Calreticulin Regulates Neointima Formation and Collagen Deposition following Carotid Artery Ligation.
The endoplasmic reticulum (ER) stress protein, calreticulin (CRT), is required for the production of TGF-β-stimulated extracellular matrix (ECM) by fibroblasts. Since TGF-β regulates vascular fibroproliferative responses and collagen deposition, we investigated the effects of CRT knockdown on vascular smooth-muscle cell (VSMC) fibroproliferative responses and collagen deposition. Using a carotid artery ligation model of vascular injury, Cre-recombinase-IRES-GFP plasmid was delivered with microbubbles (MB) to CRT-floxed mice using ultrasound (US) to specifically reduce CRT expression in the carotid artery. In vitro, Cre-recombinase-mediated CRT knockdown in isolated, floxed VSMCs decreased the CRT transcript and protein, and attenuated the induction of collagen I protein in response to TGF-β. TGF-β stimulation of collagen I was partly blocked by the NFAT inhibitor 11R-VIVIT. Following carotid artery ligation, CRT staining was upregulated with enhanced expression in the neointima 14-21 days after injury. Furthermore, Cre-recombinase-IRES-GFP plasmid delivered by targeted US reduced CRT expression in the neointima of CRT-floxed mice and led to a significant reduction in neointima formation and collagen deposition. The neointimal cell number was also reduced in mice, with a local, tissue-specific knockdown of CRT. This work establishes a novel role for CRT in mediating VSMC responses to injury through the regulation of collagen deposition and neointima formation.


Stabilization and ribosome association of unspliced pre-mRNAs in a yeast upf1- mutant.
Nonsense-mediated mRNA decay, the accelerated turnover of mRNAs transcribed from genes containing early nonsense mutations, is dependent on the product of the UPF1 gene in yeast. Mutations that inactivate UPF1 lead to the selective stabilization of mRNAs containing early nonsense mutations but have no effect on the half-lives of almost all other mRNAs. Since the transcripts of nonsense alleles are not typical cellular constituents, we sought to identify those RNAs that comprise normal substrates of the nonsense-mediated mRNA decay pathway. Many yeast pre-mRNAs contain early in-frame nonsense codons and we consider it possible that a role of this pathway is to accelerate the degradation of pre-mRNAs present in the cytoplasm. Consistent with this hypothesis, we find that, in a strain lacking UPF1 function, the CYH2, RP51B, and MER2 pre-mRNAs are stabilized 2- to 5-fold and are associated with ribosomes. We conclude that a major source of early nonsense codon-containing cytoplasmic transcripts in yeast is pre-mRNAs and that the UPF1 protein may be part of a cellular system that ensures that potentially deleterious nonsense fragments of polypeptides do not accumulate.


CT coronary angiography predicts the outcome of percutaneous coronary intervention of chronic total occlusion.
The success rate of percutaneous coronary intervention (PCI) of chronic total occlusions (CTO) is relatively low. Further evaluation of CTO lesion with CT coronary angiography (CT-CA) may help to better select patients that would benefit from percutaneous revascularization. We aimed to test the possible association between failed PCI and transluminal calcification of CTO as assessed by CT-CA. Patients with CTO awaiting PCI were scanned with a 16-slice CT. A cardiologist and a radiologist assessed transluminal calcification of CTO lesions on CT images while an interventional cardiologist at a core laboratory assessed conventional variables of invasive fluoroscopic coronary angiography (FCA) associated with failed PCI of CTO. The significance of CT and FCA variables in association with failed PCI were analyzed. In a cohort of 39 patients with 43 CTO lesions, 24 lesions were successfully revascularized. Transluminal calcification > or =50% as assessed on CT-CA was strongly associated with failed PCI (odds ratio [OR] of PCI success = 0.10, 95% confidence interval [CI]: 0.02-0.47, P = 0.003). Blunt stump as seen on FCA was also associated with failed PCI (OR of PCI success = 0.24, 95% CI: 0.07-0.86, P = 0.029). There was no significant evidence to support that the duration of CTO, presence of side branch and bridging collaterals, and the absence of microchannels as assessed with FCA were associated with failed PCI. On multivariate analysis, transluminal calcification > or =50% on CT-CA was the only significant predictor of failed PCI. Heavy transluminal calcification as assessed with CT-CA is an independent predictor of failed PCI of CTO. CT-CA may have a role in the work-up of CTO patients prior to PCI.


Occupational Therapy Practice Guidelines for Adults With Multiple Sclerosis.
Occupational therapy practitioners play an important role in addressing the occupational performance and participation needs of adults with multiple sclerosis (MS) and their caregivers. This Practice Guideline aims to help occupational therapy practitioners, as well as the people who manage, reimburse, or set policy regarding occupational therapy services, understand occupational therapy's role in providing services to adults with MS and their caregivers. This guideline can also serve as a reference for health care professionals, health care managers, educators, regulators, third-party payers, managed care organizations, and researchers. We examined, synthesized, and integrated the results of four systematic reviews into clinical recommendations. Three systematic reviews specified occupational domains as outcomes of interest, and one focused on interventions for caregivers of people with MS. Twenty-one articles from the systematic reviews with strong or moderate strength of evidence served as the basis for the clinical recommendations. Four interventions benefited participation in the domains of activities of daily living or sleep. Two interventions improved participation in the domain of instrumental activities of daily living. One intervention improved work participation. Two interventions benefited caregivers and the quality of the relationship between the caregiver and person with MS. Other potentially appropriate interventions or areas to address on the basis of existing or emerging evidence are discussed in the Limitations: Gaps in the Evidence and Conclusions sections. What This Article Adds: This Practice Guideline provides a summary and application of the current evidence supporting occupational therapy intervention for adults with MS. It includes case examples and decision-making algorithms to support occupational therapy practitioners in addressing client goals.


Molecular identification and antifungal susceptibility profile of Aspergillus flavus isolates recovered from clinical specimens in Kuwait.
Within the genus Aspergillus, A. flavus is the second most important species of clinical significance. It is predominantly associated with infections involving sinuses, eye and skin, mostly in geographic regions with hot and arid climate, including the Middle East. Recent reports on emergence of resistance to triazoles among Aspergillus spp. is a cause of concern for treatment of patients with invasive aspergillosis. In this study we present data on genetic characterization and antifungal susceptibility profile of clinical and environmental isolates of A. flavus. Ninety-nine Aspergillus section Flavi isolates, originating from clinical (n=92) and environmental (n=7) sources, initially identified by morphological characteristics, were analyzed by partial sequencing of β-tubulin and calmodulin gene fragments and their susceptibilities to six antifungal agents was determined by Etest on RPMI1640 and Muller-Hinton agar media. Etest minimum inhibitory concentrations (MICs) of amphotericin B and voriconazole were also compared with zone of inhibition diameters obtained by disc diffusion test on RPMI agar medium. The identity of all clinical and environmental isolates was confirmed as A. flavus species by combined analysis of β-tubulin and calmodulin genes. The mean MIC90 (μg/ml) values on RPMI medium for amphotericin B, voriconazole, posaconazole, anidulafungin, micafungin and caspofungin were 3, 0.25, 0.25, 0.002, 0.002 and 0.032, respectively. No environmental isolate exhibited MIC value of >2 μg/ml for amphotericin B. For clinical isolates, the zone of inhibition diameters for amphotericin B and voriconazole ranged from 7-16 mm and 24-34 mm, respectively. Linear regression analysis between Etest MIC values and disk diffusion diameters revealed a significant inverse correlation with amphotericin B (p <0.001) and voriconazole (p<0.003). The β-tubulin and calmodulin gene sequences confirmed that all 92 clinical isolates identified phenotypically belonged to A. flavus taxon, thus suggesting that the other species within Aspergillus section Flavi are of little clinical significance. Triazoles and echinocandins showed very good in vitro activity against the A. flavus, however, 10% clinical isolates showed MICs of >2 μg/ml for amphotericin B.


The Phox2b transcription factor coordinately regulates neuronal cell cycle exit and identity.
In the vertebrate neural tube, cell cycle exit of neuronal progenitors is accompanied by the expression of transcription factors that define their generic and sub-type specific properties, but how the regulation of cell cycle withdrawal intersects with that of cell fate determination is poorly understood. Here we show by both loss- and gain-of-function experiments that the neuronal-subtype-specific homeodomain transcription factor Phox2b drives progenitor cells to become post-mitotic. In the absence of Phox2b, post-mitotic neuronal precursors are not generated in proper numbers. Conversely, forced expression of Phox2b in the embryonic chick spinal cord drives ventricular zone progenitors to become post-mitotic neurons and to relocate to the mantle layer. In the neurons thus generated, ectopic expression of Phox2b is sufficient to initiate a programme of motor neuronal differentiation characterised by expression of Islet1 and of the cholinergic transmitter phenotype, in line with our previous results showing that Phox2b is an essential determinant of cranial motor neurons. These results suggest that Phox2b coordinates quantitative and qualitative aspects of neurogenesis, thus ensuring that neurons of the correct phenotype are generated in proper numbers at the appropriate times and locations.


Improving viewing region of 4f optical system for holographic displays.
A 4f optical system with a single-sideband filter has been used for electronic holographic displays in order to obtain a reconstructed image without a conjugate image and zero-order diffraction light. However, the viewing region is inclined, and the viewing region in which an entire reconstructed image can be viewed is limited. In the present study, one of the Fourier transform lenses constituting the 4f optical system is shifted to correct the viewing region inclination. Moreover, a screen lens is added in the image plane of the 4f optical system to maximize the viewing region. The inclination of the viewing region can also be corrected by shifting the screen lens instead of shifting the Fourier transform lens. Experimental verifications of these corrections are described.


Development and applications of remote stereocontrol using allylic organobismuth reagents.
Reactions of 5-benzyloxy-4-methylpent-2-enyl(tributyl)stannane with aldehydes promoted by bismuth(III) iodide were usefully stereoselective in favour of the (E)-1,5-anti-6-benzyloxy-5-methylalk-3-en-1-ols. Similar stereoselectivity was observed for reactions of analogous 5-benzyloxy-4-methylpent-2-enyl bromides with aldehydes when promoted by a low valency bismuth species prepared by reduction of bismuth(III) triiodide with powdered zinc so providing a "tin-free" procedure. The analogous reactions of 4-benzyloxypent-2-enyl(tributyl)stannane with aldehydes promoted by bismuth(III) iodide were also stereoselective but gave lower yields. Attempted 1,6-stereocontrol using these reactions resulted in only modest stereoselectivities. Aspects of the chemistry of the products were studied in particular their stereoselective conversion into aliphatic compounds with methyl bearing stereogenic centres at 1,5,9,13- and 1,3,5-positions along the aliphatic chain. Mechanistically, allylic organobismuth species may be involved in both sets of reactions but this was not confirmed although the similar stereoselectivities observed for both the bismuth(III) iodide mediated reactions of the pent-2-enylstannanes and the low-valency bismuth promoted reactions of the pent-2-enyl bromides are consistent with participation of similar intermediates.


Diversionary role of hoofed game in the transmission of Lyme disease spirochetes.
To determine whether the presence of ungulates may inhibit transmission of the agent of Lyme disease (Borrelia burgdorferi) while promoting the abundance of its European vector tick (Ixodes ricinus), we compared the feeding density of subadult ticks on roe deer (Capreolus capreolus), red deer (Cervus elaphus), fallow deer (Dama dama), and wild sheep (Ovis ammon) near Berlin and in Brandenburg State, Germany. The prevalence of spirochetal infection in these ticks was compared with that in ticks swept from nearby vegetation. Spirochetes are present in nearly one-fifth of nonfed, questing nymphal and adult wood ticks in the region. Many ungulates in this intensely enzootic region fail to mount a detectable humoral response against the agent of Lyme disease, even when exposed to numerous infected ticks. During the height of the summer, each ungulate may support the feeding of hundreds of subadult ticks. Larvae feed lower on the bodies of hoofed game than do nymphs. Few ticks retain infection by the Lyme disease spirochete after feeding on hoofed game animals. We conclude that numerous I. ricinus ticks feed on ungulates, but that such host-contact fails to infect these ticks while eliminating pre-existing spirochetal infection.


Evolution of DS-1-like human G2P[4] rotaviruses assessed by complete genome analyses.
Group A rotaviruses (RVAs) are a leading cause of viral gastroenteritis in children, with G2P[4] RVA being one of the most common human strains worldwide. The complete genome sequences of nine G2P[4] RVA strains, selected from a 26-year archival collection (1985-2011) established in Palermo, Italy, were determined. A strain associated with a peak of G2P[4] RVA activity in 1996 resembled a reassortant strain identified in Kenya in 1982 and differed completely in genomic make up from more recent strains that circulated during 2004-2011. Conversely, the 2004-2011 G2P[4] RVAs were genetically more similar to contemporary RVA strains circulating globally. Recent G2P[4] strains possessed either single or multiple genome segments (VP1, VP3 and/or NSP4) likely derived from ruminant viruses through intra-genotype reassortment. Amino acid substitutions were selected and maintained over time in the VP7 and VP8* antigenic proteins, allowing the circulation of two contemporary G2P[4] variants to be distinguished. Altogether, these findings suggest that major changes in the genomic composition of recent G2P[4] RVAs occurred in the early 2000s, leading to the appearance of a novel variant of the DS-1-like genotype constellation. Whether the modifications observed in the neutralizing antigens and in the genome composition of modern G2P[4] RVAs may affect the long-term effectiveness of the vaccination programmes remains to be explored.


Building capacity for public and population health research in Africa: the consortium for advanced research training in Africa (CARTA) model.
Globally, sub-Saharan Africa bears the greatest burden of disease. Strengthened research capacity to understand the social determinants of health among different African populations is key to addressing the drivers of poor health and developing interventions to improve health outcomes and health systems in the region. Yet, the continent clearly lacks centers of research excellence that can generate a strong evidence base to address the region's socio-economic and health problems. We describe the recently launched Consortium for Advanced Research Training in Africa (CARTA), which brings together a network of nine academic and four research institutions from West, East, Central, and Southern Africa, and select northern universities and training institutes. CARTA's program of activities comprises two primary, interrelated, and mutually reinforcing objectives: to strengthen research infrastructure and capacity at African universities; and to support doctoral training through the creation of a collaborative doctoral training program in population and public health. The ultimate goal of CARTA is to build local research capacity to understand the determinants of population health and effectively intervene to improve health outcomes and health systems. CARTA's focus on the local production of networked and high-skilled researchers committed to working in sub-Saharan Africa, and on the concomitant increase in local research and training capacity of African universities and research institutes addresses the inability of existing programs to create a critical mass of well-trained and networked researchers across the continent. The initiative's goal of strengthening human resources and university-wide systems critical to the success and sustainability of research productivity in public and population health will rejuvenate institutional teaching, research, and administrative systems.


The good, the bad, and the healthy: impacts of emotional disclosure of trauma on resilient self-concept and psychological distress.
This study examined the impact of disclosing traumas on resilient self-perceptions and psychological distress. Participants (N = 50) wrote about a traumatic life event or their plans for the next day and completed measures of resilience and distress before disclosing (pretest) and 3 months later (posttest). Results revealed that trauma participants increased in positive self-perceptions (mastery, personal growth, self-acceptance) and decreased in distress (depression, interpersonal sensitivity, anxiety, somatization) from pretest to posttest. Control participants showed no changes except for autonomy, on which they decreased. Results suggest that in addition to reducing psychological distress, disclosing traumas change self-perception, resulting in a more resilient self-concept.


Current clinical evidence for the use of mesenchymal stem cells in articular cartilage repair.
Articular cartilage is renowned for its poor intrinsic capacity for repair. Current treatments for osteoarthritis are limited in their ability to reliably restore the native articular cartilage structure and function. Mesenchymal stem cells (MSCs) present an attractive treatment option for articular cartilage repair, with a recent expansion of clinical trials investigating their use in patients. This paper provides a current overview of the clinical evidence on the use of MSCs in articular cartilage repair. The article demonstrates robust clinical evidence that MSCs have significant potential for the regeneration of hyaline articular cartilage in patients. The majority of clinical trials to date have yielded significantly positive results with minimal adverse effects. However the clinical research is still in its infancy. The optimum MSC source, cell concentrations, implantation technique, scaffold, growth factors and rehabilitation protocol for clinical use are yet to be identified. A larger number of randomised control trials are required to objectively compare the clinical efficacy and long-term safety of the various techniques. As the clinical research continues to evolve and address these challenges, it is likely that MSCs may become integrated into routine clinical practice in the near future.


Side-by-side comparison of the biological characteristics of human umbilical cord and adipose tissue-derived mesenchymal stem cells.
Both human adipose tissue-derived mesenchymal stem cells (ASCs) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) have been explored as attractive mesenchymal stem cells (MSCs) sources, but very few parallel comparative studies of these two cell types have been made. We designed a side-by-side comparative study by isolating MSCs from the adipose tissue and umbilical cords from mothers delivering full-term babies and thus compared the various biological aspects of ASCs and UC-MSCs derived from the same individual, in one study. Both types of cells expressed cell surface markers characteristic of MSCs. ASCs and UC-MSCs both could be efficiently induced into adipocytes, osteoblasts, and neuronal phenotypes. While there were no significant differences in their osteogenic differentiation, the adipogenesis of ASCs was more prominent and efficient than UC-MSCs. In the meanwhile, ASCs responded better to neuronal induction methods, exhibiting the higher differentiation rate in a relatively shorter time. In addition, UC-MSCs exhibited a more prominent secretion profile of cytokines than ASCs. These results indicate that although ASCs and UC-MSCs share considerable similarities in their immunological phenotype and pluripotentiality, certain biological differences do exist, which might have different implications for future cell-based therapy.


Gene expression of the liver of vaccination-protected mice in response to early patent infections of Plasmodium chabaudi blood-stage malaria.
The role of the liver for survival of blood-stage malaria is only poorly understood. In experimental blood-stage malaria with Plasmodium chabaudi, protective vaccination induces healing and, thus, survival of otherwise lethal infections. This model is appropriate to study the role of the liver in vaccination-induced survival of blood-stage malaria. Female Balb/c mice were vaccinated with a non-infectious vaccine consisting of plasma membranes isolated in the form of erythrocyte ghosts from P. chabaudi-infected erythrocytes at week 3 and week 1 before infection with P. chabaudi blood-stage malaria. Gene expression microarrays and quantitative real-time PCR were used to investigate the response of the liver, in terms of expression of mRNA and long intergenic non-coding (linc)RNA, to vaccination-induced healing infections and lethal P. chabaudi malaria at early patency on day 4 post infection, when parasitized erythrocytes begin to appear in peripheral blood. In vaccination-induced healing infections, 23 genes were identified to be induced in the liver by > tenfold at p < 0.01. More than one-third were genes known to be involved in erythropoiesis, such as Kel, Rhag, Ahsp, Ermap, Slc4a1, Cldn13 Gata1, and Gfi1b. Another group of > tenfold expressed genes include genes involved in natural cytotoxicity, such as those encoding killer cell lectin-like receptors Klrb1a, Klrc3, Klrd1, the natural cytotoxicity-triggering receptor 1 Ncr1, as well as the granzyme B encoding Gzmb. Additionally, a series of genes involved in the control of cell cycle and mitosis were identified: Ccnb1, Cdc25c, Ckap2l were expressed > tenfold only in vaccination-protected mice, and the expression of 22 genes was at least 100% higher in vaccination-protected mice than in non-vaccinated mice. Furthermore, distinct lincRNA species were changed by > threefold in livers of vaccination-protected mice, whereas lethal malaria induced different lincRNAs. The present data suggest that protective vaccination accelerates the malaria-induced occurrence of extramedullary erythropoiesis, generation of liver-resident cytotoxic cells, and regeneration from malaria-induced injury in the liver at early patency, which may be critical for final survival of otherwise lethal blood-stage malaria of P. chabaudi.


Meta-analysis of gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance imaging for the detection of liver metastases.
To determine the accuracy of MR imaging with Gd-EOB-DTPA for the detection of liver metastases. PUBMED, EMBASE, the Web of Science, and the Cochrane Library were searched for original articles published prior to February 2012. The criteria for the inclusion of articles were as follows: reported in the English language; MR imaging with Gd-EOB-DTPA was performed to detect liver metastases; histopathologic analysis (surgery, biopsy), intraoperative observation (manual palpatation, intraoperative ultrasonography), and/or follow-up US was the reference standard; and data were sufficient for the calculation of true-positive or false-negative values. The methodological quality was assessed by using the quality assessment of diagnostic studies instrument. The data were extracted to calculate sensitivity, specificity, predictive value, diagnostic odds ratio, and areas under hierarchical summary receiver operating characteristic (HSROC) curve to perform heterogeneity test and threshold effect test, as well as publication bias analysis and subgroup analyses. From 229 citations, 13 were included in the meta-analysis with a total of 1900 lesions. We detected heterogeneity between studies and evidence of publication bias. The methodological quality was moderate. The pooled weighted sensitivity with a corresponding 95% confidence interval (CI) was 0.93 (95% CI: 0.90, 0. 95), the specificity was 0.95 (95% CI: 0.91, 0.97), the positive likelihood ratio was 18.07 (95% CI: 10.52, 31.04), the negative likelihood ratio was 0.07 (95% CI: 0.05, 0.10), and the diagnostic odds ratio was 249.81 (95% CI: 125.12, 498.74). The area under the receiver operator characteristic curve was 0.98 (95% CI: 0.96, 0.99). MR imaging with Gd-EOB-DTPA is a reliable, non-invasive, and no-radiation-exposure imaging modality with a high sensitivity and specificity for detection of liver metastases. Nonetheless, it should be applied cautiously, and large scale, well-designed trials are necessary to assess its clinical value.


An extension in eligibility for free primary care and avoidable hospitalisations: a natural experiment.
In the Republic of Ireland, approximately 30 per cent of the population ('medical card patients') are entitled to free GP services. Eligibility is determined primarily on the basis of an income means test. The remaining 70 per cent of the population ('private patients') must pay the full cost of GP consultations. In July 2001, eligibility for a medical card was extended to all those over 70 years of age, regardless of income. This extension in eligibility provides a natural experiment whereby we can examine the influence of access to free GP services on avoidable hospitalisations. Avoidable hospitalisations are those that are potentially avoidable with timely and effective access to primary care services or that can be treated more appropriately in a primary care setting. Using hospital discharge data for the period 1999-2004, the purpose of this paper is to test the proposition that enhanced access to GP services for the over 70s after July 2001 led to a decline in avoidable hospitalisations among this group. The results indicate that while avoidable hospitalisations for the over 70s did decline after 2001, they also fell for the under 70s, meaning that a significant difference-in-difference effect could not be identified.


Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase.
A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase-DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.


Optically controlled reflection modulator using GaAs-AlGaAs n-i-p-i/multiple-quantum-well structures.
An optically controlled reflection modulator has been demonstrated that consists of a combination of a GaAs-AlGaAs n-i-p-i doping structure with a multiple-quantum-well structure on top of a distributed Bragg reflector, all grown by molecular-beam epitaxy. A modulation of approximately 60% is obtained on our test structure, corresponding to a differential change of absorption coefficient in the quantum wells of approximately 7500/cm. Changes in reflectance can be observed with a control beam power as low as 1.5 microW. This device structure has the potential of being developed as an optically addressed spatial light modulator for optical information processing.


Probiotics prevent intestinal barrier dysfunction in acute pancreatitis in rats via induction of ileal mucosal glutathione biosynthesis.
During acute pancreatitis (AP), oxidative stress contributes to intestinal barrier failure. We studied actions of multispecies probiotics on barrier dysfunction and oxidative stress in experimental AP. Fifty-three male Spraque-Dawley rats were randomly allocated into five groups: 1) controls, non-operated, 2) sham-operated, 3) AP, 4) AP and probiotics and 5) AP and placebo. AP was induced by intraductal glycodeoxycholate infusion and intravenous cerulein (6 h). Daily probiotics or placebo were administered intragastrically, starting five days prior to AP. After cerulein infusion, ileal mucosa was collected for measurements of E. coli K12 and (51)Cr-EDTA passage in Ussing chambers. Tight junction proteins were investigated by confocal immunofluorescence imaging. Ileal mucosal apoptosis, lipid peroxidation, and glutathione levels were determined and glutamate-cysteine-ligase activity and expression were quantified. AP-induced barrier dysfunction was characterized by epithelial cell apoptosis and alterations of tight junction proteins (i.e. disruption of occludin and claudin-1 and up-regulation of claudin-2) and correlated with lipid peroxidation (r>0.8). Probiotic pre-treatment diminished the AP-induced increase in E. coli passage (probiotics 57.4+/-33.5 vs. placebo 223.7+/-93.7 a.u.; P<0.001), (51)Cr-EDTA flux (16.7+/-10.1 vs. 32.1+/-10.0 cm/s10(-6); P<0.005), apoptosis, lipid peroxidation (0.42+/-0.13 vs. 1.62+/-0.53 pmol MDA/mg protein; P<0.001), and prevented tight junction protein disruption. AP-induced decline in glutathione was not only prevented (14.33+/-1.47 vs. 8.82+/-1.30 nmol/mg protein, P<0.001), but probiotics even increased mucosal glutathione compared with sham rats (14.33+/-1.47 vs. 10.70+/-1.74 nmol/mg protein, P<0.001). Glutamate-cysteine-ligase activity, which is rate-limiting in glutathione biosynthesis, was enhanced in probiotic pre-treated animals (probiotics 2.88+/-1.21 vs. placebo 1.94+/-0.55 nmol/min/mg protein; P<0.05) coinciding with an increase in mRNA expression of glutamate-cysteine-ligase catalytic (GCLc) and modifier (GCLm) subunits. Probiotic pre-treatment diminished AP-induced intestinal barrier dysfunction and prevented oxidative stress via mechanisms mainly involving mucosal glutathione biosynthesis.


Harm Reduction Strategies and Disinhibitors Among Women Who Use Heroin.
People who use illicit drugs face significant physical risks in the acquisition, use, and aftermath of their use. This is particularly the case among those who use heroin in view of recent spikes in heroin-associated overdoses, injuries, and deaths. Using a restrictive deterrence framework, we identify the risks that women associate with chronic heroin use and the ways they seek to manage those risks. We also examine psychological and physiological disinhibitors that contribute to women reducing use of risk reduction strategies. We find from the narratives that nearly all of the women initially engaged in specific strategies to manage risk; however, as they continued using the drug, they began to abandon even the simplest of measures. Our findings shed light on the limitations of harm reduction strategies and inform the theoretical tradition of restrictive deterrence and the importance of disinhibitors.


Epidermal Langerhans cells are not principal reservoirs of virus in HIV disease.
Several reports implicate Langerhans cells of skin as susceptible targets, reservoirs, and vectors for transmission of HIV: 1) numbers of Langerhans cells in skin of HIV-infected patients were decreased about 50% of that in control skin; 2) as many as 30% of Langerhans cells in the skin of HIV-infected patients were morphologically abnormal; 3) viral particles typical for HIV were identified in or around 2 to 5% of these cells; and 4) infectious HIV was isolated from skin biopsies of infected patients. These results were consistent with similar observations of HIV-infected macrophages in such tissues as brain, lung, and lymph node. Despite these findings, other investigators find no evidence for virus infection in the epidermis of HIV-infected patients by any of several immunohistochemical or ultrastructural criteria. To address this controversy, we obtained skin from 28 HIV-seropositive subjects at various clinical stages by full thickness biopsy or suction blister. Samples were analyzed by transmission electron microscopy for presence of HIV virions, by immunofluorescent staining for viral proteins, by in situ hybridization for HIV-specific mRNA, by polymerase chain reaction amplification of virus-specific DNA, and by direct virus isolation by coculture of epidermis onto monocyte target cells. By any of these techniques, demonstration of HIV in the epidermis of infected patients was equivocal and even then, infrequent. In contrast, viral DNA was detected from the dermis of the same skin samples (26 of 28 samples). Moreover, the number and morphology of Langerhans cells in skin of infected patients were within normal limits, regardless of stage of disease. These studies in toto suggest that a role for Langerhans cells as a principal viral reservoir or vector of transmission is highly unlikely.


Disrupted Prefrontal Regulation of Striatal Subjective Value Signals in Psychopathy.
Psychopathy is a personality disorder with strong links to criminal behavior. While research on psychopathy has focused largely on socio-affective dysfunction, recent data suggest that aberrant decision making may also play an important role. Yet, the circuit-level mechanisms underlying maladaptive decision making in psychopathy remain unclear. Here, we used a multi-modality functional imaging approach to identify these mechanisms in a population of adult male incarcerated offenders. Psychopathy was associated with stronger subjective value-related activity within the nucleus accumbens (NAcc) during inter-temporal choice and with weaker intrinsic functional connectivity between NAcc and ventromedial prefrontal cortex (vmPFC). NAcc-vmPFC connectivity strength was negatively correlated with NAcc subjective value-related activity; however, this putative regulatory pattern was abolished as psychopathy severity increased. Finally, weaker cortico-striatal regulation predicted more frequent criminal convictions. These data suggest that cortico-striatal circuit dysregulation drives maladaptive decision making in psychopathy, supporting the notion that reward system dysfunction comprises an important neurobiological risk factor.


Synthesis and electronic properties of π-extended flavins.
Flavin derivatives with an extended π-conjugation were synthesized in moderate to good yields from aryl bromides via a Buchwald-Hartwig palladium catalyzed amination protocol, followed by condensation of the corresponding aromatic amines with violuric acid. The electronic properties of the new compounds were investigated by absorption and emission spectroscopy, cyclic voltammetry, density functional theory (DFT) and time dependent density functional theory (TDDFT). The compounds absorb up to 550 nm and show strong luminescence. The photoluminescence quantum yields ϕPL measured in dichloromethane reach 80% and in PMMA (poly(methyl methacrylate)) 77%, respectively, at ambient temperature. The electrochemical redox behaviour of π-extended flavins follows the mechanism previously described for the parent flavin.


Deployable Molecular Detection of Arboviruses in the Australian Outback.
The most common causes of human infection from the arboviruses that are endemic in Australia are the arthritogenic alphaviruses: Ross River virus (RRV) and Barmah Forest virus (BFV). The most serious infections are caused by the neurotropic flaviviruses, Murray Valley encephalitis virus (MVEV) and the Kunjin subtype of West Nile virus. The greatest individual risk of arbovirus infection occurs in tropical/subtropical northern Australia because of the warm, wet summer conditions from December to June, where conventional arbovirus surveillance is difficult due to a combination of low population density, large distances between population centers, poor roads, and seasonal flooding. Furthermore, virus detection requires samples to be sent to Perth up to 2,000 km away for definitive analysis, causing delays of days to weeks before test results are available and public health interventions can be started. We deployed a portable molecular biology laboratory for remote field detection of endemic arboviruses in northern Queensland, then in tropical Western Australia and detected BFV, MVEV, and RRV RNA by polymerase chain reaction (PCR) assays of extracts from mosquitoes trapped in Queensland. We then used a field-portable compact real-time thermocycler for the samples collected in the Kimberley region of Western Australia. Real-time field PCR assays enabled concurrent endemic arbovirus distribution mapping in outback Queensland and Western Australia. Our deployable laboratory method provides a concept of operations for future remote area arbovirus surveillance.


Papillomavirus common antigen in Bowen's disease.
We studied 173 biopsies of histologically determined Bowen's disease and looked for the presence of papillomavirus antigen using immunoperoxidase staining. Fifty-nine of the lesions were located at the head, 49 at the extremities, 36 at the trunk and 29 originated from the genital region. Papillomavirus capsid antigen could be clearly identified in 39 (22.5%) cases. Eleven (38%) of the 29 lesions located on genital skin were positive for papillomavirus capsid antigen while 28 (19.4%) of the 144 biopsies from other skin regions contained viral antigen. Our findings are suggestive of an etiologic relationship between the virus and this dermatosis which represents a special variant of squamous cell carcinoma. They indicate that human papillomaviruses may play an important role in the development of cutaneous malignancies.


Bromperidol decanoate (depot) for schizophrenia.
Antipsychotic drugs are the mainstay treatment for schizophrenia. Long-acting depot injections of drugs such as bromperidol decanoate are extensively used as a means of long-term maintenance treatment. To assess the effects of depot bromperidol versus placebo, oral antipsychotics and other depot antipsychotic preparations for people with schizophrenia in terms of clinical, social and economic outcomes. For this 2012 update we searched the Cochrane Schizophrenia Group's Register (February 2012). We sought all randomised trials focusing on people with schizophrenia where depot bromperidol, oral antipsychotics or other depot preparations. Primary outcomes were clinically significant change in global function, service utilisation outcomes (hospital admission, days in hospital), relapse. For the 2011 update MP independently extracted data, CEA carried out the reliability check. We calculated fixed-effect risk ratios (RR) and 95% confidence intervals (CI) for dichotomous data, and calculated weighted or standardised means for continuous data. Where possible, we calculated the number needed to treat statistic (NNT). Analysis was by intention-to-treat.For the 2012 update, data collection and analysis was not carried out as no new studies were found. The 2012 search found no new studies, we have therefore included no new trials in this 2012 update. The number of included trials remain 4 RCTs, total n = 117. A single, small study of six months' duration compared bromperidol decanoate with placebo injection. Similar numbers left the study before completion (n = 20, 1 RCT, RR 0.4 CI 0.1 to 1.6) and there were no clear differences between bromperidol decanoate and placebo for a list of adverse effects (n = 20, 1 RCT, RR akathisia 2.0 CI 0.21 to 18.69, RR increased weight 3.0 CI 0.14 to 65.9, RR tremor 0.33 CI 0.04 to 2.69). When bromperidol decanoate was compared with fluphenazine depot, we found no important change on global outcome (n = 30, RR no clinical important improvement 1.50 CI 0.29 to 7.73). People allocated to fluphenazine decanoate and haloperidol decanoate had fewer relapses than those given bromperidol decanoate (n = 77, RR 3.92 Cl 1.05 to 14.60, NNH 6 CI 2 to 341). People allocated bromperidol decanoate required additional antipsychotic medication somewhat more frequently than those taking fluphenazine decanoate and haloperidol decanoate, but the results did not reach conventional levels of statistical significance (n = 77, 2 RCTs, RR 1.72 CI 0.7 to 4.2). The use of benzodiazepine drugs was very similar in both groups (n = 77, 2 RCTs, RR 1.08 CI 0.68 to 1.70). People left the bromperidol decanoate group more frequent than those taking other depot preparation due to any cause (n = 97, 3 RCTs, RR 2.17 CI 1.00 to 4.73). Anticholinergic adverse effects were equally common between bromperidol and other depots (n = 47, RR 3.13 CI 0.7 to 14.0) and additional anticholinergic medication was needed with equal frequency in both depot groups, although results did tend to favour the bromperidol decanoate group (n = 97, 3 RCTs, RR 0.80 CI 0.64 to 1.01). The incidence of movement disorders was similar in both depot groups (n = 77, 2 RCTs, RR 0.74 CI 0.47 to 1.17). Minimal poorly reported trial data suggests that bromperidol decanoate may be better than placebo injection but less valuable than fluphenazine or haloperidol decanoate. If bromperidol decanoate is available it may be a viable choice, especially when there are reasons not to use fluphenazine or haloperidol decanoate. Well-conducted and reported randomised trials are needed to inform practice.


[Detection of antibodies against Trypanosoma cruzi in Somoto, Nicaragua, using indirect ELISA and IFI on blood samples on filter paper].
We standardized a solid-phase enzyme-linked immunosorbent assay (ELISA) in order to study the presence of Trypanosoma cruzi antibodies in asymptomatic persons who live in an area of Nicaragua endemic for Chagas' disease. The test was standardized to analyze filter-paper blood samples, which are easy to transport. In the first phase of our investigation, ELISA was used to study 18 samples of total serum and 18 eluates of blood from patients with chronic Chagas' disease; 30 samples of serum and 30 eluates of blood from healthy people, used as negative controls; and 14 samples of serum and 14 eluates of blood from patients with cutaneous or visceral leishmaniasis, which were used to study cross-reactions. Both with the total-serum and the blood-eluate samples, the ELISA test provided 100% sensitivity and 90% specificity. Cross-reactions in the patient samples were observed only with visceral leishmaniasis. The second phase of our investigation was a population study that included eight rural communities in the area of Somoto, Nicaragua. Through random sampling, filter-paper blood samples were collected from 2,434 people (1,335 men and 1,099 women) from the communities of Aguas Calientes, El Brocal, La Manzana, Las Playas, Los Canales, Santa Isabel, Santa Rosa, and Santa Teresa. Studied by ELISA and by indirect immunofluorescence (IIF), the samples included 260 found seropositive by ELISA (10.7%), of which 207 were positive according to IIF (8.5%). With both techniques, the majority of seropositives were among women, but the difference between men and women was not statistically significant. There was a high level of agreement between the results obtained with the two techniques. There was an upward trend with age, with 5.4% of those found seropositive by ELISA being persons 10 years of age or younger and 42.7% of those found seropositive being older than 50. The vast majority of the individuals analyzed were asymptomatic.


2019 vs. 2016 ESC/EAS statin guidelines for primary prevention of atherosclerotic cardiovascular disease.
The 2019 vs. 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) dyslipidaemia guidelines contains new recommendations for primary prevention with statins; however, the potential impact of these changes is unclear. We compared the 2019 and 2016 guidelines regarding statin eligibility and potential impact on prevention of atherosclerotic cardiovascular disease (ASCVD) in the general population. We examined 45 750 individuals aged 40-75 from the Copenhagen General Population Study, all free of ASCVD and statin use at baseline. During the 9.2-year follow-up, 3337 experienced ASCVD (myocardial infarction, stroke, and cardiovascular death). For Class I/A recommendations, 32.3% (95% confidence interval: 31.8-32.7) and 15.4% (15.1-15.7) of individuals were statin eligible according to the 2019 and 2016 guidelines. The increased statin eligibility by the 2019 guidelines was explained by lower low-density lipoprotein cholesterol (LDL-C) thresholds alone (explaining 33.2%), older age range alone (49.4%), older age range in combination with lower LDL-C thresholds (14.7%), and updated SCORE risk algorithm (2.8%). If fully implemented, the estimated percentage of ASCVD events that can be prevented by using high-intensity statins for 10 years were 25% and 11% with the 2019 and 2016 guidelines. Mainly because of older age range in the 2019 guidelines, the corresponding estimated numbers needed to treat (NNT) to prevent one ASCVD event were 19 and 20. Due to lower LDL-C threshold and older age range, the 2019 vs. 2016 ESC/EAS guidelines doubles the number of individuals eligible for primary prevention with statins. This considerably improves the potential for ASCVD prevention in the general population, with similar NNT to prevent one event.


Performance comparison of the Maxim and Sedia Limiting Antigen Avidity assays for HIV incidence surveillance.
Two manufacturers, Maxim Biomedical and Sedia Biosciences Corporation, supply CDC-approved versions of the HIV-1 Limiting Antigen Avidity EIA (LAg) for detecting 'recent' HIV infection in cross-sectional incidence estimation. This study assesses and compares the performance of the two assays for incidence surveillance. We ran both assays on a panel of 2,500 well-characterized HIV-1-infected specimens. We analysed concordance of assay results, assessed reproducibility using repeat testing and estimated mean durations of recent infection (MDRIs) and false-recent rates (FRRs) for a range of normalized optical density (ODn) thresholds, alone and in combination with viral load thresholds. We defined three hypothetical surveillance scenarios, similar to the Kenyan and South African epidemics, and a concentrated epidemic. These scenarios allowed us to evaluate the precision of incidence estimates obtained by means of various recent infection testing algorithms (RITAs) based on each of the two assays. The Maxim assay produced lower ODn values than the Sedia assay on average, largely as a result of higher calibrator readings (mean OD of 0.749 vs. 0.643), with correlation of normalized readings lower (R2 = 0.908 vs. R2 = 0.938). Reproducibility on blinded control specimens was slightly better for Maxim. The MDRI of a Maxim-based algorithm at the 'standard' threshold (ODn ≤1.5 & VL >1,000) was 201 days (95% CI: 180,223) and for Sedia 171 (152,191). The difference Differences in MDRI were estimated at 32.7 (22.9,42.8) and 30.9 days (21.7,40.7) for the two algorithms, respectively. Commensurately, the Maxim algorithm had a higher FRR in treatment-naive subjects (1.7% vs. 1.1%). The two assays produced similar precision of incidence estimates in the three surveillance scenarios. Differences between the assays can be primarily attributed to the calibrators supplied by the manufacturers. Performance for surveillance was extremely similar, although different thresholds were optimal (i.e. produced the lowest variance of incidence estimates) and at any given ODn threshold, different estimates of MDRI and FRR were obtained. The two assays cannot be treated as interchangeable: assay and algorithm-specific performance characteristic estimates must be used for survey planning and incidence estimation.


An Accumulating Neural Signal Underlying Binocular Rivalry Dynamics.
During binocular rivalry, conflicting images are presented one to each eye and perception alternates stochastically between them. Despite stable percepts between alternations, modeling suggests that neural signals representing the two images change gradually, and that the duration of stable percepts are determined by the time required for these signals to reach a threshold that triggers an alternation. However, direct physiological evidence for such signals has been lacking. Here, we identify a neural signal in the human visual cortex that shows these predicted properties. We measured steady-state visual evoked potentials (SSVEPs) in 84 human participants (62 females, 22 males) who were presented with orthogonal gratings, one to each eye, flickering at different frequencies. Participants indicated their percept while EEG data were collected. The time courses of the SSVEP amplitudes at the two frequencies were then compared across different percept durations, within participants. For all durations, the amplitude of signals corresponding to the suppressed stimulus increased and the amplitude corresponding to the dominant stimulus decreased throughout the percept. Critically, longer percepts were characterized by more gradual increases in the suppressed signal and more gradual decreases of the dominant signal. Changes in signals were similar and rapid at the end of all percepts, presumably reflecting perceptual transitions. These features of the SSVEP time courses are well predicted by a model in which perceptual transitions are produced by the accumulation of noisy signals. Identification of this signal underlying binocular rivalry should allow strong tests of neural models of rivalry, bistable perception, and neural suppression.SIGNIFICANCE STATEMENT During binocular rivalry, two conflicting images are presented to the two eyes and perception alternates between them, with switches occurring at seemingly random times. Rivalry is an important and longstanding model system in neuroscience, used for understanding neural suppression, intrinsic neural dynamics, and even the neural correlates of consciousness. All models of rivalry propose that it depends on gradually changing neural activity that on reaching some threshold triggers the perceptual switches. This manuscript reports the first physiological measurement of neural signals with that set of properties in human participants. The signals, measured with EEG in human observers, closely match the predictions of recent models of rivalry, and should pave the way for much future work.


Evaluation of 4D vascular flow and tissue perfusion in cerebral arteriovenous malformations: influence of Spetzler-Martin grade, clinical presentation, and AVM risk factors.
The role of intracranial hemodynamics in the pathophysiology and risk stratification of brain AVMs remains poorly understood. The purpose of this study was to assess the influence of Spetzler-Martin grade, clinical history, and risk factors on vascular flow and tissue perfusion in cerebral AVMs. 4D flow and perfusion MR imaging was performed in 17 patients with AVMs. Peak velocity and blood flow were quantified in AVM feeding and contralateral arteries, draining veins, and the straight sinus. Regional perfusion ratios (CBF, CBV, and MTT) were calculated between affected and nonaffected hemispheres. Regarding flow parameters, high-grade AVMs (Spetzler-Martin grade of >2) demonstrated significantly increased peak velocity and blood flow in the major feeding arteries (P < .001 and P = .004) and straight sinus (P = .003 and P = .012) and increased venous draining flow (P = .001). The Spetzler-Martin grade significantly correlated with cumulative feeding artery flow (r = 0.85, P < .001) and draining vein flow (r = 0.80, P < .001). Regarding perfusion parameters, perinidal CBF and CBV ratios were significantly lower (P < .001) compared with the remote ratios and correlated negatively with cumulative feeding artery flow (r = -0.60, P = .014 and r = -0.55, P = .026) and draining vein flow (r = -0.60, P = .013 and r = -0.56, P = .025). Multiple regression analysis revealed no significant association of AVM flow or perfusion parameters with clinical presentation (rupture and seizure history) and AVM risk factors. Macrovascular flow was significantly associated with increasing Spetzler-Martin grade and correlated with perinidal microvascular perfusion in cerebral AVMs. Future longitudinal studies are needed to evaluate the potential of comprehensive cerebral flow and perfusion MR imaging for AVM risk stratification.


A novel nematic-like mesophase induced in dimers, trimers and tetramers doped with a high helical twisting power additive.
From the observation of a previously undiscovered nematic-like mesophase (NX) by Archbold et al., we report on several new binary liquid-crystalline mixtures between the high helical twisting power dopant RM1041 and a selection of dimers with varying average bend angles and conformational landscapes. We also report on mixtures between RM1041 and oligomeric LC materials. We find that dimers and oligomers exhibit not only chiral nematic and twist-bend modulated phases, but also the same NX phase reported by Archbold, indicating that this state of matter (the structure of which is yet to be definitively characterised) is exhibited by a wide range of materials. Mixtures of the dimer CB9CB with a selection of different chiral dopants suggest that it is the helical twisting power of the chiral additive that is responsible incidence of the NX phase.


Using economic evidence to support decision making: a case study of assertive community treatment within the UK National Service Framework for Mental Health.
This study illustrates a process of accessing and utilising clinical and economic evidence in health care decision making. The scenario examined was that of a UK Health Authority evaluating evidence prior to the introduction of assertive community treatment (ACT), as part of guidance from the UK National Service Framework for Mental Health. The consistency between clinical and cost evidence from a number of sources (Cochrane Database of Systematic Reviews (CDSR), Database of Reviews of Effectiveness (DARE), HTA database, NHS Economic Evaluation database (NHS EED)) was also addressed, as was the usefulness of structured abstracts on NHS EED. The findings showed that within specified caveats ACT tends to be more effective and also less costly than alternative interventions; there is general agreement between sources principally reporting effectiveness and economic evaluations; and NHS EED abstracts are useful in the decision making process where information gaps exist. In terms of health care policy in the health authority examined, two ACT teams were subsequently introduced in the city of Leicester. Although systematic reviews and appraisals of evidence are arguably the gold standard in health care decision making, the study illustrates how the use of databases of structured abstracts can assist in making optimal choices in real life decision making scenarios.


Successful repair of esophageal injury using an elastin based biomaterial patch.
An esophageal injury with significant tissue loss is very difficult to repair. We conducted an in vivo study to test our elastin based acellular biomaterial patch to repair such defect. The patch was made from porcine aorta, by decellularization and sterilization. Collagen fibers were preserved to retain mechanical strength and enhance cellular in-growth. Ten domestic pigs underwent right thoracotomy. A 2 cm circular defect was made on the distal esophagus, excising half its circumference, and was repaired using the biomaterial patch and sutures. Soon after the procedure, the animals resumed oral feeding. They were followed for clinical status, weight gain, barium studies, and endoscopic studies, and were killed after 6 weeks to 4 months. All ten animals survived long term, with a procedure success rate of 100% (10 of 10). With the exception of one pneumothorax, no complications occurred, and all animals resumed oral feeding and gained weight. Endoscopic studies showed mucosal coverage by 6 weeks, with minimal stricture at the repair site. Excised specimens showed complete mucosal coverage with regeneration of all three layers. Our biomaterial patch can be used safely and reliably for repair of esophageal injury with significant tissue loss when repaired immediately as in our experiment.


Insulin gel as an alternate to parenteral insulin: formulation, preclinical, and clinical studies.
The objective of the present study was to formulate insulin gel for intranasal administration and to evaluate with respect to in vitro release studies and hypoglycemic activity in animal model and healthy human volunteers. The insulin gel was formulated using the combination of carbopol and hydroxypropyl methylcellulose as gelling agent. The in vivo efficacy of insulin gel administered intranasally was assessed by measuring the blood glucose levels and serum insulin levels at specified time intervals in rats and humans. The use of bioadhesive nasal gel containing insulin not only promoted the prolonged contact between the drug and the absorptive sites in the nasal cavity but also facilitated direct absorption of medicament through the nasal mucosa. Absorption of the drug through the nasal mucosa was high in the first 0.5 to 1.5 hours of the study with a sharp decline in blood sugar and rise in insulin values corresponding to that decline in blood sugar. This study further demonstrates that administration of insulin intranasally in gel form is a pleasant and painless alternative to injectable insulin.


The efficacy of problem-solving treatments after deliberate self-harm: meta-analysis of randomized controlled trials with respect to depression, hopelessness and improvement in problems.
Brief problem-solving therapy is regarded as a pragmatic treatment for deliberate self-harm (DSH) patients. A recent meta-analysis of randomized controlled trials (RCTs) evaluating this approach indicated a trend towards reduced repetition of DSH but the pooled odds ratio was not statistically significant. We have now examined other important outcomes using this procedure, namely depression, hopelessness and improvement in problems. Six trials in which problem-solving therapy was compared with control treatment were identified from an extensive literature review of RCTs of treatments for DSH patients. Data concerning depression, hopelessness and improvement in problems were extracted. Where relevant statistical data (e.g. standard deviations) were missing these were imputed using various statistical methods. Results were pooled using meta-analytical procedures. At follow-up, patients who were offered problem-solving therapy had significantly greater improvement in scores for depression (standardized mean difference = -0.36; 95% CI -0.61 to -0.11) and hopelessness (weighted mean difference =-3.2; 95% CI -4.0 to -2.41), and significantly more reported improvement in their problems (odds ratio = 2.31; 95% CI 1.29 to 4.13), than patients who were in the control treatment groups. Problem-solving therapy for DSH patients appears to produce better results than control treatment with regard to improvement in depression, hopelessness and problems. It is desirable that this finding is confirmed in a large trial, which will also allow adequate testing of the impact of this treatment on repetition of DSH.


Cerebral microcirculation and oxygen tension in the human secondary cortex.
The three-dimensional spatial arrangement of the cortical microcirculatory system is critical for understanding oxygen exchange between blood vessels and brain cells. A three-dimensional computer model of a 3 × 3 × 3 mm(3) subsection of the human secondary cortex was constructed to quantify oxygen advection in the microcirculation, tissue oxygen perfusion, and consumption in the human cortex. This computer model accounts for all arterial, capillary and venous blood vessels of the cerebral microvascular bed as well as brain tissue occupying the extravascular space. Microvessels were assembled with optimization algorithms emulating angiogenic growth; a realistic capillary bed was built with space filling procedures. The extravascular tissue was modeled as a porous medium supplied with oxygen by advection-diffusion to match normal metabolic oxygen demand. The resulting synthetic computer generated network matches prior measured morphometrics and fractal patterns of the cortical microvasculature. This morphologically accurate, physiologically consistent, multi-scale computer network of the cerebral microcirculation predicts the oxygen exchange of cortical blood vessels with the surrounding gray matter. Oxygen tension subject to blood pressure and flow conditions were computed and validated for the blood as well as brain tissue. Oxygen gradients along arterioles, capillaries and veins agreed with in vivo trends observed recently in imaging studies within experimental tolerances and uncertainty.


PICK1 interacts with alpha7 neuronal nicotinic acetylcholine receptors and controls their clustering.
Central to synaptic function are protein scaffolds associated with neurotransmitter receptors. Alpha7 neuronal nicotinic acetylcholine receptors (nAChRs) modulate network activity, neuronal survival and cognitive processes in the CNS, but protein scaffolds that interact with these receptors are unknown. Here we show that the PDZ-domain containing protein PICK1 binds to alpha7 nAChRs and plays a role in their clustering. PICK1 interacted with the alpha7 cytoplasmic loop in yeast in a PDZ-dependent way, and the interaction was confirmed in recombinant pull-down experiments and by co-precipitation of native proteins. Some alpha7 and PICK1 clusters were adjacent at the surface of SH-SY5Y cells and GABAergic interneurons in hippocampal cultures. Expression of PICK1 caused decreased alpha7 clustering on the surface of the interneurons in a PDZ-dependent way. These data show that PICK1 negatively regulates surface clustering of alpha7 nAChRs on hippocampal interneurons, which may be important in inhibitory functions of alpha7 in the hippocampus.


A Novel GLP1 Receptor Interacting Protein ATP6ap2 Regulates Insulin Secretion in Pancreatic Beta Cells.
GLP1 activates its receptor, GLP1R, to enhance insulin secretion. The activation and transduction of GLP1R requires complex interactions with a host of accessory proteins, most of which remain largely unknown. In this study, we used membrane-based split ubiquitin yeast two-hybrid assays to identify novel GLP1R interactors in both mouse and human islets. Among these, ATP6ap2 (ATPase H(+)-transporting lysosomal accessory protein 2) was identified in both mouse and human islet screens. ATP6ap2 was shown to be abundant in islets including both alpha and beta cells. When GLP1R and ATP6ap2 were co-expressed in beta cells, GLP1R was shown to directly interact with ATP6ap2, as assessed by co-immunoprecipitation. In INS-1 cells, overexpression of ATP6ap2 did not affect insulin secretion; however, siRNA knockdown decreased both glucose-stimulated and GLP1-induced insulin secretion. Decreases in GLP1-induced insulin secretion were accompanied by attenuated GLP1 stimulated cAMP accumulation. Because ATP6ap2 is a subunit required for V-ATPase assembly of insulin granules, it has been reported to be involved in granule acidification. In accordance with this, we observed impaired insulin granule acidification upon ATP6ap2 knockdown but paradoxically increased proinsulin secretion. Importantly, as a GLP1R interactor, ATP6ap2 was required for GLP1-induced Ca(2+) influx, in part explaining decreased insulin secretion in ATP6ap2 knockdown cells. Taken together, our findings identify a group of proteins that interact with the GLP1R. We further show that one interactor, ATP6ap2, plays a novel dual role in beta cells, modulating both GLP1R signaling and insulin processing to affect insulin secretion.


Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae.
Vps30p/Apg6p is required for both autophagy and sorting of carboxypeptidase Y (CPY). Although Vps30p is known to interact with Apg14p, its precise role remains unclear. We found that two proteins copurify with Vps30p. They were identified by mass spectrometry to be Vps38p and Vps34p, a phosphatidylinositol (PtdIns) 3-kinase. Vps34p, Vps38p, Apg14p, and Vps15p, an activator of Vps34p, were coimmunoprecipitated with Vps30p. These results indicate that Vps30p functions as a subunit of a Vps34 PtdIns 3-kinase complex(es). Phenotypic analyses indicated that Apg14p and Vps38p are each required for autophagy and CPY sorting, respectively, whereas Vps30p, Vps34p, and Vps15p are required for both processes. Coimmunoprecipitation using anti-Apg14p and anti-Vps38p antibodies and pull-down experiments showed that two distinct Vps34 PtdIns 3-kinase complexes exist: one, containing Vps15p, Vps30p, and Apg14p, functions in autophagy and the other containing Vps15p, Vps30p, and Vps38p functions in CPY sorting. The vps34 and vps15 mutants displayed additional phenotypes such as defects in transport of proteinase A and proteinase B, implying the existence of another PtdIns 3-kinase complex(es). We propose that multiple Vps34p-Vps15p complexes associated with specific regulatory proteins might fulfill their membrane trafficking events at different sites.


Signaling by lymphocyte function-associated antigen 1 (LFA-1) in B cells: enhanced antigen presentation after stimulation through LFA-1.
To examine the role of lymphocyte function-associated antigen 1 (LFA-1) expression on murine B cells as it pertains to their function in T cell activation, we carried out antigen-presentation assays in tissue culture wells coated with a purified, secreted form of the murine intercellular adhesion molecule 1 (ICAM-1). We observed a significant decrease in the concentration of antigen required to activate a T cell hybridoma and primary T cells in wells coated with ICAM-1. This effect was dependent on the amount of ICAM-1 used to coat the wells and was also observed in wells coated with anti-LFA-1-monoclonal antibodies and was blocked by soluble anti-LFA-1 antibodies. The effect on antigen dose was most pronounced in assays carried out with an ICAM-1-deficient mutant B lymphoma cell line, small resting primary B cells, and unfractionated primary B cells at low concentrations. No decrease in the antigen dose was observed if the B cells were chemically fixed or treated with ricin, or when antigen was presented by a HeLa cell line transfected with murine class II major histocompatibility complex (MHC) genes, indicating that the immobilized ICAM-1 was mediating its effect through B cell LFA-1, and that B cell protein synthesis was required. The enhancing effect was also observed if the B cells were prepulsed with antigen, indicating that improved uptake or processing of antigen, or increased class II MHC expression were unlikely mechanisms.


C-terminal region of plant ferredoxin-like protein is required to enhance resistance to bacterial disease in Arabidopsis thaliana.
Protein phosphorylation is an important biological process associated with elicitor-induced defense responses in plants. In a previous report, we described how plant ferredoxin-like protein (PFLP) in transgenic plants enhances resistance to bacterial pathogens associated with the hypersensitive response (HR). PFLP possesses a putative casein kinase II phosphorylation (CK2P) site at the C-terminal in which phosphorylation occurs rapidly during defense response. However, the contribution of this site to the enhancement of disease resistance and the intensity of HR has not been clearly demonstrated. In this study, we generated two versions of truncated PFLP, PEC (extant CK2P site) and PDC (deleted CK2P site), and assessed their ability to trigger HR through harpin (HrpZ) derived from Pseudomonas syringae as well as their resistance to Ralstonia solanacearum. In an infiltration assay of HrpZ, PEC intensified harpin-mediated HR; however, PDC negated this effect. Transgenic plants expressing these versions indicate that nonphosphorylated PFLP loses its ability to induce HR or enhance disease resistance against R. solanacearum. Interestingly, the CK2P site of PFLP is required to induce the expression of the NADPH oxidase gene, AtrbohD, which is a reactive oxygen species producing enzyme. This was further confirmed by evaluating the HR on NADPH oxidase in mutants of Arabidopsis. As a result, we have concluded that the CK2P site is required for the phosphorylation of PFLP to enhance disease resistance.


Feasibility and coexistence of large ecological communities.
The role of species interactions in controlling the interplay between the stability of ecosystems and their biodiversity is still not well understood. The ability of ecological communities to recover after small perturbations of the species abundances (local asymptotic stability) has been well studied, whereas the likelihood of a community to persist when the conditions change (structural stability) has received much less attention. Our goal is to understand the effects of diversity, interaction strengths and ecological network structure on the volume of parameter space leading to feasible equilibria. We develop a geometrical framework to study the range of conditions necessary for feasible coexistence. We show that feasibility is determined by few quantities describing the interactions, yielding a nontrivial complexity-feasibility relationship. Analysing more than 100 empirical networks, we show that the range of coexistence conditions in mutualistic systems can be analytically predicted. Finally, we characterize the geometric shape of the feasibility domain, thereby identifying the direction of perturbations that are more likely to cause extinctions.


Persistent Primitive Olfactory Artery as Novel Collateral Channel to the Anterior Cerebral Artery in Moyamoya Disease.
There are a variety of collateral routes to compensate persistent cerebral ischemia in moyamoya disease. However, there is no report presenting the persistent primitive olfactory artery (POA) as a spontaneous collateral route to the anterior cerebral artery (ACA) in moyamoya disease. We precisely examined cerebral angiography in 84 patients with moyamoya disease to identify the collateral channel through the persistent POA. Its anatomy was evaluated on pre- and postoperative angiography. Of 84 patients, four (4.8%) had spontaneous collateral channel through the persistent POA. All of these four hemispheres were categorized into Stage 5. In all four patients, the collateral blood flow arose from the ophthalmic artery and run to the persistent POA through the ethmoidal moyamoya. The persistent POA provided collateral blood flow from the ophthalmic artery to the ACA in all four patients. Superficial temporal artery to middle cerebral artery anastomosis and encephalo-duro-myo-arterio-pericranial synangiosis was performed in three of four patients. After surgery, the collateral channel through the persistent POA completely disappeared or markedly regressed, suggesting a significant improvement of cerebral hemodynamics in the territory of not only the MCA but also the ACA. The persistent POA can potentially provide collateral blood flow to the ACA in about 5% of patients with moyamoya disease, and should be recognized as a novel collateral channel in moyamoya disease. The persistent POA may be useful to evaluate therapeutic effects of surgical revascularization on the ACA territory.


Influences of the neighbourhood food environment on adiposity of low-income preschool-aged children in Los Angeles County: a longitudinal study.
Few studies have examined the association between the food environment and adiposity in early childhood, a critical time for obesity prevention. The objective of this study was to examine the longitudinal association between neighbourhood food environment and adiposity among low-income preschool-aged children in a major metropolitan region in the USA. The study sample was 32 172 low-income preschool-aged children in Los Angeles County who had repeated weight and height measurements collected between ages 2 and 5 years through a federal nutrition assistance programme. We conducted multilevel longitudinal analyses to examine how spatial densities of healthy and unhealthy retail food outlets in the children's neighbourhoods were related to adiposity, as measured by weight-for-height z-score (WHZ), while controlling for neighbourhood-level income and education, family income, maternal education, and child's gender and race/ethnicity. Density of healthy food outlets was associated with mean WHZ at age 3 in a non-linear fashion, with mean WHZ being lowest for those exposed to approximately 0.7 healthy food outlets per square mile and higher for lesser and greater densities. Density of unhealthy food outlets was not associated with child WHZ. We found a non-linear relationship between WHZ and density of healthy food outlets. Research aiming to understand the sociobehavioural mechanisms by which the retail food environment influences early childhood obesity development is complex and must consider contextual settings.


Asymptomatic renal BCG granulomatosis: An unusual complication of intravesical BCG therapy for carcinoma urinary bladder.
Bacillus Calmette-Guerin (BCG) is considered the most effective adjunctive treatment available to treat superficial bladder carcinoma. Although BCG is well tolerated by most patients, it may be associated with adverse effects. One of these is BCG granulomas in the kidney. We herein report a case of a 52-year-old patient who, during a surveillance contrast-enhanced computed tomography (CT) scan, was found to have multiple hypodense lesions in the left kidney. Ultrasound-guided biopsy proved it to be BCG granulomas. After 3 months of anti-tubercular treatment, a repeat CT showed complete resolution of the lesions.


C-Terminal Bioconjugation of Peptides through Photoredox Catalyzed Decarboxylative Alkynylation.
We report the first decarboxylative alkynylation of the C-terminus of peptides starting from free carboxylic acids. The reaction is fast, metal-free, and proceeds cleanly to afford alkynylated peptides with a broad tolerance for the C-terminal amino acid. By the use of hypervalent iodine reagents, the introduction of a broad range of functional groups was successful. C-terminal selectivity was achieved by differentiation of the oxidation potentials of the carboxylic acids based on the use of fine-tuned organic dyes.


Equity in the use of antithrombotic drugs, beta-blockers and statins among Finnish coronary patients.
Earlier studies have mainly reported the use of antithrombotic drugs, beta-blockers and statins among hospital patient populations or MI patients. This study aimed to describe the use of these drugs among middle-aged Finnish coronary patients and to identify patient groups in risk of being prescribed inadequate medication for secondary prevention of coronary heart disease. One-year follow-up survey data from a random sample of a cohort of coronary patients were used along with register data linked to the survey. The response rate was 54% (n = 2650). The main outcome measures were use of antithrombotic drugs, beta-blockers and statins and the data were analysed using logistic regression analysis. Among men and women, respectively, 82% and 81% used beta-blockers, 95% and 89% used antithrombotic drugs, and 62% and 59% used statins. Younger men and men from higher socioeconomic groups were more likely to use statins, even after controlling for disease severity and comorbidity. In women, the age trend was reversed and no socioeconomic differences were found. Drug use increased with increased disease severity, but diabetes had only a slight effect. The use of antithrombotic drugs and beta-blockers among Finnish coronary patients seemed to be rather appropriate and, to some extent, prescription practices of preventive medication varied according to patients' risk of coronary events. However, statin use was remarkably low among men with low socio-economic status, and there is need to improve preventive drug treatment among diabetic coronary patients.


Generalized drift velocity of a cholesteric texture in a temperature gradient.
We propose a general method to calculate the drift velocity of cholesteric textures subjected to a temperature gradient when the backflow effects are negligible. The textures may be Translationally Invariant Configurations (TICs) or localized structures such as cholesteric droplets or cholesteric fingers. For the TICs and for the droplets, the drift is rotational while for the fingers, the drift is translational. We show that for the TICs, the drift is only due to the thermomechanical coupling terms of Leslie (classical term) and of Akopyan and Zel'dovich (which are additional texture-dependent terms). For the localized structures, we show that another mechanism involving the temperature variations of the elastic constants and the existence of a transverse temperature gradient can lead to a drift which adds to the one due the classical thermomechanical effects.


Disappearance of modes in planar Bragg waveguides.
We show how the forbidden bands of a Bragg reflector may shrink to points and how some classes of the guided modes of a planar Bragg waveguide may disappear altogether by shrinking with the forbidden bands. We derive the general conditions to determine the missing modes and explain these conditions with examples. It is possible, for example, to design a Bragg waveguide that rejects all antisymmetric modes and supports only symmetric modes for the TE polarization. We also highlight the effect of Brewster incidence on the interpretation of the missing modes for the TM polarization.


The TBR1-related autistic-spectrum-disorder phenotype and its clinical spectrum.
A diverse range of genetic aberrations can lead to Autistic Spectrum Disorder (ASD) and many of these have been identified via Next Generation Sequencing (NGS) as part of large scale consortium studies. ASD is a phenotypically variable disorder and detailed clinical descriptions are essential to appreciate genotype-phenotype relationships. In this report, we provide a comprehensive clinical description of a child with ASD in whom a TBR1 variant was identified. We review this case in the context of the current TBR1 literature and highlight the variable spectrum of disease associated with this gene. The phenotypic information outlined within the literature is incomplete, exemplifying the limitations of massively-parallel sequencing studies with regards to clinical annotation. We suggest that future reporting of ASD variants should include standardised phenotypic descriptions. This would develop a more thorough understanding of genotype-phenotype relationship, so allowing us to better counsel and support our patients.


DNA Methylation and Chromatin Remodeling: The Blueprint of Cancer Epigenetics.
Epigenetics deals with the interactions between genes and the immediate cellular environment. These interactions go a long way in shaping up each and every person's individuality. Further, reversibility of epigenetic interactions may offer a dynamic control over the expression of various critical genes. Thus, tweaking the epigenetic machinery may help cause or cure diseases, especially cancer. Therefore, cancer epigenetics, especially at a molecular level, needs to be scrutinised closely, as it could potentially serve as the future pharmaceutical goldmine against neoplastic diseases. However, in view of its rapidly enlarging scope of application, it has become difficult to keep abreast of scientific information coming out of various epigenetic studies directed against cancer. Using this review, we have attempted to shed light on two of the most important mechanisms implicated in cancer, that is, DNA (deoxyribonucleic acid) methylation and histone modifications, and their place in cancer pathogenesis. Further, we have attempted to take stock of the new epigenetic drugs that have emerged onto the market as well as those in the pipeline that offer hope in mankind's fight against cancer.


Why do female mice mate with multiple males?
Females often show multi-male mating (MMM), but the adaptive functions are unclear. We tested whether female house mice (Mus musculus musculus) show MMM when they can choose their mates without male coercion. We released 32 females into separate enclosures where they could choose to mate with two neighboring males that were restricted to their own territories. We also tested whether females increase MMM when the available males appeared unable to exclude intruders from their territories. To manipulate territorial intrusion, we introduced scent-marked tiles from the neighboring males into males' territories, or we rearranged tiles within males' own territories as a control. Each female was tested in treatment and control conditions and we conducted paternity analyses on the 57 litters produced. We found that 46 % of litters were multiply sired, indicating that multiple paternity is common when females can choose their mates. Intrusion did not increase multiple paternity, though multiple paternity was significantly greater in the first trial when the males were virgins compared to the second trial. Since virgin male mice are highly infanticidal, this finding is consistent with the infanticide avoidance hypothesis. We also found that multiple paternity was higher when competing males showed small differences in their amount of scent marking, suggesting that females reduce MMM when they can detect differences in males' quality. Finally, multiple paternity was associated with increased litter size but only in the intrusion treatment, which suggests that the effect of multiple paternity on offspring number is dependent on male-male interactions.


Omission of expected reward agitates Atlantic salmon (Salmo salar).
The evolutionary background for cognition and awareness is currently under ardent scrutiny. Poikilothermic vertebrates such as teleost fishes are capable of classical conditioning and have long-term memories, but it remains unknown to what degree such capabilities are associated with affective states. Here, we investigate whether the concept of frustration may apply to Atlantic salmon. In mammals, this paradigm comprises the omission of an expected reward (OER), which elicits behavioural and physiological coping responses (e.g. aggression and stress reactions). Six groups with 200 fish in each were conditioned to associate a flashing light (CS) with feeding. Conditioning over 22 days led to a change from aversion to attraction to the CS. Subsequently, 3 groups served as control, and 3 groups were subjected to an OER paradigm for 9 days, in which the expected food reward was delayed for 30 min during two out of three daily meals. Compared to controls, OER groups displayed higher levels of aggression and more heterogeneous growth rates, indicating a more pronounced social hierarchy. Cortisol levels did, however, not differ between treatments and both groups responded similarly to acute stress. These results indicate that teleost fishes, like mammals, respond aggressively to OER. The capacity to respond behaviourally to frustrating conditions thus likely reflects an adaptive response to environmental unpredictability, which has been conserved throughout vertebrate evolution.


Imported zika virus infection from the cook islands into australia, 2014.
A female resident of Townsville, Queensland, Australia has been diagnosed with Zika virus infection following a recent trip to the Cook Islands. An initial serum sample collected in March, 2014 was positive by two separate Zika virus TaqMan real-time RT-PCRs and a pan-Flavivirus RT-PCR. Nucleotide sequencing and phylogenetics of the complete Cook Islands Zika virus envelope gene revealed 99.1% homology with a previous Cambodia 2010 sequence within the Asian lineage. In addition, IgG and IgM antibody seroconversions were detected between paired acute and convalescent phase sera using recombinant Zika virus serology assays. This is the first known imported case of Zika virus infection into northern Queensland where the potential mosquito vector Aedes aegypti is present and only the second such reported case diagnosed within Australia.


Severe falciparum malaria complicated by prolonged haemolysis and rhinomaxillary mucormycosis after parasite clearance: a case report.
Severe falciparum malaria may be complicated by prolonged haemolysis and recurrent fever after parasite clearance. However, their respective etiologies are unclear and challenging to diagnose. We report the first case of severe falciparum malaria followed by prolonged haemolytic anaemia and rhinomaxillary mucormycosis in a previously healthy adult male. A 30-year old Bangladeshi man was admitted with severe falciparum malaria complicated by hyperlactataemia and haemoglobinuria. Prior to admission he was treated with intravenous quinine and upon admission received intravenous artesunate and empiric ceftriaxone. Thirty hours later the peripheral parasitaemia cleared with resolution of fever and haemoglobinuria. Despite parasite clearance, on day 3 the patient developed recurrent fever and acute haemolytic anaemia requiring seven blood transfusions over six days with no improvement of his haemoglobin or haemoglobinuria. On day 10, he was treated with high-dose dexamethasone and meropenem with discontinuation of the ceftriaxone. Two days later the haemoglobinuria resolved. Ceftriaxone-induced haemolysis was the suspected final diagnosis. On day 16, the patient had progressively worsening right-sided facial pain and swelling; a necrotic ulceration of the hard palate was observed. Rhinomaxillary mucormycosis was diagnosed supported by microscopy findings. The patient initially responded to treatment with urgent surgical debridement, itraconazole, followed by two weeks of amphotericin B deoxycholate, however was subsequently lost to follow up. This case highlights the range of potential alternative aetiologies of acute, prolonged haemolysis and recurrent fever following parasite clearance in severe falciparum malaria. It emphasizes the importance of a high degree of suspicion for alternative causes of haemolysis in order to avoid unnecessary treatments, including blood transfusion and steroids. It is critical to consider and identify common invasive bacterial and rare opportunistic co-infections as a cause of fever in severe malaria patients remaining febrile after parasite clearance to promote antimicrobial stewardship and prompt emergency care.


Differential transcriptional response to nonassociative and associative components of classical fear conditioning in the amygdala and hippocampus.
Classical fear conditioning requires the recognition of conditioned stimuli (CS) and the association of the CS with an aversive stimulus. We used Affymetrix oligonucleotide microarrays to characterize changes in gene expression compared to naive mice in both the amygdala and the hippocampus 30 min after classical fear conditioning and 30 min after exposure to the CS in the absence of an aversive stimulus. We found that in the hippocampus, levels of gene regulation induced by classical fear conditioning were not significantly greater than those induced by CS alone, whereas in the amygdala, classical fear conditioning did induce significantly greater levels of gene regulation compared to the CS. Computational studies suggest that transcriptional changes in the hippocampus and amygdala are mediated by large and overlapping but distinct combinations of molecular events. Our results demonstrate that an increase in gene regulation in the amygdala was partially correlated to associative learning and partially correlated to nonassociative components of the task, while gene regulation in the hippocampus was correlated to nonassociative components of classical fear conditioning, including configural learning.


Porous tantalum coatings prepared by vacuum plasma spraying enhance bmscs osteogenic differentiation and bone regeneration in vitro and in vivo.
Tantalum, as a potential metallic implant biomaterial, is attracting more and more attention because of its excellent anticorrosion and biocompatibility. However, its significantly high elastic modulus and large mechanical incompatibility with bone tissue make it unsuitable for load-bearing implants. In this study, porous tantalum coatings were first successfully fabricated on titanium substrates by vacuum plasma spraying (VPS), which would exert the excellent biocompatibility of tantalum and alleviate the elastic modulus of tantalum for bone tissue. We evaluated cytocompatibility and osteogenesis activity of the porous tantalum coatings using human bone marrow stromal cells (hBMSCs) and its ability to repair rabbit femur bone defects. The morphology and actin cytoskeletons of hBMSCs were observed via electron microscopy and confocal, and the cell viability, proliferation and osteogenic differentiation potential of hBMSCs were examined quantitatively by PrestoBlue assay, Ki67 immunofluorescence assay, real-time PCR technology and ALP staining. For in vivo detection, the repaired femur were evaluated by histomorphology and double fluorescence labeling 3 months postoperation. Porous tantalum coating surfaces promoted hBMSCs adhesion, proliferation, osteogenesis activity and had better osseointegration and faster new bone formation rate than titanium coating control. Our observation suggested that the porous tantalum coatings had good biocompatibility and could enhance osseoinductivity in vitro and promote new bone formation in vivo. The porous tantalum coatings prepared by VPS is a promising strategy for bone regeneration.


Individuals at high risk for type 2 diabetes invited to a lifestyle program: characteristics of participants versus non-participants (the HUNT Study) and 24-month follow-up of participants (the VEND-RISK Study).
Prevention of type 2 diabetes mellitus is possible through lifestyle programs, but the effect depends on the program's content, resources, and setting. Lifestyle programs are often confronted with high rates of non-participation and attrition. This study invited individuals at high risk for type 2 diabetes to a lifestyle program in the Norwegian primary healthcare setting. The aims were to investigate possible differences in characteristics between participants and non-participants and to study the effect of the lifestyle program at 24-month follow-up for participants. Individuals identified at high risk for type 2 diabetes during the third survey of the Nord-Trøndelag Health Study (HUNT3) from two municipalities (n=332) were invited to a lifestyle program (the VEND-RISK Study). A cross-sectional design was used to explore if the participants' characteristics differed from non-participants. A non-randomized, single-arm, pre-post examination was used to examine the effect of the lifestyle program on participants' characteristics at 24-month follow-up. Of all individuals at high risk for type 2 diabetes invited to the lifestyle program, 86% (287/332) declined to participate. Non-participating women had fewer years of education (p<0.001), compared with participating women. For men, no differences were seen between non-participants and participants. Among all participants (n=45) at 24-month follow-up, none had developed type 2 diabetes, and HbA1c (p<0.001) had decreased significantly. There was a small reduction in mean body mass index from baseline to 24 months that was not statistically significant. For women, waist circumference (-4.0 cm, p<0.001) decreased significantly. Future research regarding individuals at high risk for type 2 diabetes in the primary healthcare lifestyle program should focus on how to promote recruitment of women with low education. Participants attending this study's lifestyle program improved their cardiometabolic markers. NCT01135901; Results.


Refined phenotyping identifies links between preeclampsia and related diseases in a Norwegian preeclampsia family cohort.
Preeclampsia is a complex genetic disease of pregnancy with a heterogenous presentation, unknown cause and potential severe outcomes for both mother and child. Preeclamptic women have increased risk for atherothrombotic cardiovascular disease. We aimed to identify heritabilities and phenotypic correlations of preeclampsia and related conditions in the Norwegian Preeclampsia Family Biobank. By applying a variance components model, a total of 493 individuals (from 138 families with increased occurrence of preeclampsia) were classified according to 30 disease-related phenotypes. Of parous women, 75.7% (263/338) had experienced preeclampsia and 35.7% of women with and 22.4% without preeclampsia delivered children small for gestational age (SGA). We identified 11 phenotypes as heritable. The increased occurrence of preeclampsia was reflected by the presence [heritability (H2r) = 0.60)] and severity (H2r = 0.15) of preeclampsia and being born in a preeclamptic pregnancy (H2r = 0.25). Other heritable phenotypes identified included SGA (H2r = 0.40), chronic hypertension (H2r = 0.57), severity of atherothrombotic cardiovascular disease (H2r = 0.31), BMI (H2r = 0.60) and pulmonary disease (H2r = 0.91). The heritable phenotype preeclampsia overlapped with SGA (P = 0.03), whereas pulmonary disease was phenotypically correlated with atherothrombotic cardiovascular disease (P < 0.01), SGA (P = 0.02) and BMI (P = 0.02). This is the first study identifying the H2r of a range of health-related conditions in preeclamptic families. Our study demonstrates how refinement of phenotypes leads to better H2r estimation and the identification of a biological relationship between preeclampsia and related traits.


No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians.
Several studies have identified evidence for linkage between type 2 diabetes and the regions on chromosomes 12 and 20 containing the maturity-onset diabetes of the young (MODY) genes, hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-4alpha. Two studies examining the HNF-1alpha region have demonstrated evidence for linkage at genome-wide levels of significance, whereas four studies examining the HNF-4alpha locus have resulted in evidence for linkage at more suggestive levels of significance. The demonstration of linkage to these regions in additional patient series will strengthen the evidence that susceptibility alleles exist at these loci. We therefore assessed the evidence for linkage to these regions using a large cohort of United Kingdom Caucasian type 2 diabetes-affected sibling pairs. A maximum total of 315 affected full sibling pairs were typed for microsatellite markers across the MODY regions and, in a subset of families, for markers spanning the whole of chromosome 20. Evidence for linkage was assessed using a multipoint, mode of inheritance-free method. Linkage analysis did not reveal any significant evidence for excess allele sharing at any of the regions studied. Loci contributing sibling recurrence risks, relative to the general population risk, of 1.75 and 1.25 could be excluded for the HNF-1alpha and HNF-4alpha regions, respectively. We have not confirmed in United Kingdom Caucasians the evidence for linkage previously reported on 12q and 20q. Our results highlight further the problems of replicating previous positive linkage results across different ethnic groups.


Simulation past, present and future-a decade of progress in simulation-based education in the UK.
This review will present developments in simulation-based education (SBE) over the past decade with a focus on activity in the UK's National Health Service and the role of the national society (the Association for Simulation Practice in Healthcare). The article covers the evolution of strategic changes for the use of SBE in the UK and the operational challenges faced by clinicians and other faculty in SBE. The expansion of the evidence base to support SBE in healthcare both in technical skills and, more broadly, in interprofessional team training is explored. Finally, the wider role of simulation in patient safety and healthcare systems, including testing pathways and the development of cognitive aids and involvement of patients in SBE is considered.