Predictors of Exercise-Induced Pulmonary Hypertension in Patients with Asymptomatic Degenerative Mitral Regurgitation: Mechanistic Insights from 2D Speckle-Tracking Echocardiography.
Presence of exercise-induced pulmonary hypertension (EIPH) in asymptomatic degenerative mitral regurgitation (DMR) determines prognosis. This study aimed to elucidate the mechanism and predictors of EIPH in asymptomatic DMR. Ninety-one consecutive asymptomatic patients with DMR who underwent exercise stress echocardiography were prospectively included. We obtained various conventional echocardiographic parameters at rest and during peak exercise, as well as left atrial (LA) function at rest using 2-dimensional speckle-tracking analysis. The 25 patients (33.3%) with EIPH were significantly older and had a greater ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity during peak exercise than those without EIPH. LA strain (LAS)-s and LAS-e, indices of LA reservoir and conduit function, respectively, were significantly lower in those with EIPH than in those without EIPH. Multivariate analysis indicated that LAS-s was the only resting echocardiographic parameter that independently predicted EIPH, with a cut-off value of 26.9%. Furthermore, Kaplan-Meier curve analysis showed that symptom-free survival was markedly lower among those with reduced LAS-s. In conclusion, decreased LA reservoir function contributes to EIPH, and LAS-s at rest is a useful indicator for predicting EIPH in asymptomatic patients with DMR.


HIV Immune Recovery Inflammatory Syndrome and Central Nervous System Paracoccidioidomycosis.
The immune reconstitution inflammatory syndrome (IRIS) is a deregulated inflammatory response to invading microorganisms. It is manifested when there is an abrupt change in host immunity from an anti-inflammatory and immunosuppressive state to a pro-inflammatory state as a result of rapid depletion or removal of factors that promote immune suppression or inhibition of inflammation. The aim of this paper is to discuss and re-interpret the possibility of association of paracoccidioidomycosis (PCM) with IRIS in the central nervous system (CNS) in a case from Brazil published by Silva-Vergara ML. et al. (Mycopathologia 177:137-141, 6). An AIDS patient who was not receiving medical care developed pulmonary PCM successfully treated with itraconazole. The patient developed central nervous system PCM (NPCM) after starting the ARV therapy with recovery of immunity and control of HIV viral load, although it was not interpreted as IRIS by the authors, it fulfills the criteria for CNS IRIS. This could be the first case of NPCM associated with IRIS described. Although not frequent, IRIS must be considered in PCM patients and HIV, from endemic areas or patients that traveled to endemic areas, receiving ARV treatment and with worsening symptoms.


Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells.
Natural killer cell stimulatory factor (NKSF), or interleukin 12 (IL-12), is a 70-kD heterodimeric cytokine composed of two covalently linked chains, p40 and p35. NKSF/IL-12 has multiple effects on T and NK cells and was originally identified and purified from the supernatant fluid of Epstein-Barr virus (EBV)-transformed human B lymphoblastoid cell lines. We have produced a panel of monoclonal antibodies against both chains of NKSF/IL-12. Some of these antibodies have neutralizing activity, and several combinations of them have been used to establish sensitive radioimmunoassays detecting the free p40 chain, the free p35 chain, or the p70 heterodimer. Using these reagents, we have determined that most EBV-transformed human B lymphoblastoid cell lines constitutively produce low levels of the p70 heterodimer and an excess of the free p40 chain, whereas Burkitt lymphoma-derived, T, myeloid, and many solid tumor-derived cell lines produce neither. Production of both p40 and p70 is increased several-fold upon stimulation of the EBV-transformed cell lines with phorbol diesters. The ability of supernatant fluids from unstimulated and phorbol diester-stimulated cell lines to induce interferon gamma (IFN-gamma) production from T and NK cells, one of the effects of NKSF/IL-12, parallels the levels of production of the p70 heterodimer, known to be the biologically active form of NKSF/IL-12. Staphylococcus aureus Cowan I strain (SAC) and other stimuli induce accumulation of p40 mRNA and production of both p40 and p70 by peripheral blood mononuclear cells (PBMC). The producer cells appear to include both adherent cells and nonadherent lymphocytes, possibly B cells. The supernatant fluids from SAC-stimulated PBMC mediate the typical functions of NKSF/IL-12 (i.e., IFN-gamma induction, mitogenic effects on T/NK blasts, enhancement of NK cell cytotoxicity) at concentrations of p70 similar to those at which recombinant NKSF/IL-12 mediates the same functions. Moreover, these activities are significantly inhibited by anti-NKSF/IL-12 antibodies. The neutralizing anti-NKSF/IL-12 antibodies also inhibit 85% of the IFN-gamma production in response to SAC, an NKSF/IL-12 inducer, and approximately 50% of the IFN-gamma production in response to non-NKSF/IL-12-inducers such as IL-2, phytohemagglutinin, and anti-CD3 antibodies. These results indicate that induced or constitutively produced NKSF/IL-12 has a major role in facilitating IFN-gamma production by peripheral blood lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)


Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition.
Sepsis is a systemic inflammatory response syndrome characterized by excessive production of inflammatory cytokines and cardiovascular collapse. Postreceptor signaling events that lead to stress responses and cytokine production are sensitive to redox changes and products of lipid peroxidation. We tested the hypothesis that inflammatory signaling and cytokine generation during sepsis depend on the activity of the enzyme aldose reductase, which catalyzes the reduction of lipid peroxidation-derived aldehydes and their glutathione conjugates. The results of the present study show that pharmacological inhibition of aldose reductase by sorbinil or knockdown of the enzyme by small interfering RNA prevents the activation of nuclear factor-kappaB and the release of tumor necrosis factor-alpha from lipopolysaccharide-stimulated RAW264.7 or H9c2 cells. Increases in serum and cardiac cytokines in response to lipopolysaccharide challenge were suppressed by inhibition of aldose reductase. Treatment with sorbinil blunted the activation of protein kinase C, c-Jun NH2-terminal kinase, and p38, as well as phosphorylation of interleukin receptor-associated kinase, IkappaB-alpha, IkappaB kinase complex-alpha/beta, and phospholipase-gamma1 and -beta1. These changes were associated with decreased myocardial nuclear factor-kappaB and activating protein-1 activity, prostaglandin E2 production, induction of cyclooxygenase 2, and inducible nitric oxide synthase. Sorbinil treatment also induced functional recovery in myocardial fractional shortening in vivo and preserved contractile function of isolated perfused hearts. Inhibition of aldose reductase increased survival in mice injected with lethal doses of lipopolysaccharide. The present demonstration that aldose reductase mediates endotoxin-induced inflammation and cardiomyopathy suggests that inhibition of this enzyme may be useful to attenuate maladaptive host responses and to treat acute cardiovascular dysfunction associated with endotoxic shock.


Comparison of 7-day retrospective and prospective alcohol consumption diaries in a female population in Perth, Western Australia--methodological issues.
The summer alcohol consumption of women living in metropolitan Perth was measured using both a retrospective and prospective diary. Overall, 1356 women fully completed both the retrospective and prospective alcohol consumption diaries. The prospective diary yielded a significantly higher level (9%) of consumption (p less than 0.00001) compared with the retrospective diary. Although there was no significant difference in the percentage of women drinking at harmful levels (greater than 280 g absolute alcohol per week) between the two diary methods, there did appear to be an important percentage difference (1.9% versus 2.8%) suggesting that the prospective diary did detect a larger percentage of women at risk. This would be both practically and statistically significant in large populations. The heavier the drinker the greater the variability in reported consumption between the two diary weeks. However, it is interesting to note that the direction of the variation depended on which diary was used as the base for classifying women as different types of drinkers. Women who drank at hazardous (140-280 g per week) or harmful (greater than 280 g) levels during the retrospective diary week reported a lower level of consumption during the prospective diary week. Conversely women who drank at hazardous or harmful levels during the prospective diary week reported a lower level of consumption during the retrospective diary week. Possible explanations for these findings are explored and methodological considerations for future studies are discussed.


Green tea and black tea consumption and prostate cancer risk: an exploratory meta-analysis of observational studies.
Observational studies on tea consumption and prostate cancer (PCa) risk are still inconsistent. The authors conducted a meta-analysis to investigate the association between green tea and black tea consumption with PCa risk. Thirteen studies providing data on green tea or black tea consumption were identified by searching PubMed and ISI Web of Science databases and secondary referencing qualified for inclusion. A random-effects model was used to calculate the summary odds ratios (OR) and their corresponding 95% confidence intervals (CIs). For green tea, the summary OR of PCa indicated a borderline significant association in Asian populations for highest green tea consumption vs. non/lowest (OR = 0.62; 95% CI: 0.38-1.01); and the pooled estimate reached statistically significant level for case-control studies (OR = 0.43; 95% CI: 0.25-0.73), but not for prospective cohort studies (OR = 1.00; 95% CI: 0.66-1.53). For black tea, no statistically significant association was observed for the highest vs. non/lowest black tea consumption (OR = 0.99; 95% CI: 0.82-1.20). In conclusion, this meta-analysis supported that green tea but not black tea may have a protective effect on PCa, especially in Asian populations. Further research regarding green tea consumption across different regions apart from Asia is needed.


Lifetime exposure to adversity predicts functional impairment and healthcare utilization among individuals with chronic back pain.
Previous research has demonstrated an association between lifetime exposure to adverse events and chronic back pain (CBP), but the nature of this relationship has not been fully specified. Adversity exposure typically predicts undesirable outcomes, suggesting that lack of all adversity is optimal. However, we hypothesized that among individuals faced with CBP, a history of a low level of lifetime adversity would yield protective effects, manifested as lower impairment and healthcare utilization. Adult members of a national panel (N=396) endorsed a history of CBP when reporting their physical health status in an online survey; they further reported their functional impairment and healthcare utilization. Respondents had previously completed a survey of lifetime exposure to adverse events. Significant U-shaped quadratic relationships emerged between adversity and self-rated functional impairment (p<0.001), disabled employment status (p<0.001), frequency of physician/clinic visits for CBP (p<0.01), prescription (but not over-the-counter) analgesic use (p<0.01), and comorbid depression treatment seeking (p<0.01). Specifically, people with some lifetime adversity reported less impairment and healthcare utilization than people who had experienced either no adversity or a high level of adversity. Additional analyses failed to support alternative explanations of the findings. Implications for understanding and promoting resilience in the context of CBP are discussed.


C-2 neurectomy during atlantoaxial instrumented fusion in the elderly: patient satisfaction and surgical outcome.
The originally described technique of atlantoaxial stabilization using C-1 lateral mass and C-2 pars screws includes a C-2 neurectomy to provide adequate hemostasis and visualization for screw placement, enable adequate joint decortication and arthrodesis, and prevent new-onset postoperative C-2 neuralgia. However, inclusion of a C-2 neurectomy for this procedure remains controversial, likely due in part to a lack of studies that have specifically addressed whether it affects patient outcome. The authors' objective was to assess the surgical and clinical impact of routine C-2 neurectomy performed with C1-2 segmental instrumented arthrodesis in a consecutive series of elderly patients with C1-2 instability. Forty-four consecutive patients (mean age 71 years) underwent C1-2 instrumented fusion, including C-1 lateral mass screw insertion. Bilateral C-2 neurectomies were performed. Standardized clinical assessments were performed both pre- and postoperatively. Numbness or discomfort in a C-2 distribution was documented at follow-up. Fusion was assessed using the Lenke fusion grade. Among all 44 patients, mean blood loss was 200 ml (range 100-350 ml) and mean operative time was 129 minutes (range 87-240 minutes). There were no intraoperative complications, and no patients reported new postoperative onset or worsening of C-2 neuralgia postoperatively. Outcomes for the 30 patients with a minimum 13-month follow-up (range 13-72 months) were assessed. At a mean follow-up of 36 months, Nurick grade and pain numeric rating scale scores improved from 3.7 to 1.0 (p < 0.001) and 9.4 to 0.6 (p < 0.001), respectively. The mean postoperative Neck Disability Index score was 7.3%. The fusion rate was 97%, and the patient satisfaction rate was 93%. All 24 patients with preoperative occipital neuralgia reported relief. Seventeen patients noticed C-2 distribution numbness only during examination in the clinic, and 2 patients reported C-2 numbness, but it did not affect their daily function. In this series of C1-2 instrumented arthrodesis in elderly patients, excellent fusion rates were achieved, and patient satisfaction was not negatively affected by C-2 neurectomy. In the authors' experience, C-2 neurectomy enhanced surgical exposure of the C1-2 joint, thereby facilitating hemostasis, placement of instrumentation, and decortication of the joint space for arthrodesis. Importantly, with C-2 neurectomy in the present series, no cases of new onset postoperative C-2 neuralgia occurred, in contrast to a growing number of reports in the literature documenting new-onset C-2 neuralgia without C-2 neurectomy. On the contrary, 80% of patients in the present series had preoperative occipital neuralgia and in all of these patients this neuralgia was relieved following C1-2 instrumented arthrodesis with C-2 neurectomy.


Histological findings to five years after early conversion of kidney transplant patients from cyclosporine to everolimus: an analysis from the randomized ZEUS study.
Conversion from calcineurin inhibitor (CNI) therapy to everolimus within 6 months after kidney transplantation improves long-term graft function but can increase the risk of mild biopsy-proven acute cellular rejection (BPAR). We performed a post-hoc analysis of histological data from a randomized trial in order to further analyze histologic information obtained from indication and protocol biopsies up to 5 years after transplantation. Biopsy samples obtained up to 5 years post-transplant were analyzed from the randomized ZEUS study, in which kidney transplant patients were randomized at month 4.5 to switch to everolimus (n = 154) or remain on cyclosporine (CsA)-based immunosuppression (n = 146). All patients received mycophenolate and steroids. At least one investigator-initiated biopsy was undertaken in 53 patients in each group between randomization and year 5, with a mean (SD) of 2.6 (1.7) and 2.2 (1.4) biopsies per patient in the everolimus and CsA groups, respectively. In the everolimus and CsA groups, investigator-initiated biopsies showed (i) BPAR in 12.3 and 7.5% (p = 0.182) of patients, respectively, with episodes graded mild in 22/24 and 18/20 cases (ii) CsA toxicity lesions in 4.5 and 10.3% of patients (p = 0.076) (iii) antibody-mediated rejection in 0.6 and 2.7% of patients (p = 0.204), respectively. This analysis of histological findings in the ZEUS study to 5 years after kidney transplantation shows no increase in antibody-mediated rejection under everolimus-based therapy with a lower rate of CNI-related toxicity compared to a conventional CsA-based regimen, and confirms the preponderance of mild BPAR seen in the main study after the early switch to CsA-free everolimus therapy. ClinicalTrials.gov NCT00154310 . Date of registration: September 12, 2005.


Prostate cancer risk related to foods, food groups, macronutrients and micronutrients derived from the UK Dietary Cohort Consortium food diaries.
The influence of dietary factors remains controversial for screen-detected prostate cancer and inconclusive for clinically detected disease. We aimed to examine these associations using prospectively collected food diaries. A total of 1,717 prostate cancer cases in middle-aged and older UK men were pooled from four prospective cohorts with clinically detected disease (n=663), with routine data follow-up (means 6.6-13.3 years) and a case-control study with screen-detected disease (n=1054), nested in a randomised trial of prostate cancer treatments (ISCTRN 20141297). Multiple-day food diaries (records) completed by men prior to diagnosis were used to estimate intakes of 37 selected nutrients, food groups and items, including carbohydrate, fat, protein, dairy products, fish, meat, fruit and vegetables, energy, fibre, alcohol, lycopene and selenium. Cases were matched on age and diary date to at least one control within study (n=3528). Prostate cancer risk was calculated, using conditional logistic regression (adjusted for baseline covariates) and expressed as odds ratios in each quintile of intake (±95% confidence intervals). Prostate cancer risk was also investigated by localised or advanced stage and by cancer detection method. There were no strong associations between prostate cancer risk and 37 dietary factors. Prostate cancer risk, including by disease stage, was not strongly associated with dietary factors measured by food diaries in middle-aged and older UK men.


Fever without apparent source on clinical examination, lower respiratory infections in children, and other infectious diseases.
This section focuses on issues in infectious disease that are commonly encountered in pediatric office practice. Paul McCarthy discusses recent literature regarding the evaluation and management of acute fevers without apparent source on clinical examination in infants and children and the evaluation of children with prolonged fevers of unknown origin. Jean Klig reviews recent literature about lower respiratory tract infection in children. Finally, Jeffrey Kahn discusses recent developments concerning rotavirus vaccine.


Sex Differences Revealed in a Mouse CFA Inflammation Model with Macrophage Targeted Nanotheranostics.
Monocyte derived macrophages (MDMs) infiltrate sites of infection or injury and upregulate cyclooxygenase-2 (COX-2), an enzyme that stimulates prostaglandin-E2 (PgE2). Nanotheranostics combine therapeutic and diagnostic agents into a single nanosystem. In previous studies, we demonstrated that a nanotheranostic strategy, based on theranostic nanoemulsions (NE) loaded with a COX-2 inhibitor (celecoxib, CXB) and equipped with near-infrared fluorescent (NIRF) reporters, can specifically target circulating monocytes and MDMs. The anti-inflammatory and anti-nociceptive effects of such cell-specific COX-2 inhibition lasted several days following Complete Freund's Adjuvant (CFA) or nerve injury in male mice. The overall goal of this study was to investigate the extended (up to 40 days) impact of MDM-targeted COX-2 inhibition and any sex-based differences in treatment response; both of which remain unknown. Our study also evaluates the feasibility and efficacy of a preclinical nanotheranostic strategy for mechanistic investigation of the impact of such sex differences on clinical outcomes. Methods: CFA was administered into the right hind paws of male and female mice. All mice received a single intravenous dose of NIRF labeled CXB loaded NE twelve hours prior to CFA injection. In vivo whole body NIRF imaging and mechanical hypersensitivity assays were performed sequentially and ex vivo NIRF imaging and immunohistopathology of foot pad tissues were performed at the end point of 40 days. Results: Targeted COX-2 inhibition of MDMs in male and female mice successfully improved mechanical hypersensitivity after CFA injury. However, we observed distinct sex-specific differences in the intensity or longevity of the nociceptive responses. In males, a single dose of CXB-NE administered via tail vein injection produced significant improved mechanical hypersensitivity for 32 days as compared to the drug free NE (DF-NE) (untreated) control group. In females, CXB-NE produced similar, though less prominent and shorter-lived effects, lasting up to 11 days. NIRF imaging confirmed that CXB-NE can be detected up to day 40 in the CFA injected foot pad tissues of both sexes. There were distinct signal distribution trends between males and females, suggesting differences in macrophage infiltration dynamics between the sexes. This may also relate to differences in macrophage turnover rate between the sexes, a possibility that requires further investigation in this model. Conclusions: For the first time, this study provides unique insight into MDM dynamics and the early as well as longer-term targeted effects and efficacy of a clinically translatable nanotheranostic agent on MDM mediated inflammation. Our data supports the potential of nanotheranostics as presented in elucidating the kinetics, dynamics and sex-based differences in the adaptive or innate immune responses to inflammatory triggers. Taken together, our study findings lead us closer to true personalized, sex-specific pain nanomedicine for a wide range of inflammatory diseases.


Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.
To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with mortality from cardiovascular, cancer, or other conditions, under various circumstances. Systematic review and meta-analysis of observational studies and randomised controlled trials. Medline, Embase, Cochrane Library, and reference lists of relevant studies to August 2013; correspondance with investigators. Observational cohort studies and randomised controlled trials in adults, which reported associations between vitamin D (measured as circulating 25-hydroxyvitamin D concentration or vitamin D supplement given singly) and cause specific mortality outcomes. Data were extracted by two independent investigators, and a consensus was reached with involvement of a third. Study specific relative risks from 73 cohort studies (849,412 participants) and 22 randomised controlled trials (vitamin D given alone versus placebo or no treatment; 30,716 participants) were meta-analysed using random effects models and were grouped by study and population characteristics. In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods. Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.


Essential drugs and registration of pharmaceuticals: the Sri Lankan experience.
Many factors influence the regulation of pharmaceuticals in a country. The essential drugs concept, formulated by the World Health Organization to assist developing countries in selecting appropriate drugs, also provides a basis for regulation. Sri Lanka has long regulated pharmaceuticals as part of its health policy. Over 70% of 3436 pharmaceutical product registrations were found to be drugs (or alternatives) named in the country's essential drugs list. This is despite the fact that product registrations are mainly for the private health care sector, and the list is for the state sector. The essential drugs concept therefore appears to have influenced the pharmaceuticals registered in Sri Lanka.


Targeted delivery and endosomal cellular uptake of DARPin-siRNA bioconjugates: Influence of linker stability on gene silencing.
Specific cell targeting and efficient intracellular delivery are major hurdles for the widespread therapeutic use of nucleic acid technologies, particularly siRNA mediated gene silencing. To enable receptor-mediated cell-specific targeting, we designed a synthesis scheme that can be generically used to engineer Designed Ankyrin Repeat Protein (DARPin)-siRNA bioconjugates. Different linkers, including labile disulfide-, and more stable thiol-maleimide- and triazole- (click chemistry) tethers were employed. Crosslinkers were first attached to a 3'-terminal aminohexyl chain on the siRNA sense strands. On the protein side thiols of a C-terminal cysteine were used as anchoring sites for disulfide- and thiol-maleimide conjugate formations, while strain-promoted azido-alkyne cycloadditions were carried out at a metabolically introduced N-terminal azidohomoalanine. After establishing efficient purification methods, highly pure products were obtained. Bioconjugates of EpCAM-targeted DARPins with siRNA directed at the luciferase gene were evaluated for cell-specific binding, uptake and gene silencing. As shown by flow cytometry and fluorescence microscopy, all constructs retained the highly specific and high-affinity antigen recognition properties of the native DARPin. As expected, internalization was observed only in EpCAM-positive cell lines, and predominantly endolysosomal localization was detected. Disulfide linked conjugates showed lower serum stability against cleavage at the linker and thus lower internalization into endosomes compared to thiol-maleimide- and triazole-linked conjugates, yet induced more pronounced gene silencing. This indicates that the siRNA payload needs to be liberated from the protein in the endosome. Our data confirm the promise of DARPin-siRNA bioconjugates for tumor targeting, but also identified endosomal retention and limited cytosolic escape of the siRNA as the rate-limiting step for more efficient gene silencing.


2D motion analysis of rabbits after Achilles tendon rupture repair and histological analysis of extracted tendons: can the number of animals be reduced by operating both hind legs simultaneously?
Considering the 3Rs principle in animal experiments, there is a demand to perform research experiments with the fewest number of animals possible while warranting the welfare of the animals. Orthopaedic experimental studies involving operations on the hind legs of rabbits are either performed on one hind leg with the second hind leg serving as control or on both hind legs simultaneously (control: rabbits with no operations at all). The Achilles tendon of rabbits was transected and sutured, and the two-dimensional motion pattern of animals having only one leg operated was compared to rabbits having both hind legs operated (control: non-treated animals). Step length, maximum ankle angle, minimum ankle angle and the resulting range of motion of both hind legs were determined weekly over a time span from 3 weeks to 12 weeks post-operation. The results were fitted by a linear mixed effects model including time dependency. Moreover, all tendon specimen were analysed histologically. Tenocyte and tenoblast density, tenocyte and tenoblast nuclei width, inflammation level and collagen fibre alignment were determined. Statistically significant differences in the motion pattern were found when one-leg treated and two-leg treated animals were compared. However, the absolute differences were on average less than 20%. Histologically, 1-leg treated animals had tendon tissue with higher cell density, but lower inflammation and less ondulated collagen fibres compared to 2-leg treated animals; the nuclei width was the same for both groups. With regard to welfare, all animals were fine during the experiments. While comparative studies should be performed with one-leg treated animals due to interaction effects, for proof-of-principle studies, operating two legs per animal may be justified as the welfare of the animals is warranted. This is a great benefit in the sense of the 3Rs because up to 50% of animals can be spared.


Asymptomatic humans transmit dengue virus to mosquitoes.
Three-quarters of the estimated 390 million dengue virus (DENV) infections each year are clinically inapparent. People with inapparent dengue virus infections are generally considered dead-end hosts for transmission because they do not reach sufficiently high viremia levels to infect mosquitoes. Here, we show that, despite their lower average level of viremia, asymptomatic people can be infectious to mosquitoes. Moreover, at a given level of viremia, DENV-infected people with no detectable symptoms or before the onset of symptoms are significantly more infectious to mosquitoes than people with symptomatic infections. Because DENV viremic people without clinical symptoms may be exposed to more mosquitoes through their undisrupted daily routines than sick people and represent the bulk of DENV infections, our data indicate that they have the potential to contribute significantly more to virus transmission to mosquitoes than previously recognized.


Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement.
Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors. Here we report the case of a 45-year-old woman presenting with dyspnea and evidence of pleural effusion. She was diagnosed with malignant epithelioid pleural mesothelioma with brain metastasis and peritoneal carcinosis, refractory to initial standard chemotherapy treatment. Because of high PDL1 expression (100 %), she was treated with the anti-PD1 agent, pembrolizumab. Chemotherapy with cisplatin and pemetrexed was started, imaging studies showing stable disease after 3 treatment cycles. The patient underwent pleural decortication but rapidly progressed and thus started chemotherapy with carboplatin and gemcitabine. After 2 cycles she experienced seizures caused by a brain metastasis. This secondary lesion was surgically removed and confirmed as a metastasis from mesothelioma. Samples from both the primary tumor and the metastasis were molecularly characterized, the pleural sample proving ALK-positive and the brain sample, ALK-negative. PD-L1 was positive in 10 % of tumor cells in the pleural biopsy and 100 % in the brain lesion. Next generation sequencing analysis was negative for both samples. It was decided to start alectinib. Disease progression (peritoneal carcinosis and liver metastases) was documented after one month followed by complete bowel obstruction and recurrence in the site of the brain surgery. Alectinib was stopped and supportive care begun with parenteral nutrition via nasogastric tube. Pembrolizumab was started and after 15 days the patient's condition had significantly improved, enabling recanalization and restoration of enteral nutrition. Imaging displayed complete response of the brain metastasis, peritoneal carcinosis, bone lesions and mediastinal nodal metastases. A partial response was documented in the pleural and pulmonary nodules, with stable liver metastases. The patient is still undergoing immunotherapy and has no cancer-related symptoms. Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments.


Shengmai San, a Chinese herbal medicine protects against rat heat stroke by reducing inflammatory cytokines and nitric oxide formation.
The aim of the present study was to ascertain whether the possible occurrence of overproduction of inducible nitric oxide synthase (iNOS)-dependent nitric oxide (NO) in the brain and inflammatory cytokines in the peripheral blood exhibited during heat stroke can be reduced by prior administration of Shengmai San, a Chinese herbal medicine. Aminoguanidine, an iNOS inhibitor, was evaluated at the same time as a reference (positive control). Urethane-anesthetized rats were exposed to heat stress (ambient temperature of 43 degrees C) to induce heat stroke. Control rats were exposed to 24 degrees C. Mean arterial pressure and cerebral blood flow after the onset of heat stroke were all significantly lower than in control rats. However, cerebral iNOS immunoreactivity and NO levels were all greater after the onset of heat stroke. The serum levels of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha were all increased after the onset of heat stroke. Shengmai San (1.2 g/ml per rat) or aminoguanidine (30 micromol/ml per rat) was administered orally, daily, and consecutively for 7 days before the initiation of heat stress; and this significantly attenuated the heat stress-induced arterial hypotension, cerebral ischemia, and increased levels of brain iNOS-dependent NO production and serum cytokines formation. Shengmai San shared with the aminoguanidine almost the same efficacy in reducing iNOS-dependent NO and cytokines overproduction during heat stroke. These results suggest that Shengmai San or aminoguanidine protects against heat stroke-induced arterial hypotension and cerebral ischemia by inhibition of iNOS-dependent NO overproduction in the brain and excessive accumulation of several inflammatory cytokines in the peripheral blood stream.


Formation and Stability of Nontoxic Perovskite Precursor.
Strontium, calcium, and magnesium silicate hydrate phases are synthesized by the reaction between silica and solution of metal hydroxides. The kinetics of the reaction is recorded using a quartz crystal microbalance (QCM), continuously monitoring the change in frequency and dissipation energy. Based on QCM results, it is shown that properties of solutions like the pH-value or the type of ions play a pivotal function on the rate-determining stage of the reaction, the thickness of the diffuse layer, the formation of carbonates, as well as the kinetics of the formed phases. Further properties of the reaction products are investigated using X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and infrared spectroscopy (IR). With the help of thermogravimetric analysis (TGA) and temperature-dependent X-ray diffraction (XRD), we investigate how our synthesized phases can be turned into MSiO3 structures. Finally, the Goldschmidt rules for perovskites structures show that this might be an attractive way for new and nontoxic phases in the future.


Hydrocolloid dressings for healing diabetic foot ulcers.
Foot ulcers in people with diabetes are a prevalent and serious global health issue. Wound dressings are regarded as important components of ulcer treatment, with clinicians and patients having many different types to choose from including hydrocolloid dressings. There is a range of different hydrocolloids available including fibrous-hydrocolloid and hydrocolloid (matrix) dressings. A clear and current overview of current evidence is required to facilitate decision-making regarding dressing use. To compare the effects of hydrocolloid wound dressings with no dressing or alternative dressings on the healing of foot ulcers in people with diabetes. For this first update, in April 2013, we searched the following databases the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. There were no restrictions based on language or date of publication. Published or unpublished randomised controlled trials (RCTs) that have compared the effects on ulcer healing of hydrocolloid with alternative wound treatments in the treatment of foot ulcers in people with diabetes. Two review authors independently performed study selection, risk of bias assessment and data extraction. We included five studies (535 participants) in the review: these compared hydrocolloids with basic wound contact dressings, foam dressings, alginate dressings and a topical treatment. Meta-analysis of two studies indicated no statistically significant difference in ulcer healing between fibrous-hydrocolloids and basic wound contact dressings: risk ratio 1.01 (95% CI 0.74 to 1.38). One of these studies found that a basic wound contact dressing was more cost-effective than a fibrous-hydrocolloid dressing. One study compared a hydrocolloid-matrix dressing with a foam dressing and found no statistically significant difference in the number of ulcers healed. There was no statistically significant difference in healing between an antimicrobial (silver) fibrous-hydrocolloid dressing and standard alginate dressing; an antimicrobial dressing (iodine-impregnated) and a standard fibrous hydrocolloid dressing or a standard fibrous hydrocolloid dressing and a topical cream containing plant extracts. Currently there is no research evidence to suggest that any type of hydrocolloid wound dressing is more effective in healing diabetic foot ulcers than other types of dressing or a topical cream containing plant extracts. Decision makers may wish to consider aspects such as dressing cost and the wound management properties offered by each dressing type e.g. exudate management.


Bad stars or guiding lights? Learning from disasters to improve patient safety.
Cross-fertilisation of ideas across industries, settings and contexts potentially improves learning by providing fresh insights into error pathways. OBJECTIVES AND HYPOTHESES: To investigate six cases of human error drawn from disasters in the space, shipping, aviation, mining, rail and nuclear industries, and to apprehend similarities and differences in the antecedents to errors, the way they manifest, the course of events and the way they are tackled. The extent to which human intervention can exacerbate the problems by introducing new errors, how the cases are resolved and the lessons learnt were examined. Exemplar disaster events drawn from a very large sample of human errors. It is possible to identify and model a generic disaster pathway that applies across several industries, including healthcare. Despite differences between industries, it is clear that learning from disasters in other industries may provide important insights on how to prevent or ameliorate them in healthcare.


An analysis of amplified insulin gene products in diabetics of Indian origin.
We have previously described an increased incidence of the class 3 allele of the hypervariable region (HVR) 5' to the insulin gene in south Indian non-insulin dependent diabetics; this association is absent in Punjabi Sikhs with this disorder. Using the polymerase chain reaction we have amplified parts of the insulin gene from 130 subjects to look for mutations which may be in linkage disequilibrium with the class 3 allele and hence explain its association with non-insulin dependent diabetes (NIDDM). In 23 south Indian subjects with NIDDM, using the restriction enzyme MboII, a B chain mutant (insulin Chicago) was excluded. Two patterns (alpha and beta) were found, representing a PstI polymorphism in the 3' untranslated region of the insulin gene. In subjects homozygous for the class 1 allele, the allelic frequency for alpha was 0.94 (143/152) and for beta was 0.06, in heterozygotes (1,3) alpha 0.63 (54/86) and beta 0.37, and in homozygotes for the class 3 allele alpha 0.18 (4/22) and beta 0.82 (p less than 0.001), thus establishing linkage disequilibrium between these two loci. No differences in allelic frequency were found in the south Indians or Punjabi Sikhs between controls and the different types of non-insulin requiring diabetes (NIDDM, fibrocalculous pancreatic diabetes and maturity onset diabetes of the young) when both groups were matched for insulin genotypes. Thus, although this polymorphism in the 3' untranslated region of the insulin gene is in linkage disequilibrium with the class 3 allele, it does not appear to be any better at predicting diabetes than the class 3 allele itself.


The functional role of beta oscillations in Parkinson's disease.
Modulations of beta oscillations (13-30 Hz) during normal motor control suggest that they may act to promote current motor set at the expense of new movements. These oscillations are greatly enhanced in Parkinson's disease (PD) and there is strong correlative evidence linking beta activity at rest and beta changes in response to treatment with bradykinesia and rigidity. Some evidence that this link may be mechanistically important or causal comes from studies in which either cortical or subcortical sites have been stimulated in the beta frequency range causing modest but significant slowing of movements. However, recent trials in which high frequency deep brain stimulation (DBS) has only been delivered during periods of elevated beta activity have demonstrated major clinical effects that even exceed those of standard continuous high frequency DBS. These studies suggest that beta activity may be both causally and quantitatively important in the motor impairment of PD, and demonstrate how improvements in the understanding of the pathophysiology of PD can lead to enhanced therapeutic interventions in this condition.


Systemic gene expression after intravenous DNA delivery into adult mice.
Direct gene transfer into adult animals resulting in generalized or tissue-specific expression would facilitate rapid analysis of transgene effects and allow precise in vivo manipulation of biologic processes at the molecular level. A single intravenous injection of expression plasmid:cationic liposome complexes into adult mice efficiently transfected virtually all tissues. In addition to vascular endothelial cells, most of the extravascular parenchymal cells present in many tissues including the lung, spleen, lymph nodes, and bone marrow expressed the transgene without any apparent treatment-related toxicity. The transgene was still expressed in large numbers of cells in multiple tissues for at least 9 weeks after a single injection. Expression could be targeted to specific tissues and cell types, depending on the promoter element used.


Study protocol: improving cognition in people with progressive multiple sclerosis: a multi-arm, randomized, blinded, sham-controlled trial of cognitive rehabilitation and aerobic exercise (COGEx).
Cognitive dysfunction affects up to 70% of people with progressive MS (PMS). It can exert a deleterious effect on activities of daily living, employment and relationships. Preliminary evidence suggests that performance can improve with cognitive rehabilitation (CR) and aerobic exercise (EX), but existing data are predominantly from people with relapsing-remitting MS without cognitive impairment. There is therefore a need to investigate whether this is also the case in people with progressive forms of the disease who have objectively identified cognitive impairment. It is hypothesized that CR and EX are effective treatments for people with PMS who have cognitive impairment, in particular processing speed (PS) deficits, and that a combination of these two treatments is more effective than each individual treatment given alone. We further hypothesize that improvements in PS will be associated with modifications of functional and/or structural plasticity within specific brain networks/regions involved in PS measured with advanced MRI techniques. This study is a multisite, randomized, double-blinded, sham controlled clinical trial of CR and aerobic exercise. Three hundred and sixty subjects from 11 sites will be randomly assigned into one of four groups: CR plus aerobic exercise; CR plus sham exercise; CR sham plus aerobic exercise and CR sham plus sham exercise. Subjects will participate in the assigned treatments for 12 weeks, twice a week. All subjects will have a cognitive and physical assessment at baseline, 12 weeks and 24 weeks. In an embedded sub-study, approximately 30% of subjects will undergo structural and functional MRI to investigate the neural mechanisms underlying the behavioral response. The primary outcome is the Symbol Digit Modalities Test (SDMT) measuring PS. Secondary outcome measures include: indices of verbal and non-verbal memory, depression, walking speed and a dual cognitive-motor task and MRI. The study is being undertaken in 6 countries (11 centres) in multiple languages (English, Italian, Danish, Dutch); with testing material validated and standardized in these languages. The rationale for this approach is to obtain a robustly powered sample size and to demonstrate that these two interventions can be given effectively in multiple countries and in different languages. The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated.


Potent degradation of neuronal miRNAs induced by highly complementary targets.
MicroRNAs (miRNAs) regulate target mRNAs by silencing them. Reciprocally, however, target mRNAs can also modulate miRNA stability. Here, we uncover a remarkable efficacy of target RNA-directed miRNA degradation (TDMD) in rodent primary neurons. Coincident with degradation, and while still bound to Argonaute, targeted miRNAs are 3' terminally tailed and trimmed. Absolute quantification of both miRNAs and their decay-inducing targets suggests that neuronal TDMD is multiple turnover and does not involve co-degradation of the target but rather competes with miRNA-mediated decay of the target. Moreover, mRNA silencing, but not TDMD, relies on cooperativity among multiple target sites to reach high efficacy. This knowledge can be harnessed for effective depletion of abundant miRNAs. Our findings bring insight into a potent miRNA degradation pathway in primary neurons, whose TDMD activity greatly surpasses that of non-neuronal cells and established cell lines. Thus, TDMD may be particularly relevant for miRNA regulation in the nervous system.


Transcript profiles of Blumeria graminis development during infection reveal a cluster of genes that are potential virulence determinants.
High-density cDNA microarrays (2,027 unigenes) were used to analyze transcript profiles of the plant-pathogenic fungus Blumeria graminis f. sp. hordei throughout its asexual life cycle and development of infection. RNA was obtained from four stages preceding penetration and four stages after penetration of the host cells. The microarray data was validated by comparing the expression of a plasma membrane H+-ATPase and fructose-1,6-bis phosphatase with the data obtained from a quantitative polymerase chain reaction (PCR) assay. The results showed that there was a global switch in expression between the pre- and postpenetrative stages. This was largely due to accumulation of RNA encoding protein biosynthesis genes in the late stages. Other functional clusters, such as virulence-related genes and sterol metabolism genes, are up-regulated in pre- and postpenetration stages, respectively. A group of RNAs whose abundance correlated with the expression of cap20, a gene known to be required for virulence in Colletotrichum gloeosporioides, identified genes that are strong candidates for pathogenicity factors in B. graminis.


Impaired expression of interleukin-2 receptor (IL2R) in the immunosuppressed burned patient: reversal by exogenous IL2.
The capability of exogenous recombinant Interleukin 2 (rIL2) to increase expression of the IL2 receptor (IL2R), and to augment the in vitro proliferative response of lymphocytes from immunosuppressed burned patients (5-80% full-thickness burns) was examined. Throughout the postburn period the percentage of IL2R-bearing cells in Concanavalin A-activated cultures of patients' peripheral blood mononuclear cells (PBMC) was measured by direct immunofluorescence with monoclonal anti-IL2R antibodies. Mitogen-induced IL2R expression was decreased by 40-90% in cultures of patients' PBMC, parallel to their reduced alloreactivity. During this period of immunosuppression supplementation of the mitogen-activated cultures with recombinant IL2 (20 U/ml) significantly increased the number of IL2R-expressing cells in all patients studied. However, IL2-induced enhancement of blastogenesis in the MLR was observed only with the patients who, in mitogen-activated cultures, sustained numbers of IL2R-endowed cells at least 50% of their baseline (the level within the first 24 hours postburn). Also, unstimulated PBMC of the same responding patients demonstrated a restoration of proliferation in the presence of rIL2. These patients were survivors. Thus the proliferative response correlated well with the number of Con A- but not rIL2-induced IL2R-expressing cells. These results suggest that in burned patients, IL2 up-regulates its receptors, but they may represent low-affinity nonfunctional receptors. Thus thermal injury appears to affect expression of functional (high-affinity) receptors.


Cultural scripts for multiple and concurrent partnerships in southern Africa: why HIV prevention needs anthropology.
Multiple and concurrent sexual partnerships have been identified as southern Africa's key behavioural driver of HIV, resulting in calls to make partner reduction programming central to an intensified HIV prevention focus. Various efforts are currently being made in the region in response to this call. Such efforts will likely have as limited success as past prevention efforts if the cultural milieu in which sexual partnering practices are located and reproduced remains poorly understood, unaccounted for, and unaddressed in prevention programming. Focussed ethnographic discussions were held between October 2007 and November 2008 with 228 members of southern African non-government organisations representing seven countries. Discussions formed part of follow-up activities to a high level regional meeting and were aimed at exploring contextual factors in HIV transmission, most especially the role of culture in relation to multiple and concurrent partnerships. Common patterns in cultural scripts for the performance of sexuality were discernable. Several predominant scripts that tend to affirm and lend cultural legitimacy to multiple and concurrent partnering were identified, discussed and analysed. Effectuating change at the level of cultural scripting to discourage multiple and concurrent partnerships is required for sustainable long-term protection of people and communities against HIV. The success of partner reduction programs will be largely determined by the extent to which they are informed by anthropological knowledge and work with cultural logics to allow people to envision how they can transform obstacles into support for risk reduction.


Treating shoulder impingement using the supraspinatus synchronization exercise.
More and more athletes are seeking care in the chiropractic office for athletic injuries. This article presents a case report of a young athletic patient suffering from bilateral shoulder pain-shoulder impingement and presents a review of the literature and a review of shoulder anatomy. This report introduces the supraspinatus synchronization exercise with discussion and illustrations. This patient was treated using the supraspinatus synchronization exercise. A 16-yr-old female was seen suffering from a 4-month history of shoulder pain. She was a competitive swimmer in high school athletics and the pain was made worse by swimming the backstroke. A clinical diagnosis of bilateral stage I impingement of the shoulder (Neer's classification) was made. The patient was given instructions on how to perform the supraspinatus synchronization exercise, conservative therapies including chiropractic manipulative therapy, ice, high-voltage electrical muscle stimulation and rehabilitation exercise band exercises were also used. The patient was treated for seven treatments over a 4-wk period with resolution of the condition. The shoulder is a very complex joint, and many authors discuss the necessity of smooth synchronous movement to keep it pain free without going into how one measures this synchronous movement. The case presented in this report responded quickly to conservative treatment using the supraspinatus synchronization exercise. A good well-designed clinical trial needs to be set up to check the efficacy of this exercise.


What is a healthy body mass index for women in their seventies? Results from the Australian longitudinal study on women's health.
This study examines the relevance of the World Health Organization (WHO) optimal range for body mass index (BMI) of 18.5-25 kg/m(2) to morbidity in older women. Data were from 11,553 women who completed five mailed surveys at 3-year intervals between 1996 (age 70-75 years) and 2008 (age 82-87 years). Incidence and prevalence of diabetes mellitus (DM), hypertension, heart disease, and osteoporosis; hospital admissions; and mortality were assessed. The association between BMI in 1996 and each outcome was examined using logistic regression models with repeated measures and a proportional hazards model for survival. There were consistent associations between increasing BMI and increasing incidence and prevalence of DM, hypertension, and heart disease and between increasing BMI and decreasing risk of osteoporosis. The association with hospital admission was J shaped and lowest for BMI of 22-24 kg/m(2), whereas the association with mortality was U shaped, being lowest for BMI of 25-27 kg/m(2). These associations were not affected by excluding women with cancer or excluding the first 5 years of follow-up. These results illustrate the complexity of determining the optimal BMI range for women who survived to age 70-75 years. Although the WHO recommendation is appropriate for DM, hypertension, heart disease, and hospitalization, a slightly higher BMI range may be optimal for osteoporosis and mortality.


The effects of dipeptidyl peptidase-4 inhibitors on kidney outcomes.
To summarize evidence from randomized controlled trials (RCTs) concerning the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on kidney outcomes in patients with type 2 diabetes mellitus (T2DM). The Medline, EMBASE and Cochrane databases were searched for RCTs comparing DPP-4 inhibitors with a placebo, active comparator or standard care, with at least 500 person-years follow-up in patients with T2DM and with reporting of kidney outcomes. Treatment effects were summarized using random-effects meta-analysis. Ten trials including 47 955 patients (mean estimated glomerular filtration rate [eGFR] 71 mL/min/1.73m2 , mean follow-up 10 762 patient-years per trial) were eligible for inclusion. DPP-4 inhibitors were compared with placebo (five trials), active comparator (three trials), and standard care (two trials). Overall, treatment with DPP-4 inhibitors was associated with a greater decline in eGFR than treatment with the comparators (weighted mean difference -1.12 mL/min/1.73m2 , 95% confidence interval [CI] -1.61, -0.62; high-certainty evidence). There were no detectable effects of DPP-4 inhibitors on rates of doubling serum creatinine (risk ratio [RR] 1.10, 95% CI 0.90, 1.34; high-certainty evidence), end-stage kidney disease (RR 0.97, 95% CI 0.77, 1.23; high-certainty evidence), death from kidney causes (RR 1.81, 95% CI 0.67, 4.93; low-certainty evidence), or all-cause mortality (RR 1.01, 95% CI 0.95, 1.09; high-certainty evidence). DPP-4 inhibitors significantly reduced the risks of the surrogate kidney outcome of new albuminuria (RR 0.88, 95% CI 0.8, 0.98; moderate-certainty evidence) and worsening albuminuria (RR 0.88, 95% CI 0.82, 0.94; moderate-certainty evidence). There was no difference in the safety outcome of acute kidney injury (RR 1.04, 95% CI 0.57, 1.87; high-certainty evidence). Dipeptidyl peptidase-4 inhibitors are associated with a greater decline in eGFR, despite reducing the development and progression of albuminuria, and have no clear effect on other key kidney outcomes.


Domain Generalization and Adaptation Using Low Rank Exemplar SVMs.
Domain adaptation between diverse source and target domains is challenging, especially in the real-world visual recognition tasks where the images and videos consist of significant variations in viewpoints, illuminations, qualities, etc. In this paper, we propose a new approach for domain generalization and domain adaptation based on exemplar SVMs. Specifically, we decompose the source domain into many subdomains, each of which contains only one positive training sample and all negative samples. Each subdomain is relatively less diverse, and is expected to have a simpler distribution. By training one exemplar SVM for each subdomain, we obtain a set of exemplar SVMs. To further exploit the inherent structure of source domain, we introduce a nuclear-norm based regularizer into the objective function in order to enforce the exemplar SVMs to produce a low-rank output on training samples. In the prediction process, the confident exemplar SVM classifiers are selected and reweigted according to the distribution mismatch between each subdomain and the test sample in the target domain. We formulate our approach based on the logistic regression and least square SVM algorithms, which are referred to as low rank exemplar SVMs (LRE-SVMs) and low rank exemplar least square SVMs (LRE-LSSVMs), respectively. A fast algorithm is also developed for accelerating the training of LRE-LSSVMs. We further extend Domain Adaptation Machine (DAM) to learn an optimal target classifier for domain adaptation, and show that our approach can also be applied to domain adaptation with evolving target domain, where the target data distribution is gradually changing. The comprehensive experiments for object recognition and action recognition demonstrate the effectiveness of our approach for domain generalization and domain adaptation with fixed and evolving target domains.


Ultrahigh-Energy Accelerators: Eventually physicists will push into the domain of superintensity as well as that of superenergy.
Summarizing, one can say that the construction of ultrahigh-energy accelerators will be justifiable even at presently predictable costs. There is little doubt that eventually physicists will push into the domain of superintensity as well as that of superenergy. If they do this, it will be because the information that will then become available will be needed in order to formulate a more complete picture of nature. For the time being, we should examine the results of the 30-Gev synchrotrons in the light of their bearing on these large constructions of the future. But if these projects are to be realized in a time comparable to our lifetime, then those study projects which have become a necessary prelude to actual construction should be started now (3).


Systemic protection through remote ischemic preconditioning is spread by platelet-dependent signaling in mice.
Remote ischemic preconditioning (RIPC), the repetitive transient mechanical obstruction of vessels at a limb remote to the operative site, is a novel strategy to mitigate distant organ injury associated with surgery. In the clinic, RIPC has demonstrated efficacy in protecting various organs against ischemia reperfusion (IR), but a common mechanism underlying the systemic protection has not been identified. Here, we reasoned that protection may rely on adaptive physiological responses toward local stress, as is incurred through RIPC. Standardized mouse models of partial hepatic IR and of RIPC to the femoral vascular bundle were applied. The roles of platelets, peripheral serotonin, and circulating vascular endothelial growth factor (Vegf) were studied in thrombocytopenic mice, Tph1(-) (/) (-) mice, and through neutralizing antibodies, respectively. Models of interleukin-10 (Il10) and matrix metalloproteinase 8 (Mmp8) deficiency were used to assess downstream effectors of organ protection. The protection against hepatic IR through RIPC was dependent on platelet-derived serotonin. Downstream of serotonin, systemic protection was spread through up-regulation of circulating Vegf. Both RIPC and serotonin-Vegf induced differential gene expression in target organs, with Il10 and Mmp8 displaying consistent up-regulation across all organs investigated. Concerted inhibition of both molecules abolished the protective effects of RIPC. RIPC was able to mitigate pancreatitis, indicating that it can protect beyond ischemic insults. We have identified a platelet-serotonin-Vegf-Il10/Mmp8 axis that mediates the protective effects of RIPC. The systemic action, the conservation of RIPC effects among mice and humans, and the protection beyond ischemic insults suggest that the platelet-dependent axis has evolved as a preemptive response to local stress, priming the body against impending harm.


A prospective longitudinal study of children's theory of mind and adolescent involvement in bullying.
Theory of mind (ToM) allows the understanding and prediction of other people's behaviours based on their mental states (e.g. beliefs). It is important for healthy social relationships and thus may contribute towards children's involvement in bullying. The present study investigated whether children involved in bullying during early adolescence had poor ToM in childhood. Participants were members of the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative sample of 2,232 children and their families. We visited families when children were 5, 7, 10 and 12 years. ToM was assessed when the children were 5 years using eight standardized tasks. Identification of those children who were involved in bullying as victims, bullies and bully-victims using mothers', teachers' and children's reports was carried out when they were 12 years' old. Poor ToM predicted becoming a victim (effect size, d = 0.26), bully (d = 0.25) or bully-victim (d = 0.44) in early adolescence. These associations remained for victims and bully-victims when child-specific (e.g. IQ) and family factors (e.g. child maltreatment) were controlled for. Emotional and behavioural problems during middle childhood did not modify the association between poor ToM and adolescent bullying experiences. Identifying and supporting children with poor ToM early in life could help reduce their vulnerability for involvement in bullying and thus limit its adverse effects on mental health.


Serum Metabolomic Signatures for Knee Cartilage Volume Loss over 10 Years in Community-Dwelling Older Adults.
Osteoarthritis (OA) is the most prevalent joint disorder characterized by joint structural pathological changes with the loss of articular cartilage as its hallmark. Tools that can predict cartilage loss would help identify people at high risk, thus preventing OA development. The recent advance of the metabolomics provides a new avenue to systematically investigate metabolic alterations in disease and identify biomarkers for early diagnosis. Using a metabolomics approach, the current study aimed to identify serum metabolomic signatures for predicting knee cartilage volume loss over 10 years in the Tasmania Older Adult Cohort (TASOAC). Cartilage volume was measured in the medial, lateral, and patellar compartments of the knee by MRI at baseline and follow-up. Changes in cartilage volume over 10 years were calculated as percentage change per year. Fasting serum samples collected at 2.6-year follow-up were metabolomically profiled using the TMIC Prime Metabolomics Profiling Assay and pairwise metabolite ratios as the proxies of enzymatic reaction were calculated. Linear regression was used to identify metabolite ratio(s) associated with change in cartilage volume in each of the knee compartments with adjustment for age, sex, and BMI. The significance level was defined at α = 3.0 × 10−6 to control multiple testing. A total of 344 participants (51% females) were included in the study. The mean age was 62.83 ± 6.13 years and the mean BMI was 27.48 ± 4.41 kg/m2 at baseline. The average follow-up time was 10.84 ± 0.66 years. Cartilage volume was reduced by 1.34 ± 0.72%, 1.06 ± 0.58%, and 0.98 ± 0.46% per year in the medial, lateral, and patellar compartments, respectively. Our data showed that the increased ratios of hexadecenoylcarnitine (C16:1) to tetradecanoylcarnitine (C14) and C16:1 to dodecanoylcarnitine (C12) were associated with 0.12 ± 0.02% reduction per year in patellar cartilage volume (both p < 3.03 × 10−6). In conclusion, our data suggested that alteration of long chain fatty acid β-oxidation was involved in patellar cartilage loss. While confirmation is needed, the ratios of C16:1 to C14 and C12 might be used to predict long-term cartilage loss.


Butyrylcholinesterase in metabolic syndrome.
Butyrylcholinesterase may have a role in a number of metabolic functions and could affect the expression of insulin resistance syndrome. We present our integrated work using clinical, biochemical and bioinformatic approaches to delineate the possible function of this enzyme. Initially, we constructed a phylogenic tree with nucleotides and amino acid sequences and showed the existence of similar sequences in bacteria, plants and in other animals. We also demonstrated a possible pathogenic role for BChE in the common existence of insulin resistance, type 2 diabetes and Alzheimer's disease by in silico method and followed it up with a diabetic mouse study where cognition was slowed along with changes in BChE levels. In the next group of in silico studies, we employed THEMATICS method to identify the amino acids at the active site and later performed docking studies with drugs. THEMATICS predicted two clusters of ionisable amino acid residues that are in proximity: one with two residues and another with 11 showed perturbation in the THEMATICS curves. Using ISIS/Draw 2.5SP4, ARGUSLAB 4.0.1 and HEX 5.1. software. 3-D ligands were docked with BChE motif (from PDB). We did not find any of the ligands studied with significant docking distance, indicating they did not have direct interaction with the active site. Subsequently we performed in silico studies to compare the secondary structure and domain of BChE. Protein-protein interaction showed the following intersections with BChE UBE21, CHAT, APOE, AATF, DF ALDH9A1, PDHX, PONI PSME3 and ATP6VOA2. The integrative physiological roles of proteins with poorly known functions can be approached by generating leads in silico, which can be studied in vivo, setting into movement an iterative process.


Hepatic encephalopathy: Diagnosis and management.
Hepatic encephalopathy (HE) is a peculiar kind of brain dysfunction caused by liver insufficiency and/or portal-systemic shunting. It is related to gut-derived substances. It is a relevant cause of morbidity and hospitalisation for patients with cirrhosis. The prognosis of HE is important in terms of survival and re-hospitalisation. It is related to impaired quality of life, falls and poor driving; presents a relevant burden for caregivers and health services; and may negatively impact on patient's job and income. Proper diagnosis and classification are expected to improve HE management. Once diagnosed, the management and therapeutic options for HE are generally clear. The improvement of knowledge in recent years has also clarified which are the further aims of research in this field of medicine. Prophylaxis of overt HE should always be performed, and this is generally secondary prophylaxis. Primary prophylaxis should be done immediately after upper gastrointestinal bleeding. Great advances in the detection and treatment of mild forms of HE are expected to lead to further improvement in patient management.


Inc A/C plasmids are prevalent in multidrug-resistant Salmonella enterica isolates.
Bacterial plasmids are fragments of extrachromosomal double-stranded DNA that can contain a variety of genes that are beneficial to the host organism, like those responsible for antimicrobial resistance. The objective of this study was to characterize a collection of 437 Salmonella enterica isolates from different animal sources for their antimicrobial resistance phenotypes and plasmid replicon types and, in some cases, by pulsed-field gel electrophoresis (PFGE) in an effort to learn more about the distribution of multidrug resistance in relation to replicon types. A PCR-based replicon typing assay consisting of three multiplex PCRs was used to detect 18 of the 26 known plasmid types in the Enterobacteriaceae based on their incompatibility (Inc) replicon types. Linkage analysis was completed with antibiograms, replicon types, serovars, and Inc A/C. Inc A/C plasmids were prevalent in multidrug-resistant isolates with the notable exception of Salmonella enterica serovar Typhimurium. Cluster analysis based on PFGE of a subset of 216 isolates showed 155 unique types, suggesting a variable population, but distinct clusters of isolates with Inc A/C plasmids were apparent. Significant linkage of serovar was also seen with Inc replicon types B/O, I1, Frep, and HI1. The present study showed that the combination of Salmonella, the Inc A/C plasmids, and multiple-drug-resistant genes is very old. Our results suggest that some strains, notably serovar Typhimurium and closely related types, may have once carried the plasmid but that the resistance genes were transferred to the chromosome with the subsequent loss of the plasmid.


The benefits of a model of interval comprehensive assessments (MICA) in hereditary cancer Syndromes: Hereditary diffuse gastric cancer (HDGC) as an example.
A high percentage of individuals at risk for hereditary cancer syndromes are unaware of their risk. This is especially detrimental in syndromes such as hereditary diffuse gastric cancer due to a CDH1 germline mutation, for which lifesaving prevention is possible. Surveillance for diffuse gastric cancer in the syndrome is limited, hence the recommendation for prophylactic total gastrectomy for mutation carriers. Genetic counseling and testing is crucial in suspected families but initial contact could be limited, leading to the importance of an interval comprehensive review every 5-8 years to identify and screen additional high-risk individuals. Our contact with a hereditary diffuse gastric cancer family in Jordan in 2011 led to a number of family members receiving education and genetic counseling. Our model of interval comprehensive assessment (MICA) was constructed and implemented by conducting family information service, video call and emails to the high-risk individuals 7 years after initial contact. Using an updated family pedigree we reached out to an additional thirteen high-risk members in six different countries and provided them with genetic education, counseling, and testing. Six members agreed to CDH1 testing (46%). Four tested positive (66%) and one member (25%) underwent prophylactic total gastrectomy.


Dynamics of strongly-coupled spiking neurons.
We present a dynamical theory of integrate-and-fire neurons with strong synaptic coupling. We show how phase-locked states that are stable in the weak coupling regime can destabilize as the coupling is increased, leading to states characterized by spatiotemporal variations in the interspike intervals (ISIs). The dynamics is compared with that of a corresponding network of analog neurons in which the outputs of the neurons are taken to be mean firing rates. A fundamental result is that for slow interactions, there is good agreement between the two models (on an appropriately defined timescale). Various examples of desynchronization in the strong coupling regime are presented. First, a globally coupled network of identical neurons with strong inhibitory coupling is shown to exhibit oscillator death in which some of the neurons suppress the activity of others. However, the stability of the synchronous state persists for very large networks and fast synapses. Second, an asymmetric network with a mixture of excitation and inhibition is shown to exhibit periodic bursting patterns. Finally, a one-dimensional network of neurons with long-range interactions is shown to desynchronize to a state with a spatially periodic pattern of mean firing rates across the network. This is modulated by deterministic fluctuations of the instantaneous firing rate whose size is an increasing function of the speed of synaptic response.


Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer.
In prostate cancer, androgen receptor (AR) binding and androgen-responsive gene expression are defined by hormone-independent binding patterns of the pioneer factors FoxA1 and GATA2. Insufficient evidence of the mechanisms by which GATA2 contributes to this process precludes complete understanding of a key determinant of tissue-specific AR activity. Our observations suggest that GATA2 facilitates androgen-responsive gene expression by three distinct modes of action. By occupying novel binding sites within the AR gene locus, GATA2 positively regulates AR expression before and after androgen stimulation. Additionally, GATA2 engages AR target gene enhancers prior to hormone stimulation, producing an active and accessible chromatin environment via recruitment of the histone acetyltransferase p300. Finally, GATA2 functions in establishing and/or sustaining basal locus looping by recruiting the Mediator subunit MED1 in the absence of androgen. These mechanisms may contribute to the generally positive role of GATA2 in defining AR genome-wide binding patterns that determine androgen-responsive gene expression profiles. We also find that GATA2 and FoxA1 exhibit both independent and codependent co-occupancy of AR target gene enhancers. Identifying these determinants of AR transcriptional activity may provide a foundation for the development of future prostate cancer therapeutics that target pioneer factor function.


Carbon sources for the Palaeozoic giant fungus Prototaxites inferred from modern analogues.
A wide range of carbon isotope values in the Devonian fossil Prototaxites has been interpreted to support heterotrophy and the classification of Prototaxites as a giant fungus. This inference remains controversial because of the huge size of Prototaxites relative to co-occurring terrestrial vegetation and the lack of existing fungal analogues that display equally broad isotopic ranges. Here, we show wide isotopic variability in the modern saprotrophic fungus Arrhenia obscurata collected adjacent to shallow meltwater pools of a sparsely vegetated glacial succession in the Washington Cascades, USA. Soils collected specifically around the edges of these pools were up to 5 per thousand higher in delta(13)C than adjacent soils consistent with C(3) origin. Microbial sources of primary production appear to cause these high delta(13)C values, and the environment may be analogous to that of the Early Devonian landscapes, where Prototaxites individuals with extreme isotopic variance were found. Carbon isotopes are also compared in Prototaxites, Devonian terrestrial vascular plants, and Devonian algal-derived lake sediments. Prototaxites isotopic values show little correspondence with those of contemporaneous tracheophytes, providing further evidence that non-vascular land plants or aquatic microbes were important contributors to its carbon sources. Thus, a saprotrophic fungal identity is supported for Prototaxites, which may have relied on deposits of algal-derived organic matter in floodplain environments that were less dominated by vascular plants than a straight reading of the macrofossil record might suggest.


Which device should be considered the best for lung isolation: double-lumen endotracheal tube versus bronchial blockers.
This review is a clinical comparison between double-lumen endotracheal tubes and bronchial blockers to determine which device is considered the best for lung isolation. Double-lumen endotracheal tubes and bronchial blockers have been found to be clinically equivalent in terms of performance in providing lung collapse for patients with normal airways. In the last five years, however, numerous reports have indicated a preference for the use of bronchial blockers in patients with airway abnormalities. For nonthoracic anesthesiologists who have limited experience in thoracic anesthesia cases, none of the devices (double-lumen tubes or bronchial blockers) have been shown to provide any advantage while in use due to a high incidence of unrecognized malpositions. Overall, each device provides advantages depending upon the case, such as absolute lung separation with a double-lumen endotracheal tube or the use of a bronchial blocker in a difficult airway for a patient requiring lung isolation. Double-lumen endotracheal tubes and bronchial blockers should be part of the armamentarium of every anesthesiologist involved in lung isolation techniques and every device should be tailored to specific case needs.


The effect of exogenous gonadotropins on ovarian function in goats actively immunized against inhibin.
The aim of this investigation was to compare the ovarian response to superovulatory treatments in does before and after inhibin immunization, with a view to optimizing the superovulatory potential of the caprine ovary. To avoid interference by the ovarian cycle, the experiment was conducted out-of-season. At the onset of the experiment 48 does were subjected to treatment with an sc implant of the progestogen norgestomet, combined with a gonadotropin; eight does each received a single injection of 1200 IU eCG, 400 IU eCG or 2 mL physiological saline (control) or six injections (at 12 h intervals) constituting 16 or 5.4 AU pFSH. The does were mated and subjected to embryo collection 6 to 7 d later. Throughout the experiment ovarian function (by ultrasonography) and plasma levels of inhibin antibodies and progesterone were monitored. Of 40 does treated during the first part of the experiment, 48% showed estrus. The ovarian response in does treated with a high or low dose of eCG or a low dose of pFSH was barely in excess of the ovarian response in the saline-treated controls, whereas a superovulatory dose of pFSH (16 AU) gave a satisfactory response of, on average, 14.5 ovulations (yielding 8.8 flushed ova and embryos). Immediately after the does had been subjected to embryo collection they were actively immunized against inhibin by administering two injections of a recombinant α-subunit of ovine inhibin at four week intervals. All immunized does produced antibodies with the maximal titer reached two weeks after the second injection. Groups of immunized does were subjected to the same gonadotropin treatments as before (avoiding allocation of individuals to the same treatments). This time all does showed estrous symptoms. The ovulatory response to the various treatments, including the saline controls, was virtually identical, the overall average being 21.8 follicles and 9.1 ovulations. The average embryo yield per doe was 5.7. The results imply that inhibin acted as the key factor in determining the ovulatory response since no impact of any of the supplementary gonadotropins was noted in inhibin-immunized does. This finding gives rise to the notion that inhibin antibodies may act primarily by an intraovarian paracrine action rather than by reducing the suppressive action of inhibin on pituitary FSH release. Further, these findings confirm earlier reports that eCG is less suitable than FSH for inducing superovulation in goats, and indicate that active immunization against inhibin may be considered a viable alternative to using exogenous gonadotropin for inducing superovulation in goats.


Age and Number of Surgeries Increase Risk for Complications in Polytrauma Patients with Operative Maxillofacial Fractures.
Poly-trauma patients often sustain complex head/neck injuries requiring prolonged hospitalizations and multiple operations. Few studies have evaluated the associated injury patterns and risk factors for poor clinical outcomes. Consecutive poly-trauma patients with operative maxillofacial fractures treated at a level 1 trauma medical center between 1995 and 2013 were evaluated. Concomitant head/neck injuries to identify potential injury patterns were numerated. Lastly, a multivariate analysis was performed to determine independent risk factors for complications during the acute hospitalization period. Totally, 232 poly-trauma patients presented with operative maxillofacial fractures, while 38.8% of patients had a secondary maxillofacial fracture, 16.4% had intracranial hemorrhage, 23.7% had skull fractures, and 12.1% had spinal fractures. The rate of complication during admission was 28.3%. Multivariate analysis revealed advanced patient age and increased number of operations to predict the rate of complication. Patients requiring more than one operation had a 1.8-fold increase in complication rate (p<0.01) and older patients had a 4.5% increase in complication rate (p<0.05) for every year of increased age. Poly-trauma patients have a high incidence of secondary maxillofacial fractures, concomitant head/neck injury, and inpatient complication rate. Knowledge of associated injury patterns can help increased awareness and can guide physician decision-making to avoid missed/delayed injuries.


Metformin does not affect risk of biochemical recurrence following radical prostatectomy: results from the SEARCH database.
While epidemiologic studies suggest that metformin use among diabetics may decrease prostate cancer (PC) incidence, the effect of metformin use on PC outcome is unclear. We investigated the association between pre-operative metformin use, dose and duration of use and biochemical recurrence (BCR) in PC patients with diabetes who underwent radical prostatectomy (RP). We conducted a retrospective cohort analysis within the Shared Equal Access Regional Cancer Hospital (SEARCH) database of 371 PC patients with diabetes who underwent RP. Time to BCR between metformin users and non-users, and by metformin dose and duration of use was assessed using multivariable Cox proportional analysis adjusted for demographic, clinical and/or pathologic features. Time to castrate-resistant PC (CRPC), metastases and PC-specific mortality were explored as secondary outcomes using unadjusted analyses. Of 371 diabetic men, 156 (42%) were using metformin before RP. Metformin use was associated with more recent year of surgery (P<0.0001) but no clinical or pathologic characteristics. After adjustment for year of surgery, clinical and pathologic features, there were no associations between metformin use (hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.61-1.41), high metformin dose (HR 0.96; 95% CI 0.57-1.61) or duration of use (HR 1.00; 95% CI 0.99-1.02) and time to BCR. A total of 14 patients (3.8%) developed CRPC, 10 (2.7%) distant metastases and 8 (2.2%) died from PC. Unadjusted analysis suggested that high metformin dose vs non-use was associated with increased risk of CRPC (HR 5.1; 95% CI 1.6-16.5), metastases (HR 4.8; 95% CI 1.2-18.5) and PC-specific mortality (HR 5.0; 95% CI 1.1-22.5). Metformin use, dose or duration of use was not associated with BCR in this cohort of diabetic PC patients treated with RP. The suggestion that higher metformin dose was associated with increased risk of CRPC, metastases and PC-specific mortality merits testing in large prospective studies with longer follow-up.


GSH or palmitate preserves mitochondrial energetic/redox balance, preventing mechanical dysfunction in metabolically challenged myocytes/hearts from type 2 diabetic mice.
In type 2 diabetes, hyperglycemia and increased sympathetic drive may alter mitochondria energetic/redox properties, decreasing the organelle's functionality. These perturbations may prompt or sustain basal low-cardiac performance and limited exercise capacity. Yet the precise steps involved in this mitochondrial failure remain elusive. Here, we have identified dysfunctional mitochondrial respiration with substrates of complex I, II, and IV and lowered thioredoxin-2/glutathione (GSH) pools as the main processes accounting for impaired state 4→3 energetic transition shown by mitochondria from hearts of type 2 diabetic db/db mice upon challenge with high glucose (HG) and the β-agonist isoproterenol (ISO). By mimicking clinically relevant conditions in type 2 diabetic patients, this regimen triggers a major overflow of reactive oxygen species (ROS) from mitochondria that directly perturbs cardiac electro-contraction coupling, ultimately leading to heart dysfunction. Exogenous GSH or, even more so, the fatty acid palmitate rescues basal and β-stimulated function in db/db myocyte/heart preparations exposed to HG/ISO. This occurs because both interventions provide the reducing equivalents necessary to counter mitochondrial ROS outburst and energetic failure. Thus, in the presence of poor glycemic control, the diabetic patient's inability to cope with increased cardiac work demand largely stems from mitochondrial redox/energetic disarrangements that mutually influence each other, leading to myocyte or whole-heart mechanical dysfunction.


Social value of a nutritional counselling and support program for breastfeeding in urban poor settings, Nairobi.
In Kenya, poor maternal nutrition, suboptimal infant and young child feeding practices and high levels of malnutrition have been shown among the urban poor. An intervention aimed at promoting optimal maternal infant and young child nutrition (MIYCN) practices in urban poor settings in Nairobi, Kenya was implemented. The intervention involved home-based counselling of pregnant and breastfeeding women and mothers of young children by community health volunteers (CHVs) on optimal MIYCN practices. This study assesses the social impact of the intervention using a Social Return on Investment (SROI) approach. Data collection was based on SROI methods and used a mixed methods approach (focus group discussions, key informant interviews, in-depth interviews, quantitative stakeholder surveys, and revealed preference approach for outcomes using value games). The SROI analysis revealed that the MIYCN intervention was assessed to be highly effective and created social value, particularly for mothers and their children. Positive changes that participants experienced included mothers being more confident in child care and children and mothers being healthier. Overall, the intervention had a negative social impact on daycare centers and on health care providers, by putting too much pressure on them to provide care without providing extra support. The study calculated that, after accounting for discounting factors, the input ($USD 419,716) generated $USD 8 million of social value at the end of the project. The net present value created by the project was estimated at $USD 29.5 million. $USD 1 invested in the project was estimated to bring USD$ 71 (sensitivity analysis: USD$ 34-136) of social value for the stakeholders. The MIYCN intervention showed an important social impact in which mothers and children benefited the most. The intervention resulted in better perceived health of mothers and children and increased confidence of mothers to provide care for their children, while it resulted in negative impacts for day care center owners and health care providers.


An assessment of the phototoxic hazard of a personal product ingredient using in vitro assays.
Where substances are intended for use in personal products applied to the skin an assessment of potential phototoxic hazard is required. This report describes a tiered testing strategy involving in vitro assays used for the phototoxic hazard assessment of a personal product ingredient (Ingredient X). The initial assay was measurement of a UV/visible absorption spectrum to identify absorption at relevant wavelengths. This was followed by in vitro assays for phototoxicity (3T3 cell neutral red uptake phototoxicity test) and photoallergy (photobinding to human serum albumin). These in vitro screens gave equivocal results for Ingredient X which appeared to suggest a weak phototoxic reaction. To further evaluate the phototoxic hazard of Ingredient X to human skin, a phototoxicity assay using a 3-D human skin model was conducted. Ingredient X did not cause phototoxicity in this assay. Overall conclusions from these studies were that although Ingredient X showed slight intrinsic potential for photoactivation, it was unlikely to present a hazard to human skin. This report illustrates the value in a step-wise strategy of the use of human skin models to help interpret the results of other in vitro phototoxicity assays.


Unintended Consequences of Systemic and Ablative Oncologic Therapy in the Abdomen and Pelvis.
Human cancers are genetically complex and diverse. Although advances in oncologic therapy aim to define and target unique steps in carcinogenesis, oncologists often rely on less discriminate anticancer therapies that have consequences for normal tissues. Even many of the so-called targeted therapies currently employed can adversely affect normal cells, leading to complications that necessitate dose reductions or cessation of specific therapies. This article explores the unintended consequences of currently employed systemic and ablative anticancer therapies that might manifest at imaging examinations of the abdomen and pelvis, including cytotoxic, molecular targeted, and immunologic agents; ablation; and hematopoietic stem cell transplant. Each of these treatments can have both major and minor unintended effects in the targeted organ(s), in local or adjacent structures, or at distant sites. Timely detection and reporting of adverse consequences of anticancer therapies by the astute imager can result in critical treatment modifications and/or lifesaving interventions; therefore, knowledge of these unintended effects is paramount for radiologists interpreting the results of imaging examinations in cancer patients. ©RSNA, 2018.


Neuronal signal transduction pathways: wasteland or the promised land?
Proteins used in signal transduction pathways are commonly found in different cell types and organs. However, specific proteins whose expression is highly restricted are also utilized for allowing discrete responsiveness to signals that are otherwise ignored by other cells. How the brain uses common and specific signal proteins for communication within and beyond the cerebrum has been an area of intense study. A new book concentrates on the signaling that occurs in the brain under normal and pathological conditions--memory, apoptosis, neurodegeneration, depression, and drug dependence--and is filled with chapters written by experts in neurobiology and neurophysiology. Bryan Roth reviews the book and discusses in detail several chapters that may lead to promising future research.


Tissue composition regulates distinct viscoelastic responses in auricular and articular cartilage.
It is well-accepted that articular (ART) cartilage composition and tissue architecture are intimately related to mechanical properties. On the other hand, very little information about other cartilage tissues is available, such as elastin-rich auricular (AUR) cartilage. While thorough investigation of ART cartilage has enhanced osteoarthritis research, ear cartilage reconstruction and tissue engineering (TE) could benefit in a similar way from in-depth analysis of AUR cartilage properties. This study aims to explore the constituent-function relationships of AUR cartilage, and how elastin influences mechanical behavior. Stress-relaxation indentation and tensile tests were performed on bovine ART and AUR cartilage. Elastase incubation was performed to simultaneously deplete elastin and sulfated glycosaminoglycans (sGAG), while hyaluronidase incubation was used to deplete sGAG-only, in order to systematically investigate matrix components in material behavior. ART and AUR cartilages showed different viscoelastic behaviors, with AUR cartilage exhibiting a more elastic behavior. Higher equilibrium properties and limited viscous dissipation of strain energy were observed in AUR cartilage, while ART cartilage exhibited a rapid viscous response and high resistance to instantaneous loading. In conclusion, loss of sGAG had no effect on auricular mechanics in contrast to articular cartilage where GAG loss clearly correlated with mechanical properties. Auricular cartilage without elastin lost all compressive mechanical integrity, whereas in articular cartilage this was provided by collagen. This work shows for the first time the involvement of elastin in the mechanical behavior of ear cartilage. In future, this data can be used in AUR cartilage TE efforts to support reproduction of tissue-specific mechanical properties.


The argument for integrating vector control with multiple drug administration campaigns to ensure elimination of lymphatic filariasis.
There is a danger that mass drug administration campaigns may fail to maintain adequate treatment coverage to achieve lymphatic filariasis elimination. Hence, additional measures to suppress transmission might be needed to ensure the success of the Global Program for the Elimination of Lymphatic Filariasis. Vector control successfully eliminated lymphatic filariasis when implemented alone or with mass drug administration. Challenges to lymphatic filariasis elimination include uncertainty of the exact level and duration of microfilarial suppression required for elimination, the mobility of infected individuals, consistent non-participation of some infected individuals with mass drug administration, the possible development of anti-filarial drug resistance and treatment strategies in areas co-endemic with loasis. Integration of vector control with mass drug administration can address some of these challenges. The potential benefits of vector control would include: (1) the ability to suppress filariasis transmission without the need to identify all individual 'foci of infection'; (2) minimizing the risk of reestablishment of transmission from imported microfilaria positive individuals; and (3) decreasing the risk of dengue or malaria transmission where, respectively, Aedes or Anopheles are lymphatic filariasis vectors. With adequate sustained treatment coverage, mass drug administration should meet the criteria for elimination of lymphatic filariasis. However, it may be difficult to sustain sufficiently high mass drug administration coverage to achieve lymphatic filariasis elimination in some areas, particularly, where Aedes species are the vectors. Since vector control was effective in controlling and even eliminating lymphatic filariasis transmission, integration of vector control with mass drug administration will ensure the sustainability of transmission suppression and thereby better ensure the success of national filariasis elimination programs. Although trials of some vector control interventions are needed, proven vector control strategies are ready for immediate integration with mass drug administration for many important vectors. Vector control is the only presently available additional lymphatic filariasis control measure with the potential for immediate implementation.


Closure devices and vascular complications among percutaneous coronary intervention patients receiving enoxaparin, glycoprotein IIb/IIIa inhibitors, and clopidogrel.
The objectives of this study were to explore the rate of vascular complications using closure devices (CDs) vs. manual compression (MC) among percutaneous coronary intervention (PCI) patients receiving enoxaparin, clopidogrel, aspirin, and GP IIb/IIIa inhibitors. The Evaluating Enoxaparin Clotting Times (ELECT) study enrolled patients receiving enoxaparin, clopidogrel, and GP IIb/IIIa inhibitors when necessary. Any approved CD or MC was allowed post-PCI, and clinical outcome data were prospectively collected. Four hundred forty-five patients had anti-Xa levels measured by a core laboratory and by a novel point-of-care device that reports ENOX times. All received enoxaparin, aspirin, and clopidogrel, and 75% received a concomitant GP IIb/IIIa inhibitor. Major and minor bleeding were defined according to TIMI criteria. "Any bleeding" included the occurrence of access site complications including hematoma, significant rebleeding, or bleeding delaying hospital discharge. TIMI major plus minor bleeding occurred in 1.5% of the patients who received CD vs. 1.8% of patients with MC (P = 0.83). Any bleeding occurred in 12.2% of CD vs. 5.7% MC (P = 0.02), and in 9.5% of patients receiving GP IIb/IIIa inhibitor vs. 2.8% (P = 0.01) among those who did not. For patients receiving both a GP IIb/IIIa inhibitor and CD, any bleeding was observed in 13.7% vs. 3.4% (P = 0.006) among patients who received neither. While minor and major TIMI bleeding remained very low in both groups, CD was associated with a twofold increase in risk of any-bleeding event when compared to MC, especially when using GP IIb/IIIa inhibitors.