Widespread prevalence of a CREBRF variant amongst Maori and Pacific children is associated with weight and height in early childhood.

OBJECTIVE: Investigating a large and ethnically diverse cohort from the Pacific region, we aimed to replicate and extend the recently reported findings that a CREBRF genetic variant is strongly associated with body mass index in Samoans. METHODS: A birth cohort of more than six thousand children was utilised. In this study, genotyping of two markers (rs12513649 and rs373863828) was undertaken in Maori, Pacific, European and Asian individuals in the cohort. RESULTS: We report that these CREBRF genetic variants are not confined to Samoans but are prevalent in all other Pacific populations sampled, including Maori. We found that the rs373863828 variant was significantly associated with growth at 4 years of age. On average, we observed allele-specific increases in weight (P=0·004, +455 g, s.e. 0.158), height (P=0·007, +0·70 cm, s.e. 0.26) and waist circumference (P=0·004, +0·70 cm, s.e. 0.24) at 4 years of age. The rs373863828 variant was not associated with birth weight (P=0·129). CONCLUSIONS: We replicated the finding that a CREBRF variant is associated with increased body mass. We then built on the original findings by demonstrating the prevalence of the rs12513649 and rs373863828 variants in multiple Pacific population groups and by demonstrating that the rs373863828 variant is associated with growth in early childhood. Pacific population groups experience a disproportionately high burden of obesity, starting in early childhood. This new knowledge offers potential for evidence-based interventions aimed at establishing healthy growth trajectories from the earliest possible age.

A multidisciplinary, biopsychosocial treatment for non-cardiac chest pain.

BACKGROUND: Non-cardiac chest pain (NCCP) affects up to 80% of patients attending chest pain clinics, but its treatment is suboptimal. AIM: To describe the outcomes of a pilot, stepped care, biopsychosocial management programme in terms of improvements in chest pain, psychosocial scores and use of healthcare resources. METHODS: Of 198 referrals, 77 patients were suitable for the clinic and received a one hour biopsychosocial assessment. Stepped care consisted of assessment only, low intensity Cognitive Behaviour Therapy (CBT), or high intensity CBT. RESULTS: The proportion with pain occurring more than once monthly fell from 100% at baseline to 61% at 3 months (p < 0.001). Pain interference reduced significantly (p < 0.001) from 5.9 [SD 2.2] at baseline to 3.2 [SD 2.6] at 3 months. Depression scores improved from a mean 8.8 to 5.4 (p < 0.05) and anxiety from 6.9 to 4.6 (p < 0.05). Use of healthcare resources improved with a fall in consultations for chest pain over 6 months from a mean 2.6 to 0.1 (p < 0.05). The impact on work and social functioning reduced from 10.4 [SD 10.4] to 3.9 [SD 7.5]: [t (70) = 6.3, p < 0.001). Further improvements occurred at 6 months for chest pain frequency (which fell to 51%, p = 0.003), interference (2.6 [SD 2.1], p < 0.05) and avoidance of exercise (p = 0.03). Otherwise improvements were maintained between 3 and 6 months. CONCLUSION: A stepped-care biopsychosocial approach to NCCP is effective in reducing chest pain frequency and improving behaviour and wellbeing. It can be delivered in part by a nurse allowing integration into any chest pain clinic.

Non-cardiac chest pain: time to extend the rapid access chest pain clinic?

Non-cardiac chest pain is common. It has a low risk of coronary events, but causes considerable physical and social disability and inappropriate health-care usage. It is a heterogeneous condition, which may be caused by or associated with gastro-oesophageal, musculoskeletal or psychiatric abnormalities and sustained by psychological factors including catastrophisation, avoidance behaviour and abnormal help-seeking. These may coexist and their relative contributions may vary in different patients or at different times in an individual patient. The absence of a unitary cause probably explains why treatment studies show only moderate success. An individualised biopsychosocial approach takes account of all causative and sustaining processes and has been shown to work in pain syndromes at other sites. We suggest that this approach should be tried for chest pain using a multidisciplinary clinic model including cardiologists, psychologists and nurses linked with a Rapid Access Chest Pain Clinic.

Spinal cord intramedullary cavernoma: A case report.

BACKGROUND: Spinal Cord Intramedullary Cavernoma is a rare disease. It is a vascular disorder composed of capillary-liked vessels without intervening neurons within a spinal lesion. It may only be discovered incidentally or may be diagnosed after a neurologic deficit. Patients may present with weakness which could mimic other neurologic pathology. CASE: A case of a 65 year old with history of hypertension and diabetes mellitus. He had previous microdissectomy of the lumbar L4-L5 disc. He presented with progressive lower leg paresis, urinary retention and obstipation. An MRI revealed a cavernous angioma at the T5 level. CONCLUSION: A multitude of neurologic deficits could lead to a patient presenting with a Spinal Cord Cavernoma. Prompt imaging is warranted in cases presenting with the symptoms to allow appropriate diagnoses and treatment. The clinician must be aware of this rare, but debilitating disease complex.

Intrusions in trauma and psychosis: information processing and phenomenology.

BACKGROUND: Intrusions are common symptoms of both post-traumatic stress disorder (PTSD) and schizophrenia. It has been suggested that an information processing style characterized by weak trait contextual integration renders psychotic individuals vulnerable to intrusive experiences. This 'contextual integration hypothesis' was tested in individuals reporting anomalous experiences in the absence of a need for care. METHOD: Twenty-six low schizotypes and 23 individuals reporting anomalous experiences were shown a traumatic film with and without a concurrent visuospatial task (VST). Participants rated post-traumatic intrusions for frequency and form, and completed self-report measures of information processing style. It was predicted that, because of their weaker trait contextual integration, the anomalous experiences (AE) group would (1) exhibit more intrusions following exposure to the trauma film, (2) display intrusions characterized by more PTSD qualities and (3) show a greater reduction of intrusions with the concurrent VST. RESULTS: As predicted, the AE group reported a lower level of trait contextual integration and more intrusions than the low schizotypes, both immediately after watching the film and during the following 7 days. Their post-traumatic intrusive memories were more PTSD-like (more intrusive, vivid and associated with emotion). The VST had no effect on the number of intrusions in either group. CONCLUSIONS: These findings provide some support for the proposal that weak trait contextual integration underlies the development of intrusions within both PTSD and psychosis.

Knowledge, attitudes and behaviours associated with the provision of hepatitis C care by Canadian family physicians.

The role of primary care physicians in providing care for hepatitis C virus (HCV) infection is increasingly emphasized, but many gaps and challenges remain. This study explores family physicians' knowledge, attitudes and practices associated with providing care for HCV infection. Seven hundred and forty-nine members of the College of Family Physicians of Canada (CFPC) completed a self-administered survey examining knowledge, attitudes and behaviours regarding HCV infection screening and care. Multivariate analyses were performed using the outcome, HCV care provision, and variables based on a conceptual model of practice guideline adherence. Family physicians providing basic-advanced HCV care were more likely to be older, practice in a rural setting, have injection drug users (IDU) in their practice and have higher levels of knowledge about the initial assessment (OR = 1.77; 95% CI = 1.23-2.54) and treatment of HCV (OR = 1.74; 95% CI = 1.24-2.43). They were also less likely to believe that family physicians do not have a role in HCV care (OR = 0.41; 95% CI = 0.30-0.58). Educational programmes should target physicians less likely to provide HCV care, namely family physicians practicing in urban areas and those who do not care for any IDU patients. Training and continuing medical education programmes that aim to shift family physicians' attitudes about the provision of HCV care by promoting their roles as integral to HCV care could contribute to easing the burden on consultant physicians and lead to improved access to treatment for HCV infection.

Author Correction: Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pesticides: insecticides and fungicides are chitin synthesis inhibitors.

Several important groups of fungicides and insecticides are specific inhibitors of chitin synthesis in a Phycomyces enzyme system and in insect organ cultures. The recently discovered benzoylphenylurea insecticides, which prevent chitin synthesis in insect tissues, are apparently not direct-acting chitin synthetase inhibitors. These insecticides may prevent insect chitin synthesis by interfering with the proteolytic activation of the chitin synthetase zymogen.

Cockroach leg regeneration: effects of ecdysterone in vitro.

Regenerating epithelial tissue from the cockroach leg forms two cuticular coverings. The first of these consists of a protein-carbohydrate complex that is replaced before molting. The second covering represents the cuticle containing chitin. The deposition of the cuticle can be induced in vitro by adding ecdysterone to the culture medium.

Cognitive behavioural therapy for insomnia (CBTi) as a treatment for tinnitus-related insomnia: protocol for a randomised controlled trial.

BACKGROUND: A significant proportion of patients with chronic tinnitus report clinical levels of sleep disturbance (insomnia). Despite the significant health and functioning implications of this, no rigorous trials have investigated treatments that target tinnitus-related insomnia. This is the first randomised controlled trial evaluating Cognitive Behavioural Therapy for insomnia (CBTi) in tinnitus compared with other psychological treatments. METHODS/DESIGN: The study will test the efficacy of group CBTi as a treatment for tinnitus-related insomnia in a single-centre randomised controlled trial. Participants will be 102 patients with chronic, clinically significant tinnitus and insomnia in the absence of organic sleep disorders. Participants will be randomised to one of three intervention arms: six sessions of CBTi or six sessions of sleep support group or two sessions of audiologically based care. The primary outcomes will be changes in sleep as measured on the Insomnia Severity Index and key outcomes on a 2-week sleep diary (sleep efficiency and total sleep time). Outcomes will be collected 3, 10, 14 and 34 weeks post-randomisation. Secondary measures include sleep quality, sleep beliefs, tinnitus severity, psychological distress and quality of life. A sub-sample of participants will provide two weeks of actigraphy data at the same time points. Data on satisfaction and treatment experience will be collected at 10 and 34 weeks post-randomisation from all participants. DISCUSSION: Findings from the study will be submitted to a peer-reviewed journal. It is anticipated that findings may inform future clinical practice in the treatment of tinnitus-related insomnia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03386123. Retrospectively registered on 29 December 2017.

Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation.

Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40-/- murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.

A Feasibility Study of High-Strength Bi-2223 Conductor for High-Field Solenoids.

We performed a feasibility study on a high-strength Bi2-x Pb x Sr2Ca2Cu3O10-x (Bi-2223) tape conductor for high-field solenoid applications. The investigated conductor, DI-BSCCO Type HT-XX, is a pre-production version of Type HT-NX, which has recently become available from Sumitomo Electric Industries (SEI). It is based on their DI-BSCCO Type H tape, but laminated with a high-strength Ni-alloy. We used stress-strain characterizations, single- and double-bend tests, easy- and hard-way bent coil-turns at various radii, straight and helical samples in up to 31.2 T background field, and small 20-turn coils in up to 17 T background field to systematically determine the electro-mechanical limits in magnet-relevant conditions. In longitudinal tensile tests at 77 K, we found critical stress- and strain-levels of 516 MPa and 0.57%, respectively. In three decidedly different experiments we detected an amplification of the allowable strain with a combination of pure bending and Lorentz loading to ≥ 0.92% (calculated elastically at the outer tape edge). This significant strain level, and the fact that it is multi-filamentary conductor and available in the reacted and insulated state, makes DI-BSCCO HT-NX highly suitable for very high-field solenoids, for which high current densities and therefore high loads are required to retain manageable magnet dimensions.

Re-engineering the target specificity of Clostridial neurotoxins - a route to novel therapeutics.

The ability to chemically couple proteins to LH(N)-fragments of clostridial neurotoxins and create novel molecules with selectivity for cells other than the natural target cell of the native neurotoxin is well established. Such molecules are able to inhibit exocytosis in the target cell and have the potential to be therapeutically beneficial where secretion from a particular cell plays a causative role in a disease or medical condition. To date, these molecules have been produced by chemical coupling of the LH(N)-fragment and the targeting ligand. This is, however, not a suitable basis for producing pharmaceutical agents as the products are ill defined, difficult to control and heterogeneous. Also, the molecules described to date have targeted neuroendocrine cells that are susceptible to native neurotoxins, and therefore the benefit of creating a molecule with a novel targeting domain has been limited. In this paper, the production of a fully recombinant fusion protein from a recombinant gene encoding both the LH(N)-domain of a clostridial neurotoxin and a specific targeting domain is described, together with the ability of such recombinant fusion proteins to inhibit secretion from non-neuronal target cells. Specifically, a novel protein consisting of the LH(N)-domains of botulinum neurotoxin type C and epidermal growth factor (EGF) that is able to inhibit secretion of mucus from epithelial cells is reported. Such a molecule has the potential to prevent mucus hypersecretion in asthma and chronic obstructive pulmonary disease.

Thymosin ß4: Roles in Development, Repair, and Engineering of the Cardiovascular System.

The burden of cardiovascular disease is a growing worldwide issue that demands attention. While many clinical trials are ongoing to test therapies for treating the heart after myocardial infarction (MI) and heart failure, there are few options doctors able to currently give patients to repair the heart. This eventually leads to decreased ventricular contractility and increased systemic disease, including vascular disorders that could result in stroke. Small peptides such as thymosin ß4 (Tß4) are upregulated in the cardiovascular niche during fetal development and after injuries such as MI, providing increased neovasculogenesis and paracrine signals for endogenous stem cell recruitment to aid in wound repair. New research is looking into the effects of in vivo administration of Tß4 through injections and coatings on implants, as well as its effect on cell differentiation. Results so far demonstrate Tß4 administration leads to robust increases in angiogenesis and wound healing in the heart after MI and the brain after stroke, and can differentiate adult stem cells toward the cardiac lineage for implantation to the heart to increase contractility and survival. Future work, some of which is currently in clinical trials, will demonstrate the in vivo effect of these therapies on human patients, with the goal of helping the millions of people worldwide affected by cardiovascular disease.

Reduced susceptibility to syncope during postural tilt in old age. Is beta-blockade protective?

Clinical studies of syncope suggest a decreased prevalence of vasovagal syncope in old age. To examine this possibility and its pathophysiologic implications, we report the results of two studies. The first evaluated responses to head-up tilt in young and old subjects. Presyncopal vasovagal symptoms occurred in 4 of 9 young subjects and only 1 of 22 old subjects. The second study asked whether decreased beta-adrenergic responsiveness protected the old during tilt via unopposed alpha-adrenergic-mediated vasoconstriction. Blood pressure, heart rate, and forearm vascular resistance responses to tilt in 11 healthy young subjects randomized to receive intravenous propranolol hydrochloride or saline were compared with those of 10 healthy elderly. Propranolol attenuated heart rate and forearm vascular resistance responses. Vasovagal symptoms occurred in 4 young and no old subjects; 2 were symptomatic during propranolol administration. Thus, presyncopal vasovagal symptoms are less common during tilt in old age. Propranolol did not prevent the vasovagal reaction or enhance forearm vasoconstriction. Propranolol's attenuation of vasoconstriction may be due to decreased activation of cardiopulmonary baroreceptors during beta-blockade.

Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model.

B cells have been reported to promote graft rejection through alloantibody production. However, there is growing evidence that B cells can contribute to the maintenance of tolerance. Here, we used a mouse model of MHC-class I mismatched skin transplantation to investigate the contribution of B cells to graft survival. We demonstrate that adoptive transfer of B cells prolongs skin graft survival but only when the B cells were isolated from mice housed in low sterility "conventional" (CV) facilities and not from mice housed in pathogen free facilities (SPF). However, prolongation of skin graft survival was lost when B cells were isolated from IL-10 deficient mice housed in CV facilities. The suppressive function of B cells isolated from mice housed in CV facilities correlated with an anti-inflammatory environment and with the presence of a different gut microflora compared to mice maintained in SPF facilities. Treatment of mice in the CV facility with antibiotics abrogated the regulatory capacity of B cells. Finally, we identified transitional B cells isolated from CV facilities as possessing the regulatory function. These findings demonstrate that B cells, and in particular transitional B cells, can promote prolongation of graft survival, a function dependent on licensing by gut microflora.

Effect of alterations in extracellular fluid volume on urinary kallikrein in the conscious rat.

The effect of alterations in extracellular fluid volume (ECV) and solute concentration on excretion of urinary kallikrein was examined in conscious Sprague-Dawley rats. Animals were given infusions of either dextrose and water, saline, or albumin according to a variety of protocols. These were designed to evaluate possible relationships between excretion of kallikrein, volume, sodium, and potassium. A reproducible pattern of kallikrein excretion was noted in all volume expanded groups. This consisted of a short lived increase during the initial hour of expansion with a subsequent fall to lower levels than baseline and a gradual recovery. To define the role of aldosterone in these studies, an adrenalectomized group and a group of appropriately prepared sham controls were expanded with saline. Adrenalectomy did not effect this pattern. We postulate a tubular "washout" phenomenon as the etiology of these observations. Results of these studies fail to demonstrate a consistent relationship between urinary volume, sodium, or potassium and the simultaneous amount of kallikrein found in the urine.

CBF measured by Xe-CT: approach to analysis and normal values.

Normal reference values and a practical approach to CBF analysis are needed for routine clinical analysis and interpretation of xenon-enhanced computed tomography (CT) CBF studies. We measured CBF in 67 normal individuals with the GE 9800 CT scanner adapted for CBF imaging with stable Xe. CBF values for vascular territories were systematically analyzed using the clustering of contiguous 2-cm circular regions of interest (ROIs) placed within the cortical mantle and basal ganglia. Mixed cortical flows averaged 51 +/- 10ml.100g-1.min-1. High and low flow compartments, sampled by placing 5-mm circular ROIs in regions containing the highest and lowest flow values in each hemisphere, averaged 84 +/- 14 and 20 +/- 5 ml.100 g-1.min-1, respectively. Mixed cortical flow values as well as values within the high flow compartment demonstrated significant decline with age; however, there were no significant age-related changes in the low flow compartment. The clustering of systematically placed cortical and subcortical ROIs has provided a normative data base for Xe-CT CBF and a flexible and uncomplicated method for the analysis of CBF maps generated by Xe-enhanced CT.

Zinc deficiency in pregnant rhesus monkeys: effects on behavior of infants.

Zinc deprivation from day 110 to 150 of gestation in rhesus monkeys resulted in rash, alopecia, anorexia, decreased feed efficiency, and low plasma zinc in the mothers. Infants of the dams that had been deprived of zinc during gestation displayed a more rapid postnatal growth rate than infants of the control mothers. Infants of the zinc-deprived dams played and explored less than the control infants. They also associated with their mothers a greater percentage of the time and were less active. This study has shown that third trimester maternal zinc deprivation in nonhuman primates can impair behavioral development of offspring.

Alterations in systemic haemodynamics induced by atriopeptin III.

The mechanism of the hypotensive response to the intravenous administration of atriopeptin III was investigated in rats of the Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) Okamoto strains. Cardiac performance and the systemic haemodynamic response to acute volume loading were evaluated before and during atriopeptin infusion. Cardiac output was measured by a thermo-dilution technique in conscious rats, and left ventricular pressures with differential (dP/dt) calculations were obtained in anaesthetized animals. Bolus injections followed by a 1-h continuous infusion of atriopeptin caused a progressive decrease in mean arterial pressure (MAP) and cardiac output with no significant change in heart rate. In addition there was a transient decrease, maximal at 5 min, and a subsequent increase in peripheral resistance. Atriopeptin did not alter the maximal cardiac output achieved following acute volume expansion. In the anaesthetized animals, bolus injection with a subsequent 15-min continuous infusion of atriopeptin III significantly reduced left ventricular pressures, dP/dt and mean arterial pressure. Volume expansion fully restored intraventricular pressures and dP/dt while increasing mean arterial pressure toward baseline. We conclude that the steady decrease in mean arterial pressure produced by atriopeptin III is due to a decrease in cardiac output secondary to a fall in stroke volume caused by a lowered filling pressure.