Phase-mismatched localized fields in A-PPLN waveguide devices.
Highly phase-mismatched nonlinear interactions can generate spatially localized optical fields that can affect the performance of nonlinear optical devices. We present a theoretical description of the generation of such spatially localized optical fields by ultrafast pulses. The effects of temporal walk-off and pump depletion are discussed, along with methods for suppression of the localized field while maintaining the performance of the nonlinear device. The model is validated by the measurement of the spatial profile of the localized field in a quasi-phase-matched (QPM) aperiodically poled lithium niobate (A-PPLN) waveguide. Finally, we fabricate and characterize A-PPLN devices with a 33% duty cycle to reduce the locally generated field by 90%.


Reading fluent speech from talking faces: typical brain networks and individual differences.
Listeners are able to extract important linguistic information by viewing the talker's face-a process known as ''speechreading.'' Previous studies of speechreading present small closed sets of simple words and their results indicate that visual speech processing engages a wide network of brain regions in the temporal, frontal, and parietal lobes that are likely to underlie multiple stages of the receptive language system. The present study further explored this network in a large group of subjects by presenting naturally spoken sentences which tap the richer complexities of visual speech processing. Four different baselines (blank screen, static face, nonlinguistic facial gurning, and auditory speech) enabled us to determine the hierarchy of neural processing involved in speechreading and to test the claim that visual input reliably accesses sound-based representations in the auditory cortex. In contrast to passively viewing a blank screen, the static-face condition evoked activation bilaterally across the border of the fusiform gyrus and cerebellum, and in the medial superior frontal gyrus and left precentral gyrus (p < .05, whole brain corrected). With the static face as baseline, the gurning face evoked bilateral activation in the motion-sensitive region of the occipital cortex, whereas visual speech additionally engaged the middle temporal gyrus, inferior and middle frontal gyri, and the inferior parietal lobe, particularly in the left hemisphere. These latter regions are implicated in lexical stages of spoken language processing. Although auditory speech generated extensive bilateral activation across both superior and middle temporal gyri, the group-averaged pattern of speechreading activation failed to include any auditory regions along the superior temporal gyrus, suggesting that f luent visual speech does not always involve sound-based coding of the visual input. An important finding from the individual subject analyses was that activation in the superior temporal gyrus did reach significance (p < .001, small-volume corrected) for a subset of the group. Moreover, the extent of the left-sided superior temporal gyrus activity was strongly correlated with speechreading performance. Skilled speechreading was also associated with activations and deactivations in other brain regions, suggesting that individual differences ref lect the efficiency of a circuit linking sensory, perceptual, memory, cognitive, and linguistic processes rather than the operation of a single component process.


Glutamate carboxypeptidase activity in human skin biopsies as a pharmacodynamic marker for clinical studies.
Glutamate excitotoxicity is thought to be involved in the pathogenesis of neurodegenerative disease. One potential source of glutamate is N-acetyl-aspartyl-glutamate (NAAG) which is hydrolyzed to glutamate and N-acetyl-aspartate (NAA) in a reaction catalyzed by glutamate carboxypeptidase (GCP). As a result, GCP inhibition is thought to be beneficial for the treatment of neurodegenerative diseases where excess glutamate is presumed pathogenic. Both pharmacological and genetic inhibition of GCP has shown therapeutic utility in preclinical models and this has led to GCP inhibitors being pursued for the treatment of nervous system disorders in human clinical trials. Specifically, GCP inhibitors are currently being developed for peripheral neuropathy and neuropathic pain. The purpose of this study was to develop a pharmacodynamic (PD) marker assay to use in clinical development. The PD marker will determine the effect of GCP inhibitors on GCP enzymatic activity in human skin as measure of inhibition in peripheral nerve and help predict drug doses required to elicit pharmacologic responses. GCP activity was first characterized in both human skin and rat paw pads. GCP activity was then monitored in both rodent paw pads and sciatic nerve from the same animals following peripheral administration of various doses of GCP inhibitor. Significant differences among measurements were determined using two-tailed distribution, equal variance student's t test. We describe for the first time, a direct and quantifiable assay to evaluate GCP enzymatic activity in human skin biopsy samples. In addition, we show that GCP activity in skin is responsive to pharmacological manipulation; GCP activity in rodent paws was inhibited in a dose response manner following peripheral administration of a potent and selective GCP inhibitor. Inhibition of GCP activity in rat paw pads was shown to correlate to inhibition of GCP activity in peripheral nerve. Monitoring GCP activity in human skin after administration of GCP inhibitors could be readily used as PD marker in the clinical development of GCP inhibitors. Enzymatic activity provides a simple and direct measurement of GCP activity from tissue samples easily assessable in human subjects.


Blood pressure monitoring in high-risk pregnancy to improve the detection and monitoring of hypertension (the BUMP 1 and 2 trials): protocol for two linked randomised controlled trials.
Self-monitoring of blood pressure (BP) in pregnancy could improve the detection and management of pregnancy hypertension, while also empowering and engaging women in their own care. Two linked trials aim to evaluate whether BP self-monitoring in pregnancy improves the detection of raised BP during higher risk pregnancies (BUMP 1) and whether self-monitoring reduces systolic BP during hypertensive pregnancy (BUMP 2). Both are multicentre, non-masked, parallel group, randomised controlled trials. Participants will be randomised to self-monitoring with telemonitoring or usual care. BUMP 1 will recruit a minimum of 2262 pregnant women at higher risk of pregnancy hypertension and BUMP 2 will recruit a minimum of 512 pregnant women with either gestational or chronic hypertension. The BUMP 1 primary outcome is the time to the first recording of raised BP by a healthcare professional. The BUMP 2 primary outcome is mean systolic BP between baseline and delivery recorded by healthcare professionals. Other outcomes will include maternal and perinatal outcomes, quality of life and adverse events. An economic evaluation of BP self-monitoring in addition to usual care compared with usual care alone will be assessed across both study populations within trial and with modelling to estimate long-term cost-effectiveness. A linked process evaluation will combine quantitative and qualitative data to examine how BP self-monitoring in pregnancy is implemented and accepted in both daily life and routine clinical practice. The trials have been approved by a Research Ethics Committee (17/WM/0241) and relevant research authorities. They will be published in peer-reviewed journals and presented at national and international conferences. If shown to be effective, BP self-monitoring would be applicable to a large population of pregnant women. NCT03334149.


Family Diabetes Camp: Fostering Resiliency Among Campers and Parents.
Youth with diabetes frequently have limited access to traditional camps because of the need for accessible medical staff. With organized camping becoming more specialized with regard to meeting the needs of youth, there is an increased interest in developing and examining the efficacy of programs that serve individuals in specific illness groups, such as youth with type 1 diabetes. In a collaborative effort between a local university, a diabetes center of a local hospital, and the Lions Club, a diabetes camp was created to assist youth in the management of their diabetes. Data were collected over the 3-day family diabetes camp through three approaches: a pre- and post-program resiliency-based questionnaire, the 14-item Camper Learning Scale, and open-ended questions for parents of children with diabetes who were involved in camp. Wilcoxon t tests were used to analyze any differences between pre- and post-program scores on resiliency. The results indicated a positive increase of parents' perceptions of their child's resiliency (Z = -1.833, P = 0.67). Findings from the Camper Learner Scale indicated that 77.14% of campers felt they "learned a little" or "learned a lot" about crucial youth development outcomes (e.g., independence). Finally, direct content analysis of the qualitative measures indicated several themes among parent respondents, which were generalized into three categories: motivation, community, and challenges. Diabetes camps and family diabetes camps have a great opportunity to address some of the challenges young people face while living with the second most common chronic illness facing youth.


Detection of a charge-separated catalyst precursor state in a linked photosensitizer-catalyst assembly.
We have designed two new supramolecular assemblies based on Co(ii)-templated coordination of Ru(bpy)3(2+) (bpy = 2,2'-bipyridyl) analogues as photosensitizers and electron donors to a cobaloxime macrocycle, which are of interest as proton reduction catalysts. The self-assembled photocatalyst precursors were structurally characterized by Co K-edge X-ray absorption spectroscopy and solution-phase X-ray scattering. Visible light excitation of one of the assemblies has yielded instantaneous electron transfer and charge separation to form a transient Co(i) state which persists for 26 ps. The development of a linked photosensitizer-cobaloxime architecture supporting efficient Co(i) charge transfer is significant since it is mechanistically critical as the first photo-induced electron transfer step for hydrogen production, and has not been detected in previous photosensitizer-cobaloxime linked dyad assemblies. X-band EPR spectroscopy has revealed that the Co(ii) centres of both assemblies are high spin, in contrast to most previously described cobaloximes, and likely plays an important role in facilitating photoinduced charge separation. Based on the results obtained from ultrafast and nanosecond transient absorption optical spectroscopies, we propose that charge recombination occurs through multiple ligand states present within the photosensitizer modules. The studies presented here will enhance our understanding of supramolecular photocatalyst assembly and direct new designs for artificial photosynthesis.


Head injuries in children.
Two-hundred children with head injury admitted consecutively to paediatric wards in the two main hospitals in Newcastle upon Tyne have been studied. Eight children required neurosurgical operation. There were two deaths. Details of the cause and consequences of the accidents have been analysed and an attempt has been made to identify psychological or physical factors that may predispose to injury. There was a slightly higher proportion of children with what are regarded as adverse personality factors among the head injuries than in a control group and there were more left-handed children than would be expected in the general population. The results suggest that the modern "high-rise" bicycle may carry a special risk of head injury.


Seminal plasma proteins inhibit in vitro- and cooling-induced capacitation in boar spermatozoa.
Dilute boar seminal plasma (SP) has been shown to inhibit in vitro capacitation and cooling-induced capacitation-like changes in boar spermatozoa, as assessed by the ability of the spermatozoa to undergo an ionophore-induced acrosome reaction. We hypothesised that the protein component of SP is responsible for this effect. To test this hypothesis, varying concentrations of total SP protein or SP proteins fractionated by heparin binding were assayed for their ability to inhibit in vitro capacitation, as well as cooling- and cryopreservation-induced capacitation-like changes. In vitro capacitation and cooling-induced capacitation-like changes were prevented by 10% whole SP, as well as by total proteins extracted from SP at concentrations greater than 500 microg mL(-1). No amount of SP protein was able to prevent cryopreservation-induced capacitation-like changes. Total SP proteins were fractionated based on their heparin-binding properties and the heparin-binding fraction was shown to possess capacitation inhibitory activity at concentrations as low as 250 microg mL(-1). The proteins in the heparin-binding fraction were subjected to mass spectrometry and identified. The predominant proteins were three members of the spermadhesin families, namely AQN-3, AQN-1 and AWN, and SP protein pB1. We conclude that one or more of these heparin-binding SP proteins is able to inhibit in vitro capacitation and cooling-induced capacitation-like changes, but not cryopreservation-induced capacitation-like changes, in boar spermatozoa.


High-dose glucose-insulin-potassium has hemodynamic benefits and can improve cardiac remodeling in acute myocardial infarction treated with primary percutaneous coronary intervention: From a randomized controlled study.
To evaluate the effects of high-dose glucose-insulin-potassium (GIK) solution on hemodynamics and cardiac remodeling in patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI). We observed the changes in the hemodynamic parameters in 26 patients with AMI. All patients received primary PCI before entering the study. All patients in the study were randomized into the GIK group (n = 14) or the control group (n = 12). Patients in the GIK group received high-dose GIK solution (25% glucose, 80 mmol/L KCl and 50 IU/L insulin; 1.5 ml/kg/h) over 24 h. Patients in the control group received standard therapy. We monitored the hemodynamic parameters at baseline and after 6 h, 12 h, 18 h and 24 h, respectively. Then, we followed-up the cardiac function with echocardiography after 7 days, 1 month and 6 months. The basic clinical data was similar between the groups. Primary PCI was performed successfully in 25 patients. The two groups were indistinguishable in all factors measured. GIK solution did not have a deleterious effect on the hemodynamic parameters. The pulmonary capillary wedge pressure increased during the first 12-h period and then decreased smoothly (F = 3.75, P = 0.02). The trends were similar between the two groups. The system vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI) decreased during the first 12 h in the GIK group but increased in the control group. The GIK solution significantly influenced SVRI (F = 4.71, P = 0.02). GIK solution improved the cardiac function measured by stroke volume (F = 4.11, P = 0.03) and cardiac index (F = 4.40, P = 0.02). In the 6-month follow-up, GIK improved cardiac remodeling (left ventricular diastolic diameter: 49.2 ± 2.89 vs. 53.9 ± 2.48, P < 0.001; left ventricular systolic diameter: 32.9 ± 2.24 vs. 35.9 ± 2.78, P < 0.01). High-dose GIK solution had no adverse effects on the hemodynamics in AMI patients treated with primary PCI. It can improve cardiac function by lowering SVRI. In the 6-month follow-up, it improved cardiac remodeling.


Effect of storage temperature on cultured epidermal cell sheets stored in xenobiotic-free medium.
Cultured epidermal cell sheets (CECS) are used in regenerative medicine in patients with burns, and have potential to treat limbal stem cell deficiency (LSCD), as demonstrated in animal models. Despite widespread use, short-term storage options for CECS are limited. Advantages of storage include: flexibility in scheduling surgery, reserve sheets for repeat operations, more opportunity for quality control, and improved transportation to allow wider distribution. Studies on storage of CECS have thus far focused on cryopreservation, whereas refrigeration is a convenient method commonly used for whole skin graft storage in burns clinics. It has been shown that preservation of viable cells using these methods is variable. This study evaluated the effect of different temperatures spanning 4°C to 37°C, on the cell viability, morphology, proliferation and metabolic status of CECS stored over a two week period in a xenobiotic-free system. Compared to non-stored control, best cell viability was obtained at 24°C (95.2±9.9%); reduced cell viability, at approximately 60%, was demonstrated at several of the temperatures (12°C, 28°C, 32°C and 37°C). Metabolic activity was significantly higher between 24°C and 37°C, where glucose, lactate, lactate/glucose ratios, and oxygen tension indicated increased activation of the glycolytic pathway under aerobic conditions. Preservation of morphology as shown by phase contrast and scanning electron micrographs was best at 12°C and 16°C. PCNA immunocytochemistry indicated that only 12°C and 20°C allowed maintenance of proliferative function at a similar level to non-stored control. In conclusion, results indicate that 12°C and 24°C merit further investigation as the prospective optimum temperature for short-term storage of cultured epidermal cell sheets.


Immunoglobulin expressions are only associated with MCPyV-positive Merkel cell carcinomas but not with MCPyV-negative ones: comparison of prognosis.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer, often associated with Merkel cell polyomavirus (MCPyV). Recently, immunoglobulin (Ig) expression was reported in MCC, thereby suggesting that B cells might be their cellular ancestors. We tested 30 MCCs (20 MCPyV-positive and 10 MCPyV-negative) using immunohistochemistry for the expressions of IgG, IgA, IgM, Igκ, Igλ, terminal desoxynucleotidyl transferase, paired box gene 5 (PAX5), octamer transcription factor-2 (Oct-2), and sex-determining region Y-box 11 (SOX11). We performed in situ hybridization for Igκ-mRNA or Igλ-mRNA and Ig heavy chain (IgH) gene rearrangement (IgH-R) analyses. The expressions of PAX5, TdT, Oct-2, and SOX11 were not significantly different between MCPyV-positive and MCPyV-negative MCCs. At least 1 of IgG, IgA, IgM, or Igκ was expressed in MCPyV-positive (14/20, 70%) and none in MCPyV-negative MCCs (P=0.0003). There was a higher tendency for Igκ-mRNA expression (7/19, using in situ hybridization) and IgH-R (10/20, using polymerase chain reaction) in MCPyV-positive than in MCPyV-negative MCCs (0/10 and 2/10, respectively), thus suggesting a different Ig production pattern and pathogenesis between the 2 types of MCC. Ig expression or IgH-R in MCPyV-positive MCCs might be associated with MCPyV gene integration or expression in cancer cells but do not necessarily suggest a B-cell origin for MCCs. IgH expression or IgH-R nonsignificantly correlated with improved prognosis. However, these might be important factors that influence the survival of neoplastic cells and might allow the development of novel therapies for patients with MCPyV-positive MCCs.


DNA polymerase μ is a global player in the repair of non-homologous end-joining substrates.
The specialized DNA polymerase μ (pol μ) intervenes in the repair mechanism non-homologous end-joining (NHEJ) as an end-processing factor but its role has not been fully elucidated. Pol μ has been shown to participate in DNA synthesis at junctions in vitro, including on unpaired substrates, and to promote annealing. However, the phenotypes observed in vivo poorly recapitulate the functions of pol μ reported in vitro. We analysed the repair of DNA double-strand breaks (DSBs) in a cellular context using improved NHEJ substrates. These substrates do not replicate in mammalian cells, thereby result in clonal repair events, which allows the measure of the efficiency of repair. We validated this paradigm by comparing the repair of NHEJ substrates to the repair reported for chromosome DSBs in mouse cells. Molecular analysis and, in most cases sequencing of more than 1500 repair events on a variety of NHEJ substrates in wild type and pol μ(-/-) mouse embryonic fibroblasts shows that, unexpectedly, the absence of pol μ decreases the efficiency of joining of all types of DSBs, including those that do not undergo end-processing. Importantly, by reducing the efficiency of accurate events, lack of pol μ also affects the overall fidelity of the repair process. We also show that, although pol μ does not help protect DNA ends from resection, the efficiency of repair of resected ends is reduced in the absence of pol μ. Interestingly, the DNA synthesis activity of pol μ, including on non-aligned substrates, appears negligible at least in a cellular context. Our data point to a critical role for pol μ as a global repair player that increases the efficiency and the fidelity of NHEJ.


Intervening with healthcare workers' hand hygiene compliance, knowledge, and perception in a limited-resource hospital in Indonesia: a randomized controlled trial study.
Hand hygiene is recognized as an important measure to prevent healthcare-associated infections. Hand hygiene adherence among healthcare workers is associated with their knowledge and perception. This study aimed to evaluate the effect of three different educational programs on improving hand hygiene compliance, knowledge, and perception among healthcare workers in a tertiary care hospital in Indonesia. The study was performed from May to October 2014 and divided into a pre-intervention, intervention, and post-intervention phase. This cluster randomized controlled trial allocated the implementation of three interventions to the departments, including role model training-pediatrics, active presentation-surgery, a combination of role model training and active presentation-internal medicine, and a control group-obstetrics-gynecology. Both direct observation and knowledge-perception survey of hand hygiene were performed using WHO tools. Hand hygiene compliance was observed during 2,766 hand hygiene opportunities, and knowledge-perception was assessed among 196 participants in the pre-intervention and 88 in the post-intervention period. After intervention, the hand hygiene compliance rate improved significantly in pediatrics (24.1% to 43.7%; P < 0.001), internal medicine (5.2% to 18.5%; P < 0.001), and obstetrics-gynecology (10.1% to 20.5%; P < 0.001). The nurses' incorrect use of hand rub while wearing gloves increased as well (P < 0.001). The average knowledge score improved from 5.6 (SD = 2.1) to 6.2 (SD = 1.9) (P < 0.05). In the perception survey, "strong smell of hand alcohol" as a reason for non-compliance increased significantly in the departments with intervention (10.1% to 22.9%; P = 0.021). The educational programs improved the hand hygiene compliance and knowledge among healthcare workers in two out of three intervention departments in a limited-resource hospital in Indonesia. Role model training had the most impact in this setting. However, adjustments to the strategy are necessary to further improve hand hygiene.


The relationship between oscillatory activity and motor reaction time in the parkinsonian subthalamic nucleus.
Averaging techniques have demonstrated that movement preparatory cues and movement itself are associated with marked reductions in the oscillatory synchrony of local neuronal populations in the area of the human parkinsonian subthalamic nucleus (STN), as indexed by 8-30 Hz local field potential (LFP) activity. In order to examine the detailed nature and strength of the relationship between reductions in oscillatory activity and movement we examined single-trial LFP activity recorded from the STN area of parkinsonian subjects engaged in a choice reaction task. In this task an initial warning cue was either fully predictive or non-predictive of the hand required to make a later motor response. This motor response was elicited by a second go cue to which data were aligned. We observed a significant linear relationship between the onset time of oscillation reduction after go cues and subsequent motor response time across single trials within subjects. Consistent with this observation we also found a positive correlation of power with response time following go cues. In addition, we observed shorter durations of suppression in fully predictive trials where selection of the response could precede go cue presentation. The results are consistent with the hypothesis that reductions in 8-30 Hz population synchrony in the STN area are related to the processing required for motor preparation, particularly response selection.


Mass spectrometry-based identification of MHC-bound peptides for immunopeptidomics.
Peptide antigens bound to molecules encoded by the major histocompatibility complex (MHC) and presented on the cell surface form the targets of T lymphocytes. This critical arm of the adaptive immune system facilitates the eradication of pathogen-infected and cancerous cells, as well as the production of antibodies. Methods to identify these peptide antigens are critical to the development of new vaccines, for which the goal is the generation of effective adaptive immune responses and long-lasting immune memory. Here, we describe a robust protocol for the identification of MHC-bound peptides from cell lines and tissues, using nano-ultra-performance liquid chromatography coupled to high-resolution mass spectrometry (nUPLC-MS/MS) and recent improvements in methods for isolation and characterization of these peptides. The protocol starts with the immunoaffinity capture of naturally processed MHC-peptide complexes. The peptides dissociate from the class I human leukocyte antigens (HLAs) upon acid denaturation. This peptide cargo is then extracted and separated into fractions by HPLC, and the peptides in these fractions are identified using nUPLC-MS/MS. With this protocol, several thousand peptides can be identified from a wide variety of cell types, including cancerous and infected cells and those from tissues, with a turnaround time of 2-3 d.


Multiple forms of the catalytic centre, CuZ, in the enzyme nitrous oxide reductase from Paracoccus pantotrophus.
Nitrous oxide reductase catalyses the reduction of nitrous oxide to dinitrogen at a unique tetranuclear copper site, called Cu(Z), which has a central inorganic sulphide ligand. Limited incubation with oxygen during the preparation of nitrous oxide reductase from Paracoccus pantotrophus results in changed redox properties of the catalytic centre by comparison with anaerobic preparations. While the anaerobically purified enzyme has a catalytic centre which performs a single electron step at a midpoint potential of E(m)=+60 mV versus the standard hydrogen electrode (n=1), the altered centre shows no redox change under similar experimental conditions. Spectroscopic properties of this 'redox fixed' centre are similar to spectra of the reduced 'redox active' form of CuZ, although the positions and intensities of a number of transitions are changed in the optical spectrum. These observations are interpreted in terms of two forms of the catalytic centre, called CuZ and CuZ*. The structural relationship between these forms is unclear. EPR and magnetic circular dichroism spectra suggest that the basic Cu4S structure is common to both. Curiously, steady-state activity of the aerobic enzyme preparation is slightly increased despite the fact the catalytic centre does not undergo detectable redox changes.


Chronic Toxoplasma infection modifies the structure and the risk of host behavior.
The intracellular parasite Toxoplasma has an indirect life cycle, in which felids are the definitive host. It has been suggested that this parasite developed mechanisms for enhancing its transmission rate to felids by inducing behavioral modifications in the intermediate rodent host. For example, Toxoplasma-infected rodents display a reduction in the innate fear of predator odor. However, animals with Toxoplasma infection acquired in the wild are more often caught in traps, suggesting that there are manipulations of intermediate host behavior beyond those that increase predation by felids. We investigated the behavioral modifications of Toxoplasma-infected mice in environments with exposed versus non-exposed areas, and found that chronically infected mice with brain cysts display a plethora of behavioral alterations. Using principal component analysis, we discovered that most of the behavioral differences observed in cyst-containing animals reflected changes in the microstructure of exploratory behavior and risk/unconditioned fear. We next examined whether these behavioral changes were related to the presence and distribution of parasitic cysts in the brain of chronically infected mice. We found no strong cyst tropism for any particular brain area but found that the distribution of Toxoplasma cysts in the brain of infected animals was not random, and that particular combinations of cyst localizations changed risk/unconditioned fear in the host. These results suggest that brain cysts in animals chronically infected with Toxoplasma alter the fine structure of exploratory behavior and risk/unconditioned fear, which may result in greater capture probability of infected rodents. These data also raise the possibility that selective pressures acted on Toxoplasma to broaden its transmission between intermediate predator hosts, in addition to felid definitive hosts.


Tumor Sidedness and Enriched Gene Groups for Efficacy of First-line Cetuximab Treatment in Metastatic Colorectal Cancer.
Molecular differences in tumor locations may contribute to the sidedness-specific response to cetuximab in metastatic colorectal cancer (mCRC). We investigated genes associated with the response to cetuximab treatment depending on tumor sidedness. Our study included 77 patients with mCRC (13/63, right/left) with KRAS exon 2 wild-type tumors from phase II trials of first-line therapy with cetuximab. Expression levels of 2,551 genes were measured in tissue samples by HTG EdgeSeq Oncology Biomarker Panel. Univariate Cox regression analysis using log2 values of counts per million (CPM) was conducted in each sidedness to assess associations with clinical outcomes, and to define the optimal cut-off point for clinically significant genes. In addition, a gene set enrichment analysis (GSEA) was performed to identify significant gene pathways in each sidedness. Sixty-nine patients were assessable for gene expression data. Overexpression of BECN1 [log2(CPM) ≥ 6.8] was associated with favorable survival, regardless of tumor sidedness. High expression of NOTCH1 [log2(CPM) ≥ 7.5] predicted significantly longer progression-free survival (PFS; median 14.7 vs. 11.1 months, HR 0.43, P = 0.01) and overall survival (OS; median 42.8 vs. 26.5 months, HR 0.35, P = 0.01) in left side but not in right side. The GSEA showed that regulation of DNA replication gene set correlated with favorable survival in the left, whereas the subcellular component and leukocyte migration gene sets were associated with good survival in the right. In conclusion, genes contributing to the efficacy of cetuximab treatment may differ according to the sidedness in mCRC. NOTCH1 may potentially discriminate favorable responders to cetuximab in patients with left-sided tumors.


Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline.
To formulate clinical practice guidelines for hormonal replacement in hypopituitarism in adults. The participants include an Endocrine Society-appointed Task Force of six experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology co-sponsored this guideline. The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the Pituitary Society, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Using an evidence-based approach, this guideline addresses important clinical issues regarding the evaluation and management of hypopituitarism in adults, including appropriate biochemical assessments, specific therapeutic decisions to decrease the risk of co-morbidities due to hormonal over-replacement or under-replacement, and managing hypopituitarism during pregnancy, pituitary surgery, and other types of surgeries.


Antisense RNA-mediated inhibition of mouse hepatitis virus replication in L2 cells.
We have successfully used antisense RNA to inhibit replication of the mouse hepatitis virus (MHV) in a cell culture system. MHV is a single-stranded RNA virus of positive polarity. Mouse L2 cells were stably transfected with an antisense construct that targets regions of genes 5 and 6 of the virus. High levels of expression from this construct, which is under control of the human elongation factor 1 alpha promoter, were found. After infection of the antisense cell lines with MHV, replication of the virus was significantly reduced compared with control cells. In a viral plaque assay, smaller plaques were found in the antisense cell lines. In addition, up to a 92% inhibition in the number of viral particles produced in one antisense cell line could be seen. This inhibitory effect decreased at longer (> 16 hour) infection times. It was possible to both increase the amount of inhibition and prolong the inhibitory effect by reducing the multiplicity of infection. Our results suggest that antisense RNA may be an effective tool to slow down progression of MHV infection in mice.


Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors.
The stability of protein-protein interfaces can be essential for protein function. For ionotropic glutamate receptors, a family of ligand-gated ion channels vital for normal function of the central nervous system, such an interface exists between the extracellular ligand binding domains (LBDs). In the full-length protein, the LBDs are arranged as a dimer of dimers. Agonist binding to the LBDs opens the ion channel, and briefly after activation the receptor desensitizes. Several residues at the LBD dimer interface are known to modulate desensitization, and conformational changes around these residues are believed to be involved in the state transition. The general hypothesis is that the interface is disrupted upon desensitization, and structural evidence suggests that the disruption might be substantial. However, when cross-linking the central part of this interface, functional data suggest that the receptor can still undergo desensitization, contradicting the hypothesis of major interface disruption. Here, we illustrate how opening the dimer interface using steered molecular dynamics (SMD) simulations, and analyzing the work values required, provides a quantitative measure for interface stability. For one subtype of glutamate receptors, which is regulated by ion binding to the dimer interface, we show that opening the interface without ions bound requires less work than with ions present, suggesting that ion binding indeed stabilizes the interface. Likewise, for interface mutants with longer-lived active states, the interface is more stable, while the work required to open the interface is reduced for less active mutants. Moreover, a cross-linked mutant can still undergo initial interface opening motions similar to the native receptor and at similar energetic cost. Thus, our results support that interface opening is involved in desensitization. Furthermore, they provide reconciliation of apparently opposing data and demonstrate that SMD simulations can give relevant biological insight into longer time scale processes without the need for expensive calculations.


Screening alpha-glucosidase and alpha-amylase inhibitors from natural compounds by molecular docking in silico.
The alpha-glucosidase inhibitor is a common oral anti-diabetic drug used for controlling carbohydrates normally converted into simple sugars and absorbed by the intestines. However, some adverse clinical effects have been observed. The present study seeks an alternative drug that can regulate the hyperglycemia by down-regulating alpha-glucosidase and alpha-amylase activity by molecular docking approach to screen the hyperglycemia antagonist against alpha-glucosidase and alpha-amylase activities from the 47 natural compounds. The docking data showed that Curcumin, 16-hydroxy-cleroda-3,13-dine-16,15-olide (16-H), Docosanol, Tetracosanol, Antroquinonol, Berberine, Catechin, Quercetin, Actinodaphnine, and Rutin from 47 natural compounds had binding ability towards alpha-amylase and alpha-glucosidase as well. Curcumin had a better biding ability of alpha-amylase than the other natural compounds. Analyzed alpha-glucosidase activity reveals natural compound inhibitors (below 0.5 mM) are Curcumin, Actinodaphnine, 16-H, Quercetin, Berberine, and Catechin when compared to the commercial drug Acarbose (3 mM). A natural compound with alpha-amylase inhibitors (below 0.5 mM) includes Curcumin, Berberine, Docosanol, 16-H, Actinodaphnine/Tetracosanol, Catechin, and Quercetin when compared to Acarbose (1 mM). When taken together, the implication is that molecular docking is a fast and effective way to screen alpha-glucosidase and alpha-amylase inhibitors as lead compounds of natural sources isolated from medicinal plants.


Two-dimensional polymer formation on surfaces: insight into the roles of precursor mobility and reactivity.
We report on a combined scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), and density functional theory (DFT) study on the surface-assisted assembly of the hexaiodo-substituted macrocycle cyclohexa-m-phenylene (CHP) toward covalently bonded polyphenylene networks on Cu(111), Au(111), and Ag(111) surfaces. STM and XPS indicate room temperature dehalogenation of CHP on either surface, leading to surface-stabilized CHP radicals (CHPRs) and coadsorbed iodine. Subsequent covalent intermolecular bond formation between CHPRs is thermally activated and is found to proceed at different temperatures on the three coinage metals. The resulting polyphenylene networks differ significantly in morphology on the three substrates: On Cu, the networks are dominated by "open" branched structures, on the Au surface a mixture of branched and small domains of compact network clusters are observed, and highly ordered and dense polyphenylene networks form on the Ag surface. Ab initio DFT calculations allow one to elucidate the diffusion and coupling mechanisms of CHPRs on the Cu(111) and Ag(111) surfaces. On Cu, the energy barrier for diffusion is significantly higher than the one for covalent intermolecular bond formation, whereas on Ag the reverse relation holds. By using a Monte Carlo simulation, we show that different balances between diffusion and intermolecular coupling determine the observed branched and compact polyphenylene networks on the Cu and Ag surface, respectively, demonstrating that the choice of the substrate plays a crucial role in the formation of two-dimensional polymers.


Acute blood pressure changes are related to chronic effects of resistance exercise in medicated hypertensives elderly women.
A previous study observed that the chronic effects of aerobic training on blood pressure (BP) are related to acute BP responses after a single bout of aerobic exercise. However, whether similar responses are observed with resistance exercise (RE) remains obscure. Thus, this study analysed the relationship between the acute BP responses to a single bout of RE and chronic changes in resting BP after a RE training in medicated hypertensive elderly women. Twenty medicated hypertensive women participated in the study. They underwent an acute RE bout where BP and heart rate (HR) were obtained at rest and for 60 min after the RE. Subsequently, the participants underwent a progressive RE training for 12 weeks at 60-80% of maximal strength test. Resting BP and HR were also obtained after the RE training. The chronic decreases in systolic and diastolic BP were significantly greater in the participants who experienced acutely decreased systolic and diastolic BP, respectively (P<0·05). The changes in systolic BP after acute RE were correlated with the chronic changes in resting systolic BP after RE training (r = 0·47; P = 0·03). Similar correlations between acute and chronic responses were also observed for diastolic BP (r = 0·70; P = 0·01), mean BP (r = 0·58; P = 0·01), HR (r = 0·73; P<0·01) and RPP (r = 0·52; P = 0·01). Similar to previously work involving aerobic exercise, BP responses to a single bout of RE are strongly related to chronic effects of RE training on BP in medicated hypertensive elderly women.


Increased extrafollicular expression of the B-cell stimulatory molecule CD70 in HIV-1-infected individuals.
CD70 molecules expressed by activated T cells provide potent B cell stimulatory signals. We hypothesized that an altered CD70 expression might contribute to B cell abnormalities during HIV-1 infection. CD70 expression and the functional and migratory properties of the CD4CD70 T lymphocytes were analyzed in HIV-1-infected patients and in humanized mice. Correlations were tested between CD70 expression and features of B-cell activation, apoptosis sensitivity and functional exhaustion. CD4CD70 T cells were analyzed in cohorts of CD4 T-cell lymphopenic, viremic or nonlymphopenic, nonviremic HIV-1-infected patients and in noninfected individuals. CD70 upregulation was also followed in HIV-1-infected humanized mice. CD38, CD95, LAIR1 and PD-1 expressions were monitored on B-cell subpopulations, Ki67 was assessed to estimate B-cell proliferation and antibody levels were measured in plasma. Blood CD4CD70 T-cell frequencies increased in response to CD4 T-cell depletion or high viremia levels as a possible consequence of increased activation and proliferation in this subset. CD4CD70 T cells produced T-helper 1-type cytokines and expressed chemokine receptors mobilizing toward sites of inflammation but not to lymphoid follicles. High CD70 expression was observed in HIV-1-infected humanized mice at extrafollicular sites (peritoneum, bone-marrow). CD4CD70 T-cell frequencies correlated with the expression of the activation marker CD38 and the death receptor CD95 on various memory B-cell subsets, with B-cell proliferation and with plasma IgG levels. CD4CD70 T cells may contribute to B cell hyperactivation and accelerated memory B-cell turnover during HIV-1 infection.


Application of the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation assay to a flow injection system for the evaluation of antioxidant activity of some pure compounds and beverages.
The 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS(*)(+)) assay was adapted to a flow injection (FI) system to obtain a sensitive and rapid technique for the monitoring of antioxidant activity of pure compounds and complex matrixes, such as beverages and food extracts. The FI system includes a HPLC pump that flows the mobile phase (a solution of ABTS(*)(+) in ethanol) through a 20 microL loop injector, a single bead string reactor filled with acid-washed silanized beads, a delay coil and a photodiode array UV-visible detector. The technique was very sensitive, with limits of detection and of quantification of 4.14 and 9.29 micromol of Trolox/L, respectively, and demonstrated high repeatability and reproducibility. The proposed technique was then applied to the evaluation of the antioxidant activity of some pure compounds, demonstrating good agreement with published data obtained by the original spectrophotometric ABTS(*)(+) assay. Finally, the total antioxidant activity of 10 beverages was determined by both the proposed and the original method. The values ranged from 0.09 mmol L(-)(1) for cola to 49.24 mmol L(-)(1) for espresso coffee and did not result significantly different from those obtained by the original spectrophotometric ABTS(*)(+) assay (Student's paired t-test: t = 1.4074, p = 0.1929). In conclusion, the proposed FI technique seems suitable for the direct, rapid and reliable monitoring of total antioxidant activity of pure compounds and beverages and, due to the ability to operate in continuous, it allows the analysis of about 30 samples h(-)(1) making the assay particularly suitable for large screening of total antioxidant activity in food samples.


Transcutaneous Carbon Dioxide Improves Contractures After Spinal Cord Injury in Rats.
Joint contractures are a major complication in patients with spinal cord injuries. Positioning, stretching, and physical therapy are advocated to prevent and treat contractures; however, many patients still develop them. Joint motion (exercise) is crucial to correct contractures. Transcutaneous carbon dioxide (CO2) therapy was developed recently, and its effect is similar to that of exercise. This therapy may be an alternative or complementary approach to exercise. Using an established model of spinal cord injury in rats with knee flexion contractures, we sought to clarify whether transcutaneous CO2 altered (1) contracture, as measured by ROM; (2) muscular and articular factors contributing to the loss of ROM; (3) fibrosis and fibrosis-related gene expression in muscle; and (4) the morphology of and fibrosis-related protein expression in the joint capsule. Thirty-six Wistar rats were divided into three equal groups: caged control, those untreated after spinal cord injury, and those treated with CO2 after spinal cord injury. The rats were treated with CO2 from either the first day (prevention) or 15th day (treatment) after spinal cord injury for 2 or 4 weeks. The hindlimbs of rats in the treated group were exposed to CO2 gas for 20 minutes once daily. Knee extension ROM was measured with a goniometer and was measured again after myotomy. We calculated the muscular and articular factors responsible for contractures by subtracting the post-myotomy ROM from that before myotomy. We also quantified histologic muscle fibrosis and evaluated fibrosis-related genes (collagen Type 1, α1 and transforming growth factor beta) in the biceps femoris muscle with real-time polymerase chain reaction. The synovial intima's length was measured, and the distribution of fibrosis-related proteins (Type I collagen and transforming growth factor beta) in the joint capsule was observed with immunohistochemistry. Knee flexion contractures developed in rats after spinal cord injuries at all timepoints. CO2 therapy improved limited-extension ROM in the prevention group at 2 weeks (22° ± 2°) and 4 weeks (29° ± 1°) and in the treatment group at 2 weeks (31° ± 1°) compared with untreated rats after spinal cord injuries (35° ± 2°, mean difference, 13°; 39° ± 1°, mean difference, 9°; and 38° ± 1°, mean difference, 7°, respectively) (95% CI, 10.50-14.86, 8.10-10.19, and 4.73-9.01, respectively; all p < 0.001). Muscular factors decreased in treated rats in the prevention group at 2 weeks (8° ± 2°) and 4 weeks (14°± 1°) and in the treatment group at 2 weeks (14 ± 1°) compared with untreated rats (15° ± 1°, 4.85-9.42; 16° ± 1°, 1.24-3.86; and 17° ± 2°, 1.16-5.34, respectively; all p < 0.05). The therapy improved articular factors in the prevention group at 2 weeks (4° ± 1°) and 4 weeks (6° ± 1°) and in the treatment group at 2 weeks (8° ± 1°) compared with untreated rats (10° ± 1°, 4.05-7.05; 12° ± 1°, 5.18-8.02; and 11° ± 2°, 1.73-5.50, respectively; all p < 0.05). CO2 therapy decreased muscle fibrosis in the prevention group at 2 weeks (p < 0.001). The expression of collagen Type 1, α1 mRNA in the biceps femoris decreased in treated rats in the prevention group at 2 and 4 weeks compared with untreated rat (p = 0.002 and p = 0.008, respectively), although there was little difference in the expression of transforming growth factor beta (p > 0.05). CO2 therapy did not improve shortening of the synovial intima at all timepoints (all p > 0.05). CO2 therapy decreased transforming growth factor beta immunolabeling in joint capsules in the rats in the prevention group at 2 weeks. The staining intensity and Type I collagen pattern showed no differences among all groups at all timepoints. CO2 therapy may be useful for preventing and treating contractures after spinal cord injuries. CO2 therapy particularly appears to be more effective as a prevention and treatment strategy in early-stage contractures before irreversible degeneration occurs, as shown in a rat model. Our findings support the idea that CO2 therapy may be able to improve the loss of ROM after spinal cord injury.


Optimization of Single- and Dual-Color Immunofluorescence Protocols for Formalin-Fixed, Paraffin-Embedded Archival Tissues.
Performance of immunofluorescence staining on archival formalin-fixed paraffin-embedded human tissues is generally not considered to be feasible, primarily due to problems with tissue quality and autofluorescence. We report the development and application of procedures that allowed for the study of a unique archive of thymus tissues derived from autopsies of individuals exposed to atomic bomb radiation in Hiroshima, Japan in 1945. Multiple independent treatments were used to minimize autofluorescence and maximize fluorescent antibody signals. Treatments with NH3/EtOH and Sudan Black B were particularly useful in decreasing autofluorescent moieties present in the tissue. Deconvolution microscopy was used to further enhance the signal-to-noise ratios. Together, these techniques provide high-quality single- and dual-color fluorescent images with low background and high contrast from paraffin blocks of thymus tissue that were prepared up to 60 years ago. The resulting high-quality images allow the application of a variety of image analyses to thymus tissues that previously were not accessible. Whereas the procedures presented remain to be tested for other tissue types and archival conditions, the approach described may facilitate greater utilization of older paraffin block archives for modern immunofluorescence studies.


Electrophysiological correlates of perceiving and evaluating static and dynamic facial emotional expressions.
Recent evidence suggests that dynamic facial expressions of emotion unfolding over time are better recognized than static images. However, the mechanisms underlying this facilitation are unclear. Here, participants performed expression categorizations for faces displaying happy, angry, or neutral emotions either in a static image or dynamically evolving within 150 ms. Performance replicated facilitation of emotion evaluation for happy expressions in dynamic over static displays. An initial emotion effect in event-related brain potentials evidenced in the early posterior negativity (EPN) was both enhanced and prolonged when participants evaluated dynamic in comparison to static facial expressions. Following the common interpretation of the EPN, this finding suggests that the facilitation for dynamic expressions is related to enhanced activation in visual areas starting as early as 200 ms after stimulus onset, presumably due to shifts of visual attention. Enhancement due to dynamic display was also found for the late positive complex (LPC), indicating a more elaborative processing of emotional expressions under this condition at subsequent stages.


Premelting at defects within bulk colloidal crystals.
Premelting is the localized loss of crystalline order at surfaces and defects at temperatures below the bulk melting transition. It can be thought of as the nucleation of the melting process. Premelting has been observed at the surfaces of crystals but not within. We report observations of premelting at grain boundaries and dislocations within bulk colloidal crystals using real-time video microscopy. The crystals are equilibrium close-packed, three-dimensional colloidal structures made from thermally responsive microgel spheres. Particle tracking reveals increased disorder in crystalline regions bordering defects, the amount of which depends on the type of defect, distance from the defect, and particle volume fraction. Our observations suggest that interfacial free energy is the crucial parameter for premelting in colloidal and atomic-scale crystals.


A view from Cheyenne Mountain: Generation III's perspective of Keystone III.
In October 2000 the family of family medicine convened the Keystone III conference at Cheyenne Mountain Resort. Keystone III participants included members of Generation I (entered practice before 1970), Generation II (entered 1970-1990), and Generation III (entered after 1990). They represented a wide range of family physicians, from medical students to founders of the discipline, and from small-town solo practice to academic medicine. During the conference, the three generations worked together and separately thinking about the past, present, and future of family medicine, our roles in it, and how the understanding of a family physician and our discipline had and would continue to evolve. After the conference, the 10 Generation III members wrote the article published here, reflecting on our experiences as new physicians and physicians in training, and the similarities and differences between our experiences and those of physicians in Generations I and II. Key similarities included commitment to whole-person care, to a wide scope of practice, to community health, and to ongoing engagement with our discipline. Key differences included our understanding of availability, the need for work-life balance, the role of technology in the physician-patient relationship, and the perceptions of the relationship between medicine and a range of outside forces such as insurance and government. This article, presented with only minor edits, thus reflects accurately our perceptions in late 2000. The accompanying editorial reflects our current perspective.


Promoting effects of a single Rhodopseudomonas palustris inoculant on plant growth by Brassica rapa chinensis under low fertilizer input.
Several Rhodopseudomonas palustris strains have been isolated from rice paddy fields in Taiwan by combining the Winogradsky column method and molecular marker detection. These isolates were initially screened by employing seed germination and seedling vigor assays to evaluate their potential as inoculants. To fulfill the demand in the present farming system for reducing the application of chemical fertilizers, we assessed the plant growth-promoting effects of the R. palustris YSC3, YSC4, and PS3 inoculants on Brassica rapa chinensis (Chinese cabbage) cultivated under a half quantity of fertilizer. The results obtained showed that supplementation with approximately 4.0×10(6) CFU g(-1) soil of the PS3 inoculant at half the amount of fertilizer consistently produced the same plant growth potential as 100% fertility, and also increased the nitrogen use efficiency of the applied fertilizer nutrients. Furthermore, we noted that the plant growth-promotion rate elicited by PS3 was markedly higher with old seeds than with new seeds, suggesting it has the potential to boost the development of seedlings that were germinated from carry-over seeds of poor quality. These beneficial traits suggest that the PS3 isolate may serve as a potential PGPR inoculant for integrated nutrient management in agriculture.


Deportation experiences and depression among U.S. citizen-children with undocumented Mexican parents.
There is a critical need to document the mental health effects of immigration policies and practices on children vulnerable to parental deportation. Few studies capture the differential experiences produced by U.S. citizen-children's encounters with immigration enforcement, much less in ways that analyse mental health outcomes alongside the psychosocial contexts within which those outcomes arise. We explore the psychosocial dimensions of depression in U.S. citizen-children with undocumented Mexican parents to examine differences between citizen-children affected and not affected by parental deportation. An exploratory mixed-method design was used to integrate a quantitative measure of depression symptoms (CDI-2) within qualitative data collected with 48 citizen-children aged 8 to 15 with and without experiences of parental deportation. Stressors elicited by citizen-children in the qualitative interview included an inability to communicate with friends, negative perceptions of Mexico, financial struggles, loss of supportive school networks, stressed relation with parent(s) and violence. Fifty percent of citizen-children with probable depression - regardless of experiences with parental deportation - cited 'stressed relation with parents,' compared to 9% without depression. In contrast, themes of 'loss of supportive school network' and 'violence' were mentioned almost exclusively by citizen-children with probable depression and affected by parental deportation. While citizen-children who suffer parental deportation experience the most severe consequences associated with immigration enforcement, our findings also suggest that the burden of mental health issues extends to those children concomitantly affected by immigration enforcement policies that target their undocumented parents.


Inpatient Glycemic Management in the Setting of Renal Insufficiency/Failure/Dialysis.
Chronic diabetic nephropathy and renal dysfunction from other causes are common in hospitalized patients with diabetes. Available diabetes management guidelines aim to reduce hyperglycemia and hypoglycemia, both independent risk factors for hospital outcomes. Renal dysfunction, which increases the risk of hypoglycemia, adds a layer of complexity in diabetes management. Therefore, modified glucose goals and treatment regimens may be required. Recent prospective and retrospective studies provide direction on safe insulin therapy for diabetes inpatients with renal compromise. Studies of newer diabetes pharmacotherapy provide data on oral agent use in the inpatient setting. Diabetes therapy should be modified with changing renal function. Glucose management in patients on peritoneal or hemodialysis is challenging. Reducing weight-based doses of insulin and use of newer insulins can reduce hypoglycemia risk. Safety and efficacy of DPP-4 inhibitors has been evaluated in the hospital and nursing home setting. Metformin, SGLT-2 inhibitors, and GLP1 receptor agonists can be used in several stages of renal dysfunction prior to and at discharge.


Link Between Perceived Body Weight and Smoking Behavior Among Adolescents.
This study investigates a relationship between overweight perception and smoking among adolescents. Data were retrieved from the Youth Risk Behavior Survey (YRBS), a biennial survey of a nationally representative sample of students in grades 9 through 12 in the United States. We analyze five waves of repeated cross-sections (N = 73 376) for the years 2005-2013. We estimate a recursive simultaneous-equations system in which body weight perception, which is a function of actual weight, influences smoking status. Outcome measures are binary indicators for current smoking and frequent current smoking. Perceived weight is categorized into very overweight perception, slightly overweight perception, and about the right weight/underweight perception. In comparison to adolescents who perceive themselves to be the right weight or underweight, adolescents who perceive themselves to be very overweight are 6.1 percentage points (pp) (standard error [SE] = 1.6pp) more likely to currently smoking and 3.3pp (SE = 1.2pp) more likely to frequently smoke. Adolescents with slightly overweight perception are 7.9pp (SE = 1.0pp) and 2.5pp (SE = 0.6pp) more likely to currently smoke and frequently smoke, respectively, as compared to those with the right weight/underweight perception. The relationships are larger for females, and appear to be mediated by weight-loss activity. In an era of tight budgets, it is crucial to address both obesity and smoking in manners that do not work at cross purposes. Strategies to combat youth smoking may be more effective if the perception of being overweight is considered an important risk factor, especially among female adolescents. We find that perception of being overweight is an important causal risk factor for adolescent smoking. Main findings of this study imply that even a slight change in the perception of body weight may lead to a significant change in smoking behavior among adolescents, especially among females and that the perception of being overweight induces adolescents to smoke regularly. Unlike most prior studies, we discovered a positive effect of slight overweight perception on smoking for adolescent males. Our findings emphasize the importance of addressing both obesity and smoking in manners that do not work at cross purposes.


Rates of morbidity and mortality after closure of loop and end colostomy.
The purported ease and safety of closure of loop colostomy are cited as reasons for avoiding end colostomy, with or without resection. However, data comparing the complications of loop colostomy closure and end colostomy takedown and anastomosis are sparse. We analyzed data from 93 consecutive colostomy closures, of which 62 were loop and 31 were end colostomies. The two groups were comparable with respect to age, the underlying disease and risk factors, such as coronary artery disease, diabetes, hypertension, steroid dependence, hypoalbuminemia and smoking. Closure of end colostomies took longer and was associated with more loss of blood than closure of loop colostomies. However, the mortality rates for closure of loop (4.8 per cent) and end (3.2 per cent) colostomies were not significantly different. The complication rates were identical (16 per cent). Although none of the other risk factors were associated with increased rates of mortality or morbidity, the detrimental effects of steroid dependence and preoperative hypoalbuminemia were striking. All four of the deaths and 60 per cent of the complications occurred in patients with steroid dependence or hypoalbuminemia, or both. The rates of wound infection after primary or secondary closure of the stoma site were not significantly different. We concluded that loop colostomy closure is not associated with fewer complications than closure of end colostomy, even though the latter takes longer and is more difficult. Hypoalbuminemic and steroid-dependent patients should undergo colostomy closure with caution, if at all. Primary closure of the stomal site is safe and reduces the length of hospital stay.


Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism.
Overuse of the d-dimer to screen for possible pulmonary embolism (PE) can have negative consequences. This study derives and tests clinical criteria to justify not ordering a d-dimer. The test threshold was estimated at 1.8% using the method of Pauker and Kassirer. The PE rule-out criteria were derived from logistic regression analysis with stepwise backward elimination of 21 variables collected on 3148 emergency department patients evaluated for PE at 10 US hospitals. Eight variables were included in a block rule: Age < 50 years, pulse < 100 bpm, SaO(2) > 94%, no unilateral leg swelling, no hemoptysis, no recent trauma or surgery, no prior PE or DVT, no hormone use. The rule was then prospectively tested in a low-risk group (1427 patients from two hospitals initially tested for PE with a d-dimer) and a very low-risk group (convenience sample of 382 patients with chief complaint of dyspnea, PE not suspected). The prevalence of PE was 8% (95% confidence interval: 7-9%) in the low-risk group and 2% (1-4%) in the very low-risk group on longitudinal follow-up. Application of the rule in the low-risk and very low-risk populations yielded sensitivities of 96% and 100% and specificities of 27% and 15%, respectively. The prevalence of PE in those who met the rule criteria was 1.4% (0.5-3.0%) and 0% (0-6.2%), respectively. The derived eight-factor block rule reduced the pretest probability below the test threshold for d-dimer in two validation populations, but the rule's utility was limited by low specificity.


Prevention of Endothelial Dysfunction and Cardiovascular Disease by n-3 Fatty Acids-Inhibiting Action on Oxidative Stress and Inflammation.
Prospective cohort studies and randomized controlled trials have shown the protective effect of n-3 fatty acids against cardiovascular disease (CVD). The effect of n-3 fatty acids on vascular endothelial cells indicates their possible role in CVD prevention. Here, we describe the effect of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on endothelial dysfunction-caused by inflammation and oxidative stress-and their role in the development of CVD. We reviewed epidemiological studies done on n-3 fatty acids in CVD. The effect of DHA and EPA on vascular endothelial cells was examined with regard to changes in various markers, such as arteriosclerosis, inflammation, and oxidative stress, using cell and animal models. Epidemiological studies revealed that dietary intake of EPA and DHA was associated with a reduced risk of various CVDs. EPA and DHA inhibited various events involved in arteriosclerosis development by preventing oxidative stress and inflammation associated with endothelial cell damage. In particular, EPA and DHA prevented endothelial cell dysfunction mediated by inflammatory responses and oxidative stress induced by events related to CVD. DHA and EPA also increased eNOS activity and induced nitric oxide production. The effects of DHA and EPA on vascular endothelial cell damage and dysfunction may involve the induction of nitric oxide, in addition to antioxidant and anti-inflammatory effects. n-3 fatty acids inhibit endothelial dysfunction and prevent arteriosclerosis. Therefore, the intake of n-3 fatty acids may prevent CVDs, like myocardial infarction and stroke.


Noise in phase shifting interferometry.
We present a theoretical analysis to estimate the amount of phase noise due to noisy interferograms in Phase Shifting Interferometry (PSI). We also analyze the fact that linear filtering transforms corrupting multiplicative noise in Electronic Speckle Pattern Interferometry (ESPI) into fringes corrupted by additive gaussian noise. This fact allow us to obtain a formula to estimate the standard deviation of the noisy demodulated phase as a function of the spectral response of the preprocessing spatial filtering combined with the PSI algorithm used. This phase noise power formula is the main result of this contribution.


The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes.
Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease.


Timing of the formation and migration of giant planets as constrained by CB chondrites.
The presence, formation, and migration of giant planets fundamentally shape planetary systems. However, the timing of the formation and migration of giant planets in our solar system remains largely unconstrained. Simulating planetary accretion, we find that giant planet migration produces a relatively short-lived spike in impact velocities lasting ~0.5 My. These high-impact velocities are required to vaporize a significant fraction of Fe,Ni metal and silicates and produce the CB (Bencubbin-like) metal-rich carbonaceous chondrites, a unique class of meteorites that were created in an impact vapor-melt plume ~5 My after the first solar system solids. This indicates that the region where the CB chondrites formed was dynamically excited at this early time by the direct interference of the giant planets. Furthermore, this suggests that the formation of the giant planet cores was protracted and the solar nebula persisted until ~5 My.


Alpha2beta1 integrin and development of atherosclerosis in a mouse model: assessment of risk.
The alpha2beta1 integrin serves as a collagen or collagen/laminin receptor on many cell types, including endothelial cells and platelets. Many studies indicate that the alpha2beta1 integrin is a critical mediator of platelet adhesion to collagen. Epidemiologic studies suggest a direct correlation between the genetically determined platelet surface density of the alpha2beta1 integrin and the risk of thrombotic diseases, such as myocardial infarction and stroke, in the young, which are well-established complications of atherosclerosis. We have now used the alpha2beta1 integrin-deficient mouse to evaluate the contributions of the alpha2beta1 integrin to the development of atherosclerosis. We generated wild-type (alpha2+/+) or alpha2beta1 integrin-deficient (alpha2-/-) mice that were also deficient in the apolipoprotein E (ApoE) gene (ApoE-/-) and compared atherosclerotic lesion development in alpha2+/+ ApoE-/- and alpha2-/- ApoE-/- mice that were fed a high-fat, cholesterol-containing diet for 6 or 15 weeks. Total lesional area did not differ significantly between the alpha2-null animals and the wild-type animals at either 6 or 15 weeks. Our results suggest that risk for arterial thrombotic disease associated with high-level alpha2beta1 integrin expression is not attributable to enhanced development of atherosclerosis per se but may rather be a consequence of thrombotic complications at the plaques.


Patient-reported outcomes in randomized clinical trials: development of ISOQOL reporting standards.
To develop expert consensus on a suite of reporting standards for HRQL outcomes of RCTs. A Task Force of The International Society of Quality of Life Research (ISOQOL) undertook a systematic review of the literature to identify candidate reporting standards for HRQL in RCTs. Subsequently, a web-based survey was circulated to the ISOQOL membership. Respondents were asked to rate candidate standards on a 4-point Likert scale based on their perceived value in reporting studies in which HRQL was a study outcome (primary or secondary). Results were synthesized into draft reporting guidelines, which were further reviewed by the membership to inform the final guidance. Forty-six existing candidate standards for reporting HRQL results in RCTs were synthesized to produce a 40 item survey that was completed electronically by 161 respondents. The majority of respondents rated all 40 items to be either 'essential' or 'desirable' when HRQL was a primary RCT outcome. Ratings changed when HRQL was a secondary study outcome. Feedback on the survey findings resulted in the Task Force generalizing the guidance to include patient-reported outcomes (PROs). The final guidance, which recommends standards for use in reporting PROs generally, and more specifically, for PROs identified as primary study outcomes, was approved by the ISOQOL Board of Directors. ISOQOL has developed a suite of recommended standards for reporting PRO results of RCTs. Improved reporting of PROs will enable accurate interpretation of evidence to inform patient choice, aid clinical decision making, and inform health policy.


Characteristics of Exceptional or Super Responders to Cancer Drugs.
To summarize case reports of exceptional and super responders already published in the biomedical literature. We searched for published case reports or abstracts of exceptional or super responders to a cancer drug using PubMed and Google Scholar search engines. Pooling such reports is widely considered a promising research strategy and the subject of several ongoing investigations, including the National Cancer Institute's Exceptional Responders Initiative. All articles were read in full, including relevant references. We extracted clinical characteristics of exceptional or super responders, including age, tumor type, drug, genetic mutations, depth of response, duration of response, number of previous lines of therapy, duration of response to a previous line of therapy, and the number of patients treated similarly to identify the exceptional case. This study was performed between March 1, 2015, and April 30, 2015. Among 489 articles, 32 exceptional responders were identified. The most common malignancies described were renal cell cancer (5 of 32 [16%]) and urothelial carcinoma (4 of 32 [13%]). The use of targeted agents was common in these cases (26 of 32 [81%]), particularly inhibitors of the mTOR pathway (16 of 32 [50%]). The median duration of response among responders was 17.5 months, and 59% (19 of 32) of the patients were last known to be alive with continuing response or stable disease. Notably, 46% (12 of 26) of the patients had received 2 or more previous lines of therapy and 6 of the 32 cases (19%) did not report this information. Few authors report the number of patients treated similarly to observe the super response (12 of 32 [38%]). Exceptional or super responders to cancer drugs have been described in the literature; however, there is incompleteness in the reporting of relevant data that may help clarify whether such responses are secondary to treatment or reflect underlying biology.


Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes: The TRACER Trial.
The Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed. This study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries). We analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death. During follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1); the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35; 95% confidence interval: 5.59 to 9.68; p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05; 95% confidence interval: 5.41 to 18.69; p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding. In patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736]; NCT00527943).


Long-term carrier-envelope-phase stabilization of a femtosecond laser by the direct locking method.
We have developed a practical solution to implement the direct locking method for the carrier-envelope phase (CEP) stabilization of femtosecond laser pulses and achieved 24-hour CEP stabilization without realignment of any optical components. The direct locking method realizes the CEP stabilization in the time domain by directly quenching the beat signal from an f-to-2f interferometer and, thereby, locking every pulse to a same CEP. We have accomplished the long-term CEP stabilization using commercially available standard feedback electronics, and maintained the CEP stabilization with low jitter without using any frequency-analyzing components, greatly facilitating the accessibility of the CEP stabilization.


The political challenges that may undermine health reform.
As with all major social legislation, years of decisions and disputes over implementation lie ahead for the Patient Protection and Affordable Care Act. Opponents at the state and national levels may seek the law's judicial overturn or repeal. However, a far more serious effort to undermine the law will come about through challenges to various administrative arrangements, taxes, and subsidies to fund expansions of coverage. The redistributive aspects of health reform will be especially at risk, as business interests and groups of more-privileged citizens press for lower taxes, looser regulations, and reduced subsidies for low-income people.


Pancreatic cancer cells enhance the ability of collagen internalization during epithelial-mesenchymal transition.
Extracellular matrix (ECM) remodeling is predominantly mediated by fibroblasts using intracellular and extracellular pathways. Although it is well known that extracellular degradation of the ECM by proteases derived from cancer cells facilitates cellular invasion, the intracellular degradation of ECM components by cancer cells has not been clarified. The aim of this study was to characterize collagen internalization, which is the initial step of the intracellular degradation pathway in pancreatic cancer cells, in light of epithelial-mesenchymal transition (EMT). We analyzed the function of collagen internalization in two pancreatic cancer cell lines, SUIT-2 and KP-2, and pancreatic stellate cells (PSCs) using Oregon Green 488-gelatin. PSCs had a strong ability for collagen uptake, and the pancreatic cancer cells also internalized collagen although less efficiently. The collagen internalization abilities of SUIT-2 and KP-2 cells were promoted by EMT induced by human recombinant transforming growth factor β1 (P<0.05). Expression of Endo180, a collagen uptake receptor, was high in mesenchymal pancreatic cancer cell lines, as determined by EMT marker expression (P<0.01). Quantitative RT-PCR and western blot analyses showed that Endo180 expression was also increased by EMT induction in SUIT-2 and KP-2 cells. Endo180 knockdown by RNA interference attenuated the collagen uptake (P<0.01) and invasive abilities (P<0.05) of SUIT-2 and KP-2 cells. Pancreatic cancer cells are capable of collagen internalization, which is enhanced by EMT. This ECM clearance system may be a novel mechanism for cellular invasion and a potential therapeutic target in pancreatic cancer.


Lateral mobility of plasma membrane lipids in bull spermatozoa: heterogeneity between surface domains and rigidification following cell death.
Compartmentalization of surface membrane antigens into discrete regions or domains is a characteristic feature of differentiated cells. In mammalian spermatozoa at least 5 surface domains are known, implying the presence of barriers or boundaries within the plasma membrane. Using the technique of fluorescence recovery after photobleaching (FRAP) to measure diffusibility of fluorescent lipid analogues 1,1'-dihexadecyl-3,3,3'3'-tetramethylindocarbocyanine (DiIC[16]) and 5-(N-octa-decanoyl) aminofluorescein (ODAF), we have investigated lipid topology and dynamics in the plasma membrane of ejaculated bull spermatozoa. Contrary to reports in the literature, we have found that DiIC(16) stains only dead or damaged spermatozoa whereas ODAF intercalates into the plasma membrane of both live and dead cells, each type showing a distinctive staining pattern. FRAP analysis with ODAF revealed that diffusion coefficients on live spermatozoa are significantly faster on the acrosome and postacrosome (29.3x10(-9) cm2/second) than on the midpiece and principal piece (11.8x10(-9) cm2/second). Recovery (R) is >90% in all domains. ODAF diffusion also shows regionalized temperature-sensitivity with a 4-fold increase over the sperm head and a 1.8-fold increase on the tail between 20 degrees C and 37 degrees C. Remarkably, dead or permeabilized spermatozoa rapidly develop a large immobile phase (R<25%) over the whole plasma membrane. This rigidification is temperature insensitive and irreversible suggesting major changes in the physical state of membrane lipids. It is concluded that lipid diffusion in the plasma membrane of live bull spermatozoa is rapid and varies significantly between surface domains. Following permeabilization or cell death, however, a large immobile phase develops indicating substantial changes in membrane lipid disposition.


Development and evaluation of the Good Grief program for young people bereaved by familial cancer.
Adolescents and young adults (AYAs) bereaved by the death of a parent or sibling from cancer report unique psychosocial needs and can have difficulty adjusting to their loss. Unaddressed, this can result in poor long-term bereavement outcomes. This paper describes the development and evaluation of Good Grief - a 3-day camp-based program focused on meeting coping, social support, and respite needs of AYAs bereaved by familial cancer. One hundred and nine Australian AYAs (68% female; age: 12-25 years, M = 16.63) participated in the evaluation. Grief intensity (Texas Revised Inventory of Grief), meaning-making (Grief and Meaning Reconstruction Inventory), trauma coping (Perceived Ability to Cope with Trauma Scale) and unmet needs (Bereaved Cancer Needs Instrument) measures were administered pre-program and 3-months post-program. Acceptability was measured after each session and at the program's conclusion. Appropriateness was measured at 3-month follow-up. Thirteen participants were interviewed three months post-program on their perceptions of the program. Participants reported high program satisfaction, engagement with psychosocial sessions, and enjoyment of recreational activities. Significant improvements were observed in trauma coping abilities and reductions in unmet needs for managing emotions, social support, respite, future planning, and accessing information and support domains. No change was evident in grief intensity or meaning-making as measured quantitatively. Interviews supported these quantitative findings but also identified evidence of personal growth, a component of meaning-making. Good Grief is a highly acceptable and beneficial intervention that addresses the unique needs of AYAs bereaved by familial cancer.


[Cytogenetic alterations in field workers routinely exposed to pesticides in Bogota flowers farms].
Frequency of cytogenetic alterations (micronuclei and chromosome aberrations), DNA repair deficiencies and acetylcholinesterase activity was determined for field workers in Bogotá, Colombia. These workers were regularly exposed to organophosphate and carbamate insecticides while employed on farms for flower growing. Interviews were conducted with 31 workers associated with occupational risk of pesticides exposure and 30 without exposure. A standard cytogenetic assay was used to determine chromosome aberrations and micronuclei frequencies. In addition, a challenge assay assessed response to gamma-rays as an indication of DNA repair deficiencies--cells were exposed to gamma-rays in vitro and the frequencies of chromosome aberrations in post-irradiation metaphase cells were quantified. The data were evaluated for percentage of aberrant cells, cells with chromosome aberrations and frequencies of chromatid breaks per 100 metaphase cells in each worker. The exposed group had a significantly higher frequency of cells with chromosome aberrations and micronuclei as compared with the non-exposed group (p = 0.02). However, the challenge assay did not indicate a significant difference (p > 0.1). These findings require confirmation by further analytical studies involving larger sample. Cytogenetic and toxicological studies, in conjunction with thorough clinical examination are recommended.


A New Kind of Spatial Inattention Associated With Chronic Limb Pain?
Pathological limb pain patients show decreased attention to some stimuli on the painful limb and increased attention to others, a paradox that has dogged the field for over a decade. We hypothesized that pathological pain involves a spatial inattention confined to bodily representations. Patients showed inattention to the painful side for visual processing of body parts but not letters, tactile processing but not auditory, and body-part bisection tasks but not line bisection tasks. We propose the new term "somatospatial inattention" to describe bodily-specific spatial inattention associated with pathological limb pain.


Impact of Maternal HIV Seroconversion during Pregnancy on Early Mother to Child Transmission of HIV (MTCT) Measured at 4-8 Weeks Postpartum in South Africa 2011-2012: A National Population-Based Evaluation.
Mother-to-child transmission of HIV (MTCT) depends on the timing of HIV infection. We estimated HIV-seroconversion during pregnancy (HSP) after having a HIV-negative result antenatally, and its contribution to early MTCT in South Africa (SA). Between August 2011 and March 2012, we recruited a nationally representative sample of mother-infant pairs with infants aged 4-to-8 weeks from 578 health facilities. Data collection included mother interviews, child health-card reviews, and infant dried-blood-spots sample (iDBS). iDBS were tested for HIV antibodies and HIV-deoxyribonucleic-acid (HIV-DNA). HSP was defined as maternal self-report of an HIV-negative test during this pregnancy, no documented use of antiretroviral drugs and a matched HIV sero-positive iDBS. We used 20 imputations from a uniform distribution for time from reported antenatal HIV-negative result to delivery to estimate time of HSP. Early MTCT was defined based on detection of HIV-DNA in iDBS. Estimates were adjusted for clustering, nonresponse, and weighted by SA's 2011 live-births. Of 9802 mother-infant pairs, 2738 iDBS were HIV sero-positive, including 212 HSP, resulting in a nationally weighted estimate of 3.3% HSP (95% Confidence Interval: 2.8%-3.8%). Median time of HIV-seroconversion was 32.8weeks gestation;28.3% (19.7%- 36.9%) estimated to be >36 weeks. Early MTCT was 10.7% for HSP (6.2%-16.8%) vs. 2.2% (1.7%-2.8%) for mothers with known HIV-positive status. Although they represent 2.2% of all mothers and 6.7% of HIV-infected mothers, HSP accounted for 26% of early MTCT. Multivariable analysis indicated the highest risk for HSP was among women who knew the baby's father was HIV-infected (adjusted-hazard ratio (aHR) 4.71; 1.49-14.99), or who had been screened for tuberculosis (aHR 1.82; 1.43-2.32). HSP risk is high and contributes significantly to early MTCT. Identification of HSP by repeat-testing at 32 weeks gestation, during labor, 6 weeks postpartum, in tuberculosis-exposed women, and in discordant couples might reduce MTCT.


Evaluation of the psoriasis transcriptome across different studies by gene set enrichment analysis (GSEA).
Our objective was to develop a consistent molecular definition of psoriasis. There have been several published microarray studies of psoriasis, and we compared disease-related genes identified across these different studies of psoriasis with our own in order to establish a consensus. We present a psoriasis transcriptome from a group of 15 patients enrolled in a clinical study, and assessed its biological validity using a set of important pathways known to be involved in psoriasis. We also identified a key set of cytokines that are now strongly implicated in driving disease-related pathology, but which are not detected well on gene array platforms and require more sensitive methods to measure mRNA levels in skin tissues. Comparison of our transcriptome with three other published lists of psoriasis genes showed apparent inconsistencies based on the number of overlapping genes. We extended the well-established approach of Gene Set Enrichment Analysis (GSEA) to compare a new study with these other published list of differentially expressed genes (DEG) in a more comprehensive manner. We applied our method to these three published psoriasis transcriptomes and found them to be in good agreement with our study. Due to wide variability in clinical protocols, platform and sample handling, and subtle disease-related signals, intersection of published DEG lists was unable to establish consensus between studies. In order to leverage the power of multiple transcriptomes reported by several laboratories using different patients and protocols, more sophisticated methods like the extension of GSEA presented here, should be used in order to overcome the shortcomings of overlapping individual DEG approach.


Revealing student nurses' perceptions of human dignity through curriculum co-design.
Dignity is a slippery concept to define - yet it has been at the heart of media and policy debates around the provision of health and social care in recent years; particularly in the United Kingdom following the Mid-Staffordshire scandal and subsequent Francis Inquiry. This paper considers the concept of dignity in care from the perspective of student nurses. Thus, it allows us to discuss how professional nurses-to-be conceptualise dignity and also how they consider it should/could be taught at undergraduate and postgraduate levels of training, and as part of their Continuing Professional Development. It is only through understanding how student nurses conceptualise and experience human dignity, and the giving and receiving of dignity in care, that it will be possible to support its facilitation in the preparation of practitioners. This paper reports on findings from a series of participatory research workshops held with undergraduate nursing students in Scotland in 2013-14 that were designed to engage the students in the development of educational resources to support the teaching of dignity in care within the nursing curriculum. The outputs from each workshop, along with analysis of transcripts of the workshop discussions, demonstrate the value of co-design as a methodology for involving students in the development of interdisciplinary resources. We observed a desire from students to actively enhance their understandings of dignity - to be able to recognise it; to see dignity in care being practiced; to experience providing such care and to have the appropriate tools to reflect on their own experience. Overall, the research revealed a rich understanding of the ways in which human dignity is conceptualised by nursing students as an embodied practice, associated with memory and personal to an individual. It was understood by the students as shifting, experiential and fragile.


Gender differences in health care-seeking behavior for sexually transmitted diseases: a population-based study in Nairobi, Kenya.
Health care-seeking behavior for sexually transmitted diseases (STDs) is important in STD/HIV control. The goal of this study was to describe the proportion seeking care, patient delay, and choice of provider among men and women with STD-related complaints in Nairobi, Kenya. A population-based questionnaire was administered in 7 randomly selected clusters (small geographic areas covering approximately 150 households each). Of the 291 respondents reporting complaints, 20% of men versus 35% of women did not seek care, mainly because symptoms were not considered severe, symptoms had disappeared, or as a result of lack of money. Of those who sought care, women waited longer than men (41 vs. 16 days). Most men and women went to the private sector (72% and 57%, respectively), whereas the informal sector was rarely visited (13% and 16%, respectively). Relatively more women visited the government sector (28% vs. 15%). Because women were mostly monogamous, they did not relate their complaints to sexual intercourse, which hampered prompt care-seeking. Women should be convinced to seek care promptly, eg, through health education in communities.


Spontaneous pneumocephalus caused by pneumococcal meningitis.
Pneumocephalus is a condition characterized by the presence of air in the cranium, and it is mainly caused by trauma or a neurosurgical procedure. In the absence of head trauma or a neurosurgical procedure, meningitis is an extremely rare cause of pneumocephalus. Here, the authors present a rare case of spontaneous pneumocephalus caused by pneumococcal meningitis, in which simple lateral radiography and computed tomography (CT) findings of the skull suggested the diagnosis. Cerebrospinal fluid analysis showed bacterial meningitis which later revealed streptococcus pneumonia. The patient was treated with antibiotics and responded remarkably well. Repeat CT performed after 2 weeks of treatment showed complete resolution of the intracranial gas. Here, the authors report an unusual case of a pneumocephalus caused by meningitis in the absence of head trauma or a neurosurgical procedure.


Knowledge, skills and professional behaviours required by occupational therapist and physiotherapist beginning practitioners in work-related practice: a systematic review.
Occupational therapists and physiotherapists have established roles in work-related practice. However, there is limited information about the attributes required by these professions for competent practice in this field. The aim of this systematic review was to evaluate the research literature to determine the knowledge, skills and professional behaviours required by occupational therapists and physiotherapists, including new graduates, in work-related practice. A systematic search was conducted of standard databases using keywords and phrases. All types of studies and reports were included from empirical research to descriptive reports. Included literature was appraised by standard critical appraisal tools by two reviewers. Words, phrases or themes related to the attributes required for work practice were manually extracted and a meta-synthesis conducted. Seven observational studies, six professional practice guidelines, one book chapter, one journal editorial and seven opinion pieces met the inclusion criteria. Observational studies and descriptive reports were low on the evidence hierarchy. Meta-synthesis determined that key attributes required by occupational therapists and physiotherapists in work-related practice were knowledge of injury prevention and management, skills in communication, and professional behaviours of self-reflection and evaluation. Findings from this systematic review provided credible evidence about attributes required by occupational therapists and physiotherapists but not including new graduates, in work-related practice. However, due to low evidence levels findings will need to be applied with caution. More rigorous research is needed to evaluate occupational therapy and physiotherapy workplace interventions to guide practice and to assist occupational therapists and physiotherapists promote the effectiveness of their services.


Fiber-optic accelerometer with hydrophone applications.
A fiber-optic linear accelerometer based on intensity modulation produced by lateral displacement of a cantilevered fiber has been fabricated and tested. The model reported on is constructed with multimode fiber and has a displacement sensitivity of 6.4 x 10(-13) m. The device has general application as a linear accelerometer with the inherent advantages of remote optical fiber sensing. Particular attention is given to sono-buoy hydrophone applications in which the present model has a sensitivity limit corresponding to 75 dB relative to 1 microPa at 1 kHz. Means for substantially improving the accelerometer's sensitivity as a hydrophone are discussed.


A prestimulation evaluation protocol for patients with drug resistant epilepsy.
Neurostimulation is making its way into the therapeutic armamentarium of the epileptologists, with several invasive neurostimulation modalities available today and several less invasive modalities under investigation. Clinicians will soon face a choice that should not be made randomly. We introduce the concept of a prestimulation evaluation protocol, consisting of a series of rationally chosen investigations that evaluate the presence of biomarkers for response to various neurostimulation therapies. These biomarkers should reflect the susceptibility of the individual's epileptic network to a given neurostimulation technique. This will require elucidation of the specific mechanism(s) of action of the different neurostimulation modalities. This manuscript provides a hypothetical framework that may be more applicable in the near future when pre-clinical research progresses and can be translated into human applications.