Comparative genomics of the T cell receptor µ locus in marsupials and monotremes.

T cells are a primary component of the vertebrate adaptive immune system. There are three mammalian T cell lineages based on their T cell receptors (TCR). The αß T cells and γδ T cells are ancient and found broadly in vertebrates. The more recently discovered γµ T cells are uniquely mammalian and only found in marsupials and monotremes. In this study, we compare the TCRµ locus (TRM) across the genomes of two marsupials, the gray short-tailed opossum and Tasmanian devil, and one monotreme, the platypus. These analyses revealed lineage-specific duplications, common to all non-eutherian mammals described. There is conserved synteny in the TRM loci of both marsupials but not in the monotreme. Our results are consistent with an ancestral cluster organization which was present in the last common mammalian ancestor which underwent lineage-specific duplications and divergence among the non-eutherian mammals.

Human health impacts of exposure to phthalate plasticizers: An overview of reviews.

In this review of reviews, we overview the current global body of available evidence from structured reviews of epidemiological studies that explore human health outcomes associated with exposure to phthalates (chemical plasticisers commonly found in plastics). We found robust evidence for an association with lower semen quality, neurodevelopment and risk of childhood asthma, and moderate to robust evidence for impact on anogenital distance in boys. We identified moderate evidence for an association between phthalates/metabolites and low birthweight, endometriosis, decreased testosterone, ADHD, Type 2 diabetes and breast/uterine cancer. There was some evidence for other outcomes including anofourchette distance, fetal sex hormones, pre-term birth, lower antral follicle count, reduced oestrodiol, autism, obesity, thyroid function and hearing disorders. We found no reviews of epidemiological human studies on the impact of phthalates from recycled plastics on human health. We recommend that future research should use urine samples as exposure measures, consider confounders in analyses and measure impacts on female reproductive systems. Our findings align with emerging research indicating that health risks can occur at exposure levels below the "safe dose" levels set out by regulators, and are of particular concern given potential additive or synergistic "cocktail effects" of chemicals. This raises important policy and regulatory issues for identifying and controlling plastics and health related impacts and highlights a need for more research into substances of concern entering plastics waste streams via recycling.

Indoor PM2.5, VOCs and asthma outcomes: A systematic review in adults and their home environments.

INTRODUCTION: As the amount of time people spend indoors increases globally, exposure to indoor air pollutants has become an important public health concern. Asthma is a complex disease caused and/or exacerbated by increased exposure to diverse chemical, physical and biological exposures from multiple indoor and outdoor sources. This review aims to investigate the relationship between increased indoor PM and VOC concentrations (i.e. objectively measured) and the risk of adult asthma in higher-income countries. METHODS: Eleven databases were systematically searched on the February 1, 2019 and again on the February 2, 2020. Articles were limited to those published since 1990. Reference lists were independently screened by three reviewers and authors were contacted to identify relevant articles. Backwards and forward citation chasing was used to identify further studies. Data were extracted from included studies meeting our eligibility criteria by three reviewers and assessed for quality using the Newcastle-Ottawa scale designed for case-control and cohort studies. RESULTS: Twelve studies were included in a narrative synthesis. We found insufficient evidence to determine the effect of PM2.5 on asthma in the indoor home environment. However, there was strong evidence to suggest that VOCs, especially aromatic compounds, and aliphatic compounds, were associated with increased asthma symptoms. DISCUSSION & CONCLUSION: Although no single exposure appears to be responsible for the development of asthma or its associated symptoms, the use of everyday products may be associated with increased asthma symptoms. To prevent poor health outcomes among the general population, health professionals and industry must make a concerted effort to better inform the general population of the importance of appropriate use of and storage of chemicals within the home as well as better health messaging on product labelling.

The effect of dietary alterations during rearing on feather condition in broiler breeder females.

In commercial production, broiler breeders are severely feed restricted to maintain healthy BW. This restriction can induce stereotypic behavior, including feather pecking, which has negative welfare implications for both the victim and performer. It has been suggested that the problem may be symptomatic of chronic hunger or the frustration of feeding motivation. In this study, we determined whether feather condition, as an indirect measure of feather pecking, could be improved via dietary manipulation. Six dietary treatments were tested, each with 5 replicate pens of 9 to 12 birds. Control diets (C) were fed on a daily or skip-a-day (SAD) basis. Alternative diets included soybean hulls as a bulking ingredient and calcium propionate (CaP) as an appetite suppressant of either a feed grade (F) or purified (P) quality. Both alternative diets were fed on either a daily or SAD basis. Five or 6 birds were randomly chosen from each pen and feather scored at 10, 14, 20, 26, and 36 wk of age. Six body parts (neck, back, wings, legs, vent area, tail) were given a score from 0 to 5 (0 = no feather damage, and 5 ≥ 50% feather loss with tissue damage). Scores were summed for each bird and averaged for each pen. Data were analyzed with room and feeding frequency as main factors and diet as the subfactor with repeated measures. There was an interaction between diet and time (P < 0.01) with the feather condition of the C birds worsening more quickly in comparison with the F and P birds. There was an interaction between feeding frequency and time (P = 0.015), with SAD-fed birds scoring better than daily-fed birds at 20, 26, and 36 wk. This interaction could indicate that SAD feeding increased satiety after the birds became accustomed to the schedule. Because feather condition was better with the alternative diets, this may indicate a reduction in stereotyped feather pecking with these diets. This suggests that the alternative diets increase satiety compared with the control diets.

The effect of dietary alterations during rearing on growth, productivity, and behavior in broiler breeder females.

Parent stocks of meat birds are severely feed restricted to avoid obesity-related health and fertility problems. This restriction often leads to chronic hunger, accompanied by stereotypic behavior. Research based in the United Kingdom has shown that using diets containing fiber and appetite suppressants may relieve some of the symptoms of hunger. However, few data are available regarding North American-sourced ingredients or nondaily feeding regimens. This study investigated the effects of 2 alternative diets, in combination with 2 feeding frequencies on growth, productivity, and behavior in broiler breeders. Six dietary treatments were tested, each with 5 replicate pens of 12 or 13 birds. Control diets consisted of a commercial crumble, fed on a daily or skip-a-day (SAD) basis. Alternative diets included soybean hulls as a fiber source, and calcium propionate as an appetite suppressant of either a feed-grade or purified quality, fed on either a daily or SAD basis. Birds were weighed weekly and egg production was recorded daily. Video cameras were used to record behavior during and following the morning feeding bout every 2 wk from 11 to 28 wk. Data were analyzed with a mixed model ANOVA, with repeated measures. Diet, feeding frequency, time, or an interaction of the 3 had significant effects on all observed behavior during rearing. These differences appeared to diminish during lay, with most stereotypic behavior no longer present. Very little object pecking and aggression was observed during and immediately following feeding bouts; however, daily-fed control birds still displayed this behavior more often, especially during rearing (P = 0.015). During feeding bouts, SAD birds feather pecked (P = 0.003) and rested more (P = 0.0002) than daily-fed birds. Control birds feather pecked most often (P = 0.033) after feeding bouts. Overall, the feed-grade diet appeared most effective at reducing hunger-related behavior, and the control diet appeared the least effective. There was little conclusive evidence to show that daily feeding was more effective at reducing hunger.

Risk of desmoid tumours after open and laparoscopic colectomy in patients with familial adenomatous polyposis.

BACKGROUND: Desmoid tumour (DT) is a main cause of death after prophylactic colectomy in patients with familial adenomatous polyposis (FAP). The purpose of this study was to evaluate the impact of prophylactic laparoscopic colectomy on the risk of developing DT in patients with FAP. METHODS: The database of a single institution was reviewed. Patients with classical FAP with defined genotype who underwent either open or laparoscopic colectomy between 1947 and 2011 were included in the study. The impact of various demographic and clinical features on the risk of developing DT was assessed. RESULTS: A total of 672 patients underwent prophylactic colectomy: 602 by an open and 70 by a laparoscopic approach. With a median (range) follow-up of 132 (0-516) months in the open group and 60 (12-108) months in the laparoscopic group, 98 patients (16·3 per cent) developed DT after an open procedure compared with three (4 per cent) following laparoscopic surgery. The estimated cumulative risk of developing DT at 5 years after surgery was 13·0 per cent in the open group and 4 per cent in the laparoscopic group (P = 0·042). In multivariable analysis, female sex (hazard ratio (HR) 2·18, 95 per cent confidence interval 1·40 to 3·39), adenomatous polyposis coli mutation distal to codon 1400 (HR 3·85, 1·90 to 7·80), proctocolectomy (HR 1·67, 1·06 to 2·61), open colectomy (HR 6·84, 1·96 to 23·98) and year of surgery (HR 1·04, 1·01 to 1·07) were independent risk factors for the diagnosis of DT after prophylactic surgery. CONCLUSION: Laparoscopic surgery decreased the risk of DT after prophylactic colectomy in patients with FAP.

The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin.

Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.-66T → C, rs2252281) and MATE2 (g.-130G → A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients.

The UCSF-FDA TransPortal: a public drug transporter database.

Drug transporters play a key role in the absorption, distribution, and elimination of many drugs, and they appear to be important determinants of therapeutic and adverse drug activities. Although a large body of data pertaining to drug transporters is available, there are few databases that inform drug developers, regulatory agencies, and academic scientists about transporters that are important in drug action and disposition. In this article, we inform the scientific community about the UCSF-FDA TransPortal, a new and valuable online resource for research and drug development.

Discovery of regulatory elements in human ATP-binding cassette transporters through expression quantitative trait mapping.

ATP-binding cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic basis and functional outcome of ABC transporter expression level variation. We used genotype and mRNA transcript level data from human lymphoblastoid cell lines to assess population and gender differences in ABC transporter expression, and to guide the discovery of genomic regions involved in transcriptional regulation. Nineteen of 49 ABC genes were differentially expressed between individuals of African, Asian and European descent, suggesting an important influence of race on expression level of ABC transporters. Twenty-four significant associations were found between transporter transcript levels and proximally located genetic variants. Several of the associations were experimentally validated in reporter assays. Through influencing ABC expression levels, these single-nucleotide polymorphisms may affect disease susceptibility and response to drugs.

Allogeneic hematopoietic SCT for primary cutaneous T cell lymphomas.

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas that are considered incurable. The role of allogeneic hematopoietic SCT (HSCT) in the treatment of CTCL is not well defined but may provide potent graft-vs-lymphoma (GVL) activity independent of the conditioning therapy. We present outcomes of 12 extensively-pretreated patients with CTCL who underwent allogeneic HSCT using, most commonly, a reduced intensity conditioning regimen. Median age at diagnosis of CTCL was 49 years, and median time to transplantation from diagnosis was 3.3 years. Transplantation induced and maintained CR in six patients with active disease, supporting the presence of a GVL effect. TRM was low, and 42% of patients were alive and disease-free a median duration of 22 months after transplant. Two patients showed strong and direct evidence of a GVL-effect with a direct response to withdrawal of immunosuppression or to donor leukocyte infusion. Our data show that HSCT can provide long-term disease control in patients with advanced CTCL, which otherwise was refractory to immunotherapy and chemotherapy.

A common 5'-UTR variant in MATE2-K is associated with poor response to metformin.

Multidrug and toxin extrusion 2 (MATE2-K (SLC47A2)), a polyspecific organic cation exporter, facilitates the renal elimination of the antidiabetes drug metformin. In this study, we characterized genetic variants of MATE2-K, determined their association with metformin response, and elucidated their impact by means of a comparative protein structure model. Four nonsynonymous variants and four variants in the MATE2-K basal promoter region were identified from ethnically diverse populations. Two nonsynonymous variants-c.485C>T and c.1177G>A-were shown to be associated with significantly lower metformin uptake and reduction in protein expression levels. MATE2-K basal promoter haplotypes containing the most common variant, g.-130G>A (>26% allele frequency), were associated with a significant increase in luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1 (MZF-1). Patients with diabetes who were homozygous for g.-130A had a significantly poorer response to metformin treatment, assessed as relative change in glycated hemoglobin (HbA1c) (-0.027 (-0.076, 0.033)), as compared with carriers of the reference allele, g.-130G (-0.15 (-0.17, -0.13)) (P=0.002). Our study showed that MATE2-K plays a role in the antidiabetes response to metformin.

Multiple-technique analytical characterization of a mixture containing chemical-weapons simulant from a munition.

An amber yellow organic liquid was found in a munition shell at Dugway Proving Grounds, UT, USA, that was likely used as a simulant of chemical weapons. The primary analytical techniques to characterize the mixture were gas chromatography-infrared detection-mass spectral detection (GC-IR-MS); liquid chromatography-mass spectrometry (LC-MS); nuclear magnetic resonance (NMR) using the nuclei 1H, 13C and 31P; and gas chromatography-atomic emission detection (GC-AED). Six major phosphorus-containing components were identified and confirmed by at least three techniques, and several additional phosphorus-containing components of lower concentration have been identified by GC-IR-MS and LC-MS. Five major non-phosphorus components, including ethyl acetate, diethyl sulfide and dibutylamine, have been identified by multiple techniques. The major phosphorus compound (23.9+/-0.4 wt.%) was O,O,O-triethyl phosphorothioate (I) and the second most abundant (14.4+/-0.2 wt.%) was O,O,S-triethyl phosphorothioate (III). No VX, G-agent, or pesticide was observed in the sample, although III may be a cholinesterase inhibitor which produces delayed toxic response. III also produces a false hit for the pesticide cyanthoate when analyzed by GC-MS-EI. The mixture appears to have been formulated as a chemical warfare agent simulant, most likely as a challenge of agent detection techniques.

IV glycine and oral D-cycloserine effects on plasma and CSF amino acids in healthy humans.

BACKGROUND: The amino acid glycine, modulates neurotransmission via actions at GLY-A receptor and GLY-B receptor. The latter are coagonist sites associated with N-Methyl-D-Aspartate (NMDA) glutamate receptors. The central bioavailability of peripherally administered glycine has not been adequately characterized in humans. METHODS: Healthy human subjects were administered either oral D-cycloserine (50 mg or placebo) and intravenous glycine (saline, 100 mg/kg or 200 mg/kg) in random order over 4 test days under double-blind conditions. Cerebrospinal fluid was collected by lumbar puncture performed on the first test day was analyzed to determine amino acid levels. The acoustic startle response was measured on the second test day. RESULTS: Intravenous glycine dose-dependently increased both serum and CSF glycine and serine levels. Neither glycine nor DCS produced any significant effects on behavior, cognition or the acoustic startle response. Neither IV glycine nor DCS were associated with any toxicity. CONCLUSIONS: Thus, peripheral glycine administration raised CSF glycine levels without producing any clear central nervous system effects. Glycine and D-cycloserine did not worsen cognitive test performance and did not induce behavioral symptoms on their own. The possibility that glycine and D-cycloserine enhanced cognitive test performance cannot be excluded given the psychometric limitations of the test battery.

The effects of mesh bioprosthesis on the spermatic cord structures: a preliminary report in a canine model.

PURPOSE: The use of mesh bioprosthesis during inguinal herniorrhaphy is now considered routine. To our knowledge, no studies have examined the effects of mesh induced fibrosis on the structure and function of the adjacent spermatic cord. We present our experience in a canine model. MATERIALS AND METHODS: Unilateral inguinal hernia defects were created in 12 male beagle dogs. Half were repaired using Marlex mesh and half using a classic Shouldice technique. The inguinal anatomy was then re-examined at 6 and 12 months. Testicular temperature and volume, peripheral and testicular vein testosterone levels, testicular blood flow, vasography, testicular and cord histology, and sperm motility/morphology were recorded. Groups were compared with each other as well as to the non-operated (control) side. RESULTS: Although post-operative testicular volumes from both the mesh and Shouldice groups were similar to controls (p >0.05), there was a downward trend after mesh repair (17.8 cc pre versus 12.6 cc post) but this did not reach statistical significance (p = 0.17). Testicular temperatures and blood flow did not differ between experimental groups and controls. While testicular vein testosterone levels were significantly higher than peripheral venous levels after Shouldice repair, this difference was lost after mesh repair. Contralateral (control) testicular vein testosterone levels were higher in animals repaired with mesh than by an anatomic Shouldice repair (p <0.05). There was a significant decrease in cross sectional vasal luminal diameter in both the anatomic and mesh repair groups versus their respective contralateral controls (p <0.05). This was correlated with a marked foreign body reaction to the mesh in the soft tissues surrounding the vas in spermatic cords exposed to Marlex. All vasograms demonstrated patency. Gross pathology was abnormal in 3/6 dogs with mesh repair (2 hydroceles and 1 ischemic testis) and 0/6 animals after Shouldice repair. A traumatic neuroma was identified in the mesh group. Sperm morphology and motility did not differ between the two groups. CONCLUSIONS: Half of the testicles had gross abnormalities after mesh repair versus none in the control and Shouldice dogs. Although all vasograms were patent, vasal luminal size was significantly decreased with a marked soft tissue foreign body reaction identified after mesh repair. A traumatic neuroma was identified suggesting nerve entrapment in the fibrotic mesh reaction, which may account for post-operative pain seen in some patients. Marlex mesh may adversely affect spermatic cord structure and function and further work is required to fully elucidate its effects.

Appendiceal CT in 140 cases. Diagnostic criteria for acute and necrotizing appendicitis.

Computed tomography (CT) was performed in 140 patients with suspected acute appendicitis. Thin collimation (5 mm), intravenous contrast enhancement, 1-second scan times, and supplementary cecal air insufflation were emphasized. CT accuracy was 98% overall (137/140), and 99% in the 124 cases with early surgery. Necrotizing appendicitis was diagnosed by CT with 86% accuracy and 90% positive predictive value.

Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.

DNA content of rectal scrapings from individuals at low and high risk for the development of colorectal cancer. A feasibility study.

Scrapings of superficial rectal mucosa were collected from 31 patients with colorectal carcinoma, 66 patients with sporadic adenoma, and 53 control subjects with no personal or family history of colorectal cancer. The DNA ploidy level and proliferative patterns of each specimen were analyzed by flow cytometry (FCM). A GMS index, calculated as the ratio of G2 + M:S, was found to be significantly lower in control subjects than in any of the high-risk groups studied. Aneuploidy was more prevalent in rectal scrapings from cancer patients and adenoma patients than in those from control subjects. Aneuploid cell populations were detected in apparently normal rectal scrapings from two control subjects. Some high-risk individuals (i.e., cancer patients and patients with adenomas and a family history of cancer) exhibited higher proportions of tetraploid (designated G2/M) cells and a higher G2/M:S phase ratio than control subjects. The results accumulated thus far show that the rectal scraping procedure is safe and easy to perform. Our limited findings give hope that the DNA content analysis of cells obtained by rectal scraping may eventually prove useful in mass screening for colorectal cancer risk. However, definitive evaluation will require further refinement and elaboration of analytic technique and testing on more patients at various levels of predetermined risk.