Regulation of constitutive and induced NF-kappaB activation in malignant melanoma cells by capsaicin modulates interleukin-8 production and cell proliferation.

In the present study, we demonstrate that upregulation of interleukin-1beta(IL-1beta)-mediated and tumor necrosis factor-alpha (TNF-alpha)-mediated IL-8 expression in human malignant melanoma cells is modulated by the activation of nuclear factor-kappaB (NF-kappaB). Addition of capsaicin (8-methyl-N-vanillyl-6-nonenamide), a known inhibitor of NF-kappaB, resulted in the inhibition of constitutive as well as IL-1beta-induced and TNF-alpha-induced IL-8 expression in melanoma cells. The inhibition of IL-8 expression was dependent on the concentration of capsaicin and duration of treatment. Further, electrophoretic mobility shift assay (EMSA) of nuclear extracts from melanoma cells showed a constitutive activation of NF-kappaB and activated protein 1 (AP-1), which was upregulated following treatment with IL-1beta. Treatment of melanoma cells with capsaicin inhibited activation of constitutive and IL-1beta-induced NF-kappaB, but not AP-1, leading to inhibition of IL-8 expression. Further, downregulation of IL-8 expression in capsaicin-treated melanoma cells resulted in inhibition of in vitro cell proliferation. These results demonstrate that constitutive and induced NF-kappaB activation regulates IL-8 expression in melanoma cells. Downregulation of constitutive and induced NF-kappaB activation in malignant melanoma cells leads to inhibition of IL-8 production and in vitro cell proliferation.     

Nutrition health profile and intervention strategies for underprivileged adolescent girls in India: a selected review

Four studies conducted between 1979 and 1986 showed that girls 10-15 years old had growth deficiencies. About 50-66% of girls in the study samples were either wasted, stunted, or both wasted and stunted, based on Waterlow's classification. Girls also showed weight-for-height deficits. Greater deficits were apparent for weight-for-age measures than for height-for-age measures. Over 66% of girls had weights below 75% of the standards. Over 33% had heights below 90% of the standards. An Indian Council of Medical Research study published in 1972 indicated that girls from lower socioeconomic groups and 10-18 years old gained an average of 17.7 kg of weight compared to the NCHS standard of 25.4kg. Weight was lower than the standard for girls even in the high-income group. Height deficits were not as great. A National Nutrition Monitoring Bureau reported in 1981 that low-income group adolescents had height, weight, and growth rates about 70-80% those of high-income adolescents. Studies in 1985 by Tripathi and in 1976 by Chadha reported similar findings. These studies also reported that girls from low-income groups had delayed menarche and maturation of breast and genitalia. A Government of India report in 1988 indicated that a girl's growth spurt was arrested and full physical maturation was prevented due to repeated adolescent pregnancies. Rohde in 1986 reported that about 50% of first borns to adolescent girls were low birth weight infants. Some evidence has been presented by Gopalan and Srikantia that adolescent girls catch up on their growth, particularly rural girls. Hyderabad found that girls with severely stunted growth showed larger height increases at 18 years than girls with moderate or normal growth retardation. Studies have shown that short girls menstruate later than tall girls and low income girls have later ages of menarche. Studies have indicated that about 25-50% of adolescent girls had ocular signs of vitamin A deficiency: conjunctival xerosis and Bitot spots. About 60% of adolescent girls were anemic. Caloric intake deficiencies were most prominent at ages 1-3 and 15-20 years. One suggestion was to compensate for deficiencies in pre-adolescence with 60 mg of iron for 60 days two times a year and with vitamin A.     

Granulomatous Variant of Giant Centrifugal Miliaria Profunda

Abstract: Two infants presented with multiple asymptomatic papules and geographic and annular plaques over the extensor aspect of the upper and lower extremities and trunk. Skin biopsy of both lesions showed plugged and hyperplastic dilated acrosryingia and deep dermal ducts, along with granulomatous inflammatory reaction. These lesions showed self‐healing with complete resolution. A previous report described similar clinical and histopathologic features and labeled it giant centrifugal miliaria profunda. Because of the large granulomatous plaques and deep infiltrate, we propose that it was a granulomatous variant of giant centrifugal miliaria profunda. We report these cases for their rarity and self‐healing nature.     

Acute Disseminated Encephalomyelitis following Seasonal Influenza Vaccination in an Elderly Patient

Although such occurrences are rare, it should be recognized that certain vaccines might trigger serious neurological immune phenomena such as Guillain-Barre syndrome, seizures, cranial neuropathy, and acute disseminated encephalomyelitis (ADEM). Here we report on an elderly woman with ADEM following seasonal influenza vaccination who recovered after plasma exchange.     

Case report and review of nonischemic spontaneous papillary muscle rupture reports between 2000 and 2015

Spontaneous papillary muscle rupture (PMR) is a rare cardiovascular emergency. We present a 63‐year‐old male who presents with acute dyspnea who was found to have an anterior PMR, with no evidence of coronary artery disease, infection, or trauma. A review of cases of nonischemic spontaneous PMR published in 2000–2015 identified 11 additional cases of spontaneous PMR. Posterior and anterior papillary muscles involvement was identified in 54.5% and 45.5% of cases, respectively. Rapid identification due to advances in imaging modalities and improved surgical management has led to optimal outcomes in patients with spontaneous PMR.     

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation

Activation of CD4⁺ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4⁺ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4⁺ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4⁺ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4⁺ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.     

Dysregulation of innate immunity in hepatitis C virus genotype 1 IL28B-unfavorable genotype patients: impaired viral kinetics and therapeutic response

Recent studies have shown that a single-nucleotide polymorphism upstream of the interleukin-28B (IL28B) gene plays a major role in predicting therapeutic response in hepatitis C virus (HCV)-infected patients treated with pegylated interferon (PEG-IFN)/ribavirin. We sought to investigate the mechanism of the IL28B polymorphism, specifically as it relates to early HCV viral kinetics, IFN pharmacokinetics, IFN pharmacodynamics, and gene expression profiles. Two prospective cohorts (human immunodeficiency virus [HIV]/HCV-coinfected and HCV-monoinfected) completing treatment with IFN/ribavirin were enrolled. Patients were genotyped at the polymorphic site rs12979860. In the HIV/HCV cohort, frequent serum sampling was completed for HCV RNA and IFN levels. DNA microarray of peripheral blood mononuclear cells and individual expression of IFN-stimulated genes (ISGs) were quantified on IFN therapy. The IL28B-favorable (CC) genotype was associated with improved therapeutic response compared with unfavorable (CT or TT) genotypes. Patients with a favorable genotype had greater first- and second-phase viral kinetics (P = 0.004 and P = 0.036, respectively), IFN maximum antiviral efficiency (P = 0.007) and infected cell death loss (P = 0.009) compared with unfavorable genotypes. Functional annotation analysis of DNA microarray data was consistent with depressed innate immune function, particularly of natural killer cells, from patients with unfavorable genotypes (P <0.004). Induction of innate immunity genes was also lower in unfavorable genotypes. ISG expression at baseline and induction with IFN was independent of IL28B genotype. CONCLUSION: Carriers of the IL28B-favorable genotype were more likely to have superior innate immune response to IFN therapy compared with unfavorable genotypes, suggesting that the unfavorable genotype has aberrant baseline induction of innate immune response pathways resulting in impaired virologic response. IL28B genotype is associated with more rapid viral kinetics and improved treatment response outcomes independent of ISG expression.