Fully alloyed metal nanorods with highly tunable properties.
Alloyed metal nanorods offer a unique combination of enhanced plasmonic and photothermal properties with a wide variety in optical and catalytic properties as a function of the alloy composition. Here, we show that fully alloyed anisotropic nanoparticles can be obtained with complete retention of the particle shape via thermal treatment at surprisingly low temperatures. By coating Au-Ag, Au-Pd and Au-Pt core-shell nanorods with a protective mesoporous silica shell the transformation of the rods to a more stable spherical shape was successfully prevented during alloying. For the Au-Ag core-shell NRs the chemical stability was drastically increased after alloying, and from Mie-Gans and finite-difference time-domain (FDTD) calculations it followed that alloyed AuAg rods also exhibit much better plasmonic properties than their spherical counterparts. Finally, the generality of our method is demonstrated by alloying Au-Pd and Au-Pt core-shell NRs, whereby the AuPd and AuPt alloyed NRs showed a surprisingly high increase in thermal stability of several hundred degrees compared with monometallic silica coated Au NRs.


Patients' experiences when accessing their on-line electronic patient records in primary care.
Patient access to on-line primary care electronic patient records is being developed nationally. Knowledge of what happens when patients access their electronic records is poor. To enable 100 patients to access their electronic records for the first time to elicit patients' views and to understand their requirements. In-depth interviews using semi-structured questionnaires as patients accessed their electronic records, plus a series of focus groups. Secure facilities for patients to view their primary care records privately. One hundred patients from a randomised group viewed their on-line electronic records for the first time. The questionnaire and focus groups addressed patients' views on the following topics: ease of use; confidentiality and security; consent to access; accuracy; printing records; expectations regarding content; exploitation of electronic records; receiving new information and bad news. Most patients found the computer technology used acceptable. The majority found viewing their record useful and understood most of the content, although medical terms and abbreviations required explanation. Patients were concerned about security and confidentiality, including potential exploitation of records. They wanted the facility to give informed consent regarding access and use of data. Many found errors, although most were not medically significant. Many expected more detail and more information. Patients wanted to add personal information. Patients have strong views on what they find acceptable regarding access to electronic records. Working in partnership with patients to develop systems is essential to their success. Further work is required to address legal and ethical issues of electronic records and to evaluate their impact on patients, health professionals and service provision.


Clinical assessment and crisis intervention for the suicidal bipolar disorder patient.
Suicidal behaviour is common in people suffering with bipolar disorder, and suicide is a leading cause of death in this group. Our aim in this review is to provide an overview of key assessment and management strategies, highlight research findings relevant to suicide prevention, and identify important areas for future research. We reviewed the published literature regarding the risk factors for and management of suicida\l behaviour in individuals with bipolar disorder using the Pubmed and PsychINFO databases. Where available, we focused our search on systematic reviews. Suicide is usually associated with a depressive phase, although mixed affective states also convey increased risk. All individuals with bipolar disorder should have an up-to-date crisis management plan which outlines the action to be taken should suicidal behaviour emerge. Timely clinical assessment is essential in ensuring that those at high risk are identified. This should include mental state examination, consideration of risk factors, and evaluation of issues such as access to means, preparatory acts before suicide, and also protective factors. While pharmacological approaches are the mainstay of management, less specific measures, such as the removal of access to means, are also important in ensuring safety in the acute situation. Intensifying the clinical support of both patients and relatives, and the sharing of risk information with other health agencies are essential in management. Specific psychological treatments are likely to be helpful in preventing crises, although the evidence base is limited. The aetiology of suicidal behaviour in bipolar disorder is multifactorial and requires proactive crisis planning and management. A range of issues need to be addressed in the assessment of at-risk patients. Determining the efficacy of interventions specific to reducing suicidality in bipolar disorder should be a research priority.


Innovatively Therapeutic Strategy on Lung Cancer by Daily Drinking Antioxidative Plasmon-Induced Activated Water.
Many human diseases are inflammation-related, such as cancer and those associated with aging. Previous studies demonstrated that plasmon-induced activated (PIA) water with electron-doping character, created from hot electron transfer via decay of excited Au nanoparticles (NPs) under resonant illumination, owns reduced hydrogen-bonded networks and physchemically antioxidative properties. In this study, it is demonstrated PIA water dramatically induced a major antioxidative Nrf2 gene in human gingival fibroblasts which further confirms its cellular antioxidative and anti-inflammatory properties. Furthermore, mice implanted with mouse Lewis lung carcinoma (LLC-1) cells drinking PIA water alone or together with cisplatin treatment showed improved survival time compared to mice which consumed only deionized (DI) water. With the combination of PIA water and cisplatin administration, the survival time of LLC-1-implanted mice markedly increased to 8.01 ± 0.77 days compared to 6.38 ± 0.61 days of mice given cisplatin and normal drinking DI water. This survival time of 8.01 ± 0.77 days compared to 4.62 ± 0.71 days of mice just given normal drinking water is statistically significant (p = 0.009). Also, the gross observations and eosin staining results suggested that LLC-1-implanted mice drinking PIA water tended to exhibit less metastasis than mice given only DI water.


Intracellular secretory leukoprotease inhibitor modulates inositol 1,4,5-triphosphate generation and exerts an anti-inflammatory effect on neutrophils of individuals with cystic fibrosis and chronic obstructive pulmonary disease.
Secretory leukoprotease inhibitor (SLPI) is an anti-inflammatory protein present in respiratory secretions. Whilst epithelial cell SLPI is extensively studied, neutrophil associated SLPI is poorly characterised. Neutrophil function including chemotaxis and degranulation of proteolytic enzymes involves changes in cytosolic calcium (Ca(2+)) levels which is mediated by production of inositol 1,4,5-triphosphate (IP3) in response to G-protein-coupled receptor (GPCR) stimuli. The aim of this study was to investigate the intracellular function of SLPI and the mechanism-based modulation of neutrophil function by this antiprotease. Neutrophils were isolated from healthy controls (n = 10), individuals with cystic fibrosis (CF) (n = 5) or chronic obstructive pulmonary disease (COPD) (n = 5). Recombinant human SLPI significantly inhibited fMet-Leu-Phe (fMLP) and interleukin(IL)-8 induced neutrophil chemotaxis (P < 0.05) and decreased degranulation of matrix metalloprotease-9 (MMP-9), hCAP-18, and myeloperoxidase (MPO) (P < 0.05). The mechanism of inhibition involved modulation of cytosolic IP3 production and downstream Ca(2+) flux. The described attenuation of Ca(2+) flux was overcome by inclusion of exogenous IP3 in electropermeabilized cells. Inhibition of IP3 generation and Ca(2+) flux by SLPI may represent a novel anti-inflammatory mechanism, thus strengthening the attractiveness of SLPI as a potential therapeutic molecule in inflammatory airway disease associated with excessive neutrophil influx including CF, non-CF bronchiectasis, and COPD.


Hepatic tissue engineering using scaffolds: state of the art.
Severe hepatic failure accounts for many deaths and raises medical costs each year worldwide. Currently, liver transplantation is the most common therapeutic option for patients with end-stage chronic liver disease. Due to decrease in the number of organ donors, many in need of transplantation continue to remain on the waiting list. Hepatic Tissue Engineering is a step toward alleviating the need for organ donors. Regenerative medicine and tissue engineering require two complementary key ingredients as follows: 1) biologically compatible scaffolds that can be readily adopted by the body system without harm, and 2) suitable cells including various stem cells or primary cells that effectively replace the damaged tissues without adverse consequences. Yet many challenges must be overcome such as scaffold choice, cell source and immunological barriers. Today, hepatogenic differentiation of stem cells has created trust and promise for use of these cells in hepatic tissue engineering and liver replacement. However, using suitable scaffolds is an important key to achieving the necessary functions required for hepatic replacement. In recent years, different scaffolds have been used for liver tissue engineering. In this review, we have presented different concepts in using cell /scaffold constructs to guide hepatic tissue engineering.


Differential expression of Candida albicans phospholipase B (PLB1) under various environmental and physiological conditions.
Candida is the fourth most common organism responsible for bloodstream infections in many intensive care units, with Candida albicans being the most predominant species isolated in such cases. It has previously been shown that candidal phospholipase B, encoded by the PLB1 gene, is an important virulence factor for C. albicans pathogenesis. In this study, the effects of environmental factors (carbohydrate source and pH) and physiological conditions (serum, phospholipids and temperature) on the expression of PLB1 by C. albicans cells grown in rich [Sabouraud dextrose broth (SB) or yeast extract/peptone/dextrose] or chemically defined [Lee's, RPMI-1640 or yeast nitrogen base (YNB)] media were investigated. Northern blot analyses revealed that PLB1 mRNA was expressed in C. albicans cells grown in rich media at 30 degrees C but not at 37 degrees C. However, the protein Plb1p was detected in fungal cells growing at 37 degrees C in SB, as determined by Western blot analysis, indicating that although the mRNA for this gene was not detected, the actual gene product was present at this temperature. Expression of PLB1 was detected in cells grown in YNB/glucose at 30 degrees C but not at 37 degrees C. However, growth of C. albicans in YNB/glucose supplemented with serum and phospholipids resulted in expression of PLB1 at 37 degrees C also. Additionally, acidic pH induced higher levels of PLB1 mRNA expression compared to neutral pH, while the morphological form of C. albicans did not have any influence on the expression of this gene. The studies described here show that the expression of PLB1 is regulated by nutritional supplementation, environmental factors and the growth phase of the C. albicans cells, as well as by physiological conditions. The differential expression of PLB1 in response to environmental factors may be correlated to host-specific components available to C. albicans during infection.


Characterization of target mRNAs for grapevine microRNAs with an integrated strategy of modified RLM-RACE, newly developed PPM-RACE and qPCRs.
MicroRNAs (miRNAs) regulate target gene expression by mediating target gene cleavage or inhibition of translation at transcriptional and post-transcriptional levels in higher plants. Until now, many grapevine microRNAs (Vv-miRNAs) have been identified and quite a number of miRNA target genes were also verified by various analysis. However, global interaction of miRNAs with their target genes still remained to perform more research. We reported experimental validation of a number of miRNA target genes in table grapevine that had been previously identified by bioinformatics in our earlier studies. To verify more predicted target genes of Vv-miRNAs and elucidate the modes by which these Vv-miRNAs work on their target genes, 31 unverified potential target genes for 18 Vv-miRNAs were experimentally verified by a new integrated strategy employing a modified 5'-RLM-RACE (RNA ligase-mediated 5' rapid amplification of cDNA ends), 3'-PPM-RACE (poly(A) polymerase-mediated 3' rapid amplification of cDNA ends) and qRT-PCRs of cleavage products. The results showed that these Vv-miRNAs negatively regulated expression of their target messenger RNAs (mRNAs) through guiding corresponding target mRNA cleavage, of which about 94.4% Vv-miRNAs cleaved their target mRNAs mainly at the tenth nucleotide of 5'-end of miRNAs. Expression levels of both miRNAs and their target mRNAs in eight tissues exhibited inverse relationships, and expressions both of cleaved targets and miRNAs indicated a cleavage mode of Vv-miRNAs on their target genes. Our results confirm the importance of Vv-miRNAs in grapevine growth and development, and suggest more study on Vv-miRNAs and targets can enrich the knowledge of miRNA mediated-regulation in grapevine.


Regionally isolated populations of an imperiled Caribbean coral, Acropora palmata.
The movements of larvae between marine populations are difficult to follow directly and have been the subject of much controversy, especially in the Caribbean. The debate centres on the degree to which populations are demographically open, such that depleted populations can be replenished by recruitment from distant healthy populations, or demographically closed and thus in need of local management. Given the depressed state of many tropical reef populations, the understanding of these movements now bears critically on the number, placement, and size of marine reserves. Most genetic analyses assume that dispersal patterns have been stable for thousands of generations, thus they commonly reflect past colonization histories more than ongoing dispersal. Recently developed multilocus genotyping approaches, however, have the demonstrated ability to detect both migration and population isolation over far shorter timescales. Previously, we developed five microsatellite markers and demonstrated them to be both Mendelian and coral-specific. Using these markers and Bayesian analyses, we show here that populations of the imperiled reef-building coral, Acropora palmata, have experienced little or no recent genetic exchange between the western and the eastern Caribbean. Puerto Rico is identified as an area of mixing between the two subregions. As a consequence of this regional isolation, populations in the western and eastern Caribbean should have the potential to adapt to local conditions and will require population-specific management strategies.


Compensation following bilateral vestibular damage.
Bilateral loss of vestibular inputs affects far fewer patients than unilateral inner ear damage, and thus has been understudied. In both animal subjects and human patients, bilateral vestibular hypofunction (BVH) produces a variety of clinical problems, including impaired balance control, inability to maintain stable blood pressure during postural changes, difficulty in visual targeting of images, and disturbances in spatial memory and navigational performance. Experiments in animals have shown that non-labyrinthine inputs to the vestibular nuclei are rapidly amplified following the onset of BVH, which may explain the recovery of postural stability and orthostatic tolerance that occurs within 10 days. However, the loss of the vestibulo-ocular reflex and degraded spatial cognition appear to be permanent in animals with BVH. Current concepts of the compensatory mechanisms in humans with BVH are largely inferential, as there is a lack of data from patients early in the disease process. Translation of animal studies of compensation for BVH into therapeutic strategies and subsequent application in the clinic is the most likely route to improve treatment. In addition to physical therapy, two types of prosthetic devices have been proposed to treat individuals with bilateral loss of vestibular inputs: those that provide tactile stimulation to indicate body position in space, and those that deliver electrical stimuli to branches of the vestibular nerve in accordance with head movements. The relative efficacy of these two treatment paradigms, and whether they can be combined to facilitate recovery, is yet to be ascertained.


The dynamics of saliency-driven and goal-driven visual selection as a function of eccentricity.
Both saliency and goal information are important factors in driving visual selection. Saliency-driven selection occurs primarily in early responses, whereas goal-driven selection happens predominantly in later responses. Here, we investigated how eccentricity affects the time courses of saliency-driven and goal-driven visual selection. In three experiments, we asked people to make a speeded eye movement toward a predefined target singleton which was simultaneously presented with a non-target singleton in a background of multiple homogeneously oriented other items. The target singleton could be either more or less salient than the non-target singleton. Both singletons were presented at one of three eccentricities (i.e., near, middle, or far). The results showed that, even though eccentricity had only little effect on overall selection performance, the underlying time courses of saliency-driven and goal-driven selection altered such that saliency effects became protracted and relevance effects became delayed for far eccentricity conditions. The protracted saliency effect was shown to be modulated by expectations as induced by the preceding trial. The results demonstrate the importance of incorporating both time and eccentricity as factors in models of visual selection.


A new species of Megatibicen endemic to Mescalero-Monahans shinnery sands (Hemiptera: Auchenorrhyncha: Cicadidae).
Megatibicen harenosus sp. n. is described from the Mescalero-Monahans shinnery sands of New Mexico and Texas, U.S.A. The new species is diagnosed from similar species, especially M. tremulus which it resembles closely, by male genital morphology, color pattern, calling song, and ecology. Seven characters from the male calling song are described from analysis of field recordings, of which all four temporal song characters are significantly different from M. tremulus. With one of the most southwestern distribution of any Megatibicen species, M. harenosus is a new addition to the rich, endemic, and understudied Mescalero-Monahans shinnery sands biota. The possibility that M. harenosus and M. tremulus are sister species is raised. The ecological, biological, and evolutionary species concepts support species status for M. harenosus, and an hypothesis of peripatric speciation in peripheral isolation is advanced.


Transforming Summary Statistics from Logistic Regression to the Liability Scale: Application to Genetic and Environmental Risk Scores.
Stratified medicine requires models of disease risk incorporating genetic and environmental factors. These may combine estimates from different studies, and the models must be easily updatable when new estimates become available. The logit scale is often used in genetic and environmental association studies; however, the liability scale is used for polygenic risk scores and measures of heritability, but combining parameters across studies requires a common scale for the estimates. We present equations to approximate the relationship between univariate effect size estimates on the logit scale and the liability scale, allowing model parameters to be translated between scales. These equations are used to build a risk score on the liability scale, using effect size estimates originally estimated on the logit scale. Such a score can then be used in a joint effects model to estimate the risk of disease, and this is demonstrated for schizophrenia using a polygenic risk score and environmental risk factors. This straightforward method allows the conversion of model parameters between the logit and liability scales and may be a key tool to integrate risk estimates into a comprehensive risk model, particularly for joint models with environmental and genetic risk factors.


Whole genomic analysis of bovine group A rotavirus strains A5-10 and A5-13 provides evidence for close evolutionary relationship with human rotaviruses.
Bovine group A rotavirus (RVA) is an important cause of acute diarrhea in calves worldwide. In order to obtain precise information on the origin and evolutionary dynamics of bovine RVA strains, we determined and analyzed the complete nucleotide sequences of the whole genomes of six archival bovine RVA strains; four Thai strains (RVA/Cow-tc/THA/A5-10/1988/G8P[1], RVA/Cow-tc/THA/A5-13/1988/G8P[1], RVA/Cow-tc/THA/61A/1989/G10P[5], and RVA/Cow-tc/THA/A44/1989/G10P[11]), one American strain (RVA/Cow-tc/USA/B223/1983/G10P[11]), and one Japanese strain (RVA/Cow-tc/JPN/KK3/1983/G10P[11]). On whole genomic analysis, the 11 gene segments of strains A5-10, A5-13, 61A, A44, B223, and KK3 were found to be considerably genetically diverse, but to share a conserved non-G/P genotype constellation except for the NSP1 gene (I2-R2-C2-M2-(A3/11/13/14)-N2-T6-E2-H3), which is commonly found in RVA strains from artiodactyls such as cattle. Furthermore, phylogenetic analysis revealed that most genes of the six strains were genetically related to bovine and bovine-like strains. Of note is that the VP1, VP3, and NSP2 genes of strains A5-10 and A5-13 exhibited a closer relationship with the cognate genes of human DS-1-like strains than those of other RVA strains. Furthermore, the VP6 genes of strains A5-10 and A5-13 appeared to be equally related to both human DS-1-like and bovine strains. Thus, strains A5-10 and A5-13 were suggested to be derived from the same evolutionary origin as human DS-1-like strains, and were assumed to be examples of bovine RVA strains that provide direct evidence for a close evolutionary relationship between bovine and human DS-1-like strains. Our findings will provide important insights into the origin of bovine RVA strains, and into evolutionary links between bovine and human RVA strains.


The RCPCH care pathway for children with urticaria, angio-oedema or mastocytosis: an evidence and consensus based national approach.
The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies; the urticaria, angio-oedema or mastocytosis pathway is the fifth pathway. The pathways focus on defining the competences required to improve the equity of care received by children with allergic conditions. The urticaria, angio-oedema or mastocytosis pathway was developed by a multidisciplinary working group and was based on a comprehensive review of evidence. The pathway was reviewed by a broad group of stakeholders including the public and approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. Three pathways are described: urticaria with or without angio-oedema, angio-oedema without weals, and mastocytosis. The results are presented in four parts: evidence review, mapping, external review and core knowledge documents. Acute urticaria has many causes and is often not allergic in origin. It is frequently of relatively short duration and easily managed with antihistamines alone. However, at the other extreme, causes of chronic urticaria and angio-oedema are difficult to diagnose and treatment can be complex. Thus defining the competence required for each extreme is critical to ensure optimal care. The evidence review identified that allergy testing and thyroid function testing were helpful in the investigation of chronic urticaria, that increasing the dose of antihistamine was effective in treating urticaria and that ciclosporin A and prednisolone were effective second line treatments. From the common presentation of acute (intermittent) urticaria to the uncommon presentations of chronic urticaria, angio-oedema and cutaneous mastocytosis, this pathway is a tool to assist health professionals to differentiate and manage these conditions.


Focal liver lesions: comparison of dual-phase CT and multisequence multiplanar MR imaging including dynamic gadolinium enhancement.
The purpose of this study was to compare dual-phase spiral computed tomography (CT) and magnetic resonance imaging (MRI) using dynamic gadolinium enhancement for liver lesion detection and characterization. Twenty-two consecutive patients underwent dual-phase spiral CT and MRI for the evaluation of focal liver disease within a 1-month period. Spiral CT and MR images were interpreted prospectively, in a blinded fashion by separate, individual, experienced investigators, to determine lesion detection and characterization. Liver lesions were confirmed by surgery and pathology in 6 patients, and by clinical and imaging follow-up in the other 16 patients. Pathological correlation of a primary extrahepatic malignancy was available in 5 of the 16 patients who had metastatic liver disease. Spiral CT and MRI detected 53 and 63 lesions, and characterized 39 and 62 true positive lesions, respectively. A kappa statistic test was applied to assess agreement between MR and CT results. MR versus CT for lesion detection resulted in a kappa statistic of 0.54 (95% confidence interval), indicating moderate agreement, and 0.32 (95% confidence interval) for lesion characterization, indicating only slight agreement. More lesions were detected on MR images than CT images in 6 (27%) patients, with lesions detected only on MR images in 4 (18%) patients. More lesions were characterized on MR images in 9 (41%) patients. In 9 patients with a discrepancy between MR and CT findings, the MR images added information considered significant to patient management in all 9 cases. MRI was moderately superior to dual-phase spiral CT for lesion detection, and was markedly superior for lesion characterization, with these differences having clinical significance.


Comparison of clinical and histopathological evaluation of tonsils in pediatric and adult patients.
The aim of this study was to determine clinical features that could predict the presence of tonsillar malignancy in children and adults. A retrospective review of the histopathologic reports of the children, who underwent tonsillectomy (753 cases) during the past 16 years (January 1991-December 2006) in a busy district general hospital, was undertaken. We compared the results to the pre-operative data of the patients, for risk factors of malignancy. Such proposed risk factors were tonsillar asymmetry, palpable firmness, visible lesions, neck adenopathy, history of malignancy, and systemic symptoms. The same data (history, risk factors and histopathologic results) were reviewed for an adult group (>16 years old, 1,027 cases) who underwent tonsillectomy during that period, and the results of the two groups were compared. In the pediatric group only one case was diagnosed as lymphoma (0.13%) and the rest as chronic inflammation (47%), reactive tonsil tissue (26%), lymphoid hyperplasia (19%) and actinomycosis (8%). In the lymphoma case, the diagnosis was suspected preoperatively by history and clinical manifestations. In the adult group, there were 21 cases of malignancy out of 1,027 cases (2.04%), again with one or more positive risk factors in the pre-surgery history. Based on our review, it is concluded that histopathology of tonsillectomy is not necessary in children unless there is clinical suspicion based on preoperative findings. A protocol based on proposed risk factors which may be predictive of possible malignancy can be used as a guide to intraoperative histology.


Distinct Commensal Bacterial Signature in the Gut Is Associated With Acute and Long-Term Protection From Ischemic Stroke.
Background and Purpose- Commensal gut bacteria have a profound impact on stroke pathophysiology. Here, we investigated whether modification of the microbiota influences acute and long-term outcome in mice subjected to stroke. Methods- C57BL/6 male mice received a cocktail of antibiotics or single antibiotic. After 4 weeks, fecal bacterial density of the 16S rRNA gene was quantitated by qPCR, and phylogenetic classification was obtained by 16S rRNA gene sequencing. Infarct volume and hemispheric volume loss were measured 3 days and 5 weeks after middle cerebral artery occlusion, respectively. Neurological deficits were tested by the Tape Test and the open field test. Results- Mice treated with a cocktail of antibiotics displayed a significant reduction of the infarct volume in the acute phase of stroke. The neuroprotective effect was abolished in mice recolonized with a wild-type microbiota. Single antibiotic treatment with either ampicillin or vancomycin, but not neomycin, was sufficient to reduce the infarct volume and improved motorsensory function 3 days after stroke. This neuroprotective effect was correlated with a specific microbial population rather than the total bacterial density. In particular, random forest analysis trained for the severity of the brain damage revealed that Bacteroidetes S24.7 and the enzymatic pathway for aromatic metabolism discriminate between large versus small infarct size. Additionally, the microbiota signature in the ampicillin-treated mice was associated with a reduced gut inflammation, long-term favorable outcome shown by an amelioration of the stereotypic behavior, and a reduction of brain tissue loss in comparison to control and was predictive of a regulation of short-chain fatty acids and tryptophan pathways. Conclusions- The findings highlight the importance of the intestinal microbiota in short- and long-term outcomes of ischemic stroke and raises the possibility that targeted modification of the microbiome associated with specific microbial enzymatic pathways may provide a preventive strategy in patients at high risk for stroke. Visual Overview- An online visual overview is available for this article.


Risk factors for relapse following treatment for first episode psychosis: a systematic review and meta-analysis of longitudinal studies.
Preventing relapse is an essential element of early intervention in psychosis, but relevant risk factors and precise relapse rates remain to be clarified. The aim of this study was to systematically compile and analyse risk factors for and rates of relapse in the early course of psychosis. Systematic review and meta-analysis of English and non-English language, peer-reviewed, longitudinal studies, with a minimum 12-month follow-up and at least 80% of participants diagnosed with a first episode of psychosis (FEP) that reported risk factors for relapse. Of 153 potentially relevant articles, 29 were included in the study. Pooled prevalence of relapse of positive symptoms was 28% (range=12-47%), 43% (35-54%), 54% (40-63%) at 1, 1.5-2, and 3 years follow-up, in that order. A total of 109 predictors were analysed, with 24 being assessed in at least 3 studies. Of those, 20 predictors could be extracted for meta-analysis. Medication non-adherence, persistent substance use disorder, carers' critical comments (but not overall expressed emotion) and poorer premorbid adjustment, increased the risk for relapse 4-fold, 3-fold, 2.3-fold and 2.2-fold, respectively. Clinical variables and general demographic variables have little impact on relapse rates. Conversely, non-adherence with medication, persistent substance use disorder, carers' criticism and poorer premorbid adjustment significantly increase the risk for relapse in FEP. Future studies need to address the methodological limitations of the extant research (e.g. definition of relapse), focus on the identification of protective factors and evaluate theoretically derived models of relapse.


Synaptic vesicle pools at diaphragm neuromuscular junctions vary with motoneuron soma, not axon terminal, inactivity.
Both spinal hemisection (SH) at C2 and tetrodotoxin (TTX) phrenic nerve blockade result in diaphragm muscle paralysis and inactivity of the phrenic axon terminals. However, phrenic motoneuron somata are inactive with SH but remain active with TTX phrenic nerve blockade. Neuromuscular transmission failure with repeated activation decreases following SH and increases following TTX phrenic nerve blockade, suggesting that matching (or mismatching) of somal and synaptic inactivities of phrenic motoneurons differentially regulates synaptic vesicle pools at diaphragm neuromuscular junctions. At individual type-identified rat diaphragm presynaptic terminals, the size of the releasable pool of synaptic vesicles was analyzed by fluorescence confocal microscopy of N-(3-triethylammoniumpropyl)-4-(6-(4-(diethylamino)phenyl)hexatrienyl) pyridinium dibromide (FM4-64) uptake and synaptic vesicle density at active zones was determined using transmission electron microscopy. After 14 days of SH and TTX-induced diaphragm muscle inactivity, neuromuscular junction size was not different at type I or IIa fibers, but increased at type IIx and/or IIb fibers (by 51% in SH and 35% in TTX) compared with control. With SH, synaptic vesicle pool size and density increased at presynaptic terminals innervating type I or IIa fibers (17 and 63%, respectively; P<0.001) and type IIx and/or IIb fibers (41 and 31%, respectively; P<0.001) when compared with controls. Following TTX, synaptic vesicle pool size and density decreased by 64 and 17%, respectively, at presynaptic terminals innervating type I or IIa fibers, and by 50 and 36%, respectively, at type IIx and/or IIb fibers (P<0.001, for all comparisons). Thus, matching motoneuron soma and axon terminal inactivity (SH) increases the size and density of releasable synaptic vesicle pools at adult rat diaphragm neuromuscular junctions. Mismatching motoneuron soma and axon terminal inactivities (TTX) results in converse presynaptic adaptations. Inactivity-induced neuromuscular plasticity reflects specific adaptations in the size and density of synaptic vesicle pools that depend on motoneuron soma rather than axon terminal (or muscle fiber) inactivity.


Cooperative group research efforts in thoracic malignancies 2009: a review from the 10th Annual International Lung Cancer Congress.
Critical advances in the treatment of patients with lung cancer have occurred in the past few years. The cooperative groups in North America and internationally have played crucial roles in these advances. The leaders of the groups meet on a regular basis to review the progress of their trials. However, they rarely have a chance to discuss all ongoing and planned trials, except at the annual Lung Cancer Congress held each June. This article captures this exchange from the 10th Annual Lung Cancer Congress held in June 2009. Exciting efforts are ongoing for all stages of non-small-cell lung cancer, small-cell lung cancer, and mesothelioma. A major focus of the groups at this time is a push toward more personalized medicine, as reflected in the selection criteria for many of the trials, along with planned correlates to better define populations most likely to benefit. Agents targeting the vascular endothelial growth factor (VEGF) pathway, including many tyrosine kinase inhibitors against the VEGF receptor, and those targeting the epidermal growth factor receptor pathway, are under extensive development with many combination trials ongoing.


A CD133-related gene expression signature identifies an aggressive glioblastoma subtype with excessive mutations.
Cancer cells are heterogeneous and, it has been proposed, fall into at least two classes: the tumor-initiating cancer stem cells (CSC) and the more differentiated tumor cells. The transmembrane protein CD133 has been widely used to isolate putative CSC populations in several cancer types, but its validity as a CSC marker and hence its clinical ramifications remain controversial. Here, we conducted transcriptomic profiling of sorted CD133(+) and CD133(-) cells from human glioblastoma multiforme (GBM) and, by subtractive analysis, established a CD133 gene expression signature composed of 214 differentially expressed genes. Extensive computational comparisons with a compendium of published gene expression profiles reveal that the CD133 gene signature transcriptionally resembles human ES cells and in vitro cultured GBM stem cells, and this signature successfully distinguishes GBM from lower-grade gliomas. More importantly, the CD133 gene signature identifies an aggressive subtype of GBM seen in younger patients with shorter survival who bear excessive genomic mutations as surveyed through the Cancer Genome Atlas Network GBM mutation spectrum. Furthermore, the CD133 gene signature distinguishes higher-grade breast and bladder cancers from their lower-grade counterparts. Our systematic analysis provides molecular and genetic support for the stem cell-like nature of CD133(+) cells and an objective means for evaluating cancer aggressiveness.


Development and validation of a preference weight multiattribute health outcome measure for rheumatoid arthritis.
To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to report health states and estimate preference weights. Survey materials were mailed to 748 patients. Factor analysis, an item response theory-based model, and an internal consistency test were used to identify attributes and evaluate items. Two multiattribute preference weight functions (MAPWF) were constructed. Construct validity of the new measures was then tested. Four hundred eighty-seven patients returned the survey; 24 items on 6 health attributes were selected to form the new outcomes measure. Two MAPWF were derived with preference weights measured with time tradeoff and visual analog scales as dependent variables. All validity test results were statistically significant. Our results reveal that the new measures are reliable and valid in assessing health states and associated preference weights of patients with RA.


Programmed reduction of ABC transporter activity in sea urchin germline progenitors.
ATP-binding cassette (ABC) transporters protect embryos and stem cells from mutagens and pump morphogens that control cell fate and migration. In this study, we measured dynamics of ABC transporter activity during formation of sea urchin embryonic cells necessary for the production of gametes, termed the small micromeres. Unexpectedly, we found small micromeres accumulate 2.32 times more of the ABC transporter substrates calcein-AM, CellTrace RedOrange, BoDipy-verapamil and BoDipy-vinblastine, than any other cell in the embryo, indicating a reduction in multidrug efflux activity. The reduction in small micromere ABC transporter activity is mediated by a pulse of endocytosis occurring 20-60 minutes after the appearance of the micromeres--the precursors of the small micromeres. Treating embryos with phenylarsine oxide, an inhibitor of endocytosis, prevents the reduction of transporter activity. Tetramethylrhodamine dextran and cholera toxin B uptake experiments indicate that micromeres have higher rates of bulk and raft-associated membrane endocytosis during the window of transporter downregulation. We hypothesized that this loss of efflux transport could be required for the detection of developmental signaling molecules such as germ cell chemoattractants. Consistent with this hypothesis, we found that the inhibition of ABCB and ABCC-types of efflux transporters disrupts the ordered distribution of small micromeres to the left and right coelomic pouches. These results point to tradeoffs between signaling and the protective functions of the transporters.


The E211 G>A androgen receptor polymorphism is associated with a decreased risk of metastatic prostate cancer and androgenetic alopecia.
The androgen receptor (AR) gene encodes a transcription factor, which mediates androgen action in target tissues, including the prostate. Prostate cancer is androgen dependent, implicating AR in susceptibility to this male condition. Male pattern balding, androgenetic alopecia, has recently been associated with prostate cancer, suggesting shared androgen pathways. The CAG and GGC repeats in the AR have been studied extensively as markers of prostate cancer susceptibility, with inconclusive findings, whereas the AR-E211 G>A polymorphism has been associated with androgenetic alopecia. We assessed the repeat linked single nucleotide polymorphism as a marker of risk association in prostate cancer, including androgenetic alopecia, in an Australian population-based case-control study. In 815 prostate cancer cases and 719 controls, the proportion of A-allele carriers was the same in each group. Overall, there was no evidence for an association between the A allele and risk of prostate cancer, however, the proportion of A-allele carriers in metastatic prostate cancer (5%) was lower than in less advanced disease (16%, P = 0.03). The proportion of A-allele carriers was 24% in nonbald men but it was lower in men with vertex alopecia alone (13%, P = 0.001) or in combination with frontal alopecia (7%, P < 0.0001). This inverse association between the A allele and baldness was independent of prostate cancer status (P for interaction = 0.2). These results suggest that the AR-E211 A allele, in linkage with the functional repeat sequences, is associated with a lower risk of metastatic prostate cancer and a lower risk of alopecia.


BRAF and RAS mutations in human lung cancer and melanoma.
BRAF encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Recently, we have identified activating BRAF mutations in 66% of melanomas and a smaller percentage of many other human cancers. To determine whether BRAF mutations account for the MAP kinase pathway activation common in non-small cell lung carcinomas (NSCLCs) and to extend the initial findings in melanoma, we screened DNA from 179 NSCLCs and 35 melanomas for BRAF mutations (exons 11 and 15). We identified BRAF mutations in 5 NSCLCs (3%; one V599 and four non-V599) and 22 melanomas (63%; 21 V599 and 1 non-V599). Three BRAF mutations identified in this study are novel, altering residues important in AKT-mediated BRAF phosphorylation and suggesting that disruption of AKT-induced BRAF inhibition can play a role in malignant transformation. To our knowledge, this is the first report of mutations documenting this interaction in human cancers. Although >90% of BRAF mutations in melanoma involve codon 599 (57 of 60), 8 of 9 BRAF mutations reported to date in NSCLC are non-V599 (89%; P < 10(-7)), strongly suggesting that BRAF mutations in NSCLC are qualitatively different from those in melanoma; thus, there may be therapeutic differences between lung cancer and melanoma in response to RAF inhibitors. Although uncommon, BRAF mutations in human lung cancers may identify a subset of tumors sensitive to targeted therapy.


Overexpression of ubiquitin-specific peptidase 15 in systemic sclerosis fibroblasts increases response to transforming growth factor β.
Ubiquitination of proteins leads to their degradation by the proteasome, and is regulated by ubiquitin ligases and substrate-specific ubiquitin-specific peptidases (USPs). The ubiquitination process also plays important roles in the regulation of cell metabolism and cell cycle. Here, we found that the expression of several USPs is increased in SSc tenosynovial and skin biopsies, and we demonstrated that USP inhibition decreases TGF-β signalling in primary fibroblast cell lines. High-density transcriptomic studies were performed using total RNA obtained from SSc tenosynovial samples. Confirmatory immunostaining experiments were performed on tenosynovial and skin samples. In vitro experiments were conducted in order to study the influence of USP modulation on responses to TGF-β stimulation. Tenosynovial biopsies from SSc patients overexpressed known disease-associated gene pathways: fibrosis, cytokines and chemokines, and Wnt/TGF-β signalling, but also several USPs. Immunohistochemistry experiments confirmed the detection of USPs in the same samples, and in SSc skin biopsies. Exposure of primary fibroblast cell lines to TGF-β induced USP gene expression. The use of a pan-USP inhibitor decreased SMAD3 phosphorylation, and expression of COL1A1, COL3A1 and fibronectin gene expression in TGF-β-stimulated fibroblasts. The effect of the USP inhibitor resulted in increased SMAD3 ubiquitination, and was blocked by a proteasome inhibitor, thereby confirming the specificity of its action. Overexpression of several USPs, including USP15, amplifies fibrotic responses induced by TGF-β, and is a potential therapeutic target in SSc.


Cell wounding activates phospholipase D in primary mouse keratinocytes.
Plasma membrane disruptions occur in mechanically active tissues such as the epidermis and can lead to cell death if the damage remains unrepaired. Repair occurs through fusion of vesicle patches to the damaged membrane region. The enzyme phospholipase D (PLD) is involved in membrane traffickiing; therefore, the role of PLD in membrane repair was investigated. Generation of membrane disruptions by lifting epidermal keratinocytes from the substratum induced PLD activation, whereas removal of cells from the substratum via trypsinization had no effect. Pretreatment with 1,25-dihydroxyvitamin D₃, previously shown to increase PLD1 expression and activity, had no effect on, and a PLD2-selective (but not a PLD1-selective) inhibitor decreased, cell lifting-induced PLD activation, suggesting PLD2 as the isoform activated. PLD2 interacts functionally with the glycerol channel aquaporin-3 (AQP3) to produce phosphatidylglycerol (PG); however, wounding resulted in decreased PG production, suggesting a potential PG deficiency in wounded cells. Cell lifting-induced PLD activation was transient, consistent with a possible role in membrane repair, and PLD inhibitors inhibited membrane resealing upon laser injury. In an in vivo full-thickness mouse skin wound model, PG accelerated wound healing. These results suggest that PLD and the PLD2/AQP3 signaling module may be involved in membrane repair and wound healing.


Compared Heritability of Chronotype Instruments in a Single Population Sample.
It is well established that the oldest chronotype questionnaire, the morningness-eveningness questionnaire (MEQ), has significant heritability, and several associations have been reported between MEQ score and polymorphisms in candidate clock genes, a number of them reproducibly across populations. By contrast, there are no reports of heritability and genetic associations for the Munich chronotype questionnaire (MCTQ). Recent genome-wide association studies (GWAS) from large cohorts have reported multiple associations with chronotype as assessed by a single self-evaluation question. We have taken advantage of the availability of data from all these instruments from a single sample of 597 participants from the Brazilian Baependi Heart Study. The family-based design of the cohort allowed us to calculate the heritability (h2) for these measures. Heritability values for the best-fitted models were 0.37 for MEQ, 0.32 for MCTQ, and 0.28 for single-question chronotype (MEQ Question 19). We also calculated the heritability for the two major factors recently derived from MEQ, "Dissipation of sleep pressure" (0.32) and "Build-up of sleep pressure" (0.28). This first heritability comparison of the major chronotype instruments in current use provides the first quantification of the genetic component of MCTQ score, supporting its future use in genetic analysis. Our findings also suggest that the single chronotype question that has been used for large GWAS analyses captures a larger proportion of the dimensions of chronotype than previously thought.


Local delivery of allogeneic bone marrow and adipose tissue-derived mesenchymal stromal cells for cutaneous wound healing in a porcine model.
Wound healing remains a major challenge in modern medicine. Bone marrow- (BM) and adipose tissue- (AT) derived mesenchymal stromal/stem cells (MSCs) are of great interest for tissue reconstruction due to their unique immunological properties and regenerative potential. The purpose of this study was to characterize BM and AT-MSCs and evaluate their effect when administered in a porcine wound model. MSCs were derived from male Göttingen Minipigs and characterized according to established criteria. Allogeneic BM- or AT-MSCs were administered intradermally (1 x 10(6) cells) into partial-thickness wounds created on female animals, and covered with Vaseline® gauze or fibrin in a randomized pattern. Animals were euthanized at 7, 10, 14 and 21 days. Tissues were analyzed visually for healing and by microscopic examination for epidermal development and remodelling. Polymerase chain reaction (PCR) was used to detect the presence of male DNA in the specimens. All wounds were healed by 14 days. MSC-injected wounds were associated with improved appearance and faster re-epithelialization compared to saline controls. Evaluation of rete ridge depth and architecture showed that MSC treatment promoted a faster rate of epidermal maturation. Male DNA was detected in all samples at days 7 and 10, suggesting the presence of MSCs. We showed the safety, feasibility and potential efficacy of local injection of allogeneic BM- and AT-MSCs for treatment of wounds in a preclinical model. Our data in this large animal model support the potential use of BM- and AT-MSC for treatment of cutaneous wounds through modulation of healing and epithelialization.


Two reactivity modes in the heterogeneous cyclohexene ozonolysis under tropospherically relevant ozone-rich and ozone-limited conditions.
Important mechanistic differences regarding C=C double-bond oxidation processes under ozone-limited and ozone-rich reaction conditions for cyclohexene-functionalized fused silica substrates serving as model systems for studying heterogeneous C=C double bond oxidation chemistry in the troposphere are evaluated. By using broadband vibrational sum frequency generation (SFG), we track heterogeneous ozone reactions in real time. Ozone levels span three orders of magnitude and represent environments ranging from pristine remote continental regions to highly polluted urban centers, ranging from 30 ppb to 3 ppm (from 7 x 10(11) molecules cm(-3) to 7 x 10(13) molecules cm(-3)). We determine reaction rates and reactive uptake coefficients (gamma values). At these tropospherically relevant ozone levels, the heterogeneous reaction rates follow a Langmuir-Hinshelwood-type mechanism. The product formation rates, which we determine as a function of ozone concentrations, are found to be half of the olefin reaction rates. This ratio is consistent with the previously proposed reaction pathway involving the breaking of one C=C double bond containing two olefinic CH moieties to form a product containing only one methyl group and one polar carbonyl moiety. Contact angle histograms show that out of a total of 60 measurements, there are about 25 more measurements with contact angles up to ten degrees below the mean recorded prior to reaction when ozone levels resemble remote continental conditions (50 ppb) than when ozone levels resemble urban conditions (1 ppm). The implication of these results are that the methyl formation pathway in heterogeneous ozonolysis may be less favorable than the carboxylic acid- and secondary ozonide-production pathway for ozone-limited conditions (i.e., in the remote continental troposphere or during urban nighttime) as opposed to ozone-rich (i.e., polluted urban atmosphere) conditions.


Lipid profile and socioeconomic status in healthy middle aged women in Sweden.
To examine the relationship between socioeconomic status (SES) and full lipid profile in middle aged healthy women. These comprised 300 healthy Swedish women between 30 and 65 years who constitute the control group of the Stockholm female coronary risk study, a population based, case-control study of women with coronary heart disease (CHD). The age matched control group, drawn from the census register of greater Stockholm, was representative of healthy Swedish women aged 30-65 years. Five measures of SES were used; educational level, occupation, decision latitude at work, annual income, and size of house or apartment. Swedish women with low decision latitude at work, low income, low educational level, blue collar jobs, and who were living in small houses or apartments had an unhealthy lipid profile, suggesting an increased risk of CHD. Part of this social gradient in lipids was explained by an unhealthy lifestyle, but the lipid gradients associated with decision latitude at work and annual income were independent of these factors. Decision latitude, educational level, and annual income had the strongest associations with lipid profile. These associations were independent of age, menopausal status, smoking, sedentary lifestyle, alcohol consumption, obesity, excess abdominal fat, and unhealthy dietary habits. Of the lipid variables, low high density lipoprotein cholesterol (HDL) levels were most consistently associated with low SES. Decision latitude at work was the strongest SES predictor of HDL levels in healthy middle aged Swedish women, after simultaneous adjustment for other SES measures, age, and all lifestyle factors in the multivariable regression model.


Phalloplasty: A Review of Techniques and Outcomes.
Acquired or congenital absence of the penis can lead to severe physical limitations and psychological outcomes. Phallic reconstruction can restore various functional aspects of the penis and reduce psychosocial sequelae. Moreover, some female-to-male transsexuals desire creation of a phallus as part of their gender transition. Because of the complexity of phalloplasty, there is not an ideal technique for every patient. This review sets out to identify and critically appraise the current literature on phalloplasty techniques and outcomes. A comprehensive literature search of the MEDLINE, PubMed, and Google Scholar databases was conducted for studies published through July of 2015 with multiple search terms related to phalloplasty. Data on techniques, outcomes, complications, and patient satisfaction were collected. A total of 248 articles were selected and reviewed from the 790 identified. Articles covered a variety of techniques on phalloplasty. Three thousand two hundred thirty-eight patients underwent phalloplasty, with a total of 1753 complications reported, although many articles did not explicitly comment on complications. One hundred four patients underwent penile replantation and two underwent penile transplantation. Satisfaction was high, although most studies did not use validated or quantified approaches to address satisfaction. Phalloplasty techniques are evolving to include a number of different flaps, and most techniques have high reported satisfaction rates. Penile replantation and transplantation are also options for amputation or loss of phallus. Further studies are required to better compare different techniques to more robustly establish best practices. However, based on these studies, it appears that phalloplasty is highly efficacious and beneficial to patients.


Transcriptomes of antigen presenting cells in human thymus.
Antigen presenting cells (APCs) in the thymus play an essential role in the establishment of central tolerance, i.e. the generation of a repertoire of functional and self-tolerant T cells to prevent autoimmunity. In this study, we have compared the transcriptomes of four primary APCs from human thymus (mTECs, CD19+ B cells, CD141+ and CD123+ DCs). We investigated a set of genes including the HLA genes, genes encoding transcriptional regulators and finally, tissue-enriched genes, i.e, genes with a five-fold higher expression in a particular human tissue. We show that thymic CD141+ DCs express the highest levels of all classical HLA genes and 67% (14/21) of the HLA class I and II pathway genes investigated in this study. CD141+ DCs also expressed the highest levels of the transcriptional regulator DEAF1, whereas AIRE and FEZF2 expression were mainly found in primary human mTECs. We found expression of "tissue enriched genes" from the Human Protein Atlas (HPA) in all four APC types, but the mTECs were clearly dominating in the number of uniquely expressed tissue enriched genes (20% in mTECs, 7% in CD19+ B cells, 4% in CD123+ DCs and 2% in CD141+ DCs). The tissue enriched genes also overlapped with reported human autoantigens. This is, to our knowledge, the first study that performs RNA sequencing of mTECs, CD19+ B cells, CD141+ and CD123+ DCs isolated from the same individuals and provides insight into the transcriptomes of these human thymic APCs.


'Timed Up and Go' test: Age, gender and cognitive impairment stratified normative values of older adults.
The aim of this study was to establish 'Timed up and Go' test (TUG) normative data among community dwelling older adults stratified based on cognitive status, gender and age groups. A total of 2084 community dwelling older adults from wave I and II were recruited through a multistage random sampling method. TUG was performed using the standard protocol and scores were then stratified based on with and without mild cognitive impairment (MCI), gender and in a 5-year age groups ranging from ages of 60's to 80's. 529(16%) participants were identified to have MCI. Past history of falls and medical history of hypertension, heart disease, joint pain, hearing and vision problem, and urinary incontinence were found to have influenced TUG performance. Cognitive status as a mediator, predicted TUG performance even when both gender and age were controlled for (B 0.24, 95% CI (0.02-0.47), β 0.03, t 2.10, p = 0.36). Further descriptive analysis showed, participants with MCI, women and older in age took a longer time to complete TUG, as compared to men with MCI across all age groups with exceptions for some age groups. These results suggested that MCI needs to be taken into consideration when testing older adults using TUG, besides age and gender factors. Data using fast speed TUG may be required among older adults with and without MCI for further understanding.


Trends in use of oral hypoglycemic agents 1964-1986.
Oral hypoglycemic (OH) agents have been available in the United States for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) for almost 30 yr. During this time they have been subject to considerable controversy. In this article, we present pharmaceutical marketing research data that provide a review of several facets of OH use. The number of OH prescriptions dispensed peaked in 1973, decreased through 1980, and has been increasing since that year. In 1986, OH agents accounted for 21.5 million prescriptions: 1% of all prescriptions dispensed that year. Chlorpropamide is currently the most frequently ingested OH agent; it is used by 33% of the market. The two OH agents introduced in 1984, glyburide and glipizide, had acquired 41% of the OH market by the end of 1986. The rate of OH use per 1000 diabetes mellitus visits increases with patient's age. Patients aged 60 yr and older received OH prescriptions at a rate of 478 per 1000 diabetes mellitus visits in 1986. Data estimating both the number of patients diagnosed with diabetes and the number of diabetic patients taking OH agents indicate that the percentage receiving OH treatment has increased over the past 5 yr, with approximately 35% of all diabetic patients taking OH agents in 1986.


Molecular effects of nicarbazin on avian reproduction.
Nicarbazin (NCZ) is an anticoccidial drug routinely used in the poultry industry that can negatively affect reproduction by reducing egg production, egg weight, and egg hatchability. The molecular mechanisms by which NCZ affects reproduction are unknown. Lipoprotein lipase, vitellogenin, transglutaminase, and calcium are all involved in egg formation and embryogenesis. Therefore, in vitro assays were used to evaluate 4 potential mechanisms of action of NCZ on egg formation and embryogenesis. First, a lipoprotein lipase assay was conducted to determine if NCZ increases lipoprotein lipase activity. Second, vitellogenin phosphorylation was evaluated to determine if NCZ acts as a vitellogenin phosphatase. Third, transglutaminase activity was measured to determine if NCZ inhibits transglutaminase activity. Finally, bull sperm was used as a model to determine if specific channel-mediated calcium uptake can be blocked by NCZ. Nicarbazin increased the activity of lipoprotein lipase in vitro at 3.9 and 7.8 microg of NCZ/mL. Nicarbazin increased intracellular calcium levels in bull sperm, suggesting it also acts as a calcium ionophore. The portion of the NCZ molecule responsible for the increase in intracellular calcium is 2-hydroxy-4,6-dimethylpyrimidine. Nicarbazin affected vitellogenin phosphorylation but only at a concentration many times higher than expected plasma values. Nicarbazin also inhibited transglutaminase activity in vitro. Whereas the 4,4'-dinitrocarbanilide portion of the NCZ molecule inhibited transglutaminase activity, the 2-hydroxy-4,6-dimethylpyrimidine portion increased transglutaminase activity. All of these assays were conducted in vitro; therefore these results should be viewed as preliminary findings to aid in directing further research on the effect of NCZ on reproduction in vivo. Because NCZ increases lipoprotein lipase activity and acts as a calcium ionophore, future experiments should investigate these effects in particular.


L-form bacteria, cell walls and the origins of life.
The peptidoglycan wall is a defining feature of bacterial cells and was probably already present in their last common ancestor. L-forms are bacterial variants that lack a cell wall and divide by a variety of processes involving membrane blebbing, tubulation, vesiculation and fission. Their unusual mode of proliferation provides a model for primitive cells and is reminiscent of recently developed in vitro vesicle reproduction processes. Invention of the cell wall may have underpinned the explosion of bacterial life on the Earth. Later innovations in cell envelope structure, particularly the emergence of the outer membrane of Gram-negative bacteria, possibly in an early endospore former, seem to have spurned further major evolutionary radiations. Comparative studies of bacterial cell envelope structure may help to resolve the early key steps in evolutionary development of the bacterial domain of life.


Successful careers and cognitive style: a follow-up study of childhood family discontinuity.
It was predicted that those participants who experienced discontinuity (death, divorce, and separations) from their parent(s) in childhood and who had successful careers in adulthood would manifest more innovative than adaptive cognitive styles on the Kirton Adaption-Innovation Inventory. The original research showed 61% of the sample members (n = 41) experienced family discontinuity. Ninety percent (n = 37) of the previous participants responded and showed 59% family discontinuity. Fifty-four percent in the follow-up study chose an alternative career path (counterstriving), the same percentage as in the original sample. When both family discontinuity and counterstriving were present, statistically significant innovation scores occurred. Family discontinuity in childhood and a successful career in adulthood are likely to be associated with high striving-motivation and an innovative (paradigm-breaking) problem-solving style.


Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center.
Medically refractory epilepsy continues to be a challenge worldwide, and despite an increasing number of medical therapies, approximately 1 in 3 patients continues to have seizures. Cannabidiol (CBD), one of many constituents of the Cannabis sativa or marijuana plant, has received renewed interest in the treatment of epilepsy. While highly purified CBD awaits Food and Drug Administration (FDA) approval, artisanal formulations of CBD are readily available and are seeing increased use in our patient population. Although randomized controlled trials of CBD are ongoing and promising, data regarding artisanal formulations of CBD are minimal and largely anecdotal. Here, we report a retrospective study to define the efficacy of artisanal CBD preparations in children with epilepsy. Given the known interaction between CBD and clobazam, we also conducted a subgroup comparison to determine if clobazam use was related to any beneficial effects of CBD. Additionally, we compared response rates with CBD and with clobazam alone within an overlapping patient cohort. A pediatric cohort with epilepsy of 108 patients was identified through a medical record search for patients using CBD oil. The addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The responder rate for clobazam was similar. No patients achieved CBD monotherapy, although the weaning of other antiepileptic drugs (AEDs) became possible in 22% of patients. A comparable proportion had AED additions during CBD therapy. With concomitant use of clobazam, 44% of patients had a 50% reduction in seizures upon addition of CBD compared with 33% in the population not taking clobazam; this difference was not statistically significant. The most common reported side effect of CBD was sedation in less than 4% of patients, all of whom were also taking clobazam. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. Benefits were more marked in the CBD alone group, in contrast to the CBD and clobazam group, but this difference was not statistically significant. In summary, these findings support efficacy of artisanal CBD preparations in seizure reduction with few significant side effects. The response to CBD was independent of concurrent clobazam use, although clobazam may contribute to the sedation seen with concurrent CBD use.


Polo-like kinase 1 is overexpressed in colorectal cancer and participates in the migration and invasion of colorectal cancer cells.
Polo-like kinase 1 (PLK1) is an important molecule in proliferation of many human cancers. The aim of study is to clarify the expression patterns and potential function of PLK1 in colorectal cancers. Fifty-six colorectal cancers samples were collected and arranged onto a tissue array and the expression of PLK1 were detected by immunohistochemistry and correlated with clinico-pathological characteristics and expression of PCNA. Expression of PLK1 in 9 colorectal cancer cells lines was investigated by RT-PCR and Western blot, then SW1116 cells lines were treated with PLK1 siRNA and the efficiency was examined by Western blot. Transwell test was applied to detect the migration and invasion capability of cancer cells by counting the number of cells passing through the membranes. Cell proliferation and apoptosis were examined by Cell Counting Kit-8 (CCK-8) and Annexin-V Kit. PLK1 was positively expressed in 73.2% (41/56) of colorectal cancers tissues, but in only 3.6% (2/56) of normal tissues, and was associated with Duke's stage (P<0.01), tumor size (P<0.01), invasion extent (P<0.05) and lymphatic metastasis (P<0.01). The expression of PLK1 was correlated with expression of PCNA (R=0.553, P<0.01). PLK1 was inhibited in SW1116 cells by treating with PLK1 siRNA oligos, which resulted in a decreased number of cells passing through the membrane as compared with control groups (P<0.01) at 24 hours after transfection. Cell proliferation was inhibited from 48 hours after transfection, while cells apoptosis was induced from 72 hours after transfection. PLK1 could be a progression marker for colorectal cancer patients and PLK1 depletion can inhibit migration and invasion capability of colorectal cancer cells SW1116, suggesting that PLK1 might be involved in metastasis and invasion of colorectal cancer. Therapeutic strategies targeting PLK1 may be a new approach to colorectal cancer.


Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke.
Glycoprotein (GP) IIb-IIIa inhibitors are antiplatelet agents that act by antagonising GP IIb-IIIa receptors on the platelet surface and block the final common pathway to platelet aggregation by preventing the binding of fibrinogen molecules that form bridges between adjacent platelets. Thus, GP IIb-IIIa inhibitors could favour endogenous thrombolysis by reducing thrombus growth and preventing thrombus re-formation through competitive inhibition with fibrinogen and, due to their mechanism of action, are likely to have a more profound antiplatelet effect with more rapid onset than conventional antiplatelet agents, such as aspirin or clopidogrel. Currently used in clinical practice for the treatment of individuals with acute coronary syndromes and during coronary angioplasty, GP IIb-IIIa inhibitors could also be useful for the treatment of people with acute ischaemic stroke. To assess the use of GP IIb-IIIa inhibitors in people with acute ischaemic stroke to evaluate whether such treatments (1) reduce the proportion of patients who die or remain dependent, and (2) are sufficiently safe for general use. We wished to examine the effects GP IIb-IIIa inhibitors alone or in combination with thrombolytic agents. We searched the Cochrane Stroke Group trials register (last searched 10 June 2013), MEDLINE (1966 to June 2013), EMBASE (1980 to June 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 5, 2013), and major ongoing clinical trials registers (June 2013). We also searched reference lists and contacted trial authors and pharmaceutical companies. We aimed to analyse unconfounded randomised controlled trials (RCTs) of GP IIb-IIIa inhibitors in the treatment of people with acute ischaemic stroke. Only individuals who started treatment within six hours of stroke onset were included. We independently selected trials for inclusion, assessed trial quality and extracted the data. We included four trials involving 1365 participants. Three trials compared the intravenous GP IIb-IIIa inhibitor Abciximab with intravenous placebo (1215 participants) and one trial compared the intravenous GP IIb-IIIa inhibitor Tirofiban with intravenous aspirin (150 participants). Treatment with either of these GP IIb-IIIa inhibitors did not significantly reduce long-term death or dependency (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.77 to 1.22, for the comparison between Abciximab and placebo; OR 1.00, 95% CI 0.52 to 1.92, for the comparison between Tirofiban and aspirin) and had no effect on deaths from all causes (OR 1.08, 95% CI 0.77 to 1.53, for the comparison between Abciximab and placebo; OR 1.00, 95% CI 0.35 to 2.82, for the comparison between Tirofiban and aspirin). Abciximab was associated with a significant increase in symptomatic intracranial haemorrhage (OR 4.6, 95% CI 2.01 to 10.54) and with a non-significant increase in major extracranial haemorrhage (OR 1.81, 95% CI 0.96 to 3.41), whereas the only small trial comparing Tirofiban with aspirin showed no increased risk of bleeding complications with Tirofiban (OR 0.32, 95% CI 0.03 to 3.19, for symptomatic intracranial haemorrhage; OR 3.04, 95% CI 0.12 to 75.83, for major extracranial haemorrhages). There was no significant inconsistency across the studies. The available trial evidence showed that, for individuals with acute ischaemic stroke, GP IIb-IIIa inhibitors are associated with a significant risk of intracranial haemorrhage with no evidence of any reduction in death or disability in survivors. These data do not support their routine use in clinical practice. The conclusion is driven by trials of Abciximab, which contributed 89% of the total number of study participants considered.


Typicality and Predictive Distributions in Discriminant Function Analysis.
While discriminant function analysis is an inherently Bayesian method, researchers attempting to estimate ancestry in human skeletal samples often follow discriminant function analysis with the calculation of frequentist-based typicalities for assigning group membership. Such an approach is problematic because it fails to account for admixture and for variation in why individuals may be classified as outliers or nonmembers of particular groups. This article presents an argument and methodology for employing a fully Bayesian approach in discriminant function analysis applied to cases of ancestry estimation. The approach requires adding the calculation, or estimation, of predictive distributions as the final step in ancestry-focused discriminant analyses. The methods for a fully Bayesian multivariate discriminant analysis are illustrated using craniometrics from identified population samples within the Howells published data. The article also presents ways to visualize predictive distributions calculated in more than three dimensions, explains the limitations of typicality measures, and suggests an analytical route for future studies of ancestry and admixture based in discriminant function analysis.


Rule of rescue or the good of the many? An analysis of physicians' and nurses' preferences for allocating ICU beds.
To examine intensive care unit (ICU) clinicians' willingness to trade off societal benefits in favor of a small chance of rescuing an identifiable critically ill patient. We sent mixed-methods questionnaires to national samples of US ICU clinicians, soliciting their preferences for allocating their last bed to a gravely ill patient with little chance to survive, versus a deceased or dying patient for whom aggressive management could help others through organ donation. Complete responses were obtained from 684 of 2,206 physicians (31.0%) and 438 of 988 nurses (44.3%); there was no evidence of non-response bias. Physicians were more likely than nurses to adhere to the "rule of rescue" by allocating the last bed to the gravely ill patient (45.9 vs. 32.6%, difference = 13.2%; 95% CI 9.1-17.3%). The magnitude of the social benefit to be obtained through organ donor management (5 or 30 life-years added for transplant recipients) had small and inconsistent effects on clinicians' willingness to prioritize the donor. In qualitative analyses, the most common reason for allocating the last bed to an identifiable patient (identified by 65% of physicians and 75% of nurses) was that clinicians perceived strong obligations to identifiable living patients. More than one-third of ICU clinicians forewent substantial social benefits so as to devote resources to an individual patient unlikely to benefit from them. Such allegiance to the rule of rescue suggests challenges for efforts to reform ICU triage practices.


Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment.
The protein-tyrosine phosphatase Shp2 plays an essential role in growth factor and integrin signaling, and Shp2 mutations cause developmental defects and/or malignancy. Previous work has placed Shp2 upstream of Ras. However, the mechanism of Shp2 action and its substrate(s) are poorly defined. Additional Shp2 functions downstream of, or parallel to, Ras/Erk activation also are proposed. Here, we show that Shp2 promotes Src family kinase (SFK) activation by regulating the phosphorylation of the Csk regulator PAG/Cbp, thereby controlling Csk access to SFKs. In Shp2-deficient cells, SFK inhibitory C-terminal tyrosines are hyperphosphorylated, and the tyrosyl phosphorylation of multiple SFK substrates, including Plcgamma1, is decreased. Decreased Plcgamma1 phosphorylation leads to defective Ras activation on endomembranes, and may help account for impaired Erk activation in Shp2-deficient cells. Decreased phosphorylation/activation of other SFK substrates may explain additional consequences of Shp2 deficiency, including altered cell spreading, stress fibers, focal adhesions, and motility.


Membrane permeability of hydrocarbon-cross-linked peptides.
Schafmeister, Po, and Verdine (another study) introduced a method using a hydrocarbon linker (staple) to stabilize a peptide in a helical configuration. One intended goal of this scheme is to facilitate the delivery of peptide drugs into target cells. Here, we investigate whether stapled peptides are intrinsically membrane permeable, by performing a case study on a stapled 12-mer peptide named NYAD-1. We found that the native peptide CAI (an HIV-1 inhibitor) does not bind to lipid bilayers, however NYAD-1 indeed permeates through lipid bilayers even at low solution concentrations. To understand the reason for the membrane permeability, we investigated the physical properties of NYAD-1 as a function of bound peptide/lipid molar ratio P/L. We found that NYAD-1 spontaneously binds to a lipid bilayer. At low P/L, the peptide primarily binds on the polar-apolar interface with its helical axis parallel to the bilayer, which has the effect of stretching the membrane area and thinning the membrane. The membrane thinning reaches its maximum at P/L ∼1/15-1/12 in DOPC bilayers. Additional bound peptides have little thinning effect and their helical axes are normal to the plane of bilayers. Thus, the stapled peptide has a membrane interaction behavior similar to helical antimicrobial peptides, such as magainin and melittin. We emphasize that not all peptides that bind to lipid bilayers in the α-helical form behave this way.


The contribution of HLA genes to IBD susceptibility and phenotype.
The human leukocyte antigen (HLA) region located on chromosome 6p encodes the highly polymorphic, classical class I and II genes essential for normal lymphocyte function; it also encodes a further 224 genes. Many early studies investigating this region were limited by small sample size, poor statistical methodology, population stratification and variable disease definition. Although more recent studies have improved study design, investigators are still challenged by the complex patterns of linkage disequilibrium across this gene-dense region, and by the disease heterogeneity characteristic of all genetically complex disorders. However, a number of important observations have emerged from recent studies: (1) the HLA harbours gene(s) that determine susceptibility to colonic inflammation in both ulcerative colitis (UC) and Crohn's disease (CD); (2) most of the specific associations with UC and CD appear to differ; (3) associations between different ethnic groups differ; (4) markers in the HLA might predict the course of disease and the development of complications, notably the extraintestinal manifestations of disease.


Bonamia exitiosus n. sp. (Haplosporidia) infecting flat oysters Ostrea chilensis in New Zealand.
Bonamia sp. is a pathogenic parasite that occurs in the haemocytes of dredge oysters Ostrea chilensis Philippi in New Zealand. Ultrastructurally it resembles other haplosporidians in the possession of haplosporosomes, haplosporogenesis, persistence of mitotic microtubules during interphase and of the nuclear envelope during mitosis, and occurrence of a diplokaryotic or multi-nucleate plasmodial stage. Another stage containing a large vacuole derived from enlargement of 1 or more mitochondria has not previously been described from other haplosporidians. It most closely resembles B. ostreae Pichot et al., 1979, which parasitises and is pathogenic in haemocytes of European flat oysters, O. edulis. However, B. ostreae is smaller and denser, and has fewer lipoid bodies and haplosporosomes. We have nearly completely sequenced the small ribosomal gene of the organism from O. chilensis. Initial comparisons of these sequences with those of other protozoans showed similarities to B. ostreae. Polymorphism within Bonamia sp. was confirmed by restriction fragment length polymorphism analysis. On the basis of ultrastructural and molecular considerations it is proposed that this organism be named Bonamia exitiosus sp. nov.


The aliphatic oxidation of salmeterol to alpha-hydroxysalmeterol in human liver microsomes is catalyzed by CYP3A.
Salmeterol xinafoate (Serevent) is a long-acting beta2-adrenoceptor agonist, used in the treatment of asthma, that has bronchodilator and anti-inflammatory action. Salmeterol is extensively metabolized by aliphatic oxidation in humans, with the major metabolite being alpha-hydroxysalmeterol. The aim of this investigation was to identify the specific cytochrome P450 (P450) isoform or isoforms involved in the formation of alpha-hydroxysalmeterol in human liver microsomes. [14C]Salmeterol was incubated with a pooled sample (N = 19) of human liver microsomes in the absence or presence of selective chemical inhibitors of the major human P450 isoforms. One microM ketoconazole, a selective inhibitor of CYP3A, substantially inhibited the metabolism of salmeterol to alpha-hydroxysalmeterol. Disulfiram caused a small but consistent decrease in the amount of alpha-hydroxysalmeterol formed, possibly reflecting less than total selectivity for CYP2E1 under the conditions used. Other selective inhibitors had no significant effect on the metabolism of salmeterol. The rates of formation of alpha-hydroxysalmeterol in 10 individual liver microsomal samples showed an approximately 10-fold variation and were found to be highly correlated (r2 = 0.94; p < 0.001) with rates of metabolism of midazolam to 1'-hydroxymidazolam, a marker of CYP3A activity, in the same microsomal samples. No significant correlation was evident for the metabolism of salmeterol with levels of total P450 or other markers of human P450 activities in the same microsomal samples, thus indicating that the formation of alpha-hydroxysalmeterol is catalyzed predominantly by CYP3A. Insect cell microsomes that coexpressed human CYP3A and NADPH-P450 reductase were able to metabolize [14C]salmeterol to alpha-hydroxysalmeterol, thus confirming the role of CYP3A in catalyzing this reaction. The therapeutic dose of salmeterol is very low, so it is unlikely that any clinically relevant interactions will be observed as a consequence of the coadministration of salmeterol and other pharmaceutical agents that are metabolized by CYP3A.


Moderating influences of baseline activity levels in school physical activity programming for children: the Ready for Recess project.
A limitation of traditional outcome studies from behavioral interventions is the lack of attention given to evaluating the influence of moderating variables. This study examined possible moderation effect of baseline activity levels on physical activity change as a result of the Ready for Recess intervention. Ready for Recess (August 2009-September 2010) was a controlled trial with twelve schools randomly assigned to one of four conditions: control group, staff supervision, equipment availability, and the combination of staff supervision and equipment availability. A total of 393 children (181 boys and 212 girls) from grades 3 through 6 (8-11 years old) were asked to wear an Actigraph monitor during school time on 4-5 days of the week. Assessments were conducted at baseline (before intervention) and post intervention (after intervention). Initial MVPA moderated the effect of Staff supervision (β = -0.47%; p < .05), but not Equipment alone and Staff + Equipment (p > .05). Participants in the Staff condition that were 1 standard deviation (SD) below the mean for baseline MVPA (classified as "low active") had lower MVPA levels at post-intervention when compared with their low active peers in the control condition (Mean diff = -10.8 ± 2.9%; p = .005). High active individuals (+1SD above the mean) in the Equipment treatment also had lower MVPA values at post-intervention when compared with their highly active peers in the control group (Mean diff = -9.5 ± 2.9%; p = .009). These results indicate that changes in MVPA levels at post-intervention were reduced in highly active participants when recess staff supervision was provided. In this study, initial MVPA moderated the effect of Staff supervision on children's MVPA after 6 months of intervention. Staff training should include how to work with inactive youth but also how to assure that active children remain active.


Interplay between an AAA module and an integrin I domain may regulate the function of magnesium chelatase.
In chlorophyll biosynthesis, insertion of Mg(2+) into protoporphyrin IX is catalysed in an ATP-dependent reaction by a three-subunit (BchI, BchD and BchH) enzyme magnesium chelatase. In this work we present the three-dimensional structure of the ATP-binding subunit BchI. The structure has been solved by the multiple wavelength anomalous dispersion method and refined at 2.1 A resolution to the crystallographic R-factor of 22.2 % (R(free)=24.5 %). It belongs to the chaperone-like "ATPase associated with a variety of cellular activities" (AAA) family of ATPases, with a novel arrangement of domains: the C-terminal helical domain is located behind the nucleotide-binding site, while in other known AAA module structures it is located on the top. Examination by electron microscopy of BchI solutions in the presence of ATP demonstrated that BchI, like other AAA proteins, forms oligomeric ring structures. Analysis of the amino acid sequence of subunit BchD revealed an AAA module at the N-terminal portion of the sequence and an integrin I domain at the C terminus. An acidic, proline-rich region linking these two domains is suggested to contribute to the association of BchI and BchD by binding to a positively charged cleft at the surface of the nucleotide-binding domain of BchI. Analysis of the amino acid sequences of BchI and BchH revealed integrin I domain-binding sequence motifs. These are proposed to bind the integrin I domain of BchD during the functional cycle of magnesium chelatase, linking porphyrin metallation by BchH to ATP hydrolysis by BchI. An integrin I domain and an acidic and proline-rich region have been identified in subunit CobT of cobalt chelatase, clearly demonstrating its homology to BchD. These findings, for the first time, provide an insight into the subunit organisation of magnesium chelatase and the homologous colbalt chelatase.


High complement factor I activity in the plasma of children with autism spectrum disorders.
Autism spectrum disorders (ASDs) are neurodevelopmental and behavioural syndromes affecting social orientation, behaviour, and communication that can be classified as developmental disorders. ASD is also associated with immune system abnormality. Immune system abnormalities may be caused partly by complement system factor I deficiency. Complement factor I is a serine protease present in human plasma that is involved in the degradation of complement protein C3b, which is a major opsonin of the complement system. Deficiency in factor I activity is associated with an increased incidence of infections in humans. In this paper, we show that the mean level of factor I activity in the ASD group is significantly higher than in the control group of typically developed and healthy children, suggesting that high activity of complement factor I might have an impact on the development of ASD.


The idea of philosophical sociology.
This article introduces the idea of philosophical sociology as an enquiry into the relationships between implicit notions of human nature and explicit conceptualizations of social life within sociology. Philosophical sociology is also an invitation to reflect on the role of the normative in social life by looking at it sociologically and philosophically at the same: normative self-reflection is a fundamental aspect of sociology's scientific tasks because key sociological questions are, in the last instance, also philosophical ones. For the normative to emerge, we need to move away from the reductionism of hedonistic, essentialist or cynical conceptions of human nature and be able to grasp the conceptions of the good life, justice, democracy or freedom whose normative contents depend on more or less articulated conceptions of our shared humanity. The idea of philosophical sociology is then sustained on three main pillars and I use them to structure this article: (1) a revalorization of the relationships between sociology and philosophy; (2) a universalistic principle of humanity that works as a major regulative idea of sociological research, and; (3) an argument on the social (immanent) and pre-social (transcendental) sources of the normative in social life. As invitations to embrace posthuman cyborgs, non-human actants and material cultures proliferate, philosophical sociology offers the reminder that we still have to understand more fully who are the human beings that populate the social world.


Patient-reported outcome after rheumatoid arthritis-related surgery in the lower extremities: a report from the Swedish National Register of Rheuma Surgery (RAKIR).
Although decreasing with the development of effective pharmacological regimes, joint surgery has improved the function and quality of life of patients with rheumatoid arthritis (RA). Few studies have assessed patient-reported outcomes after RA surgery to the lower extremities. Here we report patient-relevant outcome after RA-related surgery based on the first data from the Swedish National Register of Rheuma Surgery (RAKIR). 258 RA patients (212 women) who had joint surgery performed at the Department of Orthopaedics, Spenshult Hospital between September 2007 and June 2009 were included. Mean age at surgery was 64 (20-86) years. The patients completed the SF-36 and HAQ questionnaires preoperatively and 6 months postoperatively, and 165 patients completed them after 12 months. Improvement was seen as early as at 6 months. At 12 months, 165 patients (141 women)-including hip (n = 15), knee (n = 27), foot (n = 102), and ankle (n = 21) patients-reported statistically significant improvements from preoperatively to 12 months postoperatively in HAQ (mean change: -0.11) and SF-36 subscales physical function (11), role physical (12), bodily pain (13), social functioning (6.4), and role emotional (9.4). Hip and knee patients reported the greatest improvements. Orthopedic RA-related surgery of the lower extremities has a strong effect on pain and physical function. Improvement is evident as early as 6 months postoperatively and remains after 12 months.


Current knowledge on pancreatic cancer.
Pancreatic cancer is the fourth leading cause of cancer death with a median survival of 6 months and a dismal 5-year survival rate of 3-5%. The development and progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways. Therefore, the strategies targeting these molecules as well as their downstream signaling could be promising for the prevention and treatment of pancreatic cancer. However, although targeted therapies for pancreatic cancer have yielded encouraging results in vitro and in animal models, these findings have not been translated into improved outcomes in clinical trials. This failure is due to an incomplete understanding of the biology of pancreatic cancer and to the selection of poorly efficient or imperfectly targeted agents. In this review, we will critically present the current knowledge regarding the molecular, biochemical, clinical, and therapeutic aspects of pancreatic cancer.


Molecular Epidemiology of HIV-1 Subtype B Reveals Heterogeneous Transmission Risk: Implications for Intervention and Control.
The impact of HIV pre-exposure prophylaxis (PrEP) depends on infections averted by protecting vulnerable individuals as well as infections averted by preventing transmission by those who would have been infected if not receiving PrEP. Analysis of HIV phylogenies reveals risk factors for transmission, which we examine as potential criteria for allocating PrEP. We analyzed 6912 HIV-1 partial pol sequences from men who have sex with men (MSM) in the United Kingdom combined with global reference sequences and patient-level metadata. Population genetic models were developed that adjust for stage of infection, global migration of HIV lineages, and changing incidence of infection through time. Models were extended to simulate the effects of providing susceptible MSM with PrEP. We found that young age <25 years confers higher risk of HIV transmission (relative risk = 2.52 [95% confidence interval, 2.32-2.73]) and that young MSM are more likely to transmit to one another than expected by chance. Simulated interventions indicate that 4-fold more infections can be averted over 5 years by focusing PrEP on young MSM. Concentrating PrEP doses on young individuals can avert more infections than random allocation.


Benign Orofacial Lesions in Libyan Population: A 17 Years Retrospective Study.
To analyze the frequency and type of benign orofacial lesions submitted for diagnosis at Tripoli Medical Centre over 17 years period (1997-2013). Entries for specimens from patients were retrieved and compiled into 9 diagnostic categories and 82 diagnoses. During the 17 years period, a total of 975 specimens were evaluated, it comprised a male-female ratio of 0.76:1. The mean age of biopsied patients was 36.3±18.32 years. The diagnostic category with the highest number of specimens was skin and mucosal pathology (22.87%); and the most frequent diagnosis was pyogenic granuloma (14.05%). Pyogenic granuloma, lichen planus, radicular cyst and fibroepithelial polyp were found to be the most predominant diagnoses. Frequencies of most benign orofacial diseases were comparable to similar studies in the literature and to those reported from the eastern region of Libya. Further surveys are needed to define the epidemiology of orofacial diseases in Libyan population.


Stentless bioprosthesis provided excellent hemodynamic performance in a military scuba diver with infective endocarditis.
Infective endocarditis is a diagnostic and therapeutic challenge that ultimately requires surgical intervention in 20% of all cases. Surgical treatment of active infective endocarditis requires not only hemodynamic repair, but also special emphasis on the eradiation of the infectious focus to prevent recurrence. This goal can be achieved by the combination of aggressive debridement of infective tissue and appropriate and adequate antibiotic treatment. We report a case of Streptococcus viridans induced aortic valve perforation related to aortic valve and root endocarditis, which was successfully treated with aortic root replacement using stentless bioprosthesis. This bioprosthesis thus seems to be a valuable option for active endocarditis, provides excellent hemodynamics with low gradients. Acceptable operative risk can be achieved by full root stentless valve replacement in physically active patients such as divers.


The effects of nursing home placement on the perceived levels of caregiver burden.
Providing care for an aging parent can be one of the most fulfilling life experiences for an adult child. It can also be one of the most exhausting physically, emotionally, and financially. A caregiver experiences psychological and emotional changes when their dependent parent or spouse is placed into formal care. This research project uses the Montgomery Borgatta Caregiver Burden Scale, amended with a questionnaire, in a self-administered, anonymous survey to explore perceptions of caregiving burden before and after the nursing home placement periods. This research showed that numerous factors influence caregivers' perceptions of burden and the quality of relationships among family members.


Retroviral envelope syncytin capture in an ancestrally diverged mammalian clade for placentation in the primitive Afrotherian tenrecs.
Syncytins are fusogenic envelope (env) genes of retroviral origin that have been captured for a function in placentation. Syncytins have been identified in Euarchontoglires (primates, rodents, Leporidae) and Laurasiatheria (Carnivora, ruminants) placental mammals. Here, we searched for similar genes in species that retained characteristic features of primitive mammals, namely the Malagasy and mainland African Tenrecidae. They belong to the superorder Afrotheria, an early lineage that diverged from Euarchotonglires and Laurasiatheria 100 Mya, during the Cretaceous terrestrial revolution. An in silico search for env genes with full coding capacity within a Tenrecidae genome identified several candidates, with one displaying placenta-specific expression as revealed by RT-PCR analysis of a large panel of Setifer setosus tissues. Cloning of this endogenous retroviral env gene demonstrated fusogenicity in an ex vivo cell-cell fusion assay on a panel of mammalian cells. Refined analysis of placental architecture and ultrastructure combined with in situ hybridization demonstrated specific expression of the gene in multinucleate cellular masses and layers at the materno-fetal interface, consistent with a role in syncytium formation. This gene, which we named "syncytin-Ten1," is conserved among Tenrecidae, with evidence of purifying selection and conservation of fusogenic activity. To our knowledge, it is the first syncytin identified to date within the ancestrally diverged Afrotheria superorder.