An intronic SNP in the thyroid hormone receptor β gene is associated with pituitary cell-specific over-expression of a mutant thyroid hormone receptor β2 (R338W) in the index case of pituitary-selective resistance to thyroid hormone

<p>Abstract</p> <p>Background</p> <p>The syndrome of resistance to thyroid hormone (RTH) is caused by mutations in the thyroid hormone receptor β gene (<it>THRB</it>). The syndrome varies from asymptomatic to diffuse hypothyroidism, to pituitary-selective resistance with predominance of hyperthyroid signs and symptoms. The wide spectrum of clinical presentation is not completely attributable to specific <it>THRB </it>mutations. The <it>THRB </it>gene encodes two main isoforms, TR β1 which is widely distributed, and TR β2, whose expression is limited to the cochlea, retina, hypothalamus, and pituitary. Recent data demonstrated that in mice an intron enhancer region plays a critical role in the pituitary expression of the β2 isoform of the receptor. We thus hypothesized that polymorphisms in the human homologous region could modulate the pituitary expression of the mutated gene contributing to the clinical presentation of RTH.</p> <p>Methods</p> <p>Screening and <it>in vitro </it>characterization of polymorphisms of the intron enhancer region of the <it>THRB </it>gene in the index case of pituitary-selective RTH.</p> <p>Results</p> <p>The index case of pituitary-selective resistance is characterized by the missense R338W exon 9 mutation in <it>cis </it>with two common SNPs, rs2596623T and rs2596622C, located in the intron enhancer region of the <it>THRB </it>gene. Reporter gene assay experiments in GH3 pituitary-derived cells indicate that rs2596623T generates an increased pituitary cell-specific activity of the TR β2 promoter suggesting that rs2596623T leads to pituitary over-expression of the mutant allele.</p> <p>Conclusions</p> <p>The combined coding mutation and non-coding SNP therefore generate a tissue-specific dominant-negative condition recapitulating the patient's peculiar phenotype. This case illustrates the role of regulatory regions in modifying the clinical presentation of genetic diseases.</p

Patients with MEN1 are at an increased risk for venous thromboembolism VTE risk in MEN1

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder predisposing to the development of multiple functional and non-functional neuroendocrine tumors (NETs). Only uncommon MEN1-associated functional NETs such as glucagonomas (&lt;1%) and ACTH-producing tumors (&lt;5%) are known to be associated with hypercoagulability. It is unknown if patients with MEN1 generally have increased risk of VTE. Methods: We queried a prospective natural history study of germline mutation positive MEN1 patients (n=286) between 1991-2019 for all lifetime events of VTE. Search terms were: DVT, thromb, embol, PE, pulmonary embolism, clot, hematology consult, anticoagulant, coumadin, lovenox, xarelto, warfarin, aspirin, rivaroxaban and apixaban. Incidence rates were calculated accounting for age and sex. Comparison was made to published incidence rates in healthy populations, different types of cancer, and Cushing's syndrome. Results: Thirty-six subjects (median age 45 years, range 16-75) experienced a VTE event, yielding a prevalence rate of 12.9%. The age-sex adjusted incidence rate of VTE is 9.11 per 1,000 patient-years, with a sex-adjusted lifetime incidence rate of 2.81 per 1,000 patient-years. MEN1-associated lifetime incidence rates are ~two-fold higher than the estimated annual incidence rate in the general population and are comparable to known risk in the setting of various types of cancer. Approximately 80% were diagnosed with pancreatic NETs, of which 24% were insulinomas. Fourteen patients (42%) experienced peri-operative VTE events. Conclusions: MEN1 patients have an increased risk of VTE. Further mechanistic investigation and validation from other MEN1 cohorts are needed to confirm the increased prevalence of VTE in MEN1

The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE) : study protocol for a randomized controlled trial

Peer reviewedPublisher PD

The Vital Role of Social Workers in Community Partnerships: The Alliance for Gay, Lesbian, Bisexual, Transgender and Questioning Youth

The account of The Alliance for Gay, Lesbian, Bisexual, Transgender, and Questioning (GLBTQ) Youth formation offers a model for developing com- munity-based partnerships. Based in a major urban area, this university-community collaboration was spearheaded by social workers who were responsible for its original conceptualization, for generating community support, and for eventual staffing, administration, direct service provision, and program evaluation design. This article presents the strategic development and evolution of this community- based service partnership, highlighting the roles of schools of social work, academics, and social work students in concert with community funders, practitioners and youth, in responding to the needs of a vulnerable population

Kepler-21b: A 1.6REarth Planet Transiting the Bright Oscillating F Subgiant Star HD 179070

We present Kepler observations of the bright (V=8.3), oscillating star HD 179070. The observations show transit-like events which reveal that the star is orbited every 2.8 days by a small, 1.6 R_Earth object. Seismic studies of HD 179070 using short cadence Kepler observations show that HD 179070 has a frequencypower spectrum consistent with solar-like oscillations that are acoustic p-modes. Asteroseismic analysis provides robust values for the mass and radius of HD 179070, 1.34{\pm}0.06 M{\circ} and 1.86{\pm}0.04 R{\circ} respectively, as well as yielding an age of 2.84{\pm}0.34 Gyr for this F5 subgiant. Together with ground-based follow-up observations, analysis of the Kepler light curves and image data, and blend scenario models, we conservatively show at the >99.7% confidence level (3{\sigma}) that the transit event is caused by a 1.64{\pm}0.04 R_Earth exoplanet in a 2.785755{\pm}0.000032 day orbit. The exoplanet is only 0.04 AU away from the star and our spectroscopic observations provide an upper limit to its mass of ~10 M_Earth (2-{\sigma}). HD 179070 is the brightest exoplanet host star yet discovered by Kepler.Comment: Accepted to Ap

Hydrologically-driven crustal stresses and seismicity in the New Madrid Seismic Zone

The degree to which short-term non-tectonic processes, either natural and anthropogenic, influence the occurrence of earthquakes in active tectonic settings or ‘stable’ plate interiors, remains a subject of debate. Recent work in plate-boundary regions demonstrates the capacity for long-wavelength changes in continental water storage to produce observable surface deformation, induce crustal stresses and modulate seismicity rates. Here we show that a significant variation in the rate of microearthquakes in the intraplate New Madrid Seismic Zone at annual and multi-annual timescales coincides with hydrological loading in the upper Mississippi embayment. We demonstrate that this loading, which results in geodetically observed surface deformation, induces stresses within the lithosphere that, although of small amplitude, modulate the ongoing seismicity of the New Madrid region. Correspondence between surface deformation, hydrological loading and seismicity rates at both annual and multi-annual timescales indicates that seismicity variations are the direct result of elastic stresses induced by the water load

A Kinome RNAi Screen Identified AMPK as Promoting Poxvirus Entry through the Control of Actin Dynamics

Poxviruses include medically important human pathogens, yet little is known about the specific cellular factors essential for their replication. To identify genes essential for poxvirus infection, we used high-throughput RNA interference to screen the Drosophila kinome for factors required for vaccinia infection. We identified seven genes including the three subunits of AMPK as promoting vaccinia infection. AMPK not only facilitated infection in insect cells, but also in mammalian cells. Moreover, we found that AMPK is required for macropinocytosis, a major endocytic entry pathway for vaccinia. Furthermore, we show that AMPK contributes to other virus-independent actin-dependent processes including lamellipodia formation and wound healing, independent of the known AMPK activators LKB1 and CaMKK. Therefore, AMPK plays a highly conserved role in poxvirus infection and actin dynamics independent of its role as an energy regulator

A systematic review of population health interventions and Scheduled Tribes in India

<p>Abstract</p> <p>Background</p> <p>Despite India's recent economic growth, health and human development indicators of Scheduled Tribes (ST) or <it>Adivasi </it>(India's indigenous populations) lag behind national averages. The aim of this review was to identify the public health interventions or components of these interventions that are effective in reducing morbidity or mortality rates and reducing risks of ill health among ST populations in India, in order to inform policy and to identify important research gaps.</p> <p>Methods</p> <p>We systematically searched and assessed peer-reviewed literature on evaluations or intervention studies of a population health intervention undertaken with an ST population or in a tribal area, with a population health outcome(s), and involving primary data collection.</p> <p>Results</p> <p>The evidence compiled in this review revealed three issues that promote effective public health interventions with STs: (1) to develop and implement interventions that are low-cost, give rapid results and can be easily administered, (2): a multi-pronged approach, and (3): involve ST populations in the intervention.</p> <p>Conclusion</p> <p>While there is a growing body of knowledge on the health needs of STs, there is a paucity of data on how we can address these needs. We provide suggestions on how to undertake future population health intervention research with ST populations and offer priority research avenues that will help to address our knowledge gap in this area.</p

Testing the Accuracy of Aerial Surveys for Large Mammals: An Experiment with African Savanna Elephants (Loxodonta africana)

Accurate counts of animals are critical for prioritizing conservation efforts. Past research, however, suggests that observers on aerial surveys may fail to detect all individuals of the target species present in the survey area. Such errors could bias population estimates low and confound trend estimation. We used two approaches to assess the accuracy of aerial surveys for African savanna elephants (Loxodonta africana) in northern Botswana. First, we used double-observer sampling, in which two observers make observations on the same herds, to estimate detectability of elephants and determine what variables affect it. Second, we compared total counts, a complete survey of the entire study area, against sample counts, in which only a portion of the study area is sampled. Total counts are often considered a complete census, so comparing total counts against sample counts can help to determine if sample counts are underestimating elephant numbers. We estimated that observers detected only 76% ± SE of 2% of elephant herds and 87 ± 1% of individual elephants present in survey strips. Detectability increased strongly with elephant herd size. Out of the four observers used in total, one observer had a lower detection probability than the other three, and detectability was higher in the rear row of seats than the front. The habitat immediately adjacent to animals also affected detectability, with detection more likely in more open habitats. Total counts were not statistically distinguishable from sample counts. Because, however, the double-observer samples revealed that observers missed 13% of elephants, we conclude that total counts may be undercounting elephants as well. These results suggest that elephant population estimates from both sample and total counts are biased low. Because factors such as observer and habitat affected detectability of elephants, comparisons of elephant populations across time or space may be confounded. We encourage survey teams to incorporate detectability analysis in all aerial surveys for mammals