The frequency and presentation of upper thoracic spinous process deviations, their relationship to articular morphology, and the potential influence on static palpation techniques.

BACKGROUND: Static palpation of vertebral spinous process deviations from the midline are often utilized by manual therapists as a means to determine area for treatment of manipulable lesions. Previous research has discussed the diagnostic validity of this technique, but no correlation to vertebral morphology has been presented. AIM: To evaluate the frequency and presentation of vertebral spinous process deviations and their relationship with articular morphology, and the impact this may have in terms of static palpation techniques in the upper thoracic spine. SETTING: This study was conducted on human T1-T6 vertebrae. METHOD: A skeletal sample consisting of 58 humans T1-T6 vertebrae were photographed and linear and angular measurements taken utilizing ImageJ software and non-metric visual observations. RESULTS: Spinous process deviations in the entire sample group (n = 348) were found to occur in a frequency ranging from 19% (n = 11) at T1 to 41.4% (n = 24) at T3. However, when evaluated in terms of frequency within an individual's T1-T6, 83.3% (n = 25) of males and 67.86% (n = 19) of females demonstrated this feature, with an overall incidence of 77.59% (n = 45). Age of individuals did not show an increase in frequency, and no clear pattern could be identified regarding metric measurements and its presence. CONCLUSION: Spinous process deviations in the upper thoracic spine are most probably the result of random normal variations between individuals and are more frequent in males. Static palpation without pain criteria is not a reliable diagnostic technique to determine areas needing manual treatment, as these may be considered normal osseous anatomical variations.

The Management of Major Depressive Disorder: Synopsis of the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

DESCRIPTION: In February 2022, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline (CPG) for the management of major depressive disorder (MDD). This synopsis summarizes key recommendations. METHODS: Senior leaders within the VA and the DoD assembled a team to update the 2016 CPG for the management of MDD that included clinical stakeholders and conformed to the National Academy of Medicine's tenets for trustworthy CPGs. The guideline panel developed key questions, systematically searched and evaluated the literature, created two 1-page algorithms, and distilled 36 recommendations for care using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Select recommendations that were identified by the authors to represent key changes from the prior CPG are presented in this synopsis. RECOMMENDATIONS: The scope of the CPG is diverse; however, this synopsis focuses on key recommendations that the authors identified as important new evidence and changes to prior recommendations on pharmacologic management, pharmacogenomics, psychotherapy, complementary and alternative therapies, and the use of telemedicine.

The Effects of Photobiomodulation Therapy on Porcine Islet Insulin Secretion.

Background and objective: Xenotransplantation of porcine islets to human recipients has been investigated as a potential cure for type 1 diabetes. However, the porcine islets have poor insulin secretion capacity compared with human islets. The objective of this study was to evaluate the effect of photobiomodulation therapy (PBMT) in insulin secretion on isolated porcine islets. Methods: Eight pancreata were harvested from crossbred market porcine and the islets were isolated from the pancreas. The isolated islets were treated with PBMT (wavelength: 633 nm and dosages: 0.0, 15.6, and 31.3 J/cm2) followed by 30-min incubation in low (3.0 mM) or high (16.7 mM) glucose. The relative percentage differences on insulin secretion between three dosages were compared in low and high glucose, respectively. Results: Insulin secretion was higher in samples exposed to 15.6 J/cm2 PBMT in low glucose (p < 0.05), but not in high glucose. When evaluating sex differences, male islets had higher insulin secretion by 15.6 J/cm2 PBMT in low glucose compared with females (p < 0.05). No significant differences were seen in high glucose. When compared within the control groups (0.0 J/cm2 PBMT), the relative changes on insulin secretion in high glucose was significantly higher on male islets (p < 0.05), but not on female islets. Conclusions: PBMT may increase insulin secretion on isolated porcine islets in basal condition, but it may not improve islets' glucose responsiveness to secrete insulin. Male porcine islets may respond to PBMT and glucose stimuli better than female islets on insulin secretion.

'Pain-free TRUS B': a phase 3 double-blind placebo-controlled randomized trial of methoxyflurane with periprostatic local anaesthesia to reduce the discomfort of transrectal ultrasonography-guided prostate biopsy (ANZUP 1501).

OBJECTIVE: To determine whether the addition of inhaled methoxyflurane to periprostatic infiltration of local anaesthetic (PILA) during transrectal ultrasonography-guided prostate biopsies (TRUSBs) improved pain and other aspects of the experience. PATIENTS AND METHODS: We conducted a multicentre, placebo-controlled, double-blind, randomized phase 3 trial, involving 420 men undergoing their first TRUSB. The intervention was PILA plus a patient-controlled device containing either 3 mL methoxyflurane, or 3 mL 0.9% saline plus one drop of methoxyflurane to preserve blinding. The primary outcome was the pain score (0-10) reported by the participant after 15 min. Secondary outcomes included ratings of other aspects of the biopsy experience, willingness to undergo future biopsies, urologists' ratings, biopsy completion, and adverse events. RESULTS: The mean (SE) pain scores 15 min after TRUSB were 2.51 (0.22) in those assigned methoxyflurane vs 2.82 (0.22) for placebo (difference 0.31, 95% confidence interval [CI] -0.75 to 0.14; P = 0.18). Methoxyflurane was associated with better scores for discomfort (difference -0.48, 95% CI -0.92 to -0.03; P = 0.035, adjusted [adj.] P = 0.076), whole experience (difference -0.50, 95% CI -0.92 to -0.08; P = 0.021, adj. P = 0.053), and willingness to undergo repeat biopsies (odds ratio 1.67, 95% CI 1.12-2.49; P = 0.01) than placebo. Methoxyflurane resulted in higher scores for drowsiness (difference +1.64, 95% CI 1.21-2.07; P < 0.001, adj. P < 0.001) and dizziness (difference +1.78, 95% CI 1.31-2.24; P < 0.001, adj. P < 0.001) than placebo. There was no significant difference in the number of ≥ grade 3 adverse events. CONCLUSIONS: We found no evidence that methoxyflurane improved pain scores at 15 min, however, improvements were seen in patient-reported discomfort, overall experience, and willingness to undergo repeat biopsies.

Elevated Dietary Inflammation Among Supplemental Nutrition Assistance Program Recipients Provides Targets for Precision Public Health Intervention.

INTRODUCTION: The Supplemental Nutrition Assistance Program was designed to prevent food insecurity among low-income Americans and has been linked to improvements in pregnancy health, long-term child development, and criminal recidivism. However, the pursuit of food security does not ensure nutritional sufficiency, and the program has not improved diet quality or cardiometabolic mortality (i.e., heart disease, stroke, diabetes). In this study, longitudinal cohort data are used to identify by Supplemental Nutrition Assistance Program status the proinflammatory characteristics that predispose to chronic disease. METHODS: Between 2015 and 2018, annual 24-hour dietary recalls were conducted with 409 residents from low-income, urban neighborhoods in Columbus and Cleveland, Ohio (statistical analysis started in 2019). The Dietary Inflammatory Index was calculated. It provides empirically validated estimates of the internal inflammation that each diet should produce; higher Dietary Inflammatory Index scores have been associated with elevated inflammatory biomarkers. Finally, associations between Supplemental Nutrition Assistance Program and Dietary Inflammatory Index were evaluated, and dietary components that differed by Supplemental Nutrition Assistance Program status were identified. RESULTS: Supplemental Nutrition Assistance Program recipients had higher Dietary Inflammatory Index scores (+0.40, 95% CI=0.09, 0.70) and a consistently lower intake of 4 anti-inflammatory nutrients (dietary fiber, ß-carotene, magnesium, vitamin E) than nonrecipients. Vitamin D intake did not differ by Supplemental Nutrition Assistance Program status but was well below the Recommended Daily Allowance in this sample. CONCLUSIONS: Supplemental Nutrition Assistance Program recipients had elevated Dietary Inflammatory Index scores, implying higher diet-driven inflammation. This was due, in part, to low intake of 4 anti-inflammatory food components, which were higher yet still nutritionally insufficient among nonrecipients. Findings highlight specific nutritional targets for improving public health through dietary change.

Low Omega-3 intake is associated with high rates of depression and preterm birth on the country level.

Low circulating levels of long chain omega-3 polyunsaturated fatty acids (LC omega-3 PUFA) have been linked to major depressive disorder (MDD) and preterm birth (PTB), and prenatal depression associates with PTB. We therefore hypothesized that low Omega-3 intake would associate with higher MDD and PTB rates on the country-level. To test this hypothesis, we obtained country-level estimates for omega-3 intake, MDD prevalence, PTB rate, and per capita income for 184 countries in 2010. We then estimated the LC omega-3 PUFA levels that these intakes produce by accounting for direct consumption and the endogenous conversion of ingested plant-based precursors. Penalized splines indicated that MDD and PTB rates decreased linearly with increasing LC omega-3 PUFA, up to ~ 1000 mg/day for MDD and up to ~ 550 mg/day for PTB. Adjusted linear regression models below these thresholds revealed that a one standard deviation increase in LC omega-3 PUFA (380 mg/day) was associated with an MDD decrease of 5 cases/1000 people and a PTB decrease of 15 cases/1000 livebirths. In light of the extensive prior evidence on the individual-level, these findings indicate that low intake of LC omega-3 PUFA and its precursors may be elevating MDD and PTB rates in 85% of the countries studied.

Are convergence lines associated with high asthma presentation days? A case-control study in Melbourne, Australia.

BACKGROUND: In epidemic thunderstorm asthma (ETSA) events a large number of people develop asthma symptoms over a short period of time. This is thought to occur because of a unique combination of high amounts of pollen and certain meteorological conditions. However, the exact cause and mechanism of epidemic thunderstorm asthma remains unclear. OBJECTIVES: The objective of this study was to test the hypothesis that convergence lines may be a causative factor in ETSA events, by investigating whether convergence line weather events are associated with the occurrence of high asthma presentations days during the Victorian grass pollen season (October-December). METHODS: A case control method was used. All public hospitals within 75 km of the Melbourne weather radar were included, and data were taken from 2009 to 2017 during the Victorian grass pollen season. Cases hospital days were hospitals with a high number of asthma presentations within a 24-h period, and controls were hospitals with an expected number of asthma presentations. Exposure was defined as geographical proximity of a convergence line to the hospital case or control. RESULTS: Eighty-one case hospital days and 157 hospital day controls were included in the study. The odds of exposure to a convergence line were significantly higher for cases than for controls at all exposure distances. At 4 km, 80 of the 81 cases had been exposed to a convergence line. CONCLUSION: Convergence lines appear to be a necessary, but not sufficient, element in the cause of epidemic thunderstorm asthma. This is the first study to show a clear link between epidemic thunderstorm asthma and convergence lines.

Omega-3 polyunsaturated fatty acid intake norms and preterm birth rate: a cross-sectional analysis of 184 countries.

BACKGROUND: The preponderance of evidence now indicates that elevated long-chain omega-3 polyunsaturated fatty acid (LC omega-3 PUFA) intake is often associated with reduced risk of preterm birth (PTB). This conclusion is based on recent meta-analyses that include several studies that reported null findings. We probed the reasons for this heterogeneity across studies and its implications for PTB prevention using country-level data. METHODS: We analysed the relationship between national PTB rates (<37 weeks of gestation) and omega-3 PUFA intake norms from 184 countries for the year 2010. To estimate the total LC omega-3 PUFA levels (eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA]) that these norms produce we utilised a metric that accounts for (1) seafood-based omega-3 intake (EPA/DHA) and (2) plant-based omega-3 intake (alpha-linolenic acid [ALA]), ~20% of which is converted to EPA/DHA in vivo. We then assessed the shape of the omega-3-PTB relationship with a penalised spline and conducted linear regression analyses within the linear sections of the relationship. RESULTS: Penalised spline analyses indicated that PTB rates decrease linearly with increasing omega-3 levels up to ~600 mg/day. Income-adjusted linear regression analysis among the countries in this exposure range indicated that the number of PTBs per 100 live births decreases by 1.5 (95% CI 2.8 to 0.3) for each 1 SD increase in omega-3 intake norms (383 mg/day). CONCLUSIONS: Taken with prior evidence for a causal association on the individual level, our findings indicate that omega-3 PUFA deficiency may be a widespread contributing factor in PTB risk. Consideration of baseline omega-3 PUFA levels is critical in the design of future interventions.

A Placebo-Controlled Double-Blinded Randomized Pilot Study of Combination Phytotherapy in Biochemically Recurrent Prostate Cancer.

BACKGROUND: Men with biochemical recurrence of prostate cancer following local therapies often use natural supplements in an attempt to delay metastases and/or avoid the need for more aggressive treatments with undesirable side-effects. While there is a growing body of research into phytotherapeutic agents in this cohort, with some promising results, as yet no definitive recommendations can be made. This pilot study was undertaken to assess the feasibility of a fully-powered study to examine the effects of this phytotherapeutic intervention (containing turmeric, resveratrol, green tea and broccoli sprouts) on PSA doubling time in men with biochemical recurrence with a moderate PSA rise rate. METHODS: A double blind, randomized, placebo-controlled parallel trial was conducted with 22 men with biochemically recurrent prostate cancer and a moderate rise rate (PSA doubling time of 4-15 months and no evidence of metastases from conventional imaging methods). Patients were randomized to either the active treatment arm or placebo for 12 weeks. The primary endpoints were feasibility of study recruitment and procedures, and measurement of proposed secondary endpoints (prostate symptoms, quality of life, anxiety, and depression as measured on the EORTC QLQ-C30 and PR-25, the IPSS and HADS). Data were collected to estimate PSA-log slopes and PSA-doubling times, using a mixed model, for both the pre-intervention and post-intervention periods. RESULTS: Adherence to study protocol was excellent, and the phytotherapeutic intervention was well-tolerated, with similar numbers of mild-to-moderate adverse events in the active and placebo arms. Both the intervention and data collection methods were acceptable to participants. No statistical difference between groups on clinical outcomes was expected in this pilot study. There was between-subject variation in the PSA post treatment, but on average the active treatment group experienced a non-significant increase in the log-slope of PSA (pre-treatment doubling time = 10.2 months, post-treatment doubling time = 5.5 months), and the placebo group experienced no change in the log-slope of PSA (pre-treatment doubling time = 10.8 months, post-treatment doubling time = 10.9 months). CONCLUSION: The findings suggest that a fully powered study of this combination is feasible in men with biochemically recurrent prostate cancer and a moderate PSA rise rate. Prostate 77:765-775, 2017. © 2017 Wiley Periodicals, Inc.

Phytotherapeutic interventions in the management of biochemically recurrent prostate cancer: a systematic review of randomised trials.

OBJECTIVE: To evaluate the evidence from randomised trials for the efficacy and safety of phytotherapeutic interventions in the management of biochemically recurrent (BCR) prostate cancer, indicated by prostate-specific antigen (PSA) progression, numbers progressing to/time to initiation of androgen-deprivation therapy or salvage therapy. PATIENTS AND METHODS: MEDLINE (Ovid), EMBASE (Ovid), AMED (Ovid), CINAHL (EBSCO) and the Cochrane Library databases were searched. Clinical trials investigating phytotherapeutic interventions as dietary supplements or dietary components, including multi-component herbal formulations, in men with BCR prostate cancer were located. Eight of nine authors contacted for further information responded. Methodological quality was assessed using the Cochrane Collaboration's risk of bias assessment tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews was followed. RESULTS: Of 23 full-text articles assessed for eligibility, five met the criteria for inclusion. Two studies were placebo controlled; two were active control trials; and one a high-/low-dose trial. The interventions were administered as isolated phytochemicals (sulphoraphane), phytotherapeutic extracts [Pomi-T (pomegranate, turmeric, green tea and broccoli sprout extract), soy, lycopene, and POMx (pomegranate extract)], or plant-derived dietary items (soy and lycopene). All studies found serum PSA levels to stabilise, decrease or rise more slowly in a significant number of men, and three studies reported stabilising or lengthening of PSA-doubling time. Studies were generally of good quality, but sample sizes were predominantly small, and durations short. CONCLUSIONS: High-quality studies in this area are lacking. Sulphoraphane, lycopene, soy isoflavones, POMx, and Pomi-T are safe and well tolerated. There is limited evidence that they can affect PSA dynamics. No recommendation can be made for the use of these agents in managing prostate cancer morbidity and mortality until high-quality, fully powered studies are available. Recommendations are made for improving reproducibility and translation of findings with regard to study population, study endpoints, design, and the reporting of phytotherapeutic interventions.

Soy and soy isoflavones in prostate cancer: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the evidence from randomized controlled trials (RCTs) on the efficacy and safety of soy/isoflavones in men with prostate cancer (PCa) or with a clinically identified risk of PCa. PATIENTS AND METHODS: MEDLINE, EMBASE, the Allied and Complementary Medicine (AMED), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane Library databases were searched. We identified RCTs investigating soy/soy isoflavones as dietary supplements or dietary components for the secondary prevention or treatment of PCa in men with PCa or with a clinically identified risk of developing PCa. Studies of multi-component formulations were excluded. Six authors were contacted for further information for the meta-analyses. Methodological quality was assessed using the Cochrane Collaboration's risk-of- bias tool. The PRISMA statement for reporting systematic reviews was followed. RESULTS: Of the eight RCTs that met the inclusion criteria, six restricted recruitment to men diagnosed with PCa, while two included men with clinically identified risk of PCa. A large degree of heterogeneity was found with respect to dosages and preparations of soy/isoflavones administered. Most studies had small sample sizes and were of short duration. The risk of bias was assessed as low in all assessed studies except for one, for which the risk of bias was unclear. Meta-analyses of the two studies including men with identified risk of PCa found a significant reduction in PCa diagnosis after administration of soy/soy isoflavones (risk ratio = 0.49, 95% CI 0.26, 0.95). Meta-analyses indicated no significant differences between groups for prostate-specific antigen (PSA) levels or sex steroid endpoints (sex hormone-binding globulin [SHBG], testosterone, free testosterone, oestradiol and dihydrotestosterone). CONCLUSIONS: The results of a meta-analysis of two studies suggest there may be support for epidemiological findings of a potential role for soy/soy isoflavones in PCa risk reduction; however, a clear understanding of the impact of soy/isoflavones on PSA, total testosterone, free testosterone and SHBG levels in men with, or at identified risk of, PCa could not be derived from these data, given the limitations of sample size and study duration in individual trials. A good safety profile is shown by this meta-analysis for soy/soy isoflavones supplementation.

Effects of developmental bisphenol A exposure on reproductive-related behaviors in California mice (Peromyscus californicus): a monogamous animal model.

Bisphenol A (BPA), a pervasive, endocrine disrupting compound (EDC), acts as a mixed agonist-antagonist with respect to estrogens and other steroid hormones. We hypothesized that sexually selected traits would be particularly sensitive to EDC. Consistent with this concept, developmental exposure of males from the polygynous deer mouse, Peromyscus maniculatus, to BPA resulted in compromised spatial navigational ability and exploratory behaviors, while there was little effect on females. Here, we have examined a related, monogamous species, the California mouse (Peromyscus californicus), where we predicted that males would be less sensitive to BPA in terms of navigational and exploratory behaviors, while displaying other traits related to interactions with females and territorial marking that might be vulnerable to disruption. As in the deer mouse experiments, females were fed either a phytoestrogen-free CTL diet through pregnancy and lactation or the same diet supplemented with BPA (50 mg/kg feed weight) or ethinyl estradiol (EE) (0.1 part per billion) to provide a "pure" estrogen control. After weaning, pups were maintained on CTL diet until they had reached sexual maturity, at which time behaviors were evaluated. In addition, territorial marking was assessed in BPA-exposed males housed alone and when a control male was visible in the testing arena. In contrast to deer mice, BPA and EE exposure had no effect on spatial navigational skills in either male or female California mice. While CTL females exhibited greater exploratory behavior than CTL males, BPA exposure abolished this sex difference. BPA-exposed males, however, engaged in less territorial marking when CTL males were present. These studies demonstrate that developmental BPA exposure can disrupt adult behaviors in a sex- and species-dependent manner and are consistent with the hypothesis that sexually selected traits are particularly vulnerable to endocrine disruption and should be a consideration in risk assessment studies.

A randomised trial of robotic and open prostatectomy in men with localised prostate cancer.

BACKGROUND: Prostate cancer is the most common male cancer in the Western world however there is ongoing debate about the optimal treatment strategy for localised disease. While surgery remains the most commonly received treatment for localised disease in Australia more recently a robotic approach has emerged as an alternative to open and laparoscopic surgery. However, high level data is not yet available to support this as a superior approach or to guide treatment decision making between the alternatives. This paper presents the design of a randomised trial of Robotic and Open Prostatectomy for men newly diagnosed with localised prostate cancer that seeks to answer this question. METHODS/DESIGN: 200 men per treatment arm (400 men in total) are being recruited after diagnosis and before treatment through a major public hospital outpatient clinic and randomised to 1) Robotic Prostatectomy or 2) Open Prostatectomy. All robotic prostatectomies are being performed by one surgeon and all open prostatectomies are being performed by one other surgeon. Outcomes are being measured pre-operatively and at 6 weeks and 3, 6, 12 and 24 months post-surgery. Oncological outcomes are being related to positive surgical margins, biochemical recurrence +/- the need for further treatment. Non-oncological outcome measures include: pain, physical and mental functioning, fatigue, summary (preference-based utility scores) and domain-specific QoL (urinary incontinence, bowel function and erectile function), cancer specific distress, psychological distress, decision-related distress and time to return to usual activities. Cost modelling of each approach, as well as full economic appraisal, is also being undertaken. DISCUSSION: The study will provide recommendations about the relative benefits of Robotic and Open Prostatectomy to support informed patient decision making about treatment for localised prostate cancer; and to assist in treatment services planning for this patient group. TRIAL REGISTRATION: ACTRN12611000661976.

Percentage of positive biopsy cores: a better risk stratification model for prostate cancer?

PURPOSE: To assess the prognostic value of the percentage of positive biopsy cores (PPC) and perineural invasion in predicting the clinical outcomes after radiotherapy (RT) for prostate cancer and to explore the possibilities to improve on existing risk-stratification models. METHODS AND MATERIALS: Between 1993 and 2004, 1,056 patients with clinical Stage T1c-T3N0M0 prostate cancer, who had four or more biopsy cores sampled and complete biopsy core data available, were treated with external beam RT, with or without a high-dose-rate brachytherapy boost at William Beaumont Hospital. The median follow-up was 7.6 years. Multivariate Cox regression analysis was performed with PPC, Gleason score, pretreatment prostate-specific antigen, T stage, PNI, radiation dose, androgen deprivation, age, prostate-specific antigen frequency, and follow-up duration. A new risk stratification (PPC classification) was empirically devised to incorporate PPC and replace the T stage. RESULTS: On multivariate Cox regression analysis, the PPC was an independent predictor of distant metastasis, cause-specific survival, and overall survival (all p < .05). A PPC >50% was associated with significantly greater distant metastasis (hazard ratio, 4.01; 95% confidence interval, 1.86-8.61), and its independent predictive value remained significant with or without androgen deprivation therapy (all p < .05). In contrast, PNI and T stage were only predictive for locoregional recurrence. Combining the PPC (≤50% vs. >50%) with National Comprehensive Cancer Network risk stratification demonstrated added prognostic value of distant metastasis for the intermediate-risk (hazard ratio, 5.44; 95% confidence interval, 1.78-16.6) and high-risk (hazard ratio, 4.39; 95% confidence interval, 1.70-11.3) groups, regardless of the use of androgen deprivation and high-dose RT (all p < .05). The proposed PPC classification appears to provide improved stratification of the clinical outcomes relative to the National Comprehensive Cancer Network classification. CONCLUSIONS: The PPC is an independent and powerful predictor of clinical outcomes of prostate cancer after RT. A risk model replacing T stage with the PPC to reduce subjectivity demonstrated potentially improved stratification.

Bioinformatics challenges for genome-wide association studies.

MOTIVATION: The sequencing of the human genome has made it possible to identify an informative set of >1 million single nucleotide polymorphisms (SNPs) across the genome that can be used to carry out genome-wide association studies (GWASs). The availability of massive amounts of GWAS data has necessitated the development of new biostatistical methods for quality control, imputation and analysis issues including multiple testing. This work has been successful and has enabled the discovery of new associations that have been replicated in multiple studies. However, it is now recognized that most SNPs discovered via GWAS have small effects on disease susceptibility and thus may not be suitable for improving health care through genetic testing. One likely explanation for the mixed results of GWAS is that the current biostatistical analysis paradigm is by design agnostic or unbiased in that it ignores all prior knowledge about disease pathobiology. Further, the linear modeling framework that is employed in GWAS often considers only one SNP at a time thus ignoring their genomic and environmental context. There is now a shift away from the biostatistical approach toward a more holistic approach that recognizes the complexity of the genotype-phenotype relationship that is characterized by significant heterogeneity and gene-gene and gene-environment interaction. We argue here that bioinformatics has an important role to play in addressing the complexity of the underlying genetic basis of common human diseases. The goal of this review is to identify and discuss those GWAS challenges that will require computational methods.

Haplotype diversity in four genes (CLCNKA, CLCNKB, BSND, NEDD4L) involved in renal salt reabsorption.

OBJECTIVE: Differences exist among various populations with regards to hypertension prevalence, severity, progression and response to therapy. Such differences may be due to genetic or environmental factors. We characterized the genetic variation and haplotype diversity of four hypertension candidate genes (CLCNKA, CLCNKB, BSND, NEDD4L) in four different ethnic groups (Caucasian Americans, African-Americans, Han Chinese, and Mexican-Americans). METHODS: We genotyped 42 single nucleotide polymorphisms across the four genes in equal numbers of each ethnically defined population, then tested for linkage disequilibrium, computed allelic and haplotype frequencies, and compared data across the different ethnic groups. RESULTS: We identified significant genotype and allele frequency differences among ethnic groups. The strongest differences were observed between African-American and Mexican-Americans and between Caucasian and Mexican-Americans. In addition, haplotype blocks were defined for BSND, CLCNKA_B and NEDD4L in the four populations examined. Completely mismatched ('yin yang') haplotypes were also observed. We found that the number of inferred halpotypes varied gene to gene and in some instances between the populations for a given gene indicating substantial haplotype diversity. The haplotype diversity among the various ethnic populations observed in our study was greater than that reported in Perlegen database. CONCLUSIONS: Haplotype diversity in hypertension candidate genes has important implications for designing and evaluating candidate gene or genome-wide blood pressure association studies that consider these genes.

PTPome-wide functional RNA interference screening methods.

The elucidation of the entire complement of genes encoding protein tyrosine phosphatases (PTPs) in human genome, the human 'PTPome', has made it possible to experimentally address the entire family in an unbiased manner. Here we describe a functional RNA interference-based assay, in which we evaluate 87 of the known 107 PTPs for effects on cell survival in a high throughput manner. The details of assay rationale and design, instrumentation, pitfalls, data analysis, and further validation steps are described. We also discuss the suitability of this technology for further assay development and application to other functional read-outs and signaling pathways.

Genomics, nutrition, obesity, and diabetes.

PURPOSE: To present evidence of genetic and environmental interactions as they relate to nutrition, diabetes, and obesity. METHODS: A review of seminal literature related to genetics, obesity, and diabetes. FINDINGS: Multifactorial interactions are important in the development of nutrition-related disorders, but the challenge remains to explain how these interactions are expressed. Treating subpopulations of people might be important and useful to some extent at present, but in the future treating people of given genetic predispositions and other personal and environmental factors will have greater effects on quality-of-life indicators and life expectancies. CONCLUSIONS: Individualization coupled with multifactorial interactions will lead to new and more effective preventive and treatment modalities of nutrition-related disorders. With obesity and diabetes, genomics will bridge the traditional use of diet, exercise, and weight reduction with other environmental factors, ultimately leading to healthier lives.

VHY, a novel myristoylated testis-restricted dual specificity protein phosphatase related to VHX.

The human DUSP15 gene encodes an uncharacterized 235-amino acid member of the subfamily of small dual specificity protein phosphatases related to the Vaccinia virus VH1 phosphatase. Similar to VHR-related MKPX (VHX) (DUSP22), the predicted protein has an N-terminal myristoylation recognition sequence, and we show here that both are indeed modified by the attachment of a myristate to Gly-2. In recognition of this relatedness to VHX, we refer to the DUSP15-encoded protein as VH1-related member Y (VHY). We report that VHY is expressed at high levels in the testis and barely detectable levels in the brain, spinal cord, and thyroid. A VHY-specific antiserum detected a protein with an apparent molecular mass of 26 kDa, and histochemical analysis showed that VHY was readily detectable in pachytene spermatocytes (midstage of meiotic division I) and round spermatids and weakly in Leydig cells (somatic cells outside of the seminiferous tubules). When expressed in 293T or NIH-3T3 cells, VHY was concentrated at the plasma membrane with some staining of vesicular structures in the Golgi region. Mutation of the myristoylation site Gly-2 abrogated membrane location. Finally, we demonstrate that VHY is an active phosphatase in vitro. We conclude that VHY is a new member of a subgroup of myristoylated VH1-like small dual specificity phosphatases.