Age-dependent decline in EGF-induced signaling is independent of intracellular thiols

Loss of proliferative capacity is common in many tissue types during aging. We have shown that mitogenic signaling through the epidermal growth factor (EGF) receptor declines in hepatocytes from old rats. Specifically, we showed that in old hepatocytes there is a decrease in autophosphorylation of EGF receptor at Tyr-1173. This results in loss of recruitment of the adapter protein Shc to the membrane and decreased ERK MAP kinase pathway activation. Because EGF receptor signaling also requires intracellular generation of H₂0₂, we next questioned whether altering the intracellular GSH/thiol concentration may also affect the age-dependent decline in EGF receptor signaling. Surprisingly, decreased intracellular GSH had no effect on EGF receptor signaling in hepatocytes from either young or old animals. However, increasing the thiol concentration dramatically attenuated EGF receptor signaling in hepatocytes from both young and old animals. Unexpectedly, loss of EGF receptor signaling was due to a specific decrease in EGF receptor number, but not in other components of the EGF receptor signaling pathway such as ERK MAP kinase. These results suggest that age-dependent mechanisms of alteration in EGF receptor signaling are independent of thiol regulation of EGF receptor signaling.     

脾切除对结直肠癌切除术后的影响：一项多中心、嵌入式、配对队列研究

目的探讨医源性脾脏损伤脾切除对结直肠癌切除患者术后长期生存的影响。方法对1990年1月1日至1999年12月31日10年间行结直肠癌手术切除并附带脾切除患者进行病例配对回顾研究。分析患者年龄、性别、依据美国麻醉学医师协会（ASA）标准评估的身体状况、疾病分期、手术类型及预后等资料。配对病例来自同一医疗中心，性别、年龄、疾病分期及手术类型完全相同。手术附带脾切除患者为试验组，未切脾者为对照组。结果55例患者行医源性脾切除术，对照组在年龄、性别、身体状况、疾病分期及手术类型上与之匹配。随访时间（从手术开始到患者死亡或者最后一次随访1为2～205个月（中位随访时间为43个月）。Cox比例危险度模型进行Kaplan-Meier法生存分析发现两组间差异有显著性意义，不切除脾脏对患者生存有利（危险度1．8，95％可信区间为1-3．3，P=0．0399），未切脾组与切脾组5年生存率分别为70％和47％，10年生存率分别为55％和38％。结论结直肠癌患者在行结肠或直肠切除时，因医源性脾脏损伤而切除脾脏者，预后较差。     

Superparamagnetic iron oxide-enhanced MR imaging: pulse sequence optimization for detection of liver cancer

The effects of magnetic resonance (MR) pulse sequences and timing parameters on tumor-liver contrast were studied in an animal model of metastatic liver cancer. Six spin-echo (SE), three inversion-recovery (IR), and four gradient-echo (GRE) sequences were evaluated at 0.6 T before and after injection of super-paramagnetic iron oxide. GRE techniques, irrespective of echo time and flip angle, showed the greatest change in signal intensity (enhancement) of the liver after administration of iron oxide. Single-acquisition GRE sequences (16 seconds) matched the contrast-to-noise ratio (C/N) performance of the most effective 6.4-minute SE sequences. Multiexcitation GRE sequences showed tumor-liver C/Ns per unit time that were significantly (P less than .05) higher than those achieved with SE and IR sequences. GRE sequences, which recruit intravoxel dephasing as an additional source of transverse relaxation enhancement (T2*), show a higher C/N per unit time and in this respect seem superior to SE and IR sequences for MR imaging with superparamagnetic iron oxide.     

Pathogenesis of unexplained drowning: new insights from a molecular autopsy

OBJECTIVE: To perform a molecular autopsy involving the RyR2-encoded cardiac ryanodine receptor/calcium release channel to determine whether mutations responsible for catecholaminergic polymorphic ventricular tachycardia (CPVT) represent a novel pathogenic basis for unexplained drownings. METHODS: A cardiac channel molecular autopsy was performed on 2 individuals who died of unexplained drowning and whose cases were referred to the Sudden Death Genomics Laboratory at the Mayo Clinic in Rochester, Minn. Comprehensive mutational analysis of all 60 protein-encoded exons of the 5 long QT syndrome-causing cardiac channel genes and a targeted analysis of 18 RyR2 exons known to host RyR2-mediated CPVT-causing mutations (CPVT1) was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. RESULTS: Both individuals harbored novel mutations in RyR2. Postmortem mutational analysis revealed a familial missense mutation in exon 14, R414C, in a 16-year-old girl. A 9-year-old boy possessed a sporadic missense mutation in exon 49, V2475F. Both amino acid positions involve highly conserved residues that localize to critical functional domains in the calcium release channel. Neither substitution was present in 1000 reference alleles. CONCLUSIONS: This molecular autopsy study provides proof of principle that RyR2 mutations can underlie some unexplained drownings. A population-based genetic epidemiology study that involves molecular autopsies of individuals who die of unexplained drowning is needed to determine the prevalence and spectrum of KCNQ1 and now RyR2 mutations as potential pathogenic mechanisms for drowning.     

The T‐13910C polymorphism in the lactase phlorizin hydrolase gene is associated with differences in serum calcium levels and calcium intake

The C‐variant of a T‐13910C polymorphism (rs4988235; NT_022135.15:g.25316568G > A) upstream of the lactase phlorizin hydrolase (LPH) gene causes lactose intolerance. Association studies with differences in bone parameters and fracture risk have been inconclusive. The objective of this study was to examine the association of LPH rs4988235 with body height and bone parameters and calcium homeostasis in two elderly populations of Dutch Caucasians and assess interaction with vitamin D receptor (VDR) polymorphisms. Genotyping of LPH and VDR polymorphisms was performed in 6367 individuals from the Rotterdam Study and 844 from the Longitudinal Aging Study Amsterdam (LASA). Associations with age, height, weight, bone mineral density (BMD), skeletal morphometric parameters and serum vitamin D and calcium levels, and dietary calcium intake were assessed using ANOVA or analysis of covariance, and allele dose effect was assessed using linear regression analysis. Fracture risk was analyzed using Cox's proportional hazard regression analysis. Associations with body height (p = 2.7 × 10^?8) and vertebral area (p = .048) found in the Rotterdam Study were explained by population stratification, as assessed by principal‐component analyses, and disappeared after additional adjustments. No associations with femoral neck or lumbar spine BMD or with fracture risk were detected. Calcium intake and serum ionized serum calcium were significantly lower in C‐homozygotes (p = 9.2 × 10^?7, p = .02, respectively). For none of the parameters studied was interaction between the T‐13910C polymorphism and VDR block 5 haplotype 1 observed. We show that the C allele of the T‐13910C polymorphism causing lactose intolerance is associated with lower dietary calcium intake and serum calcium levels but not with BMD or fractures. The associations observed with height and vertebral area were the result of population stratification. This demonstrates the impact of population stratification and urges researchers to carefully take this into account in genetic associations, in particular, in dietary intake–related phenotypes, of which LPH and lactose intolerance are a strong example. © 2010 American Society for Bone and Mineral Research     

Predictors of growth and body composition in HIV‐infected children beginning or changing antiretroviral therapy

Objectives

The aim of the study was to describe growth and body composition changes in HIV‐positive children after they had initiated or changed antiretroviral therapy (ART) and to correlate these with viral, immune and treatment parameters.

Methods

Ninety‐seven prepubertal HIV‐positive children were observed over 48 weeks upon beginning or changing ART. Anthropometry and bioelectrical impedance analysis results were compared with results from the National Health and Nutrition Examination Survey 1999–2002 (NHANES) to generate z‐scores and with results for HIV‐exposed, uninfected children from the Women and Infants Transmission Study (WITS). Multivariate analysis was used to evaluate associations between growth and body composition and disease parameters.

Results

All baseline lean and fat mass measures were below those of controls from NHANES. Weight, height and fat free mass (FFM) index (FFM/height²) z‐scores increased over time (P=0.004, 0.037 and 0.027, respectively) and the waist:height ratio z‐score decreased (P=0.045), but body mass index and per cent body fat z‐scores did not change. Measures did not increase more than in uninfected WITS controls. In multivariate analysis, baseline height, mid‐thigh circumference and FFM z‐scores related to CD4 percentage (P=0.029, P=0.008 and 0.020, respectively) and change in FFM and FFM index z‐scores to CD4 percentage increase (P=0.010 and 0.011, respectively). Compared with WITS controls, baseline differences in height and mid‐thigh muscle circumference were also associated with CD4 percentage. Case–control differences in change in both subscapular skinfold (SSF) thickness and the SSF:triceps skinfold ratio were inversely associated with viral suppression. No measures related to ART class(es) at baseline or over time.

Conclusions

In these HIV‐positive children, beginning or changing ART was associated with improved growth and lean body mass (LBM), as indicated by FFM index. Height and LBM related to CD4 percentage at baseline and over time. Altered fat distribution and greater central adiposity were associated with detectable virus but not ART class(es) received.     

Association between labour market trends and trends in young people's mental health in ten European countries 1983-2005

Background  

Mental health problems have become more common among young people over the last twenty years, especially in certain countries. The reasons for this have remained unclear. The hypothesis tested in this study is that national trends in young people's mental health are associated with national trends in young people's labour market.