Paradoxical euthyroid hormone profile in a case of Graves' disease with cardiac failure

Cardiac failure is an uncommon complication of juvenile hyperthyroidism. We describe an adolescent boy with Graves' disease who developed manifestations of heart failure while on antithyroid medications. There was no evidence of any underlying cardiac disease. He had paradoxical euthyroid hormone profile which rose to hyperthyroid range when the manifestations of the cardiac failure subsided. The case highlights several unusual features of Graves' disease

PIM2 Induced COX-2 and MMP-9 Expression in Macrophages Requires PI3K and Notch1 Signaling

Activation of inflammatory immune responses during granuloma formation by the host upon infection of mycobacteria is one of the crucial steps that is often associated with tissue remodeling and breakdown of the extracellular matrix. In these complex processes, cyclooxygenase-2 (COX-2) plays a major role in chronic inflammation and matrix metalloproteinase-9 (MMP-9) significantly in tissue remodeling. In this study, we investigated the molecular mechanisms underlying Phosphatidyl-myo-inositol dimannosides (PIM2), an integral component of the mycobacterial envelope, triggered COX-2 and MMP-9 expression in macrophages. PIM2 triggers the activation of Phosphoinositide-3 Kinase (PI3K) and Notch1 signaling leading to COX-2 and MMP-9 expression in a Toll-like receptor 2 (TLR2)-MyD88 dependent manner. Notch1 signaling perturbations data demonstrate the involvement of the cross-talk with members of PI3K and Mitogen activated protein kinase pathway. Enforced expression of the cleaved Notch1 in macrophages induces the expression of COX-2 and MMP-9. PIM2 triggered significant p65 nuclear factor -κB (NF-κB) nuclear translocation that was dependent on activation of PI3K or Notch1 signaling. Furthermore, COX-2 and MMP-9 expression requires Notch1 mediated recruitment of Suppressor of Hairless (CSL) and NF-κB to respective promoters. Inhibition of PIM2 induced COX-2 resulted in marked reduction in MMP-9 expression clearly implicating the role of COX-2 dependent signaling events in driving the MMP-9 expression. Taken together, these data implicate PI3K and Notch1 signaling as obligatory early proximal signaling events during PIM2 induced COX-2 and MMP-9 expression in macrophages

Candidates in Astroviruses, Seadornaviruses, Cytorhabdoviruses and Coronaviruses for +1 frame overlapping genes accessed by leaky scanning

<p>Abstract</p> <p>Background</p> <p>Overlapping genes are common in RNA viruses where they serve as a mechanism to optimize the coding potential of compact genomes. However, annotation of overlapping genes can be difficult using conventional gene-finding software. Recently we have been using a number of complementary approaches to systematically identify previously undetected overlapping genes in RNA virus genomes. In this article we gather together a number of promising candidate new overlapping genes that may be of interest to the community.</p> <p>Results</p> <p>Overlapping gene predictions are presented for the astroviruses, seadornaviruses, cytorhabdoviruses and coronaviruses (families <it>Astroviridae</it>, <it>Reoviridae</it>, <it>Rhabdoviridae </it>and <it>Coronaviridae</it>, respectively).</p

Global Burden of Double Malnutrition: Has Anyone Seen It?

Background. Low- to middle-income countries (LMICs) are believed to be characterized by the coexistence of underweight and overweight. It has also been posited that such coexistence is appearing among the low socioeconomic status (SES) groups. Methods. We conducted a cross-sectional analysis of nationally representative samples of 451321 women aged 20–49 years drawn from 57 Demographic and Health Surveys conducted between 1994 and 2008. Body Mass Index (BMI in $kg/m^2$), was used to define underweight and overweight following conventional cut-points. Covariates included age, household wealth, education, and residence. We estimated multinomial multilevel models to assess the extent to which underweight $(BMI<18.5 kg/m^2)$ and overweight $(BMI≥25.0 kg/m^2)$ correlate at the country-level, and at the neighborhood-level within each country. Results. In age-adjusted models, there was a strong negative correlation between likelihood of being underweight and overweight at country- (r = −0.79, p<0.001), and at the neighborhood-level within countries (r = −0.51, P<0.001). Negative correlations ranging from −0.11 to −0.90 were observed in 46 of the 57 countries at the neighborhood-level and 29/57 were statistically significant $(p\leq 0.05)$. Similar negative correlations were observed in analyses restricted to low SES groups. Finally, the negative correlations across countries, and within-countries, appeared to be stable over time in a sub-set of 36 countries. Conclusion. The explicitly negative correlations between prevalence of underweight and overweight at the country-level and at neighborhood-level suggest that the hypothesized coexistence of underweight and overweight has not yet occurred in a substantial manner in a majority of LMICs

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity