A Straightforward Electrochemical Approach to Imine- and Amine-bisphenolate Metal Complexes with Facile Control Over Metal Oxidation State

Synthetic methods to prepare organometallic and coordination compounds such as Schiff-base complexes are diverse, with the route chosen being dependent upon many factors such as metal–ligand combination and metal oxidation state. In this work we have shown that electrochemical methodology can be employed to synthesize a variety of metal–salen/salan complexes which comprise diverse metal–ligand combinations and oxidation states. Broad application has been demonstrated through the preparation of 34 complexes under mild and ambient conditions. Unprecedented control over metal oxidation state (MII/III/IV where M=Fe, Mn) is presented by simple modification of reaction conditions. Along this route, a general protocol-switch is described which allows access to analytically pure FeII/III–salen complexes. Tuning electrochemical potential, selective metalation of a Mn/Ni alloy is also presented which exclusively delivers MnII/IV–salen complexes in high yield

Utilisation of Postnatal Care among Rural Women in Nepal

Background: Postnatal care is uncommon in Nepal, and where it is available the quality is often poor. Adequate utilisation of postnatal care can help reduce mortality and morbidity among mothers and their babies. Therefore, our study assessed the utilisation of postnatal care at a rural community level. Methods: A descriptive, cross-sectional study was carried out in two neighbouring villages in early 2006. A total of 150 women who had delivered in the previous 24 months were asked to participate in the study using a semi-structured questionnaire. Results: The proportion of women who had received postnatal care after delivery was low (34%). Less than one in five women (19%) received care within 48 hours of giving birth. Women in one village had less access to postnatal care than women in the neighbouring one. Lack of awareness was the main barrier to the utilisation of postnatal care. The woman's own occupation and ethnicity, the number of pregnancies and children and the husband's socio-economic status, occupation and education were significantly associated with the utilisation of postnatal care. Multivariate analysis showed that wealth as reflected in occupation and having attended antenatal are important factors associated with the uptake of postnatal care. In addition, women experiencing health problems appear strongly motivated to seek postnatal care. Conclusion: The postnatal care has a low uptake and is often regarded as inadequate in Nepal. This is an important message to both service providers and health-policy makers. Therefore, there is an urgent need to assess the actual quality of postnatal care provided. Also there appears to be a need for awareness-raising programmes highlighting the availability of current postnatal care where this is of sufficient quality

The prevalence and experience of oral diseases in Adelaide nursing home residents

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.Background: The twenty-first century will see the evolution of a population of dentate older Australians with dental needs very different from those of older adults in past years. This study provided comprehensive information concerning oral disease prevalence in older South Australian nursing home residents. Methods: This paper presents cross-sectional baseline results. Results: Most of the 224 residents, from seven randomly selected nursing homes, were functionally dependent, medically compromised, cognitively impaired and behaviourally difficult older adults who presented many complex challenges to carers and to dental professionals. Two-thirds (66 per cent) were edentulous with many dental problems and treatment needs. Dentate residents had a mean of 11.9 teeth present, higher than previously reported. The prevalence and experience of coronal and root caries and plaque accumulation was very high in dentate residents; especially males, those admitted more than three years previously, those who ate fewer food types and those who were severely cognitively impaired. These residents had more retained roots, decayed teeth and missing teeth, and fewer filled teeth when compared with data for community-dwelling older adults. Conclusions: This study highlighted the poor oral health status of these nursing home residents and the great impact of dementia on their high levels of oral diseases.JM Chalmers, C Hodge, JM Fuss, AJ Spencer, KD Carte

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Circuit dissection of the role of somatostatin in itch and pain

Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+ neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide

Monounsaturated fats and immune function

Animal studies suggest that olive oil is capable of modulating functions of cells of the immune system in a manner similar to, albeit weaker than, fish oils. There is some evidence that the effects of olive oil on immune function in animal studies are due to oleic acid rather than to trace elements or antioxidants. Importantly, several studies have demonstrated effects of oleic acid-containing diets on in vivo immune responses. In contrast, consumption of a monounsaturated fatty acid (MUFA)-rich diet by humans does not appear to bring about a general suppression of immune cell functions. The effects of this diet in humans are limited to decreasing aspects of adhesion of peripheral blood mononuclear cells, although there are trends towards decreases in natural killer cell activity and proliferation. The lack of a clear effect of MUFA in humans may be attributable to the higher level of monounsaturated fat used in the animal studies, although it is ultimately of importance to examine the effects of intakes which are in no way extreme. The effects of MUFA on adhesion molecules are potentially important, since these molecules appear to have a role in the pathology of a number of diseases involving the immune system. This area clearly deserves further exploration

Suicidal Behavior and Depression in Smoking Cessation Treatments

BACKGROUND: Two treatments for smoking cessation--varenicline and bupropion--carry Boxed Warnings from the U.S. Food and Drug Administration (FDA) about suicidal/self-injurious behavior and depression. However, some epidemiological studies report an increased risk in smoking or smoking cessation independent of treatment, and differences between drugs are unknown. METHODOLOGY: From the FDA's Adverse Event Reporting System (AERS) database from 1998 through September 2010 we selected domestic, serious case reports for varenicline (n = 9,575), bupropion for smoking cessation (n = 1,751), and nicotine replacement products (n = 1,917). A composite endpoint of suicidal/self-injurious behavior or depression was defined as a case with one or more Preferred Terms in Standardized MedDRA Query (SMQ) for those adverse effects. The main outcome measure was the ratio of reported suicide/self-injury or depression cases for each drug compared to all other serious events for that drug. RESULTS: Overall we identified 3,249 reported cases of suicidal/self-injurious behavior or depression, 2,925 (90%) for varenicline, 229 (7%) for bupropion, and 95 (3%) for nicotine replacement. Compared to nicotine replacement, the disproportionality results (OR (95% CI)) were varenicline 8.4 (6.8-10.4), and bupropion 2.9 (2.3-3.7). The disproportionality persisted after excluding reports indicating concomitant therapy with any of 58 drugs with suicidal behavior warnings or precautions in the prescribing information. An additional antibiotic comparison group showed that adverse event reports of suicidal/self-injurious behavior or depression were otherwise rare in a healthy population receiving short-term drug treatment. CONCLUSIONS: Varenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior. Bupropion for smoking cessation had smaller increased risks. The findings for varenicline, combined with other problems with its safety profile, render it unsuitable for first-line use in smoking cessation

Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide

<p>Abstract</p> <p>Background</p> <p>Nearly one-third of the United States adult population suffers from hypertension. Hydrochlorothiazide (HCTZ), one of the most commonly used medications to treat hypertension, has variable efficacy. The renal epithelial sodium channel (ENaC) provides a mechanism for fine-tuning sodium excretion, and is a major regulator of blood pressure homeostasis. <it>DOT1L, MLLT3, SIRT1</it>, and <it>SGK1 </it>encode genes in a pathway that controls methylation of the histone H3 globular domain at lysine 79 (H3K79), thereby modulating expression of the ENaCα subunit. This study aimed to determine the role of variation in these regulatory genes on blood pressure response to HCTZ, and secondarily, untreated blood pressure.</p> <p>Methods</p> <p>We investigated associations between genetic variations in this candidate pathway and HCTZ blood pressure response in two separate hypertensive cohorts (clinicaltrials.gov NCT00246519 and NCT00005520). In a secondary, exploratory analysis, we measured associations between these same genetic variations and untreated blood pressure. Associations were measured by linear regression, with only associations with <it>P </it>≤ 0.01 in one cohort and replication by <it>P </it>≤ 0.05 in the other cohort considered significant.</p> <p>Results</p> <p>In one cohort, a polymorphism in <it>DOT1L </it>(rs2269879) was strongly associated with greater systolic (<it>P </it>= 0.0002) and diastolic (<it>P </it>= 0.0016) blood pressure response to hydrochlorothiazide in Caucasians. However, this association was not replicated in the other cohort. When untreated blood pressure levels were analyzed, we found directionally similar associations between a polymorphism in <it>MLLT3 </it>(rs12350051) and greater untreated systolic (<it>P </it>< 0.01 in both cohorts) and diastolic (<it>P </it>< 0.05 in both cohorts) blood pressure levels in both cohorts. However, when further replication was attempted in a third hypertensive cohort and in smaller, normotensive samples, significant associations were not observed.</p> <p>Conclusions</p> <p>Our data suggest polymorphisms in <it>DOT1L, MLLT3, SIRT1</it>, and <it>SGK1 </it>are not likely associated with blood pressure response to HCTZ. However, a possibility exists that rs2269879 in <it>DOT1L </it>could be associated with HCTZ response in Caucasians. Additionally, exploratory analyses suggest rs12350051 in <it>MLLT3 </it>may be associated with untreated blood pressure in African-Americans. Replication efforts are needed to verify roles for these polymorphisms in human blood pressure regulation.</p

Coordination of Cell Differentiation and Migration in Mathematical Models of Caudal Embryonic Axis Extension

Vertebrate embryos display a predominant head-to-tail body axis whose formation is associated with the progressive development of post-cranial structures from a pool of caudal undifferentiated cells. This involves the maintenance of active FGF signaling in this caudal region as a consequence of the restricted production of the secreted factor FGF8. FGF8 is transcribed specifically in the caudal precursor region and is down-regulated as cells differentiate and the embryo extends caudally. We are interested in understanding the progressive down-regulation of FGF8 and its coordination with the caudal movement of cells which is also known to be FGF-signaling dependent. Our study is performed using mathematical modeling and computer simulations. We use an individual-based hybrid model as well as a caricature continuous model for the simulation of experimental observations (ours and those known from the literature) in order to examine possible mechanisms that drive differentiation and cell movement during the axis elongation. Using these models we have identified a possible gene regulatory network involving self-repression of a caudal morphogen coupled to directional domain movement that may account for progressive down-regulation of FGF8 and conservation of the FGF8 domain of expression. Furthermore, we have shown that chemotaxis driven by molecules, such as FGF8 secreted in the stem zone, could underlie the migration of the caudal precursor zone and, therefore, embryonic axis extension. These mechanisms may also be at play in other developmental processes displaying a similar mode of axis extension coupled to cell differentiation