Effectiveness of the Dader Method for pharmaceutical care in patients with bipolar I disorder: EMDADER-TAB: study protocol for a randomized controlled trial.
Bipolar I disorder (BD-I) is a chronic mental illness characterized by the presence of one or more manic episodes, or both depressive and manic episodes, usually separated by asymptomatic intervals. Pharmacists can contribute to the management of BD-I, mainly with the use of effective and safe drugs, and improve the patient's life quality through pharmaceutical care. Some studies have shown the effect of pharmaceutical care in the achievement of therapeutic goals in different illnesses; however, to our knowledge, there is a lack of randomized controlled trials designed to assess the effect of pharmacist intervention in patients with BD. The aim of this study is to assess the effectiveness of the Dader Method for pharmaceutical care in patients with BD-I. Randomized, controlled, prospective, single-center clinical trial with duration of 12 months will be performed to compare the effect of Dader Method of pharmaceutical care with the usual care process of patients in a psychiatric clinic. Patients diagnosed with BD-I aged between 18 and 65 years who have been discharged or referred from outpatients service of the San Juan de Dios Clinic (Antioquia, Colombia) will be included. Patients will be randomized into the intervention group who will receive pharmaceutical care provided by pharmacists working in collaboration with psychiatrists, or into the control group who will receive usual care and verbal-written counseling regarding BD. Study outcomes will be assessed at baseline and at 3, 6, 9, and 12 months after randomization. The primary outcome will be to measure the number of hospitalizations, emergency service consultations, and unscheduled outpatient visits. Effectiveness, safety, adherence, and quality of life will be assessed as secondary outcomes. Statistical analyses will be performed using two-tailed McNemar tests, Pearson chi-square tests, and Student's t-tests; a P value <0.05 will be considered as statistically significant. As far as we know, this is the first randomized controlled trial to assess the effect of the Dader Method for pharmaceutical care in patients with BD-I and it could generate valuable information and recommendations about the role of pharmacists in the improvement of therapeutic goals, solution of drug-related problems, and adherence. Registration number NCT01750255 on August 6, 2012. First patient randomized on 24 November 2011.


Direct observation of breaking of the intramolecular H-bond, and slowing down of the proton motion and tuning its mechanism in an HBO derivative.
We report on spectroscopic and photodynamical behaviours of 5-amino-2-(2'-hydroxyphenyl)benzoxazole (5A-HBO) in different solutions. The dye undergoes an ultrafast ICT reaction (<50 fs) (comparable to that observed for its methylated derivative, 5A-MBO), in agreement with the results of TD-DFT theoretical calculations (gas phase). Depending on the used solvent, the ICT reaction can be followed by a reversible/irreversible excited-state intramolecular proton transfer (ESIPT) reaction or by breaking of the intramolecular hydrogen bond (IHB). 5A-HBO in n-heptane solution exhibits an irreversible and slow (20 ps) ESIPT reaction, while that of the parent compound, HBO, takes place in less than 150 fs. Compared to excited HBO behaviour, theoretical calculations on 5A-HBO suggest a higher energy barrier (∼4 kcal mol(-1)) between the relaxed enol and keto tautomers, in addition to a less stabilization of the latter, which is in agreement with experiments in n-heptane. On the other hand, in dichloromethane, after the ICT reaction a subsequent and reversible proton motion occurs in an extraordinary slower regime (ns-time scale). No isotopic effect (OH/OD exchange) was observed in this solvent reflecting that the reversible ESIPT reaction evolves along the IHB and solvent coordinates. Using tetrahydrofurane and acetonitrile, we observed a breaking of the IHB due to specific intermolecular interactions with solvent molecules. This leads to the formation of open-enol forms, which undergo an ICT reaction as it occurs in 5A-MBO. These results bring new findings in the coupled ICT and ESIPT reactions. The photobehaviour of this new dye remarkably changes with the solvent nature, opening up the window for further research and possible applications in sensing polarity or H-bonding of media similar to that of the biological ones.


Experiences and perceptions of youth living with HIV in Western Uganda on school attendance: barriers and facilitators.
The globally recognized socio-economic benefits of education have stirred many countries in Sub-Saharan Africa like Uganda to promote universal access to schooling by removing fiscal barricades for those in primary and secondary schools. However, the proportion of Youth Living With HIV/AIDS (YLWHA) missing school, studying with difficulties and dropping out of school in Uganda has been observed to be higher than that of other youth. This study aimed at understanding the barriers and facilitators for YLWHA in Uganda to attend school. We conducted a qualitative inquiry with 35 purposively selected YLWHA aged 12 to 19 years, including 16 females at three accredited Antiretroviral Therapy (ART) treatment centres in Kabarole district in Western Uganda. Individual semi-structured interviews were tape-recorded, transcribed verbatim and subjected to thematic inductive analysis. We identified five main themes in which barriers to attend school were reported and four main themes in which facilitators were reported by participants. The main themes for barriers were: 1) management of ART and illnesses, 2) fear, negative thoughts and self-devaluation, 3) lack of meaningful and supportive relationships, 4) reactionary attitudes and behaviours from others at school, 5) financial challenges. The main themes for facilitators were: 1) practical support at school, home and community, 2) counselling, encouragement and spirituality, 3) individual coping strategies, 4) hopes, dreams and opportunities for the future. Most of the barriers reported arose from HIV-related stigma and financial challenges whose genesis transcends school boundaries. While YLWHA reported measures to cope, and support from other people, these were non-sustainable and on a limited scale due to disclosure apprehension at school and the indiscretion of those who learnt about their status. To promote supportive school environments for YLWHA, integrated curricular and extracurricular interventions are necessary to increase HIV knowledge, dispel misconceptions about HIV and consequently transform the school community from a stigmatizing one to a supportive one.


Identification of developmentally regulated PCP-responsive non-coding RNA, prt6, in the rat thalamus.
Schizophrenia and similar psychoses induced by NMDA-type glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, usually develop after adolescence. Moreover, adult-type behavioral disturbance following NMDA receptor antagonist application in rodents is observed after a critical period at around 3 postnatal weeks. These observations suggest that the schizophrenic symptoms caused by and psychotomimetic effects of NMDA antagonists require the maturation of certain brain neuron circuits and molecular networks, which differentially respond to NMDA receptor antagonists across adolescence and the critical period. From this viewpoint, we have identified a novel developmentally regulated phencyclidine-responsive transcript from the rat thalamus, designated as prt6, as a candidate molecule involved in the above schizophrenia-related systems using a DNA microarray technique. The transcript is a non-coding RNA that includes sequences of at least two microRNAs, miR132 and miR212, and is expressed strongly in the brain and testis, with trace or non-detectable levels in the spleen, heart, liver, kidney, lung and skeletal muscle, as revealed by Northern blot analysis. The systemic administration of PCP (7.5 mg/kg, subcutaneously (s.c.)) significantly elevated the expression of prt6 mRNA in the thalamus at postnatal days (PD) 32 and 50, but not at PD 8, 13, 20, or 24 as compared to saline-treated controls. At PD 50, another NMDA receptor antagonist, dizocilpine (0.5 mg/kg, s.c.), and a schizophrenomimetic dopamine agonist, methamphetamine (4.8 mg/kg, s.c.), mimicked a significant increase in the levels of thalamic prt6 mRNAs, while a D2 dopmamine receptor antagonist, haloperidol, partly inhibited the increasing influence of PCP on thalamic prt6 expression without its own effects. These data indicate that prt6 may be involved in the pathophysiology of the onset of drug-induced schizophrenia-like symptoms and schizophrenia through the possible dysregulation of target genes of the long non-coding RNA or microRNAs in the transcript.


Diagnosis and management of endometriosis: the role of the advanced practice nurse in primary care.
To discuss the etiology, clinical presentation, diagnosis, and management of endometriosis for the advanced practice nurse (APN) in primary care. Selected research, clinical studies, clinical practice guidelines, and review articles. Commonly encountered by the APN in primary care, endometriosis is a chronic, progressive inflammatory disease characterized by endometrial lesions, cysts, fibrosis, or adhesions in the pelvic cavity, causing chronic pelvic pain and infertility in women of reproductive age. Because of its frequently normal physical examination findings, variable clinical presentations, and nonspecific, overlapping symptoms with other conditions, endometriosis can be difficult to diagnose. As there currently are no accurate noninvasive diagnostic tests specific for endometriosis, it is imperative for the APN to become knowledgeable about the etiology, clinical presentation, diagnosis, and current treatment options of this disease. The APN in primary care plays an essential role in health promotion through disease management and infertility prevention by providing support and much needed information to the patient with endometriosis. APNs can also facilitate quality of care and manage treatments effectively to improve quality of life, reduce pain, and prevent further progression of disease. Practice recommendations include timely diagnosis, pain management, infertility counseling, patient education, and support for quality of life issues.


Color constancy at a pixel.
In computational terms we can solve the color constancy problem if device red, green, and blue sensor responses, or RGB's, for surfaces seen under an unknown illuminant can be mapped to corresponding RGB's under a known reference light. In recent years almost all authors have argued that this three-dimensional problem is too hard. It is argued that because a bright light striking a dark surface results in the same physical spectra as those of a dim light incident on a light surface, the magnitude of RGB's cannot be recovered. Consequently, modern color constancy algorithms attempt only to recover image chromaticities under the reference light: They solve a two-dimensional problem. While significant progress has been made toward achieving chromaticity constancy, recent work has shown that the most advanced algorithms are unable to render chromaticity stable enough so that it can be used as a cue for object recognition [B. V. Funt, K. Bernard, and L. Martin, in Proceedings of the Fifth European Conference on Computer Vision (European Vision Society, Springer-Verlag, Berlin, 1998), Vol. II, p. 445.] We take this reductionist approach a little further and look at the one-dimensional color constancy problem. We ask, Is there a single color coordinate, a function of image chromaticities, for which the color constancy problem can be solved? Our answer is an emphatic yes. We show that there exists a single invariant color coordinate, a function of R, G, and B, that depends only on surface reflectance. Two corollaries follow. First, given an RGB image of a scene viewed under any illuminant, we can trivially synthesize the same gray-scale image (we simply code the invariant coordinate as a gray scale). Second, this result implies that we can solve the one-dimensional color constancy problem at a pixel (in scenes with no color diversity whatsoever). We present experiments that show that invariant gray-scale histograms are a stable feature for object recognition. Indexing on invariant distributions supports almost perfect recognition for a dataset of 11 objects viewed under five colored lights. In contrast, object recognition based on chromaticity histograms (post-color constancy preprocessing) delivers much poorer recognition.


Evaluation of Rapid, Early Warning Approaches to Track Shellfish Toxins Associated with Dinophysis and Alexandrium Blooms.
Marine biotoxin-contaminated seafood has caused thousands of poisonings worldwide this century. Given these threats, there is an increasing need for improved technologies that can be easily integrated into coastal monitoring programs. This study evaluates approaches for monitoring toxins associated with recurrent toxin-producing Alexandrium and Dinophysis blooms on Long Island, NY, USA, which cause paralytic and diarrhetic shellfish poisoning (PSP and DSP), respectively. Within contrasting locations, the dynamics of pelagic Alexandrium and Dinophysis cell densities, toxins in plankton, and toxins in deployed blue mussels (Mytilus edulis) were compared with passive solid-phase adsorption toxin tracking (SPATT) samplers filled with two types of resin, HP20 and XAD-2. Multiple species of wild shellfish were also collected during Dinophysis blooms and used to compare toxin content using two different extraction techniques (single dispersive and double exhaustive) and two different toxin analysis assays (liquid chromatography/mass spectrometry and the protein phosphatase inhibition assay (PP2A)) for the measurement of DSP toxins. DSP toxins measured in the HP20 resin were significantly correlated (R² = 0.7-0.9, p < 0.001) with total DSP toxins in shellfish, but were detected more than three weeks prior to detection in deployed mussels. Both resins adsorbed measurable levels of PSP toxins, but neither quantitatively tracked Alexandrium cell densities, toxicity in plankton or toxins in shellfish. DSP extraction and toxin analysis methods did not differ significantly (p > 0.05), were highly correlated (R² = 0.98-0.99; p < 0.001) and provided complete recovery of DSP toxins from standard reference materials. Blue mussels (Mytilus edulis) and ribbed mussels (Geukensia demissa) were found to accumulate DSP toxins above federal and international standards (160 ng g-1) during Dinophysis blooms while Eastern oysters (Crassostrea virginica) and soft shell clams (Mya arenaria) did not. This study demonstrated that SPATT samplers using HP20 resin coupled with PP2A technology could be used to provide early warning of DSP, but not PSP, events for shellfish management.


Going the distance: Memory and control processes in active dependency construction.
Filler-gap dependencies make strong demands on working memory in language comprehension because they cannot always be immediately resolved. In a series of three reading-time studies, we test the idea that these demands can be decomposed into active maintenance processes and retrieval events. Results indicate that the fact that a displaced phrase exists and the identity of its basic syntactic category both immediately impact comprehension at potential gap sites. In contrast, specific lexical details of the displaced phrase show an immediate effect only for short dependencies and a much later effect for longer dependencies. We argue that coarse-grained information about the filler is actively maintained and is used to make phrase structure parsing decisions, whereas finer grained information is more quickly released from active maintenance and consequently has to be retrieved at the gap site.


Dissociative alterations in body image among individuals reporting out-of-body experiences: a conceptual replication.
A conceptual replication of the link between self-reported dissociative alterations in body-image under experimental conditions and the reporting of prior out-of-body experiences in a recent data set was undertaken. Also examined was whether this relationship would hold for experiences reported during the experimental context and whether it is independent of self-reported New Age belief. Data from mostly undergraduates (N= 40; M age = 33.5, SD = 12.5; 27 women) in a mirror-gazing study were retrospectively analyzed. The 9 individuals who reported prior out-of-body experiences, relative to those 31 who did not, exhibited significantly greater self-reported dissociative alterations in body-image during the mirror-gazing task, even when the influence of scores on New Age belief was controlled for statistically. The same differential relationship was not found between 6 individuals who did and 34 who did not report out-of-body experiences during the task.


Antibody Dependent Enhancement Due to Original Antigenic Sin and the Development of SARS.
Human coronavirus (HCoV) is one of the most common causes of respiratory tract infections throughout the world. Two phenomena observed so far in the development of the SARS-CoV-2 pandemic deserve further attention. First, the relative absence of clinical signs of infections in children, second, the early appearance of IgG in certain patients. From the point of view of immune system physiology, such an early rise of specific IgG is expected in secondary immune responses when memory to a cross-reactive antigen is present, usually from an earlier infection with a coronavirus. It is actually typical for the immune system to respond, to what it already knows, a phenomenon that has been observed in many infections with closely related viruses and has been termed "original antigenic sin." The question then arises whether such cross-reactive antibodies are protective or not against the new virus. The worst scenario would be when such cross-reactive memory antibodies to related coronaviruses would not only be non-protective but even enhance infection and the clinical course. Such a phenomenon of antibody dependent enhancement (ADE) has already been described in several viral infections. Thus, the development of IgG against SARS-CoV-2 in the course of COVID-19 might not be a simple sign of viral clearance and developing protection against the virus. On the contrary, due to cross-reaction to related coronavirus strains from earlier infections, in certain patients IgG might enhance clinical progression due to ADE. The patient's viral history of coronavirus infection might be crucial to the development of the current infection with SARS-CoV-2. Furthermore, it poses a note of caution when treating COVID-19 patients with convalescent sera.


Increased prevalence of anxiety symptoms in women with polycystic ovary syndrome: systematic review and meta-analysis.
To perform a systematic review and meta-analysis of studies that compared the prevalence of anxiety symptoms in women with polycystic ovary syndrome (PCOS) and control women. Meta-analysis and systematic review. University practice. Cross-sectional studies comparing PCOS subjects and geographically matched clearly defined non-PCOS control subjects with data on age and body mass index (BMI). Anxiety screening tool. The primary analysis contrasted prevalence of anxiety. Cochrane Review Manager 5.0.24 software was used to construct forest plots comparing frequency of anxiety symptoms in case and control subjects. Of 613 screened articles, nine met our selection criteria for a systematic review and four were included in the meta-analysis. The prevalence of generalized anxiety symptoms was available in four studies and was significantly greater in PCOS subjects (42/206, 20.4%) compared to controls (8/204, 3.9%). The odds for anxiety symptoms were significantly greater in women with PCOS compared with control subjects (odds ratio 6.88, 95% confidence interval 2.5-18.9). The mean anxiety score was significantly increased in three of the remaining five studies. Other anxiety disorders, such as social phobia, panic attacks, and obsessive compulsive disorders, were assessed infrequently. Our systematic review suggests an increased odds of anxiety symptoms in women with PCOS, underscoring the importance of screening all women with PCOS for anxiety symptoms. Follow-up evaluation and treatment are essential, because generalized anxiety disorder is a chronic condition. Potential contributors for anxiety symptoms, such as hirsutism, obesity, and/or infertility may be specific to women with PCOS but need further investigation.


Acute effect of Ghrelin on ischemia/reperfusion injury in the rat spinal cord.
Ghrelin, a 28-amino acid peptide, is mainly secreted by the stomach. Ghrelin has been shown to have neuroprotective effects. However, whether ghrelin protects the spinal cord from ischemia/reperfusion (I/R) injury is unknown. To investigate this, 60 rats were randomly divided into three different groups: the sham group (n = 20), the vehicle group (n = 20), and the Ghrelin group (100 μg/kg, n = 20). Rats were sacrificed 12, 24, 48 and 72 h after ischemia. After the evaluation of neurologic function (48 h), the spinal cords were immediately removed for the determination of myeloperoxidase (MPO) activity (12-72 h). Apoptosis was quantitatively measured using the terminal transferase UTP nick end-labeling (TUNEL) method (24 h). The expression of bax and bcl-2 were evaluated by Western blot analysis (1 h), and GHSR-1a mRNA expression was detected using reverse transcriptase polymerase chain reaction (24 h). The neurological motor function was evaluated by 'Tarlov's score'. The neurologic outcomes in the ghrelin-group were significantly better than those in the vehicle group (p < 0.05). Serum tumor necrosis factor (TNF-α) levels were assessed in the peripheral venous blood. Ghrelin decreased the serum TNF-α levels and ameliorated the down regulation of spinal cord MPO activity. The expression of ghrelin receptors (GHSR-1a) in the rat spinal cord was decreased by I/R injury and increased by ghrelin. Ghrelin reduced the TUNEL-positive rate. Greater bcl-2, HSP27, HSP70, and attenuated bax expression were observed in the ghrelin-treated rats. Our results suggest that ghrelin administration may inhibit spinal I/R injury. Moreover, the improvement of neurologic function in rats was increased after the ghrelin treatment.


Functionalization of microstructured open-porous bioceramic scaffolds with human fetal bone cells.
Bone substitute materials allowing trans-scaffold migration and in-scaffold survival of human bone-derived cells are mandatory for development of cell-engineered permanent implants to repair bone defects. In this study, we evaluated the influence on human bone-derived cells of the material composition and microstructure of foam scaffolds of calcium aluminate. The scaffolds were prepared using a direct foaming method allowing wide-range tailoring of the microstructure for pore size and pore openings. Human fetal osteoblasts (osteo-progenitors) attached to the scaffolds, migrated across the entire bioceramic depending on the scaffold pore size, colonized, and survived in the porous material for at least 6 weeks. The long-term biocompatibility of the scaffold material for human bone-derived cells was evidenced by in-scaffold determination of cell metabolic activity using a modified MTT assay, a repeated WST-1 assay, and scanning electron microscopy. Finally, we demonstrated that the osteo-progenitors can be covalently bound to the scaffolds using biocompatible click chemistry, thus enhancing the rapid adhesion of the cells to the scaffolds. Therefore, the different microstructures of the foams influenced the migratory potential of the cells, but not cell viability. Scaffolds allow covalent biocompatible chemical binding of the cells to the materials, either localized or widespread integration of the scaffolds for cell-engineered implants.


Sensory analysis and consumer surveys of fat- and salt-reduced meat products and their use in an energy-reduced diet in overweight individuals.
Meat and meat products are of high nutritional value; however, they frequently provide salt and fat in high amounts, which can have negative health effects when consumed in excess. We investigated salt- and fat-reduced meat products, i.e. sensory evaluation and consumer surveys were carried out as well as a dietary intervention study was carried out in overweight individuals who used salt- and fat-reduced products as a part of an energy-restricted diet. Although differences were detected in the sensory evaluation between reduced and regular meat products, the participants in the consumer surveys and in the dietary intervention study gave good ratings for the fat and fat-reduced meat products. The intervention study led to weight loss and improved cardiovascular risk, but did not reveal side effects associated with the consumption of these products. Our study indicates that such products are well accepted by potential consumers and can be included successfully in a weight loss programme.


Distribution of TTAGG-specific telomerase activity in insects.
In most eukaryotes, telomeres consist of tandem arrays of a short repetitive DNA sequence. Insect telomeres are generally constituted by a (TTAGG)n repeat motif. Usually, telomeres are maintained by telomerase, a specialized reverse transcriptase that adds this sequence to chromosome ends. We examined telomerase activity in 15 species across Insecta. Telomerase activity was revealed in Isoptera, Blattaria, Lepidoptera, Hymenoptera, Trichoptera, Coleoptera, and Sternorrhyncha. In contrast, we were not able to detect telomerase activity in Orthoptera, Zygentoma, and Phasmida. Because we found telomerase activity in phylogenetically distant species, we conclude that a distribution pattern of (TTAGG)n sequence in Insecta is generally consistent with that of telomerase activity. Thus, the TTAGG-telomerase system is functional across the Insecta. Using real-time quantitative telomeric repeat amplification protocol (RTQ-TRAP) system, we quantified telomerase activity in different developmental stages and different tissues of a cockroach, Periplaneta americana. We show that telomerase is upregulated in young instars and gradually declines during development. In adults, it is most active in testes and ovaries. Thus, the telomerase activity of hemimetabolous insects seems to be associated with cell proliferation and organismal development.


Effective use of statins to prevent coronary heart disease.
Primary and secondary prevention trials have shown that use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (also known as statins) to lower an elevated low-density lipoprotein cholesterol level can substantially reduce coronary events and death from coronary heart disease. In 1987 and 1993, the National Cholesterol Education Program promulgated guidelines for cholesterol screening and treatment. Thus far, however, primary care physicians have inadequately adopted these guidelines in clinical practice. A 1991 study found that cholesterol screening was performed in only 23 percent of patients. Consequently, many patients with elevated low-density lipoprotein levels and a high risk of primary or recurrent ischemic events remain unidentified and untreated. A study published in 1998 found that fewer than 15 percent of patients with known coronary heart disease have low-density lipoprotein levels at the recommended level of below 100 mg per dL (2.60 mmol per L). By identifying patients with elevated low-density lipoprotein levels and instituting appropriate lipid-lowering therapy, family physicians could help prevent cardiovascular events and death in many of their patients.


Education to return nonpracticing physicians to clinical activity: a case study in physician reentry.
Physician shortages in the United States are estimated to reach as high as 85 000 by 2020. One strategy for addressing the shortage is to encourage physicians who left clinical practice to return to work, but few programs exist to prepare physicians to reenter practice. The Divisions of Continuing Medical Education and Graduate Medical Education (GME), Oregon Health & Science University, collaborated with clinical departments to establish a physician reentry program. A case-study of education designed to return nonpracticing physicians to clinical activity was undertaken. Fourteen candidates were accepted into the program. Accepted candidates were appointed special fellows at the university and provided with restricted institutional license and liability coverage. Based on retraining assessment and planned scope of practice, applicants and program directors designed individualized curricula. As trainees demonstrated clinical proficiency, their level of independence increased in a condensed version of the residency training model. Of the 14 accepted candidates, 13 successfully completed the program and are actively engaged in clinical practice. One trainee did not successfully complete the program. This reentry program reintroduced clinically inactive physicians into supervised direct patient care. Use of the GME model allowed acceptance of special fellows and provided institutional malpractice coverage for them.


Controlling the extent of viral genome release by a combination of osmotic stress and polyvalent cations.
While several in vitro experiments on viral genome release have specifically studied the effects of external osmotic pressure and of the presence of polyvalent cations on the ejection of DNA from bacteriophages, few have systematically investigated how the extent of ejection is controlled by a combination of these effects. In this work we quantify the effect of osmotic pressure on the extent of DNA ejection from bacteriophage lambda as a function of polyvalent cation concentration (in particular, the tetravalent polyamine spermine). We find that the pressure required to completely inhibit ejection decreases from 38 to 17 atm as the spermine concentration is increased from 0 to 1.5 mM. Further, incubation of the phage particles in spermine concentrations as low as 0.15 mM--the threshold for DNA condensation in bulk solution-is sufficient to significantly limit the extent of ejection in the absence of osmolyte; for spermine concentrations below this threshold, the ejection is complete. In accord with recent investigations on the packaging of DNA in the presence of a condensing agent, we observe that the self-attraction induced by the polyvalent cation affects the ordering of the genome, causing it to get stuck in a broad range of nonequilibrated structures.


Variation in fitness of the longhorned beetle, Dectes texanus, as a function of host plant.
Dectes texanus LeConte (Coleoptera: Cerambycidae) has become a serious pest of two different crops in the American Midwest, sunflower, Helianthus annuus L. and soybean, Glycines max (L.). Laboratory and field studies were used to compare the effects of these two host plants on D. texanus life history and behavior. Insects from soybean were 40-60% smaller than those from sunflower and larval weight at collection was strongly correlated with survival to adulthood, whereas it was not in sunflower, suggesting that body size was more limiting to immature survival in soybean. Pupal weights increased more rapidly with increasing stem diameter in soybean than in sunflower and the correlation was stronger, indicating that body size was more limited by plant size in soybean. Adults collected as larvae from soybean had shorter longevities when starved, fed soybean, or fed an alternating diet of soybean and cultivated sunflower, than did those collected from sunflower, suggesting a negative larval legacy of soybean on adult fitness. Adult beetles that developed in soybean lived longer when fed soybean than when starved, but an adult diet of sunflower doubled longevity compared to soybean for beetles that developed in sunflower, and tripled it for those that developed in soybean. An adult diet of wild H. annuus yielded survivorship equivalent to cultivated H. annuus in one trial, and slightly lower in another. Larval host plant did not influence the numbers of ovipunctures or eggs laid by females in field trials, but adult diet did. Sunflower-fed females punctured more, and laid more eggs, on sunflowers than on soybeans in field cages and the reverse trend was evident, but not significant, in soybean-fed females. It can be concluded that H. annuus is a superior food source to G. max for both larval and adult D. texanus, and that wild sunflowers may represent a valuable food for adults during the pre-reproductive period, prior to invasion of soybean fields, even though they rarely host larvae. We also showed that stable isotope ratios of N can be used to distinguish the larval host plant of beetles regardless of their adult diet.


Interaction between workers during a short time window is required for bacterial symbiont transmission in Acromyrmex leaf-cutting ants.
Stable associations between partners over time are critical for the evolution of mutualism. Hosts employ a variety of mechanisms to maintain specificity with bacterial associates. Acromyrmex leaf-cutting ants farm a fungal cultivar as their primary nutrient source. These ants also carry a Pseudonocardia Actinobacteria exosymbiont on their bodies that produces antifungal compounds that help inhibit specialized parasites of the ants' fungal garden. Major workers emerge from their pupal cases (eclose) symbiont-free, but exhibit visible Actinobacterial coverage within 14 days post-eclosion. Using subcolony experiments, we investigate exosymbiont transmission within Acromyrmex colonies. We found successful transmission to newly eclosed major workers fostered by major workers with visible Actinobacteria in all cases (100% acquiring, n = 19). In contrast, newly eclosed major workers reared without exosymbiont-carrying major workers did not acquire visible Actinobacteria (0% acquiring, n = 73). We further show that the majority of ants exposed to major workers with exosymbionts within 2 hours of eclosion acquired bacteria (60.7% acquiring, n = 28), while normal acquisition did not occur when exposure occurred later than 2 hours post-eclosion (0% acquiring, n = 18). Our findings show that transmission of exosymbionts to newly eclosed major workers occurs through interactions with exosymbiont-covered workers within a narrow time window after eclosion. This mode of transmission likely helps ensure the defensive function within colonies, as well as specificity and partner fidelity in the ant-bacterium association.


An ontological approach to identifying cases of chronic kidney disease from routine primary care data: a cross-sectional study.
Accurately identifying cases of chronic kidney disease (CKD) from primary care data facilitates the management of patients, and is vital for surveillance and research purposes. Ontologies provide a systematic and transparent basis for clinical case definition and can be used to identify clinical codes relevant to all aspects of CKD care and its diagnosis. We used routinely collected primary care data from the Royal College of General Practitioners Research and Surveillance Centre. A domain ontology was created and presented in Ontology Web Language (OWL). The identification and staging of CKD was then carried out using two parallel approaches: (1) clinical coding consistent with a diagnosis of CKD; (2) laboratory-confirmed CKD, based on estimated glomerular filtration rate (eGFR) or the presence of proteinuria. The study cohort comprised of 1.2 million individuals aged 18 years and over. 78,153 (6.4%) of the population had CKD on the basis of an eGFR of < 60 mL/min/1.73m2, and a further 7366 (0.6%) individuals were identified as having CKD due to proteinuria. 19,504 (1.6%) individuals without laboratory-confirmed CKD had a clinical code consistent with the diagnosis. In addition, a subset of codes allowed for 1348 (0.1%) individuals receiving renal replacement therapy to be identified. Finding cases of CKD from primary care data using an ontological approach may have greater sensitivity than less comprehensive methods, particularly for identifying those receiving renal replacement therapy or with CKD stages 1 or 2. However, the possibility of inaccurate coding may limit the specificity of this method.


A multi-faceted genotoxic network of alpha-synuclein in the nucleus and mitochondria of dopaminergic neurons in Parkinson's disease: Emerging concepts and challenges.
α-Synuclein is a hallmark amyloidogenic protein component of the Lewy bodies (LBs) present in dopaminergic neurons affected by Parkinson's disease (PD). Despite an enormous increase in emerging knowledge, the mechanism(s) of α-synuclein neurobiology and crosstalk among pathological events that are critical for PD progression remains enigmatic, creating a roadblock for effective intervention strategies. One confounding question is about the potential link between α-synuclein toxicity and genome instability in PD. We previously reported that pro-oxidant metal ions, together with reactive oxygen species (ROS), act as a "double whammy" in dopaminergic neurons by not only inducing genome damage but also inhibiting their repair. Our recent studies identified a direct role for chromatin-bound, oxidized α-synuclein in the induction of DNA strand breaks, which raised the question of a paradoxical role for α-synuclein's DNA binding in neuroprotection versus neurotoxicity. Furthermore, recent advances in our understanding of α-synuclein mediated mitochondrial dysfunction warrants revisiting the topics of α-synuclein pathophysiology in order to devise and assess the efficacy of α-synuclein-targeted interventions. In this review article, we discuss the multi-faceted neurotoxic role of α-synuclein in the nucleus and mitochondria with a particular emphasis on the role of α-synuclein in DNA damage/repair defects. We utilized a protein-DNA binding simulation to identify potential residues in α-synuclein that could mediate its binding to DNA and may be critical for its genotoxic functions. These emerging insights and paradigms may guide new drug targets and therapeutic modalities.


m-Chlorophenylpiperazine decreases food intake in a test meal.
We studied the effect of the 5-HT receptor agonist, m-chlorophenylpiperazine (mCPP) (0.4 mg/kg), on food intake in 12 healthy female volunteers, in a double-blind placebo controlled design. Compared to placebo, mCPP significantly lowered food intake in a test meal. Treatment with mCPP also caused significant increases in ratings of nausea and light-headedness, though these effects had remitted by the time of the test meal. The results suggest that activation of brain 5-HT2C receptors may lower food intake in humans; it is also possible, however, that the hypophagic effect of mCPP in the present study could be a consequence of its adverse subjective side effects.


Who shalt not kill? Individual differences in working memory capacity, executive control, and moral judgment.
Recent findings suggest that exerting executive control influences responses to moral dilemmas. In our study, subjects judged how morally appropriate it would be for them to kill one person to save others. They made these judgments in 24 dilemmas that systematically varied physical directness of killing, personal risk to the subject, inevitability of the death, and intentionality of the action. All four of these variables demonstrated main effects. Executive control was indexed by scores on working-memory-capacity (WMC) tasks. People with higher WMC found certain types of killing more appropriate than did those with lower WMC and were more consistent in their judgments. We also report interactions between manipulated variables that implicate complex emotion-cognition integration processes not captured by current dual-process views of moral judgment.


Sugarcoated isolation: evidence that social avoidance is linked to higher basal glucose levels and higher consumption of glucose.
The human brain adjusts its level of effort in coping with various life stressors as a partial function of perceived access to social resources. We examined whether people who avoid social ties maintain a higher fasting basal level of glucose in their bloodstream and consume more sugar-rich food, reflecting strategies to draw more on personal resources when threatened. In Study 1 (N = 60), we obtained fasting blood glucose and adult attachment orientations data. In Study 2 (N = 285), we collected measures of fasting blood glucose and adult attachment orientations from older adults of mixed gender, using a measure of attachment style different from Study 1. In Study 3 (N = 108), we examined the link between trait-like attachment avoidance, manipulation of an asocial state, and consumption of sugar-rich food. In Study 4 (N = 115), we examined whether manipulating the social network will moderate the effect of attachment avoidance on consumption of sugar-rich food. In Study 1, fasting blood glucose levels corresponded with higher attachment avoidance scores after statistically adjusting for time of assessment and interpersonal anxiety. For Study 2, fasting blood glucose continued to correspond with higher adult attachment avoidance even after statistically adjusting for interpersonal anxiety, stress indices, age, gender, social support and body mass. In Study 3, people high in attachment avoidance consume more sugar-rich food, especially when reminded of asocial tendencies. Study 4 indicated that after facing a stressful task in the presence of others, avoidant people gather more sugar-rich food than more socially oriented people. RESULTS are consistent with the suggestion that socially avoidant individuals upwardly adjust their basal glucose levels and consume more glucose-rich food with the expectation of increased personal effort because of limited access to social resources. Further investigation of this link is warranted.


The role of Area 10 (BA10) in human multitasking and in social cognition: a lesion study.
A role for rostral prefrontal cortex (BA10) has been proposed in multitasking, in particular, the selection and maintenance of higher order internal goals while other sub-goals are being performed. BA10 has also been implicated in the ability to infer someone else's feelings and thoughts, often referred to as theory of mind. While most of the data to support these views come from functional neuroimaging studies, lesion studies are scant. In the present study, we compared the performance of a group of frontal patients whose lesions involved BA10, a group of frontal patients whose lesions did not affect this area (nonBA10), and a group of healthy controls on tests requiring multitasking and complex theory of mind judgments. Only the group with lesions involving BA10 showed deficits on multitasking and theory of mind tasks when compared with control subjects. NonBA10 patients performed more poorly than controls on an executive function screening tool, particularly on measures of response inhibition and abstract reasoning, suggesting that theory of mind and multitasking deficits following lesions to BA10 cannot be explained by a general worsening of executive function. In addition, we searched for correlations between performance and volume of damage within different subregions of BA10. Significant correlations were found between multitasking performance and volume of damage in right lateral BA10, and between theory of mind and total BA10 lesion volume. These findings stress the potential pivotal role of BA10 in higher order cognitive functions.


Increased thrombin generation and activity in patients with systemic lupus erythematosus and anticardiolipin antibodies: evidence for a prothrombotic state.
The objective of this study is to determine whether patients with systemic lupus erythematosus (SLE) and anticardiolipin antibodies (ACA) have biochemical evidence of an ongoing prothrombotic state. Using a cross-sectional analysis of a cohort design in an outpatient SLE clinic setting, 43 consecutive patients with SLE participated. Patients underwent clinical and laboratory evaluations on two separate occasions at least 3 months apart. As part of the clinical evaluation, the following were ascertained: (1) the ongoing use of warfarin therapy; (2) the presence of prior venous and arterial thromboembolic disease by history, critical review of objective tests, and examination for reflux in the deep veins of the legs as an indicator of venous thrombosis; and (3) disease-related activity by performing a lupus activity criteria count (LACC). As part of the laboratory evaluation, blood was taken on both occasions and assayed for prothrombin fragments (F1 + 2) and fibrinopeptide A (FPA), as indices of thrombin generation and activity, respectively, and ACA. For the analyses, patients were classified as ACA+ if the assay was abnormal on both occasions and ACA- if the assay was negative on both occasions or negative on one occasion and positive on the other. ACA+ patients had: (1) a significantly higher mean level of F1 + 2 (1.07 nmol/L) than ACA- patients (0.79 nmol/L; P = .02) and patients receiving warfarin (0.47 nmol/L; P = .009) and (2) a significantly higher mean level of FPA (1.01 nmol/L) than ACA- patients (0.45 nmol/L; P = .02). When patients with prior thromboembolism were excluded from the analysis, significant differences in the mean levels of F1 + 2 and FPA between ACA+ and ACA- patients were still seen, whereas when patients with prior thromboembolism and/or active disease were excluded from the analysis, a significant difference in the mean level of FPA and a nonsignificant trend in the mean level of F1 + 2 were seen. The results of this study support the hypothesis that the presence of ACA in SLE patients is associated with an ongoing prothrombotic state.


The influence of hospital volume on long-term oncological outcome after rectal cancer surgery.
The association between hospital volume and outcome in rectal cancer surgery is still subject of debate. The purpose of this study was to assess the impact of hospital volume on outcomes of rectal cancer surgery in the Netherlands in 2011. In this collaborative research with a cross-sectional study design, patients who underwent rectal cancer resection in 71 Dutch hospitals in 2011 were included. Annual hospital volume was stratified as low (< 20), medium (20-50), and high (≥ 50). Of 2095 patients, 258 patients (12.3%) were treated in 23 low-volume hospitals, 1329 (63.4%) in 40 medium-volume hospitals, and 508 (24.2%) in 8 high-volume hospitals. Median length of follow-up was 41 months. Clinical tumor stage, neoadjuvant therapy, extended resections, circumferential resection margin (CRM) positivity, and 30-day or in-hospital mortality did not differ significantly between volume groups. Significantly, more laparoscopic procedures were performed in low-volume hospitals, and more diverting stomas in high-volume hospitals. Three-year disease-free survival for low-, medium-, and high-volume hospitals was 75.0, 74.8, and 76.8% (p = 0.682). Corresponding 3-year overall survival rates were 75.9, 79.1, and 80.3% (p = 0.344). In multivariate analysis, hospital volume was not associated with long-term risk of mortality. No significant impact of hospital volume on rectal cancer surgery outcome could be observed among 71 Dutch hospitals after implementation of a national audit, with the majority of patients being treated at medium-volume hospitals.


Gait Analysis From a Single Ear-Worn Sensor: Reliability and Clinical Evaluation for Orthopaedic Patients.
Objective assessment of detailed gait patterns after orthopaedic surgery is important for post-surgical follow-up and rehabilitation. The purpose of this paper is to assess the use of a single ear-worn sensor for clinical gait analysis. A reliability measure is devised for indicating the confidence level of the estimated gait events, allowing it to be used in free-walking environments and for facilitating clinical assessment of orthopaedic patients after surgery. Patient groups prior to or following anterior cruciate ligament (ACL) reconstruction and knee replacement were recruited to assess the proposed method. The ability of the sensor for detailed longitudinal analysis is demonstrated with a group of patients after lower limb reconstruction by considering parameters such as temporal and force-related gait asymmetry derived from gait events. The results suggest that the ear-worn sensor can be used for objective gait assessments of orthopaedic patients without the requirement and expense of an elaborate laboratory setup for gait analysis. It significantly simplifies the monitoring protocol and opens the possibilities for home-based remote patient assessment.


The association between cytokines and intestinal mucosal immunity among broilers fed on diets supplemented with fluorine.
Fluorine (F) bioaccumulation has been reported in the organs and tissues of organisms, including intestine. The intestinal mucosa is very important to the immune development. Meanwhile, cytokines are present in the normal intestinal mucosal and play an important role in the immune function. Thus, changes of the cytokine contents are related to the state of intestinal mucosal immunity. In this study, we investigated the changes in contents of cytokines such as interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interferon gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) induced by dietary high F in the mucosa of different parts of intestines (duodenum, jejunum, and ileum) by enzyme-linked immunosorbent assay. A total of 280 one-day-old healthy avian broilers were randomly divided into four groups and fed on a corn-soybean basal diet as control diet (F 22.6 mg/kg) or the same basal diet supplemented with 400, 800, and 1,200 mg F/kg (high F groups I, II, and III) in the form of sodium fluoride for 42 days. The experimental data showed that the contents of IL-2, IL-4, IL-6, IFN-γ, and TNF-α in the intestinal mucosa were significantly decreased in the high F groups II and III when compared with those of the control group from 14 to 42 days of age. It was concluded that dietary F in the range of 800-1,200 mg/kg significantly reduced the contents of aforementioned cytokines in the intestinal mucosa of broilers, which could impact the function of intestinal mucosal immunity through the pathways that decreased the lymphocyte population and/or lymphocyte activation.


Density of healthcare providers and patient outcomes: evidence from a nationally representative multi-site HIV treatment program in Uganda.
We examined the association between density of healthcare providers and patient outcomes using a large nationally representative cohort of patients receiving combination antiretroviral therapy (cART) in Uganda. We obtained data from The AIDS Support Organization (TASO) in Uganda. Patients 18 years of age and older who initiated cART at TASO between 2004 and 2008 contributed to this analysis. The number of healthcare providers per 100 patients, the number of patients lost to follow-up per 100 person years and number of deaths per 100 person years were calculated. Spearman correlation was used to identify associations between patient loss to follow-up and mortality with the healthcare provider-patient ratios. We found no significant associations between the number of patients lost to follow-up and physicians (p = 0.45), nurses (p = 0.93), clinical officers (p = 0.80), field officers (p = 0.56), and healthcare providers overall (p = 0.83). Similarly, no significant associations were observed between mortality and physicians (p = 0.65), nurses (p = 0.49), clinical officers (p = 0.73), field officers (p = 0.78), and healthcare providers overall (p = 0.73). Patient outcomes, as measured by loss to follow-up and mortality, were not significantly associated with the number of doctors, nurses, clinical officers, field officers, or healthcare providers overall. This may suggest that that other factors, such as the presence of volunteer patient supporters or broader political or socioeconomic influences, may be more closely associated with outcomes of care among patients on cART in Uganda.


Enhancement strategies for transdermal drug delivery systems: current trends and applications.
Transdermal drug delivery systems have become an intriguing research topic in pharmaceutical technology area and one of the most frequently developed pharmaceutical products in global market. The use of these systems can overcome associated drawbacks of other delivery routes, such as oral and parenteral. The authors will review current trends, and future applications of transdermal technologies, with specific focus on providing a comprehensive understanding of transdermal drug delivery systems and enhancement strategies. This article will initially discuss each transdermal enhancement method used in the development of first-generation transdermal products. These methods include drug/vehicle interactions, vesicles and particles, stratum corneum modification, energy-driven methods and stratum corneum bypassing techniques. Through suitable design and implementation of active stratum corneum bypassing methods, notably microneedle technology, transdermal delivery systems have been shown to deliver both low and high molecular weight drugs. Microneedle technology platforms have proven themselves to be more versatile than other transdermal systems with opportunities for intradermal delivery of drugs/biotherapeutics and therapeutic drug monitoring. These have shown that microneedles have been a prospective strategy for improving transdermal delivery systems.


Effects of gadoxetate disodium (Eovist(®)) contrast on magnetic resonance imaging characteristics of the liver in clinically healthy dogs.
Gadoxetate disodium (Gd-EOB-DTPA; gadolinium-ethoxybenzyl-diethylene triamine penta-acetic acid) is a newly developed paramagnetic contrast agent reported to have a high specificity for the hepatobiliary system in humans. The purpose of this prospective study was to describe effects of Gd-EOB-DTPA contrast administration on MRI characteristics of the liver in eight clinically healthy dogs. Precontrast dorsal and transverse T1-weighted spin echo, T2-weighted fast spin echo, and transverse T1-weighted 3D gradient echo (VIBE; volume-interpolated body examination) pulse sequences were acquired for each dog. Dogs were assigned to four groups based on contrast dose administered (0.0125 mmol/kg or 0.025 mmol/kg), and pulse sequences acquired after contrast administration (T1-weighted spin echo and T1-weighted 3D gradient echo). Liver signal intensity ratios were calculated and compared between the two contrast dose groups and two postcontrast pulse sequence groups using ANOVA. No adverse effects of contrast administration were observed. All dogs exhibited homogeneous contrast enhancement of the liver with no statistical difference in enhancement between the two different contrast doses. Contrast enhancement in all dogs peaked between 1 and 10 min after intravenous injection. There was a significant difference in mean signal intensity ratios between sequences (P = 0.035) but not between doses (P = 0.421). Postcontrast signal intensities of the liver parenchyma were significantly higher for the T1-weighted 3D gradient echo images when compared to the T1-weighted spin echo sequences. Findings indicated that Gd-EOB-DTPA contrast administration is safe in healthy dogs and causes homogeneous enhancement of the liver that is more pronounced in T1-weighted 3D gradient echo MRI pulse sequences.


Fast and accurate MAS-DNP simulations of large spin ensembles.
A deeper understanding of parameters affecting Magic Angle Spinning Dynamic Nuclear Polarization (MAS-DNP), an emerging nuclear magnetic resonance hyperpolarization method, is crucial for the development of new polarizing agents and the successful implementation of the technique at higher magnetic fields (>10 T). Such progress is currently impeded by computational limitation which prevents the simulation of large spin ensembles (electron as well as nuclear spins) and to accurately describe the interplay between all the multiple key parameters at play. In this work, we present an alternative approach to existing cross-effect and solid-effect MAS-DNP codes that yields fast and accurate simulations. More specifically we describe the model, the associated Liouville-based formalism (Bloch-type derivation and/or Landau-Zener approximations) and the linear time algorithm that allows computing MAS-DNP mechanisms with unprecedented time savings. As a result, one can easily scan through multiple parameters and disentangle their mutual influences. In addition, the simulation code is able to handle multiple electrons and protons, which allows probing the effect of (hyper)polarizing agents concentration, as well as fully revealing the interplay between the polarizing agent structure and the hyperfine couplings, nuclear dipolar couplings, nuclear relaxation times, both in terms of depolarization effect, but also of polarization gain and buildup times.


Losing independence--the lived experience of being long-term sick-listed.
Sickness absence is a multifaceted problem. Much is known about risk factors for being long-term sick-listed, but there is still little known about the various aftermaths and experiences of it. The aim of this qualitative study was to describe, analyze and understand long-term sickness-absent people's experiences of being sick-listed. The design was descriptive and had a phenomenological approach. Sixteen long-term sickness-absent individuals were purposively sampled from three municipalities in Sweden in 2011, and data were collected through semi-structured, individual interviews. The interview questions addressed how the participants experienced being sick-listed and how the sick-listing affected their lives. Transcribed interviews were analysed using Giorgi's phenomenological method. The interviews revealed that the participants' experiences of being sick-listed was that they lost their independence in the process of stepping out of working society, attending the mandatory steps in the rehabilitation chain and having numerous encounters with professionals. The participants described that their life-worlds were radically changed when they became sick-listed. Their experiences of their changing life-worlds were mostly highly negative, but there were also a few positive experiences. The most conspicuous findings were the fact that stopping working brought with it so many changes, the participants' feelings of powerlessness in the process, and their experiences of offensive treatment by and/or encounters with professionals. Sick-listed persons experienced the process of being on long-term sickness absent as very negative. The negative experiences are linked to consequences of stopping to work, consequences of social insurance rules and to negative encounters with professionals handling the sickness absence. The positive experiences of being sick-listed were few in the present study. There is a need to further examine the extent of these negative experiences are and how they affect sick-listed people's recovery and return to work. Long-term sickness absence; sick leave; experiences; interviews; phenomenology; Sweden.


CHSMiner: a GUI tool to identify chromosomal homologous segments.
The identification of chromosomal homologous segments (CHS) within and between genomes is essential for comparative genomics. Various processes including insertion/deletion and inversion could cause the degeneration of CHSs. Here we present a Java software CHSMiner that detects CHSs based on shared gene content alone. It implements fast greedy search algorithm and rigorous statistical validation, and its friendly graphical interface allows interactive visualization of the results. We tested the software on both simulated and biological realistic data and compared its performance with similar existing software and data source. CHSMiner is characterized by its integrated workflow, fast speed and convenient usage. It will be useful for both experimentalists and bioinformaticians interested in the structure and evolution of genomes.


Plasmonic nanofocusing using a metal-coated axicon prism.
We propose an excitation method for the localization of photons at the apex of a metal coated axicon prism. The cone angle of the prism and the metallic film thickness are designed to match the excitation conditions for surface plasmons. The plasmons propagate along the sides of the prism and converge at its apex. The resulting nanofocusing was investigated by simulating the intensity distributions around the apex of the prism using a finite-difference time-domain algorithm. For incident radial polarization, a localized and field enhanced spot is generated by the constructive interference of surface plasmons.


New methods for capturing the mystery lipid, PtdIns5P.
The enormous versatility of phosphatidylinositol as a mediator of intracellular signalling is due to its variable phosphorylation on every combination of the 3', 4' and 5' positions, as well as an even more complex range of phosphorylated products when inositol phosphate is released by phospholipase C activity. The phosphoinositides are produced by distinct enzymes in distinct intracellular membranes, and recruit and regulate downstream signalling proteins containing binding domains [PH (pleckstrin homology), PX (Phox homology), FYVE etc.] that are relatively specific for these lipids. Specific recruitment of downstream proteins presumably involves a coincidence detection mechanism, in which a combination of lipid-protein and protein-protein interactions define specificity. Of the seven intracellular phosphoinositide, quantification of PtdIns5P levels in intact cells has remained difficult. In this issue of the Biochemical Journal, Sarkes and Rameh describe a novel HPLC-based approach which makes possible an analysis of the subcellular distribution of PtdIns5P and other phosphoinositides.


Methods of delivering the placenta at caesarean section.
Worldwide, caesarean section is the most common major operation performed on women. Some of the reported short-term morbidities include haemorrhage, postoperative fever and endometritis. The method of delivering the placenta is one procedure that may contribute to an increase or decrease in the morbidity of caesarean section. Two common methods used to deliver the placenta at caesarean section are cord traction and manual removal. To compare the effects of manual removal of the placenta with cord traction at caesarean section. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2007). All randomised controlled trials comparing manual removal and cord traction or spontaneous of delivery of the placenta. Two authors independently assessed studies and extracted data. We included 15 studies (4694 women). There was significant heterogeneity for the duration of surgery, blood loss and haematological outcomes. The only possible contributing factor found was greater protection from blood loss in two trials in which cord traction was combined with uterine massage. A random-effects model meta-analysis was used for these outcomes. Manual removal of the placenta was associated with more endometritis (relative risk (RR) 1.64, 95% confidence interval (CI) 1.42 to 1.90; 4134 women, 13 trials); more blood loss (ml) (weighted mean difference (WMD) 94.42 ml, 95% CI 17.19 to 171.64; 2001 women, eight trials); more blood loss > 1000 ml (RR 1.81, 95% CI 1.44 to 2.28; 872 women, two trials); lower haematocrit after delivery (%) (WMD -1.55, 95% CI -3.09 to -0.01; 384 women, two trials); greater haematocrit fall after delivery (%) (WMD 0.39, 95% CI 0.00 to 0.78; 1777 women, five trials); longer duration of hospital stay (days) (WMD 0.39 days, 95% CI 0.17 to 0.61; 546 women, three trials). The duration of surgery was shorter in one trial but not overall. There were no significant differences in feto-maternal haemorrhage, blood transfusion, puerperal fever (numbers studied for these outcomes were small). Delivery of the placenta with cord traction at caesarean section has more advantages compared to manual removal. These are less endometritis; less blood loss; less decrease in haematocrit levels postoperatively; and shorter duration of hospital stay. Future trials should provide information on interval between the delivery of the infant and of the placenta, change in lochia, blood splashing during placental removal and uterine pain after operation, as well as the effects of delayed cord clamping.


Fetal effects of environmental exposure of pregnant women to organophosphorus compounds in a rural farming community in Sri Lanka.
The possible deleterious effects of low-grade, chronic environmental and occupational exposure to organophosphorus compounds (OPCs) are not well documented. To investigate the possible effects of low-level, chronic exposure of pregnant mothers to OPCs on the fetus by measuring OPC levels, and using markers of OPC exposure, oxidative stress and oxidative tissue damage. Toxicity was assessed by measuring (i) OPC levels in breast milk and plasma from maternal and cord blood using gas chromatography, (ii) maternal and fetal butyrylcholinesterase (BChE) activity using inhibition assays, (iii) antioxidant status of the fetus using superoxide dismutase activity assays, (iv) oxidative stress in the fetus by determining malondialdehyde (MDA) concentrations, and (v) examining for fetal DNA fragmentation using electrophoresis. Samples were obtained from consenting mothers living in a farming community in southern Sri Lanka at the end of the pesticide spray season (study group) and just before the commencement of the spray season (in-between spray season; control group). Organophosphate residues were detected in only two subjects (chlorpyrifos in maternal and cord blood of one during the spray season and dimethoate in breast milk of another during the in between spray season), but the test employed was capable of only detecting concentrations above 0.05 mg/l. However, cord blood obtained during the spray season showed significant inhibition of BChE activity, increased oxidative stress and more DNA fragmentation when compared with cord blood obtained during the in-between spray season. Inhibition of cord blood BChE activity indicates fetal exposure to organophosphorus compounds during times when there is a high probability of environmental drift. This provides a plausible explanation for the increased oxidative stress and high DNA fragmentation in the fetus. Long-term outcomes of such exposures are unknown.


Optical coherence tomography angiography and photoacoustic imaging in dermatology.
Optical coherence tomography angiography (OCTA) is a relatively novel functional extension of the widely accepted ophthalmic imaging tool named optical coherence tomography (OCT). Since OCTA's debut in ophthalmology, researchers have also been trying to expand its translational application in dermatology. The ability of OCTA to resolve microvasculature has shown promising results in imaging skin diseases. Meanwhile, photoacoustic imaging (PAI), which uses laser pulse induced ultrasound waves as the signal, has been studied to differentiate human skin layers and to help in skin disease diagnosis. This perspective article gives a short review of OCTA and PAI in the field of photodermatology. After an introduction to the principles of OCTA and PAI, we describe the most updated results of skin disease imaging using these two optical imaging modalities. We also place emphasis on dual modality imaging combining OCTA and photoacoustic tomography (PAT) for dermatological applications. In the end, the challenges and prospects of these two imaging modalities in dermatology are discussed.


Antioxidant Effects of Oleuropein on Hydrogen Peroxide-Induced Neuronal Stress- An In Vitro Study.
Persistent oxidative stress can lead to chronic inflammation and mediate most chronic diseases including neurological disorders. Oleuropein has been shown to be a potent antioxidant molecule in olive oil leaf having antioxidative properties. The aim of this study was to investigate the protective effects of oleuropein against oxidative stress in human glioblastoma cells. Human glioblastoma cells (U87) were pretreated with oleuropein (OP) essential oil 10 µM. After 30 minutes, 100 µM H2O2 was added to the cells for three hours. Cell survival was quantified by colorimetric MTT assay. Glutathione level, total oxidant capacity, total antioxidant capacity and nitric oxide levels were determined by using specific spectrophotometric methods. The relative gene expression level of iNOS was performed by qRT-PCR method. According to viability results, the effective concentration of H2O2 (100µM) significantly decreased cell viability and oleuropein pretreatment significantly prevented the cell losses. Oleuropein regenerated total antioxidant capacity and glutathione levels decreased by H2O2 exposure. In addition, nitric oxide and total oxidant capacity levels were also decreased after administration of oleuropein in treated cells. Oleuropein was found to have potent antioxidative properties in human glioblastoma cells. However, further studies and validations are needed in order to understand the exact neuroprotective mechanism of oleuropein.


Synthesis and characterization of the magnetic molecularly imprinted polymer nanoparticles using N, N-bis methacryloyl ethylenediamine as a new cross-linking agent for controlled release of meloxicam.
The novel magnetic molecularly imprinted polymers (MMIPs) had been synthesized using N,N-bis methacryloyl ethylenediamine as a cross-linker for the controlled release of meloxicam at a pH of 1.0 (simulated gastric fluid), at a pH of 6.8 (simulated intestinal fluid) and at a pH of 7.4 (simulated biological fluids). The MMIPs were prepared via precipitation polymerization, using Fe3O4 as a magnetic component, meloxicam as a template molecule, methacrylic acid (MAA) as a functional monomer and N,N-bis methacryloyl ethylenediamine as a new cross-linker in acetonitrile/dimethyl sulfoxide porogen. Magnetic non-molecularly imprinted polymers (MNIPs) were also prepared with the same synthesis procedure as with MMIPs only without the presence of the template. The obtained MMIPs were characterized using transmission electron microscopy (TEM) and Fourier transform infrared (FT-IR), dynamic light scattering (DLS), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX) and vibrating sample magnetometer (VSM). The performance of the MMIPs for the controlled release of meloxicam was assessed, and the results indicated that the magnetic MIPs also had potential applications in drug controlled release.


Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription.
Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. To identify key features associated with the delayed parasite clearance phenotype, we employed DNA microarrays to profile the physiological gene expression pattern of the resistant isolates. In the ring and trophozoite stages, we observed reduced expression of many basic metabolic and cellular pathways which suggests a slower growth and maturation of these parasites during the first half of the asexual intraerythrocytic developmental cycle (IDC). In the schizont stage, there is an increased expression of essentially all functionalities associated with protein metabolism which indicates the prolonged and thus increased capacity of protein synthesis during the second half of the resistant parasite IDC. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of regulatory proteins such as transcription factors or chromatin remodeling associated proteins. In addition, there is a unique and uniform copy number variation pattern in the Cambodian parasites which may represent an underlying genetic background that contributes to the resistance phenotype. The decreased metabolic activities in the ring stages are consistent with previous suggestions of higher resilience of the early developmental stages to artemisinin. Moreover, the increased capacity of protein synthesis and protein turnover in the schizont stage may contribute to artemisinin resistance by counteracting the protein damage caused by the oxidative stress and/or protein alkylation effect of this drug. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides insight to the complexities of the molecular basis of pathogens with drug resistance phenotypes in vivo.


Diurnal variation is lost in preterm deliveries before 28 weeks of gestation.
Preterm delivery is the primary cause of neonatal mortality and morbidity worldwide. Labour at term occurs as a culmination of maturational events in both the fetus and maternal uterus. This process exhibits diurnal variation, with the onset of labour being more common at night. We have confirmed that this diurnal variation is present in gestations between 28 and 36 weeks, but is absent below 28 weeks. We hypothesise that this is because before 28 weeks of gestation, the onset of labour may result from a pathological rather than a physiological process. This may have important implications regarding any pharmacological approach to the prevention and/or treatment of very early preterm labour.


Evaluating antimalarial efficacy in single-armed and comparative drug trials using competing risk survival analysis: a simulation study.
Antimalarial efficacy studies in patients with uncomplicated Plasmodium falciparum are confounded by a new infection (a competing risk event) since this event can potentially preclude a recrudescent event (primary endpoint of interest). The current WHO guidelines recommend censoring competing risk events when deriving antimalarial efficacy. We investigated the impact of considering a new infection as a competing risk event on the estimation of antimalarial efficacy in single-armed and comparative drug trials using two simulation studies. The first simulation study explored differences in the estimates of treatment failure for areas of varying transmission intensities using the complement of the Kaplan-Meier (K-M) estimate and the Cumulative Incidence Function (CIF). The second simulation study extended this to a comparative drug efficacy trial for comparing the K-M curves using the log-rank test, and Gray's k-sample test for comparing the equality of CIFs. The complement of the K-M approach produced larger estimates of cumulative treatment failure compared to the CIF method; the magnitude of which was correlated with the observed proportion of new infection and recrudescence. When the drug efficacy was 90%, the absolute overestimation in failure was 0.3% in areas of low transmission rising to 3.1% in the high transmission settings. In a scenario which is most likely to be observed in a comparative trial of antimalarials, where a new drug regimen is associated with an increased (or decreased) rate of recrudescences and new infections compared to an existing drug, the log-rank test was found to be more powerful to detect treatment differences compared to the Gray's k-sample test. The CIF approach should be considered for deriving estimates of antimalarial efficacy, in high transmission areas or for failing drugs. For comparative studies of antimalarial treatments, researchers need to select the statistical test that is best suited to whether the rate or cumulative risk of recrudescence is the outcome of interest, and consider the potential differing prophylactic periods of the antimalarials being compared.


Microtensile bond strength distributions of three composite materials with different polymerization shrinkages bonded to dentin.
To assess the detrimental effects that polymerization contraction causes on the interfacial microtensile bond strength (μTBS) to dentin of three light-curing resin composites: two conventional bis-GMA-based composite resins (Filtek Z250, TPH Spectrum) and a low shrinkage material (Filtek Silorane [SIL]). Flat surfaces of labial dentin were made in 46 bovine teeth and restored in single (group A) or in three separate (group B) one-increment visible-light cured resin composite blocks, with similar locations among teeth. After 24 h, restored teeth were sectioned perpendicular to interfaces, producing rectangular compound specimens (385 specimens were produced in group A, and 132 in group B), and submitted to tension (crosshead speed 1mm/min) until failure. μTBS results were adjusted to bonded area and transformed to percentages of maximum values within each tooth (PTens). In A groups, distances of specimens to the gingival ends of each restoration were transformed to PDistances: the percentage of that distance within its specimen. Spearman's nonparametric correlation test showed that for Z250, TPH and SIL, in A groups, a material's correlation coefficient was positive for the first half of restorations (0% to 50% PDistances) and negative for the second (50% to 100%). For all materials, PTens values in extremes of restorations (pooled 0 and 100% PDistances) in A groups were smaller than corresponding values in B groups. These differences were statistically significantly (Student's t-test) only for Z250 and TPH. Even in cases of favorable configuration factor, polymerization shrinkage in large restorations can reduce interface mechanical characteristics. The relevance of this decrease has still to be established.


The clinical relevance of animal models in Sjögren's syndrome: the interferon signature from mouse to man.
Mouse models have been widely used to elucidate the pathogenic mechanisms of human diseases. The advantages of using these models include the ability to study different stages of the disease with particular respect to specific target organs, to focus on the role of specific pathogenic factors and to investigate the effect of possible therapeutic interventions. Sjögren's syndrome (SS) is a systemic autoimmune disease, characterised by lymphocytic infiltrates in the salivary and lacrimal glands. To date, effective therapy is not available and treatment has been mainly symptomatic. Ongoing studies in murine models are aimed at developing more effective and targeted therapies in SS. The heterogeneity of SS will most probably benefit from optimising therapies, tailored to specific subgroups of the disease. In this review, we provide our perspective on the importance of subdividing SS patients according to their interferon signature, and recommend choosing appropriate mouse models for interferon-positive and interferon-negative SS subtypes. Murine models better resembling human-disease phenotypes will be essential in this endeavour.


Bariatric surgery.
Bariatric surgery is currently the only effective long-term treatment of morbid obesity and its related co-morbidities. Gastric bypass, adjustable gastric banding, and duodenal switch with biliopancreatic diversion are the three most common operations performed in the United States to induce sustained weight loss. Patient selection is important since compliance postoperatively leads to a successful outcome in over 80% of patients. Preoperative psychological and behavioral problems may lead to maladaptive eating habits postoperatively that defeat the purpose of the surgery. To date, we do not have a 100% reliable method of profiling patients who will fail to keep weight off for the long term. It is therefore important that patients who have preoperative psychological problems that may lead to failure to lose or keep weight off after surgery are offered postoperative counseling along with group support.


The predictive value of the NICE "red traffic lights" in acutely ill children.
Early recognition and treatment of febrile children with serious infections (SI) improves prognosis, however, early detection can be difficult. We aimed to validate the predictive rule-in value of the National Institute for Health and Clinical Excellence (NICE) most severe alarming signs or symptoms to identify SI in children. The 16 most severe ("red") features of the NICE traffic light system were validated in seven different primary care and emergency department settings, including 6,260 children presenting with acute illness. We focussed on the individual predictive value of single red features for SI and their combinations. Results were presented as positive likelihood ratios, sensitivities and specificities. We categorised "general" and "disease-specific" red features. Changes in pre-test probability versus post-test probability for SI were visualised in Fagan nomograms. Almost all red features had rule-in value for SI, but only four individual red features substantially raised the probability of SI in more than one dataset: "does not wake/stay awake", "reduced skin turgor", "non-blanching rash", and "focal neurological signs". The presence of ≥ 3 red features improved prediction of SI but still lacked strong rule-in value as likelihood ratios were below 5. The rule-in value of the most severe alarming signs or symptoms of the NICE traffic light system for identifying children with SI was limited, even when multiple red features were present. Our study highlights the importance of assessing the predictive value of alarming signs in clinical guidelines prior to widespread implementation in routine practice.


Structural basis of JAZ repression of MYC transcription factors in jasmonate signalling.
The plant hormone jasmonate plays crucial roles in regulating plant responses to herbivorous insects and microbial pathogens and is an important regulator of plant growth and development. Key mediators of jasmonate signalling include MYC transcription factors, which are repressed by jasmonate ZIM-domain (JAZ) transcriptional repressors in the resting state. In the presence of active jasmonate, JAZ proteins function as jasmonate co-receptors by forming a hormone-dependent complex with COI1, the F-box subunit of an SCF-type ubiquitin E3 ligase. The hormone-dependent formation of the COI1-JAZ co-receptor complex leads to ubiquitination and proteasome-dependent degradation of JAZ repressors and release of MYC proteins from transcriptional repression. The mechanism by which JAZ proteins repress MYC transcription factors and how JAZ proteins switch between the repressor function in the absence of hormone and the co-receptor function in the presence of hormone remain enigmatic. Here we show that Arabidopsis MYC3 undergoes pronounced conformational changes when bound to the conserved Jas motif of the JAZ9 repressor. The Jas motif, previously shown to bind to hormone as a partly unwound helix, forms a complete α-helix that displaces the amino (N)-terminal helix of MYC3 and becomes an integral part of the MYC N-terminal fold. In this position, the Jas helix competitively inhibits MYC3 interaction with the MED25 subunit of the transcriptional Mediator complex. Our structural and functional studies elucidate a dynamic molecular switch mechanism that governs the repression and activation of a major plant hormone pathway.


Design and clinical characteristics of a homogeneous schizophrenia pedigree sample from Tamil Nadu, India.
The genetic complexity of schizophrenia may be compounded by the diagnostic imprecision inherent in distinguishing schizophrenia from closely related mood and substance use disorders. Further complexity may arise from studying genetically and/or environmentally diverse ethnic groups. Reported here are the ascertainment, demographic features and clinical characteristics, of a diagnostically and ethnically homogeneous schizophrenia pedigree sample from Tamil Nadu, India. Also reported is the theoretical power to detect genetic linkage in the subset of affected sibling pairs. Affected sibling pair and trio pedigrees were identified by caste/ethnicity. Affected probands and siblings fulfilled DSM-IV criteria for schizophrenia or schizoaffective disorder. The present sample consisted of 159 affected sibling pairs and 187 parent-offspring trios originating primarily from the Tamil Brahmin caste, but also incorporating pedigrees from genetically similar, geographically proximal caste groups. Consistent with previous studies in Tamil Nadu, a very low prevalence of affective psychoses such as schizoaffective disorder, was observed, with most affected individuals having schizophrenia (499/504). Also observed were extremely low rates of nicotine (12.4%), alcohol (1.1%) and illicit drug use (0%). Most affected individuals exhibited negative symptoms (>90%) and a severe, chronic course. All participants lived in the same geographic and climatic region and most affected individuals resided with close family members, increasing uniformity of the sociocultural environment. In affected sibling pairs, power to detect linkage to small-effect risk loci was modest, but this homogeneous sample may be enriched for loci of larger effect. This Indian schizophrenia sample exhibits diagnostic and ethnic homogeneity with high consistency of sociocultural environmental features. These characteristics should assist efforts to identify risk genes for schizophrenia.


His595Tyr polymorphism in the methionine synthase reductase (MTRR) gene is associated with pancreatic cancer risk.
This study attempts to elucidate a part of the genetic predisposition to the sporadic invasive ductal adenocarcinoma of the pancreas focusing on the genes implicated in the gene-environment interactions in carcinogenesis. First, 227 single nucleotide polymorphisms (SNPs) of 46 genes were genotyped on 198 cases and 182 controls. The SNPs, which showed a significant association, were further genotyped on additional samples to perform a joint analysis (total 317 cases vs 1232 controls). The gene selected by joint analysis was resequenced for a high-density SNP typing and a haplotype analysis on 702 cases and 785 controls. Function of the risk and wild-type haplotypes was assessed using cells transfected with complementary DNA (cDNA). The joint analysis with multiple testing adjustment identified 2 SNPs on the methionine synthase reductase (MTRR) gene: rs162049 (intronic SNP), Fisher exact test, P = .0018; OR, 1.33; 95% CI: 1.11-1.60 and rs10380 (His595Tyr), Fisher exact test, P = .0063; OR, 1.45; 95% CI: 1.11-1.88. The SNPs remained significant in the recessive model after the permutation test for multiple testing (rs162049, P = .024; rs10380, P = .023) in the high-density analysis. Stable transfectants of the risk haplotype MTRR cDNA showed significantly elevated homocysteine levels in a culture medium, a lower level of the LINE-1 methylation, and a lower expression of the MTRR protein than did the transfectants with the wild-type haplotype cDNA. Our study suggested a common missense SNP of the MTRR gene as a novel pancreatic cancer susceptibility factor with a functional significance in folate-related metabolism and the genome-wide methylation status.


Dipeptidyl peptidase-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels in patients with type 2 diabetes: A randomized controlled trial.
Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.


Dopamine enhances both electrotonic coupling and chemical excitatory postsynaptic potentials at mixed synapses.
The transmitter dopamine reduces electrotonic coupling between retinal horizontal cells and increases their sensitivity to glutamate. Since in other systems single afferents establish mixed electrotonic and chemical excitatory synapses with their targets, dopamine might be expected there to depress one component of excitation while enhancing the other. This hypothesis was tested by applying dopamine locally in the vicinity of the lateral dendrite of the goldfish Mauthner cell (M cell) and monitoring the composite electrotonic and chemical excitatory postsynaptic potentials and currents evoked by ipsilateral eighth nerve stimulation. Dopamine produces persistent enhancements of both components of the postsynaptic response while it also increases input conductance. All these dopamine actions are prevented by superfusing the brain with saline containing the dopamine D1 receptor antagonist SCH-23390. Postsynaptic injections of the cAMP-dependent protein kinase inhibitor (Walsh inhibitor, or PKI5-24) block the dopamine-induced changes in synaptic transmission, implicating a cAMP-dependent mechanism. Furthermore, there is a dopaminergic innervation of the M cell, as demonstrated immunohistochemically with antibodies against dopamine and the rate-limiting enzyme in its synthetic pathway, tyrosine hydroxylase. Varicose immunoreactive fibers lie in the vicinity of the distal part of the lateral dendrite between the large myelinated club endings that establish the mixed synapses. As determined with electron microscopy, the dopaminergic fibers contain small vesicles, and they do not have synaptic contacts with either the afferents or the M cell, remaining instead in the synaptic bed. Taken together, these results suggest that dopamine released at a distance from these terminals increases the gain of this primary sensory input to the M cell, most likely through a phosphorylation mechanism.


Circumcision and STD in the United States: cross sectional and cohort analyses.
Male circumcision status has been shown to be associated with sexually transmitted disease (STD) acquisition in some, but not all, studies. Most studies have been cross sectional. We examined the association between circumcision status and the prevalence and incidence of gonorrhoea, chlamydia, and syphilis. We analysed cross sectional and cohort study data from a multicentre controlled trial in the United States. Between July 1993 and September 1996, 2021 men visiting public inner city STD clinics in the United States were examined by a clinician at enrolment and 1456 were examined at follow up visits 6 and 12 months later. At each visit, men had laboratory tests for gonorrhoea, chlamydia, and syphilis and were examined for circumcision status. We used multiple logistic regression to compare STD risk among circumcised and uncircumcised men adjusted for potentially confounding factors. Uncircumcised men were significantly more likely than circumcised men to have gonorrhoea in the multivariate analyses, adjusted for age, race, and site, in both the cross sectional (odds ratio (OR), 1.3; 95% confidence interval (CI), 0.9 to 1.7) and in the cohort analysis (OR, 1.6; 95% CI, 1.0 to 2.6). There was no association between lack of circumcision and chlamydia in either the cross sectional (OR, 1.0; 95% CI 0.7-1.4) or the cohort analysis (OR, 0.9; 95% CI 0.5-1.5). The magnitude of association between lack of circumcision and syphilis was similar in the cross sectional (OR, 1.4; 95% CI 0.6 to 3.3) and cohort analysis (OR, 1.5; 95% CI 0.4 to 6.1). Uncircumcised men in the United States may be at increased risk for gonorrhoea and syphilis, but chlamydia risk appears similar in circumcised and uncircumcised men. Our results suggest that risk estimates from cross sectional studies would be similar to cohort findings.


Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1.
Ultrastable cyclic peptide frameworks offer great potential for drug design due to their improved bioavailability compared to their linear analogues. Using the sunflower trypsin inhibitor-1 (SFTI-1) peptide scaffold in combination with systematic N-methylation of the grafted pharmacophore led to the identification of novel subtype selective melanocortin receptor (MCR) agonists. Multiple bicyclic peptides were synthesized and tested toward their activity at MC1R and MC3-5R. Double N-methylated compound 18 showed a p Ki of 8.73 ± 0.08 ( Ki = 1.92 ± 0.34 nM) and a pEC50 of 9.13 ± 0.04 (EC50 = 0.75 ± 0.08 nM) at the human MC1R and was over 100 times more selective for MC1R. Nuclear magnetic resonance structural analysis of 18 emphasized the role of peptide bond N-methylation in shaping the conformation of the grafted pharmacophore. More broadly, this study highlights the potential of cyclic peptide scaffolds for epitope grafting in combination with N-methylation to introduce receptor subtype selectivity in the context of peptide-based drug discovery.


Using electronic health records to improve quality and efficiency: the experiences of leading hospitals.
An examination of nine hospitals that recently implemented a comprehensive electronic health record (EHR) system finds that clinical and administrative leaders built EHR adoption into their strategic plans to integrate inpatient and outpatient care and provide a continuum of coordinated services. Successful implementation depended on: strong leadership, full involvement of clinical staff in design and implementation, mandatory staff training, and strict adherence to timeline and budget. The EHR systems facilitate patient safety and quality improvement through: use of checklists, alerts, and predictive tools; embedded clinical guidelines that promote standardized, evidence-based practices; electronic prescribing and test-ordering that reduces errors and redundancy; and discrete data fields that foster use of performance dashboards and compliance reports. Faster, more accurate communication and streamlined processes have led to improved patient flow, fewer duplicative tests, faster responses to patient inquiries, redeployment of transcription and claims staff, more complete capture of charges, and federal incentive payments.


The effects of estrogens and antiestrogens on hormone-responsive human breast cancer in long-term tissue culture.
We have established or characterized six lines of human breast cancer maintained in long-term tissue culture for at least 1 year and have examined these lines for estrogen responsiveness. One of these cell lines, MCF-7, shows marked stimulation of macromolecular synthesis and cell division with physiological concentrations of estradiol. Antiestrogens are strongly inhibitory, and at concentrations greater than 3 X 10(-7) M they kill cells. Antiestrogen effects are prevented by simultaneous treatment with estradiol or reversed by addition of estradiol to cells incubated in antiestrogen. Responsive cell lines contain high-affinity specific estradiol receptors. Antiestrogens compete with estradiol for these receptors but have a lower apparent affinity for the receptor than estrogens. Stimulation of cells by estrogens is biphasic, with inhibition and cell death at concentrations of 17beta-estradiol or diethylstilbestrol exceeding 10(-7) M. Killing by high concentrations of estrogen is probably a nonspecific effect in that we observe this response with 17alpha-estradiol at equivalent concentrations and in the otherwise unresponsive cells that contain no estrogen receptor sites.


Aryne multifunctionalization with benzdiyne and benztriyne equivalents.
One of the most distinct characters of aryne chemistry over other synthetic methodologies is its ability to simultaneously functionalize the vicinal two positions of a benzene ring with diverse combinations of substituents. Moreover, the functionalization of the remaining four positions can be also achieved through multiaryne equivalents, in which more than one triple bond is generated on the different locations of the same benzene ring. This tutorial review summarizes the applications of benzdiyne and benztriyne equivalents from the standpoint of synthetic organic chemistry as well as in the preparation of polycyclic aromatic functional frameworks.