Genetics of hand grip strength in mid to late life

Hand grip strength (GS) is a predictor of mortality in older adults and is moderately to highly heritable, but no genetic variants have been consistently identified. We aimed to identify single nucleotide polymorphisms (SNPs) associated with GS in middle-aged to older adults using a genome-wide association study (GWAS). GS was measured using handheld dynamometry in community-dwelling men and women aged 55–85 from the Hunter Community Study (HCS, N = 2088) and the Sydney Memory and Ageing Study (Sydney MAS, N = 541). Genotyping was undertaken using Affymetrix microarrays with imputation to HapMap2. Analyses were performed using linear regression. No genome-wide significant results were observed in HCS nor were any of the top signals replicated in Sydney MAS. Gene-based analyses in HCS identified two significant genes (ZNF295, C2CD2), but these results were not replicated in Sydney MAS. One out of eight SNPs previously associated with GS, rs550942, located near the CNTF gene, was significantly associated with GS (p = 0.005) in the HCS cohort only. Study differences may explain the lack of consistent results between the studies, including the smaller sample size of the Sydney MAS cohort. Our modest sample size also had limited power to identify variants of small effect. Our results suggest that similar to various other complex traits, many genetic variants of small effect size may influence GS. Future GWAS using larger samples and consistent measures may prove more fruitful at identifying genetic contributors for GS in middle-aged to older adults.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-015-9745-5) contains supplementary material, which is available to authorized users.     

Promoting informal and professional help‐seeking for adolescent dating violence

The present study examined factors that differentiate adolescents with varied intentions of informal and professional help seeking for dating violence. Help‐seeking intentions among 518 ethnically diverse adolescents from a rural South Carolina county who participated in a longitudinal study of teen dating violence were categorized into 3 groups: adolescents unlikely to seek any help, adolescents likely to seek only informal help, and adolescents likely to seek informal and professional help. Multinomial logistic regression found that gender, family functioning, problem‐solving competency, dating status, having an adult to talk to about a dating relationship, and acceptability of family violence significantly predicted membership in the help‐seeking groups. Implications for promoting informal and professional help seeking and recommendations for future research are discussed.     

Mutational Analysis of the Chlamydia muridarum Plasticity Zone

Pathogenically diverse Chlamydia spp. can have surprisingly similar genomes. Chlamydia trachomatis isolates that cause trachoma, sexually transmitted genital tract infections (chlamydia), and invasive lymphogranuloma venereum (LGV) and the murine strain Chlamydia muridarum share 99% of their gene content. A region of high genomic diversity between Chlamydia spp. termed the plasticity zone (PZ) may encode niche-specific virulence determinants that dictate pathogenic diversity. We hypothesized that PZ genes might mediate the greater virulence and gamma interferon (IFN-γ) resistance of C. muridarum compared to C. trachomatis in the murine genital tract. To test this hypothesis, we isolated and characterized a series of C. muridarum PZ nonsense mutants. Strains with nonsense mutations in chlamydial cytotoxins, guaBA-add, and a phospholipase D homolog developed normally in cell culture. Two of the cytotoxin mutants were less cytotoxic than the wild type, suggesting that the cytotoxins may be functional. However, none of the PZ nonsense mutants exhibited increased IFN-γ sensitivity in cell culture or were profoundly attenuated in a murine genital tract infection model. Our results suggest that C. muridarum PZ genes are transcribed—and some may produce functional proteins—but are dispensable for infection of the murine genital tract.     

Romidepsin in peripheral and cutaneous T‐cell lymphoma: mechanistic implications from clinical and correlative data

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T‐cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long‐term disease control and the ability to retreat patients relapsing off‐therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third‐line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re‐initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics‐mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T‐cell lymphoma, but suggests a complex mechanism of action.     

High-pressure superconducting phase diagram of 6Li: Isotope effects in dense lithium

We measured the superconducting transition temperature of ⁶Li between 16 and 26 GPa, and report the lightest system to exhibit superconductivity to date. The superconducting phase diagram of ⁶Li is compared with that of ⁷Li through simultaneous measurement in a diamond anvil cell (DAC). Below 21 GPa, Li exhibits a direct (the superconducting coefficient, α, T_c ∝ M^?α,  is positive), but unusually large isotope effect, whereas between 21 and 26 GPa, lithium shows an inverse superconducting isotope effect. The unusual dependence of the superconducting phase diagram of lithium on its atomic mass opens up the question of whether the lattice quantum dynamic effects dominate the low-temperature properties of dense lithium.Light elements (low Z) and their compounds have been the subject of many recent studies for their potential as high-temperature superconductors (e.g., refs. 1–5). Due to their low mass, the physical properties of the low-Z compounds can be strongly influenced by zero-point effects (lattice quantum dynamics) (6), and mass-related isotope effects may be present in their thermodynamics of vibrational degrees of freedom. Such effects will influence the superconducting properties of these materials. Dependence of superconductivity on isotopic variations of low-Z compounds can be used to probe and determine the magnitude of mass-related effects. This in turn allows better development of models to determine their superconducting properties.Under ambient pressure, lithium is the lightest elemental metallic and superconducting system, and it exhibits one of the highest superconducting transition temperatures of any elemental superconductor under compression (7–11). Despite the large mass difference between the stable isotopes of lithium (∼15%), isotope effects in superconductivity of lithium have not been studied before.In systems with long-range attractive potential, the ratio of lattice zero-point displacements to interatomic distances may increase under compression (increase to the Lindemann ratio at high densities), provided they retain their long-range interactions (12, 13). (This is opposed to systems with short-range interactions, e.g., helium, in which the lattice becomes more classical under compression.) In these systems, more deviations from the static lattice behavior are expected at higher densities. At sufficiently low temperatures, where thermal energy is small, lattice quantum dynamics can play a more dominant role in the bulk properties. Sound velocity measurements on stable isotopes of lithium at 77 K and up to 1.6 GPa show that quantum solid effects in lithium, at least in the pressure range studied, do not decrease as a function of pressure (14). Raman spectroscopy studies between 40 and 123 GPa and at 177 K report a reduced isotope effect in high-frequency vibrational modes of Li, which may be related to quantum solid behavior (15). Up to this point, no experiments have reported a comparison of any physical properties of lithium isotopes at low temperatures and high pressures concurrently. Because the superconducting transition of lithium occurs in a relatively low temperature range (16–18), studying its superconducting isotope effect provides excellent conditions to search for zero-point lattice effects and their evolution as a function of pressure.In the present study, we have measured the superconducting isotope effects in the stable isotopes of lithium under pressure. Lithium is a simple metallic system that is expected to exhibit conventional phonon-mediated superconductivity and a well-defined superconducting isotope effect with nominal pressure dependence of the relative T_c values (19) [according to the model by Treyeva and Trapezina (19), using theoretical values of Coulomb coupling constant, μ*(P) (20) by Christensen and Novikov and equation of state (EOS) of lithium (21) by Hanfland et al., assuming similar structures for the two isotopes, α should not vary by more than 10% for 15?GPa < P < 25?GPa]. Because phonon-mediated superconductivity depends on lattice and electronic properties of a material, any unusual isotopic mass dependence of the superconducting phase diagram can be indicative of the effects of large lattice dynamics on electronic and/or structural properties.     

Erlotinib-Cisplatin Combination Inhibits Growth and Angiogenesis through c-MYC and HIF-1α in EGFR-Mutated Lung Cancer In Vitro and In Vivo

Combination treatment for non–small cell lung cancer (NSCLC) is becoming more popular due to the anticipation that it may be more effective than single drug treatment. In addition, there are efforts to genetically screen patients for specific mutations in light of attempting to administer specific anticancer agents that are most effective. In this study, we evaluate the anticancer and anti-angiogenic effects of low dose erlotinib-cisplatin combination in NSCLC in vitro and in vivo. In NSCLC cells harboring epidermal growth factor receptor (EGFR) mutations, combination erlotinib-cisplatin treatment led to synergistic cell death, but there was minimal efficacy in NSCLC cells with wild-type EGFR. In xenograft models, combination treatment also demonstrated greater inhibition of tumor growth compared to individual treatment. The anti-tumor effect observed was secondary to the targeting of angiogenesis, evidenced by decreased vascular endothelial growth factor (VEGF) levels and decreased levels of CD31 and microvessel density. Combination treatment targets angiogenesis through down-regulation of the c-MYC/hypoxia inducible factor 1-alpha (HIF-1α) pathway. In fact, cell lines with EGFR exon 19 deletions expressed high basal levels of c-MYC and HIF-1α and correlate with robust responses to combination treatment. These results suggest that low dose erlotinib-cisplatin combination exhibits its anti-tumor activity by targeting angiogenesis through the modulation of the c-MYC/HIF-1α/VEGF pathway in NSCLC with EGFR exon 19 deletions. These findings may have significant clinical implications in patients with tumors harboring EGFR exon 19 deletions as they may be particularly sensitive to this regimen.     

Efficacy of Titanium Mesh Osteosynthesis in Maxillofacial Fractures

Introduction

Trauma is steadily increasing in the modern world and thus becoming a major public problem. Maxillofacial injuries constitute a substantial proportion of cases of trauma and occur in a variety of situations like road traffic accidents, interpersonal violence, falls or as a result of contact sports. The aim of this prospective study was to evaluate the efficacy of titanium mesh for osteosynthesis of maxillofacial fractures.

Materials and Methods

Fifteen patients of maxillofacial fractures who were treated with titanium mesh were included in this prospective study. The patients were evaluated preoperatively, intraoperatively and postoperatively at 7th day, 3rd week, 6th week and 12th week.

Results

The mean age of fifteen patients was 31.3 years with a male:female ratio of 14:1. The most common mode of injury was road traffic accident (86.6%). The mean time interval between injury and surgical procedure was found to be 7.6 days. The majority of fracture sites (88%) were comminuted. 93.3% of the patients achieved good occlusion by 12th week postoperatively. Postoperative complications included residual hypoaesthesia in four patients and wound dehiscence in one patient.

Conclusion

We conclude that titanium mesh is a versatile option for maxillofacial fractures. It provided good stabilization especially in comminuted fractures. As a fixation method, it was quick in placement and highly adaptable, and thus, it proved to be valuable in restoring the form and function in maxillofacial trauma patients.

     

Revisiting "her" infertility: medicalized embodiment, self-identification and distress

Prior research emphasizes women's distress and responsibility for a couple's infertility because of gendered, pronatalist norms. Yet some studies suggest that being personally diagnosed and/or undergoing treatment differentially shapes reactions. We focused on differences in women's experiences with diagnosis and treatment, conceptualized as the medicalized embodiment of infertility. Using regression analysis, we examined two psychosocial outcomes (self-identification as infertile and fertility-specific distress) in a sample of 496 heterosexual, U.S. women from the National Survey of Fertility Barriers. Medicalized embodiment was salient to women's reactions, but had different relationships to self-identification versus distress. Although women experienced distress regardless of type of diagnosis, they were generally less likely to self-identify as infertile unless personally diagnosed. As such, we cannot assume that all women universally experience infertility. Future research should also address self-identification and distress as separate as opposed to simultaneous psychosocial outcomes.