuolations, and distorted cytoarchitecture, compared signals into motor commands that control orienting

7with the control animals exposed to cotton wool smoke, behaviours .which showed few vacuolated spaces only on day 21. Furthermore, tobacco smoke is an exogenous These histological changes were most likely due to the source of reactive oxygen species, with a broad oxidative stress and ischaemia resulting from the spectrum of oxidant-ionising radiation which generates cigarette smoke and the increased LDH enzyme 8

free radicals in exposed tissues . Due to a low oxygen activities in the superior colliculus. tension, anaerobic glycolytic pathway is utilized to

supply the brain with its ATP requirement. Some Keywords: cigarette, cotton wool smoke, LDH, membrane markers, such as alkaline phosphatase, that superior colliculus facilitate transport across the membranes are adversely

affected by smoking, leading to increased leakage of LDH through the cell membrane, and hence elevated

9,10levels of this enzyme . The current study aimed at determining the structural changes that occur in the superior colliculus of Wistar rats when exposed to cigarette smoke.

Materials And MethodsExperimental Animals

Following appropriate ethical guidelines, twenty (20) adult Wistar rats were used for the study. They were housed in the Animal Holding of the Anatomy Department, University of Ilorin. They were fed on rat pellets and water ad libitum and allowed to

G.O. Omotosho et al/ The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

38

acclimatise before commencing the experiment. The formol calcium for 24 hrs at room temperature, and animals, with an average weight of 219.5 g, were histological preparations were carried out using randomly divided into a control Group A and a Haematoxylin and Eosin staining techniques.treatment Group B. Lactate Dehydrogenase Studies (LDH)Treatment of Animals Both serum and the supernatant of the

Each animal in Group A (Control) was allowed homogenate collected on Day 14 were used to to inhale smoke from burnt cotton wool of equal weight determine the activity of LDH in the superior colliculi, with the tobacco content of a stick of cigarette, while via the process of spectrophotometry. The assay for this Group B was exposed to smoke from a stick of cigarette enzyme was carried out using RANDOX Kit (Antrim,

® 13(Benson and Hedges brand ) containing 0.735 g of UK) . This was done at a wavelength of 340 nm and 11 Temperature of 37ºC. 0.05 ml of sample and 3.0 ml of tobacco. Each cigarette was completely burnt within

reagent were pipetted into a cuvette. This was mixed 15 min of exposure. All exposure was done once daily thoroughly and the initial absorbance read after 0.5 at 1900 h, and an improvised exposure chamber was min. Thereafter it was read after 1, 2 and 3 min.used for the experiment which lasted 21 days. The Resultschoice of cotton wool smoke as control was to allow all

The serum LDH level was lower in the group animals have a common exposure to smoke, while the exposed to cigarette smoke compared to those exposed tobacco content of cigarette distinguished Group B

12 to cotton wool smoke, whereas in the superior colliculi, from the Control Group A .the average LDH activity was noticed to increase in Animal Sacrifice and Specimen Collectionanimals treated with cigarette smoke compared with The animals were exposed to smoke for a total the Control (Figure 1); though these differences were period of 21 days; however, they were sacrificed by not statistically significant.cervical dislocation (in three batches) on Days 7, 14 and

The histological findings of the SC on Day 7 21. Blood sample was collected intracardially and revealed that in animals exposed to cotton wool smoke, dispensed in lithium heparin bottles on Day 14. The the neurons were numerous with preserved cranium was gently opened to expose the brain, and the architecture. Majority of these neurons were superior colliculi (SC) were identified, excised and multipolar, with few binucleate cells, and the weighed. Some of the tissue specimens of SC on Day supportive fibre network was adequately distributed 14 were placed in chilled 0.25 M sucrose solution, and within the background. The nuclear membranes were homogenized using a homogenizer. The homogenate intact, and there were no signs of cellular degeneration was centrifuged at 5000 rpm for 5 min using a (Figure 2). Those exposed to cigarette smoke for the centrifuge (Gallenkomp, England). The supernatants same duration exhibited most of the aforementioned collected, using Pasteur pipettes, were stored at -20°C, features except that the neurons were sparsely and thereafter analysed for LDH activity. The tissues dispersed, and there was reduction in the density of the for histological studies were also immediately fixed in

1. FIGURES

Figure 1: Activity of lactate dehydrogenase (LDH) in serum and superior colliculi (SC)

on Day 14 of exposure

(p > 0.05).


39

MP

MPN

BN

Figure 2. Photomicrograph of the Superior Colliculus of animals in the Cotton wool smoke (Control) Group after 7 days of exposure, showing numerous m u l t i p o l a r n e u r o n s ( M P N ) , normochromic nuclei, few binucleate cells (BNC) and normal architecture (H&E X250).

Figure 3. Photomicrograph of the Superior Colliculus of animals in the Cigarette smoke Group after 7 days of exposure showing sparsely dispersed neurons and reduced density of neuronal bodies (H&E X250).

Figure 4. Photomicrograph of the superior colliculus of the rats in the Cotton wool Group after 14 days of exposure, showing numerous cells at this magnification (H&E X100).

VCS

Figure 5. Photomicrograph of the Superior Colliculus of animals in the Cigarette smoke Group after 14 days of exposure, showing numerous vacuolar spaces (VCS), and

Figure 6. Photomicrograph of the Superior Colliculus of animals in the cotton wool smoke group on Day 21, showing vacuolated

Figure 7. Photomicrograph of the Superior Colliculus of animals in treatment group exposed to cigarette smoke for 21 days, showing criss-crossed afferent and efferent fibres (arrows), and some forms of distorted architecture; the staining intensity was also lighter than the control group (H&E x250).

neuronal bodies (Figure 3). of neurons, most of which were multipolar; there were The SC of animals exposed to cotton wool dense aggregations with criss-crossed afferent and

smoke showed numerous neurons and lightly stained efferent nerve fibres, and the entire architecture was slide on Day 14 (Figure 4), while the treatment group somewhat slightly distorted (Figure 7). The degree of exposed to cigarette smoke showed many cells having degeneration and disintegration in the superior colliculi vacuolar spaces and hypochromic nuclei on Day 14 of treated animals exposed to cigarette smoke (Figure 5). increased, with increasing duration of exposure.After 21 days of exposures to smoke, the cotton wool group showed moderate cells which were deeply Discussion

Oxidative stress and ischemic processes are stained. There were also vacuolations in the cytoplasm, 3

and the fibre network appeared to be regularly arranged part of the mechanism of action of nicotine . The vascular abnormality resulting from the latter (Figure 6). Neuron cell bodies of the SC of animals in mechanism leads to reduction in supply of oxygen and the cigarette group stained hyperchromatic; numerous nutrients to the brain tissue, leading to various forms of vacuolar spaces were present with degenerating axons

40

degeneration of the tissue. In the presence of low exposure and ascorbic acid intake on gene expression oxygen tension or absence of oxygen, the brain derives

of antioxidant enzymes and other related enzymes in its ATP requirements through anaerobic glycolysis, and

the livers and lungs of Shionogi rats with osteogenic lactate dehydrogenase (LDH) is needed for the disorders. Toxicological Sciences 2003;73: 339-47.conversion of lactate to pyruvate.2. Yuan H, Shyy JY, Martins-Green M. Second-LDH in the SC of rats that inhaled cigarette hand smoke stimulates lipid accumulation in the liver smoke was higher than those with cotton wool smoke in by modulating AMPK and SREBP-1. J Hepatol this study. Carbon monoxide from cotton wool smoke

and cigarette smoke (which also contains carbon 2009;51:535-47.monoxide) can both induce oxidative stress in the rat's 3. Swan GE, Lessov-Schlaggar CN. The Effects of brain, resulting in the increased activity of the enzymes Tobacco Smoke and Nicotine on Cognition and the of carbohydrate metabolism following the initiation of

Brain. Neuropsychol Rev. 2007;17:259-273.12anaerobic glycolysis .

4. Ritter JM, Lewis LD, Mart TGK. Drug and Administration of nicotine causes an increased alcohol abuse in clinical pharmacology 3rd ed. London,

LDH activity, with an attendant disturbance in cellular Arnold; 1995; pp 673-675.9membrane integrity , and chronic cigarette smoking in

14 5. Bennett PN, Brown MJ. Non-medical use of man enhances the activity of LDH in the serum . Ho 10 drugs: Tobacco. In, Clinical Pharmacology. 9th ed. and Chang also observed that Nicotine elevates LDH

Edinburgh, Churchill Livingstone; 2003: pp173-178.leakage in a dose-dependent manner. The increase in the levels of LDH in the SC as observed in the current 6. Wurtz RH, Goldberg ME. The primate superior study shows that exposure to cigarette smoke induced colliculus and the shift of visual attention. Invest. oxidative stress. Ophthalmol 1972;11:441-450.

Alkaline phosphatase is an enzyme 7. Doubell TP, Skaliora I, Baron J, King AJ. responsible for transport across cell membranes. Functional connectivity between the superficial and Following exposure to smoke, its level of activity deep layers of the superior colliculus: An anatomical increases, causing alteration in the integrity of the cell

substrate for sensorimotor integration. J. Neurosci membrane and its ability to mediate normal membrane 12 2003;23:6596-6607.transport . Due to this, leakage of LDH through the

10 8. Borek C. Antioxidant Health Effects of Aged membranes could be facilitated .Garlic Extract. J. Nutr 2001;131:1010S-1015S.

Exposure to smoke caused varying degrees of 9. Yildiz D, Ercal N, Armstrong DW. Nicotine cellular degeneration of the superior colliculi. The enantiomers and oxidative stress. Toxicology changes were more evident in animals exposed to

cigarette smoke compared to those that inhaled only 1998;130:155-165.cotton wool smoke. The longer the duration of 10. Ho Y, Chang Y. Neuropharmacology: Regulation exposure, the more the degree of architectural of nicotine-induced cyclooxygenase–2 protein distortions, cellular degeneration and vacuolation, and expression in human gingival fibroblasts. Acta the more the depletion in neuronal population.

Pharmacologica Sinica 2006;27:409-413.Meanwhile, for animals exposed only to carbon 11. Ayres PH, Hayes JR, Higuchi, MA, Mosberg, AT, monoxide from burnt cotton wool smoke, the severity Sagartz JW. Subchronic inhalation by rats of of these effects tends to be a little bit delayed, compared

with cigarette smoke exposure of the same duration and mainstream smoke from a cigarette that primarily heats number of days. A breach in the consistency of the tobacco compared to a cigarette that burns tobacco. membranes would affect the transport mechanism Inhal Toxicol 2001;13(2):149-86.across the membranes, leading to a disequilibrium in

12. Omotoso GO, Akinola OB, Caxton-Martins EA, the composition of substances within and/or outside the

Kadir RE, Akinyinka A. Histoenzymic Effects of cytoplasm. These, doubtlessly, contribute to the effects Cigarette Smoke on the Superior Colliculus Of Rattus nicotine has on cellular processes, ranging from

induction of gene expression to secretion of hormones norvegicus.. The Internet Journal of Toxicology. 9and modulation of enzymatic activities . 2010;8:1.

13. RANDOX Laboratories Ltd., Ardmore, The histological and enzymic abnormalities in Diamond Road, Crumlin, Co. Antrim, United the SC of animals studied in the current work suggests

that exposure to cigarette smoke is deleterious to the Kingdom, BT29 4QY.functions of the superior colliculus. Padmavathi P, Reddy VD, Varadacharyulu N.

Influence of Chronic smoking on serum biochemical References

profile in male human volunteers. J. of Health Sci., 1. Ueta E, Tadokoro Y, Yamamoto T, Yamane C,

2009;55(2):265-270.Suzuki E, Nanba E, et al. The effects of cigarette smoke



Abstract DM represents one of the greatest threats to modern Diabetes mellitus represents one of the greatest global health. In order to overcome the consequences, a

threats to modern global health. It contributes to sub- group of drugs known as anti-diabetic drugs have fertility in females and also impairs normal menstrual proved to improve insulin sensitivity in the liver and cycle and ovulation. The study was designed to muscles and suppress hepatic glucose production investigate the effect of oral administration of through the inhibition of gluconeogenesis and

16metformin on FSH, LH, oestrogen and progesterone in glycogenolysis . However, research shows that DM diabetic rats. has effect on reproduction; it will affect females prior to

Twenty female rats were divided into four their reproductive age. DM contributes to sub-fertility experimental groups of five rats each; Group A serves in females, it impairs female fertility as well as as Control, and received distilled water ad libitum, impairment of normal menstrual cycle and ovulation. while Groups B, C and D were the experimental Hence, rising rates of DM suggests high prevalence of

17groups; Diabetic untreated, metformin treated and infertility .Diabetic treated with metformin, respectively. At the The inhibitory influences of DM on follicular end of the experimental period of four weeks, animals function have been attributed to various portions of the in all groups were sacrificed and blood samples were hypothalamo-hypophyseal-ovarian axis, and all three taken for the determination of FSH, LH, oestrogen, parts of the axis may be affected under different

8progesterone and glucose level. conditions .The result showed significant (P<0.05) Insulin resistance has been defined as a state in

reduction in FSH and LH levels in all experimental which a greater than normal amount of insulin is 9groups when compared to control and significant required to elicit a quantitatively normal response . It

increases (P<0.05) in the progesterone level in Groups leads to increased insulin secretion by β-cells and B and D when compared to control. compensatory hyperinsulinemia. Hyperinsulinemia

The result suggest that metformin has a direct may stimulate the ovaries directly or indirectly through effect on the ovary and that its effect on insulin- increase in LH secretion and inhibition of IGF binding

1sensitivity may not solely be responsible for its protein and SHBG synthesis and secretion . This may ovulation-inducing effect. lead to anovulation, amenorrhea and infertility. Hence,

the improvement of insulin sensitivity by insulin Keywords: metformin, diabetes, oestrogen, sensitizers may be of therapeutic value in the progesterone, LH, FSH management of clinical manifestation of DM.

Considering the huge resources required for Introduction delivering sustainable health care to diabetics and

Diabetes mellitus simply referred to as predominant poverty in the Sub-Saharan region, more diabetes is a group of metabolic diseases in which a efforts to elucidate the pathogenic mechanism of DM person has high blood sugar, either because the body and accessibility of affordable modalities of disease does not produce enough insulin, or because the cells management is advocated. Advent of new medical do not respond to the insulin that is produced. technologies and healthy lifestyle could significantly

improve the quality of lifestyle for people with diabetes.

One of the drugs used in the treatment of this disorder is metformin (an oral anti-diabetic drug of the biguanide class). It is the first line drug of choice for the treatment of diabetes in particular, overweight and obese people and those with normal kidney function. It is the treatment of choice for patients with non-insulin dependent DM, after dietary manipulation, showing

4consistent results in terms of glycaemic control .

41

Correspondence to:

1 Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria2 Department of Pharmacy, University of Ilorin, Ilorin, Nigeria

3 Department of Physiology, Ladoke Akintola University of Technology, College of Health Sciences, Ogbomoso, Nigeria4 Department of Physiology, College of Medicine, University of Lagos, Idi-Araba, Nigeria 5 Department of Chemical Pathology and Immunology, University of Ilorin, Ilorin, Nigeria

The Effect of Metformin on Serum Levels of FSH, LH, Oestrogen and Progesterone in Diabetic Rats

1 5 1 2 3 1 4L.S. Ojulari , S.A. Biliaminu , T.T. Ahmed , F.I. Abdulazeez , O.S. Oyekunle , F.A. Niyi-Odumosu , O.A. Adegoke

L.S. Ojulari Department of PhysiologyFaculty of Basic Medical SciencesUniversity of Ilorin, Iloirn, NigeriaE-mail: [email protected]

Results of several studies have demonstrated that Induction of diabetes:metformin can induce regular menstrual cycles and Diabetes was induced by a s ingle

10 intraperitoneal injection of 100mg/kg of alloxan increase ovulation in patients with PCOS . The exact monohydrate obtained from Sigma Chemical Co, (St. mechanism of action of metformin in patients with Louis, MO, USA). Diabetes was confirmed by glucose PCOS is still unknown. However, metformin exerts a oxidase method using glucometer (One Basic, Inc.). systemic action on the regulation of glucose

11 After 72 h of alloxan injection, rats with plasma glucose metabolism by insulin , and indices of insulin resistance are strong predictors of the efficiency of level ≥ 200mg/dl were separated and used as diabetic in

11metformin therapy which suggest that a drug could this study.act to induce ovulation as a result of improved At the end of the experimental period, rats were fasted

10metabolic control . for 12 h and sacrificed. Blood was collected by cardiac In addition, peripheral effects to metformin have been puncture and transferred into EDTA bottles for found to be dependent on or independent of insulin hormonal assays'sensitization in several experimental studies, but thus Biochemical analysis:far, the available data has been unable to clarify the The hormonal evaluation consisted of assays exact mechanism by which metformin restores ovarian of serum FSH, LH, progesterone and oestradiol. All

9 hormone concentration were analysed using the function .Enzyme-linked immunnosorbent assay (ELISA) kits, We now report the effect of metformin administration (Monobind Inc. Lake Forest, USA). The process therapy on reproductive /ovarian hormone levels in involves linking enzymes which generate a colour alloxan induced diabetic rats as a means to further product when appropriate substrates are added.clarify the mechanisms by which metformin restores Statistical analysis:ovarian function.

All results were expressed as mean ± SEM. Data was analysed by one-way analysis of variance Materials And Methods(ANOVA) and Duncan New Multiple Range Test Experimental protocol:(DMRT). Differences in means were considered Twenty female rats (mean weight 150-180g) significant at P<0.05. All analysis was performed using were maintained under standard laboratory conditions SPSS 17.and were allowed free access to food and water ad

libitum. Animals were divided randomly into four Resultsgroups. Group A (drug vehicle); group B- non

Mean FSH, LH, oestrogen, progesterone and diabetic/metformin (100mg/kg twice daily for 28 glucose levels of control and experimental groups are days); group C- diabetic (drug vehicle); and group D- shown in table 1 below. The mean FSH in control group diabetic/metformin (100mg/kg daily for 28 days)was 1.70±0.10 as against experimental group B Drug, Route and Duration of Treatment:(diabetic untreated) 1.02±0.01, group C (metformin The drug was prepared with a known mass of treated) 1.25±0.30 and group D (diabetic/metformin) metformin powder suspended in distilled water to yield 1.05±0.01. All experimental groups showed significant a suspension of 25mg per ml. Dose selected was reductions (P<0.05) when compared to control.100mg/kg (Choi et al; 2006). The suspension was

The mean LH in control group was 3.12±0.21 administered by oral cannula for 28 days before as against experimental groups B (2.20±0.05), C sacrifice

L.S. Ojulari et al/ The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

Table1: Effect of Metformin on plasma glucose level, progesterone, oestrogen, LH and FSH

Variable Control (distilled Water) (n=5)

Diabetic untreated (n=5)

Metformin treated (n=5)

Diabetic/Met (n=5)

Plasma glucose (mg/dl)

139.75±6.20 277.75±38.58 134.85±5.11 162.75±5.97*

FSH 1.70±0.10 1.02±0.01** 1.25.±0.30** 1.05±0.01**

LH 3.12±0.21 2.20±0.05** 0.95±0.01** 2.25±0.06**

Oestrogen 140.00±11.40 119.00±1.83 120.00±13.1 125.00±6.19

Progesterone 0.58±0.09 2.43±0.15** 0.70±0.11 2.75±0.19**

Values are expressed as mean ± SEM, ** P<0.05 when compared to Control, * significantly

reduced when compared to Diabetic untreated (Group B)

42


(0.95±0.01) and D (2.25±0.06). All experimental to improvements in the systemic hormonal and /or groups showed significant reductions (P<0.05) when metabolic pattern. compared to control, with group C (metformin treated) Although there was a significant reduction showing the greatest decrease. (P<0.05) in FSH and LH levels in the diabetic rats,

8.7.3The mean oestrogen level in control group was similar to other findings ; this can be explained by the 140.00±11.40 as against experimental groups B probable negative feedback mechanism that could have (100.00±1.83), C (120.00±13.1) and D (94.00±6.19). been caused by the significantly raised progesterone All experimental groups showed a reduction in levels. Oestrogen in small amounts has a strong effect oestrogen level but these changes were insignificant in inhibiting the production of both LH and FSH. Also, (P>0.05). when progesterone is available, the inhibitory effect of

Progesterone levels in groups B (diabetic oestrogen is multiplied, even though progesterone by untreated) 2.43±0.15 and D (diabetic/metformin) itself has little effect. The feedback effects seem to 2.75±0.19 show significant increase (P<0.05) when operate mainly directly on the anterior pituitary gland compared to control, while group C shows an but to a lesser extent on the hypothalamus to decrease insignificant reduction (P>0.05). secretion of GnRH, especially by altering the

frequency of the GnRH pulses. This also further Discussion: explains a possible mechanism by which anovulation

Drug interactions are usually seen in clinical complicates diabetes mellitus. The decreased levels of practice and the mechanism of interactions are usually LH can interfere with the LH-surge required for evaluated in animal models. We studied the influence ovulation to occur. Without the initial preovulatory of metformin on FSH, LH, Oestrogen and Progesterone surge of LH, ovulation will not occur. This can lead to in normal and diabetic rats. The normal rat model anovulation, amenorrhoea and infertility.served to quickly identify the interactions and diabetic In conclusion, our study has shown and further rat model served to validate the same response in the affirms that the ovulation-induction effect of actually used condition of the drug. metformin is probably due to its direct effect on the

Metformin is an anti-diabetic drug that ovary and not solely to the systemic effect of the drug increases glucose utilization in insulin-sensitive on insulin sensitivity and / or hyperandrogenism. tissues. In women with PCOS, metformin treatment reduces hyperinsulinemia, corrects menstrual Acknowledgement:irregularity in majority, results in higher ovulation We acknowledge the contributions of Prof

2rates, independently of changes in body weight . As A.B. Okesina (Dept. of Chemical Pathology, PCOS and diabetes share some altered parameters such University of Ilorin Teaching Hospital), and Dr B.V. as abnormal glucose-insulin ration altered lipid Owoyele (Dept. of Physiology, University of Ilorin)

4 whose contributions were of immense value to the metabolism and insulin-resistance syndrome , the use development of this publication. We also acknowledge of metformin in diabetes may also have some effects in the staff members of the Department of Physiology and modulating the secondary infertility that can be caused Anatomy laboratory, University of Ilorin, Ilorin. Of by this disease. particular note are Mrs Olawale Bello, Mr Emmanuel, The systemic effect of metformin has been O. A. and Mr Awolola, O.P., who assisted in procuring demonstrated extensively, in fact, several experimental some of the equipment used in this research. and clinical studies most of them translated from a

population of patients with type 2 diabetes mellitus, References:have shown that this drug acts by systemic effects on

hepatic gluconeogenesis and the production of SHBG, 1. Ciaraldi TP. Molecular defects of insulin intestinal free fatty acid oxidation and glucose use and action in the polycystic ovary syndrome: possible

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Any Association Between ABO /Rh Blood

Groups And Breast Cancer ?

1 2 1A.S. Oguntola, E.O. Akanni , M.L. Adeoti

1.Department of surgery and 2. Haematology Division, Department of Biomedical Science College of Health Sciences, Lautech Ogbomoso. Nigeria.

Dr Oguntola A SDepartment of Surgery,Ladoke Akintola University of Technology.Ogbomoso.E-mail [email protected] [email protected] +2348033815807

Correspondence to:

Abstract The ABO blood type has been associated with The ABO blood type has been associated with many diseases, though the explanation for the

many diseases, though the explanation for the association remains unclear. Reports on association 2association remains unclear. There are many between blood group A and gastric cancer , A and

,(3)conflicting reports on association of ABO and Rhesus ovarian cancer and O blood group in skin and 4blood groups with breast cancer. This study aimed at melanoma are available.

finding any such possible relationship. Negative association was established between Blood specimen was taken from all inheritance of Rhesus D antigen and the development

consecutive breast cancer patients who attended the of cancer of the breast in Lagos Nigeria, the authors general surgery clinics at the LAUTECH Teaching concluded that Rhesus D antigen phenotype may be

5 6 hospital Osogbo, between August and December 2010. protective against cancer of the breast . Dede et.al The subjects were classified into respective ABO could not find any association between the ABO blood groups using monoclonal blood grouping reagents by group and breast cancer in Turkey but Michael

7 applying tube technique. Stamatakos et al found that blood group A is often Forty- four breast cancer cases and 90 associated with ductal breast cancer in contrast to the

controls were compared. . About 28%, 4.54%, 6.8% other blood groups among the Greek women. Adelusi B 8 9and 61.4% of the cases belong to blood group A, B, AB and Williams OA could not find any association

and O respectively, all were Rhesus antigen positive. between any blood group type and cervical cancer and Among the controls, 22.2%, 18.8% , 3.3 and 55.6% for Burkitts tumour respectively in Ibadan, Nigeria.A, B, AB and O respectively, 3 were Rh negative. The Though frequency of distribution of the blood groups appears similar in both groups with the exception of blood group B which is significantly lower in the breast cancer group ( x2= 3.88, p value 0.048, Fischer exact 0.033).

This finding shows significant negative association of incidence of breast cancer with blood group B. Presence of B antigen may be “protective” against development of breast cancer. Materials And Methods

Blood specimen was taken from all Key Words; ABO/Rh antigen, breast cancer, disease consecutive breast cancer patients who attended the association general surgery clinics at the LAUTECH Teaching

hospital Osogbo for over a 4- month period between Introduction August and December 2010. This was done after due

The major human blood group system is ABO. consent from both patients and the hospital ethical The blood group of a person depends upon the presence committee has been taken for the study. All specimens or absence of two genes, A and B. The majority of ABO were treated at the academic research laboratory of our determinants are expressed on the ends of long centre. Consented 90 apparently healthy individuals 1polylactosamine chains . including hospital staffs and patient relatives were used

as controls. About three millilitres of blood was collected from patients and control subjects by vene-puncture from the ante-cubital vein which was transferred into dry bottle for serum retraction. The subjects were classified into respective ABO and Rhesus groups using monoclonal blood grouping reagents from Carper laboratories Ltd, UK by applying tube technique as described by Dacie and Lewis (15. The

The ABO blood group distribution varies in different geographical and ethnic groups, and

10socio-economic groups , Blood group O is the most common and about 95%- 98% are Rh positive in South

9,11-14western Nigeria . Assessing a possible association between breast cancer and blood group antigens will help to determine if the presence of any of these may be considered a possible risk factor in its aetiology.

45

patient's red cells (diluted in phosphate buffered saline (included 2 males) was found to be 22.2%, 18.8% , 3.3 [PBS]) were tested against monoclonal anti-A and anti- and 55.6% for A, B, AB and O respectively. The B grouping reagents. Equal volumes ( 2 drops from the frequency of distribution of the blood groups appears commercial reagent dropper ) of liquid reagents and 2% similar in both groups with the exception of blood cell suspensions are used Spin-tube tests were group B which is significantly lower in the breast performed using 75 × 10 or 75 × 12 mm plastic tubes cancer group ( x2= 3.88, p value 0.048, Fischer exact they were left for 15 min at room temperature (about 0.033). The P- value for blood groups A, AB,, O and Rh 20°C) before centrifugation for 1 min at 150 g. were 0.66, 0.637, 0.65 and 0.546 respectively. (Table Agglutination then read. The patient's serum or plasma 1)were also. tested against A and B reagent red cells 1

Discussion(reverse grouping). Similar studies were done with the The relation between genetic markers and blood specimens collected from the matched controls.

malignant lesions has been investigated by several Result from patient and control groups were compared workers. Association of blood group types with breast using Epi-info. 7cancer has been reported by various authors, some of these have produced contradicting results. These Resultsincluded increased incidence with B group or A group, Forty- four cases of breast cancers were seen

(16)no relation to any blood group , increased incidence during the study period; only one was a male with ages

(17) (18).with B and O group and increased with B group ranging from 27 to 68 years. The mean age for cases

There is however evidence that ABO blood and controls were 42 .3 and 41.9 years respectively.groups may be important, since the antigens of blood . About 28%, 4.54%, 6.8% and 61.4% of these groups seems to have a significant biological role in the belong to blood group A, B, AB and O respectively, immunological system, thereby promoting the none was found to have the Rhesus antigen (Figure 1) . development of some tumors, including breast cancer The ABO-Rh grouping for the ninety controls which

FIG 1; ABO BLOOD GROUP DISTRIBUTION IN 44 BREAST CANCER PATIENTS

Table 1. ABO blood group and breast cancer; comparing cases with controls

BL

OO

DG

RO

UP

CA

SE

S

PE

RC

EN

TA

GE

CO

NT

RO

LS

PE

RC

EN

TA

GE

X2

test

GR

OU

PV

sO

ther

s

P-

VA

LU

E(

2ta

il

Fis

cher

Exa

ctT

est

A

12 27.7 20 22.22 0.1834 0.666 0.524

B 2 4.54 17 18.88 3.88 0.048 0.033 AB 3 6.8 3 3.33 0.22 0.637 0.393

O 27 61.36 50 55.55 0.204 0.650 0.579TOTAL 44 90 Rh positive

44 87 0.363 0.546 0.550

Rh Negative

0 3

A.S. Oguntola et al/ The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

46

(19) significant for patients with blood group B and O Rh but the role of inheritance in breast tumorigenesis 30

has been clearly established with the presence of negatives.BRCA1, BRCA 2 genes among others for breast Limitations to this study include the low cancer. number of cases. There is also a possibility of false

Alexander in 1921 reported that patients with positive detection of antigens in the presence of in-vitro blood group B and AB were more vulnerable to bacterial contamination while non detection of antigen developing malignancy which can be more aggressive may be due to failure to add reagent or reduce potency than neoplasms occurring in patients with other blood of reagent.

(20)groups . Many other investigators have also

Conclusion; We found a negative association between implicated the ABO blood group as independent (19,21- breast cancer and blood group B in this case controlled predisposing and prognostic factor in breast cancer

23) study how ever further studies with larger number of patients are needed to establish this. Other blood The findings in this study shows significant groups were not found to be associated. Blood type negative association of incidence of breast cancer with needs to be considered along with other known risk blood group B, thus presence of B antigen may be factors in order to properly assess an individual's risk of “protective” against development of breast cancer. It developing breast cancer.has been reported that women with blood Gp O may

have some protection against development of breast (22) Referencescancer, also with favourable prognosis if it occurs .

(24) 1. Daniels G. Human blood groups. 2nd ed. Oxford, Similar result was found by Trygvadottir et al for O UK: Blackwell Scientific; 2002.and B blood groups , infact patients with blood group B 2. Aird I, Bentall HH, Roberts JA: A relationship are at a higher risk of being re-affected by breast between cancer of stomach and the ABOmalignancy compared with women of other blood blood groups. Br Med J 1953,4814:799-801.groups because they have better prognosis. However 3. Henderson J, Seagroatt V, Goldacre M. Ovarian higher prevalence of blood group B in familial cases of cancer and ABO blood groups. J Epidemiol breast cancer than sporadic cases was reported by the Community Health. 1993 Aug;47(4):287-9.same author, supporting the presence of a genetic factor

(24) 4. Karakousis CP, Evlogimenos E, Suh O. Blood in the etiology of familial breast cancer groups and malignant melanoma. J Surg Oncol. 1986 The proportion of blood groups A and AB is higher in Sep;33(1):24-6.breast cancer patients compared to the controls in this 5. AS Akammu, AT Ajekighe, FAA Durusinmi-Etti, L study, this is however not significant. Previous studies Akinsete, EE Emuveyan, FB Abdul-Kaareem, CS have shown that women with A blood group are Ugwaudu, DA Dawotola. The Association Between generally prone to developing cancers with poor

(22,23, 25,26) Cancer Of The Breast And The ABO and Rhesus D prognosis and aggressive biological behaviour . (27) Antigen Phenotypes In Lagos, Nigeria; A Case-Control Kamleish et al showed that blood group A apparently

Study. Nigerian Journal of Clinical Practice Vol.5(2) increases the risk for cancer; breast cancer has the 2002: 81-86strongest association with the blood type. This was also

(28) 6. Didem S. Dede Sercan Aksoy Omer Dizdar Pamir supported by Anderson and Hass in 1984 , though he Cerci Ibrahim Gullu Yavuz Ozisik Kadri Altundag. reiterated that that the effect of blood type A on breast Blood ABO groups and risk of breast cancer. Med cancer development was capable of being masked by Oncol (2010) 27:1433the effect of breast cancer susceptibility genes and/or 7. Michael Stamatakos, Konstantinos Kontzoglou, that the inherited or non-inherited types involve Panagiotis Safioleas, Constnatinos Safioleas, Christina different etiologic mechanisms. However Seth Manti and Michael Safioleas . Breast cancer incidence Rummell and his team 1Clinical Breast Care Project, in Greek women in relation to ABO blood groups and Windber Research Institute, Windber, USA. Found Rh factor. International Seminars in Surgical that the minor allele of rs505922 and the resulting non-Oncology 2009, 6:14O blood group types are not associated with increased 8. Adelusi B. Haemoglobin genotype, ABO blood risk or less favorable tumor characteristics or prognosis

29 groups and carcinoma of the cervix. J Trop Med Hyg. in breast cancer.1977 Jul;80(7):152-4.The Rhesus antigen was found in all the 9. Williams AO. Haemoglobin genotypes, ABO blood patients in this study, this may be due to the small groups, and Burkitt's tumour. J Med Genet. 1966 number of cases though the prevalence of Rhesus Sep;3(3):177-9.antigen is between 95- 98% among Nigerians. Akanmu 10 Beardmore JA, Karimi-Booshehri F. ABO genes (5)

et al reported that presence of the antigen could be are differentially distributed in socio-economic groups “protective” against breast cancer. Likewise Urun Y et in England. Nature 1983 Jun 9-15; 303(5917):522-4.al from Turkey found that Rh negative patients had 11., Egesie OJ, Usar I, Johnbull TO Distribution of more frequent family cancer history and this was


47

ABO, Rhesus blood and haemoglobin electrophoresis 21. Vogel F. Controversy in human genetics. ABO among the undergraduate students of Niger Delta State blood groups and disease. Am J Hum Genet 1970, University, Nigeria. Niger J Physiol Sci. 2008 Jun-Dec 22(4):464-75.23(1-2):5-8. 22. Anderson DE. Some characteristics of familial 12. Enosolease ME, Bazuaye GN. Distribution of breast cancer. Cancer 1971, 28:1500-04.ABO and Rh-D blood groups in the Benin area of 23. Easton DF. Familial risks of breast cancer. Breast Niger-Delta: Implication for regional blood Cancer Res 2002, 4(5):179-81.transfusion. Asian J Transfus Sci. 2008 Jan;2(1):3-5. 24. Tryggvadottir L, Tulinius H, Robertson JM. 13. Kulkarni AG, Peter B, Ibazebo R, Dash B, Fleming Familial and sporadic breast cancer cases in Iceland: a AF. The ABO and Rhesus groups in the north of comparison related to ABO blood groups and risk of Nigeria. Ann Trop Med Parasitol. 1985 Feb;79(1):83- bilateral breast cancer. Int J Cancer 1988, 42(4):499-8. 501. 14. Ahmed OA, Agomo PU, Olukoya DK, Esan GJ. 25. Skolnick MH, Thompson EA, Bishop DT, The prevalence of ABO blood group antigens and Cannon LA. Possible linkage of a breast cancer-antibodies in Lagos State, Nigeria. 1993 Sep;22(3):49- susceptibility locus to the ABO locus: sensitivity of 53. LOD scores to a single new recombinant observation.

Genet Epidemiol 1984, 1(4):363-73.15 Meagan Rowley and Clare Milkins (2008). th 26. Mourali, N., Muenz, L.R., Tabbane, F., Belhassen, Practical Haematology (10 edition) edited by Dacie

S., Bahi,J. and Levine, P.H. Epidemiologic features of and Lewis. Laboratory aspects of blood transfusion, rapidly progressing breast cancer in Tunisia. Churchill Livingstone. 523-554. Cancer,(1980) 46: 2741-2746 . 16. Jayant, K.: Relationship of ABO blood groups to 27. Kamlesh Guleria, Hardeep Pal Singh, Harpreet certain types of cancer common in Western India. Ind. Kaur and Vasudha Sambyal. ABO Blood Groups in J. Cancer,(1971) 8: 185-188.Gastrointestinal Tract (GIT) and Breast Carcinoma 17. Tyagi, S.P., Pradhan, S. and Agarwal, S.S. Blood Patients. Anthropologist, (2005) 7(3): 189-192 .groups in malignant disease. J. Ind. Med. Assoc.,(1965) 28. Anderson, D.E. and Haas, C.: Blood type A and 45: 645-650.familial breast cancer. Cancer, (1984) 54: 1845- 1849 18. Surekha, D., Shrinivisan, A., Sailaja, K., Roa, D.N. .and Vishnupriya, S. Association of esterase D and 29.Seth Rummel Craig D Shriver2 and Rachel E ABO blood group in breast cancer (Abstract), p. 122. Ellsworth3et al.: Relationships between the ABO blood In: Trends in Human Genetics, Biotechnology and group SNP rs505922 and breast cancer phenotypes: a Bioinformatics: Next 5 years. 29th Annual Conference genotype-phenotype correlation study. BMC Medical of Indian Society of Human Genetics, Bangalore Genetics 2012, 13:41.(2004).30. Urun Y, Utkan G, Altundag K, Arslan O, Onur H, 19. Costantini M, Fassio T, Canobbio L, Landucci M, Arslan UY, Kocer M, Dogan I, Senler FC, Yalcin B, Resasco M, Boccardo F. Role of blood groups as Demirkazik A, Akbulut H, Icli F . ABO and Rh blood prognostic factors in primary breast cancer. Oncology groups frequency in women with HER2 positive breast 1990, 47(4):308-12.cancer. Journal of B.U.ON. [Official Journal of the 20. Alexander W. An inquiry into distribution of the Balkan Union of Oncology] (2012), 17(3):457-460. blood groups in patients suffering from malignant

disease. Brit J Exp Path 1921, 2:66.


48

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https://www.researchgate.net/publication/17334677_Blood_groups_in_malignant_diseases?el=1_x_8&enrichId=rgreq-18865aac9404a94dbb920c30fbe2e466-XXX&enrichSource=Y292ZXJQYWdlOzIzNTYxMTA0MjtBUzoxMjI3MTk4MDY5NTU1MjBAMTQwNjI3MDA5MDIxNg==






Correspondence to:

49

Challenges Of Haematuria In Pregnancy In The Tropics

1,2 3 1,2 1,2 2 2A.A. Popoola, K. Adesina, S.A. Kuranga, A.L. Babata, I.Oseni, O. Abiola1Department of Surgery, University of Ilorin

2 Division of urology, Department of Surgery, University of Ilorin Teaching Hospital3Department of Obstetrics & Gynaecology University of Ilorin Teaching Hospital

Dr. Ademola A. PopoolaUrology Division, Department of SurgeryUniversity of Ilorin /University of Ilorin Teaching HospitalGPO Box 4718, Ilorin, Kwara state Nigeria [email protected], [email protected]

Abstract However, microscopic hematuria which is Haematuria is considered an ominous sign very common during pregnancy has been recognized to

until proven otherwise. The causes of hematuria in the be largely inconsequential and rarely signifies a 2general population range from inconsequential causes, disorder likely to impact on the pregnancy outcome .

to those that are life threatening, requiring early or Investigating the underlying causes of gross HIP poses urgent intervention. Hematuria could either be a challenge because of the pregnancy state. It is further microscopic, macroscopic or frank. Hematuria in compounded in resource poor countries where pregnancy (HIP) presents a desperate situation of facilities for investigations are not readily available and apprehension, distress and uncertainty. Investigating affordable; coupled with the inadequacy of blood loss

3the underlying causes of gross HIP poses challenges replacement facility, especially in sub Saharan Africa . because of the pregnancy state. It is further Therefore this report will focus mainly on the challenge compounded in resource poor countries where of management of frank or gross haematuria in facilities for investigations are not readily available and pregnancy in a resource poor setting. affordable; coupled with inadequacy of blood We wish to present this case series of 4 patients replacement facility and socio-cultural behaviours seen in our hospital with haematuria at different especially in sub Saharan Africa trimesters.The paper intends to highlight the challenges involved in the management of HIP Case report for case reports Case presentations of patients with HIP are presented highlighting the Case 1: AO, 24 year old house wife who was a G3P2+0 challenges of managing these patients. (2alive) who presented at about 23 weeks of pregnancy HIP is a challenging situation to the pregnant woman, with right flank pain and total hematuria. There was unborn child, family members and the attending associated right flank pain which was colicky and physicians. There is a need for a guideline for the radiated to the suprapubic region. The haematuria was management of patients with HIP. associated with the passing of blood clot. There was no

previous episode of haematuria. There was neither Key words: Pregnancy, Hematuria, Challenges, vomiting nor change in bowel habits. There was no Management bleeding from any other parts of the body. The patient

neither smoked tobacco nor drank alcohol. Her Introduction: hemoglobin genotype was AS and she had no history of Hematuria is considered an ominous sign until proven trauma to the abdomen. At presentation, she was an otherwise. The aetiology of hematuria in the general asthenic young woman; who was in distress and was

ocpopulation, range from inconsequential causes, to apprehensive. She was pale, febrile (37.5 ) and was not those that are life threatening, requiring early or urgent jaundiced. There were no features of chronic liver intervention. Hematuria could either be microscopic, disease.

1macroscopic or frank Hematuria in pregnancy (HIP) The previous 2 pregnancies were not presents a desperate situation of apprehension, distress associated with haematuria and they both ended in and uncertainty. The desperation often sets in, in an uncomplicated spontaneous deliveries. Her vital signs otherwise healthy woman whose joy of being a mother on admission were: Pulse 92/minutes; BP soon, is being threatened by a clinical condition. 100/60mmHg. The abdomen was mildly tender in the

right flank and suprapubic region and the uterine size corresponded to 24 weeks gestation with palpable contractions. Vaginal examination revealed a closed os of the cervix and the examination finger was stained with mucus. The digital rectal examination was unremarkable. The packed cell volume (PCV) was 20%. The abdomino-pelvic ultrasound showed a life fetus. A diagnosis of haematuria in pregnancy with threatened abortion was made. She was transfused with

.

3 units of whole blood and the PCV rose to 30 %. Discussion:Cystoscopy was carried out and no bladder pathology Generally, gross haematuria is potentially an noted. A request for intravenous urography was turned ominous sign, and should therefore be reasonably down by the radiology department on account of risk of investigated without delay, as much as possible, in teratogenicity to the unborn child. The uterine order to come to a diagnosis. However, it must be stated contraction continued unabated despite tocolytics and that not all the time is a definite diagnosis made after she eventually expelled the fetus. The patient was exhausting the available investigation armamentarium discharged few days after the abortion with no more such as radiological, endourological etc. A diagnosis of gross haematuria. exclusion, essential hematuria, may then be made.

Few months afterwards, she was seen in the However, this is not an easy diagnosis to make in the clinic with her father who came to ask for means of developing countries where reasonable levels of preventing future HIP. The patient reported that her diagnostic equipment are not available in most centers

4husband had separated from her on account of the fear . Making a definitive investigation is also made of possible recurring haematuria in future pregnancies. difficult by the refusal of patients to undergo Case report 2: O K was a 27 year primigravida comprehensive investigation especially after presented at a gestational age of 30 weeks with total haematuria has subsided. This was recorded in some of hematuria. She had no previous history of haematuria our patients and in patients from other reports on HIP and there was no history of trauma to the abdomen. Although gross HIP, could be due to causes of Clinical examination revealed a young woman who haematuria as in the general population, it has been was asthenic and worried. She was pale. Abdominal largely attributed to certain self-limiting, pregnancy examination revealed a gravid uterus which was about related causes. These pregnancy- related causes 34 weeks with no tenderness. Abdomino pelvic include the 'nut cracker phenomenon'. This usually ultrasound scan confirmed a bulky uterus with twin refers to the compression of the left renal artery gestation; both fetuses had normal heart activities. She between the descending aorta and the superior

5had urethrocystoscopy which did not reveal any mesenteric artery . The nutcracker phenomenon may abnormality. The Haemoglobin genotype was SC. The also occur on the right side when, there is right renal

6haematuria continued unabated and she was transfused vein hypertension . The pregnancy related causes also 7with 4 units of blood. A request for a 'single shot' include urinary bladder varicosity . These causes could

intravenous urogram was turned down by the hospital be explained by the increase in the levels of some radiologists on account of teratogenicity. Days later, a hormones and mechanical factors. The mechanical repeat abdominal ultrasound examination showed that factor is related to the increased intravascular pressure only one fetal heart was seen, and a diagnosis of due to the compression of blood vessels by the gravid vanishing twin syndrome was made. Despite the uterus resulting in the dilatation of these vessels and ongoing haematuria, the patient eventually requested subsequent rupture in the collecting system, renal for a transfer to another hospital on account of pelvis and in the urinary bladder mucosa. Usually they proximity to family relations. Informal information are self-limiting and they may recur in subsequent received later revealed that haematuria later stopped pregnancies. Another self-limiting cause with a spontaneously and she had normal delivery. different pathogenesis is papillary necrosis from sickle Case 3: SK A 27 year old lady with HbSC, G2P1+0(1 cell haemoglobinopathy. A series of HIP from this was

8alive) presented at 37 weeks gestation with a 2 day documented by Kassam et al . It is also instructive that history of haematuria which was total and lasted for the three patients of the four in this series with known further two days. There was no bleeding from other hemoglobin genotypes had traits of sickle cell sites. The pregnancy ended at 38 weeks with the normal haemoglobinopathy. Although papillary necrosis in delivery of a normal baby boy. The hematuria resolved patients with haemoglobinopathy is not limited to the spontaneously after about 1 week post-delivery. She pregnancy state, it could occur in any patient had haematuria in her first pregnancy which ended in experiencing stress; and pregnancy is a stressful the delivery of a boy at term. There was no need for condition.blood transfusion. The patient did not agree to There are other causes of haematuria in cystoscopy and further investigation apart from pregnancy which are ominous and require prompt and haemogram which was normal until labour. accurate diagnosis. These causes include bladder Case 4: AA a 31 year old woman unbooked tumours [9] and retroperitoneal rupture of renal

10multiparous woman who was admitted on account of tumour . Complications of therapy have also been haematuria at about 34 weeks of pregnancy. She denied identified as causes of HIP. A documented example is previous episodes of hematuria at any time. The patient following the treatment of anti-phospholipid refused investigations and within few days on syndrome, which is a systemic autoimmune disease admission the haematuria resolved and the patient with thrombotic tendency. Severe hematuria has been asked for discharged against medical advice. reported following the treatment of anti – phospholipid

A.A. Popoola et al/ The Tropical Journal of Health Sciences Vol 20 No 1 (January 2013)

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syndrome based on consensus guidelines with low- 0.00007rad and the most sensitive time period is the 10 dose aspirin combined with unfractionated or low- -17 weeks of gestation. Oftentimes, the cause of molecular-weight heparin because if not treated, anti- controversies among physicians and radiologists as to

11 why a pregnant woman cannot have an important phospholipid syndrome may cause habitual abortions .radiological investigation is the lack of the knowledge Although hematuria often resolves of the scientific basis of imaging [14]. A single spontaneously in many of the cases of HIP, with no long exposure of intravenous urogram has been found to be term sequelae, but the fact that HIP could be due to safe as the estimated fetal dose per examination is causes as in the general population, therefore, requires 1.398rad and multiple views of abdominal x-ray gives a that the patient should be investigated and the exact

15diagnosis made as much as possible. The need for cumulative fetal dose 0.245 rad . This implies that a prompt diagnosis and intervention cannot be over pregnant woman beyond the period when the fetus is emphasized and this is supported a report from Canada vulnerable could safely have between 3 and 20 sessions of delayed diagnosis of renal cell carcinoma in a of the aforementioned investigations respectively. This pregnant woman who first had macroscopic hematuria controversy was observed in the management of the at 21 week gestation without comprehensive patients in our series as the radiologists turned down the investigation until delivery. This patient's cancer request for intravenous urogram in two patients despite progressed rapidly and she died within a year after she the fact that the pregnancies had progressed beyond 20

12 weeks gestation. Based on this fact, we advise that delivered the baby . Unfortunately, in our report, two intravenous urogram could be safely carried out after out of four of our patients did not agree to have further, 24 weeks of pregnancy when considered necessary in investigations especially after delivery when hematuria making diagnosis. Added to this, as it occurred in our has subsided. This fact and the limitation of series, once the patient delivers and haematuria stopped inadequacy of investigations, made it difficult for us to it is difficult to get the patient back to have complete have definite diagnoses in our series. The refusal of investigations. It is important to note that the two patients to have further investigations after delivery patients in our series that had cystoscopies had no and cessation of hematuria was observed not to be abnormalities in the lower urinary tract. The upper limited to our patients as Venyo also reported similar

13 tracts were not adequately investigated and IVU which behaviourwould have helped in assessing the upper tract could Hematuria in any patient should be reasonably have been safely carried.investigated. Because microscopic hematuria has been

Also the dilemma as to when to intervene reported to be mostly innocuous in pregnancy elaborate when there is a need for surgical intervention is also investigations are usually not necessary. However, genuine when fetal survival is considered. Two of the gross HIP as in all patients needs to be adequately patients in our series were each transfused with at least investigated. Although, the definitive diagnosis is not three units of blood. In Nigeria, availability of always made but common dangerous or life threatening allogeneic blood transfusion is often an uphill task. causes should be ruled out. Since bleeding into the Usually, there are no altruistic donors. The system urinary tract could occur from any part of the urinary requires that relations of patients donate blood for their tract, the whole urinary tract should be investigated as sick loved ones. The need to replace blood loss urgently much as possible. The processes of making definite in these patients cannot be over emphasized. The two diagnosis and treatment may pose significant risks to patients in our series who needed to be transfused with the integrity of the pregnancy. The examination of the blood were the ones that had fetal losses. The entire urinary tract may be necessary and this usually management of patients with HIP in the Nigeria is involves the appropriate use of endoscopy and imaging therefore compounded by the challenges of not having techniques. Rigid cystoscopy is usually not convenient enough blood to replace losses from haematuria. In for the pregnant woman; the gravid uterus makes this series, there were two cases of fetal losses. In the positioning inconvenient and could trigger uterine four cases in our series, one of the women was a contractions and subsequent abortion or premature primigravida while two were secundigravidae. The delivery. Investigation of the upper urinary tract fourth patient was in the third pregnancy. This showed involves mainly radiological investigations. These that haematuria in pregnancy could happen during any usually involve the use of radiation which is potentially pregnancy and could be recurrent in subsequent teratogenic and radiologists are usually unwilling to pregnancies as was the case in two of the patients. This expose pregnant women irrespective of the stage of probably showed that the earlier the patient presents pregnancy. The fear of teratogenicity in all pregnant with haematuria in pregnancy the higher the risk of patients is scientifically baseless because the accepted fetal loss. This assertion is supported by Itoh et al who cumulative dose of ionizing radiation in pregnancy is 5 reported fetal survival in a case in which haematuria rad, and no single diagnostic study exceeds this started in the third trimester [5]. The reason for fetal maximum. For example , the amount of exposure to the loss may be related to the fact that the younger the fetal fetus from 2 views of chest radiographs of the mother is


51

age the more likely they succumb to hypoxia from 4. Olapade- Olaopa E O, Onawola K A. Challenges for anaemia. This then requires that hemodynamic

urology in sub- Saharan Africa in 2006. Jmhg 2006; 3 disturbance from haemorrhage must be avoided as

(1): 109- 16 much as possible in pregnancy and blood loss through 5. Itoh S, Yoshida K, Nakamura Y, Mitsuhashi N haematuria in pregnancy or due to any other cause Aggravation of the nutcracker syndrome during should be corrected promptly. Any patient with HIP

which is severe enough to require blood transfusion pregnancy. Obstet Gynecol. 1997;90(4 Pt 2):661-3. should be treated with all attentions and regular fetal 6. Radisic MV, Feldman D, Diaz C, Froment RO monitoring should be done; and if the fetus has attained Unexplained hematuria during pregnancy: right-sided reasonable viability status, it may be wise to deliver the nutcracker phenomenon. Int Urol Nephrol. 2007; pregnancy and nurse the neonates in the neonatal

39(3):709-11.intensive care units.

7. Hallamore SL, Grills RJ, Neerhut G, Lawrentschuk HIP is a distressful condition to the patients; N Submucosal vesical varicosities causing hematuria relations, especially the husband or partner; and the and retention of urine in pregnancy: cystovarix . Am J attending physicians. It is distressing to the patients

because of the physical and psychological trauma of Obstet Gynecol. 2007;196(5):29-30having blood in the urine. Often the haematuria is 8. Kassam SH, Hadi HA, Fadel HE, Sanchez-Ramos associated with clot retention causing the patient L, Milner PF Sickle-cell-induced hematuria in significant discomfort. The thought of losing the

pregnancy. The current diagnostic and therapeutic pregnancy which is real, adds to the psychological

approach J Reprod Med. 1984; 29(2):117-21.trauma. It is distressing to the partner because of the 9. Hernández Castrillo A, Villanueva Peña A, Diego fear of possible loss of a partner and or the pregnancy. de Rodríguez E, Colina Martín A, Corral Mones JM . The fear of recurrence in subsequent pregnancies

which occurred in one of the patients in this series in her Hematuria during pregnancy caused by bladder second pregnancy may be another source of concern to tumour. Report of 2 cases. Actas Urol Esp. 2005; the patient and the spouse. This may also be a source of 29(10):981-4.marital disharmony as reported in the aforementioned 10. Gyimadu AO, Kara O, Basaran D, Esinler patient who was divorced by the husband after the

Conservative management of a retroperitoneal recurrence in the second pregnancy. HIP presents a lot

h e m o r r h a g e f o l l o w i n g a r u p t u r e d r e n a l of challenges to the gynaecologists and the urologists in angiomyolipoma in pregnancy. J Obstet Gynaecol Res. attendance.2011; 37(2):156-9.

Conclusion: There is a need to have guidelines for the 11. Kawaguchi S, Izumi K, Nohara T, Miyagi T, management of patients with HIP. This is to improve Konaka H, Mizokami A, Koh E, Namiki M. Severe patient safety, reduce fetal loss and avoid unnecessary renal hemorrhage in a pregnant woman complicated controversies between physicians in the management with antiphospholipid syndrome: a case report. Adv of these patients.

Urol. 2011;2011:791094. Epub 2011

12. Bettez M, Carmel M, Temmar R, Côté AM, Sauvé ReferencesN, Asselah J, Sabbagh R. Fatal fast-growing renal cell 1. Ooi WL, Lee F, Wallace DM, Hayne D. 'One stop' carcinoma during pregnancy. J Obstet Gynaecol Can. hematuria clinic in Fremantle Hospital, Western 2011 ;33(3):258-61.Australia: a report of the first 500 patients. BJU int. 13. Venyo A. recurrent hematuria in pregnancy: a 2011; 108 suppl 2: 62-6.doi:10.1111/j.1464-410X.case report and a review of the literature. 2. Brown MA, Holt JL, Mangos GJ, Murray N, Curtis Webmedcentral UROLOGY 2010;(12): WMC001341J, Homer C. Microscopic hematuria in pregnancy: 14. Bent RL.The effect of embryonic and fetal relevance to pregnancy outcome. Am J Kidney Dis. exposure to xrays: counseling the pregnant and non-2005;45(4):667-73.pregnant patients about these risks. Semin oncol 1989; 3. Erhabor O, Adias TC.The challenges of meeting 16:347-68.blood transfusion requirements in sub Saharan Africa: 15. Cunningham FG, MacDonald PC, Gant NF, the need for the development of alternatives to

thLeveno KJ, Gilstrap LC, eds . Williams Obstetrics. 20 allogenic blood. Journal of blood medicine 2001; 2: 7 - ed. Stamford, Conn.:Appleton & Lange, 1997:1045-5721


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