Nifurtimox plus Eflornithine for Late-Stage Sleeping Sickness in Uganda: A Case Series

African sleeping sickness (Human African Trypanosomiasis, or HAT), due to the parasite Trypanosoma brucei gambiense, threatens millions across remote and conflict-affected regions of sub-Saharan Africa, and causes about 15 000 reported cases every year. Untreated HAT progresses from stage 1 (infection of the blood and lymph) to stage 2 (invasion of the central nervous system), and ultimately death. Drugs for stage 2 are few. The historical mainstay, melarsoprol, is highly toxic and inefficacious in some areas due to parasite resistance. Eflornithine is the only viable alternative, already established as safe and efficacious, but difficult to administer and at risk of resistance if used in monotherapy. This paper reports on a series of 48 Ugandan patients treated with a novel combination of nifurtimox (a drug registered for Chagas disease) and eflornithine, 17 as part of a terminated trial, and 31 in a subsequent case series study. Despite the low sample size, findings are promising: no cases of treatment failure, no treatment terminations, and no HAT- or treatment-related deaths. Nifurtimox plus eflornithine may be the best treatment hope for stage 2 HAT patients in the next decade, while new drugs are developed. A larger, multi-centric trial of the combination is ongoing

The incidence of arthropathy adverse events in efalizumab-treated patients is low and similar to placebo and does not increase with long-term treatment: pooled analysis of data from Phase III clinical trials of efalizumab

A large-scale, pooled analysis of safety data from five Phase III clinical trials (including open-label extensions of two of these studies) and two Phase III open-label clinical trials of efalizumab was conducted to explore whether arthropathy adverse events (AEs) were associated with efalizumab treatment in patients with moderate-to-severe chronic plaque psoriasis. Data from patients who received subcutaneous injections of efalizumab or placebo were stratified for analysis into phases according to the nature and duration of treatment. These included: the ‘first treatment’ phase (0–12-week data from patients who received either efalizumab, 1 mg/kg once weekly, or placebo in the five placebo-controlled studies); the ‘extended treatment’ phase (13–24-week data from seven trials for all efalizumab-treated patients); and the ‘long-term treatment’ phase (data from efalizumab-treated patients who received treatment for up to 36 months in two long-term trials). Descriptive statistics were performed and the incidence of arthropathy AEs per patient-year was calculated using 95% confidence intervals (CIs). During the first treatment phase, a similar proportion of patients had an arthropathy AE in the efalizumab group (3.3%; 58/1740 patients) compared with the placebo group (3.5%; 34/979 patients); the incidence of arthropathy AEs per patient-year was 0.15 in the efalizumab group (95% CI 0.11–0.19) and 0.16 in the placebo group (95% CI 0.11–0.22). Analysis of first treatment phase data from one study (n = 793) showed that the incidence of psoriatic arthropathy per patient-year was lower in efalizumab-treated patients (0.10; 95% CI 0.05–0.18) than in those given placebo (0.17; 95% CI 0.08–0.30). During the extended treatment phase, the incidence of arthropathy remained low (0.17; 95% CI 0.14–0.22). Data from two long-term studies showed that there was no increase in the incidence of arthropathy AEs over time in patients treated with efalizumab for up to 36 months. Patients who had an arthropathy AE during treatment with efalizumab appeared to be more likely to have a history of arthropathy prior to treatment. Efalizumab does not appear to increase the risk of arthropathy AEs compared with placebo

Dendritic cells are defective in breast cancer patients: a potential role for polyamine in this immunodeficiency

INTRODUCTION: Dendritic cells (DCs) are antigen-presenting cells that are currently employed in cancer clinical trials. However, it is not clear whether their ability to induce tumour-specific immune responses when they are isolated from cancer patients is reduced relative to their ability in vivo. We determined the phenotype and functional activity of DCs from cancer patients and investigated the effect of putrescine, a polyamine molecule that is released in large amounts by cancer cells and has been implicated in metastatic invasion, on DCs. METHODS: The IL-4/GM-CSF (granulocyte–macrophage colony-stimulating factor) procedure for culturing blood monocyte-derived DCs was applied to cells from healthy donors and patients (17 with breast, 7 with colorectal and 10 with renal cell carcinoma). The same peroxide-treated tumour cells (M74 cell line) were used for DC pulsing. We investigated the effects of stimulation of autologous lymphocytes by DCs pulsed with treated tumour cells (DC-Tu), and cytolytic activity of T cells was determined in the same target cells. RESULTS: Certain differences were observed between donors and breast cancer patients. The yield of DCs was dramatically weaker, and expression of MHC class II was lower and the percentage of HLA-DR(-)Lin(- )cells higher in patients. Whatever combination of maturating agents was used, expression of markers of mature DCs was significantly lower in patients. Also, DCs from patients exhibited reduced ability to stimulate cytotoxic T lymphocytes. After DC-Tu stimulation, specific cytolytic activity was enhanced by up to 40% when DCs were from donors but only up to 10% when they were from patients. IFN-γ production was repeatedly found to be enhanced in donors but not in patients. By adding putrescine to DCs from donors, it was possible to enhance the HLA-DR(-)Lin(- )cell percentage and to reduce the final cytolytic activity of lymphocytes after DC-Tu stimulation, mimicking defective DC function. These putrescine-induced deficiencies were reversed by treating DCs with all-trans retinoic acid. CONCLUSION: These data are consistent with blockade of antigen-presenting cells at an early stage of differentiation in patients with breast cancer. Putrescine released in the microenvironmement of DCs could be involved in this blockade. Use of all-trans retinoic acid treatment to reverse this blockade and favour ex vivo expansion of antigen-specific T lymphocytes is of real interest

Communication Impairments in Mice Lacking Shank1: Reduced Levels of Ultrasonic Vocalizations and Scent Marking Behavior

Autism is a neurodevelopmental disorder with a strong genetic component. Core symptoms are abnormal reciprocal social interactions, qualitative impairments in communication, and repetitive and stereotyped patterns of behavior with restricted interests. Candidate genes for autism include the SHANK gene family, as mutations in SHANK2 and SHANK3 have been detected in several autistic individuals. SHANK genes code for a family of scaffolding proteins located in the postsynaptic density of excitatory synapses. To test the hypothesis that a mutation in SHANK1 contributes to the symptoms of autism, we evaluated Shank1−/− null mutant mice for behavioral phenotypes with relevance to autism, focusing on social communication. Ultrasonic vocalizations and the deposition of scent marks appear to be two major modes of mouse communication. Our findings revealed evidence for low levels of ultrasonic vocalizations and scent marks in Shank1−/− mice as compared to wildtype Shank1+/+ littermate controls. Shank1−/− pups emitted fewer vocalizations than Shank1+/+ pups when isolated from mother and littermates. In adulthood, genotype affected scent marking behavior in the presence of female urinary pheromones. Adult Shank1−/− males deposited fewer scent marks in proximity to female urine than Shank1+/+ males. Call emission in response to female urinary pheromones also differed between genotypes. Shank1+/+ mice changed their calling pattern dependent on previous female interactions, while Shank1−/− mice were unaffected, indicating a failure of Shank1−/− males to learn from a social experience. The reduced levels of ultrasonic vocalizations and scent marking behavior in Shank1−/− mice are consistent with a phenotype relevant to social communication deficits in autism.National Institute of Mental Health (U.S.) (Intramural Research Program)Simons Foundatio

Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: A cohort study

<p>Abstract</p> <p>Background</p> <p>The mortality in patients with persistent low CD4 count despite several years of HAART with sustained viral suppression is poorly documented. We aimed to identify predictors for inadequate CD4 cell recovery and estimate mortality in patients with low CD4 count but otherwise successful HAART.</p> <p>Method</p> <p>In a nationwide cohort of HIV patients we identified all individuals who started HAART before 1 January 2005 with CD4 cell count ≤ 200 cells/μL and experienced three years with sustained viral suppression. Patients were categorized according to CD4 cell count after the three years suppressed period (≤ 200 cells/μL; immunological non-responders (INRs), >200 cells/μL; immunological responders (IRs)). We used logistic regression and Kaplan-Meier analysis to estimated risk factors and mortality for INRs compared to IRs.</p> <p>Results</p> <p>We identified 55 INRs and 236 IRs. In adjusted analysis age > 40 years and > one year from first CD4 cell count ≤ 200 cells/μL to start of the virologically suppressed period were associated with increased risk of INR. INRs had substantially higher mortality compared to IRs. The excess mortality was mainly seen in the INR group with > one year of immunological suppression prior to viral suppression and injection drug users (IDUs).</p> <p>Conclusion</p> <p>Age and prolonged periods of immune deficiency prior to successful HAART are risk factors for incomplete CD4 cell recovery. INRs have substantially increased long-term mortality mainly associated with prolonged immunological suppression prior to viral suppression and IDU.</p

Marine Biodiversity in South Africa: An Evaluation of Current States of Knowledge

Continental South Africa has a coastline of some 3,650 km and an Exclusive Economic Zone (EEZ) of just over 1 million km2. Waters in the EEZ extend to a depth of 5,700 m, with more than 65% deeper than 2,000 m. Despite its status as a developing nation, South Africa has a relatively strong history of marine taxonomic research and maintains comprehensive and well-curated museum collections totaling over 291,000 records. Over 3 million locality records from more than 23,000 species have been lodged in the regional AfrOBIS (African Ocean Biogeographic Information System) data center (which stores data from a wider African region). A large number of regional guides to the marine fauna and flora are also available and are listed

A new mutant genetic resource for tomato crop improvement by TILLING technology

<p>Abstract</p> <p>Background</p> <p>In the last decade, the availability of gene sequences of many plant species, including tomato, has encouraged the development of strategies that do not rely on genetic transformation techniques (GMOs) for imparting desired traits in crops. One of these new emerging technology is TILLING (Targeting Induced Local Lesions In Genomes), a reverse genetics tool, which is proving to be very valuable in creating new traits in different crop species.</p> <p>Results</p> <p>To apply TILLING to tomato, a new mutant collection was generated in the genetic background of the processing tomato cultivar Red Setter by treating seeds with two different ethylemethane sulfonate doses (0.7% and 1%). An associated phenotype database, LycoTILL, was developed and a TILLING platform was also established. The interactive and evolving database is available online to the community for phenotypic alteration inquiries. To validate the Red Setter TILLING platform, induced point mutations were searched in 7 tomato genes with the mismatch-specific ENDO1 nuclease. In total 9.5 kb of tomato genome were screened and 66 nucleotide substitutions were identified. The overall mutation density was estimated and it resulted to be 1/322 kb and 1/574 kb for the 1% EMS and 0.7% EMS treatment respectively.</p> <p>Conclusions</p> <p>The mutation density estimated in our collection and its comparison with other TILLING populations demonstrate that the Red Setter genetic resource is suitable for use in high-throughput mutation discovery. The Red Setter TILLING platform is open to the research community and is publicly available via web for requesting mutation screening services.</p

Evaluation of drug administration errors in a teaching hospital

<p>Abstract</p> <p>Background</p> <p>Medication errors can occur at any of the three steps of the medication use process: prescribing, dispensing and administration. We aimed to determine the incidence, type and clinical importance of drug administration errors and to identify risk factors.</p> <p>Methods</p> <p>Prospective study based on disguised observation technique in four wards in a teaching hospital in Paris, France (800 beds). A pharmacist accompanied nurses and witnessed the preparation and administration of drugs to all patients during the three drug rounds on each of six days per ward. Main outcomes were number, type and clinical importance of errors and associated risk factors. Drug administration error rate was calculated with and without wrong time errors. Relationship between the occurrence of errors and potential risk factors were investigated using logistic regression models with random effects.</p> <p>Results</p> <p>Twenty-eight nurses caring for 108 patients were observed. Among 1501 opportunities for error, 415 administrations (430 errors) with one or more errors were detected (27.6%). There were 312 wrong time errors, ten simultaneously with another type of error, resulting in an error rate without wrong time error of 7.5% (113/1501). The most frequently administered drugs were the cardiovascular drugs (425/1501, 28.3%). The highest risks of error in a drug administration were for dermatological drugs. No potentially life-threatening errors were witnessed and 6% of errors were classified as having a serious or significant impact on patients (mainly omission). In multivariate analysis, the occurrence of errors was associated with drug administration route, drug classification (ATC) and the number of patient under the nurse's care.</p> <p>Conclusion</p> <p>Medication administration errors are frequent. The identification of its determinants helps to undertake designed interventions.</p

Update on inflammatory breast cancer

Inflammatory breast cancer (IBC) is both the least frequent and the most severe form of epithelial breast cancer. The diagnosis is based on clinical inflammatory signs and is reinforced by pathological findings. Significant progress has been made in the management of IBC in the past 20 years. Yet survival among IBC patients is still only one-half that among patients with non-IBC. Identification of the molecular determinants of IBC would probably lead to more specific treatments and to improved survival. In the present article we review recent advances in the molecular pathogenesis of IBC. A more comprehensive view will probably be obtained by pan-genomic analysis of human IBC samples, and by functional in vitro and in vivo assays. These approaches may offer better patient outcome in the near future