Hypoxia-Induced Loss of Consciousness in Multiple Synchronized Swimmers During a Workout

Hyperventilation by swimmers can lead to hypoxia and loss of consciousness. In this retrospective case series we describe the simultaneous onset of hypoxia in multiple 13-15-year-old female synchronized swimmers of an elite synchronized swim team based on review of Health Department and emergency medical service reports. All six swimmers performing hypoxic drills developed hypoxic symptoms (fatigue, inability to move legs, disorientation, tunnel vision, and/or loss of consciousness) and four required rescue. All swimmers regained consciousness at the scene and recovered. Two swimmers not performing hypoxic drills were unaffected. Of the environmental evaluations, only pool water temperature was higher than the recommended levels. Hyperventilation with hypoxic training can be life-threatening and should be prohibited. Duration of hypoxic drills should be limited. Emergency response plans should be practiced

Cardiomyocyte Contractile Dysfunction in the APPswe/PS1dE9 Mouse Model of Alzheimer's Disease

Ample clinical and experimental evidence indicated that patients with Alzheimer's disease display a high incidence of cardiovascular events. This study was designed to examine myocardial histology, cardiomyocyte shortening, intracellular Ca(2+) homeostasis and regulatory proteins, electrocardiogram, adrenergic response, endoplasmic reticulum (ER) stress and protein carbonyl formation in C57 wild-type (WT) mice and an APPswe/PS1dE9 transgenic (APP/PS1) model for Alzheimer's disease.Cardiomyocyte mechanical properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR), maximal velocity of shortening and relengthening (+/-dL/dt), intracellular Ca(2+) transient rise and decay.Little histological changes were observed in APP/PS1 myocardium. Cardiomyocytes from APP/PS1 but not APP or PS1 single mutation mice exhibited depressed PS, reduced+/-dL/dt, normal TPS and TR compared with WT mice(.) Rise in intracellular Ca(2+) was lower accompanied by unchanged resting/peak intracellular Ca(2+) levels and intracellular Ca(2+) decay in APP/PS1 mice. Cardiomyocytes from APP/PS1 mice exhibited a steeper decline in PS at high frequencies. The responsiveness to adrenergic agonists was dampened although beta(1)-adrenergic receptor expression was unchanged in APP/PS1 hearts. Expression of the Ca(2+) regulatory protein phospholamban and protein carbonyl formation were downregulated and elevated, respectively, associated with unchanged SERCA2a, Na(+)-Ca(2+) exchanger and ER stress markers in APP/PS1 hearts. Our further study revealed that antioxidant N-acetylcysteine attenuated the contractile dysfunction in APP/PS1 mice.Our results depicted overt cardiomyocyte mechanical dysfunction in the APP/PS1 Alzheimer's disease model, possibly due to oxidative stress

A design for cancer case–control studies using only incident cases: experience with the GEM study of melanoma

BACKGROUND: The population-based case-control study is not suited to the evaluation of rare genetic (or environmental) factors. The use of a novel case-control design in which cases have second primaries and controls are cancer survivors has been proposed for this purpose. METHODS: We report results from an international study of melanoma that involved population-based ascertainment of incident cases of second or subsequent primary melanoma as the 'case' group and incident cases of first primary melanoma as the 'control' group. We evaluate the validity of the study design by comparing the results obtained for phenotypic factors that have been shown consistently to be associated with melanoma in previous conventional studies with the results from a conventional case-control study conducted in Connecticut and from literature reviews. RESULTS: All but one of the known risk factors for melanoma were shown to be significantly associated with melanoma in our study, though the individual odds ratios appear to be somewhat attenuated relative to the magnitudes typically observed in the literature. CONCLUSIONS: Patients with a second or subsequent primary cancer of a single type represent a potentially valuable and under-utilized resource for the study of cancer aetiology

CDKN2A Germline Mutations in Individuals with Cutaneous Malignant Melanoma

Cyclin-dependent kinase inhibitor type 2A (CDKN2A) has been identified as a major melanoma susceptibility gene based on the presence of germline mutations in high-risk melanoma families. In this study, we sought to identify and characterize the spectrum of CDKN2A mutations affecting p16 inhibitor of cyclin-dependent kinase type 4 (INK4a) in individuals with melanoma using a population-based study design. DNA samples from 1189 individuals with incident multiple primary melanoma (MPM) and 2424 with incident single primary melanoma unselected for family history of melanoma were available for screening of CDKN2A (p16INK4a) mutations. Variants were classified for functional impact based on intragenic position, existing functional data, sequence, and structural analysis. The impact of individual mutations and functional groupings was assessed by comparing frequencies in cases of MPM versus cases with a single first primary melanoma, and by comparing the reported incidence rates in first-degree relatives. Our results show that mutations occur infrequently in these high-risk groups, and that they occur mainly in exons 1alpha and 2. Rare coding variants with putative functional impact are observed to increase substantially the risk of melanoma. With the exception of the variant in position -34 of CDKN2A of known functional consequence, the remaining rare variants in the non-coding region have no apparent impact on risk

Anatomical atlas-guided diffuse optical tomography of brain activation

We describe a neuroimaging protocol that utilizes an anatomical atlas of the human head to guide diffuse optical tomography of human brain activation. The protocol is demonstrated by imaging the hemodynamic response to median-nerve stimulation in three healthy subjects, and comparing the images obtained using a head atlas with the images obtained using the subject-specific head anatomy. The results indicate that using the head atlas anatomy it is possible to reconstruct the location of the brain activation to the expected gyrus of the brain, in agreement with the results obtained with the subject-specific head anatomy. The benefits of this novel method derive from eliminating the need for subject-specific head anatomy and thus obviating the need for a subject-specific MRI to improve the anatomical interpretation of diffuse optical tomography images of brain activation.National Institutes of Health (U.S.) (U54-EB-005149)National Institutes of Health (U.S.) (P41-RR14075)National Institutes of Health (U.S.) (P41-RR13218

Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Topical antibiotics for preventing surgical site infection in wounds healing by primary intention

BACKGROUND: Surgical site infections (SSI) can delay wound healing, impair cosmetic outcome and increase healthcare costs. Topical antibiotics are sometimes used to reduce microbial contaminant exposure following surgical procedures, with the aim of reducing SSIs.OBJECTIVES: The primary objective of this review was to determine whether the application of topical antibiotics to surgical wounds that are healing by primary intention reduces the incidence of SSI and whether it increases the incidence of adverse outcomes (allergic contact dermatitis, infections with patterns of antibiotic resistance and anaphylaxis).SEARCH METHODS: In May 2015 we searched: the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process &amp; Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL. We also searched clinical trial registries for ongoing studies, and bibliographies of relevant publications to identify further eligible trials. There was no restriction of language, date of study or setting. The search was repeated in May 2016 to ensure currency of included studies.SELECTION CRITERIA: All randomized controlled trials (RCTs) and quasi-randomised trials that assessed the effects of topical antibiotics (any formulation, including impregnated dressings) in people with surgical wounds healing by primary intention were eligible for inclusion.DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and independently extracted data. Two authors then assessed the studies for risk of bias. Risk ratios were calculated for dichotomous variables, and when a sufficient number of comparable trials were available, trials were pooled in a meta-analysis.MAIN RESULTS: A total of 10 RCTs and four quasi-randomised trials with 6466 participants met the inclusion criteria. Six studies involved minor procedures conducted in an outpatient or emergency department setting; eight studies involved major surgery conducted in theatre. Nine different topical antibiotics were included. We included two three-arm trials, two four-arm trials and 10 two-arm trials. The control groups comprised; an alternative topical antibiotic (two studies), topical antiseptic (six studies) and no topical antibiotic (10 studies), which comprised inert ointment (five studies) no treatment (four studies) and one study with one arm of each.The risk of bias of the 14 studies varied. Seven studies were at high risk of bias, five at unclear risk of bias and two at low risk of bias. Most risk of bias concerned risk of selection bias.Twelve of the studies (6259 participants) reported infection rates, although we could not extract the data for this outcome from one study. Four studies (3334 participants) measured allergic contact dermatitis as an outcome. Four studies measured positive wound swabs for patterns of antimicrobial resistance, for which there were no outcomes reported. No episodes of anaphylaxis were reported. Topical antibiotic versus no topical antibioticWe pooled the results of eight trials (5427 participants) for the outcome of SSI. Topical antibiotics probably reduce the risk of SSI in people with surgical wounds healing by primary intention compared with no topical antibiotic (RR 0.61, 95% CI 0.42 to 0.87; moderate-quality evidence downgraded once for risk of bias). This equates to 20 fewer SSIs per 1000 patients treated with topical antibiotics (95% CI 7 to 29) and a number needed to treat for one additional beneficial outcome (NNTB) (i.e. prevention of one SSI) of 50.We pooled the results of three trials (3012 participants) for the outcome of allergic contact dermatitis, however this comparison was underpowered, and it is unclear whether topical antibiotics affect the risk of allergic contact dermatitis (RR 3.94, 95% CI 0.46 to 34.00; very low-quality evidence, downgraded twice for risk of bias, once for imprecision). Topical antibiotic versus antiseptic We pooled the results of five trials (1299 participants) for the outcome of SSI. Topical antibiotics probably reduce the risk of SSI in people with surgical wounds healing by primary intention compared with using topical antiseptics (RR 0.49, 95% CI 0.30 to 0.80; moderate-quality evidence downgraded once for risk of bias). This equates to 43 fewer SSIs per 1000 patients treated with topical antibiotics instead of antiseptics (95% CI 17 to 59) and an NNTB of 24.We pooled the results of two trials (541 participants) for the outcome of allergic contact dermatitis; there was no clear difference in the risk of dermatitis between topical antibiotics and antiseptics, however this comparison was underpowered and a difference cannot be ruled out (RR 0.97, 95% CI 0.52 to 1.82; very low-quality evidence, downgraded twice for risk of bias and once for imprecision). Topical antibiotic versus topical antibioticOne study (99 participants) compared mupirocin ointment with a combination ointment of neomycin/polymyxin B/bacitracin zinc for the outcome of SSI. There was no clear difference in the risk of SSI, however this comparison was underpowered (very low-quality evidence downgraded twice for risk of bias, once for imprecision).A four-arm trial involved two antibiotic arms (neomycin sulfate/bacitracin zinc/polymyxin B sulphate combination ointment versus bacitracin zinc, 219 participants). There was no clear difference in risk of SSI between the combination ointment and the bacitracin zinc ointment. The quality of evidence for this outcome was low, downgraded once for risk of bias, and once for imprecision.AUTHORS' CONCLUSIONS: Topical antibiotics applied to surgical wounds healing by primary intention probably reduce the risk of SSI relative to no antibiotic, and relative to topical antiseptics (moderate quality evidence). We are unable to draw conclusions regarding the effects of topical antibiotics on adverse outcomes such as allergic contact dermatitis due to lack of statistical power (small sample sizes). We are also unable to draw conclusions regarding the impact of increasing topical antibiotic use on antibiotic resistance. The relative effects of different topical antibiotics are unclear.</p

Risk of Non-Melanoma Cancers in First-Degree Relatives of CDKN2A Mutation Carriers

The purpose of this study was to quantify the risk of cancers other than melanoma among family members of CDKN2A mutation carriers using data from the Genes, Environment and Melanoma study. Relative risks (RRs) of all non-melanoma cancers among first-degree relatives (FDRs) of melanoma patients with CDKN2A mutations (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were calculated as the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs noncarriers with exact Clopper–Pearson-type tests and 95% confidence intervals (CIs). All statistical tests were two-sided. There were 56 (13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and 2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers had an increased risk of any cancer other than melanoma (56 cancers among 429 FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands; RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429 FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands; RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429 FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands; RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to 352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%) by the kin-cohort method, under the standard assumptions of Mendelian genetics on the genotype distribution of FDRs conditional on proband genotype