The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals

Genetic polymorphisms of DNA double strand break gene Ku70 and gastric cancer in Taiwan

<p>Abstract</p> <p>Background and aim</p> <p>The DNA repair gene <it>Ku70</it>, an important member of non-homologous end-joining repair system, is thought to play an important role in the repairing of DNA double strand breaks. It is known that defects in double strand break repair capacity can lead to irreversible genomic instability. However, the polymorphic variants of <it>Ku70</it>, have never been reported about their association with gastric cancer susceptibility.</p> <p>Methods</p> <p>In this hospital-based case-control study, the associations of <it>Ku70 </it>promoter T-991C (rs5751129), promoter G-57C (rs2267437), promoter A-31G (rs132770), and intron 3 (rs132774) polymorphisms with gastric cancer risk in a Taiwanese population were investigated. In total, 136 patients with gastric cancer and 560 age- and gender-matched healthy controls recruited from the China Medical Hospital in Taiwan were genotyped.</p> <p>Results</p> <p>As for <it>Ku70 </it>promoter T-991C, the ORs after adjusted by age and gender of the people carrying TC and CC genotypes were 2.41 (95% CI = 1.53-3.88) and 3.21 (95% CI = 0.96-9.41) respectively, compared to those carrying TT wild-type genotype. The <it>P </it>for trend was significant (<it>P </it>< 0.0001). In the dominant model (TC plus CC versus TT), the association between <it>Ku70 </it>promoter T-991C polymorphism and the risk for gastric cancer was also significant (adjusted OR = 2.48, 95% CI = 1.74-3.92). When stratified by age and gender, the association was restricted to those at the age of 55 or elder of age (TC vs TT: adjusted OR = 2.52, 95% CI = 1.37-4.68, <it>P </it>= 0.0139) and male (TC vs TT: adjusted OR = 2.58, 95% CI = 1.33-4.47, <it>P </it>= 0.0085). As for the other three polymorphisms, there was no difference between both groups in the distributions of their genotype frequencies.</p> <p>Conclusion</p> <p>In conclusion, the <it>Ku70 </it>promoter T-991C (rs5751129), but not the <it>Ku70 </it>promoter C-57G (rs2267437), promoter A-31G (rs132770) or intron 3 (rs132774), is associated with gastric cancer susceptibility. This polymorphism may be a novel useful marker for gastric carcinogenesis.</p

Current trends in the cardiovascular clinical trial arena (I)

The existence of effective therapies for most cardiovascular disease states, coupled with increased requirements that potential benefits of new drugs be evaluated on clinical rather than surrogate endpoints, makes it increasingly difficult to substantiate any incremental improvements in efficacy that these new drugs might offer. Compounding the problem is the highly controversial issue of comparing new agents with placebos rather than active pharmaceuticals in drug efficacy trials. Despite the recent consensus that placebos may be used ethically in well-defined, justifiable circumstances, the problem persists, in part because of increased scrutiny by ethics committees but also because of considerable lingering disagreement regarding the propriety and scientific value of placebo-controlled trials (and trials of antihypertensive drugs in particular). The disagreement also substantially affects the most viable alternative to placebo-controlled trials: actively controlled equivalence/noninferiority trials. To a great extent, this situation was prompted by numerous previous trials of this type that were marked by fundamental methodological flaws and consequent false claims, inconsistencies, and potential harm to patients. As the development and use of generic drugs continue to escalate, along with concurrent pressure to control medical costs by substituting less-expensive therapies for established ones, any claim that a new drug, intervention, or therapy is "equivalent" to another should not be accepted without close scrutiny. Adherence to proper methods in conducting studies of equivalence will help investigators to avoid false claims and inconsistencies. These matters will be addressed in the third article of this three-part series

Preterm birth and small for gestational age in relation to alcohol consumption during pregnancy: stronger associations among vulnerable women? Results from two large Western-European studies

Pfinder M, Kunst AE, Feldmann R, van Eijsden M, Vrijkotte TGM. Preterm birth and small for gestational age in relation to alcohol consumption during pregnancy: stronger associations among vulnerable women? Results from two large Western-European studies. BMC Pregnancy and Childbirth. 2013;13(1): 49.BACKGROUND: Inconsistent data on the association between prenatal alcohol exposure and a range of pregnancy outcomes, such as preterm birth (PTB) and small for gestational age (SGA) raise new questions. This study aimed to assess whether the association between low-moderate prenatal alcohol exposure and PTB and SGA differs according to maternal education, maternal mental distress or maternal smoking. METHODS: The Amsterdam Born Children and their Development (ABCD) Study (N=5,238) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) (N=16,301) are both large studies. Women provide information on alcohol intake in early pregnancy, 3 months postpartum and up to 17 years retrospectively. Multivariate logistic regression analyses and stratified regression analyses were performed to examine the association between prenatal alcohol exposure and PTB and SGA, respectively. RESULTS: No association was found between any level of prenatal alcohol exposure (non-daily, daily, non-abstaining) and SGA. The offspring of daily drinkers and non-abstainers had a lower risk of PTB [ABCD: odds ratio (OR) 0.31, 95% confidence interval (CI) 0.13, 0.77; KiGGS: OR 0.75, 95% CI 0.57, 0.99]. Interactions with maternal education, maternal distress or maternal smoking were not significant. CONCLUSIONS: Although these results should be interpreted with caution, both studies showed no adverse effects of low-moderate prenatal alcohol exposure on PTB and SGA, not even in the offspring of women who were disadvantaged in terms of low education, high levels of distress, or smoking during pregnancy

Toward a theory‐based specification of non‐pharmacological treatments in aging and dementia: Focused reviews and methodological recommendations

INTRODUCTION: Non-pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results. METHODS: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System. RESULTS: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols. DISCUSSION: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area

Human Cytomegalovirus Impairs the Function of Plasmacytoid Dendritic Cells in Lymphoid Organs

Human dendritic cells (DCs) are the main antigen presenting cells (APC) and can be divided into two main populations, myeloid and plasmacytoid DCs (pDCs), the latter being the main producers of Type I Interferon. The vast majority of pDCs can be found in lymphoid organs, where the main pool of all immune cells is located, but a minority of pDCs also circulate in peripheral blood. Human cytomegalovirus (HCMV) employs multiple mechanisms to evade the immune system. In this study, we could show that pDCs obtained from lymphoid organs (tonsils) (tpDCs) and from blood (bpDCs) are different subpopulations in humans. Interestingly, these populations react in opposite manner to HCMV-infection. TpDCs were fully permissive for HCMV. Their IFN-α production and the expression of costimulatory and adhesion molecules were altered after infection. In contrast, in bpDCs HCMV replication was abrogated and the cells were activated with increased IFN-α production and upregulation of MHC class I, costimulatory, and adhesion molecules. HCMV-infection of both, tpDCs and bpDCs, led to a decreased T cell stimulation, probably mediated through a soluble factor produced by HCMV-infected pDCs. We propose that the HCMV-mediated impairment of tpDCs is a newly discovered mechanism selectively targeting the host's major population of pDCs residing in lymphoid organs

Prevalence of sexual dimorphism in mammalian phenotypic traits

The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a large proportion of mammalian traits both in wildtype and mutants are influenced by sex. This result has implications for interpreting disease phenotypes in animal models and humans

A Gene-Phenotype Network for the Laboratory Mouse and Its Implications for Systematic Phenotyping

The laboratory mouse is the pre-eminent model organism for the dissection of human disease pathways. With the advent of a comprehensive panel of gene knockouts, projects to characterise the phenotypes of all knockout lines are being initiated. The range of genotype-phenotype associations can be represented using the Mammalian Phenotype ontology. Using publicly available data annotated with this ontology we have constructed gene and phenotype networks representing these associations. These networks show a scale-free, hierarchical and modular character and community structure. They also exhibit enrichment for gene coexpression, protein-protein interactions and Gene Ontology annotation similarity. Close association between gene communities and some high-level ontology terms suggests that systematic phenotyping can provide a direct insight into underlying pathways. However some phenotypes are distributed more diffusely across gene networks, likely reflecting the pleiotropic roles of many genes. Phenotype communities show a many-to-many relationship to human disease communities, but stronger overlap at more granular levels of description. This may suggest that systematic phenotyping projects should aim for high granularity annotations to maximise their relevance to human disease

Micron-scale mapping of megagauss magnetic fields using optical polarimetry to probe hot electron transport in petawatt-class laser-solid interactions

The transport of hot, relativistic electrons produced by the interaction of an intense petawatt laser pulse with a solid has garnered interest due to its potential application in the development of innovative x-ray sources and ion-acceleration schemes. We report on spatially and temporally resolved measurements of megagauss magnetic fields at the rear of a 50-μm thick plastic target, irradiated by a multi-picosecond petawatt laser pulse at an incident intensity of ~1020 W/cm2. The pump-probe polarimetric measurements with micron-scale spatial resolution reveal the dynamics of the magnetic fields generated by the hot electron distribution at the target rear. An annular magnetic field profile was observed ~5 ps after the interaction, indicating a relatively smooth hot electron distribution at the rear-side of the plastic target. This is contrary to previous time-integrated measurements, which infer that such targets will produce highly structured hot electron transport. We measured large-scale filamentation of the hot electron distribution at the target rear only at later time-scales of ~10 ps, resulting in a commensurate large-scale filamentation of the magnetic field profile. Three-dimensional hybrid simulations corroborate our experimental observations and demonstrate a beam-like hot electron transport at initial time-scales that may be attributed to the local resistivity profile at the target rear