Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group

The widely used pentafluorosulfanyl group (SF5) was deployed as a bioisosteric replacement for a chloro-group in the benzodiazepine diazepam (Valium™). Reaction of 2-amino-5-pentafluorosulfanyl-benzophenone with chloroacetyl chloride followed by hexamethylenetetramine, in the presence of ammonia, led to 7-sulfurpentafluoro-5-phenyl-1H-benzo[1,4]diazepin-2(3H)-one (2c). The latter was able to undergo a Pd-catalysed ortho-arylation, demonstrating that these highly fluorinated benzodiazepines can be further modified to form more complicated scaffolds. The replacement of Cl by the SF5 group, led to a loss of potency for potentiating GABAA receptor activation, most likely because of a lost ligand interaction with His102 in the GABAA receptor α subunit. Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry

The Hidden Curriculum of Veterinary Education: Mediators and Moderators of Its Effects

The “hidden curriculum” has long been supposed to have an effect on students' learning during their clinical education, and in particular in shaping their ideas of what it means to be a professional. Despite this, there has been little evidence linking specific changes in professional attitudes to the individual components of the hidden curriculum. This study aimed to recognize those components that led to a change in students' professional attitudes at a UK veterinary school, as well as to identify the attitudes most affected. Observations were made of 11 student groups across five clinical rotations, followed by semi-structured interviews with 23 students at the end of their rotation experience. Data were combined and analyzed thematically, taking both an inductive and deductive approach. Views about the importance of technical competence and communication skills were promoted as a result of students' interaction with the hidden curriculum, and tensions were revealed in relation to their attitudes toward compassion and empathy, autonomy and responsibility, and lifestyle ethic. The assessment processes of rotations and the clinical service organization served to communicate the messages of the hidden curriculum, bringing about changes in student professional attitudes, while student-selected role models and the student rotation groups moderated the effects of these influences

Cantú syndrome with coexisting familial pituitary adenoma

Context: Pseudoacromegaly describes conditions with an acromegaly related physical appearance without abnormalities in the growth hormone (GH) axis. Acromegaloid facies, together with hypertrichosis, are typical manifestations of Cantú syndrome. Case description: We present a three-generation family with 5 affected members, with marked acromegaloid facies and prominent hypertrichosis, due to a novel missense variant in the ABCC9 gene. The proband, a 2-year-old girl, was referred due to marked hypertrichosis, noticed soon after birth, associated with coarsening of her facial appearance. Her endocrine assessment, including of the GH axis, was normal. The proband's father, paternal aunt, and half-sibling were referred to the Endocrine department for exclusion of acromegaly. Although the GH axis was normal in all, two subjects had clinically non-functioning pituitary macroadenomas, a feature which has not previously been associated with Cantú syndrome. Conclusions: Activating mutations in the ABCC9 and, less commonly, KCNJ8 genes—representing the two subunits of the ATP-sensitive potassium channel—have been linked with Cantú syndrome. Interestingly, minoxidil, a well-known ATP-sensitive potassium channel agonist, can cause a similar phenotype. There is no clear explanation why activating this channel would lead to acromegaloid features or hypertrichosis. This report raises awareness for this complex condition, especially for adult or pediatric endocrinologists who might see these patients referred for evaluation of acromegaloid features or hirsutism. The link between Cantú syndrome and pituitary adenomas is currently unclear

Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies

<p>Abstract</p> <p>Background</p> <p>The relatively short durations of the initial pivotal randomized placebo-controlled trials involving atomoxetine HCl for the treatment of attention-deficit/hyperactivity disorder (ADHD) provided limited insight into the time courses of ADHD core symptom responses to this nonstimulant, selective norepinephrine reuptake inhibitor. The aim of this analysis was to evaluate time courses of treatment responses or remission, as assessed by attainment of prespecified scores on the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) and the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scales, during up to 1 year of atomoxetine treatment in children with ADHD.</p> <p>Methods</p> <p>Using pooled data from three Canadian open-label studies involving 338 children ages 6-11 years with ADHD who were treated with atomoxetine for 3, 6 and 12 months, and survival analysis methods for interval-censored data, we estimated the time to: 1) improvement and robust improvement defined by ≥25% and ≥40% reductions from baseline ADHDRS-IV-PI total scores, respectively; and 2) remission using two definitions: a final score of ADHDRS-IV-PI ≤18 or a final score of CGI-ADHD-S ≤2.</p> <p>Results</p> <p>The median time to improvement was 3.7 weeks (~1 month), but remission of symptoms did not occur until a median of 14.3 weeks (~3.5 months) using the most stringent CGI-ADHD-S threshold. Probabilities of robust improvement were 47% at or before 4 weeks of treatment; 76% at 12 weeks; 85% at 26 weeks; and 96% at 52 weeks. Probabilities of remission at these corresponding time points were 30%, 59%, 77%, and 85% (using the ADHDRS-IV scale) and 8%, 47%, 67%, and 75% (using the CGI-ADHD-S scale). The change from atomoxetine treatment month 5 to month 12 of -1.01 (1.03) was not statistically significant (<it>p </it>= .33).</p> <p>Conclusions</p> <p>Reductions in core ADHD symptoms during atomoxetine treatment are gradual. Although approximately one-half of study participants showed improvement at 1 month of atomoxetine treatment, remission criteria were not met until about 3 months. Understanding the time course of children's responses to atomoxetine treatment may inform clinical decision making and also influence the durations of trials comparing the effects of this medication with other ADHD treatments.</p> <p>Trial Registrations</p> <p>clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00191633">NCT00191633</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00216918">NCT00216918</a>, <a href="http://www.clinicaltrials.gov/ct2/show/NCT00191880">NCT00191880</a>.</p

Chlamydia trachomatis ompA Variants in Trachoma: What Do They Tell Us?

Trachoma is an important cause of blindness resulting from transmission of the bacterium Chlamydia trachomatis. One way to understand better how this infection is transmitted and how the human immune system controls it is to study the strains of bacteria associated with infection. Comparing strains before and after treatment might help us learn if someone has a new infection or the same one as before. Identifying differences between disease-causing strains should help us understand how infection leads to disease and how the human host defences work. We chose to study variation in the chlamydial gene ompA because it determines the protein MOMP, one of the leading candidates for inclusion in a vaccine to prevent trachoma. If immunity to MOMP is important in natural trachoma infections, we would expect to find evidence of this in the way the strains varied. We did not find this, but instead found that two common strains seemed to cause different types of disease. Although their MOMPs were very slightly different, this did not really explain the differences. We conclude that methods of typing strains going beyond the ompA gene will be needed to help us understand the interaction between Chlamydia and its human host

Forward-time simulation of realistic samples for genome-wide association studies

<p>Abstract</p> <p>Background</p> <p>Forward-time simulations have unique advantages in power and flexibility for the simulation of genetic samples of complex human diseases because they can closely mimic the evolution of human populations carrying these diseases. However, a number of methodological and computational constraints have prevented the power of this simulation method from being fully explored in existing forward-time simulation methods.</p> <p>Results</p> <p>Using a general-purpose forward-time population genetics simulation environment, we developed a forward-time simulation method that can be used to simulate realistic samples for genome-wide association studies. We examined the properties of this simulation method by comparing simulated samples with real data and demonstrated its wide applicability using four examples, including a simulation of case-control samples with a disease caused by multiple interacting genetic and environmental factors, a simulation of trio families affected by a disease-predisposing allele that had been subjected to either slow or rapid selective sweep, and a simulation of a structured population resulting from recent population admixture.</p> <p>Conclusions</p> <p>Our algorithm simulates populations that closely resemble the complex structure of the human genome, while allows the introduction of signals of natural selection. Because of its flexibility to generate different types of samples with arbitrary disease or quantitative trait models, this simulation method can simulate realistic samples to evaluate the performance of a wide variety of statistical gene mapping methods for genome-wide association studies.</p

Roles of Coactivators in Hypoxic Induction of the Erythropoietin Gene

Hypoxia-inducible expression of the erythropoietin (EPO) gene is mediated principally by hypoxia-inducible factor 2alpha (HIF-2alpha) in Hep3B cells under physiologic conditions. How/whether p300/CBP and the members of p160 coactivator family potentiate hypoxic induction of endogenous EPO and other HIF-2alpha and hypoxia-inducible factor 1alpha (HIF-1alpha) target genes remains unclear.We demonstrate, using chromatin immunoprecipitation (ChIP) analysis, that the histone acetyl transferase (HAT) coactivators p300, SRC-1 and SRC-3 are recruited to the 3' enhancer of the EPO gene upon hypoxic stimulation, and that each associates with the enhancer in a periodic fashion. Hypoxia induced acetylation of the EPO gene 5' promoter at histone 4 and lysine 23 of histone 3. Knocking down SRC-3, but not SRC-1 or SRC-2, using short interfering RNAs (siRNAs), reduced EPO transcriptional activity. Knocking down p300 resulted in dramatic down-regulation of hypoxic stimulation of EPO gene transcription, negated recruitment of RNA polymerase II to the gene's promoter, and eliminated hypoxia-stimulated acetylation at the promoter and recruitments of SRC-1 and SRC-3 to the enhancer. The inhibitory effects of knocking down p300 and the chromatin remodeling coactivator, Brm/Brg-1, on EPO transcription were additive, suggesting that p300 and Brm/Brg-1 act independently. p300 was also required for hypoxia induced transcription of the HIF-1alpha target gene, VEGF, but was dispensable for induction of two other HIF-1alpha target genes, PGK and LDHA. Knocking down CBP, a homolog of p300, augmented hypoxic induction of VEGF, LDHA and PGK. Different HIF target genes also exhibited different requirements for members of the p160 coactivator family.p300 plays a central coactivator role in hypoxic induction of EPO. The coactivators exhibit different specificities for different HIF target genes and each can behave differently in transcriptional regulation of different target genes mediated by the same transcription factor

Aiming to increase birth weight: a randomised trial of pre-pregnancy information, advice and counselling in inner-urban Melbourne

BACKGROUND: In the 1980s there was substantial interest in early pregnancy and pre-pregnancy interventions to increase birth weight and reduce preterm birth. We developed an inter-pregnancy intervention, implemented in a randomised controlled trial, to be provided by midwives at home soon after women's first birth. METHODS: MCH nurses invited women to take part during their home visit to new mothers. Women's contact details, with their permission, were passed to the study midwife. She had a randomisation schedule to which women's names were added before she met the women or their partners. All women recruited had a home visit from the study midwife with a discussion of their first pregnancy, labour and birth and the postpartum experience. Women in the intervention arm received in addition a pre-pregnancy intervention with discussion of social, health or lifestyle problems, preparation and timing for pregnancy, family history, rubella immunisation, referrals for health problems, and a reminder card. The primary outcome was defined as a birth weight difference in the second birth of 100 g (one-sided) in favour of the intervention. Additional data collected were gestational age, perinatal deaths and birth defects. Analyses used EPI-INFO and STATA. RESULTS: Intervention and comparison groups were comparable on socioeconomic factors, prior reproductive history and first birth outcomes. Infant birth weight in the second birth was lower (-97.4 g,)) among infants in the intervention arm. There were no significant differences between intervention and comparison arms in the proportion of women having a preterm birth, an infant with low birthweight, or an infant with a birth weight <10(th )percentile. There were more adverse outcomes in the intervention arm: ten births <32 weeks), compared with one in standard care, and more infants with a birth weight <2000 g, 16 compared with two in standard care CONCLUSION: As the primary outcome was envisaged to be either improved birth weight or no effect, the study was not designed to identify the alternative outcome with confidence. Despite widespread support for pre-pregnancy interventions to improve maternal and perinatal health, this first randomised controlled trial of a multi-component intervention provided at home, did not have a beneficial outcome

Clinical symptoms and performance on the continuous performance test in children with attention deficit hyperactivity disorder between subtypes: a natural follow-up study for 6 months

<p>Abstract</p> <p>Background</p> <p>The aims of this study were to determine the time course of improvements in attention deficit hyperactivity disorder (ADHD) clinical symptoms and neurocognitive function in a realistic clinical setting, and the differences in ADHD symptom improvement using different classifications of ADHD subtypes.</p> <p>Methods</p> <p>The Child Behavior Checklist (CBCL) was completed by parents of ADHD children at the initial visit. The computerized Continuous Performance Test (CPT), Swanson, Nolan, and Pelham, and Version IV Scale for ADHD (SNAP-IV), and ADHD Rating Scale (ADHD-RS) were performed at baseline, one month, three months, and six months later, respectively. Patient care including drug therapy was performed at the discretion of the psychiatrist. The ADHD patients were divided into DSM-IV subtypes (Inattentive, Hyperactive-impulsive and Combined type), and were additionally categorized into aggressive and non-aggressive subtypes by aggression scale in CBCL for comparisons.</p> <p>Results</p> <p>There were 50 ADHD patients with a mean age of 7.84 ± 1.64 years; 15 of them were inattentive type, 11 were hyperactive-impulsive type, and 24 were combined type. In addition, 28 of the ADHD patients were grouped into aggressive and 22 into non-aggressive subtypes. There were significant improvements in clinical symptoms of hyperactivity and inattention, and impulsivity performance in CPT during the 6-month treatment. The clinical hyperactive symptoms were significantly different between ADHD patients sub-grouping both by DSM-IV and aggression. Non-aggressive patients had significantly greater changes in distraction and impulsivity performances in CPT from baseline to month 6 than aggressive patients.</p> <p>Conclusions</p> <p>We found that ADHD symptoms, which included impulsive performances in CPT and clinical inattention and hyperactivity dimensions, had improved significantly over 6 months under pragmatic treatments. The non-aggressive ADHD patients might have a higher potential for improving in CPT performance than aggressive ones. However, it warrant further investigation whether the different classifications of ADHD patients could be valid for predicting the improvements in ADHD patients' clinical symptoms and neurocognitive performance.</p

Rescue of Dystrophic Skeletal Muscle by PGC-1α Involves a Fast to Slow Fiber Type Shift in the mdx Mouse

Increased utrophin expression is known to reduce pathology in dystrophin-deficient skeletal muscles. Transgenic over-expression of PGC-1α has been shown to increase levels of utrophin mRNA and improve the histology of mdx muscles. Other reports have shown that PGC-1α signaling can lead to increased oxidative capacity and a fast to slow fiber type shift. Given that it has been shown that slow fibers produce and maintain more utrophin than fast skeletal muscle fibers, we hypothesized that over-expression of PGC-1α in post-natal mdx mice would increase utrophin levels via a fiber type shift, resulting in more slow, oxidative fibers that are also more resistant to contraction-induced damage. To test this hypothesis, neonatal mdx mice were injected with recombinant adeno-associated virus (AAV) driving expression of PGC-1α. PGC-1α over-expression resulted in increased utrophin and type I myosin heavy chain expression as well as elevated mitochondrial protein expression. Muscles were shown to be more resistant to contraction-induced damage and more fatigue resistant. Sirt-1 was increased while p38 activation and NRF-1 were reduced in PGC-1α over-expressing muscle when compared to control. We also evaluated if the use a pharmacological PGC-1α pathway activator, resveratrol, could drive the same physiological changes. Resveratrol administration (100 mg/kg/day) resulted in improved fatigue resistance, but did not achieve significant increases in utrophin expression. These data suggest that the PGC-1α pathway is a potential target for therapeutic intervention in dystrophic skeletal muscle