Once malaria occurs, deaths can be prevented by prompt treatment with relatively affordable and efficacious drugs. Yet this goal is elusive in Africa. The paradox of a continuing but easily preventable cause of high mortality raises important questions for policy makers concerning care-seeking and access to health systems. Although patterns of care-seeking during uncomplicated malaria episodes are well known, studies in cases of fatal malaria are rare. Care-seeking behaviours may differ between these groups.This study documents care-seeking events in 320 children less than five years of age with fatal malaria seen between 1999 and 2001 during over 240,000 person-years of follow-up in a stable perennial malaria transmission setting in southern Tanzania. Accounts of care-seeking recorded in verbal autopsy histories were analysed to determine providers attended and the sequence of choices made as the patients' condition deteriorated.As first resort to care, 78.7% of malaria-attributable deaths used modern biomedical care in the form of antimalarial pharmaceuticals from shops or government or non-governmental heath facilities, 9.4% used initial traditional care at home or from traditional practitioners and 11.9% sought no care of any kind. There were no differences in patterns of choice by sex of the child, sex of the head of the household, socioeconomic status of the household or presence or absence of convulsions. In malaria deaths of all ages who sought care more than once, modern care was included in the first or second resort to care in 90.0% and 99.4% with and without convulsions respectively.In this study of fatal malaria in southern Tanzania, biomedical care is the preferred choice of an overwhelming majority of suspected malaria cases, even those complicated by convulsions. Traditional care is no longer a significant delaying factor. To reduce mortality further will require greater emphasis on recognizing danger signs at home, prompter care-seeking, improved quality of care at health facilities and better adherence to treatment. Malaria continues to be the largest single component of the burden of disease in sub-Saharan Africa, even though simple, effective and affordable treatments exist. Malaria's pervasive morbidity and high mortality persist because of failed transactions between those at risk of malaria transmission and available preventive and curative health systems. The consequence is not just an intolerable burden for individuals, their families and national health systems, but is also a devastating and continuing impediment to socio-economic development on the continent. Unlike HIV and TB, the other major fatal communicable diseases in Africa, malaria deaths can be prevented by prompt treatment with relatively affordable and efficacious drugs. Yet this goal continues to be elusive. The paradox of a continuing, but easily preventable, cause of high mortality raises important questions for policy makers and health systems in Africa.). Malaria is the leading cause of out-patient and in-patient health service attendance for all the ages and the leading cause of death in both children and adults in all regions of Tanzania  you are able to recognize an episode of degedege in one day. It begins with mild fever and the next day the fever becomes more severe and results in symptoms of epilepsy. The child opens the eyes wide and the black spot cannot be seen, he begins to twist the arm and leg, and then, even if you pour cold water over the child, does not react..." .Although the local population distinguish between the illness "homa" and malaria the distinction is not always very clear to them. Analysis of case studies revealed that the illness term "malaria" has been obtained from modern health care. When mothers take their children to these health services with what had been diagnosed at home as "homa", they are told it is malaria. The following is illustrative of experiences reported:"I first thought it was normal homa (fever) and I could see the child had homa. Now, when I took the child to the hospital, they checked the child's blood and informed me the child had malaria. [...] the child was not playing. I touched the child and the body was like fire (mwili wake ulikuwa wa moto), the body was very hot". .Anaemia is not often recognized, and where recognized, is not associated with malaria.Although "homa" and especially "malaria" were seen as associated with malaria and mosquitoes, in most cases the signs and symptoms of "degedege" are not attributed to malaria. Life threatening malaria with convulsions is not only perceived as a different illness from malaria through local symptom definition but is attributed to different causes than malaria. Few households mention the mosquito as a cause of the illness described as "degedege". Popular beliefs as to the cause of "degedege" were found to include: fever, evil spirits and a change in weather/wind. The following translation is typical of quotes obtained from respondents on perceived causes of "degedege":"....Evil spirits or demons cause degedege. If it happens that evil spirits or demons pass in front of the child, then the child is likely to get degedege. This may result in paralysis of the body or leg or arm or any part of the body..." ."Homa" and "malaria" are seen as conditions that can be managed at least initially at home with modern medicine available from shops and from health facilities. But "degedege" is perceived as a serious life-threatening condition for which prompt treatment-seeking is required. People reported different sources of care they used for the treatment of "degedege". These sources encompass more than the biomedical health system and fall into three broad categories: home treatment, traditional healers and biomedical. Home treatment was reported to include the use of modern medicines, such as aspirin from local shops, in the early stages the illness. If the illness reaches a severe stage (convulsions) people claim to use traditional healers in the home or outside the home. Biomedical care ranging across government hospitals, health centres, dispensaries and equivalent private facilities was used in the later stage, when convulsions had subsided. However, some respondents perceive traditional healers as not competent to deal with such illness and claim to seek care from biomedical providers at the beginning of the illness."We use traditional remedies only to treat degedege. They (remedies) must have a very bad smell for this will chase away the evil spirit. It is just like telling you to stay in the latrine; surely you will have to find another place because of the bad smell. This is just the same case for the evil spirit attacking the child because of the bad smell it will have to find another place to stay...." ."I had gone to the dispensary for treatment; my child was suffering from homa. The first day he was given panadol tablets and chloroquine injection and was asked to return the next day for chloroquine injection. The next day while I was there at the dispensary waiting for treatment my child started convulsing. This I believed to be a sign of degedege. Immediately I left the dispensary in search of a traditional healer. Degedege is never treated in the dispensary. Child may die after being injected." ."When my child developed degedege I was at Kibiti. I had to look for transport to take the child to Songa Hospital . There you have reliable service because you find almost all kinds of investigations. I don't like going to traditional healers because they are not reliable and do not have equipment to investigate well your child. They end up telling you things related to superstition." .In the period January 1999 to December 2001 inclusive, the Rufiji DSS conducted 243,042 person years of follow-up. In this series, 3,023 deaths occurred to resident members and 2,953 (97.7%) verbal autopsies were conducted. Of these, 24.4% (722) had a cause of death suggestive of malaria as the direct or underlying cause, of which 44.3% (320) were in children less than five years of age. Among these child deaths, there was no difference in frequency between sexes, with 51.3% being male and 48.7% female. Of the child malaria-attributed deaths, 282 (88.1%) sought care at least once before death, while 38 (11.9%) did not, or could not, seek care. Convulsions  were recorded in 30 (9.4%) of these fatal cases.The verbal autopsies contained both an open-ended narrative account of the final illness and a specific chronological account of where and in what sequence care was sought. There were 13 possible sources of treatment that were collapsed for purposes of certain analyses into three sub-categories of care types  and into six sub-categories of provider types . Table Within modern care, government providers were most prominent (44.7%) followed by home care with antimalarials from private shops (20%) Table . ChildreCases with convulsions were as likely to receive initial modern care as cases without convulsions (77.8% and 78.9% respectively) Table . HoweverAmong children for whom care was actively sought, 82.4% of those with convulsions and 90.3% without convulsions sought modern care as the initial care  of malaria-attributable child deaths failed to seek modern care (9.4%) or any care (11.9%). This is considerably better than was seen in the mid-eighties, when 55% of children who died had not utilized any modern care . It is aThis study shows that most patients now include modern care early in their treatment seeking patterns for eventually severe and fatal malaria, including malaria with convulsions. So why is malaria still the largest single component in the burden of mortality? With belief systems for malaria treatment seeking now firmly on the side of modern care, there is obviously something still failing in 1) the transaction to obtain this care; 2) the quality of the care and referral once it is reached; and/or 3) patient adherence to treatment once it is obtained. This would suggest that policies, efforts and implementation research aimed at improving early recognition of symptoms and danger signs at home, prompt treatment or treatment seeking, the quality and efficacy of the antimalarial available and compliance with the full course of treatment, are now, more than ever, highly justified. When appropriate care-seeking is as high as it is in Tanzania, continuing malaria deaths should be considered as sentinel events deserving of close scrutiny and audit to identify the best remedial strategies for the health system.There are promising developments. IMCI has recently been introduced in the study area. It places heavy emphasis on training care-givers on early recognition of danger signs and the need for prompt treatment and on improving quality of assessment and care at primary health facilities ,49. ReplThis preliminary study examined what families of children who died from malaria in a holoendemic setting in Africa actually did in terms of treatment-seeking choices and sequence. It confirms that modern medicine in the form of antimalarial pharmaceuticals from shops or government or non-governmental heath facilities is now the preferred choice in an overwhelming majority of cases (78.7% and 97% as their first or second choice respectively). Traditional medicine could only be implicated in a possible delay of modern care in 9.4% of cases. 11.9% sought no care of any kind. There were no differences in these broad patterns of choice by sex of the child, sex of head of household, socioeconomic status of the household or presence or absence of convulsions. Contrary to what is concluded from much of the historical and qualitative work on this subject, modern care is now the care of first choice, even for those who seek care for children with malaria with convulsions (82.4%), although traditional medicine also played an important role in later choices. But despite high rates of modern care-seeking for all forms of malaria, and despite relatively high attendance and utilization of modern care as seen in Tanzania, malaria mortality remains high. This must, therefore, be due to excessive delay in seeking modern care, and/or poor quality of modern care (providers and/or drugs) once sought, and/or poor patient adherence to treatment regimens once obtained.Certain policy and practice implications arise: 1) public messages need to focus aggressively on improving early recognition of malaria and severe malaria at home and improving promptness of treatment seeking ; 2) quality of modern care providers and modern care must be improved in all sectors, private, NGO and Government; and 3) patient adherence with modern care at home must be simplified and reinforced.DSA Demographic Surveillance AreaDSS Demographic Surveillance SystemGIS Geographic Information SystemHBS Household Budget SurveyHH HouseholdIMCI Integrated Management of Childhood IllnessITN Insecticide-treated nettingMARA Mapping Malaria Risk in Africa CollaborationSP Sulfadoxine-pyrimethamineTM Traditional MedicineVA Verbal AutopsyDD conceived the study, participated in the design, coordination and quantitative analysis and co-wrote the article. CM conceived, conducted and analysed the qualitative studies and co-wrote the article. HM led the analysis of quantitative data. EM managed the surveillance system and participated in design and coordination. AM managed and cleaned the quantitative data. YM managed the field work. CM, HK and GR participated in the coordination and management of the study.


Information on the extent of postpartum maternal morbidity in developing countries is extremely limited. In many settings, data from hospital-based studies is hard to interpret because of the small proportion of women that have access to medical care. However, in those areas with good uptake of health care, the measurement of the type and incidence of complications severe enough to require hospitalisation may provide useful baseline information on the acute and severe morbidity that women experience in the early weeks following childbirth. An analysis of health services data from Lusaka, Zambia, is presented.Six-month retrospective review of hospital registers and 4-week cross-sectional study with prospective identification of postpartum admissions.Both parts of the study identified puerperal sepsis and malaria as, respectively, the leading direct and indirect causes of postpartum morbidity requiring hospital admission. Puerperal sepsis accounted for 34.8% of 365 postpartum admissions in the 6-month period. Malaria and pneumonia together accounted for one-fifth of all postpartum admissions (14.5% & 6% respectively). At least 1.7% of the postpartum population in Lusaka will require hospital-level care for a maternal morbidity.In developing country urban settings with high public health care usage, meticulous review of hospital registers can provide baseline information on the burden of moderate-to-severe postpartum morbidity. Maternal morbidity refers to complications that have arisen during the pregnancy, delivery or postpartum period. Every year an estimated 50 million women are affected by maternal morbidity. Defining, interpreting and measuring maternal morbidity, however, is recognised to be difficult and the prevalence of such morbidity  has been poorly described  dFortney & Smith  have desA network of 23 public sector clinics and a single referral hospital, the University Teaching Hospital (UTH), comprise the public health care system for Lusaka's population of approximately 1.5 million. There is also a small private sector (2% of deliveries)  and therAt the University Teaching Hospital, which acts as the district referral hospital for the city, admission and discharge registers are kept in each ward and department. In an earlier retrospective study, analysing referrals for all pregnancy-related complications, undertaken at UTH ,13, 4% oData collection was carried out by LV between July and September 2000. Ethical clearance for the study was obtained from the University of Zambia Research Ethics Committee.For the purpose of this study, the WHO definition of the postpartum period (from delivery until 6 weeks after delivery) was used as the time period inclusion criteria . All womRelevant admission and discharge registers at UTH were reviewed for the six-month period July-December 1999. Dependent on the type, timing and severity of a postpartum problem, women may be referred or may self-refer to one of three different units within the hospital: (i) Women with early postpartum complications, defined as problems occurring within 24 hours of delivery, are admitted through the labour ward admission room; (ii) Women with postpartum problems occurring more than 24 hours after delivery are referred or may present themselves to the gynaecology filter clinic, from where they may then be referred on to the emergency admission ward; (iii) Cases of breast abscess are generally admitted though the surgical unit. From any of the units women may be then admitted onto a longer stay gynaecology ward for further management and treatment. Women admitted to hospital irrespective of the length of stay were included in the data capture.Table Cases were crosschecked by name and age between the emergency admission and gynaecology wards and between the short and longer stay surgical wards, to prevent double counting. Cases of breast abscess were also crosschecked between the surgical unit and the gynaecology department to ensure cases had not been referred. Data was entered on Epi. Inf. 6.04 for analysis.Routine health service statistics for the same six-month study period (July-December 1999) were also collated. There were 19,691 deliveries within UTH and the satellite clinics , of which 1,021 were by caesarean section (an average of 39 per week). Women delivering either at UTH or the clinics were instructed to attend the local satellite clinic for postnatal follow-up visits at week 1 after delivery and again at 6 weeks. Some women were seen at UTH for a postnatal visit at week 1 to follow-up on some complication while those who had a caesarean section were reviewed at 6 weeks. Recorded postnatal check-up at the clinics at 1-week was 40% and 21% at 6 weeks; however, this data was incomplete for some clinics. At UTH, an average of 42 women per week attend the postnatal clinic – most of them after a caesarean section. During the same six-month period, there were 93 maternal deaths at UTH. Of these maternal deaths 8 (8.5%) were known to be due to puerperal sepsis. A much larger number of the women who died had sepsis and stigmata of AIDS .Due to the limitations of the routine data sources used in the retrospective review, a small cross sectional study was also conducted using prospective identification of cases in order to verify the findings. Over a 4-week period, from 14 August to 10 September 2000, all early postpartum admissions to the maternity unit at UTH were identified through the labour ward admission register. Obstetric case notes were sought and reviewed. Late postpartum cases (>24 hours and up to 6 weeks after delivery) for the same time-period were also identified and recorded by the same means as described for the retrospective study. On the gynaecology ward, cases were identified through daily review of the ward round books, to identify new admissions, and through consultation with the senior ward sister and the ward clerk.After crosschecking of data to prevent double counting, 365 maternal postpartum admissions to the hospital were positively identified for the 6-month study period July-December 1999. Cases of retained placenta (n = 55), removed in theatre, were not included in the final analysis as it was not possible to differentiate between clinic referrals and UTH deliveries.Of the 365 admissions, 236 (65%) cases were identified through the emergency admission ward, 120 were identified on the gynaecology ward and the remaining 9 cases were identified on the surgical wards. More than half of the emergency admission ward cases were referred from the satellite MCH clinics , more than half were aged between 20–29 years, a reflection of the fact that the largest number of births takes place within this age group.There were 39 different recorded diagnoses across the 365 cases Table . PuerperMalaria was the second most common diagnosis accounting for 14.5% of all cases. Hypertensive disorders including hypertension, pre-eclampsia and eclampsia accounted for 10.9%.at least 1.7% . Because this incidence refers only to women admitted live to hospital in the postpartum period, the actual incidence will be somewhat higher, with the addition of postpartum morbidities that occurred in women who were already hospital in-patients, any maternal deaths that occurred outside of the hospital, and any missed late postpartum admissions to medical wards.Using MacKeith et al.'s  estimateOver the one-month period August-September 2000, 64 admissions to the hospital for postpartum maternal morbidity were identified. The routine hospital procedures differentiate between "early" (up to 24 hours postpartum) and "late" (after 24 hours) postpartum admissions. The former are admitted through the labour ward admissions and the latter through the emergency gynaecology ward. Twenty women (31%) were "early" referrals and 44 (69%) were "late". This categorisation of the data therefore concerns time elapsed between delivery and admission to hospital, and not between time of delivery and onset of the condition.Just over one-third (7/20) of the maternal referrals in the first 24 hours after delivery were for retained placenta and just over one-third were for pregnancy- related hypertension or eclampsia (7/20). Three referrals were for postpartum haemorrhage. There were no maternal deaths in this group.Referrals from the satellite clinics accounted for 73% of all "late" (>24 hours after delivery) postpartum admissions to UTH; the remaining cases were mainly self-referral. The diagnoses of the 44 cases of late-postpartum admissions in the one-month period are shown in Table Twenty-one cases (47%) were admitted to the longer stay gynaecology ward. More than half of all cases (52%) were in the 20–29 years age group. Among the 44 women admitted to hospital at more than 24 hours postpartum, 4 died; 2 of these deaths occurred on the longer stay ward. Of the 4 deaths, one could be directly linked to obstetric events (anaemia); the others were related to non-obstetric causes .This hospital study used time-period based inclusion criteria in its identification of cases of maternal morbidity sufficiently severe to require hospital admission. The majority of morbidity thus identified was directly linked to obstetric causes e.g. puerperal sepsis, infected wounds, and pregnancy-induced hypertension. However, non-obstetric conditions, including malaria and pneumonia were found to have accounted for at least one-fifth of all postpartum admissions in the retrospective review. This mirrors the increased role that indirect causes have been found to be playing in maternal mortality rates in countries such as Zambia .We have already outlined some of the practical difficulties with using routine hospital data sources such as admission registers. Admission rates estimated from the small prospective part of the study do not suggest, however, that many cases were lost in the identification process in the larger retrospective part. The former identified an average of 11 late-postpartum maternal admissions to hospital per week in the month observed, and the latter, an average of 14 late-postpartum maternal admissions per week over the six months reviewed. In both parts of the study, puerperal sepsis and malaria were identified as leading causes of postpartum morbidity requiring hospital admission. In the prospective identification of postpartum morbidity requiring hospital admission, puerperal sepsis, malaria and hypertensive disease each accounted for the same number of admission (5 in each) but the numbers are too small to draw any conclusions. Some inaccuracy in the classification of certain morbidities may be expected due to the use of admission diagnoses. It is also a limitation in the design of this element of our study that data collection did not extend to the medical wards. It is therefore not possible for us to ascertain whether, or to what extent, there are medical ward admissions of women in the late puerperium with non-obstetric conditions such as malaria.Puerperal sepsis was the leading cause of postpartum hospital admissions in this population, accounting for 34.8% of all identified postpartum cases in the retrospective part of this study. Other hospital-based studies as well as surveys of women's self-reports of postpartum morbidity report puerperal sepsis as a leading cause of postpartum morbidity in developing countries ,6,15-18.Puerperal sepsis cases identified through the retrospective data collection part of the study accounted for more than twice as many cases as the second commonest postpartum morbidity requiring hospital admission, malaria. For the retrospective study the overall rate of puerperal sepsis cases requiring hospital-level care and admission was 0.64% of all supervised deliveries in the public sector services, a rate that falls in between those estimates from earlier hospital-based studies in Niger: 0.22% ; and in A number of other obstetric-related postpartum morbidities including anaemia, breast abscess, symphisiotomy, puerperal psychosis, after-pains, urinary tract infection, secondary postpartum haemorrhage and retained products of conception were also identified as late-postpartum referrals through the retrospective study. Anaemia in the postpartum period is not an uncommon health problem . SurveysMalaria and pneumonia together accounted for one-fifth of all the postpartum hospital admissions that we identified. This finding suggests the usefulness of an approach that employs a "time-period" definition to identify cases rather than simply a set of purely obstetrically-related diagnostic categories.In all, 14.5% of identified postpartum maternal admissions to hospital were due to malaria. While it is widely recognised that the severity and frequency of malaria is greater in pregnant, compared to non-pregnant women, until recently it was generally thought that the importance of pregnancy-related malaria ends with delivery  and malaA number of factors may modify susceptibility to malaria in the postpartum period. The age at which partial immunity to malaria is acquired is critically dependent on transmission intensity ,24. WidePneumonia and Pulmonary TB were important causes of postnatal morbidity in this study and were likely related to HIV/AIDS. The HIV serostatus was rarely available of the index postpartum cases, though unlinked anonymous testing of HIV in the antenatal population in 4 sentinel sites in Lusaka during 1998 showed a high HIV prevalence of 27.4% . HIV posReview of registers on the labour ward, for both the retrospective and prospective aspects of this study suggest that the majority of referrals in the early-postnatal period (first 24 hours) were for infant rather than maternal indications. Of the early postpartum referrals for maternal indications, retained placenta is the leading reason for referral from clinics to the hospital. This reflects the urban context of the study and the relative ease of transportation that permits a district policy of removal of placenta at hospital level rather than by the practitioner with essential obstetric care skills at the delivery clinic.The high public sector maternity care usage in this community permits the low-cost review of routine data to be reasonably meaningful. The caveats are those associated with extraction of data from health facility admission registers, which are not always complete, and which cannot take account of changes in diagnosis or subsequently arising complications. In the absence of more robust data, such reviews, if carried out meticulously, do offer the opportunity to identify the extent of moderate-to-severe postpartum morbidity and the principle causes. They thus may provide the groundwork for detailed condition-specific research to take place exploring aetiology, duration, time of onset and outcome, and the implications for health care provision.The author(s) declare that they have no competing interests.LV: Conceived of the study, conducted the field data collection and data analysis and contributed to the paper.SFM: Wrote the first draft of the paper, participated in the study design and advised on the data collection and analysis.YA: Contributed to the study design, advised on the data collection and analysis and contributed to the paper.All authors read and approved the final manuscript. The views expressed in this article are those of the authors and not of their institutions.The pre-publication history for this paper can be accessed here:


Endometrial polyps (EMPs) are commonly encountered in routine surgical pathology practice, but opinions differ on whether they are intrinsically a marker for concurrent or subsequent malignancy. The objectives of the present study are 1) to investigate the age-group in which EMP are most commonly encountered 2) to document the age-group in which EMP are most commonly associated with malignancies 3) To investigate whether the age of diagnosis of the various carcinoma subtypes in EMPs is congruent with published data on similar malignancies arising in non-polypoid endometrium and 4) To investigate whether the histologic subtype distribution of malignancies associated with EMPs are similar or different from the distribution of malignancies arising from non-polypoid endometrium based on published data.All cases of EMPs were retrieved from the files of Yale-New Haven Hospital for the period 1986–1995. The patients were divided into 5 age groups: Each group was further subclassified based on an association (or lack thereof) of EMPs with endometrial carcinoma. Chi-square test was used to compare the proportion of malignancy associated EMPs between the age groups.We identified 513 EMPs, of which 209 (41%) were from biopsy specimens and 304 (59%) from hysterectomy specimens. Sixty six (13%) of all EMPs were malignant. The 66 malignant EMPs included 58 endometrioid, 6 serous, 1 carcinosarcoma, and 1 clear cell carcinoma. In age group >35, only 1(2.5%) of 40 EMPs was associated with endometrial malignancy. In contrast, 37(32%) of 115 EMPs were associated with malignancy in the age group > 65. The frequency of malignant EMPs increased with age and reached statistical significance in the age group >65 (p < 0.001). The most common histologic type of malignancy was endometrioid adenocarcinoma.EMPs show statistically significant age dependent association with malignant tumor involvement. Careful search for malignancy, particularly in women with multiple risk factors is advised in daily practice. Additional studies are needed to address the histological features and immunohistochemical profiles in the context of association between endometrioid and high-grade endometrial carcinoma and endometrial polyps. Endometrial polyps (EMPs) are generally considered benign proliferative lesions and are commonly encountered in routine surgical pathology practice. The usual histological pattern of endometrial polyps is characterized by irregular proliferative glands, with a fibrotic stroma containing thick-walled blood vessels . The morMost standard pathology texts list endometrial polyps as being most prevalent in perimenopausal women and suggest possible association between polyps and malignant involvement ,11. HoweAll cases with a diagnosis of EMP were retrieved from the computerized database of the Pathology Department at Yale-New Haven Hospital for the 10-year-period from 1986 to1995. All cases were further investigated for involvement of endometrial cancers including malignancies without myometrial invasion; histologic subtypes of all malignant tumors were catalogued. Histologic types of endometrial malignancies were characterized according to the WHO classification . All casFor comparative purposes, the patients were divided into 5 age groups: 25–35; 36–45; 46–55; 56–65; and >65 years; and each group was further classified based on an association (or lack thereof) with endometrial carcinoma. A starting point of 25 years of age was selected due to the very low incidence of endometrial polyps in patients below this age. Two patients (ages 18 and 19) were excluded from the study as they did not represent a sufficiently large for statistical analysis group. The proportion of both groups  and polyps not associated with malignancies (benign polyps) were statistically compared for each of the aforementioned age-groups. Subsequently, we merged the younger age groups and preserved the >65 year group, which we referred to as "postmenopausal", since significant differences were observed in this specific subset of patients. Larger age groups were arbitrarily designated as reproductive years (25–45), perimenopause  and postmenopause (>65) and statistically analyzed. The postmenopausal status of all women above the age of 65 was verified and the term "postmenopausal" was occasionally used when referring to this particular age group. Our use of this term, although arbitrary, was important in order to put the emphasis on the fact that any pathomorphological findings in this age group are unlikely to be attributed to changes characteristic of the cycling endometrium.Chi-square test was used to compare the proportion of malignancy associated EMPs between the age groups and in regards to particular histological type of malignancies.p < 0.001) in the age group >65 years  endometrial biopsies/curetting samples, and 209 (41%) hysterectomy specimens. In cases in which endometrial biopsies and hysterectomies both showed presence of EMP, only the hysterectomy specimen was considered. The age of patients ranged from 18–91 years with a median of 54 years. Sixty-six (13%) of 513 EMPs were malignant. The histological subtype distribution of those 66 malignancies included 58 endometrioid (87%), 6 serous (9%), 1 carcinosarcoma, and 1 clear cell carcinoma. No mixed histological type of endometrial cancer was found in our series. The incidence of EMP peaked at age group 46–55 years, which was similar to previous reports. In age group 25–35, only 1 (2.5%) of 40 EMPs was associated with endometrial malignancy. In contrast, 37 (32%) of 115 EMPs were associated with malignancy in the age group >65 years  of endometrial carcinomas associated with EMPs were of endometrioid, followed by the serous type (9%). These relative proportions of both major histological subtypes are in accordance with the well-known distribution of similar subtypes of endometrial carcinoma in non-polypoid endometrium  and thuset al.,  reached et al.,  or the eet al., ,19.et al., [This study also confirms previous findings that EMPs are most prevalent in the perimenopausal age group. The reason(s) for this age-segregation, which has remained remarkably consistent across various studies since the mid-fifties, is unclear. Chavez et al.,  speculatDespite the supportive evidence of no difference in the clinico-pathological features and overall distribution of carcinomas arising from EMPs with those arising from non-polypoid endometrium, our data suggest a strong age dependent association between the presence of EMPs and involvement by endometrial carcinoma. The pathogenesis and mechanisms underlying such association are complex and not well established. Recently published data, however, provided some clue of significant differences in receptor expression, response to stimuli, and apoptosis regulation in EMPs compared to benign non-polypoid endometrium which could potentially elucidate some aspects of the possible malignant potential of EMPs. Estrogen and progesterone act as modulators of endometrial proliferation and differentiation through their receptors. Glandular epithelial expression of estrogen and progesterone receptors in polyps is not significantly different from that of the normal cycling endometrium. However, fewer stromal cells express estrogen and progesterone receptors in polyps which suggests that EMPs may result from a decrease in estrogen and progesterone receptors in the stromal cells . In addiet al., who found that 10 (76%) of 13 Tamoxifen-related endometrial carcinomas were associated with EMPs [Another significant histological finding is the glandular epithelia hyperplasia in C-erbB2 -positive polyps as opposed to rather atrophic architecture in C-erbB2 -negative polyps . These fith EMPs .One potential limitation of our study is our lack of consideration of the impact of variables such as hypertension, obesity and family history. However, since data regarding such possible confounders were not available to us, we set the goals of our investigation to be primarily focused on age related distribution of coinciding morphologic findings. Although we are aware of the limitations of our study and the introduced analytical bias, drawbacks that certainly pertain to any similar retrospective pathomorphologic study, we feel that we have adequately addressed the proposed investigative tasks according to the initially set scope of the study. By using the database of Yale-New Haven Hospital, we collected and analyzed a significant number of cases over an extensive period of time and thereby our study population constituted an adequate representation of the general population in respect to the morphological parameters we investigated.In summary, the age distribution, histological subtype distribution, and peak incidence of EMPs was similar to previous reports. In contrast, EMPs in postmenopausal women showed a significantly higher association with malignant tumor involvement. Careful microscopic search for malignancy in patients with multiple risk factors, particularly in postmenopausal women is advised in daily surgical pathology practice.The author(s) declare that they have no competing interests.DH wrote the original version of the manuscript.OF made substantial contributions to the content of the manuscript and participated in manuscript preparation.MM collected clinical and pathological data and revised the final version.WZ analyzed and interpreted the data and supervised the entire project.All authors have read and approved the final manuscript.


Plasmodium falciparum multiple epitope (ME)– thrombospondin-related adhesion protein (TRAP) candidate vaccines are designed to potently induce effector T cells and so are a departure from earlier malaria vaccines evaluated in the field in terms of their mechanism of action. ME-TRAP vaccines encode a polyepitope string and the TRAP sporozoite antigen. Two vaccine vectors encoding ME-TRAP, plasmid DNA and modified vaccinia virus Ankara (MVA), when used sequentially in a prime-boost immunisation regime, induce high frequencies of effector T cells and partial protection, manifest as delay in time to parasitaemia, in a clinical challenge model.Many malaria vaccines are currently in development, although very few have been evaluated for efficacy in the field. P. falciparum. Analysis was per protocol.A total of 372 Gambian men aged 15–45 y were randomised to receive either DNA ME-TRAP followed by MVA ME-TRAP or rabies vaccine (control). Of these men, 296 received three doses of vaccine timed to coincide with the beginning of the transmission season (141 in the DNA/MVA group and 155 in the rabies group) and were followed up. Volunteers were given sulphadoxine/pyrimethamine 2 wk before the final vaccination. Blood smears were collected weekly for 11 wk and whenever a volunteer developed symptoms compatible with malaria during the transmission season. The primary endpoint was time to first infection with asexual p = 0.49). Incidence of malaria infection decreased with increasing age and was associated with ethnicity.DNA ME-TRAP and MVA ME-TRAP were safe and well-tolerated. Effector T cell responses to a non-vaccine strain of TRAP were 50-fold higher postvaccination in the malaria vaccine group than in the rabies vaccine group. Vaccine efficacy, adjusted for confounding factors, was 10.3% (95% confidence interval, −22% to +34%; DNA/MVA heterologous prime-boost vaccination is safe and highly immunogenic for effector T cell induction in a malaria-endemic area. But despite having produced a substantial reduction in liver-stage parasites in challenge studies of non-immune volunteers, this first generation T cell–inducing vaccine was ineffective at reducing the natural infection rate in semi-immune African adults. Inducing an immune response is just one part of what a vaccine needs to do before it will protect against episodes of malaria. Plasmodium falciparum parasites [Anopheline spp. vectors [P. falciparum [P. falciparum malaria, were manufactured to explore this approach [The disease burden of malaria has increased in recent years partly because of the rise of drug-resistant arasites  and inse vectors . There ilciparum ,6,7,8,9.lciparum ,11. DNA approach . γ-interapproach .DNA and modified vaccinia virus Ankara (MVA)'s excellent safety profiles in malaria-naïve and semi-immune volunteers have been discussed previously . In seve8 plaque-forming units, produced very strong vaccine-induced CD4+ and CD8+ T cell responses in previous phase I studies in the United Kingdom [Priming with three 2-mg intramuscular DNA ME-TRAP vaccinations at 3-wk intervals, followed by boosting with one intradermal MVA ME-TRAP vaccination of 1.5 × 10 Kingdom . The imm Kingdom . DNA ME- Kingdom .P. falciparum infection. We chose a two-DNA prime, one-MVA boost regimen with 3-wk between doses because this is a three-dose regimen that would be amenable to integration with the World Health Organization/United Nations Children's Fund Expanded Program on Immunization, with the necessary supporting safety and immunogenicity data both from adults in the United Kingdom and Gambia. We used 3-wk intervals because 4-wk intervals had not been evaluated in phase I trials previously, hence bridging studies would be necessary to bridge to the three-dose, 4-wk interval Expanded Program on Immunization schedule.To follow up these encouraging findings in volunteers, we have conducted a randomised, controlled trial of DNA ME-TRAP/MVA ME-TRAP in a rural part of Gambia to explore whether this vaccine combination could provide protection against natural P. falciparum antigens. It also contains two non-malarial CD4+ T cell epitopes [P. falciparum TRAP [P. falciparum used to produce the vaccine construct is T9/96. The candidate malaria vaccines were manufactured to Good Manufacturing Practice by contract manufacturers . DNA ME-TRAP was supplied as a single dose of2 mg in 2-ml vials. MVA ME-TRAP was supplied as two-dose vials, each containing 3 × 108 plaque-forming units in 0.8 ml. The rabies vaccine  was supplied as a lyophilised single-dose vial with accompanying diluent and syringe. This vaccine was chosen because of its public health benefit in Gambia.The malarial DNA sequence is known as ME-TRAP. The ME string contains 14 CD8+ T cell epitopes, one CD4+ T cell epitope, and two B cell epitopes from six pre-erythrocytic epitopes . The ME rum TRAP ,24,25. Trum TRAP . The strApproval was obtained from the Joint Gambian Government/Medical Research Council Ethics Committee, the Oxford Tropical Research Ethics Committee, and the London School of Hygiene and Tropical Medicine Ethics Committee. An independent Data and Safety Monitoring Board provided oversight for the trial. In addition, independent clinical trial monitors monitored the trial for adherence to International Committee on Harmonisation Good Clinical Practice guidelines.Malaria incidence is highly seasonal in Gambia. The climate is typical of sub-Sahelian Africa, with a long dry season followed by a relatively short rainy season from July to October. Rainfall averages about 600 mm per year. Morbidity and mortality from malaria both occur more frequently during the rainy season. However, in 2002, Gambia experienced a drought, and the malaria season was delayed, with few disease episodes before October. The entomological inoculation rate varies between less than 1 and greater than 100 in Gambia . Based oBefore recruitment, meetings were held with village heads and elders, followed by general village meetings at which the study was explained. Volunteers received information sheets and consent forms translated into the three local languages in Arabic script, as well as in English. After written informed consent was obtained by a study physician, age and identity were checked, pre-test HIV counselling occurred, and potential volunteers underwent clinical evaluation, including a full medical history and clinical examination. They were screened for haematological (full blood count), renal (plasma creatinine), and hepatic  dysfunction, and duplicate malaria smears were made. Exclusion criteria included any chronic illness detected by clinical evaluation, ALT greater than 42 , creatinine greater than 130 (micromoles/litre), packed cell volume less than 30%, positive antibody ELISA to HIV-1 or HIV-2, simultaneous participation in another clinical trial, blood transfusion in the month prior to vaccination, previous experimental malaria vaccination, administration of another vaccine within 2 wk of vaccination, previous rabies vaccination, allergy to any previous vaccine or to sulphadoxine/pyrimethamine, history of splenectomy, and any treatment with immunosuppressive drugs. Eligible volunteers were given a unique study number and a photographic identity card. Parental written informed consent was obtained for volunteers aged 15–17 y.A member of the Data and Safety Monitoring Board generated and held the randomisation code that associated each study number with a specific vaccine. A blocking procedure was used, and whole villages were enrolled with sequential study numbers to ensure balanced numbers in each group. During the course of the study investigators and volunteers did not know the size of the blocks, nor were they aware of which vaccine preparation was administered to a particular volunteer. Opaque sealed envelopes were used for vaccine allocation. Study numbers were not preprinted on vials but were written on vials at vaccination. Used vials were checked for correct allocation off-site. Vaccination was performed by nurses who played no other part in the trial.8-plaque-forming-units dose of MVA ME-TRAP or (2) three doses of rabies vaccine; injections were given on days 0, 21, and 42, timed to coincide with the start of the rainy season. The first two doses of vaccine consisted of two intramuscular injections, one into each deltoid muscle. DNA ME-TRAP was given as 1 ml and rabies vaccine as 0.5 ml into each arm. The third dose of vaccine was given as four intradermal injections into the skin overlying the deltoid muscle, with two injections into each arm. The malaria vaccine group received MVA ME-TRAP as four 0.1-ml injections, whereas the control group received four 0.05-ml injections of rabies vaccine. Two weeks before administration of the third dose, all volunteers received three tablets of sulphadoxine/pyrimethamine to clear blood-stage P. falciparum infections [Volunteers were randomly assigned to receive either (1) two 2-mg doses of DNA ME-TRAP followed by a single 1.5 × 10fections .After each vaccination volunteers were observed for 1 h and visited at home on the first, second, and seventh day postvaccination for assessment of local adverse events , systemic adverse events , and unsolicited adverse events. One week and 13 wk after the third vaccination, venous blood was collected for repeated measurement of full blood count, ALT, and creatinine.P. falciparum parasites at any parasitaemia with either an axillary temperature of 37.5 °C or more or one or more of the following symptoms: headache, myalgia, arthralgia, malaise, nausea, dizziness, or abdominal pain.Since vaccination with MVA causes a characteristic local reactogenicity in some subjects, specific steps were taken to ensure that the participants were evaluated in a double-blinded manner. Field workers who assessed reactogenicity after the third dose were different from those who undertook surveillance during the parasitological follow-up period. During the surveillance period, starting 2 wk after the third dose of vaccine, volunteers were visited twice weekly and asked whether they had attended a health centre. At weekly visits blood smears and axillary temperatures were taken. At midweek visits, blood smears and temperature were taken if symptoms compatible with malaria were present. Investigators and field supervisors made random visits to ensure accurate data collection. This active case detection was supplemented by passive case detection by study nurses to whom volunteers had 24-h access at three of the study villages and by a clinic at Medical Research Council Farafenni (20 km from the study villages). Symptomatic malaria was defined as the presence of asexual P. falciparum parasites was confirmed by a supervisor before a slide was declared positive. The arithmetic mean of the A and B slides was used to determine parasite density. If parasite densities for A and B slides were markedly discrepant, a third read was performed by the supervisor and this read was used for analysis. Parasite density was expressed per microlitre . Full blood counts were performed and packed cell volumes were measured in a CA620 cell analyser . ALT  and creatinine (micromoles/litre) were measured in a Visual analyser .When blood smears were obtained, two sets of duplicate blood smears  were made. A Field's stain was performed on films obtained from subjects with possible clinical malaria and the films read immediately. Two further smears (“A” and “B” slides) were stained with Giemsa after overnight drying; 100 high-power fields were read by two slide readers before a film was declared negative. The presence of 5 peripheral blood mononuclear cells (PBMCs) were assayed as described [P. falciparum.Effector T cell responses were assessed in ex vivo γ-interferon enzyme-linked immunospot (ELISPOT) assays for 98 volunteers randomly selected from a substudy list containing a 3:1 ratio of participants receiving malaria vaccines to participants receiving rabies (control) vaccines. For this assay, 4 × 10escribed , using MP. falciparum, defined as the number of days from the start of the surveillance period to the date of the first positive slide. Vaccine efficacy was calculated from the hazard ratio estimated by Cox's regression, adjusting for the effects of prognostic variables. Volunteers who received fewer than three doses or who were parasitaemic both prevaccination and at the beginning of surveillance without an intervening negative blood smear were excluded from the primary analysis but included in a secondary analysis. Observations on individuals who were lost to follow-up or were missing from trial data for 3 wk were censored. Analyses were done with Stata version 7 . ELISPOT responses were analysed as follows. After subtraction of medium-alone values from each pooled peptide response, responses were summed across T9/96 and 3D7 pools. Geometric means were calculated for T9/96 TRAP, 3D7 TRAP, and ME string responses. Responses in the two groups were compared using the Mann-Whitney test.An analysis plan, written before unblinding, specified exclusion criteria, statistical methods, and important covariates . Ethnic group, though not specified as a covariate in the analysis plan, was found on analysis to be associated with the risk of infection, and was included as a covariate. The primary endpoint was time to first infection with asexual In total, 489 volunteers were screened , of whomNo clinically significant differences in packed cell volume, ALT, or creatinine were seen in either vaccine group. One volunteer who received rabies vaccine had a history of breathlessness and chest pain several years prior to enrolment, experienced a relapse of symptoms, and deteriorated and died, probably from heart disease, 3 mo after he received the last dose of vaccine. This event was regarded as unrelated to vaccination. There were no other serious adverse events. Adverse events were rare after first and second doses and were not increased in the DNA ME-TRAP group compared to the rabies vaccine group (data not shown). Injection site pain, limited arm motion, headache, and malaise in the first 24 h after vaccination  were more common after MVA ME-TRAP vaccination than rabies vaccination . Some vop <0.001, range 6.25–2148.75). A large cross-reactive T cell response to 3D7 TRAP, a strain with 6% amino acid variance to T9/96, and a weaker response to the ME string were also seen at this timepoint  per million PBMCs for T9/96 and 3D7 strains of TRAP and the ME string, respectively. In the malaria vaccine group, the effector T cell frequency to the vaccine strain of the TRAP antigen, T9/96, was geometric mean 251.1 SFCs per million PBMCs . Similar results were obtained when all participants who received at least one dose of vaccine were included in the analysis .By the end of the study, 171 participants developed parasitaemia, 80/141 (57%) in the malaria vaccine group and 91/155 (59%) in the rabies vaccine group. The distribution of time to first infection was similar in the two groups . VaccineP. falciparum densities in first infections were similar in the two groups .Geometric mean During surveillance, there were ten episodes of symptomatic malaria in the malaria vaccine group and 13 in the rabies group. The risk of malaria-related symptoms during an episode of parasitaemia was similar in both vaccine groups. Percentage mean packed cell volume at the end of the trial was similar in both groups .Within the ELISPOT substudy group, the risk of developing parasitaemia was not associated with effector T cell response to the 3D7 strain of TRAP. The 80 men from the substudy group who received three doses of either malaria vaccine (55 men) or rabies vaccine (25 men), completed 11 wk of surveillance, and had complete ELISPOT data after dose three were divided into four quartiles. Men with the highest effector T cell responses had hazard ratios for infection similar to those with the lowest after adjustment for age, bednet use, and village of residence.The incidence of parasitaemia decreased with increasing age, and was decreased in those of Fula ethnicity compared to those in the Mandinka and Wollof ethnic groups . The useP. falciparum infection rate in a semi-immune adult African population. This provides a second comparison between protection in malaria-naïve and malaria-experienced adults. RTS,S/AS02, a circumsporozoite protein malaria vaccine based on a hepatitis B surface antigen virus-like particle formulated in a proprietary adjuvant, provided about 40% sterile protection in the artificial challenge model [This trial demonstrated that vaccination with two doses of DNA ME-TRAP followed by a single dose of MVA ME-TRAP is safe and highly immunogenic for effector T cell induction but that it did not reduce the ge model  and 71% ge model . The lacge model , whereasge model . The preAnother possible reason for the observed low efficacy is that the frequency of the effector T cell response declines from 7 d after boost, and so efficacy would be prevented if very high frequencies of circulating effectors are needed for protective efficacy. Alternatively, a suboptimal regional memory T cell pool in the liver may be responsible , or, lesIn previous studies in East and West Africa, summed T cell responses to TRAP in unvaccinated semi-immune adults by ex vivo γ-interferon ELISPOT were geometric mean less than 20 SFCs per million PBMCs. The candidate regimen represents a new method for induction of unprecedented effector T cell frequencies, which are about 50-fold higher than those induced by lifelong natural exposure. Estimates of the reduction in liver-stage parasite burden induced by these vaccines in the human challenge model are of the order of 80%–90% of infected hepatocytes ,33. It iSecond-generation prime-boost vaccine strategies for malaria currently in or near to clinical evaluation include the following: use of a different viral vector as the priming agent that may lead to proportionately greater CD8+ rather than CD4+ T cell induction , as is the case with fowlpox-MVA immunisation; the use of a different antigen, the circumsporozoite protein, or polyprotein constructs  to addreWe were unable to obtain a useful estimate of the likely efficacy of the DNA ME-TRAP/MVA ME-TRAP vaccination regime against clinical disease. Even for an adult population, the incidence of clinical disease was lower than expected. Sulphadoxine/pyrimethamine was administered 4 wk before the start of surveillance in this study and in an RTS,S field efficacy study . There iThis study highlights North Bank Division in Gambia as an excellent malaria vaccine field trial site both for adults and, by extrapolation, for children. In a low-transmission year, cumulative incidence overall in men aged 15–45 y was 72% over 11 wk, which was higher than expected. Also, compliance was good despite a demanding study design, and migration from the study area was acceptably low.This paper adds to the body of data detailing the very gradual acquisition of anti-infection immunity in adults resident in sub-Saharan Africa . While sImmunological analysis of the high level of protection inducible by immunisation of humans and animals with irradiated sporozoites has encouraged attempts to generate protective immunity by subunit vaccines that induce strong cellular immune responses. To date the induction of high-level protective T cell responses against malaria and some other infectious pathogens has generally required two-component prime-boost vaccination approaches . We repoMalaria kills 1–2 million people a year, mostly children under the age of five who live in sub-Saharan Africa. Scientists are trying to develop cheap, safe, and effective vaccines that could be given to people living in regions where malaria is very common to prevent them from developing the disease.The researchers enrolled 372 Gambian men aged 15–45 years into the study. They injected half the men with two malaria vaccines, one after the other, and half the men with a rabies vaccine that does not protect against malaria  just before the rainy season, when malaria is especially prevalent. The scientists took blood smears from the men once a week and checked to see if they had been infected with the parasite that causes malaria. They found that the men who had been vaccinated became infected just as quickly as those who had not. Although the two malaria vaccines in concert did not work, neither did they cause any serious side effects. The men given the malaria vaccines did produce an immune response to the vaccines, though not one that was clinically useful.Plasmodium falciparum, the parasite that causes malaria. However, there are other vaccines in development that have not been tested yet.It looks as though the combination of these two vaccines is not effective at preventing infection with http://www.lshtm.ac.uk/gmp/Gates Malaria Partnership (which co-funded the study): http://www.malariavaccine.org/Malaria Vaccine Initiative: http://www.mmv.org/pages/page_main.htmMedicines for Malaria Venture: http://rbm.who.int/partnershipRoll Back Malaria Partnership: http://www.wellcome.ac.uk/en/malaria/The Wellcome Trust (which co-funded the study): http://www.controlled-trials.com/isrctn/trial/1/0/05221133.html.This trial has been submitted for registration in the International Standard Randomised Controlled Trial Number (ISRCTN) Register. The ISRCTN is ISRCTN05221133; Web site Table S1(55 KB DOC).Click here for additional data file.


Schistosoma mansoni and Plasmodium chabaudi develop higher P. chabaudi parasitaemia and had a higher mortality rate. This important observation deserved to be further investigated among human populations.Helminthic infections concomitant with malaria are common in inter-tropical areas. A recent study showed that mice co-infected with S. mansoni, and 175 were not. The incidence rate of malaria attacks was significantly higher among S. mansoni-infected individuals, particularly those carrying the highest worm loads, as compared to uninfected subjects . In contrast, the rate of malaria attacks was lower, without reaching significance, in medium grade S. mansoni infections. Thus, infection by S. mansoni affects susceptibility to malaria, but this can vary according to the intensity of parasite load. The immunological mechanisms underlying this dual effect need to be further explored.Malaria attacks were recorded in 512 children aged 6–15 years living in Richard Toll  among whom 336 were infected by  Schistosoma mansoni and Plasmodium chabaudi co-infected mice develop higher P. chabaudi parasitemia and higher mortality rate [Malaria is prevalent in many parts of tropical Africa, where other concomitant parasitic infections are common. However, little is known about how concurrent infections affect the expression to and/or pathogenesis of each other. A recent study showed that ity rate . This obity rate  and by fity rate .S. mansoni infection [In the Senegal river basin, where malaria is hypoendemic, extensive irrigation programmes have been developed, promoting a spread of nfection . The expThe study took place in Gallo Malick, a district of Richard Toll, which is located near a canal ensuring the irrigation of rice and sugar cane fields. The population was estimated in 1998 to reach 3,685 inhabitants. Annual rainfall amounts to around 250 mm water. The district is approximately 1 km long and 500 m wide. A dispensary is set up in the centre of the district and is thus easily accessible.In September 1998, after obtaining agreement from the parents, two stools examinations were carried out in all children aged between 5 and 15 years. From 25 mg of stools, two slides were prepared, according to the modified Kato-Katz method [Schistosoma haematobium eggs, were performed. Ten ml of urine were filtered through a 12 μ millipore membrane and the eggs on the whole filter surface were counted. A questionnaire was issued to check habits with regard to protection against mosquitoes and usage of anti-malarial drug-prophylaxis. It was also ascertained that none of the included children had been administered anti-S. mansoni treatment (praziquantel) over the past year (September 97 – September 98). In March 99, all children who presented with at least one S. mansoni positive stool examination were treated with praziquantel (40 mg/kg).The follow-up was implemented between September 1998 and April 1999. In January 1999, a further stool examination and a urine filtration for the detection of Any child presenting with a body temperature > 38°C or having a history of fever-in the 24 hours preceding the consultation and with a parasite density ≥ 5000 parasites/μl of blood was defined as suffering from a malaria attack.S. mansoni at least once was defined as S. mansoni positive. If both examinations proved positive, the highest parasitic burden was kept for further analysis. Parasite loads were classified into four categories: A) 1 to 100, B) 101 to 400, C) 401 to 1000, and D) > 1000 eggs per one gram of stools.Any child whose tool tested positive for S. mansoni but presenting other intestinal parasitic infection were excluded from the analysis.In order to exclude possible interactions with other helminthic infections, children from the group not infected by S. mansoni. This is in agreement with the distinct sources of infection, Anopheles larvae breeding in small water collections in gardens, and Schistosoma vectors in rice fields and irrigation canals.When houses where children had a malaria attack and those where the children were carrying schistosomiasis were located on a map, the two pathologies were found to be distributed in a uniform way in the whole district, without evidence of clustering of double infection malaria-S. mansoni categories eggs load and age.Comparison between children presenting at least one malaria attack and children not having presented any malaria attack was performed using a forward logistic regression model using STATA statistical software. The variables included in the model were sex, S. mansoni infections using a lifetime estimate table from the EGRET programme . Any p value lower than 0.05 was considered significant.The period between the beginning of the study and the date of a malaria attack was compared between groups of S. mansoni eggs and 189 were negative for both stool examinations.In September 1998, 525 children underwent two stool examinations. Three-hundred and thirty-six-were found to carry Schistosoma haematobium (2.7%). Among them, 11 were also positive for S. mansoni. The stool examination showed the presence of 31 other intestinal parasitic infections (Ascaris and Trichuris). Patients negative for S. mansoni and carriers of another intestinal (12 subjects) or urinary parasite (2 subjects) were excluded of the analysis.Urine filtration detected only 13 children excreting eggs of S. mansoni (65.7%) and 175 (34.3%) not infected). The prevalence increased as a function of age, reaching 80% in children older than 11 years with > 30% of children presenting with high schistosome loads, i.e. > 1,000 eggs/ 1 g of stools.In total, 511 children were included in the analysis  were attributed to a malaria attack, according to the criteria described. Only 10 children underwent two malaria attacks. In total, 18.9 % (97/511) of the children included in the analysis presented with a malaria attack at least once.S. mansoniior not. However, the malaria attack prevalence was also the same whether or not the children were sleeping under a mosquito bednet.Chemoprophylaxis for children is not recommended by the National Control Programme, but 7.9 % of the parents reported that they were giving a chemoprophylactic treatment to their children. 58.9 % stated they used a mosquito bednet. These proportions were the same in the two groups of children, infected by S. mansoni and 16.6% (29/175) in those non-infected (p = 0.40). The malarial incidence, however, varied depending on the load of eggs. It was high in all groups, but the highest (26.6 %) in those carrying the highest worm loads , except in subjects presenting medium loads (>100 and < 400 eggs/g of stools) where malarial incidence was lower than in S. mansoni negative individuals (9.4 %). Sex and age had no significant influence, which is not surprising since this is a mesoendemic area. Using a logistic regression model and taking the negative group as reference, the difference was significant with the group carrying a high load of eggs (RR = 2.24 (1.2 – 4.2) , the malaria incidence was significantly increased for low S. mansoni egg carriage (1–100) (RR = 2.51 (1.05–6) as well as high S. mansoni egg carriage  RR = 3.12(1.33–7.29).The incidence rate of malaria attacks was 20.2 % (68/336) in the group of children concomitantly infected by Out of 10 children who presented two malaria attacks, nine were infected by S.m.; four presented a schistosome load higher than 1,000 eggs/g of stools, and three > 400 and <1,000.S. mansoni loads and other groups increased over time during the follow-up  or a low load of eggs (1–100), whereas a lower attack rate was observed in children presenting a medium egg load (>100 and <400 eggs/g), although this opposite trend did not reach significance.The analysis of the incidence of the malaria attacks by amount of parasite load in Protection against falciparum malaria has been found to be associated with the preferential production of the cytophilic classes, IgG1 and IgG3, of antibodies , this beS mansoni, but only for those having the highest loads. The opposite effect was found in individuals carrying medium schistosome infections. As immunological studies could not be performed, one can only speculate about this biphasic effect. The production of cytophilic classes against malaria requires that the T-cells helper effect is provided by Th1 type of T-cells, however cytokines produced by T-cells specific for schistosome eggs or worms can influence responses to malaria. It has been reported that, during the first phase of S. mansoni infection, T-cells are stimulated which secrete cytokines belonging, in majority, to the Th1 type. The switch towards Th2 type cytokines occurs later on and is dependent on egg production [S. mansoni eggs.In the present study, this observation has been confirmed with yet another worm infection, oduction . In the Obviously, further studies, particularly of T-cell responses to both malarial and schistosome antigens are required to sort out this issue.S. mansoni infection can increase the susceptibility to malaria in subjects excreting high schistosome egg loads.Helminthic infections are a fact of life in malaria endemic areas and their influence on the course of infection and the epidemiology of malaria is a fascinating though neglected area of research. This study shows that CS, PM, JA, PC, MD were responsible for field and laboratory studies. JYL was responsible for the statistical analysis. PD inspired and designed the study


A wide range of childhood illnesses are accompanied by fever,, including malaria. Child mortality due to malaria has been attributed to poor health service delivery system and ignorance. An assessment of a mother's ability to recognize malaria in children under-five was carried out among the Bwatiye, a poorly-served minority ethnic group in north-eastern Nigeria.A three-stage research design involving interviews, participatory observation and laboratory tests was used to seek information from 186 Bwatiye mothers about their illness-related experiences with childhood fevers.Mothers classified malaria into male (fever that persists for longer than three days) and female (fever that goes away within three days) and had a system of determining when febrile illness would not be regarded as malaria. Most often, malaria would be ignored in the first 2 days before seeking active treatment. Self-medication was the preferred option. Treatment practices and sources of help were influenced by local beliefs, the parity of the mother and previous experience with child mortality.The need to educate mothers to suspect malaria in every case of febrile illness and take appropriate action in order to expose the underlying "evil" will be more acceptable than an insistence on replacing local knowledge with biological epidemiology of malaria. The challenge facing health workers is to identify and exploit local beliefs about aetiology in effecting management procedures among culturally different peoples, who may not accept the concept of biological epidemiology. Malaria is a major cause of death among children in many parts of the world, despite the availability of simple and effective treatments  and is oThe study was carried out during the malaria season (May-September) of 1999 among the Bwatiye, a minority group living in six villages along the Benue valley in Adamawa State of north-eastern Nigeria. A multiple-stage approach consisting qualitative, quantitative and laboratory techniques was used.In order to orient the data collection process, informal conversations were held with women and lay people in markets and health facilities about malaria illness experience within communities, the method of recognition and help-seeking behaviour. On the basis of received information, key informants were identified and selected  and formally interviewed about local knowledge and practices regarding malaria in children. The information was used for designing a cross-sectional household survey questionnaire. Households with children between 9 and 60 months in six Bwatiye villages were identified with the assistance of community health personnel. The study objectives and procedures were explained to household heads and mothers of children that were eligible participants in the study. It was emphasized that anyone was at liberty to decline participation and that those participating were also free to withdraw at any stage of the study. The pre-tested cross-sectional survey questionnaire was administered in the Hausa language to 186 mothers in their homes. Information on the mother's demographic, educational and parity status was collected. Mothers were also asked about symptoms used for recognizing and classifying malaria and to describe their help-seeking practices when a child has malaria. Previous history of child mortality was also recorded. The interviews were complemented with observations of fifteen mothers  identified during the interview process. The results were analysed and used for developing a group discussion guide.Six group discussions, each consisting of eight carefully selected mothers of different ages. family settings (polygamous or monogamous) and religions were held.Culturally appropriate explanations were further obtained from four key informants when the data had been analysed and a draft report written.zazzabi, meaning "hot body" with intermittent episodes of cold shivers ("when the child wants to stay in the sun") accompanied by headache as the main symptom of malaria in their children. Diarrhoea and teething were also important (44.6%) besides dehydration, sweating and vomiting (33.3%), loss of appetite (30.6%) and persistent crying (29.6%). Only very few mothers (6.5%) use faint spells, restlessness, moodiness and withdrawal as symptoms. Only 9.7% mentioned convulsion as an important symptom of malaria in children. Several symptoms were combined, although "child feels cold but has hot body" is an omnipresent clue to presuming that a child has zazzabi (Table Most mothers (88%) refer to malaria as bi Table .zazzabi as the major symptom (100%), while 79.0% of those with more than three child-births were content to presume malaria on noticing "hot-body with cold shivers" without any additional symptom. Mothers with more than three children (28.4%) and mothers with two or three children (81.0%) differed widely with respect to enteric symptoms.While the number of childbirths and previous experience with child mortality were important factors in the recognition of malaria , age and education  were not. Association between age and number of childbirths on the one hand and age and child mortality on the other were significant . Young mothers had fewer children and fewer child mortality rates than the older mothers. Among first time mothers, 47.6% identified fever with persistent crying, an association unique to this group and used A history of child death in the family plays an important role in a mother's approach to recognition of malaria. Surprisingly, education played a minor role in the recognition of childhood malaria. For mothers who had experienced a child dying, emphasis was placed on diarrhoea.zazzabi and "evil doers" are suspected to be using zazzabi to hide a more severe ailment.Malaria was classified into two categories; the female and the male. The female form goes away after a couple of days without any particular treatment other than that provided by the household or in some cases the mother. When illness defies home remedies after several days, or deteriorates, it is considered to be the male form. However, should extra-community consultants become necessary, the illness is no longer regarded as boka) rather than the health facility could handle.Convulsions or any form of complications including hallucinations were not regarded as symptoms of malaria but manifestations of other problems that the local healer  for most mothers  is strong, especially among the older mothers. The local belief is that convulsions are not curable in health facilities and a sick child taken to another village, out of reach of the local enemies, is likely to survive. Most child deaths occur at this stage. In some cases, the child is taken to the health facility, often too late to be helped. This experience, which seems common, has created a strain between the health personnel and mothers, one accusing the other of negligence. The delay action of first-time mothers is interpreted as stemming from fear of rebuke by their husband, while third-time mothers being more confident, would rather wait to be sure it was not an ordinary illness. Third-time mothers are often older, more experienced, but also more entrenched in the local beliefs about malaria aetiology than the young mothers. Although they have more responsibilities, they are economically more independent and are able to take vital decisions with respect to their children with little reference to the husbands, not the case with the younger, inexperienced mothers. Unlike the younger ones, older and multigravid mothers are assisted by their older children who serve as child-minders and help with domestic and economic tasks. When drugs are used, the habit of sharing health resources in times of illness signifying solidarity contributes to non-compliance with management regulations. A mother stops administering drug as soon as the child seems to have improved in health and the remaining drugs are kept for another episode. The act of sharing has been exploited for the development of community management of childhood malaria in Uganda. The Bwatiye and other similar societies could benefit from this management approach.As in other cultures, an attempt to differentiate between the severe and the mild forms of malaria has led to classification in order to determine at which stage a particular remedy would be required. While the Yoruba and Igbo are reported to have three classifications for malaria or fever episodes ,7 the BwThe logical categorization of malaria as female  and male (severe), the interpretation of the class of ailment and its consequences, provide useful clues in the search for healing within the local milieu. Local consultants are useful allies in appropriately managing malaria or other febrile illnesses among the Bwatiye and perhaps other ethnic groups in north-eastern Nigeria.zazzabi to cover up their evil deeds until it is too late for the affected person to seek a potent cure. This belief may not be ignored when drafting health education material. During post-analysis discussions, the women saw the logic of promptly administering antimalarial drugs at the onset of any febrile illness as a means of eliminating malaria and exposing any underlying evil that may not be malaria. The belief that malaria is incapable of killing a child without enemy intervention is a challenge to health educationists in this and other parts of Africa, where such beliefs prevail. These findings raise a number of points about what is appropriate in health education provision and empowerment for community health-care delivery. Should the development of educational materials be based on promoting biomedical aetiological theory of disease and should we insist that others accept it first, or should we work within the traditional understanding of disease transmission, which includes concepts of evil and ill intent?The Bwatiye have an all-pervading belief that enemies often use The health authorities need to consider working within cultural epidemiological parameters if the programme objective is to reduce morbidity and mortality due to malaria. Insistence on acceptance of biomedical models of disease transmission belongs to another goal that may not be directly linked to reduction in morbidity and mortality.Until mothers are empowered with the capability to recognize and treat malaria, its impact on child mortality will continue unabated. The need is to educate mothers to suspect malaria first in every case of febrile illness and take appropriate action to rid the child of malaria to expose the underlying "evil". This is a more acceptable form of education than an insistence on replacing local knowledge with biological epidemiology of malaria. The challenge before health personnel is to identify and exploit local beliefs about aetiology in effecting management procedures among culturally different peoples irrespective of their acceptance of biological models of disease transmission.OBA conceived, designed, coordinated the implementation of the protocol, analysed and developed the manuscript while KKJ led the data collection team.


Schistosoma mansoni and malaria infections are often endemic in the same communities in sub-Saharan Africa, and both have pathological effects on the liver and the spleen. Hepatosplenomegaly associated with S. mansoni is exacerbated in children with relatively high exposure to malaria. Treatment with praziquantel reduces the degree of hepatosplenomegaly, but the condition does not completely resolve in some cases. The present analysis focused on the possibility that exposure to malaria infection may have limited the resolution of hepatosplenomegaly in a cohort of Kenyan schoolchildren.S. mansoni infection, a river, was molluscicided regularly over the following three years to limit S. mansoni re-infection, whereas malaria exposure was uninterrupted. Hepatic and splenic enlargement was assessed annually outside the malaria transmission season.Ninety-six children aged 6–16, from one community in Makueni district, Kenya, were treated with praziquantel. At baseline, all children had hepatomegaly and most had splenomegaly. The source of S. mansoni exposure but high exposure to malaria, and maximal in an area with relatively low exposure to both infections.Children living in an area of relatively high exposure to both infections presented with the largest spleens before treatment and at each follow-up. Spleens of firm consistency were associated with proximity to the river. The regression of hepatomegaly was also affected by location, being minimal in an area with relatively low The outcome of treating cases of hepatosplenomegaly with praziquantel in this cohort of Kenyan children depended strongly on their level of exposure to malaria infection. Furthermore, a residual burden of hepatosplenic morbidity was observed, which was possibly attributable to the level of exposure to malaria. The results suggest that exposure to malaria infection may be a significant factor affecting the outcome of praziquantel treatment to reduce the level of hepatosplenic morbidity. Schistosoma mansoni and malaria infections are endemic. Severely enlarged and hard organs may be an indicator of increased portal pressure, as well as pointing to an increased risk of portal hypertension and its sequelae, including oesophageal varices and haematemesis [S. mansoni infection, and on a global scale up to 8.5 million individuals may be affected [S. mansoni and malaria infections are endemic [P. falciparum schizont antigen (Pfs Ag) were higher in Kenyan children with S. mansoni infection and hepatosplenomegaly compared with children with infection but no hepatosplenomegaly [Hepatosplenomegaly is a widespread but neglected condition affecting many communities in sub-Saharan Africa where both atemesis . Historiaffected , with thaffected . Enlargeaffected ,5. One paffected . However endemic ,8, and i endemic ,10. Recenomegaly , furtherS. mansoni infection and seasonal malaria infection [S. mansoni egg count and the degree of both hepatomegaly and splenomegaly [S. mansoni infections [Given that malaria and schistosome infections are often endemic in the same communities, and are both targets of large-scale but independent, intervention programmes, it is important to understand how continued exposure to one parasite may affect the outcome of intervention against the other. The current longitudinal study evaluated praziquantel treatment on the regression of hepatosplenomegaly amongst children living in an area with endemic nfection ,13. Befonomegaly . Howeverfections . The preMbeetwani is situated in the district of Makueni, half way between Nairobi and Mombasa and approximately 10 km east of the main highway. The ethnic background of the population is predominantly Akamba. During the dry seasons, the river Kambu is the main source of water. Running from west to east, the river lies to the north of the community . Area-wide application and focal spraying using backpacks was undertaken twice yearly to coincide with periods when snail populations were reduced due to environmental conditions. Snail sampling activities at 9 sites on a monthly basis were undertaken to confirm that snail numbers were kept at very low levels .Regular mollusciciding of the river Kambu was undertaken with Bayluscide ®, Shin Poon Pharmaceuticals, Seoul, Republic of Korea), at 40 mg/kg body weight. The children were again treated in 2001 and 2002 under the same regimen. No other source of treatment was available locally during this period. Tablets were administered together with a piece of bread and a soft drink in order to minimise gastrointestinal side effects. The study was approved by the Kenya Medical Research Institute Ethical Review Committee.The objectives of the study were carefully explained to the local community including the parents and teachers before the start of any activities. Informed assent was obtained from the parents or guardians of the children. After the clinical and ultrasound examination in October 1999, all children were treated with a single dose of praziquantel .Baseline data for each parameter were compared with 3 year follow up data amongst 71 children who attended the first and last surveys to estimate the number of children within each sector who presented with a lower degree of organomegaly at the end of the study. Repeated-measures ANOVA of each organ enlargement parameter was also undertaken for the 67 children who attended all surveys, with age, sex and sector of residence as fixed factors. Since ANOVA does not indicate the direction of any change, a S. mansoni egg counts and IgG3 responses within each sector are given elsewhere [S. mansoni only, and sector D was an area of low exposure to both infections.Figure lsewhere . BrieflySignificant variation in the prevalence of hard spleens over time was observed within each sector Table , attribuThe prevalence of firm livers in all sectors varied over time, except in sector B Table . In all post-hoc Wilcoxon Rank analysis . Figure MSL liver enlargement varied significantly over time , with the variation being affected by sector . There was no consistent decline in MSL hepatomegaly over time within any one sector Figure . AlthougThere was no evidence of periportal fibrosis in any of the children at any time point.S. mansoni and malaria varies over small areas [S. mansoni and malaria, but also for estimating the outcome of interventions.Many clinical surveys of sub-Saharan communities have reported that organomegaly of the spleen or liver is a very common condition, but attribution to a specific aetiology has always been problematic. Distinguishing the contribution of malaria from that of schistosome infections is particularly complex since they are often endemic in the same communities. However, it is well established that exposure to both ll areas -21, and S. mansoni and S. haematobium [S. mansoni egg counts at the western end of the study area. Such clustering is likely related to variation in the amount of surface water along the river, and hence variation in transmission potential due to the strong relationship between snail abundance and water level observed during long term studies of transmission in this area [The generation of these results was facilitated by several important features of the study design. The intermittent mollusciciding of the river Kambu was particularly important, since it reduced the potential for morbidity to rebound as a result of re-infection, as has been seen elsewhere in studies of both matobium . The timhis area . The cluhis area .Although we observed several significant changes following praziquantel treatment of the cohort, it is important to note that this was a retrospective analysis, which carries a few limitations. The observations made in this study were based on a small, case-only cohort, and therefore do not represent the outcome of an intervention programme involving mass treatment of a population. As this was a retrospective analysis, no control was possible concerning treatment for malaria during the follow-up period. The population had access to antimalarial drugs at local shops, but so far as we are aware there was no systematic intervention against malaria infection during the follow-up period. The results therefore encompass the effects of background treatment for, as well as exposure to, malaria infections.Reliability of the clinical measurements is an important factor, especially given the size of the cohort. We have assessed this procedure elsewhere and it has been found to be satisfactory (unpublished observations). The involvement of three or four clinicians at each examination also reduced the degree of imprecision in the organomegaly measurements, and previous analysis has demonstrated that interpretable changes in the measurements occurred within this cohort .S. mansoni re-infection, depended strongly on where members of the cohort were resident. Previously, we demonstrated that children within the same cohort that had relatively high-level exposure to both S. mansoni and malaria presented with significantly larger spleens before treatment than children highly exposed to either parasite alone [The major result from this analysis is that the outcome of treatment with praziquantel, combined with very limited te alone . This cote alone . Here, wS. mansoni infection [S. mansoni infection was the trigger for the improvement [Hardness of enlarged spleens at baseline was most commonly observed amongst children living close to the river, irrespective of their level of pre-treatment intensity of nfection . In the rovement . One posS. mansoni [S. mansoni infection and limiting re-infection, we may have abrogated any synergistic effects of co-infection on the spleen, and thereby uncovered the residual burden of chronic exposure to malaria. Importantly, the rate of regression of MAL splenomegaly was not affected significantly by location, which suggests that the effects of praziquantel treatment on splenomegaly attributable to S. mansoni infection are not dependent on the level of exposure to either malaria or S. mansoni.Three years after treatment with praziquantel, and with very limited re-infection by  mansoni , the preS. mansoni infection was a critical factor for improvement. However, upon analysing hepatomegaly data across sectors, it emerged that children from the sector with relatively high anti-Pfs IgG3 responses, but relatively low S. mansoni egg counts, had the lowest rate of regression. A possible explanation of this observation is that an aetiological agent other than S. mansoni was responsible for the observed hepatomegaly. A likely candidate is malaria infection. Enlargement of the liver in acute malaria infection is temporary and recedes rapidly after treatment [The effects of praziquantel treatment on hepatomegaly in this cohort were more subtle. There was gradual decline in the prevalence of hepatomegaly after praziquantel treatment  indicatireatment ; howeverreatment ,26. Our S. mansoni nor malaria infection. Alternatively, because they were relatively lightly infected with S. mansoni, and experienced relatively low exposure to malaria infection, it is possible that they were more likely to regress in terms of hepatomegaly within the follow-up period.Children from the sector with relatively low exposure to both infections experienced a significant decrease in liver enlargement along the mid sternal line when baseline data were compared with data from the third year follow-up. It is possible that hepatomegaly in these children was attributable to neither S. mansoni and malaria infections. Specifically, although the degree of hepatomegaly or splenomegaly may be correlated with S. mansoni infection, there is likely to be further exacerbation of the condition if a child is concurrently exposed to malaria. We have now observed that the apparent benefits of treating a case of hepatosplenomegaly with praziquantel may be reduced if a child lives in an area of relatively high exposure. We have therefore confirmed the long-standing, but untested, hypothesis that co-infections of S. mansoni and malaria may obscure the clinical evaluation associated with infection by either species. Our results also introduce the necessity of considering the level of exposure to malaria when evaluating the clinical outcome of praziquantel treatment for S. mansoni infection.In conclusion, our observations lend further support to the hypothesis that severity of hepatosplenomegaly in Kenyan school-aged children is related to their degree of exposure to both The author(s) declare that they have no competing interests.MB conceived of, and conducted, the analysis, and drafted the manuscript. BJV and AEB performed clinical examinations and participated in the design of the study. CA and AO conducted clinical examinations. CHK, GK, JM, JHO and EM participated in the planning and execution of field activities. DWD participated in the design of the study and in fieldwork.The pre-publication history for this paper can be accessed here: