Role of Rho and myosin phosphorylation in actin stress fiber assembly in mesangial cells.
Treatment of renal glomerular mesangial cells with adenosine 3',5'-cyclic monophosphate (cAMP)-elevating agents induces actin stress fiber disassembly, myosin light chain (MLC) dephosphorylation, loss of adhesion to the substratum and cell shape change [J. I. Kreisberg and M. A. Venkatachalam. Am. J. Physiol. 251 (Cell Physiol. 20): C505-C511, 1986]. Thrombin and vasopressin block the effects of cAMP. Because these agents are known to promote stress fiber formation via the small GTP-binding protein Rho, we investigated the effect of an activated variant of Rho on the response to cAMP elevation. Microinjecting V14-Rho completely blocked the effect of cAMP elevation on cell shape and the actin cytoskeleton, whereas inactivating Rho with botulinum C3 exoenzyme induced stress fiber disruption and cell retraction that was indistinguishable from that caused by elevations in intracellular levels of cAMP. Disruption of actin stress fibers by cAMP has previously been ascribed to MLC dephosphorylation; however, both C3 and cytochalasin D also caused dephosphorylation of MLC, whereas blocking MLC dephosphorylation failed to block the cAMP-induced loss of actin stress fibers. We conclude that Rho can modulate the effects of cAMP elevation and suggest that MLC dephosphorylation may be a consequence of actin stress fiber disassembly.


Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients.
Telomere dysfunction and fusion can drive genomic instability and clonal evolution in human tumours, including breast cancer. Telomere length is a critical determinant of telomere function and has been evaluated as a prognostic marker in several tumour types, but it has yet to be used in the clinical setting. Here we show that high-resolution telomere length analysis, together with a specific telomere fusion threshold, is highly prognostic for overall survival in a cohort of patients diagnosed with invasive ductal carcinoma of the breast (n = 120). The telomere fusion threshold defined a small subset of patients with an extremely poor clinical outcome, with a median survival of less than 12 months (HR = 21.4 (7.9-57.6), P < 0.0001). Furthermore, this telomere length threshold was independent of ER, PGR, HER2 status, NPI, or grade and was the dominant variable in multivariate analysis. We conclude that the fusogenic telomere length threshold provides a powerful, independent prognostic marker with clinical utility in breast cancer. Larger prospective studies are now required to determine the optimal way to incorporate high-resolution telomere length analysis into multivariate prognostic algorithms for patients diagnosed with breast cancer.


Sexual functioning and practices in a multi-ethnic study of midlife women: baseline results from SWAN.
This study examined the sexual practices and function of midlife women by ethnicity (African American, Caucasian, Chinese, Hispanic, Japanese) and menopausal status. Sexual behavior was compared in 3,262 women in the baseline cohort of SWAN. Participants were 42 to 52 years old, premenopausal or early perimenopausal, and not hysterectomized or using hormones. Analysis used multivariate proportional odds regression. In our sample, 79% had engaged in sex with a partner in the last 6 months, and a third considered sex to be very important. Common reasons for no sex (n = 676) were lack of partner (67%), lack of interest (33%), and fatigue (16%). Compared with Caucasians, Japanese and Chinese women were less likely, and African Americans more likely, to report sex as very important (p < 0.005). Significant ethnic differences were found for frequency of all practices. Perimenopause status was associated only with higher frequencies of masturbation and pain during intercourse.


Transfer entropy computation using the Perron-Frobenius operator.
We propose a method for computing the transfer entropy between time series using Ulam's approximation of the Perron-Frobenius (transfer) operator associated with the map generating the dynamics. Our method differs from standard transfer entropy estimators in that the invariant measure is estimated not directly from the data points, but from the invariant distribution of the transfer operator approximated from the data points. For sparse time series and low embedding dimension, the transfer operator is approximated using a triangulation of the attractor, whereas for data-rich time series or higher embedding dimension, we use a faster grid approach. We compare the performance of our methods with existing estimators such as the k nearest neighbors method and kernel density estimation method, using coupled instances of well known chaotic systems: coupled logistic maps and a coupled Rössler-Lorenz system. We find that our estimators are robust against moderate levels of noise. For sparse time series with less than 100 observations and low embedding dimension, our triangulation estimator shows improved ability to detect coupling directionality, relative to standard transfer entropy estimators.


Functional PEG-modified thin films for biological detection.
We report a general procedure to prepare functional organic thin films for biological assays on oxide surfaces. Silica surfaces were functionalized by self-assembly of an amine-terminated silane film using both vapor- and solution-phase deposition of 3'-aminopropylmethyldiethoxysilane (APMDES). We found that vapor-phase deposition of APMDES under reduced pressure produced the highest quality monolayer films with uniform surface coverage, as determined by atomic force microscopy (AFM), ellipsometry, and contact angle measurements. The amine-terminated films were chemically modified with a mixture of carboxylic acid-terminated poly(ethylene glycol) (PEG) chains of varying functionality. A fraction of the PEG chains (0.1-10 mol %) terminated in biotin, which produced a surface with an affinity toward streptavidin. When used in pseudo-sandwich assays on waveguide platforms for the detection of Bacillus anthracis protective antigen (PA), these functional PEG surfaces significantly reduced nonspecific binding to the waveguide surface while allowing for highly specific binding. Detection of PA was used to validate these films for sensing applications in both buffer and complex media. Ultimately, these results represent a step toward the realization of a robust, reusable, and autonomous biosensor.


Cancer incidence rates among South Asians in four geographic regions: India, Singapore, UK and US.
Data are limited regarding cancer incidence among Indians residing in different geographic regions around the world. Examining such rates may provide us with insights into future aetiological research possibilities as well as screening and prevention. Incidence rates for all cancers combined and 19 specific cancers were obtained for India from Globocan 2002, for Indians in Singapore from Cancer Incidence in Five Continents (VIII), and from national data sources for South Asians (SA) in the United Kingdom (UK) and for Asian Indians/Pakistanis (AIP) and whites in the United States (US). We observed the lowest total cancer incidence rates in India (111 and 116 per 100,000 among males and females, respectively, age-standardized to the 1960 world population) and the highest among US whites (362 and 296). Cancer incidence rates among Indians residing outside of India were: intermediate Singapore (102 and 132), UK (173 and 179) and US ranges 152-176 and 142-164. A similar pattern was observed for cancers of the colorectum, prostate, thyroid, pancreas, lung, breast and non-Hodgkin lymphoma. In contrast, rates for cancers of the oral cavity, oesophagus, larynx and cervix uteri were highest in India. Although little geographic variability was apparent for stomach cancer incidence, Indians in Singapore had the highest rates compared with any other region. The UK SA and the US AIP appear with adopt the cancer patterns of their host country. Variations in environmental exposures such as tobacco use, diet and infection, as well as better health care access and knowledge may explain some of the observed incidence differences.


Yeast As a Chassis for Developing Functional Assays to Study Human P53.
The finding that the well-known mammalian P53 protein can act as a transcription factor (TF) in the yeast S. cerevisiae has allowed for the development of different functional assays to study the impacts of 1) binding site [i.e., response element (RE)] sequence variants on P53 transactivation specificity or 2) TP53 mutations, co-expressed cofactors, or small molecules on P53 transactivation activity. Different basic and translational research applications have been developed. Experimentally, these approaches exploit two major advantages of the yeast model. On one hand, the ease of genome editing enables quick construction of qualitative or quantitative reporter systems by exploiting isogenic strains that differ only at the level of a specific P53-RE to investigate sequence-specificity of P53-dependent transactivation. On the other hand, the availability of regulated systems for ectopic P53 expression allows the evaluation of transactivation in a wide range of protein expression. Reviewed in this report are extensively used systems that are based on color reporter genes, luciferase, and the growth of yeast to illustrate their main methodological steps and to critically assess their predictive power. Moreover, the extreme versatility of these approaches can be easily exploited to study different TFs including P63 and P73, which are other members of TP53 gene family.


Controlled hierarchical assembly of gold nanoparticles in macroscopic films: from densely packed monolayers to networks of micropores and nanobundles.
The present study demonstrates the ability of excess, weakly amphiphilic n-alkanethiols (n = 4, 12, 18) and solvent composition to tune through a wide range of large-scale, macroscopic architectures formed by alkanethiol-capped Au nanoparticles (NPs). Both the alkanethiols and NPs are significantly hydrophobic species and compete for surface area at an air-water interface. When solutions of the two species are spread on a large (50 cm2) water surface in a Teflon well, a thin film forms and exhibits co-existing macroscopic regions with various distinct NP self-assembled architectures, namely a close packed monolayer, a network phase characterized by micron-sized pores (micropores) surrounded by quasi-linear bundles of nanoparticles, and finally aggregates. We hypothesize that the co-existence of various NP architectures results from fast, non-uniform evaporation across the large water surface. When solutions are instead deposited on a smaller (5 cm2) water surface contained within a Teflon ring to control the water surface curvature and the evaporation rate is slowed, we show for the first time that NPs form macroscopically uniform self-assemblies whose architectures can be tuned from monolayers → monolayers with micropores → extended micropore/NP bundle networks by varying excess alkanethiol concentration and solvent composition. We propose that competition between NPs and excess alkanethiols for water surface area, and alkanethiol self-assembly as well as solvent dewetting play important roles in the formation of the network phase, and discuss a potential mechanism for its formation.


Immunomodulating effects of the anti-viral agent Silibinin in liver transplant patients with HCV recurrence.
Silibinin has been shown to have anti-HCV activity and immune-modulating properties by regulating dendritic cell (DC) function. DCs are antigen-presenting cells that, together with regulatory T cells (Treg), play a pivotal role in controlling alloimmune, as well as anti-HCV immune responses. Twelve liver transplant patients with HCV recurrence received iv infusion of Silibinin (iv-SIL) for 14 consecutive days. Using flow cytometry, before and at the end of treatment, we determined the frequencies of circulating myeloid (m) and plasmacytoid (p) DC and Treg and the expression of costimulatory/coregulatory molecules by the DC subsets and Treg. Statistical analysis was performed using the paired Student's t test and Pearson correlation test. After iv-SIL treatment, we observed an elevated plasmacytoid dendritic cell (pDC)/myeloid dendritic cell (mDC) ratio, while pDC displayed lower HLA-DR and higher immunoglobulin-like transcript 4 (ILT4), CD39, and HLA-G expression compared to the pretreatment baseline. In addition, after iv-SIL, mDC showed increased inducible costimulator ligand (ICOSL) expression. No changes were detected in Treg frequency or programed death (PD)-1 expression by these cells. Moreover, several correlations between DC/Treg markers and clinical parameters were detected. This descriptive study, in liver transplant patients with HCV recurrence, reveals the impact of iv-SIL on DC and Treg. The changes observed in circulating pDC and mDC that have previously been associated with tolerogenic conditions shed new light on how iv-SIL may regulate anti-viral and alloimmunity. We have also observed multiple clinical correlations that could improve the clinical management of liver transplant patients and that deserve further analysis.


Renal cell carcinoma.
The recent contributions to renal cell carcinoma in the fields of molecular biology and the expanded use of molecularly targeted agents will be reviewed. This study is intended to update prognostic and therapeutic decision-making data and provide perspective on advances in understanding the molecular biology of this disease. Updates to the currently used prognostic algorithms for renal cell carcinoma are needed, and recently verified prognostic nomograms will be discussed. This comes in the wake of numerous advances in the use of molecularly targeted drugs, which will be reviewed. Finally, advancements in understanding the biology of renal cell carcinoma include the discovery of von Hippel-Lindau associated mechanisms involved in renal cyst formation and renewed appreciation for the influence of this pathway on the tumor cell glucose utilization profile. Renal cell carcinoma continues to evolve swiftly with the approval of new agents and the maturation of clinical trials to provide relevant structure to treatment decisions. This study will give an overview of the latest concepts in the epidemiology and biology of renal cell carcinoma and provide current surgical and systemic updates for managing renal cell carcinoma.


Irreversible structural change of a dry ionic liquid under nanoconfinement.
Studies of 1-hexyl-3-methyl-imidazolium ethylsulfate ([HMIM] EtSO4) using an extended surface forces apparatus show, for the first time, an ordered structure within the nanoconfined ionic liquid (IL) between mica surfaces that extends up to ∼60 nm from the surface. Our measurements show the growth of this ordered IL-film upon successive nanoconfinements-the structural changes being irreversible upon removal of the confinement-and the response of the structure to shear. The compressibility of this system is lower than that typically measured for ILs, while creep takes place during shear, both findings supporting a long-range liquid-to-solid transition. AFM (sharp-tip) studies of [HMIM] EtSO4 on mica only reveal ∼2 surface IL-layers, with order extending only ∼3 nm from the surface, indicating that confinement is required for the long-range IL-solidification to occur. WAXS studies of the bulk IL show a more pronounced ordered structure than is the case for [HMIM] with bis(trifluoromethylsulfonyl)imide as anion, but no long-range order is detected, consistent with the results obtained with the sharp AFM tip. These are the first force measurements of nanoconfinement-induced long-range solidification of an IL.


National health care reform: an idea whose time came and went.
Despite extensive commentary on the failure of health care reform, little systematic analysis has addressed the question of why reform became a national political issue in the early 1990s. Drawing on studies of agenda setting and examining opinion surveys, media coverage, and various measures of congressional activity, I identify the major factors that pushed health care reform onto the government agenda and explore the relationships among them. These factors fall into three categories: underlying structural changes in Congress and the interest group community that created a receptive climate for addressing health care reform; more immediate changes in the medical system, public opinion, media coverage, and the budgetary and political environments that increased attention to the issue; and a crucial political catalyst that thrust the issue to the top of the government agenda--the 1991 victory of Harris Wofford in a special Senate race in Pennsylvania. A content analysis of media coverage of that election reveals that journalists and politicians rapidly interpreted Wofford's triumph as a sign of broad-based public support for reform. This widely shared interpretation redefined the political risks and benefits of health care reform, creating an opportunity for legislative action. Party because of the way reform reached the government agenda, however, this window of opportunity was more fragile than many believed. My argument thus has implications not only for agenda-setting research but also for the failure of national health legislation and the future possibilities for reform.


Comparing the antiplaque efficacy of 0.5% Camellia sinensis extract, 0.05% sodium fluoride, and 0.2% chlorhexidine gluconate mouthwash in children.
Dental caries is a multifactorial disease which requires a susceptible host, a cariogenic microflora, and a suitable substrate that must be present for a sufficient length of time. Tea is prepared by the infusion of dried leaves of the tea plant, Camellia sinensis, which contains bioactive compounds like polyphenols, flavonoids, and catechins that are thought to be responsible for the health benefits that have traditionally been attributed to tea. These compounds have multidimensional effects such as antibacterial action, inhibitory action on the bacterial and salivary amylase, and inhibition of acid production. The aim of this study is to compare the antiplaque efficacy of 0.5% C. sinensis extract, 0.05% sodium fluoride, and 0.2% chlorhexidine gluconate mouthwash in children. A randomized blinded controlled trial with 60 healthy children of age group 9-14 years was carried out. The subjects were randomly assigned to three groups, i.e. group A - 0.2% chlorhexidine gluconate, group B - 0.05% sodium fluoride, and group C - 0.5% C. sinensis extract, with 20 subjects per group. Plaque accumulation and gingival condition were recorded using plaque index and gingival index. Oral hygiene was assessed by simplified oral hygiene index (OHIS). Salivary pH was assessed using indikrom pH strips. Plaque, gingival, and simplified OHI scores as well as salivary pH were recorded at baseline, immediately after first rinse, after 1 week, and in the 2(nd) week. The data were analyzed using a computer software program (SPSS version 17). Analysis of variance (ANOVA) tests were used to identify significant differences between the means of the study groups. Finally, paired t-tests were used to assess the significance of changes within each group between time periods. Critical P values of significance were set at 0.05 and the confidence level set at 95%. Mean plaque and gingival scores were reduced over the 2-week trial period in the experimental groups. Antiplaque effectiveness was observed in all groups, the highest being in group C (P < 0.05). Chlorhexidine gluconate and tea showed comparative effectiveness on gingiva better than sodium fluoride (P < 0.05). The salivary pH increase was sustained and significant in groups B and C compared to group A. Oral hygiene improvement was better appreciated in groups A and C. The effectiveness of 0.5% C. sinensis extract was more compared to 0.05% sodium fluoride and 0.2% chlorhexidine gluconate mouth rinses. It should be explored as a cost-effective and safe long-term adjunct to oral self-care of patients as it has prophylactic benefits with minimum side effects.


Thromboangitis Obliterans involving Bilateral Upper limb Extremities - A Rare Case Report from Malaysia.
Thromboangitis Obliterans (TAO) or Buerger's disease is a non-atherosclerotic, occlusive, progressive and highly inflammatory disorder of distal arteries seen predominantly affecting the lower limb in smokers. TAO presenting itself in upper limb or bilaterally involving the upper limb is a very rare entity. We report on a rare case of TAO in a 46-year-old gentleman who presented with bilateral upper extremity digital gangrene with 18 pack-years of smoking. Brachial and radial pulses were palpable bilaterally and were of good volume but right ulnar pulse was faintly felt, while on the left side it was not appreciated due to malunion. Further Computed Tomography (CT)- angiography showed occlusion of distal right ulnar artery, stenosis of distal left ulnar artery with bilateral poor opacification of palmar and digital arteries. This case reports on the unusual and rare presentation of TAO in upper extremity involving both limbs. The case is reported for the first time from Malaysia.


Cytoreductive surgery plus chemotherapy versus chemotherapy alone for recurrent epithelial ovarian cancer.
Most women with advanced epithelial ovarian cancer will ultimately develop recurrent disease after completion of initial treatment with primary surgery and adjuvant chemotherapy. Secondary cytoreductive surgery may have survival benefits in selected patients. However, a number of chemotherapeutic agents are active in recurrent ovarian cancer and the standard treatment of patients with recurrent ovarian cancer remains poorly defined. To evaluate the effectiveness and safety of secondary surgical cytoreduction and chemotherapy compared to chemotherapy alone for women with recurrent epithelial ovarian cancer. We searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Register of Controlled Trials, (CENTRAL) Issue 1 2009, MEDLINE and EMBASE up to February 2009. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of review articles and contacted experts in the field. We searched for RCTs, quasi-randomised trials and non-randomised studies that compared secondary cytoreductive surgery and chemotherapy to chemotherapy alonein women with recurrent epithelial ovarian cancer. Three reviewers independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found and therefore no data were analysed. The search strategy identified 1431 unique references of which all were excluded on the basis of title and abstract. We found no evidence from RCTs to inform decisions about secondary surgical cytoreduction and chemotherapy compared to chemotherapy alone for women with recurrent epithelial ovarian cancer. Ideally, a large randomised controlled trial or, at the very least, well designed non-randomised studies that use multivariate analysis to adjust for baseline imbalances are needed to compare these treatment modalities.


Projections of water, carbon, and nitrogen dynamics under future climate change in an old-growth Douglas-fir forest in the western Cascade Range using a biogeochemical model.
Statistically downscaled climate change scenarios from four General Circulation Models for two Representative Concentration Pathways (RCP) were applied as inputs to a biogeochemical model, PnET-BGC, to examine potential future dynamics of water, carbon, and nitrogen in an old-growth Douglas-fir forest in the western Cascade Range. Projections show 56% to 77% increases in stomatal conductance throughout the year from 1986-2010 to 2076-2100, and 65% to 104% increases in leaf carbon assimilation between October and June over the same period. However, future dynamics of water and carbon under the RCP scenarios are affected by a 49% to 86% reduction in foliar biomass resulting from severe air temperature and humidity stress to the forest in summer. Important implications of future decreases in foliar biomass include 1) 20% to 71% decreases in annual transpiration which increase soil moisture by 7% to 15% in summer and fall; 2) decreases in photosynthesis by 77% and soil organic matter by 62% under the high radiative forcing scenario; and 3) altered foliar and soil carbon to nitrogen stoichiometry. Potential carbon dioxide fertilization effects on vegetation are projected to 1) amplify decreases in transpiration by 4% to 9% and increases in soil moisture in summer and fall by 1% to 2%; and 2) alleviate decreases in photosynthesis by 4%; while 3) having negligible effects on the dynamics of nitrogen. Our projections suggest that future decrease in transpiration and moderate water holding capacity may mitigate soil moisture stress to the old-growth Douglas-fir forest. Future increases in nitrogen concentration in soil organic matter are projected to alleviate the decrease in net nitrogen mineralization despite a reduction in decomposition of soil organic matter by the end of the century.


Hydrogen as a novel and effective treatment of acute carbon monoxide poisoning.
Hydrogen is a major component of interstellar space and the fuel that sustains the stars. However, it is seldom regarded as a therapeutic gas. A recent study provided evidence that hydrogen inhalation exerted antioxidant and anti-apoptotic effects and protected the brain against ischemia-reperfusion injury by selectively reducing hydroxyl radical and peroxynitrite. It has been known that the mechanisms underlying the brain injury after acute carbon monoxide poisoning are interwoven with multiple factors including oxidative stress, free radicals, and neuronal nitric oxide synthase as well as abnormal inflammatory responses. Studies have shown that free radical scavengers can improve the neural damage. Based on the findings abovementioned, we hypothesize that hydrogen therapy may be an effective, simple, economic and novel strategy in the treatment of acute carbon monoxide poisoning.


Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing.
Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.


Autoantibodies in nonautoimmune individuals during infections.
Infections can act as environmental triggers inducing or promoting autoimmune disease in genetically predisposed individuals. Identification of microbial peptides similar to self-tissues may by molecular mimicry, provide the inducing mechanism for an immune response. The aim of this study was to identify autoantibodies (autoAbs) in nonautoimmune individuals during acute bacterial, viral, or parasitic infections. Specific Abs or specific infections with an increased autoAb load may shed insight into the mechanisms of autoimmune disease. Sera from 88 patients with acute infections (41 bacterial, 23 viral, 17 parasitic, and 7 rickettsial) were tested by the ELISA method for antinuclear antibodies (ANA) 8 Pro, and Abs to thyroid peroxidase (TPO), thyroglobulin, phospholipids, annexin-V, laminin, anti-Saccharomyces cervisiae (ASCA), and prothrombin, along with 80 normal controls. Elevated titers of Abs to annexin-V and prothrombin were the most prevalent in viral, parasitic, and rickettsial infections and to laminin in viral and parasitic infections. Elevated titers of ASCA and ANA were found in viral and bacterial infections. Antiphospholipid Abs were found in parasitic and Q-fever infections. Thirty-four individuals harbored elevated titers of at least two Abs. An autoAb burden was detected in individuals with hepatitis A, hepatitis B, toxoplasma or Q-fever infections. In nonautoimmune individuals with various (bacterial, viral, parasitic, and rickettsial) infections, elevated titers of Abs to annexin-V, prothrombin, laminin, ASCA, ANA, and phospholipids were most frequently detected.


Using MOOCs to Promote Digital Accessibility and Universal Design, the MOOCAP Experience.
The recently completed Massive Open Online Course for Accessibility Partnership project (MOOCAP), had the twin aims of establishing a strategic partnership around the promotion of Universal Design and Accessibility for ICT professionals and of developing a suite of Open Educational resources (OERs) in this domain. MOOCAP's eight university partners from Germany, Norway, Greece, Ireland, the UK and Austria have a significant history in developing and providing courses in the domains of Universal Design and Accessibility, as well as leading research and advocacy roles within Europe. The MOOCAP project consisted of two phases: the development of an introductory MOOC on Digital Accessibility and the delivery of set of online courses with more in-depth and focused learning topics. During the lifetime of the project over 10,000 students signed up for these courses. This paper reflects on the challenges of creating and delivering MOOCs, especially in topics around Digital Accessibility and Universal Design. It considers the outcomes, impacts and legacies of the project. Based on our experiences of integrating these materials into our courses and on feedback and project evaluations, this paper will assess the potential of MOOCs to promote Universal Design for ICT and other professionals, while pointing up the possible trials and opportunities of such activities.


Evaluation of fluid status related parameters in hemodialysis and peritoneal dialysis patients: Clinical usefulness of bioimpedance analysis.
Fluid overload is a common and serious problem that leads to severe complications in dialysis patients. We aimed to compare hydration status as measured with bioimpedance analysis (BIA) method in hemodialysis (HD) and peritoneal dialysis (PD) patients, as well as investigating the association between blood pressure, left ventricular mass index (LVMI) and hydration status. We examined 43 HD and 33 PD patients. Blood pressure was recorded. In each group, echocardiographic examinations were performed on all patients. Hydration status was assessed using multifrequency bioelectrical impedance analysis. Overhydration was defined as an overhydration (OH)/extracellular water (ECW) ratio of >0.15. The OH/ECW ratio was significantly higher in PD patients compared to post-HD patients. Overhydration was statistically more frequent in PD than in post-HD patients (30.3% vs. 11.6%, P=0.043). Systolic blood pressure (SBP) in both post-HD and PD groups, and LVMI in the PD group were found to be significantly higher in overhydrated patients than non-overhydrated patients. In multiple linear regression analyses, increased OH/ECW ratio was independently associated with higher SBP and LVMI. Fluid overload may be an even more prevalent and serious problem in PD patients. Overhydration is closely associated with increased blood pressure and LVMI. OH/ECW ratio, a derived parameter of fluid load measured by BIA, was a significant and independent determinant of SBP and LVMI.


Congressional voting behavior on hospital legislation: an exploratory study.
This paper analyzes Congressional voting behavior on the Gephardt Amendment to President Carter's hospital cost containment legislation. The impact of opposing interest groups is examined: on one side were hospital and medical interest groups; on the other was the Carter Administration and its political party, as well as states with large Medicaid expenditures. The effect of political contributions from MEDPACs is evaluated, and the relative importance of various factors affecting the vote's outcome is analyzed.


The tau S305S mutation causes frontotemporal dementia with parkinsonism.
Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.


Comparative effect of two Mediterranean diets versus a low-fat diet on glycaemic control in individuals with type 2 diabetes.
Although benefits have been attributed to the Mediterranean diet, its effect on glycaemic control has not been totally elucidated. The aim of this work was to compare the effect of two Mediterranean diets versus a low-fat diet on several parameters and indices related to glycaemic control in type 2 diabetic subjects. A multicentric parallel trial was conducted on 191 participants (77 men and 114 women) of the PREDIMED study in order to compare three dietary interventions: two Mediterranean diets supplemented with virgin olive oil (n=67; body mass index (BMI)=29.4±2.9) or mixed nuts (n=74; BMI=30.1±3.1) and a low-fat diet (n=50; BMI=29.8±2.8). There were no drop-outs. Changes in body weight and waist circumference were determined. Insulin resistance was measured by HOMA-IR index, adiponectin/leptin and adiponectin/HOMA-R ratios after 1 year of follow-up. Increased values of adiponectin/leptin ratio (P=0.043, P=0.001 and P<0.001 for low-fat, olive oil and nut diets, respectively) and adiponectin/HOMA-IR ratio (P=0.061, P=0.027 and P=0.069 for low-fat, olive oil and nut diets, respectively) and decreased values of waist circumference (P=0.003, P=0.001 and P=0.001 for low-fat, olive oil and nut diets, respectively) were observed in the three groups. In both Mediterranean diet groups, but not in the low-fat diet group, this was associated with a significant reduction in body weight (P=0.347, P=0.003 and P=0.021 for low-fat, olive oil and nut diets, respectively). Mediterranean diets supplemented with virgin olive oil or nuts reduced total body weight and improved glucose metabolism to the same extent as the usually recommended low-fat diet.


SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study.
Whether young adults who are infected with SARS-CoV-2 are at risk of subsequent infection is uncertain. We investigated the risk of subsequent SARS-CoV-2 infection among young adults seropositive for a previous infection. This analysis was performed as part of the prospective COVID-19 Health Action Response for Marines study (CHARM). CHARM included predominantly male US Marine recruits, aged 18-20 years, following a 2-week unsupervised quarantine at home. After the home quarantine period, upon arrival at a Marine-supervised 2-week quarantine facility (college campus or hotel), participants were enrolled and were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein ELISA. Participants also completed a questionnaire consisting of demographic information, risk factors, reporting of 14 specific COVID-19-related symptoms or any other unspecified symptom, and brief medical history. SARS-CoV-2 infection was assessed by PCR at weeks 0, 1, and 2 of quarantine and participants completed a follow-up questionnaire, which included questions about the same COVID-19-related symptoms since the last study visit. Participants were excluded at this stage if they had a positive PCR test during quarantine. Participants who had three negative swab PCR results during quarantine and a baseline serum serology test at the beginning of the supervised quarantine that identified them as seronegative or seropositive for SARS-CoV-2 then went on to basic training at Marine Corps Recruit Depot-Parris Island. Three PCR tests were done at weeks 2, 4, and 6 in both seropositive and seronegative groups, along with the follow-up symptom questionnaire and baseline neutralising antibody titres on all subsequently infected seropositive and selected seropositive uninfected participants (prospective study period). Between May 11, 2020, and Nov 2, 2020, we enrolled 3249 participants, of whom 3168 (98%) continued into the 2-week quarantine period. 3076 (95%) participants, 2825 (92%) of whom were men, were then followed up during the prospective study period after quarantine for 6 weeks. Among 189 seropositive participants, 19 (10%) had at least one positive PCR test for SARS-CoV-2 during the 6-week follow-up (1·1 cases per person-year). In contrast, 1079 (48%) of 2247 seronegative participants tested positive (6·2 cases per person-year). The incidence rate ratio was 0·18 (95% CI 0·11-0·28; p<0·001). Among seropositive recruits, infection was more likely with lower baseline full-length spike protein IgG titres than in those with higher baseline full-length spike protein IgG titres (hazard ratio 0·45 [95% CI 0·32-0·65]; p<0·001). Infected seropositive participants had viral loads that were about 10-times lower than those of infected seronegative participants (ORF1ab gene cycle threshold difference 3·95 [95% CI 1·23-6·67]; p=0·004). Among seropositive participants, baseline neutralising titres were detected in 45 (83%) of 54 uninfected and in six (32%) of 19 infected participants during the 6 weeks of observation (ID50 difference p<0·0001). Seropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralisation activity or immunity against subsequent infection. These findings might be relevant for optimisation of mass vaccination strategies. Defense Health Agency and Defense Advanced Research Projects Agency.


Imaging Characteristics of Choroidal Neovascular Lesions in the AREDS2-HOME Study: Report Number 4.
To characterize choroidal neovascular (CNV) lesions and the corresponding change in visual acuity (VA) in eyes that converted to neovascular age-related macular degeneration (AMD) in the Age-Related Eye Disease Study 2-HOme Monitoring of the Eye Study. (AREDS2-HOME Study). Cohort study. A total of 1520 participants at risk of developing CNV were enrolled, each of whom contributed 1 or both study eye(s) that had a best-corrected VA letter score of ≥54 letters (Snellen equivalent 20/60) and ≥1 large (≥125 μm) macular druse in the absence of neovascular AMD or central geographic atrophy. A multicenter clinical trial comparing standard care (SC) versus SC plus ForeseeHome (FH; Notal Vision, Manassas, VA) monitoring strategy in the detection of neovascular AMD. Fluorescein angiograms (FA) and OCT were evaluated by an independent reading center (RC) from the visit in which the ophthalmologist identified progression to CNV (n = 82 eyes). Development of CNV on OCT, FA, or both. The RC confirmed CNV in 67 of 82 eyes (82%); lesions were confirmed in 42 of 70 eyes (60%) with FA, 59 of 72 eyes (82%) with OCT, and on both images in 34 of 67 eyes (51%). Among the FA-confirmed cases, the median lesion size was 0.82 disc area (DA); lesions were subfoveal in 40.5%, occult CNV composition was present in 54.8%, and associated hemorrhage in 50%. Median (interquartile range [IQR]) lesion size on FA was 0.23 (0.0-0.91) DA versus 0.70 (0.0-1.50) DA, P = 0.051) in the FH and SC eyes, respectively. Among the OCT-confirmed cases median (IQR) center point thickness was 209 (175-274) μm, retinal pigment epithelial lesion complex was present in 86.4%, and subretinal fluid (SRF) was present in 76.3%. The median change in VA from baseline was -4.0 letters and -10.0 letters in the FH and SC eyes (P = 0.008) confirmed as CNV at the RC. Incident CNV lesions were more prevalent on OCT images than on FA; however, the use of both OCT and FA enhanced detection of incident lesions. Lesions were smaller and associated with less vision loss among eyes in the FH group.


Hysterectomy and its impact on the calculated incidence of cervical cancer and screening coverage in Denmark.
The incidence rates of cervical cancer and the coverage in cervical cancer screening are usually reported by including in the denominator all women from the general population. However, after hysterectomy women are not at risk anymore of developing cervical cancer. Therefore, it makes sense to determine the indicators also for the true at-risk populations. We described the frequency of total hysterectomy in Denmark and its impact on the calculated incidence of cervical cancer and the screening coverage. With data from five Danish population-based registries, the incidence rate of cervical cancer and the screening coverage for women aged 23-64 years on 31 December 2010 were calculated with and without adjustments for hysterectomies undertaken for reasons other than cervical cancer. They were calculated as the number of cases divided by 1) the total number of woman-years from the general population; and 2) the at-risk population after exclusion of post-hysterectomy woman-years. Cases were defined as women with cervical cancer (incidence), or as women screened in the recommended interval, with or without adjustment for hysterectomies (coverage). In 2010, the all-age prevalence of hysterectomy was estimated at 6%, and ≥ 16% at age ≥ 65. This translated into an overall 6% increase in the incidence rate of cervical cancer, from 12.8 (unadjusted) to 13.5 (adjusted) per 100,000 woman-years. The screening coverage increased from 76% (unadjusted) to 79% (adjusted). In Denmark, hysterectomies do not have a large overall impact on the calculated cancer incidence and screening coverage. Nevertheless, at ≥ 65 years adjusted rates would increase by almost 20% compared to unadjusted rates. This suggests that calculating disease risks per organ-years may have a role in understanding the true burden of the disease in a population at risk of developing that disease.


Elevation of intracellular free calcium levels in HEp-2 cells infected with enteropathogenic Escherichia coli.
Enteropathogenic Escherichia coli (EPEC) are a class of diarrheagenic organisms that induce a characteristic attaching and effacing lesion in enterocytes and various cultured cell lines. Infection of cultured HEp-2 cells by EPEC isolates 2036-80 (serotype O119) and E2348-69 (serotype O127) resulted in significant elevation of intracellular free calcium levels, determined quantitatively with the fluorescent calcium indicator dye 2-([2-bis(carboxymethyl)amino-5-methylphenoxy]methyl)-6-methoxy-8- bis(carboxymethyl)aminoquinoline. This effect, which was not observed on infection with non-lesion-forming E. coli strains, was inhibited by dantrolene, a drug that prevents calcium mobilization from intracellular stores. Moreover, activated protein kinase C in infected cells was dissociated from cell membranes by a process that was inhibited by cyclosporin A, suggesting involvement of the calcium-dependent protease calpain. A qualitative method for observing intracellular calcium fluxes by fluorescence microscopy with the recently described fluorescein-based indicator fluo-3 was used to screen a collection of well-characterized E. coli isolates from patients with infantile enteritis. Increased localized calcium-dependent fluo-3 fluorescence was observed only in HEp-2 cells infected with known lesion-forming EPEC strains. We propose that enhancement of intracellular free calcium levels in enterocytes infected with EPEC would result in formation of the characteristic lesion by calcium-dependent activation of actin-depolymerizing proteins, with eventual loss of absorptive capacity.


Optofluidic dye laser in a foil.
First order distributed feedback optofluidic dye lasers embedded in a 350 microm thick TOPAS((R)) foil are demonstrated. They are designed in order to give high output pulse energies. Microfluidic channels and first order distributed feedback gratings are fabricated in parallel by thermal nanoimprint into a 100 microm foil. The channels are closed by thermal bonding with a 250 microm thick foil and filled with 5.10(-3) mol/l Pyrromethene 597 in benzyl alcohol. The fluid forms a liquid core single mode slab waveguide of 1.6 microm height on a nanostructured grating area of 0.5 x 0.5 mm(2). This results in a large gain volume. Two grating periods of 185 nm and 190 nm yield single mode laser light emission at 566 nm and 581 nm respectively. High emitted pulse energies of more than 1 microJ are reported. Stable operation for more than 25 min at 10 Hz pulse repetition rate is achieved.


Usefulness of the SAGE score to predict elevated values of brachial-ankle pulse wave velocity in Japanese subjects with hypertension.
The score based on the office systolic blood pressure, age, fasting blood glucose level, and estimated glomerular filtration rate (SAGE score) has been proposed as a useful marker to identify elevated values of carotid-femoral pulse wave velocity (PWV). The present cross-sectional study was conducted to examine whether the SAGE score is also a useful marker to identify subjects with elevated brachial-ankle PWV values in Japanese subjects with hypertension. We measured the brachial-ankle PWV and calculated the SAGE score in a total of 1019 employees of a Japanese company with hypertension and 817 subjects with hypertension derived from a multicenter study cohort. The analyses in this study were based on data from these two study groups as well as on a composite population of the two (n = 1836). The receiver operating characteristic curve analysis showed that the area under the curve to identify subjects with brachial-ankle PWV values of ≥1800 cm/s was over 0.70 in each of the three study groups. Even after adjustments, a SAGE score ≥7 had a significant odds ratio for identifying subjects with brachial-ankle PWV values ≥1800 cm/s in the 1836 study subjects from the composite occupational and multicenter study cohort (odds ratio = 2.1, 95% confidence interval = 1.4-3.0, P < 0.01). Thus, in Japanese subjects with hypertension, the SAGE score may be a useful marker for identifying subjects with elevated brachial-ankle PWV values.


Generation of kidney tubular organoids from human pluripotent stem cells.
Recent advances in stem cell research have resulted in methods to generate kidney organoids from human pluripotent stem cells (hPSCs), which contain cells of multiple lineages including nephron epithelial cells. Methods to purify specific types of cells from differentiated hPSCs, however, have not been established well. For bioengineering, cell transplantation, and disease modeling, it would be useful to establish those methods to obtain pure populations of specific types of kidney cells. Here, we report a simple two-step differentiation protocol to generate kidney tubular organoids from hPSCs with direct purification of KSP (kidney specific protein)-positive cells using anti-KSP antibody. We first differentiated hPSCs into mesoderm cells using a glycogen synthase kinase-3β inhibitor for 3 days, then cultured cells in renal epithelial growth medium to induce KSP+ cells. We purified KSP+ cells using flow cytometry with anti-KSP antibody, which exhibited characteristics of all segments of kidney tubular cells and cultured KSP+ cells in 3D Matrigel, which formed tubular organoids in vitro. The formation of tubular organoids by KSP+ cells induced the acquisition of functional kidney tubules. KSP+ cells also allowed for the generation of chimeric kidney cultures in which human cells self-assembled into 3D tubular structures in combination with mouse embryonic kidney cells.


An observational study of an approach to accommodate a fourth-year to third-year neurology clerkship curricular transition.
Background: Curricular transformation can result in bulges in students' clinical placements.Objective: To report on learner outcomes associated with a competency-based opt-out approach for a required 4th-year neurology clerkship.Methods and Study Design: During Oregon Health & Science University's recent undergraduate medical education curricular transformation, a 4-week required neurology clerkship transitioned from the fourth-year to the third-year in academic year 2016-17. Because this would have resulted in the neurology clerkship accommodating double enrollment for an entire academic year, 4th year medical students from the prior curriculum (graduating class of 2017) were offered the option of opting-out of the required neurology clerkship if they demonstrated competency by passing the USA National Board of Medical Examiners (US-NBME) clinical neurology subject examination and completing a neurology faculty-observed history and complete neurological examination.Results: Fifty-seven of 133 fourth-year students (42.9%) chose to complete the required neurology clerkship with 77 (57.9%) choosing to opt-out. All opt-out students passed the neurological exam assessment and scored similarly to the students who took the clerkship (US-NBME Neurology Subject Exam mean raw score in the opt-out group 76.9 vs, 77.6; p = 0.61). Students grades did not differ. Students who opted-out tended to pursue surgical careers (e.g., general surgery -10.8% opted-out vs 0% clerkship, OB/GYN - 6.8% opted-out vs 0% clerkship, orthopedic surgery 5.4% opted-out vs 0% clerkship) where those who took the clerkship tended to choose medical residency training disciplines (family medicine -16.1% clerkship vs 10.8% opting-out; internal medicine - 32.1% clerkship vs 14.9% opting-out; psychiatry 10.7% clerkship vs 2.7% opting-out (p = 0.042)Conclusion: While undertaking the neurology clerkship would have been the desired approach, students appear not to have been harmed by the opt-out approach regarding performance on the US-NBME clinical neurology subject exam. Choices regarding opting-out versus taking the neurology clerkship appear to be associated with career choice.


Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression.
Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12). The bronchial bacterial load of Pseudomonas aeruginosa, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was measured by quantitative real-time PCR.TLR4 and NOD1 expression was increased in the bronchial mucosa of patients with severe/very severe stable COPD compared with control subjects. TLR4 bronchial epithelial expression correlated positively with CD4+ and CD8+ cells and airflow obstruction. NOD1 expression correlated with CD8+ cells. The bronchial load of P. aeruginosa was directly correlated, but H. influenzae inversely correlated, with the degree of airflow obstruction. Bacterial load did not correlate with inflammatory cells.Bronchial epithelial overexpression of TLR4 and NOD1 in severe/very severe stable COPD, associated with increased bronchial inflammation and P. aeruginosa bacterial load, may play a role in the pathogenesis of COPD.


Aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies in immune-mediated optic neuritis at long-term follow-up.
To re-evaluate serum samples from our 2007 cohort of patients with single-episode isolated ON (SION), recurrent isolated ON (RION), chronic relapsing inflammatory optic neuropathy (CRION), multiple sclerosis-associated ON (MSON) and neuromyelitis optica (NMO). We re-screened 103/114 patients with available serum on live cell-based assays (CBA) for aquaporin-4 (AQP4)-M23-IgG and myelin-oligodendrocyte glycoprotein (MOG)-α1-IgG. Further testing included oligoclonal bands, serum levels of glial fibrillar acidic and neurofilament proteins and S100B. We show the impact of updated serology on these patients. Reanalysis of our original cohort revealed that AQP4-IgG seropositivity increased from 56% to 75% for NMO, 5% to 22% for CRION, 6% to 7% for RION, 0% to 7% for MSON and 5% to 6% for SION. MOG-IgG1 was identified in 25% of RION, 25% of CRION, 10% of SION, 0% of MSON and 0% of NMO. As a result, patients have been reclassified incorporating their autoantibody status. Presenting visual acuity was significantly worse in patients who were AQP4-IgG seropositive (p=0.034), but there was no relationship between antibody seropositivity and either ON relapse rate or visual acuity outcome. The number of patients with seronegative CRION and RION has decreased due to improved detection of autoantibodies over the past decade. It remains essential that the clinical phenotype guides both antibody testing and clinical management. Careful monitoring of the disease course is key when considering whether to treat with prophylactic immune suppression.


Mineralogy and petrology of coarse particulate material from lunar surface at tranquillity base.
Five grams of coarse fines (10085,11) contains 1227 grains, mostly mafic holocrystalline rock fragments, microbreccia, and glass spatter and agglomerates with less abundant anorthosite fragments and regularly shaped glass. The crystalline lithic fragments in the coarse fines and microbreccias represent a closely related suite of gabbroid igneous rocks that have a wider range of modal analyses and textures than seen in the larger crystalline rock samples returned by Apollo 11. Petrographic evidence of shock metamorphism is common, and the abundant glass is almost all shock-produced. None of the glass observed is similar to tektite glass.


Taste and smell dysfunction in childhood cancer survivors.
Reduced or altered taste and smell function may occur as a side-effect of cancer therapy. This can lead to altered nutrient and energy intake. Some studies have suggested that taste and smell dysfunction can persist many years after treatment completion but this has not been previously assessed in survivors of childhood cancer. The aim of this study is to determine if taste and smell dysfunction is present in childhood cancer survivors (CCS). Food preference and Quality of Life was also assessed. Fifty-one child cancer survivors (mean age: 19.69±7.09years), more than five years since treatment completion, (mean: 12.4years) were recruited from the long term follow-up clinics at two Sydney-based children's hospitals. Taste function was assessed using a 25 sample taste identification test comprising five concentrations each of sweet, salty, sour and bitter tastes and water. Smell function was assessed by determining the ability of participants to identify 16 common odorants. The participants' Quality of Life was assessed using the Functional Assessment of Anorexia Cachexia scale and food preferences were assessed using a 94-item food liking tool. Taste dysfunction was found in 27.5% of participants (n=14), and smell dysfunction in 3.9% (n=2) of participants. The prevalence of taste dysfunction was higher than that seen in the non-cancer population. The child cancer survivors' appeared to "like" the less healthy food groups such as flavoured beverages, takeaway and snacks over healthier food groups such as vegetables and salad. No correlation was found between those with a taste dysfunction and their food "likes". A high level of taste dysfunction was found in CCS though there did not appear to be an issue with smell dysfunction. Further work is also needed to assess whether a taste dysfunction do play a role in the dietary habits of CCS.


Laser treatment of acne vulgaris.
Traditional medical treatments for acne vulgaris include a variety of topical and oral medications. The combination of poor compliance, lack of durable remission, and potential side effects are common drawbacks to these treatments. The use of lasers and light devices has increased dramatically in recent years due to the overall ease of treatment, predictable clinical efficacy, and minimal adverse effects. A variety of light and laser devices has been used for the treatment of acne, including the potassium titanyl phosphate (KTP) laser, the 585- and 595-nm pulsed dye lasers, the 1450-nm diode laser, radiofrequency devices, intense pulsed light sources, low-intensity light treatment, and photodynamic therapy using 5-aminolevulinic acid and indocyanine green. These devices are thought to target underlying pathogenic factors such as Propionibacterium acnes colonization, increased sebaceous gland activity, and the cutaneous inflammatory response. Lasers in particular also have a central role in the management of acne scarring, which tends to be refractory to medical therapies. Fractional photothermolysis, the 1450-nm diode laser, and pulsed dye lasers have been used in the nonablative treatment of acne scars with significant success. In this article, we review the current status of light- and laser-based treatment of acne and related conditions and briefly review the use of lasers for the treatment of acne scarring.


Aluminum effect on dissolution and precipitation under hyperalkaline conditions: I. Liquid phase transformations.
Substantial amounts of self-boiling, Al-rich, hyperalkaline, and saline high-level waste fluids (HLWF) were deposited to the vadose zone at the Hanford Site, in Washington State. The objective of this study was to investigate the effects of similar fluids on the extent of dissolution and precipitation in the sediments. Metal- and glass-free systems were used to conduct batch experiments at 323 K under CO2 and O2 free conditions. Base-induced dissolution of the soil minerals was rapid in the first 48 h as indicated by immediate releases of Si and Fe into the soil solution. Potassium release lagged behind and dissolution of K-bearing minerals (mica and K-feldspar) proceeded faster only after 2 to 3 d of the experiment. Silicon and Fe release exhibited high dependence on aqueous [Al] (rate orders <-1), because Al decreased free OH concentration in the contact solution and probably inhibited soil mineral dissolution. Initial K release exhibited low dependence on [Al] (fractional rate orders). Initial dissolution rates calculated based on Si release varied with aqueous [Al] from 29.47 to 4.35 x 10(-12) mol m(-2) s(-1). Aluminum participated in the formation of the secondary phases (precipitation rates of 10(-8) mol s(-1)) but the overall precipitation rate of alumino-silicate secondary phases was probably controlled by aqueous [Si] (rates of 10(-9), and rate constants between 0.0054 and 0.0084 h(-1)). The changes in the soil solution chemistry (release of K, Si, Fe, and other elements) may play a significant role in the fate of radionuclides and contaminants like Cs, Sr, Cr, and U in the Hanford sediments.


A novel subgroup Q5 of human Y-chromosomal haplogroup Q in India.
Y-chromosomal haplogroup (Y-HG) Q is suggested to originate in Asia and represent recent founder paternal Native American radiation into the Americas. This group is delineated into Q1, Q2 and Q3 subgroups defined by biallelic markers M120, M25/M143 and M3, respectively. Recently, a novel subgroup Q4 has been identified which is defined by bi-allelic marker M346, representing HG Q (0.41%, 3/728) in Indian population. With scanty details of HG Q in Asia, especially India, it was pertinent to explore the status of the Y-HG Q in Indian population to gather an insight to determine the extent of diversity within this region. We observed 15/630 (2.38%) Y-HG Q individuals in India with an ancestral state at M120, M25, M3 and M346 markers, indicating an absence of already known Q1, Q2, Q3 and Q4 sub-haplogroups. Interestingly, we further observed a novel 4 bp deletion/insertion polymorphism (ss4 bp, rs41352448) at 72,314 position of human arylsulfatase D pseudogene, defining a novel sub-lineage Q5 (in 5/15 individuals, i.e., 33.3 % of the observed Y-HG Q) with distributions independent of the social, cultural, linguistic and geographical affiliations in India. The study adds another sublineage Q5 in the already existing arrangement of Y-HG Q in literature. It was quite interesting to observe an ancestral state Q* and a novel sub-branch Q5, not reported elsewhere, in Indian subcontinent, though in low frequency. A novel subgroup Q4 was identified recently which is also restricted to Indian subcontinent. The most plausible explanation for these observations could be an ancestral migration of individuals bearing ancestral lineage Q* to Indian subcontinent followed by an autochthonous differentiation to Q4 and Q5 sublineages later on. However, other explanations of, either the presence of both the sub haplogroups (Q4 and Q5) in ancestral migrants or recent migrations from central Asia, cannot be ruled out till the distribution and diversity of these subgroups is explored extensively in Central Asia and other regions.


An international study on psychological coping during COVID-19: Towards a meaning-centered coping style.
This study examined the role of different psychological coping mechanisms in mental and physical health during the initial phases of the COVID-19 crisis with an emphasis on meaning-centered coping. A total of 11,227 people from 30 countries across all continents participated in the study and completed measures of psychological distress (depression, stress, and anxiety), loneliness, well-being, and physical health, together with measures of problem-focused and emotion-focused coping, and a measure called the Meaning-centered Coping Scale (MCCS) that was developed in the present study. Validation analyses of the MCCS were performed in all countries, and data were assessed by multilevel modeling (MLM). The MCCS showed a robust one-factor structure in 30 countries with good test-retest, concurrent and divergent validity results. MLM analyses showed mixed results regarding emotion and problem-focused coping strategies. However, the MCCS was the strongest positive predictor of physical and mental health among all coping strategies, independently of demographic characteristics and country-level variables. The findings suggest that the MCCS is a valid measure to assess meaning-centered coping. The results also call for policies promoting effective coping to mitigate collective suffering during the pandemic.


Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials.
The peripheral blood eosinophil count might help identify those patients with chronic obstructive pulmonary disease (COPD) who will experience fewer exacerbations when taking inhaled corticosteroids (ICS). Previous post-hoc analyses have proposed eosinophil cutoffs that are both arbitrary and limited in evaluating complex interactions of treatment response. We modelled eosinophil count as a continuous variable to determine the characteristics that determine both exacerbation risk and clinical response to ICS in patients with COPD. We analysed data from three AstraZeneca randomised controlled trials of budesonide-formoterol in patients with COPD with a history of exacerbations and available blood eosinophil counts. Patients with any history of asthma were excluded. Negative binomial regression analysis was done using splines for modelling of continuous variables to study the primary outcome of annual exacerbation rate adjusted for exposure time and study design. The trials are registered with ClinicalTrials.gov, NCT00206167, NCT00206154, and NCT00419744. 4528 patients were studied. A non-linear increase in exacerbations occurred with increasing eosinophil count in patients who received formoterol alone. At eosinophil counts of 0·10 × 109 cells per L or more, a significant treatment effect was recorded for exacerbation reduction with budesonide-formoterol compared with formoterol alone (rate ratio 0·75, 95% CI 0·57-0·99; pinteraction=0·015). Interactions were observed between eosinophil count and the treatment effects of budesonide-formoterol over formoterol on St George's Respiratory Questionnaire (pinteraction=0·0043) and pre-bronchodilator FEV1 (linear effect p<0·0001, pinteraction=0·067). Only eosinophil count and smoking history were independent predictors of response to budesonide-formoterol in reducing exacerbations (eosinophil count, pinteraction=0·013; smoking history, pinteraction=0·015). In patients with COPD treated with formoterol, blood eosinophil count predicts exacerbation risk and the clinical response to ICS. AstraZeneca.


A multimodal attempt to follow-up linkage regions using RNA expression, SNPs and CpG methylation in schizophrenia and bipolar disorder kindreds.
The complexity of schizophrenia (SZ) and bipolar disorder (BD) has slowed down progress in understanding their genetic roots. Alternative genomic approaches are needed to bypass these difficulties. We attempted a multimodal approach to follow-up on reported linkage findings in SZ and BD from the Eastern Quebec kindreds in chromosomes 3q21, 4p34, 6p22, 8p21, 8p11, 13q11-q14, 15q13, 16p12, and 18q21. First, in 498 subjects, we measured RNA expression (47 K Illumina chips) in SZ and BD patients that we compared with their non-affected relatives (NARs) to identify, for each chromosomal region, genes showing the most significant differences in expression. Second, we performed SNP genotyping (700 K Illumina chips) and cis-eQTN analysis. Third, we measured DNA methylation on genes with RNA expression differences or eQTNs. We found a significant overexpression of the gene ITGB5 at 3q25 in SZ and BD after multiple testing p value adjustment. SPCS3 gene at 4q34, and FZD3 gene at 8p21, contained significant eQTNs after multiple testing corrections, while ITGB5 provided suggestive results. Methylation in associated genes did not explain the expression differences between patients and NARs. Our multimodal approach involving RNA expression, dense SNP genotyping and eQTN analyses, restricted to chromosomal regions having shown linkage, lowered the multiple testing burden and allowed for a deeper examination of candidate genes in SZ or BD.


Surgery for malignant liver tumors.
Recent decades have witnessed an increase in liver resections. There is a need for an update on factors related to the management of liver tumors in view of newer published data. A systematic search using Medline, Embase, and Cochrane Central Register of Controlled Trials for the years 1983-2008 was performed. The IHPBA classification provides a suitable nomenclature of liver resections. While one randomized trial has provided an objective time of 30 min as optimal for intermittent pedicle occlusion, another randomized study has demonstrated the feasibility of performing liver resections without pedicle clamping. A randomized trial has demonstrated the benefit of clamp crushing over newer techniques of liver transection. Cohort studies support anatomical resections when feasible in terms of outcomes. Nonrandomized studies also support nonanatomical and ablative therapies in patients with cirrhosis and small remnant livers. A randomized trial has shown comparable long-term outcomes of radiofrequency ablation (RFA) and surgery for tumors < 5 cm. No randomized trials comparing laparoscopy and open surgery exist. Surgery remains an important treatment modality for malignant hepatic neoplasms. While anatomical resections provide improved survival, the choice of nonanatomical versus anatomical resections should be individualized taking into account factors such as cirrhosis and function of the liver remnant. A clear margin of resection is essential in all surgically resected cases. RFA is emerging as a useful, often complimentary tool, to surgery when dealing with complex tumors or tumors in patients with a poor liver function. Laparoscopic ultrasonography is useful in staging and performance of RFA.


Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2.
During feeding, increases in circulating pancreatic insulin inhibit hepatic glucose output through the activation of the Ser/Thr kinase AKT and subsequent phosphorylation of the forkhead transcription factor FOXO1 (refs 1-3). Under fasting conditions, FOXO1 increases gluconeogenic gene expression in concert with the cAMP responsive coactivator TORC2 (refs 4-8). In response to pancreatic glucagon, TORC2 is de-phosphorylated at Ser 171 and transported to the nucleus, in which it stimulates the gluconeogenic programme by binding to CREB. Here we show in mice that insulin inhibits gluconeogenic gene expression during re-feeding by promoting the phosphorylation and ubiquitin-dependent degradation of TORC2. Insulin disrupts TORC2 activity by induction of the Ser/Thr kinase SIK2, which we show here undergoes AKT2-mediated phosphorylation at Ser 358. Activated SIK2 in turn stimulated the Ser 171 phosphorylation and cytoplasmic translocation of TORC2. Phosphorylated TORC2 was degraded by the 26S proteasome during re-feeding through an association with COP1, a substrate receptor for an E3 ligase complex that promoted TORC2 ubiquitination at Lys 628. Because TORC2 protein levels and activity were increased in diabetes owing to a block in TORC2 phosphorylation, our results point to an important role for this pathway in the maintenance of glucose homeostasis.


Epidemiology, Diagnosis and Risk Factors of Helicobacter pylori Infection.
Helicobacter pylori is a human-specific pathogen, which leads to gastric pathologies including gastric cancer. It is a highly unique bacterium considered as a carcinogenic agent. H. pylori remains a major human health problem, responsible for ~90% of the gastric cancer cases. Approximately four billion individuals have been detected for H. pylori infection worldwide in 2015. At the turn of the twenty-first century, the prevalence of H. pylori has been declining in highly industrialized countries of the Western world, whereas prevalence has plateaued at a high level in developing and newly industrialized countries. However, the infection status remains high in immigrants coming from countries with high prevalence of H. pylori infection. H. pylori can be diagnosed both by invasive and non-invasive methods. Urea breath test and stool antigens detection are among the most commonly used non-invasive ones. Although the way H. pylori is transmitted remains still not fully clear, the level of contamination is strongly dependent on the familial and environmental context, with a drastic impact of living conditions with poor hygiene and sanitation. However, familial socioeconomic status is the main risk factor for H. pylori infection among children. In addition, food and water source have a high impact on the prevalence of H. pylori infection worldwide. This chapter highlights the latest knowledge in the epidemiology of H. pylori infection, its diagnosis and critical risk factors responsible for its high prevalence in some populations and geographic areas.


Molecular cytogenetic analysis of consistent abnormalities at 8q12-q22 in breast cancer.
Studies using comparative genomic hybridization (CGH) indicate that portions of chromosome arm 8q from 8q12 to 8qter are present at an increased relative copy number in a broad range of solid tumors. In this study we define an approximately 1 Mb wide region that appears to be frequently abnormal in copy number or structure in breast cancer cell lines and primary tumors. This was accomplished by fluorescence in situ hybridization (FISH) with yeast artificial chromosomes (YACs) mapped to 8q2-q22. Eleven breast cancer cell lines and ten primary tumors were analyzed. A minimal region of rearrangement was localized to the CEPH-YAC 928F9 in three breast cancer cell lines with unbalanced translocation breakpoints mapping in this region. Unbalanced translocations also were detected in two primary tumors mapping between CEPH-YAC clones 890C4 and 936B3, flanking 928F9. An increased copy number in the minimal region was detected in nine cell lines and in multiple primary tumors. This suggests the possibility that a single gene mapping to 928F9 is involved in breast cancer development or progression and may be deregulated by copy number increases in some tumors and by translocation in others. Four expressed sequence tags were mapped to YAC 928F9 and analyzed for rearrangements by Southern analysis and for abnormal expression by Northern analysis.


Crop and Non-Crop Plants as Potential Reservoir Hosts of Alfalfa mosaic virus and Cucumber mosaic virus for Spread to Commercial Snap Bean.
Diseases caused by aphid-transmitted viruses such as Alfalfa mosaic virus (AMV) and Cucumber mosaic virus (CMV) have increased in snap bean (Phaseolus vulgaris) in the Midwestern United States. Plants immediately surrounding agricultural fields may serve as primary virus inocula for aphids to acquire and transmit to bean crops. The project objectives were to (i) identify potentially important AMV and CMV reservoirs among naturally infected plants and (ii) determine the relationship between the virus inoculum potential (VIP) in adjacent crop field margins and virus incidence in P. vulgaris. From 2006 to 2008, surveys were conducted to quantify the virus incidence and percentage cover (2008 only) of plants present within 5 m of the P. vulgaris crop. In all, 4,350 individual plants representing 44 species were assayed, with overall AMV and CMV incidences averaging 12 and 1.5%, respectively. A VIP index was developed and used to rank the importance of virus-susceptible plants in adjacent field margins. The overall VIP index for AMV in field margins was weakly associated with AMV incidence in P. vulgaris and no relationship was observed between local CMV inoculum and P. vulgaris incidence, suggesting that factors additional to local inoculum sources may influence CMV epidemics in P. vulgaris.


Can't Count or Won't Count? Embedding Quantitative Methods in Substantive Sociology Curricula: A Quasi-Experiment.
This paper reports on a quasi-experiment in which quantitative methods (QM) are embedded within a substantive sociology module. Through measuring student attitudes before and after the intervention alongside control group comparisons, we illustrate the impact that embedding has on the student experience. Our findings are complex and even contradictory. Whilst the experimental group were less likely to be distrustful of statistics and appreciate how QM inform social research, they were also less confident about their statistical abilities, suggesting that through 'doing' quantitative sociology the experimental group are exposed to the intricacies of method and their optimism about their own abilities is challenged. We conclude that embedding QM in a single substantive module is not a 'magic bullet' and that a wider programme of content and assessment diversification across the curriculum is preferential.


Elevated levels of Legionella pneumophila stress protein Hsp60 early in infection of human monocytes and L929 cells correlate with virulence.
Legionella pneumophila 2064 was selectively radiolabelled in mouse L929 cells and human monocytes to identify proteins expressed early in the course of infection. Polypeptide profiles (sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography) of adherent or intracellular bacteria indicated that a 60-kDa stress protein (Hsp60) was preferentially synthesized. Hsp60 synthesis was not induced by medium alone. The synthesis of many polypeptides, including OmpS (major outer membrane protein), diminished over the 1-h period postinfection. However, by 17 h postinfection OmpS and Hsp60 were the dominant proteins synthesized by 2064. To establish whether induction of Hsp60 was a correlate of virulence, an isogenic avirulent strain (2064M) of 2064 was isolated following selection on a nonpermissive medium. 2064M did not exhibit a stress response when adherent or intracellular in L929 cells or in human monocytes and failed to abrogate phagosome-lysosome fusion. When grown in vitro, 2064M exhibited no deficiencies in the heat shock response and its polypeptide profile resembled that of 2064. Immunogold electron microscopy was used to localize Hsp60 in L. pneumophila-infected L929 cells. There was an increase in the number of gold particles associated with phagosomes for phagosomes harboring single 2064 bacteria compared with those harboring 2064M. Moreover, by 1 h postinfection, a sixfold increase in the number of gold spheres associated with the membranes of phagosomes was observed for phagosomes harboring 2064 compared with those harboring 2064M. These studies indicate that virulent, but not NaCl-tolerant avirulent, strains of L. pneumophila respond to host-cell-associated environmental signals early in the course of infection. This response includes increased synthesis and possibly extracellular secretion of Hsp60 concomitant with repression of the expression of other genes, including ompS.


Pathologic changes in biliary dyskinesia.
For children with upper abdominal pain and evaluation for acalculous biliary disease, laparoscopic cholecystectomy is an accepted treatment with inconsistent outcomes. The purpose of this study was to identify predictors of outcomes. One hundred sixty-seven children underwent laparoscopic cholecystectomy at a single children's hospital. Radiographic findings, histopathology, family history, and demographics (sex, age, height, weight, body mass index-for-age percentile) were evaluated as predictors of postoperative symptomatic resolution using a binomial probability model. The data for radiologic studies and pathologic specimens were obtained via re-review in a blinded fashion. Of 167 children, 43 (25.7%) had a preoperative diagnosis of biliary dyskinesia and 41 (95.3%) had documented follow-up. Mean follow-up was 8.4 months. Twenty-eight patients (68.3%) had symptom resolution. Ejection fraction less than or equal to 15%, pain upon cholecystokinin injection, and a family history of biliary disease were not predictors of symptomatic resolution. Nonoverweight patients (body mass index-for-age <85th percentile) were more likely to have symptom resolution than their overweight counterparts (odds ratio, 2.13). Most patients (68.3%) had a pathologic gallbladder on blinded review. However, this did not correlate with outcome. Most gallbladders removed for biliary dyskinesia are pathologic. Being overweight can be considered a relative contraindication to cholecystectomy for biliary dyskinesia.


Use of taxonomies to sequence clinical objectives.
This paper describes the use of four educational taxonomies in establishing a task grid for guiding and determining sequential learning opportunities and activities for the developmentally delayed child and for treatment planning for team members working with the child. It describes a three-dimensional grid that includes learners, areas of learning, and levels of learning. To clarify the use of this model, the grid has been applied to feeding intervention with the delayed child. Use of the task grid suggests three factors are needed in intervention with the developmentally delayed child: 1. objectives should be stated for all domains of learning since learning occurs concurrently in different areas; 2. activities should be sequenced not only for the child but also for all those directly involved with the child, since all are involved in the learning process; and 3. analytical behavior should be stimulated in the therapist so that theory-based practice can be realized.


The tyrosinase enhancer is activated by Sox10 and Mitf in mouse melanocytes.
The terminal differentiation of melanocytes is associated with the transcriptional activation of genes responsible for pigment production such as tyrosinase. Pigment cell-specific transcription factors, such as Mitf, as well as specific proximal and distal regulatory elements (DRE) are implicated in the tight control of tyrosinase expression during development and adulthood. Proper tyrosinase expression in melanocytes depends upon the presence of a DRE that is located at -15 kb and provides enhancer activity via a central element termed core-enhancer. In this report, we show that the transcription factors Sox10, Mitf and USF-1 are able to activate the core-enhancer in luciferase reporter assays. Comparative sequence analysis identified evolutionarily motifs resembling Sox10 binding sites that were required for full enhancer activity in melanoma cells and in tyrosinase::lacZ transgenic mice. Sox10 was able to bind the DRE in vitro and mutation of the conserved motifs abolished the enhancer transactivation mediated by Sox10. In addition, two highly conserved CAGCTG E-box motifs were identified that were also required for enhancer activity and for transactivation by Mitf. The results suggest that Sox10 directly, and Mitf, most likely indirectly, activate the tyrosinase enhancer, underlining the contribution of Sox10 to tyrosinase gene regulation in melanocytes.


Nuclear respiratory factor 1 co-regulates AMPA glutamate receptor subunit 2 and cytochrome c oxidase: tight coupling of glutamatergic transmission and energy metabolism in neurons.
Neuronal activity, especially of the excitatory glutamatergic type, is highly dependent on energy from the oxidative pathway. We hypothesized that the coupling existed at the transcriptional level by having the same transcription factor to regulate a marker of energy metabolism, cytochrome c oxidase (COX) and an important subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors, GluR2 (Gria2). Nuclear respiratory factor 1 (NRF-1) was a viable candidate because it regulates all COX subunits and potentially activates Gria2. By means of in silico analysis, electrophoretic mobility shift and supershift, chromatin immunoprecipitation, and promoter mutational assays, we found that NRF-1 functionally bound to Gria2 promoter. Silencing of NRF-1 with small interference RNA prevented the depolarization-stimulated up-regulation of Gria2 and COX, and over-expression of NRF-1 rescued neurons from tetrodotoxin-induced down-regulation of Gria2 and COX transcripts. Thus, neuronal activity and energy metabolism are tightly coupled at the molecular level, and NRF-1 is a critical agent in this process.


Autophagosome Proteins LC3A, LC3B and LC3C Have Distinct Subcellular Distribution Kinetics and Expression in Cancer Cell Lines.
LC3s (MAP1-LC3A, B and C) are structural proteins of autophagosomal membranes, widely used as biomarkers of autophagy. Whether these three LC3 proteins have a similar biological role in autophagy remains obscure. We examine in parallel the subcellular expression patterns of the three LC3 proteins in a panel of human cancer cell lines, as well as in normal MRC5 fibroblasts and HUVEC, using confocal microscopy and western blot analysis of cell fractions. In the cytoplasm, there was a minimal co-localization between LC3A, B and C staining, suggesting that the relevant autophagosomes are formed by only one out of the three LC3 proteins. LC3A showed a perinuclear and nuclear localization, while LC3B was equally distributed throughout the cytoplasm and localized in the nucleolar regions. LC3C was located in the cytoplasm and strongly in the nuclei (excluding nucleoli), where it extensively co-localized with the LC3A and the Beclin-1 autophagy initiating protein. Beclin 1 is known to contain a nuclear trafficking signal. Blocking nuclear export function by Leptomycin B resulted in nuclear accumulation of all LC3 and Beclin-1 proteins, while Ivermectin that blocks nuclear import showed reduction of accumulation, but not in all cell lines. Since endogenous LC3 proteins are used as major markers of autophagy in clinical studies and cell lines, it is essential to check the specificity of the antibodies used, as the kinetics of these molecules are not identical and may have distinct biological roles. The distinct subcellular expression patterns of LC3s provide a basis for further studies.


Constructal blade shape in nanofluids.
Blade configuration of nanofluids has been proven to perform much better than dispersed configuration for some heat conduction systems. The analytical analysis and numerical calculation are made for the cylinder--shaped and regular-rectangular-prism--shaped building blocks of the blade-configured heat conduction systems (using nanofluids as the heat conduction media) to find the optimal cross-sectional shape for the nanoparticle blade under the same composing materials, composition ratio, volumetric heat generation rate, and total building block volume. The regular-triangular-prism--shaped blade has been proven to perform better than all the other three kinds of blades, namely, the regular-rectangular-prism--shaped blade, the regular-hexagonal-prism--shaped blade, and the cylinder--shaped blade. Thus, the regular-triangular-prism--shaped blade is selected as the optimally shaped blade for the two kinds of building blocks that are considered in this study. It is also proven that the constructal cylinder--regular-triangular-prism building block performs better than the constructal regular-rectangular-prism--regular-triangular-prism building block.


Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has potent antitumor activity in in vitro and in vivo models of non-small cell lung cancer.
We describe the anticancer activity of ganetespib, a novel non-geldanamycin heat shock protein 90 (HSP90) inhibitor, in non-small cell lung cancer (NSCLC) models. The activity of ganetespib was compared with that of the geldanamycin 17-AAG in biochemical assays, cell lines, and xenografts, and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model. Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its cochaperone, p23, more potently than 17-AAG. In genomically defined NSCLC cell lines, ganetespib caused depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC(50) values ranging 2 to 30 nmol/L, substantially lower than those required for 17-AAG (20-3,500 nmol/L). Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants. In mice bearing NCI-H1975 (EGFR L858R/T790M) xenografts, ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t(1/2) 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, reexpression of mutant EGFR occurred by 72 hours, correlating with reversal of antiproliferative and proapoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also showed activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA. Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets, including those harboring EGFR or ERBB2 mutation.


Seizures and epileptiform activity in the early stages of Alzheimer disease.
Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease. To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity. Retrospective observational study from 2007 to 2012. SETTING Memory and Aging Center, University of California, San Francisco. We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n = 35), and AD plus subclinical epileptiform activity (n = 7). Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications. Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P = .02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P = .001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P < .001), clustering near the onset of cognitive decline. Epilepsies were most often complex partial seizures (47%) and more than half were nonconvulsive (55%). Serial or extended EEG monitoring appeared to be more effective than routine EEG at detecting interictal and subclinical epileptiform activity. Epileptic foci were predominantly unilateral and temporal. Of the most commonly prescribed antiepileptics, treatment outcomes appeared to be better for lamotrigine and levetiracetam than for phenytoin. Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.


MERS-CoV at the Animal-Human Interface: Inputs on Exposure Pathways from an Expert-Opinion Elicitation.
Nearly 4 years after the first report of the emergence of Middle-East respiratory syndrome Coronavirus (MERS-CoV) and nearly 1800 human cases later, the ecology of MERS-CoV, its epidemiology, and more than risk factors of MERS-CoV transmission between camels are poorly understood. Knowledge about the pathways and mechanisms of transmission from animals to humans is limited; as of yet, transmission risks have not been quantified. Moreover the divergent sanitary situations and exposures to animals among populations in the Arabian Peninsula, where human primary cases appear to dominate, vs. other regions in the Middle East and Africa, with no reported human clinical cases and where the virus has been detected only in dromedaries, represents huge scientific and health challenges. Here, we have used expert-opinion elicitation in order to obtain ideas on relative importance of MERS-CoV risk factors and estimates of transmission risks from various types of contact between humans and dromedaries. Fourteen experts with diverse and extensive experience in MERS-CoV relevant fields were enrolled and completed an online questionnaire that examined pathways based on several scenarios, e.g., camels-camels, camels-human, bats/other species to camels/humans, and the role of diverse biological substances (milk, urine, etc.) and potential fomites. Experts believed that dromedary camels play the largest role in MERS-CoV infection of other dromedaries; however, they also indicated a significant influence of the season (i.e. calving or weaning periods) on transmission risk. All experts thought that MERS-CoV-infected dromedaries and asymptomatic humans play the most important role in infection of humans, with bats and other species presenting a possible, but yet undefined, risk. Direct and indirect contact of humans with dromedary camels were identified as the most risky types of contact, when compared to consumption of various camel products, with estimated "most likely" incidence risks of at least 22 and 13% for direct and indirect contact, respectively. The results of our study are consistent with available, yet very limited, published data regarding the potential pathways of transmission of MERS-CoV at the animal-human interface. These results identify key knowledge gaps and highlight the need for more comprehensive, yet focused research to be conducted to better understand transmission between dromedaries and humans.


Black strings, low viscosity fluids, and violation of cosmic censorship.
We describe the behavior of 5-dimensional black strings, subject to the Gregory-Laflamme instability. Beyond the linear level, the evolving strings exhibit a rich dynamics, where at intermediate stages the horizon can be described as a sequence of 3-dimensional spherical black holes joined by black string segments. These segments are themselves subject to a Gregory-Laflamme instability, resulting in a self-similar cascade, where ever-smaller satellite black holes form connected by ever-thinner string segments. This behavior is akin to satellite formation in low-viscosity fluid streams subject to the Rayleigh-Plateau instability. The simulation results imply that the string segments will reach zero radius in finite asymptotic time, whence the classical space-time terminates in a naked singularity. Since no fine-tuning is required to excite the instability, this constitutes a generic violation of cosmic censorship.


Monoamines as Drug Targets in Chronic Pain: Focusing on Neuropathic Pain.
Monoamines are involved in regulating the endogenous pain system and indeed, peripheral and central monoaminergic dysfunction has been demonstrated in certain types of pain, particularly in neuropathic pain. Accordingly, drugs that modulate the monaminergic system and that were originally designed to treat depression are now considered to be first line treatments for certain types of neuropathic pain (e.g., serotonin and noradrenaline (and also dopamine) reuptake inhibitors). The analgesia induced by these drugs seems to be mediated by inhibiting the reuptake of these monoamines, thereby reinforcing the descending inhibitory pain pathways. Hence, it is of particular interest to study the monoaminergic mechanisms involved in the development and maintenance of chronic pain. Other analgesic drugs may also be used in combination with monoamines to facilitate descending pain inhibition (e.g., gabapentinoids and opioids) and such combinations are often also used to alleviate certain types of chronic pain. By contrast, while NSAIDs are thought to influence the monoaminergic system, they just produce consistent analgesia in inflammatory pain. Thus, in this review we will provide preclinical and clinical evidence of the role of monoamines in the modulation of chronic pain, reviewing how this system is implicated in the analgesic mechanism of action of antidepressants, gabapentinoids, atypical opioids, NSAIDs and histaminergic drugs.