Enzyme changes during development of holo- and hemi-metabolic insects

1. 1. Several carbohydrate metabolizing enzymes were examined spectrophotometrically and electrophoretically in four life stages of the holometabolic fruit fly, Drosophila pseudoobscura, and in three life stages of the hemimetabolic pea aphid, Acyrthosiphon pisum. 2. 2. Drosophila pupae exhibit significantly lower enzyme activities than third instar larvae. Most enzymes recover to larval levels or higher in adults, but some continue to decrease following eclosion. 3. 3. Enzyme activities remain relatively unchanged during development of Acyrthosiphon. 4. 4. The same isozymic forms of each enzyme are usually represented in all life stages of Drosophila, and in all life stages of Acyrthosiphon. 5. 5. Enzyme levels parallel the distinct morphological and physiological changes characterizing development of representative holo- and hemi-metabolic insects. © 1976

Projections of the current and future disease burden of hepatitis C virus infection in Malaysia

The prevalence of hepatitis C virus (HCV) infection in Malaysia has been estimated at 2.5% of the adult population. Our objective, satisfying one of the directives of the WHO Framework for Global Action on Viral Hepatitis, was to forecast the HCV disease burden in Malaysia using modelling methods.An age-structured multi-state Markov model was developed to simulate the natural history of HCV infection. We tested three historical incidence scenarios that would give rise to the estimated prevalence in 2009, and calculated the incidence of cirrhosis, end-stage liver disease, and death, and disability-adjusted life-years (DALYs) under each scenario, to the year 2039. In the baseline scenario, current antiviral treatment levels were extended from 2014 to the end of the simulation period. To estimate the disease burden averted under current sustained virological response rates and treatment levels, the baseline scenario was compared to a counterfactual scenario in which no past or future treatment is assumed.In the baseline scenario, the projected disease burden for the year 2039 is 94,900 DALYs/year (95% credible interval (CrI): 77,100 to 124,500), with 2,002 (95% CrI: 1340 to 3040) and 540 (95% CrI: 251 to 1,030) individuals predicted to develop decompensated cirrhosis and hepatocellular carcinoma, respectively, in that year. Although current treatment practice is estimated to avert a cumulative total of 2,200 deaths from DC or HCC, a cumulative total of 63,900 HCV-related deaths is projected by 2039.The HCV-related disease burden is already high and is forecast to rise steeply over the coming decades under current levels of antiviral treatment. Increased governmental resources to improve HCV screening and treatment rates and to reduce transmission are essential to address the high projected HCV disease burden in Malaysia

Internal construct validity of the Warwick-Edinburgh Mental Well-being Scale (WEMWBS): a Rasch analysis using data from the Scottish Health Education Population Survey

Background: The Warwick-Edinburgh Mental Well-Being Scale (WEMWBS) was developed to meet demand for instruments to measure mental well-being. It comprises 14 positively phrased Likert-style items and fulfils classic criteria for scale development. We report here the internal construct validity of WEMWBS from the perspective of the Rasch measurement model. Methods: The model was applied to data collected from 779 respondents in Wave 12 (Autumn 2006) of the Scottish Health Education Population Survey. Respondents were aged 16–74 (average 41.9) yrs. Results: Initial fit to model expectations was poor. The items 'I've been feeling good about myself', 'I've been interested in new things' and 'I've been feeling cheerful' all showed significant misfit to model expectations, and were deleted. This led to a marginal improvement in fit to the model. After further analysis, more items were deleted and a strict unidimensional seven item scale (the Short Warwick Edinburgh Mental Well-Being Scale (SWEMWBS)) was resolved. Many items deleted because of misfit with model expectations showed considerable bias for gender. Two retained items also demonstrated bias for gender but, at the scale level, cancelled out. One further retained item 'I've been feeling optimistic about the future' showed bias for age. The correlation between the 14 item and 7 item versions was 0.954. Given fit to the Rasch model, and strict unidimensionality, SWEMWBS provides an interval scale estimate of mental well-being. Conclusion: A short 7 item version of WEMWBS was found to satisfy the strict unidimensionality expectations of the Rasch model, and be largely free of bias. This scale, SWEMWBS, provides a raw score-interval scale transformation for use in parametric procedures. In terms of face validity, SWEMWBS presents a more restricted view of mental well-being than the 14 item WEMWBS, with most items representing aspects of psychological and eudemonic well-being, and few covering hedonic well-being or affect. However, robust measurement properties combined with brevity make SWEMWBS preferable to WEMWBS at present for monitoring mental well-being in populations. Where face validity is an issue there remain arguments for continuing to collect data on the full 14 item WEMWBS

Multi-Scalar-Singlet Extension of the Standard Model - the Case for Dark Matter and an Invisible Higgs Boson

We consider a simple extension of the Standard Model by the addition of N real scalar gauge singlets \vp that are candidates for Dark Matter. By collecting theoretical and experimental constraints we determine the space of allowed parameters of the model. The possibility of ameliorating the little hierarchy problem within the multi-singlet model is discussed. The Spergel-Steinhardt solution of the Dark Matter density cusp problem is revisited. It is shown that fitting the recent CRESST-II data for Dark Matter nucleus scattering implies that the standard Higgs boson decays predominantly into pairs of Dark Matter scalars. It that case discovery of the Higgs boson at LHC and Tevatron is impossible. The most likely mass of the dark scalars is in the range 15 GeV \lsim \mvp \lsim 50 GeV with BR(h \to \vp\vp) up to 96%.Comment: 18 pages, 15 figure

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD

Leptogenesis from loop effects in curved spacetime

We describe a new mechanism -- radiatively-induced gravitational leptogenesis -- for generating the matter-antimatter asymmetry of the Universe. We show how quantum loop effects in C and CP violating theories cause matter and antimatter to propagate differently in the presence of gravity, and prove this is forbidden in flat space by CPT and translation symmetry. This generates a curvature-dependent chemical potential for leptons, allowing a matter-antimatter asymmetry to be generated in thermal equilibrium in the early Universe. The time-dependent dynamics necessary for leptogenesis is provided by the interaction of the virtual self-energy cloud of the leptons with the expanding curved spacetime background, which violates the strong equivalence principle and allows a distinction between matter and antimatter. We show here how this mechanism is realised in a particular BSM theory, the see-saw model, where the quantum loops involve the heavy sterile neutrinos responsible for light neutrino masses. We demonstrate by explicit computation of the relevant two-loop Feynman diagrams how the size of the radiative corrections relevant for leptogenesis becomes enhanced by increasing the mass hierarchy of the sterile neutrinos, and show that for realistic phenomenological parameters this mechanism can generate the observed baryon-to-photon ratio of the Universe

Sickle cell trait and priapism: a case report and review of the literature

Background A 32 year-old African-American man presented to our institution after attempting suicide via ingestion with quetiapine. He had reported a history of several days of substance abuse with alcohol, cocaine and marijuana related to a partying binge. Following this, his partner removed him from his residence resulting in a suicide attempt. During hospitalization the patient developed priapism, a condition he had not experienced before. Case presentation Given this was his first time with priapism, an extensive work-up revealed the patient had previously undiagnosed sickle cell trait, which we postulate to have been a significant factor in his development of acute priapism. Sickle cell trait is considered to be a generally benign condition except for a few rare complications under more demanding physical conditions. However, upon reviewing the literature on the association of sickle cell trait with priapism, we believe this may not be the case. Case reports and small series that appeared in the 1960s and 1970s indicated an association between priapism and sickle trait. Little has been reported recently, and the general teaching regarding sickle cell trait does not include this information. However, one case was reported with the use of phosphodiesterase-5 (PDE-5) inhibitors and the development of priapism in a patient with sickle cell trait. These medications are now first line treatment in erectile dysfunction. They act by enhancing nitric oxide (NO) production leading to relaxation of smooth muscle in the corpora cavernosa and penile arteries. Conclusion Priapism was not reported in the initial studies of these medications. Further review of the literature indicates this may be a complex relationship. Interestingly, PDE5 inhibitors also have been postulated to be protective in sickle cell disease and perhaps also sickle cell trait because priapism might be caused by reduced NO availability. In this article, we examine the evidence linking sickle cell trait to priapism, explore the implications of PDE5 use, particularly in the setting of sickle cell trait, and propose that teaching about sickle cell trait include a discussion of priapism risk

Fecal microbiota transplant mitigates adverse outcomes in patients colonized with multidrug-resistant organisms undergoing allogeneic hematopoietic cell transplantation

The gut microbiome can be adversely affected by chemotherapy and antibiotics prior to hematopoietic cell transplantation (HCT). This affects graft success and increases susceptibility to multidrug-resistant organism (MDRO) colonization and infection. We performed an initial retrospective analysis of our use of fecal microbiota transplantation (FMT) from healthy donors as therapy for MDRO-colonized patients with hematological malignancy. FMT was performed on eight MDRO-colonized patients pre-HCT (FMT-MDRO group), and outcomes compared with 11 MDRO colonized HCT patients from the same period. At 12 months, survival was significantly higher in the FMT-MDRO group (70% versus 36% p = 0.044). Post-HCT, fewer FMT-MDRO patients required intensive care (0% versus 46%, P = 0.045) or experienced fever (0.29 versus 0.11 days, P = 0.027). Intestinal MDRO decolonization occurred in 25% of FMT-MDRO patients versus 11% non-FMT MDRO patients. Despite the significant difference and statistically comparable patient/transplant characteristics, as the sample size was small, a matched-pair analysis to non-MDRO colonized control cohorts (2:1 matching) was performed. At 12 months, the MDRO group who did not have an FMT had significantly lower survival (36.4% versus 61.9% respectively, p=0.012), and higher non relapse mortality (NRM; 60.2% versus 16.7% respectively, p=0.009) than their paired non-colonized cohort. There was no difference in survival (70% versus 43.4%, p=0.14) or NRM (12.5% versus 31.2% respectively, p=0.24) between the FMT-MDRO group and their paired cohort. Negative outcomes, including mortality associated with MDRO colonization, may be ameliorated by pre-HCT FMT, despite lack of intestinal decolonization. Further work is needed to explore the observed benefit

Glucagon-like peptide 1 improved glycemic control in type 1 diabetes

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and its agonists are under assessment in treatment of type 2 diabetes, by virtue of their antidiabetic actions, which include stimulation of insulin secretion, inhibition of glucagon release, and delay of gastric emptying. We examined the potential of GLP-1 to improve glycemic control in type 1 diabetes with no endogenous insulin secretion. METHODS: Dose-finding studies were carried out to establish mid range doses for delay of gastric emptying indicated by postponement of pancreatic polypeptide responses after meals. The selected dose of 0.63 micrograms/kg GLP-1 was administered before breakfast and lunch in 8-hour studies in hospital to establish the efficacy and safety of GLP-1. In outside-hospital studies, GLP-1 or vehicle was self-administered double-blind before meals with usual insulin for five consecutive days by five males and three females with well-controlled C-peptide-negative type 1 diabetes. Capillary blood glucose values were self-monitored before meals, at 30 and 60 min after breakfast and supper, and at bedtime. Breakfast tests with GLP-1 were conducted on the day before and on the day after 5-day studies. Paired t-tests and ANOVA were used for statistical analysis. RESULTS: In 8-hour studies time-averaged incremental (delta) areas under the curves(AUC) for plasma glucose through 8 hours were decreased by GLP-1 compared to vehicle (3.2 ± 0.9, mean ± se, vs 5.4 ± 0.8 mmol/l, p < .05), and for pancreatic polypeptide, an indicator of gastric emptying, through 30 min after meals (4.0 ± 3.1 vs 37 ± 9.6 pmol/l, p < .05) with no adverse effects. Incremental glucagon levels through 60 min after meals were depressed by GLP-1 compared to vehicle (-3.7 ± 2.5 vs 3.1 ± 1.9 ng/l, p < .04). In 5-day studies, AUC for capillary blood glucose levels were lower with GLP-1 than with vehicle (-0.64 ± 0.33 vs 0.34 ± 0.26 mmol/l, p < .05). No assisted episode of hypoglycaemia or change in insulin dosage occurred. Breakfast tests on the days immediately before and after 5-day trials showed no change in the effects of GLP-1. CONCLUSION: We have demonstrated that subcutaneous GLP-1 can improve glucose control in type 1 diabetes without adverse effects when self-administered before meals with usual insulin during established intensive insulin treatment programs

Feasibility of kilohertz frequency alternating current neuromodulation of carotid sinus nerve activity in the pig

Recent research supports that over-activation of the carotid body plays a key role in metabolic diseases like type 2 diabetes. Supressing carotid body signalling through carotid sinus nerve (CSN) modulation may offer a therapeutic approach for treating such diseases. Here we anatomically and histologically characterised the CSN in the farm pig as a recommended path to translational medicine. We developed an acute in vivo porcine model to assess the application of kilohertz frequency alternating current (KHFAC) to the CSN of evoked chemo-afferent CSN responses. Our results demonstrate the feasibility of this approach in an acute setting, as KHFAC modulation was able to successfully, yet variably, block evoked chemo-afferent responses. The observed variability in blocking response is believed to reflect the complex and diverse anatomy of the porcine CSN, which closely resembles human anatomy, as well as the need for optimisation of electrodes and parameters for a human-sized nerve. Overall, these results demonstrate the feasibility of neuromodulation of the CSN in an anesthetised large animal model, and represent the first steps in driving KHFAC modulation towards clinical translation. Chronic recovery disease models will be required to assess safety and efficacy of this potential therapeutic modality for application in diabetes treatment