Genome-wide Gene-by-Sex Interaction Studies Identify Novel Nonsyndromic Orofacial Clefts Risk Locus.

Risk loci identified through genome-wide association studies have explained about 25% of the phenotypic variations in nonsyndromic orofacial clefts (nsOFCs) on the liability scale. Despite the notable sex differences in the incidences of the different cleft types, investigation of loci for sex-specific effects has been understudied. To explore the sex-specific effects in genetic etiology of nsOFCs, we conducted a genome-wide gene × sex (GxSex) interaction study in a sub-Saharan African orofacial cleft cohort. The sample included 1,019 nonsyndromic orofacial cleft cases (814 cleft lip with or without cleft palate and 205 cleft palate only) and 2,159 controls recruited from 3 sites (Ethiopia, Ghana, and Nigeria). An additive logistic model was used to examine the joint effects of the genotype and GxSex interaction. Furthermore, we examined loci with suggestive significance (P < 1E-5) in the additive model for the effect of the GxSex interaction only. We identified a novel risk locus on chromosome 8p22 with genome-wide significant joint and GxSex interaction effects (rs2720555, p2df = 1.16E-08, pGxSex = 1.49E-09, odds ratio [OR] = 0.44, 95% CI = 0.34 to 0.57). For males, the risk of cleft lip with or without cleft palate at this locus decreases with additional copies of the minor allele (p < 0.0001, OR = 0.60, 95% CI = 0.48 to 0.74), but the effect is reversed for females (p = 0.0004, OR = 1.36, 95% CI = 1.15 to 1.60). We replicated the female-specific effect of this locus in an independent cohort (p = 0.037, OR = 1.30, 95% CI = 1.02 to 1.65), but no significant effect was found for the males (p = 0.29, OR = 0.86, 95% CI = 0.65 to 1.14). This locus is in topologically associating domain with craniofacially expressed and enriched genes during embryonic development. Rare coding mutations of some of these genes were identified in nsOFC cohorts through whole exome sequencing analysis. Our study is additional proof that genome-wide GxSex interaction analysis provides an opportunity for novel findings of loci and genes that contribute to the risk of nsOFCs.

High Schools Struggle to Adopt Evidence Based Practices for the Management of Exertional Heat Stroke.

CONTEXT: Exertional heat stroke (EHS) deaths can be prevented by adhering to best practices. OBJECTIVE: We investigated the adoption of policies and procedures for the recognition and treatment of EHS and the factors influencing the adoption of a comprehensive policy. DESIGN: Cross Sectional. SETTING: Online questionnaire. PATIENTS OR OTHER PARTICIPANTS: Athletic trainers (ATs) practicing in the high school (HS) setting. MAIN OUTCOME MEASURE(S): Using the NATA Position Statement: Exertional Heat Illness, an online questionnaire was developed and distributed to ATs to ascertain their schools' current written policies for the use of rectal temperature and cold-water immersion (CWI). The Precaution Adoption Process Model (PAPM), allowed for responses to be presented across the various health behavior stages ("Unaware if have the policy", "Unaware for the need for the policy", "Unengaged", "Undecided", "Decided Not to Act", "Decided to Act", "Acting", and "Maintaining"). Additional questions included perceptions of facilitators and barriers. Data are presented as proportions. RESULTS: A total of 531 ATs completed this questionnaire. Overall, 16.9% (n=62) report adoption of all components for proper recognition and treatment of EHS. The policy component with the highest adoption was "cool first transport second" with 74.1% (n=110) of ATs reporting "Acting" or "Maintaining." The most variability in the PAPM responses was for a rectal temperature policy, with 28.7% (n=103) of ATs reporting "Decided not to Act" and 20.1% (n=72) reporting "Maintaining." The most commonly reported facilitator and barrier for rectal temperature included state mandate from state HS athletics association (n=274,51.5%) and resistance or apprehension from parents or legal guardians (n=311,58.5%), respectively. CONCLUSIONS: ATs in the HS setting appear to be struggling to adopt a comprehensive EHS strategy, with rectal temperature continuing to appear as the biggest undertaking. Tailored strategies based on health behavior, facilitators and barriers may aid in changing this paradigm.

Associations between birthweight and overweight and obesity in school-age children.

BACKGROUND: Relationships between birthweight and future obesity risk remain unclear. OBJECTIVE: To assess associations between birthweight and later obesity in a nationally representative cohort of early school-aged children. METHODS: We used linear and logistic regression to evaluate 10 186 term- or preterm children in the Early Childhood Longitudinal Study-Kindergarten Cohort 2011 for relationships between birthweight and later obesity and change in BMI z-score from kindergarten-to-second grade. All analyses were adjusted for sex, race/ethnicity, parental education and household income. RESULTS: Compared to children born normal birthweight (NBW), high birthweight (HBW) term children and large-for-gestational-age (LGA) preterm children had significantly greater BMI z-scores from kindergarten-to-second grade (p < 0.001). Term children born HBW had higher odds of obesity by kindergarten (adjusted odds ratios [aOR] 1.91, p < 0.0001). Among preterm children, odds of obesity was higher among LGA children starting in first grade (aOR 2.34, p < 0.05) and among small-for-gestational age children in second grade (aOR 2.26, p < 0.05). Compared to NBW children, HBW children had greater change in BMI z-score between kindergarten-first grade (p < 0.01). CONCLUSIONS: High birthweight term and LGA preterm children had increased adjusted odds of obesity in school-age compared to their NBW counterparts. Physicians may provide counselling early in life for families of large infants to help prevent future obesity.

Executive functioning in low birth weight children entering kindergarten.

OBJECTIVES: Poor executive functioning is associated with life-long difficulty. Identification of children at risk for executive dysfunction is important for early intervention to improve neurodevelopmental outcomes. STUDY DESIGN: This study is designed to examine relationships between birthweight and executive functioning in US children during kindergarten. Our hypothesis was that children with higher birthweights would have better executive function scores. We evaluated data from 17506 US children from the Early Childhood Longitudinal Study-Kindergarten 2011 cohort. Birthweight and gestational age were obtained by parental survey. Executive functions were directly assessed using the number reverse test and card sort test to measure working memory and cognitive flexibility, respectively. Teacher evaluations were used for additional executive functions. Data were analyzed using SAS to run all linear and logistical regressions. RESULTS: For every kilogram of birthweight, scores of working memory increased by 1.47 (P<0.001) and cognitive flexibility increased by 0.28 (P<0.001) independent of gender, gestational age, parental education, and family income. Low birthweight infants were 1.5 times more likely to score in the bottom 20% of children on direct assessment OR=1.49 (CI 1.21-1.85) and OR=1.55 (CI 1.26-1.91). CONCLUSIONS: Infants born low birthweight are at increased risk of poor executive functioning. As birthweight increases executive function scores improve, even among infants born normal weight. Further evaluation of this population including interventions and progression through school is needed.

A comparative analysis of experimental selection on the stickleback pelvis.

Mechanisms of natural selection can be identified using experimental approaches. However, such experiments often yield nonsignificant effects and imprecise estimates of selection due to low power and small sample sizes. Combining results from multiple experimental studies might produce an aggregate estimate of selection that is more revealing than individual studies. For example, bony pelvic armour varies conspicuously among stickleback populations, and predation by vertebrate and insect predators has been hypothesized to be the main driver of this variation. Yet experimental selection studies testing these hypotheses frequently fail to find a significant effect. We experimentally manipulated length of threespine stickleback (Gasterosteus aculeatus) pelvic spines in a mesocosm experiment to test whether prickly sculpin (Cottus asper), an intraguild predator of stickleback, favours longer spines. The probability of survival was greater for stickleback with unclipped pelvic spines, but this effect was noisy and not significant. We used meta-analysis to combine the results of our mesocosm experiment with previously published experimental studies of selection on pelvic armour. We found evidence that fish predation indeed favours increased pelvic armour, with a moderate effect size. The same approach found little evidence that insect predation favours reduced pelvic armour. The causes of reduced pelvic armour in many stickleback populations remain uncertain.

Hemorrhagic Herpes Simplex Virus Type 1 Nephritis: An Unusual Cause of Acute Allograft Dysfunction.

Interstitial nephritis due to viruses is well-described after solid organ transplantation. Viruses implicated include cytomegalovirus; BK polyomavirus; Epstein-Barr virus; and, less commonly, adenovirus. We describe a rare case of hemorrhagic allograft nephritis due to herpes simplex virus type 1 at 10 days after living donor kidney transplantation. The patient had a favorable outcome with intravenous acyclovir and reduction of immunosuppression.

Expression of a mitochondrial progesterone receptor in human spermatozoa correlates with a progestin-dependent increase in mitochondrial membrane potential.

The hyperactivation of human spermatozoa necessary for fertilization requires a substantial increase in cellular energy production. The factors responsible for increasing cellular energy remain poorly defined. This article proposes a role for a novel mitochondrial progesterone receptor (PR-M) in modulation of mitochondrial activity. Basic science studies demonstrate a 38 kDa protein with western blot analysis, consistent with PR-M; whereas imaging studies with confocal and immunoelectron microscopy demonstrate a PR on the mitochondria. Treatment with a PR-specific progestin shows increased mitochondrial membrane potential, not related to induction of an acrosome reaction. The increase in mitochondrial membrane potential was inhibited by a specific PR antagonist, but not affected by an inhibitor to the progesterone-dependent Catsper voltage-activated channel. In conclusion, these studies suggest expression of a novel mitochondrial PR in human spermatozoa with a progestin-dependent increase in mitochondrial activity. This mechanism may serve to enhance cellular energy production as the spermatozoa traverse the female genital tract being exposed to increasing concentrations of progesterone.

TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia.

TAR DNA binding protein-43 (TDP-43) is found in ubiquitinated inclusions (UBIs) in some frontotemporal dementias (FTD-U). One form of FTD-U, due to mutations in the valosin containing protein (VCP) gene, occurs with an inclusion body myopathy (IBMPFD). Since IBMPFD brain has TDP-43 in UBIs, we looked for TDP-43 inclusions in IBMPFD muscle. In normal muscle, TDP-43 is present in nuclei. In IBMPFD muscle, TDP-43 is additionally present as large inclusions within UBIs in muscle cytoplasm. TDP-43 inclusions were also found in 78% of sporadic inclusion body myositis (sIBM) muscles. In IBMPFD and sIBM muscle, TDP-43 migrated with an additional band on immunoblot similar to that reported in FTD-U brains. This study adds sIBM and hereditary inclusion body myopathies to the growing list of TDP-43 positive inclusion diseases.

Comparison of teaching methods to learn a tilt and balance wheelchair skill.

Often service professionals working with individuals who use wheelchairs find themselves inadequately prepared to give hands-on or verbal assistance in wheelchair maneuverability skills. The purpose of this study was to examine the effectiveness of two methods of teaching a tilt and balance wheelchair skill, evaluated by using an obstacle course. Subjects were 30 volunteers, having no past wheelchair experience. The Instruction group viewed an instructional video followed by structured wheelchair practice. The Instruction plus Biomechanics group experienced these same interventions and received a biomechanical explanation of the wheelchair skill. The Control group received no instruction but did receive additional practice time in a wheelchair. It was hypothesized that the first two groups would improve their maneuverability in the wheelchair over the Control group. A 2-way analysis of variance, with main effects for groups followed by a Tukey post hoc test, indicated that the two instruction groups had significantly better times on the obstacle course, demonstrating better maneuverability skills than the Control group. The repeated-measures portion of the analysis of variance showed the main effect for improving time from the pretest to posttest significant for all groups with the instruction groups improving times by 30 sec. over that of the Control group. The retention test was not significantly different from the posttest, and there were no significant interactions. Results indicated a need for wheelchair users to be taught maneuverability skills systematically.

Outbreaks of acute gastroenteritis associated with Norwalk-like viruses in campus settings.

Norwalk-like viruses (NLVs) are transmitted by fecally contaminated food, water, fomites, and person-to-person contact. They are a leading cause of acute gastroenteritis epidemics in industrialized countries. NLV outbreaks are characterized by a 12- to 48-hour incubation period; nausea, vomiting, and diarrhea for 24 to 72 hours; and high secondary attack rates. NLV infections spread rapidly on college and university campuses because of close living quarters, shared bathrooms and common rooms, many food handlers, popular self-service salad bars in dining halls, and person-to-person contact through sports and recreational activities. The illness is generally mild and self-limited but an outbreak can strain the resources of campus health services and cause high absenteeism among both students and staff. Treatment is primarily through antiemetic medication and oral rehydration. Prevention and control of NLV outbreaks rests on promoting hand washing; enforcement of strict hygiene in all food preparation areas; and prompt, rigorous cleaning of potentially contaminated areas where someone has been ill.

Photophysics of pi-conjugated metal-organic oligomers: aryleneethynylenes that contain the (bpy)Re(CO)(3)Cl chromophore.

A comprehensive study of a series of four monodisperse, metal-organic pi-conjugated oligomers of varying length is reported. The oligomers are based on the aryleneethynylene architecture, and they contain a 2,2'-bipyridine-5,5'-diyl (bpy) metal binding unit. The photophysical properties of the free oligomers and their complexes with the (L)Re(I)(CO)(3)X chromophore (where L = the bpy-oligomer and X = Cl or NCCH(3)) were explored by a variety of methods including electrochemistry, UV-visible absorption, variable temperature photoluminescence (PL), transient absorption (TA), and time-resolved electron paramagnetic spectroscopy (TREPR). The absorption of the free oligomers and the metal complexes is dominated by the pi,pi* transitions of the pi-conjugated oligomers. The free oligomers feature a strong blue fluorescence that is quenched entirely in the (L)Re(I)(CO)(3)X complexes. The metal-oligomers feature a weak, relatively long-lived red photoluminescence that is assigned to emission from both the (3)pi,pi* manifold of the pi-conjugated system and the dpi Re --> pi* bpy-oligomer metal-to-ligand charge transfer ((3)MLCT) state. On the basis of a detailed analysis of the PL, TA, and TREPR results an excited-state model is developed which indicates that the oligomer-based (3)pi,pi* state and the (3)MLCT states are in close energetic proximity. Consequently the photophysical properties reflect a composite of the properties of the two excited-state manifolds.

Environmental modulation of alpha(v), alpha(2) and beta(1) integrin subunit expression in human oesophageal squamous cell carcinomas.

Integrins are cell adhesion molecules pivotal in regulating normal cell behaviour. Ectopic expression of integrins, characteristic of transformed cells, is instrumental in differentiation, proliferation, apoptosis, angiogenesis, matrix degradation and migration. Oesophageal squamous cell carcinoma (SCC) has a propensity to metastasize and hence an extremely poor prognosis. It is shown here that oesophageal SCCs express alpha(v)strongly and that normal oesophageal tissue does not express alpha(v). This makes alpha(v)a significant indicator of the transformed phenotype. alpha(2)and beta(1)integrin subunits are down-regulated in oesophageal SCCs compared to normal oesophagus. Dominance of the alpha(2)beta(1)heterodimer is symptomatic of potential loss of other beta(1)binding integrins in oesophageal SCCs. These results suggest a decrease in rigid cell adhesion possibly increasing migratory potential, whilst simultaneously permitting the adhesion and migration of SCC cells on a large repertoire of ligands due to de novo alpha(v)expression.

Enhanced green fluorescent protein as a marker for localizing murine cytomegalovirus in acute and latent infection.

A recombinant murine cytomegalovirus (mCMV) that expresses enhanced green fluorescent protein (EGFP) under control of the native immediate-early 1/3 promoter was constructed to detect directly sites of viral activity in latent and reactivated infections. The recombinant virus had acute and latent infection characteristics similar to those of wild-type mCMV. Rare green-fluorescing foci were observed in paraffin sections from lungs and spleens infected latently. Positive immunoperoxidase staining for EGFP in sections of the same lung tissues suggests that these cells may be sites of restricted viral gene expression. EGFP was detected easily in tissue explants reactivating from latent infection in vitro. Morphology and adhesion characteristics of fluorescing cells suggest that viral reactivation occurs in tissue macrophages in explant cultures. The observations presented in this study demonstrate the usefulness of EGFP-expressing recombinants as tools for direct tracking of mCMV activity in vivo and in vitro.

Direct measurement of hole transport dynamics in DNA.

Our understanding of oxidative damage to double helical DNA and the design of DNA-based devices for molecular electronics is crucially dependent upon elucidation of the mechanism and dynamics of electron and hole transport in DNA. Electrons and holes can migrate from the locus of formation to trap sites, and such migration can occur through either a single-step "superexchange" mechanism or a multistep charge transport "hopping" mechanism. The rates of single-step charge separation and charge recombination processes are found to decrease rapidly with increasing transfer distances, whereas multistep hole transport processes are only weakly distance dependent. However, the dynamics of hole transport has not yet been directly determined. Here we report spectroscopic measurements of photoinduced electron transfer in synthetic DNA that yield rate constants of approximately 5 x 10(7) s(-1) and 5 x 10(6) s(-1), respectively, for the forward and return hole transport from a single guanine base to a double guanine base step across a single adenine. These rates are faster than processes leading to strand cleavage, such as the reaction of guanine cation radical with water, thus permitting holes to migrate over long distances in DNA. However, they are too slow to compete with charge recombination in contact ion pairs, a process which protects DNA from photochemical damage.