Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus

Onchocerciasis, commonly known as river blindness, is caused by the filarial nematode Onchocerca volvulus and is transmitted by a blackfly vector. Over 37 million people are thought to be infected, with over 90 million at risk. Infection predominantly occurs in sub-Saharan Africa. Foci also exist in the Arabian Peninsula and Central and South America. Ivermectin, the sole pharmaceutical available for mass chemotherapy, has been used on a community basis for annual or semi-annual treatment since 1987. Multiple treatments with ivermectin kill the microfilariae that are responsible for the pathology of onchocerciasis. More importantly, ivermectin suppresses the reproductive activity of the adult female worms, thus delaying or preventing the repopulation of the skin with new microfilariae and thereby reducing transmission. This study extends earlier reports of sub-optimal responses to ivermectin by examining repopulation levels of microfilaria one year after treatment, worm burdens per nodule, the age structure of adult female worms recovered from nodules, and the reproductive status of adult female worms 90 days after ivermectin treatment. In some communities which have shown a pattern of sub-optimal response to treatment, the data is consistent with an emergence of ivermectin non response or resistance manifested by a loss of the effect of ivermectin on the suppression of parasite reproduction

Soy intake and breast cancer risk in Singapore Chinese Health Study

We investigated the effects of soy isoflavone intake on breast cancer in a prospective study of 35 303 Singapore Chinese women enrolled during April 1993 to December 1998 in the Singapore Chinese Health Study. At recruitment, each subject was personally administered a validated semiquantitative food frequency questionnaire covering 165 food and beverage items. As of December 31 2005, 629 had developed breast cancer following an accumulation of 338 242 person-years. Using Cox regression and adjusting for age at interview, year of interview, dialect group, education, family history of breast cancer, age when periods became regular, parity, menopausal status, body mass index (BMI), n-3 fatty acid, and other covariates, we found breast cancer risk was reduced significantly in association with high soy intake. Relative to women with lower (below median) soy intake (<10.6 mg isoflavone per 1000 Kcal), women with higher (above median) intake showed a significant 18% risk reduction (relative risk (RR)=0.82, 95% confidence interval (CI)=0.70–0.97). This inverse association was apparent mainly in postmenopausal women (RR=0.74, 95% CI=0.61–0.90), and was not observed in premenopausal women (RR=1.04, 95% CI=0.77–1. 40). Among postmenopausal women, the soy–breast cancer association was stronger in those above median BMI (RR=0.67, 95% CI=0.51–0.88) than in leaner women (RR=0.83, 95% CI=0.62–1.11). Duration of follow-up modified the soy–breast cancer association, the effect being twice as large among women with 10+ vs fewer years of follow-up. Neither oestrogen nor progesterone receptor status of the tumours materially influenced the association. These prospective findings suggest that approximately 10 mg of isoflavones per day, obtained in a standard serving of tofu, may have lasting beneficial effects against breast cancer development

Osteopetrosis

Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy

Degradation of 4-fluorophenol by Arthrobacter sp. strain IF1

A Gram-positive bacterial strain capable of aerobic biodegradation of 4-fluorophenol (4-FP) as the sole source of carbon and energy was isolated by selective enrichment from soil samples collected near an industrial site. The organism, designated strain IF1, was identified as a member of the genus Arthrobacter on the basis of 16S ribosomal RNA gene sequence analysis. Arthrobacter strain IF1 was able to mineralize 4-FP up to concentrations of 5 mM in batch culture. Stoichiometric release of fluoride ions was observed, suggesting that there is no formation of halogenated dead-end products during 4-FP metabolism. The degradative pathway of 4-FP was investigated using enzyme assays and identification of intermediates by gas chromatography (GC), GC–mass spectrometry (MS), high-performance liquid chromatography, and liquid chromatography–MS. Cell-free extracts of 4-FP-grown cells contained no activity for catechol 1,2-dioxygenase or catechol 2,3-dioxygenase, which indicates that the pathway does not proceed through a catechol intermediate. Cells grown on 4-FP oxidized 4-FP, hydroquinone, and hydroxyquinol but not 4-fluorocatechol. During 4-FP metabolism, hydroquinone accumulated as a product. Hydroquinone could be converted to hydroxyquinol, which was further transformed into maleylacetic acid and β-ketoadipic acid. These results indicate that the biodegradation of 4-FP starts with a 4-FP monooxygenase reaction that yields benzoquinone, which is reduced to hydroquinone and further metabolized via the β-ketoadipic acid pathway

Infestation of shore crab gills by a free-living mussel species

Parasitic and commensal species can impact the structure and function of ecological communities and are typically highly specialized to overcome host defences. Here, we report multiple instances of a normally free-living species, the blue mussel Mytilus edulis Linnaeus, 1758, inhabiting the branchial chamber of the shore crab Carcinus maenas (Linnaeus, 1758) collected from widely separated geographical locations. A total of 127 C. maenas were examined from four locations in the English Channel, one location in the Irish Sea and two locations at the entrance of the Baltic Sea. The branchial chambers of three crabs (one from the English Channel and two from Gullmar Fjord, Sweden) were infested with mussels resembling the genus Mytilus. Sequencing at the Me15/16 locus on the polyphenolic adhesive protein gene confirmed the identity as M. edulis. Bivalve infestation always occurred in larger red male individuals. Up to 16 mussels, ranging from 2 to 11 mm in shell length, were found in each individual, either wedged between gill lamellae or attached to the branchial chamber inner wall. This is one of the first reports of a bivalve inhabiting crustacean gills and is an intriguing case of a normally free-living prey species infesting its predato

Determinants of non- response to a second assessment of lifestyle factors and body weight in the EPIC-PANACEA study.

BACKGROUND: This paper discusses whether baseline demographic, socio-economic, health variables, length of follow-up and method of contacting the participants predict non-response to the invitation for a second assessment of lifestyle factors and body weight in the European multi-center EPIC-PANACEA study. METHODS: Over 500.000 participants from several centers in ten European countries recruited between 1992 and 2000 were contacted 2-11 years later to update data on lifestyle and body weight. Length of follow-up as well as the method of approaching differed between the collaborating study centers. Non-responders were compared with responders using multivariate logistic regression analyses. RESULTS: Overall response for the second assessment was high (81.6%). Compared to postal surveys, centers where the participants completed the questionnaire by phone attained a higher response. Response was also high in centers with a short follow-up period. Non-response was higher in participants who were male (odds ratio 1.09 (confidence interval 1.07; 1.11), aged under 40 years (1.96 (1.90; 2.02), living alone (1.40 (1.37; 1.43), less educated (1.35 (1.12; 1.19), of poorer health (1.33 (1.27; 1.39), reporting an unhealthy lifestyle and who had either a low (25, 1.08 (1.06; 1.10); especially ≥30 kg/m2, 1.26 (1.23; 1.29)). CONCLUSIONS: Cohort studies may enhance cohort maintenance by paying particular attention to the subgroups that are most unlikely to respond and by an active recruitment strategy using telephone interviews.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Genetic Selection of Low Fertile Onchocerca volvulus by Ivermectin Treatment

Onchocerca volvulus is the causative agent of onchocerciasis, or “river blindness”. Ivermectin has been used for mass treatment of onchocerciasis for up to 18 years, and recently there have been reports of poor parasitological responses to the drug and evidence of drug resistance. Drug resistance has a genetic basis. In this study, genetic changes in β-tubulin, a gene associated with ivermectin resistance in nematodes, were seen in parasites obtained from the patients exposed to repeated ivermectin treatment compared with parasites obtained from the same patients before any exposure to ivermectin. Furthermore, the extent of the genetic changes was dependent on the level of ivermectin treatment exposure. This genetic selection was associated with a lower reproductive rate in the female parasites. The data indicates that this genetic selection is for a population of O. volvulus that is more tolerant to ivermectin. This selection could have implications for the development of ivermectin resistance in O. volvulus and for the ongoing onchocerciasis control programmes. Monitoring for the possible development and spread of ivermectin resistance, as part of the control programmes, should be implemented so that any foci of resistant parasites can be treated by alternative control measures