Hookworm Infection and Environmental Factors in Mbeya Region, Tanzania: A Cross-sectional, Population-based study.

Hookworm disease is one of the most common infections and cause of a high disease burden in the tropics and subtropics. Remotely sensed ecological data and model-based geostatistics have been used recently to identify areas in need for hookworm control. Cross-sectional interview data and stool samples from 6,375 participants from nine different sites in Mbeya region, south-western Tanzania, were collected as part of a cohort study. Hookworm infection was assessed by microscopy of duplicate Kato-Katz thick smears from one stool sample from each participant. A geographic information system was used to obtain remotely sensed environmental data such as land surface temperature (LST), vegetation cover, rainfall, and elevation, and combine them with hookworm infection data and with socio-demographic and behavioral data. Uni- and multivariable logistic regression was performed on sites separately and on the pooled dataset. Univariable analyses yielded significant associations for all ecological variables. Five ecological variables stayed significant in the final multivariable model: population density (odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.63-0.73), mean annual vegetation density (OR = 0.11; 95% CI = 0.06-0.18), mean annual LST during the day (OR = 0.81; 95% CI = 0.75-0.88), mean annual LST during the night (OR = 1.54; 95% CI = 1.44-1.64), and latrine coverage in household surroundings (OR = 1.02; 95% CI = 1.01-1.04). Interaction terms revealed substantial differences in associations of hookworm infection with population density, mean annual enhanced vegetation index, and latrine coverage between the two sites with the highest prevalence of infection. This study supports previous findings that remotely sensed data such as vegetation indices, LST, and elevation are strongly associated with hookworm prevalence. However, the results indicate that the influence of environmental conditions can differ substantially within a relatively small geographic area. The use of large-scale associations as a predictive tool on smaller scales is therefore problematic and should be handled with care

Low specificity of determine HIV1/2 RDT using whole blood in south west Tanzania

Objective: To evaluate the diagnostic performance of two rapid detection tests (RDTs) for HIV 1/2 in plasma and in whole blood samples. Methods: More than 15,000 study subjects above the age of two years participated in two rounds of a cohort study to determine the prevalence of HIV. HIV testing was performed using the Determine HIV 1/2 test (Abbott) in the first (2006/2007) and the HIV 1/2 STAT-PAK Dipstick Assay (Chembio) in the second round (2007/2008) of the survey. Positive results were classified into faint and strong bands depending on the visual appearance of the test strip and confirmed by ELISA and Western blot. Results: The sensitivity and specificity of the Determine RDT were 100% (95% confidence interval = 86.8 to 100%) and 96.8% (95.9 to 97.6%) in whole blood and 100% (99.7 to 100%) and 97.9% (97.6 to 98.1%) in plasma respectively. Specificity was highly dependent on the tested sample type: when using whole blood, 67.1% of positive results were false positive, as opposed to 17.4% in plasma. Test strips with only faint positive bands were more often false positive than strips showing strong bands and were more common in whole blood than in plasma. Evaluation of the STAT-PAK RDT in plasma during the second year resulted in a sensitivity of 99.7% (99.1 to 99.9%) and a specificity of 99.3% (99.1 to 99.4%) with 6.9% of the positive results being false. Conclusions: Our study shows that the Determine HIV 1/2 strip test with its high sensitivity is an excellent tool to screen for HIV infection, but that – at least in our setting – it can not be recommended as a confirmatory test in VCT campaigns where whole blood is used

Louisville Seamount Trail: implications for geodynamic mantle flow models and the geochemical evolution of primary hotspots

The Louisville Seamount Trail is a 4300 km long volcanic chain that has been built in the past 80 m.y. as the Pacific plate moved over a persistent mantle melting anomaly or hotspot. Because of its linear morphology and its long-lived age-progressive volcanism, Louisville is the South Pacific counterpart of the much better studied Hawaiian-Emperor Seamount Trail. Together, Louisville and Hawaii are textbook examples of two primary hotspots that have been keystones in deciphering the motion of the Pacific plate relative to a set of "fixed" deep-mantle plumes. However, drilling during Ocean Drilling Program (ODP) Leg 197 in the Emperor Seamounts documented a large ~15° southward motion of the Hawaiian hotspot prior to 50 Ma. Is it possible that the Hawaiian and Louisville hotspots moved in concert and thus constitute a moving reference frame for modeling plate motion in the Pacific? Alternatively, could they have moved independently, as predicted by mantle flow models that reproduce the observed latitudinal motion for Hawaii but that predict a largely longitudinal shift for the Louisville hotspot? These two end-member geodynamic models were tested during Integrated Ocean Drilling Program (IODP) Expedition 330 to the Louisville Seamount Trail. In addition, existing data from dredged lavas suggest that the mantle plume source of the Louisville hotspot has been remarkably homogeneous for as long as 80 m.y. These lavas are predominantly alkali basalts and likely represent a mostly alkalic shield-building stage, which is in sharp contrast to the massive tholeiitic shield-building stage of Hawaiian volcanoes. Geochemical and isotopic data for the recovered lavas during Expedition 330 will provide insights into the magmatic evolution and melting processes of individual Louisville volcanoes, their progression from shield-building to postshield and (maybe) posterosional stages, the temperature and depth of partial melting of their mantle plume source, and the enigmatic long-lived and apparent geochemical homogeneity of the Louisville mantle source. Collectively, this will enable us to characterize the Louisville Seamount Trail as a product of one of the few global primary hotspots, to better constrain its plume-lithosphere interactions, and to further test the hypothesis that the Ontong Java Plateau formed from the plume head of the Louisville mantle plume around 120 Ma. During Expedition 330 we replicated the drilling strategy of Leg 197, the first expedition to provide compelling evidence for the motion of the Hawaiian mantle plume between 80 and 50 Ma. For that reason we targeted Louisville seamounts that have ages similar to Detroit, Suiko, Nintoku, and Koko Seamounts in the Emperor Seamount Trail. In total, five seamounts were drilled in the Louisville Seamount Trail: Canopus, Rigil, Burton, Achernar, and Hadar Guyots (old to young). By analyzing a large number of time-independent in situ lava flows (and other volcanic eruptive products) from these seamounts using modern paleomagnetic, 40Ar/39Ar geochronological, and geochemical techniques, we will be able to directly compare the paleolatitude estimates and geochemical signatures between the two longest-lived hotspot systems in the Pacific Ocean. We drilled into the summits of the five Louisville guyots and reached volcanic basement at four of these drilling targets. In two cases we targeted larger seamount structures and drilled near the flanks of these ancient volcanoes, and in the other three cases we selected smaller edifices that we drilled closer to their centers. Drilling and logging plans for each of these sites were similar, with coring reaching 522.0 meters below seafloor (mbsf) for Site U1374 and 232.9, 65.7, 11.5, 182.8, and 53.3 mbsf for Sites U1372, U1373, U1375, U1376, and U1377, respectively. Some Expedition 330 drill sites were capped with only a thin layer of pelagic ooze between 6.6 and 13.5 m thick, and, if present, these were cored by using a low-rotation gravity-push technique with the rotary core barrel to maximize recovery. However, at Sites U1373 and U1376 no pelagic ooze was present, and the holes needed to be started directly into cobble-rich hardgrounds. In all cases, the bulk of the seamount sediment cover comprised sequences of volcanic sandstones and various kinds of basalt breccia or basalt conglomerate, which often were interspersed with basaltic lava flows, the spatter/tephra products of submarine eruptions, or other volcanic products, including auto-brecciated flows or peperites. Also several intervals of carbonate were cored, with the special occurrence of a ~15 m thick algal limestone reef at Site U1376 on Burton Guyot. In addition, some condensed pelagic limestone units were recovered on three of the other seamounts, but these did not exceed 30 cm in thickness. Despite their limited presence in the drilled sediment, these limestones provide valuable insights for the paleoclimate record at high ~50° southern latitudes since Mesozoic times. Several Louisville sites progressed from subaerial conditions in the top of volcanic basement into submarine eruptive environments, or drilling of the igneous basement immediately started in submarine volcanic sequences, as was the case for Sites U1376 and U1377 on Burton and Hadar Guyots. At three sites we cored >100 m into the igneous basement: 187.3 m at Site U1372, 505.3 m at Site U1374, and 140.9 m at Site U1376. At the other sites we did not core into basement (Site U1375) or we cored only 38.2 m (Site U1377) because of unstable hole conditions. Even so, drilling during Expedition 330 resulted in a large number of in situ lava flows, pillow basalts, or other types of volcanic products such as auto-brecciated lava flows, intrusive sheets or dikes, and peperites. In particular, the three holes on Canopus and Rigil Guyots (the two oldest seamounts drilled in the Louisville Seamount Trail), resulted in adequate numbers of in situ lava flows to average out paleosecular variation, with probable eruption ages estimated at ~78 and 73 Ma, respectively. Remarkably, at all drill sites large quantities of hyaloclastites, volcanic sandstones, and basaltic breccias were also recovered, which in many cases show consistent paleomagnetic inclinations compared to the lava flows bracketing these units. For Site U1374 on Rigil Guyot we also observed a magnetic polarity reversal in the cored sequence. Overall, this is very promising for determining a reliable paleolatitude record for the Louisville Seamounts following detailed postcruise examinations. The deeper penetrations of several hundred meters required bit changes and reentries using free-fall funnels. Basement penetration rates were 1.8–2.5 m/h depending on drill depth. In total, 1114 m of sediment and igneous basement at five seamounts was drilled, and 806 m was recovered (average recovery = 72.4%). At Site U1374 on Rigil Guyot, a total of 522 m was drilled, with a record-breaking 87.8% recovery. Most outstandingly, nearly all Expedition 330 core material is characterized by low degrees of alteration, providing us with a large quantity of samples of mostly well-preserved basalt, containing, for example, pristine olivine crystals with melt inclusions, fresh volcanic glass, unaltered plagioclase, carbonate, zeolite and celadonite alteration minerals, various micro- and macrofossils, and, in one case, mantle xenoliths and xenocrysts. The large quantity and excellent quality of the recovered sample material allow us to address all the scientific objectives of this expedition and beyond

Helminth-Associated Systemic Immune Activation and HIV Co-receptor Expression: Response to Albendazole/Praziquantel Treatment

Background: It has been hypothesized that helminth infections increase HIV susceptibility by enhancing systemic immune activation and hence contribute to elevated HIV-1 transmission in sub-Saharan Africa. Objective: To study systemic immune activation and HIV-1 co-receptor expression in relation to different helminth infections and in response to helminth treatment. Methods: HIV-negative adults with (n = 189) or without (n = 57) different helminth infections, as diagnosed by Kato-Katz, were enrolled in Mbeya, Tanzania. Blinded to helminth infection status, T cell differentiation (CD45RO, CD27),activation (HLA-DR, CD38) and CCR5 expression was determined at baseline and 3 months after Albendazole/Praziquantel treatment. Plasma cytokine levels were compared using a cytometric bead array. Results: Trichuris and Ascaris infections were linked to increased frequencies of "activated'' CD4 and/or CD8 T cells (p< 0.05),whereas Hookworm infection was associated with a trend towards decreased HLA-DR+ CD8 T cell frequencies (p = 0.222). In Trichuris infected subjects, there was a linear correlation between HLA-DR+ CD4 T cell frequencies and the cytokines IL-1 beta and IL-10 (p<0.05). Helminth treatment with Albendazole and Praziquantel significantly decreased eosinophilia for S. mansoni and Hookworm infections (p<0.005) but not for Trichuris infection and only moderately modulated T cell activation. CCR5 surface density on memory CD4 T cells was increased by 1.2-fold during Trichuris infection (p-value: 0.053) and reduced after treatment (p = 0.003). Conclusions: Increased expression of T cell activation markers was associated with Trichuris and Ascaris infections with relatively little effect of helminth treatment

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

The intestinal mucosa displays robust virus replication and pronounced CD4+ T-cell loss during acute human immunodeficiency virus type 1 (HIV-1) infection. The ability of HIV-specific CD8+ T-cells to modulate disease course has prompted intensive study, yet the significance of virus-specific CD8+ T-cells in mucosal sites remains unclear.We evaluated five distinct effector functions of HIVgag-specific CD8+ T-cells in rectal mucosa and blood, individually and in combination, in relationship to clinical status and antiretroviral therapy (ART). In subjects not on ART, the percentage of rectal Gag-specific CD8+ T-cells capable of 3, 4 or 5 simultaneous effector functions was significantly related to blood CD4 count and inversely related to plasma viral load (PVL) (p<0.05). Polyfunctional rectal CD8+ T-cells expressed higher levels of MIP-1beta and CD107a on a per cell basis than mono- or bifunctional cells. The production of TNFalpha, IFN-gamma, and CD107a by Gag-specific rectal CD8+ T-cells each correlated inversely (p<0.05) with PVL, and MIP-1beta expression revealed a similar trend. CD107a and IFN-gamma production were positively related to blood CD4 count (p<0.05), with MIP-1beta showing a similar trend. IL-2 production by rectal CD8+ T-cells was highly variable and generally low, and showed no relationship to viral load or blood CD4 count.The polyfunctionality of rectal Gag-specific CD8+ T-cells appears to be related to blood CD4 count and inversely related to PVL. The extent to which these associations reflect causality remains to be determined; nevertheless, our data suggest a potentially important role for mucosal T-cells in limiting virus replication during chronic infection

Collaborative research between academia and industry using a large clinical trial database: a case study in Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Large clinical trials databases, developed over the course of a comprehensive clinical trial programme, represent an invaluable resource for clinical researchers. Data mining projects sponsored by industry that use these databases, however, are often not viewed favourably in the academic medical community because of concerns that commercial, rather than scientific, goals are the primary purpose of such endeavours. Thus, there are few examples of sustained collaboration between leading academic clinical researchers and industry professionals in a large-scale data mining project. We present here a successful example of this type of collaboration in the field of dementia.</p> <p>Methods</p> <p>The Donepezil Data Repository comprised 18 randomised, controlled trials conducted between 1991 and 2005. The project team at Pfizer determined that the data mining process should be guided by a diverse group of leading Alzheimer's disease clinical researchers called the "Expert Working Group." After development of a list of potential faculty members, invitations were extended and a group of seven members was assembled. The Working Group met regularly with Eisai/Pfizer clinicians and statisticians to discuss the data, identify issues that were currently of interest in the academic and clinical communities that might lend themselves to investigation using these data, and note gaps in understanding or knowledge of Alzheimer's disease that these data could address. Leadership was provided by the Pfizer Clinical Development team leader; Working Group members rotated responsibility for being lead and co-lead for each investigation and resultant publication.</p> <p>Results</p> <p>Six manuscripts, each published in a leading subspecialty journal, resulted from the group's work. Another project resulted in poster presentations at international congresses and two were cancelled due to resource constraints.</p> <p>Conclusions</p> <p>The experience represents a particular approach to optimising the value of data mining of large clinical trial databases for the combined purpose of furthering clinical research and improving patient care. Fruitful collaboration between industry and academia was fostered while the donepezil data repository was used to advance clinical and scientific knowledge. The Expert Working Group approach warrants consideration as a blueprint for conducting similar research ventures in the future.</p

Organoiridium complexes : anticancer agents and catalysts

Iridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar Ir(I) complexes, such as Crabtree's hydrogenation catalyst, an organometallic complex with cyclooctadiene, phosphane, and pyridine ligands. More recently, chemists have developed half-sandwich pseudo-octahedral pentamethylcyclopentadienyl Ir(III) complexes containing diamine ligands that efficiently catalyze transfer hydrogenation reactions of ketones and aldehydes in water using H2 or formate as the hydrogen source. Although sometimes assumed to be chemically inert, the reactivity of low-spin 5d(6) Ir(III) centers is highly dependent on the set of ligands. Cp* complexes with strong σ-donor C^C-chelating ligands can even stabilize Ir(IV) and catalyze the oxidation of water. In comparison with well developed Ir catalysts, Ir-based pharmaceuticals are still in their infancy. In this Account, we review recent developments in organoiridium complexes as both catalysts and anticancer agents. Initial studies of anticancer activity with organoiridium complexes focused on square-planar Ir(I) complexes because of their structural and electronic similarity to Pt(II) anticancer complexes such as cisplatin. Recently, researchers have studied half-sandwich Ir(III) anticancer complexes. These complexes with the formula [(Cp(x))Ir(L^L')Z](0/n+) (with Cp* or extended Cp* and L^L' = chelated C^N or N^N ligands) have a much greater potency (nanomolar) toward a range of cancer cells (especially leukemia, colon cancer, breast cancer, prostate cancer, and melanoma) than cisplatin. Their mechanism of action may involve both an attack on DNA and a perturbation of the redox status of cells. Some of these complexes can form Ir(III)-hydride complexes using coenzyme NAD(P)H as a source of hydride to catalyze the generation of H2 or the reduction of quinones to semiquinones. Intriguingly, relatively unreactive organoiridium complexes containing an imine as a monodentate ligand have prooxidant activity, which appears to involve catalytic hydride transfer to oxygen and the generation of hydrogen peroxide in cells. In addition, researchers have designed inert Ir(III) complexes as potent kinase inhibitors. Octahedral cyclometalated Ir(III) complexes not only serve as cell imaging agents, but can also inhibit tumor necrosis factor α, promote DNA oxidation, generate singlet oxygen when photoactivated, and exhibit good anticancer activity. Although relatively unexplored, organoiridium chemistry offers unique features that researchers can exploit to generate novel diagnostic agents and drugs with new mechanisms of action

Ewing Sarcoma Protein Ewsr1 Maintains Mitotic Integrity and Proneural Cell Survival in the Zebrafish Embryo

BACKGROUND:The Ewing sarcoma breakpoint region 1 gene (EWSR1), also known as EWS, is fused to a number of different partner genes as a result of chromosomal translocation in diverse sarcomas. Despite the involvement of EWSR1 in these diverse sarcomas, the in vivo function of wild type EWSR1 remains unclear. PRINCIPAL FINDINGS:We identified two zebrafish EWSR1 orthologues, ewsr1a and ewsr1b, and demonstrate that both genes are expressed maternally, and are expressed ubiquitously throughout zebrafish embryonic development. Morpholino induced knockdown of both zebrafish ewsr1 genes led to mitotic defects with multipolar or otherwise abnormal mitotic spindles starting from the bud stage (10 hour post-fertilization (hpf)). The abnormalities in mitotic spindles were followed by p53-mediated apoptosis in the developing central nervous system (CNS) leading to a reduction in the number of proneural cells, disorganization of neuronal networks, and embryonic lethality by 5 days post-fertilization. siRNA silencing of EWSR1 in Hela cells resulted in mitotic defects accompanied by apoptotic cell death, indicating that the role of EWSR1 is conserved between zebrafish and human. CONCLUSIONS:Ewsr1 maintains mitotic integrity and proneural cell survival in early zebrafish development

Histological and immunohistochemical features suggesting aetiological differences in lymph node and (muco)cutaneous feline tuberculosis lesions

Objectives To identify and describe histological and immunohistochemical criteria that may differentiate between skin and lymph node lesions associated with Mycobacterium (M.) bovis and M. microti in a diagnostic pathology setting.Materials and Methods&lt;jats:p/&gt;Archived skin and lymph node biopsies of tuberculous lesions were stained with haematoxylin and eosin, Ziehl‐Neelsen and Masson's Trichrome. Immunohistochemistry was performed to detect the expression of calprotectin, CD3 and Pax5. Samples were scored for histological parameters (i.e. granulomas with central necrosis versus small granulomas without central necrosis, percentage necrosis and/or multinucleated giant cells), number of acid‐fast bacilli (bacterial index) and lesion percentage of fibrosis and positive immunohistochemical staining.Results Twenty‐two samples were examined (M. bovis n=11, M. microti n=11). When controlling for age, gender and tissue, feline M. bovis‐associated lesions more often featured large multi‐layered granulomas with central necrosis. Conversely, this presentation was infrequent in feline M. microti‐associated lesions, where small granulomas without central necrosis predominated. The presence of an outer fibrous capsule was variable in both groups, as was the bacterial index. There were no differences in intralesional expression of immunohistochemical markers.Clinical Significance Differences in the histological appearance of skin and lymph node lesions may help to infer feline infection with either M. bovis or M. microti at an earlier stage when investigating these cases, informing clinicians of the potential zoonotic risk. Importantly, cases of tuberculosis can present with numerous acid‐fast bacilli. This implies that a high bacterial index does not infer infection with non‐zoonotic non‐tuberculous mycobacteria