Quantifying the burden of rhodesiense sleeping sickness in Urambo district, Tanzania

Sleeping sickness (human African trypanosomiasis - HAT) is a disease transmitted by tsetse flies and is always fatal if left untreated. The disease occurs in foci affecting poor communities with limited access to health service provision and as such the disease is often left undiagnosed, mistaken for more common afflictions. Even if diagnosed, sleeping sickness is costly to treat, both for health services and patients and their families in terms of costs of diagnosis, transport, hospital care, and the prolonged period of convalescence. Here we estimate the health burden of the acute form T. b. rhodesiense sleeping sickness in Urambo District, Tanzania in terms of Disability Adjusted Life Years (DALYs), the yardstick commonly used by policy makers to prioritize disease management practices, representing a year of healthy life lost to disease. In this single district, the burden of the disease over one year was estimated at 979 DALYs and the estimated monetary costs to health services for the 143 treated patients at US$11,841 and to the patients themselves at US$ 3,673 for direct medical costs and US$ 9,781 for indirect non-medical costs. Sleeping sickness thus places a considerable burden on the affected rural communities and health services

The absolute abundance calibration project: the <i>Lycopodium</i> marker-grain method put to the test

Traditionally, dinoflagellate cyst concentrations are calculated by adding an exotic marker or “spike” (such as Lycopodium clavatum) to each sample following the method of Stockmarr (1971). According to Maher (1981), the total error is controlled mainly by the error on the count of Lycopodium clavatum spores. In general, the more L. clavatum spores counted, the lower the error. A dinocyst / L. clavatum spore ratio of ~2 will give optimal results in terms of precision and time spent on a sample. It has also been proven that the use of the aliquot method yields comparable results to the marker-grain method (de Vernal et al., 1987). Critical evaluation of the effect of different laboratory procedures on the marker grain concentration in each sample has never been executed. Although, it has been reported that different processing methods (e.g. ultrasonication, oxidizing, etc.) are to a certain extent damaging to microfossils (e.g. Hodgkinson, 1991), it is not clear how this is translated into concentration calculations. It is wellknown from the literature that concentration calculations of dinoflagellate cysts from different laboratories are hard to resolve into a consistent picture. The aim of this study is to remove these inconsistencies and to make recommendations for the use of a standardized methodology. Sediment surface samples from four different localities (North Sea, Celtic Sea, NW Africa and Benguela) were macerated in different laboratories each using its own palynological maceration technique. A fixed amount of Lycopodium clavatum tablets was added to each sample. The uses of different preparation methodologies (sieving, ultrasonicating, oxidizing …) are compared using both concentrations – calculated from Lycopodium tablets - and relative abundances (more destructive methods will increase the amount of resistant taxa). Additionally, this study focuses on some important taxonomic issues, since obvious interlaboratorial differences in nomenclature are recorded

Evaluating the role of Atlantic Water advection to the Arctic Ocean on geological, historical, and observational timescales

Recent observations of enhanced oceanic heat transfer into the Arctic concomitant with the rapid sea-ice decrease temptingly suggest a direct relationship between both features. However, except for marginal areas of the Arctic Ocean where warm and saline Atlantic Water (AW) reaches the surface, the majority of AW heat is presently isolated from the sea-ice cover by a cold and fresh halocline layer. No evidence has been found to suggest a weakening of the halocline across the central Arctic basins that would enhance the AW heat transfer to the surface. A more direct link between sea-ice reduction and AW inflow is, however, seen in the inflowing Barents Sea branch in both historical and observational time series. In this presentation the AW advection into the Arctic Ocean and its influence on sea-ice variability will be reviewed from a geological point of view. Records from the geologic past are of great value as the time span of modern observations and historical data is often too short to comprehend long-term trends and causes of AW variability, changes in the marginal ice zone, and the vertical structure of the Arctic water column. Paleoceanographic studies from the recent interglacial indirectly suggest that the strength of AW advection and its propagation into the Arctic interior is effective in melting sea ice in combination with other factors such as insolation, sea level, freshwater input, and upper water mass stratification. However, to date, very little paleoceanographic work in the Arctic has focused on how the strength and position of the halocline has changed during previous interglacial periods. More direct reconstructions of the Arctic’s vertical stratification in the geologic past are needed to provide a longer-term view on the stability of the halocline, and more generally, the role of Atlantic Water inflow on the stability of sea ice in the interior basins

Novel therapeutic approach: organic arsenical (melarsoprol) alone or with all-trans -retinoic acid markedly inhibit growth of human breast and prostate cancer cells in vitro and in vivo

The organic arsenical known as melarsoprol (Mel-B) is used to treat African trypanosomiasis. Recently, another arsenical, As2O3was shown to be effective in treatment of acute promyelocytic leukaemia. We have investigated the anti-tumour activities of Mel-B either with or without all-trans -retinoic acid (ATRA) using the MCF-7 human breast cancer cells, as well as the PC-3 and DU 145 human prostate cancer cells both in vitro and in vivo. The antiproliferative effects of Mel-B and/or ATRA against breast and prostate cancer were tested in vitro using clonogenic assays and in vivo in triple immunodeficient mice. Furthermore, the mechanism of action of these compounds was studied by examining the cell cycle, levels of bcl-2, apoptosis and antiproliferative potency using a pulse-exposure assay. Clonogenic assays showed that the cancer cell lines were sensitive to the inhibitory effect of Mel-B (effective dose that inhibited 50% clonal growth [ED50]: 7 × 10−9M for MCF-7, 2 × 10−7M for PC-3, 3 × 10−7M for DU145 cells. Remarkably, the combination of Mel-B and ATRA had an enhanced antiproliferative activity against all three cancer cell lines. Furthermore, the combination of Mel-B and ATRA induced a high level of apoptosis in all three cell lines. Treatment of PC-3 and MCF-7 tumours growing in triple immunodeficient mice with Mel-B and ATRA either alone or in combination markedly retarded tumour size and weight of the tumours without major side-effects. In conclusion, our results suggest that either Mel-B alone or with ATRA may be a useful, novel therapy for breast and prostate cancers. © 2000 Cancer Research Campaig

Analysis of risk factors for T. brucei rhodesiense sleeping sickness within villages in south-east Uganda

<p>Abstract</p> <p>Background</p> <p>Sleeping sickness (HAT) caused by <it>T.b. rhodesiense </it>is a major veterinary and human public health problem in Uganda. Previous studies have investigated spatial risk factors for <it>T.b. rhodesiense </it>at large geographic scales, but none have properly investigated such risk factors at small scales, i.e. within affected villages. In the present work, we use a case-control methodology to analyse both behavioural and spatial risk factors for HAT in an endemic area.</p> <p>Methods</p> <p>The present study investigates behavioural and occupational risk factors for infection with HAT within villages using a questionnaire-based case-control study conducted in 17 villages endemic for HAT in SE Uganda, and spatial risk factors in 4 high risk villages. For the spatial analysis, the location of homesteads with one or more cases of HAT up to three years prior to the beginning of the study was compared to all non-case homesteads. Analysing spatial associations with respect to irregularly shaped geographical objects required the development of a new approach to geographical analysis in combination with a logistic regression model.</p> <p>Results</p> <p>The study was able to identify, among other behavioural risk factors, having a family member with a history of HAT (p = 0.001) as well as proximity of a homestead to a nearby wetland area (p < 0.001) as strong risk factors for infection. The novel method of analysing complex spatial interactions used in the study can be applied to a range of other diseases.</p> <p>Conclusion</p> <p>Spatial risk factors for HAT are maintained across geographical scales; this consistency is useful in the design of decision support tools for intervention and prevention of the disease. Familial aggregation of cases was confirmed for <it>T. b. rhodesiense </it>HAT in the study and probably results from shared behavioural and spatial risk factors amongmembers of a household.</p

Identification of Peptide Mimotopes of Trypanosoma brucei gambiense Variant Surface Glycoproteins

The control of human African trypanosomiasis or sleeping sickness, a deadly disease in sub-Saharan Africa, mainly depends on a correct diagnosis and treatment. The aim of our study was to identify mimotopic peptides (mimotopes) that may replace the native proteins in antibody detection tests for sleeping sickness and hereby improve the diagnostic sensitivity and specificity. We selected peptide expressing phages from the PhD.-12 and PhD.-C7C phage display libraries with mouse monoclonal antibodies specific to variant surface glycoprotein (VSG) LiTat 1.3 or LiTat 1.5 of Trypanosoma brucei gambiense. The peptide coding genes of the selected phages were sequenced and the corresponding peptides were synthesised. Several of the synthetic peptides were confirmed as mimotopes for VSG LiTat 1.3 or LiTat 1.5 since they were able to inhibit the binding of their homologous monoclonal to the corresponding VSG. These peptides were biotinylated and their diagnostic potential was assessed with human sera. We successfully demonstrated that human sleeping sickness sera recognise some of the mimotopes of VSG LiTat 1.3 and LiTat 1.5, indicating the diagnostic potential of such peptides

A "critical" climatic evaluation of last interglacial (MIS 5e) records from the Norwegian Sea

Sediment cores from the Norwegian Sea were studied to evaluate interglacial climate conditions of the marine isotope stage 5e (MIS 5e). Using planktic forminiferal assemblages as the core method, a detailed picture of the evolution of surface water conditions was derived. According to our age model, a step-like deglaciation of the Saalian ice sheets is noted between ca. 135 and 124.5 Kya, but the deglaciation shows little response with regard to surface ocean warming. From then on, the rapidly increasing abundance of subpolar forminifers, concomitant with decreasing iceberg indicators, provides evidence for the development of interglacial conditions sensu stricto (5e-ss), a period that lasted for about 9 Ky. As interpreted from the foraminiferal records, and supported by the other proxies, this interval of 5e-ss was in two parts: showing an early warm phase, but with a fresher, i.e., lower salinity, water mass, and a subsequent cooling phase that lasted until ca. 118.5 Kya. After this time, the climatic optimum with the most intense advection of Atlantic surface water masses occurred until ca. 116 Kya. A rapid transition with two notable climatic perturbations is observed subsequently during the glacial inception. Overall, the peak warmth of the last interglacial period occurred relatively late after deglaciation, and at no time did it reach the high warmth level of the early Holocene. This finding must be considered when using the last interglacial situation as an analogue model for enhanced meridional transfer of ocean heat to the Arctic, with the prospect of a future warmer climate

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal alpha-toxin

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor kappa B signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor alpha-toxin. Naturally elicited antibodies against alpha-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to alpha-toxin in nonleukocytic cells.Peer reviewe