Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood

T Cell Activation Pathways : B7, LFA-3, and ICAM-1 Shape Unique T Cell Profiles

Two signals are required for induction of cell proliferation and cytokine production in resting T cells. Occupancy of the T cell receptor by antigen/MHC complexes delivers the first signal to the T cell, while the second signal is provided by interaction with costimulatory ligands on APC. CD2, LFA-1, and CD28 are the major costimulatory and adhesive molecules on T cells and bind to the LFA-3, ICAM-1 and B7 ligands, respectively, on APC. LFA-3 plays a central role for naive and memory T helper cells during the early phase of an immune response. The LFA-3/CD2 pathway initiates strong antigen-independent cell adhesion, substantial expansion of naive T helper cells, and induction of large amounts of IFN-γ in memory cells. The release of IFN-γ may upregulate expression of ICAM-1 and B7 on APC and allows multiple adhesion pathways to amplify the immune response. The LFA- 1/ICAM-l pathway stimulates adhesion and cell proliferation more efficiently in memory T helper cells than in naive cells. Further, the results suggest that naive T helper cells express functionally inactive LFA-1 molecules on the cell surface, which may have a physiological role in keeping these cells in a resting state. B7 costimulation superinduces IL-2 production in both naive and memory T helper cells and generates long-lasting cell proliferation. This permits transition from an autocrine to a paracrine immune response. Coexpression of B7/LFA-3 provides an optimal APC function and enables a vigorous T cell response to minute amounts of antigen. AP-1 and NF-κB transcription factors are involved in the induction of several cytokine gene promoters and play a central role in the regulation of IL-2 gene transcription. LFA-3 costimulation only moderately enhances AP-1 DNA-binding activity and does not influence the NF-κB activity induced by TCR engagement, whereas B7 costimulation induces large amounts of NF-κB and AP-1 activity in T helper cells. The costimulatory ligands represent a family of adhesion molecules with considerable redundancy. Interfamily redundancy of LFA-3, B7, and ICAM ligands offers an opportunity to regulate distinct T cell response profiles in various microenvironments at separate time points of an immune response

Multicentre Phase II Trial of Paclitaxel and Carboplatin with Concurrent Radiotherapy in Locally Advanced Non-small Cell Lung Cancer

Aim: To evaluate weekly, induction chemotherapy followed by weekly concomitant chemoradiotherapy in a multicentre phase II study of patients with wiresectable stage III non-small cell lung cancer (NSCLC; stage wet IIIB excluded). Patients (aid Methods: Eligible patients received three weekly cycles of paclitaxel 100 mg/m(2) and carboplatin AUC2 followed by six weekly cycles of paclitaxel 60 mg/m(2) and carboplatin AUC2 in combination with thoracic radiotherapy (2 Gy per fraction and day to a total (lose of 60 Gy), Results: Sixty-four patients (40 males and 24 females) with a median age of 63 Years (range, 43-79 years) entered the study. T and N stage were distributed as follows: T1 2 patients (3.2%). T2 10 patients (15.6%), T3 15 patients (23.4%). T4 37 patients (57.8%), N0 10 patients (15.6%). N1 1 patient (1.6%), N2 26 patients (40.6%), N3 26 patients (40.6%), and N missing I patient (1.6%). Seven patients (10.9%) suffered from grade 314 oesophagitis. Grade 112 oesophagitis occurred in 36 patients (56.3%) and pneumonitis grade 112 occurred in 10 patients (15.6%). Sixty-three patients were evaluated on an intent-to-treat basis. The overall response rate was 74.6%. The median time to progression was 247 days and median overall survival was 461 days. According to subgroup analyses, no statistically signicant differences were noted according to gender, age (= 65 years), perfromance status, histology, or study centre. Conclusion: Induction chemotherapy followed by concurrent chemoradiotherapy with weekly cycles of paclitaxel and carboplatin is feasible and generates moderate toxicity. Efficacy is comparable to other recently published regimens. However, prognosis remains, ill general, poor for this group of patients and further work to develop better therapy is required

Influence of Social Environment on Loneliness in Older Adults: Moderation by Polymorphism in the CRHR1

Objective: Both adverse social environments and genetic factors contribute to loneliness in old age. Mixed findings between older adults' social relations with their children and their levels of loneliness suggested that a gene χ social environment interaction may be operating. We examine whether the effects of infrequent contact with children and low levels of perceived social support from children on loneliness in older adults are moderated by two candidate single nucleotide polymorphisms (i.e., rs1876831 and rs242938) in the corticotrophin releasing hormone receptor 1 (CRHR1) gene. Design: This was a longitudinal observational study. Setting: and Participants: A population-based sub-sample of 1,374 community-dwelling older adults aged 65 years and older was examined from both the 2003-2004 and 2006-2007 English Longitudinal Study of Aging assessments. Measurements: Our main outcome measure is loneliness, which was assessed by four items extracted from the ULCA loneliness scale. Results: Compared with older adults carrying the CT/TT genotypes, individuals homozygous for the C allele of rs1876831 reported higher levels of loneliness in the context of infrequent social contact with children and lower levels of perceived social support from children. No gene χ social environment interactions were found for loneliness between rs242938 and an adverse social environment related to children. Conclusions: This study provides the first evidence in humans that the CRHR1 gene interacts with exposure to a negative social environment to predict loneliness in older adults. © 2014 American Association for Geriatric Psychiatry