Are Dermatophytid Reactions in Patients with Kerion Celsi Much More Common Than Previously Thought? A Prospective Study.
Dermatophytid reactions are secondary eruptions in response to dermatophytosis. Only a few cases demonstrating an association between dermatophytid reactions and tinea capitis have been reported. Dermatophytid reactions were evaluated in patients diagnosed with kerion celsi. Patients admitted to the dermatology clinic of Van Regional Training and Research Hospital between November 22, 2012, and July 1, 2013, diagnosed with kerion celsi were evaluated for dermatophytid reactions. Six girls (32%) and 13 boys (68%) were included in this study. Dermatophytid reactions were detected in 13 of the 19 patients (68%). Seven patients (36.84%) had eczematous patches or plaques and three (15.8%) had papules. Eczematous lesions, papules, and pustules were noted in two patients (10.5%) and one (5.3%) had signs of an angioedema-like reaction. Dermatophytid reactions in all patients were observed before the initiation of therapy. According to our clinical experiences, dermatophytid reactions in patients with kerion celsi were more common than reported. Eczematous scaly patches or plaques were the most frequently seen forms of dermatophytid in patients with kerion celsi. Dermatophytid reactions may occur before or after initiation of systemic antifungal therapy. Recognition of this reaction is important so that dermatophytids can be distinguished from drug reactions and the decision can be made whether to continue or to stop the systemic antifungal treatment.


Cost Effectiveness of Case Detection Strategies for the Early Detection of COPD.
The value of early detection and treatment of chronic obstructive pulmonary disease (COPD) is currently unknown. We assessed the cost effectiveness of primary care-based case detection strategies for COPD. A previously validated discrete event simulation model of the general population of COPD patients in Canada was used to assess the cost effectiveness of 16 case detection strategies. In these strategies, eligible patients (based on age, smoking history, or symptoms) received the COPD Diagnostic Questionnaire (CDQ) or screening spirometry, at 3- or 5-year intervals, during routine visits to a primary care physician. Newly diagnosed patients received treatment for smoking cessation and guideline-based inhaler pharmacotherapy. Analyses were conducted over a 20-year time horizon from the healthcare payer perspective. Costs are in 2019 Canadian dollars ($). Key treatment parameters were varied in one-way sensitivity analysis. Compared to no case detection, all 16 case detection scenarios had an incremental cost-effectiveness ratio (ICER) below $50,000/QALY gained. In the most efficient scenario, all patients aged ≥ 40 years received the CDQ at 3-year intervals. This scenario was associated with an incremental cost of $287 and incremental effectiveness of 0.015 QALYs per eligible patient over the 20-year time horizon, resulting in an ICER of $19,632/QALY compared to no case detection. Results were most sensitive to the impact of treatment on the symptoms of newly diagnosed patients. Primary care-based case detection programs for COPD are likely to be cost effective if there is adherence to best-practice recommendations for treatment, which can alleviate symptoms in newly diagnosed patients.


Temporally precise labeling and control of neuromodulatory circuits in the mammalian brain.
Few tools exist to visualize and manipulate neurons that are targets of neuromodulators. We present iTango, a light- and ligand-gated gene expression system based on a light-inducible split tobacco etch virus protease. Cells expressing the iTango system exhibit increased expression of a marker gene in the presence of dopamine and blue-light exposure, both in vitro and in vivo. We demonstrated the iTango system in a behaviorally relevant context, by inducing expression of optogenetic tools in neurons under dopaminergic control during a behavior of interest. We thereby gained optogenetic control of these behaviorally relevant neurons. We applied the iTango system to decipher the roles of two classes of dopaminergic neurons in the mouse nucleus accumbens in a sensitized locomotor response to cocaine. Thus, the iTango platform allows for control of neuromodulatory circuits in a genetically and functionally defined manner with spatial and temporal precision.


Inductive heating kills cells that contribute to plaque: a proof-of-concept.
Inducing cell death by heating targeted particles shows promise in cancer treatment. Here, we aim to demonstrate the feasibility of extending the use of this technique to treat and remove vascular deposits and thrombosis. We used induction heating of macrophages, which are key contributors to atherosclerosis and have demonstrated clear feasibility for heating and destroying these cells using ferromagnetic and pure iron particles. Specifically, iron particles achieved maximum temperatures of 51 ± 0.5 °C and spherical particles achieved a maximum temperature of 43.9 ± 0.2 °C (N = 6) after 30 min of inductive heating. Two days of subsequent observation demonstrated that inductive heating led to a significant reduction in cell number. Prior to induction heating, cell density was 105,000 ± 20,820 cells/ml (N = 3). This number was reduced to 6,666 ± 4,410 cells/ml for the spherical particles and 16,666 ± 9,280 cells/ml for the iron particles 24 h after inductive heating. Though cell density increased on the second day following inductive heating, the growth was minimal. Cells grew to 26,667 ± 6,670 cells/ml and 30,000 ± 15,280 cells/ml respectively. Compared to cell cultures with iron and spherical particles that were not subjected to induction heating, we observed a 97% reduction in cell count for the spherical particles and a 91% reduction for the iron particles after the first 24 h. After 48 h we observed a 95% reduction in cell growth for both spherical and iron particles. Induction heating of microparticles was thus highly effective in reducing the macrophage population and preventing their growth. These results demonstrate the feasibility of targeting cells involved in atherosclerosis and warrant further research into potential clinical applications.


Similarity studies on guanidinium, imidazolinium, and imidazolium cations: toward new bradykinin antagonists.
Bradykinin (BK) is a potent nociceptive agent and its antagonists show analgesic activity. In the search for new antagonists of BK, the design of nonpeptidic derivatives with different terminal cations has been considered. Among these new antagonists, the guanidinium cations, which appear not only in the terminal arginine residues of BK but also in several nonpeptidic antagonists, will be substituted by groups with characteristics similar in terms of electrostatic potential, electron density, shape, etc. Several similarity indexes have been calculated for guanidinium, 2-aminoimidazolinium, and 2-aminoimidazolium cations and their corresponding neutral species to design new nonpeptidic BK antagonists. The geometric and electronic characteristics of the molecules were compared by means of: (1) the Carbo index, (2) the Hodgkin index, and (3) a shape similarity index based on the volume of each molecule as defined by a certain electron density. Molecular geometries and energies were optimized by ab initio calculations at the B3LYP/6311+2G** level. The molecular electrostatic potential (MEP) and the electron density (rho) were then computed in a cubic grid of points around each molecule. These molecular properties were used to calculate similarity indexes with the guanidinium cation or guanidine as the reference molecule in each family. In addition, three-dimensional similarity maps were generated to localize those molecular areas more alike in each of the sets.


Open Drug Discovery Teams: A Chemistry Mobile App for Collaboration.
The Open Drug Discovery Teams (ODDT) project provides a mobile app primarily intended as a research topic aggregator of predominantly open science data collected from various sources on the internet. It exists to facilitate interdisciplinary teamwork and to relieve the user from data overload, delivering access to information that is highly relevant and focused on their topic areas of interest. Research topics include areas of chemistry and adjacent molecule-oriented biomedical sciences, with an emphasis on those which are most amenable to open research at present. These include rare and neglected diseases, and precompetitive and public-good initiatives such as green chemistry. The ODDT project uses a free mobile app as user entry point. The app has a magazine-like interface, and server-side infrastructure for hosting chemistry-related data as well as value added services. The project is open to participation from anyone and provides the ability for users to make annotations and assertions, thereby contributing to the collective value of the data to the engaged community. Much of the content is derived from public sources, but the platform is also amenable to commercial data input. The technology could also be readily used in-house by organizations as a research aggregator that could integrate internal and external science and discussion. The infrastructure for the app is currently based upon the Twitter API as a useful proof of concept for a real time source of publicly generated content. This could be extended further by accessing other APIs providing news and data feeds of relevance to a particular area of interest. As the project evolves, social networking features will be developed for organizing participants into teams, with various forms of communication and content management possible.


Directed self-assembly of silica nanoparticles in ionic liquid-spun cellulose fibers.
The application range of man-made cellulosic fibers is limited by the absence of cost- and manufacturing-efficient strategies for anisotropic hierarchical functionalization. Overcoming these bottlenecks is therefore pivotal in the pursuit of a future bio-based economy. Here, we demonstrate that colloidal silica nanoparticles (NPs), which are cheap, biocompatible and easy to chemically modify, enable the control of the cross-sectional morphology and surface topography of ionic liquid-spun cellulose fibers. These properties are tailored by the silica NPs' surface chemistry and their entry point during the wet-spinning process (dope solution DSiO2 or coagulation bath CSiO2). For CSiO2-modified fibers, the coagulation mitigator dimethylsulphoxide allows for controlling the surface topography and the amalgamation of the silica NPs into the fiber matrix. For dope-modified fibers, we hypothesize that cellulose chains act as seeds for directed silica NP self-assembly. This results for DSiO2 in discrete micron-sized rods, homogeneously distributed throughout the fiber and for glycidoxy-surface modified DSiO2@GLYEO in nano-sized surface aggregates and a cross-sectional core-shell fiber morphology. Furthermore, the dope-modified fibers display outstanding strength and toughness, which are both characteristic features of biological biocomposites.


Evaluation of cannabimimetic effects of structural analogs of anandamide in rats.
Arachidonylethanolamide (anandamide), an endogenous ligand for the cannabinoid receptor, binds competitively to brain cannabinoid receptors and shares many, but not all, of the in vivo effects of delta9-tetrahydrocannabinol. In this study, the cannabinoid effects of anandamide analogs in which the anandamide molecule was altered were assessed in a drug discrimination model. Structural manipulations of the anandamide molecule included saturation of the arachidonyl moiety with fluorination (O-586), substitution for either the ethanolamide moiety (O-612 and O-595) or C2' hydroxyl (O-585), and addition of a methyl group at various positions (O-610, O-680, and O-689). Despite the low binding affinities of the non-methylated compounds (Ki values > 2000 nM), all of the analogs had previously shown cannabinoid activity in mice. In the present study, these analogs were tested in a more pharmacologically specific delta9-tetrahydrocannabinol discrimination procedure in rats. This animal model is predictive of the subjective effects of marijuana intoxication in humans. Whereas delta9-tetrahydrocannabinol and an aminoakylindole fully substituted for the training dose of 3 mg/kg delta9-tetrahydrocannabinol, anandamide and its non-methylated analogs were not cannabimimetic in this procedure. Methylation appeared to increase binding affinity (Ki values < 150 nM) and efficacy; however, the greatest substitution produced by the methylated analogs occurred only at doses that decreased overall rates of responding, suggesting that these analogs are not fully delta9-tetrahydrocannabinol-like. The rapid metabolism of anandamide and some of its analogs undoubtedly contribute to the differences between the pharmacological profiles of the anandamides and classical cannabinoids. These results support the prediction that the subjective effects of anandamide analogs that have been developed thus far would not be cannabimimetic except at high doses.


Muscle protein metabolism and the sarcopenia of aging.
Loss of muscle mass, strength, and oxidative capacity accompanies normal aging in humans. The mechanisms responsible for these changes remain to be clearly defined. Muscle protein mass and function depend on protein turnover. Synthesis rate of the major muscle contractile protein, myosin heavy chain (MHC), and transcript levels of fast MHC isoforms decrease in association with strength reductions, while mitochondrial protein synthesis rate declines in parallel with activities of mitochondrial enzymes and maximal oxidative capacity (VO2max). Resistance exercise training increases the synthesis rate of MHC and transcript levels of the slow MHC isoform in older humans, along with increasing muscle strength. The relationship between the synthesis of muscle proteins, and muscle size and function, with aging and exercise training are discussed in this review.


Effects of retinoic acid (RA) on the growth and phenotypic expression of several human neuroblastoma cell lines.
It has been shown that retinoic acid (RA) can promote morphologic differentiation and inhibit the growth of a human neuroblastoma cell line, LA-N-1. The present study tests the histological generality of these phenomena by determining the effects of RA on seven other human neuroblastoma cell lines. Results show that RA strongly inhibited anchorage-dependent growth and induced morphologic alterations in six of seven of the cell lines. These alternations included morphologic differentiation as evidenced by formation of neurite extensions in four of the lines, cellular enlargement and vacuolization in one culture, and formation of large, flattened epithelial or fibroblastic-like cells in another culture. Although one cell line was relatively insensitive to the effects of RA in monolayer culture, all seven were strongly inhibited by RA in soft agar assays. Cellular RA-binding proteins were detected in 2/2 lines tested. These findings suggest that, as a histological group, human neuroblastoma cells are extremely sensitive to RA-induced growth inhibition and morphological alterations generally associated with reduced expression of the malignant phenotype of this type of cancer.


Sheet-like assemblies of charged amphiphilic α/β-peptides at the air-water interface.
There is growing interest in the design of molecules that undergo predictable self-assembly. Bioinspired oligomers with well-defined conformational propensities are attractive from this perspective, since they can be constructed from diverse building blocks, and self-assembly can be directed by the identities and sequence of the subunits. Here we describe the structure of monolayers formed at the air-water interface by amphiphilic α/β-peptides with 1:1 alternation of α- and β-amino acid residues along the backbone. Two of the α/β-peptides, one a dianion and the other a dication, were used to determine differences between self-assemblies of the net negatively and positively charged oligomers. Two additional α/β-peptides, both zwitterionic, were designed to favor assembly in a 1:1 molar ratio mixture with parallel orientation of neighboring strands. Monolayers formed by these α/β-peptides at the air-water interface were characterized by surface pressure-area isotherms, grazing incidence X-ray diffraction (GIXD), atomic force microscopy and ATR-FTIR. GIXD data indicate that the α/β-peptide assemblies exhibited diffraction features similar to those of β-sheet-forming α-peptides. The diffraction data allowed the construction of a detailed model of an antiparallel α/β-peptide sheet with a unique pleated structure. One of the α/β-peptide assemblies displayed high stability, unparalleled among previously studied assemblies of α-peptides. ATR-FTIR data suggest that the 1:1 mixture of zwitterionic α/β-peptides assembled in a parallel arrangement resembling that of a typical parallel β-sheet secondary structure formed by α-peptides. This study establishes guidelines for design of amphiphilic α/β-peptides that assemble in a predictable manner at an air-water interface, with control of interstrand orientation through manipulation of Coulombic interactions along the backbone.


The effectiveness of an education intervention to prevent chlamydia infection among Greenlandic youth.
The purpose of this study was to implement a sexual health behavioural intervention in Greenland in order to reduce sexually transmitted infection rates among a population of Greenland youth. This behavioural intervention was called Inuulluataarneq (Having the Good Life). Inuulluataarneq's objects included: (1) increase Greenlandic youth's overall knowledge about sexually transmitted infections and sexual health; (2) increase parent/guardian-youth communication about topics related to sexually transmitted infections and sex; and (3) increase consistent condom use among Greenlandic youth. We hypothesised that increased awareness of sexually transmitted infections and sexual health as well as increased communication between parents/guardians and their adolescent children would influence sexual risk behaviour and reduce sexually transmitted infections among our sample population, with a focus on urine samples of chlamydia infection. Results indicate that the influence of having a parent/guardian to speak with about topics related to sex, including the consequences of pregnancy, are key protective factors in reducing sexually transmitted infections among Greenlandic youth. Inuulluataarneq demonstrates that intensive short-term education and skill-building delivered by a trained community member is an effective sexually transmitted infection prevention intervention method among young Inuit populations who live in small isolated Arctic communities.


Caries prevalence and experience of 12-year old children in Montserrat.
The aim of this study was to determine the caries experience and oral health related quality of life of 12-year-olds on the Caribbean island of Montserrat. In addition, any difference in the dental caries experience was explored by gender and socio-economic status. A total of forty-six 12-year-olds were living on the island at the time of the study and 32 (69%) participated in the survey. Caries experience was recorded using the decayed, missing and filled teeth (DMFT) index by a trained and calibrated examiner according to the British Association for the Study of Community Dentistry (BASCD) criteria. The Care Index was used to describe the level of dental care. The Child Perception Questionnaire was used to investigate the impact of oral health conditions on oral health-related quality of life. Statistical software Dental Survey Plus and SPSS were used to analyse data. The findings of this study showed that the 12-year-olds had a mean DMFT of 1.91 and 59% had active untreated caries with an overall Care Index of 16%. While the perception of oral symptoms was low, over a third of children reported a functional impact as a result of their oral condition. It is concluded that there is a need for improved delivery of restorative care coupled with oral health promotion and dental health education.


Traditional Breast Cancer Risk Factors in Filipina Americans Compared with Chinese and Japanese Americans in Los Angeles County.
Filipina Americans have one of the highest breast cancer incidence rates among Asian Americans for poorly understood reasons. Breast cancer risk factors were investigated in a population-based study of Filipina (790 cases, 587 controls), Japanese (543 cases, 510 controls), and Chinese (913 cases, 904 controls) Americans. Cases were identified by the Los Angeles County Cancer Surveillance Program, and controls were matched to cases on age, ethnicity, and neighborhood. Multivariable conditional logistic regression was performed by Asian ethnicity. In Filipina, Chinese, and Japanese Americans, breast cancer risk decreased significantly with increasing parity (all Ptrend < 0.0001). Breast cancer risk increased with increasing quartiles of cumulative menstrual months in premenopausal (Ptrend = 0.019) and postmenopausal Filipina (Ptrend = 0.008), in premenopausal (Ptrend = 0.0003) but not postmenopausal Chinese (Ptrend = 0.79), and in neither premenopausal (Ptrend = 0.092) nor postmenopausal (Ptrend = 0.75) Japanese Americans. For postmenopausal Filipina and Japanese, greater weight gain since age 18 (Ptrend = 0.019 and 0.053, respectively), high current body mass index (both Ptrend < 0.01), and greater waist circumferences (both Ptrend < 0.04) were statistically significant; these associations were weaker for postmenopausal Chinese women. Cumulative menstrual months and body size factors were statistically significant risk factors for Filipina. Total menstrual months were associated with breast cancer among Chinese but not for Japanese, while body size factors were significantly associated with risk among Japanese but not among Chinese. Characterization of breast cancer risk factors in Filipina will help to generate hypotheses for their high breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 25(12); 1572-86. ©2016 AACR.


Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis.
The two-pore domain potassium channel, K2P3.1 (TASK-1) modulates background conductance in isolated human atrial cardiomyocytes and has been proposed as a potential drug target for atrial fibrillation (AF). TASK-1 knockout mice have a predominantly ventricular phenotype however, and effects of TASK-1 inactivation on atrial structure and function have yet to be demonstrated in vivo. The extent to which genetic variation in KCNK3, that encodes TASK-1, might be a determinant of susceptibility to AF is also unknown. To address these questions, we first evaluated the effects of transient knockdown of the zebrafish kcnk3a and kcnk3b genes and cardiac phenotypes were evaluated using videomicroscopy. Combined kcnk3a and kcnk3b knockdown in 72 hour post fertilization embryos resulted in lower heart rate (p<0.001), marked increase in atrial diameter (p<0.001), and mild increase in end-diastolic ventricular diameter (p=0.01) when compared with control-injected embryos. We next performed genetic screening of KCNK3 in two independent AF cohorts (373 subjects) and identified three novel KCNK3 variants. Two of these variants, present in one proband with familial AF, were located at adjacent nucleotides in the Kozak sequence and reduced expression of an engineered reporter. A third missense variant, V123L, in a patient with lone AF, reduced resting membrane potential and altered pH sensitivity in patch-clamp experiments, with structural modeling predicting instability in the vicinity of the TASK-1 pore. These in vitro data suggest that the double Kozak variants and V123L will have loss-of-function effects on ITASK. Cardiac action potential modeling predicted that reduced ITASK prolongs atrial action potential duration, and that this is potentiated by reciprocal changes in activity of other ion channel currents. Our findings demonstrate the functional importance of ITASK in the atrium and suggest that inactivation of TASK-1 may have diverse effects on atrial size and electrophysiological properties that can contribute to an arrhythmogenic substrate.


Sulforaphane protects against acetaminophen-induced hepatotoxicity.
Oxidative stress is closely associated with acetaminophen (APAP)-induced toxicity. Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. This study investigated whether sulforaphane (SFN), as a HO-1 inducer, plays a protective role against APAP hepatotoxicity in vitro and in vivo. Pretreatment of primary hepatocyte with SFN induced nuclear factor E2-factor related factor (Nrf2) target gene expression, especially HO-1 mRNA and protein expression, and suppressed APAP-induced glutathione (GSH) depletion and lipid peroxidation, which eventually leads to hepatocyte cell death. A comparable effect was observed in mice treated with APAP. Mice were treated with 300 mg/kg APAP 30 min after SFN (5 mg/kg) administration and were then sacrificed after 6 h. APAP alone caused severe liver injuries as characterized by increased plasma AST and ALT levels, GSH depletion, apoptosis, and 4-hydroxynonenal (4-HNE) formations. This APAP-induced liver damage was significantly attenuated by pretreatment with SFN. Furthermore, while hepatic reactive oxygen species (ROS) levels were increased by APAP exposure, pretreatment with SFN completely blocked ROS formation. These results suggest that SFN plays a protective role against APAP-mediated hepatotoxicity through antioxidant effects mediated by HO-1 induction. SFN has preventive action in oxidative stress-mediated liver injury.


Evaluation of the clinical efficacy of colon capsule endoscopy in the detection of lesions of the colon: prospective, multicenter, open study.
Colon capsule endoscopy (CCE) is a new procedure for colon imaging. Limited information is available regarding visualization of flat colon lesions and patient acceptability in Japan. The aims of this study were to evaluate the sensitivity of CCE in detecting polyps and other lesions compared with optical colonoscopy (OC) and to evaluate its safety and acceptability in a cohort of Japanese patients. A prospective, open-label, clinical study in Japan. Multicenter. Patients referred for OC because of personal history of polyps ≥6 mm or any other colon lesion that required endoscopic or surgical treatment. CCE followed by therapeutic colonoscopy. The primary endpoint was per-patient sensitivity of CCE in detecting significant colon lesion. The secondary endpoints were CCE safety and patient acceptability. Sixty-six of the 72 patients enrolled in the study were evaluated for efficacy. The per-patient sensitivity was 94% (95% confidence interval [CI], 88.2%-99.7%). The per-polyp sensitivity was 86.6% (95% CI, 81.3%-91.9%) when pathology-confirmed polyps were considered true positives. There were no adverse events related to CCE, and the acceptability of CCE was high. All patients had previously confirmed colon lesions, which may have falsely elevated the sensitivity of CCE. CCE had a high sensitivity for detecting significant colon lesions. CCE was safe and had a high level of patient acceptability. ( University Hospital Medical Information Network, UMIN000007258.).


The transition to status epilepticus: how the brain meets the demands of perpetual seizure activity.
The pathophysiology leading to the development of status epilepticus (SE) remains a topic of significant scientific interest and clinical relevance. The use of multiple experimental and computational models has shown that SE relies on a complex interaction between mechanisms that operate at both a cellular and network level. In this narrative review, we will summarise the current knowledge on the factors that play a key role in allowing SE to develop and persist. These include pathological adaptations to changing ion dynamics, neuroenergetics, receptor expression and neurotransmission, which enable the brain to meet the extensive demands required to maintain ongoing synchronous hyperexcitability. We will examine how these processes converge to enable synapses to support seizure perpetuation. Lastly, we will use the concept of a perpetuating network to highlight how connections between brain regions can provide positive feedback loops that can serve to propagate seizure activity. We hope this review will collate the findings of previous research and help fuel further studies into the mechanisms that underlie how the brain can make the transition to SE.


Osteoplasty using calcium hydroxylapatite filler.
To describe a novel method using injectable calcium hydroxylapatite (Radiesse) for aesthetic correction of small bony defects in the skull. A prospective, small interventional case series was performed. Three patients were identified with bony defects of the frontal bone from prior trauma or surgery. Calcium hydroxylapatite filler was injected locally to fill the bony defects. The procedure was performed in an ambulatory surgical center with monitored anesthesia care in conjunction with eyelid surgery. Three patients were treated with 1 to 3 vials (1.3-ml vial) of injectable calcium hydroxylapatite with improvement of volume deficiency and cosmesis. There were no complications associated with the procedure. Follow-up ranged from 2 months to 7 months. This preliminary report demonstrates that injectable calcium hydroxylapatite filler provides a new, simple, semipermanent technique for aesthetic correction of small bony defects in the skull. The amount of volume replacement is easily titrated, and the procedure can be repeated if necessary until adequate volume is obtained. Although these cases were performed in a surgery center, the technique could easily be done as an office procedure with local anesthesia. A larger cohort and longer follow-up is necessary to establish the duration of effect and success of the procedure.


Modelling the budget impact of darunavir in the treatment of highly treatment-experienced, HIV-infected adults in France.
A key element for payers in the assessment of the economic profile of a medication is its anticipated impact on the evolution of healthcare budgets. To forecast the impact of the use of darunavir with low-dose ritonavir 600/100 mg twice a day (bid) in highly treatment-experienced, HIV-infected adults who have failed one or more protease inhibitor (PI)-containing regimen on the budget of the French Sickness Fund (French healthcare system) over a 3-year time horizon. A transition state model based on disease severity was developed that compared the evolution of antiretroviral and non-antiretroviral-related direct costs of care in the target population over 3 years (2007-2009) under two scenarios: (1) darunavir enters the French market in year 1; (2) darunavir is not available to the target population during 2007-2009. Model inputs were derived from a targeted analysis of the French hospital database in HIV, the darunavir POWER 1 and 2 trials and other relevant clinical studies. In the scenario where darunavir was available from year 1, the proportion of patients in the lower, more costly CD4 cell count strata (≤ 100 cells per mm³) was consistently lower than in the scenario without darunavir in each year of the model (17.0% vs 19.2%, 13.9% vs 18.3% and 10.8% vs 16.8% for years 1, 2 and 3, respectively). As a result, over the entire 3-year period, the net increase of antiretroviral drug costs (+ 5.6 million Euros; €), resulting from the substitution of older, cheaper PIs by darunavir, is expected to be fully compensated by savings in hospitalization costs (€-9.7 million) and expenditures for other HIV-related (non-antiretroviral) medications (€-7.3 million), leading to a net saving of €11.4 million or 2.9% of the total budget in the scenario without darunavir. Various sensitivity analyses confirmed these projected savings. The use of darunavir/ritonavir (DRV/r) 600/100 mg bid, in combination with other antiretroviral agents, in highly pre-treated, HIV-infected adults who have failed one or more PI-containing highly active antiretroviral therapy regimen is not expected to increase the budget of the French healthcare system, in comparison with a scenario without darunavir. Further research is needed to estimate the budget impact of the use of DRV/r in less treatment-experienced, HIV-infected individuals in France.


The efficacy and risks of preoperative embolization of spinal tumors.
The goal of preoperative embolization of spinal tumors is to improve surgical outcomes by diminishing the vascular supply to the tumor to reduce intraoperative blood loss and operative time. To report our institutional experience with spinal tumor embolization and review the present literature. Clinical records from January 1, 2001 to December 31, 2012 were reviewed and analyzed. Angiograms were used to calculate the percentage reduction in tumor vascularity, and relevant clinical and operative data were collected and analyzed. Thirty-seven patients underwent preoperative spinal tumor embolization (24 metastatic and 13 primary lesions) and were included in the study. One complication resulted in transient lower extremity weakness and was attributed to post-embolization swelling, which fully resolved after surgical resection. The transient neurological complication rate was 1/37 (3%) and the permanent rate was 0/37 (0%). The average surgical estimated blood loss (EBL) was 1946 mL (100-7000 mL) and the average operative time was 330 min (range 164-841 min). After embolization, tumor blush was reduced by 83% on average. Average pre- and postoperative modified Rankin Scale scores were 2.10 and 1.36, respectively (p=0.03). Cases in which tumor blush was decreased by ≥90% (classes 1 or 2) after embolization had significantly less operative blood loss than those cases in which <90% (classes 3 or 4) was achieved (mean EBL 1391 vs 2296 mL, respectively, p=0.05). Spinal tumor embolization is a safe procedure, is associated with few complications, and may improve surgical outcomes by limiting intraoperative blood loss and reducing operative time.


Analysis of the omega-3 fatty acid content of South African fish oil supplements: a follow-up study.
Globally the omega-3 (n-3) fatty acid supplement industry is expanding rapidly while consumers are becoming more aware of the health benefits of n-3 fatty acids. Our group conducted a survey in 2009 on 45 commercially available fish oil supplements on the South African market. The aim of the study was to determine the fatty acid composition and content of supplements for comparison with the claimed contents on the product label. The survey was repeated in 2012 on 63 supplements. Sixty-three commercially available n-3 fatty acid supplements were analysed using gas-liquid chromatography to determine their fatty acid composition and content. This analysis has shown an improvement in the accuracy of EPA content (44% in 2009) declared on supplement labels compared to the 2012 (52%) survey. It was also evident that a higher percentage of supplements (13% in 2009 vs 35% in 2012) contained DHA levels higher than declared. In 2009, 64% of supplements cost R2.01 to R5.00 or more to achieve a daily intake of 500 mg EPA + DHA, compared to 81% in 2012. Forty-four per cent of supplements were found to be in the early stages of rancidity [conjugated diene (CD) levels] compared to 73% in 2009. More than 80% of supplements had peroxide levels higher than the recommended content as specified by the Global Organisation for EPA and DHA Omega-3 (GOED). The majority (81%; n = 51) of the supplements under study in 2012 had a 1.1-1.5:1 EPA-to-DHA ratio or less, compared to 56% in 2009. Almost a third (32%) of the supplements in the 2012 survey contained ethyl esters (EE) or a combination of ethyl esters and triglycerides. Although the results of the 2012 versus the 2009 analysis were encouraging in terms of the accuracy of EPA declared on the supplement labels, the high peroxide levels found in the supplement oils are of concern. High peroxide levels are associated with potential health implications. EE were present in some of the supplements, even though the safety of EE has not been confirmed in vulnerable groups such as pregnant women and children.


The Plackett-Burman design in optimization of media components for biomass production of Lactobacillus rhamnosus OXY.
The central composite design was developed to search for an optimal medium for the growth of Lactobacillus rhamnosus OXY. The effect of various media components, such as carbon sources, simple and complex nitrogen sources, mineral agents, and growth factors (vitamins B, amino acids) was examined. The first-order model based on Plackett-Burman design showed that glucose, sodium pyruvate, meat extract and mineral salts significantly influenced the growth of the examined bacteria. The second-order polynomial regression confirmed that maximum biomass production could be achieved by the combination of glucose (12.38 g/l), sodium pyruvate (3.15 g/l), meat extract (4.08 g/l), potassium phosphate (1.46 g/l), sodium acetate (3.65 g/l) and ammonium citrate (1.46 g/l). The validation of the predicted model carried out in bioreactor conditions confirmed the usefulness of the new medium for the culture of L. rhamnosus OXY in large scale. The optimal medium makes the culture of the probiotic bacterium L. rhamnosus OXY more cost effective.


Prognostic significance of macrophage infiltration in leiomyosarcomas.
Macrophages are migratory cells that are frequently recruited to the site of tumors. Their presence is associated with poor clinical outcome in a variety of epithelial malignancies. The aim of this study is to examine the prognostic significance of tumor-associated macrophages in sarcomas. Global gene expression profiling data of a series of soft tissue tumors were analyzed for macrophage-associated gene expression. Immunohistochemistry on tissue microarrays containing leiomyosarcoma cases with known clinical outcome was used to verify the presence of macrophages and to examine the relationship between tumor-associated macrophages and clinical outcome. Gene expression profiling revealed high-level expression of several macrophage-associated genes such as CD163 and CD68 in a subset of leiomyosarcomas, indicating the presence of variable numbers of tumor-infiltrating macrophages. This was confirmed by CD68 and CD163 immunostaining of a tissue microarray containing 149 primary leiomyosarcomas. Kaplan-Meier survival analysis showed that high density of tumor-infiltrating macrophages as identified by CD163 or CD68 staining is associated with a significantly worse disease-specific survival in nongynecologic leiomyosarcomas, whereas leiomyosarcomas arising from the gynecologic tract showed no significant association between macrophage infiltration and survival. The presence of tumor necrosis did not correlate significantly with outcome. An increased density of CD163- or CD68-positive tumor-infiltrating macrophages is associated with poor outcome in nongynecologic leiomyosarcomas. This may help the clinical management of patients with leiomyosarcomas.


Developmental genetic evidence for a monophyletic origin of the bilaterian brain.
The widely held notion of an independent evolutionary origin of invertebrate and vertebrate brains is based on classical phylogenetic, neuroanatomical and embryological data. The interpretation of these data in favour of a polyphyletic origin of animals brains is currently being challenged by three fundamental findings that derive from comparative molecular, genetic and developmental analyses. First, modern molecular systematics indicates that none of the extant animals correspond to evolutionary intermediates between the protostomes and the deuterostomes, thus making it impossible to deduce the morphological organization of the ancestral bilaterian or its brain from living species. Second, recent molecular genetic evidence for the body axis inversion hypothesis now supports the idea that the basic body plan of vertebrates and invertebrates is similar but inverted, suggesting that the ventral nerve chord of protostome invertebrates is homologous to the dorsal nerve cord of deuterostome chordates. Third, a developmental genetic analysis of the molecular control elements involved in early embryonic brain patterning is uncovering the existence of structurally and functionally homologous genes that have comparable and interchangeable functions in key aspects of brain development in invertebrate and vertebrate model systems. All three of these findings are compatible with the hypothesis of a monophyletic origin of the bilaterian brain. Here we review these findings and consider their significance and implications for current thinking on the evolutionary origin of bilaterian brains. We also preview the impact of comparative functional genomic analyses on our understanding of brain evolution.


The crystal structure of human CD1d with and without alpha-galactosylceramide.
The glycolipid alpha-galactosylceramide binds with high affinity to CD1d and stimulates natural killer T cells. Here we report the crystal structure of human CD1d in complex with synthetic alpha-galactosylceramide at a resolution of 3.0 A. The structure shows a tightly fit lipid in the CD1d binding groove, with the sphingosine chain bound in the C' pocket and the longer acyl chain anchored in the A' pocket. We also present the CD1d structure without lipid, which has a more open conformation of the binding groove, suggesting a dual conformation of CD1d in which the 'open' conformation is more able to load lipids. These structures provide clues as to how CD1 molecules load glycolipids as well as data to guide the design of new therapeutic agents.


Practical management of patients on apixaban: a consensus guide.
Atrial fibrillation (AF) is a common tachyarrhythmia in Australia, with a prevalence over 10% in older patients. AF is the leading preventable cause of ischaemic stroke, and strokes due to AF have a higher mortality and morbidity. Stroke prevention is therefore a key management strategy for AF patients, in addition to rate and rhythm control. Anticoagulation with warfarin has been an enduring gold standard for stroke prevention in NVAF patients. In Australia, three novel oral anticoagulants (NOACs), apixaban, dabigatran and rivaroxaban are now approved and reimbursed for stroke prevention in patients with non-valvular AF (NVAF). International European Cardiology guidelines now recommend either a NOAC or warfarin for NVAF patients with a CHA2DS2-VASc score ≥2, unless contraindicated. Apixaban is a direct factor Xa inhibitor with a 12-hour half-life and 25% renal excretion that was found in a large trial of NVAF patients to be superior to warfarin in preventing stroke or systemic embolism. In this trial population, apixaban also resulted in less bleeding and a lower mortality rate than warfarin. Clinical experience with apixaban outside of clinical trials has been limited, and there is currently little evidence to guide the management of bleeding or invasive procedures in patients taking apixaban. The relevant currently available animal and ex vivo human data were collected, analyzed and summarized. This multi-disciplinary consensus statement has been written to serve as a guide for healthcare practitioners prescribing apixaban in Australia, with a focus on acute and emergency management. The predictable pharmacokinetics and minimal drug interactions of apixaban should allow for safe anticoagulation in the majority of patients, including temporary interruption for elective procedures. In the absence of published data, patients actively bleeding on apixaban should receive standard supportive treatment. Quantitative assays of apixaban level such as chromogenic anti-Xa assays are becoming available but their utility is unproven in this setting. Specific antidotes for novel anticoagulants, including apixaban, are in clinical development.


Growth of premature infants fed formulas with 10%, 30%, or 50% medium-chain triglycerides.
Questions regarding fat deposition and hormonal control of lipogenesis in infants fed formulas containing medium-chain triglycerides have been raised by studies in animals. To compare growth, clinical observations, and laboratory measures of infants fed the same basic isocaloric formulas with 10%, 30%, or 50% of the total fat as medium-chain triglycerides, we studied longitudinally for the first four weeks of life 22 infants who weighed 1000 to 1750 g. We found no differences in weight or skin-fold thickness between the groups. There were no clinical characteristics to distinguish one group from another. Two-hour postprandial levels of insulin and glucagon showed no differences one week to ten days after the start of the formula diet. The skin-fold thickness of all infants studied continued to increase after birth, regardless of weight loss. The increase in skin-fold thickness was comparable with the increase expected in the fetus in utero, but not significantly greater. The weight curve was parallel to the fetal weight curve but was lower, due to the first-week loss that possibly reflected a loss of body water, as suggested by the dynamic skin-fold thickness curve.


Cystinuria: genetic aspects, mouse models, and a new approach to therapy.
Cystinuria, a genetic disorder of cystine transport, is characterized by excessive excretion of cystine in the urine and recurrent cystine stones in the kidneys and, to a lesser extent, in the bladder. Males generally are more severely affected than females. The disorder may lead to chronic kidney disease in many patients. The cystine transporter (b0,+) is a heterodimer consisting of the rBAT (encoded by SLC3A1) and b0,+AT (encoded by SLC7A9) subunits joined by a disulfide bridge. The molecular basis of cystinuria is known in great detail, and this information is now being used to define genotype-phenotype correlations. Current treatments for cystinuria include increased fluid intake to increase cystine solubility and the administration of thiol drugs for more severe cases. These drugs, however, have poor patient compliance due to adverse effects. Thus, there is a need to reduce or eliminate the risks associated with therapy for cystinuria. Four mouse models for cystinuria have been described and these models provide a resource for evaluating the safety and efficacy of new therapies for cystinuria. We are evaluating a new approach for the treatment of cystine stones based on the inhibition of cystine crystal growth by cystine analogs. Our ongoing studies indicate that cystine diamides are effective in preventing cystine stone formation in the Slc3a1 knockout mouse model for cystinuria. In addition to crystal growth, crystal aggregation is required for stone formation. Male and female mice with cystinuria have comparable levels of crystalluria, but very few female mice form stones. The identification of factors that inhibit cystine crystal aggregation in female mice may provide insight into the gender difference in disease severity in patients with cystinuria.


Enhancing grain size in durum wheat using RNAi to knockdown GW2 genes.
Knocking down GW2 enhances grain size by regulating genes encoding the synthesis of cytokinin, gibberellin, starch and cell wall. Raising crop yield is a priority task in the light of the continuing growth of the world's population and the inexorable loss of arable land to urbanization. Here, the RNAi approach was taken to reduce the abundance of Grain Weight 2 (GW2) transcript in the durum wheat cultivar Svevo. The effect of the knockdown was to increase the grains' starch content by 10-40%, their width by 4-13% and their surface area by 3-5%. Transcriptomic profiling, based on a quantitative real-time PCR platform, revealed that the transcript abundance of genes encoding both cytokinin dehydrogenase 1 and the large subunit of ADP-glucose pyrophosphorylase was markedly increased in the transgenic lines, whereas that of the genes encoding cytokinin dehydrogenase 2 and gibberellin 3-oxidase was reduced. A proteomic analysis of the non-storage fraction extracted from mature grains detected that eleven proteins were differentially represented in the transgenic compared to wild-type grain: some of these were involved, or at least potentially involved, in cell wall development, suggesting a role of GW2 in the regulation of cell division in the wheat grain.


Pulmonary function testing during SARS-CoV-2: An ANZSRS/TSANZ position statement.
The Thoracic Society of Australia and New Zealand (TSANZ) and the Australian and New Zealand Society of Respiratory Science (ANZSRS) commissioned a joint position paper on pulmonary function testing during coronavirus disease 2019 (COVID-19) in July 2021. A working group was formed via an expression of interest to members of both organizations and commenced work in September 2021. A rapid review of the literature was undertaken, with a 'best evidence synthesis' approach taken to answer the research questions formed. This allowed the working group to accept findings of prior relevant reviews or societal document where appropriate. The advice provided is for providers of pulmonary function tests across all settings. The advice is intended to supplement local infection prevention and state, territory or national directives. The working group's key messages reflect a precautionary approach to protect the safety of both healthcare workers (HCWs) and patients in a rapidly changing environment. The decision on strategies employed may vary depending on local transmission and practice environment. The advice is likely to require review as evidence grows and the COVID-19 pandemic evolves. While this position statement was contextualized specifically to the COVID-19 pandemic, the working group strongly advocates that any changes to clinical/laboratory practice, made in the interest of optimizing the safety and well-being of HCWs and patients involved in pulmonary function testing, are carefully considered in light of their potential for ongoing use to reduce transmission of other droplet and/or aerosol borne diseases.


Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women.
The impact of the prophylactic vaccine against human papillomavirus (HPV) types 6, 11, 16, and 18 (HPV6/11/16/18) on all HPV-associated genital disease was investigated in a population that approximates sexually naive women in that they were "negative to 14 HPV types" and in a mixed population of HPV-exposed and -unexposed women (intention-to-treat group). This analysis studied 17 622 women aged 15-26 years who were enrolled in one of two randomized, placebo-controlled, efficacy trials for the HPV6/11/16/18 vaccine (first patient on December 28, 2001, and studies completed July 31, 2007). Vaccine or placebo was given at day 1, month 2, and month 6. All women underwent cervicovaginal sampling and Papanicolaou (Pap) testing at day 1 and every 6-12 months thereafter. Outcomes were any cervical intraepithelial neoplasia; any external anogenital and vaginal lesions; Pap test abnormalities; and procedures such as colposcopy and definitive therapy. Absolute rates are expressed as women with endpoint per 100 person-years at risk. The average follow-up was 3.6 years (maximum of 4.9 years). In the population that was negative to 14 HPV types, vaccination was up to 100% effective in reducing the risk of HPV16/18-related high-grade cervical, vulvar, and vaginal lesions and of HPV6/11-related genital warts. In the intention-to-treat group, vaccination also statistically significantly reduced the risk of any high-grade cervical lesions (19.0% reduction; rate vaccine = 1.43, rate placebo = 1.76, difference = 0.33, 95% confidence interval [CI] = 0.13 to 0.54), vulvar and vaginal lesions (50.7% reduction; rate vaccine = 0.10, rate placebo = 0.20, difference = 0.10, 95% CI = 0.04 to 0.16), genital warts (62.0% reduction; rate vaccine = 0.44, rate placebo = 1.17, difference = 0.72, 95% CI = 0.58 to 0.87), Pap abnormalities (11.3% reduction; rate vaccine = 10.36, rate placebo = 11.68, difference = 1.32, 95% CI = 0.74 to 1.90), and cervical definitive therapy (23.0% reduction; rate vaccine = 1.97, rate placebo = 2.56, difference = 0.59, 95% CI = 0.35 to 0.83), irrespective of causal HPV type. High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts, cervical cytological abnormalities, and diagnostic and therapeutic procedures. In the longer term, substantial reductions in the rates of cervical, vulvar, and vaginal cancers may follow.


Reactive oxygen species: a potential role in the pathogenesis of periodontal diseases.
The pathological events leading to the destruction of the periodontium during inflammatory periodontal diseases are likely to represent complex interactions involving an imbalance in enzymic and non-enzymic degradative mechanisms. This paper aims to review the increasing body of evidence implicating reactive oxygen species (ROS), derived from many metabolic sources, in the pathogenesis of periodontal tissue destruction. ROS are generated predominantly by polymorphonuclear leukocytes (PMN) during an inflammatory response and are regarded as being highly destructive in nature. The detection of ROS oxidation products, the elevation of iron and copper ions, which catalyse the production of the most reactive radical species, and the identification of an imbalance in the oxidant/antioxidant activity within periodontal pockets, suggests a significant role for ROS in periodontal tissue destruction. In vitro studies have shown that ROS are capable of degrading a number of extracellular matrix components including proteoglycans, resulting in the modification of amino acid functional groups, leading to fragmentation of the core protein, whilst the constituent glycosaminoglycan chains undergo limited depolymerisation. The identification and characterisation of connective tissue metabolites in gingival crevicular fluid (GCF) resulting from the degradation of periodontal tissues, notably alveolar bone, provides further evidence for a role for ROS in tissue destruction associated with inflammatory periodontal diseases.


Coordination polymers from alkaline-earth nodes and pyrazine carboxylate linkers.
A new series of alkaline-earth-metal based coordination polymers were synthesized by using a pyrazine-2,5-dicarboxylic acid (2,5-H2pzdc) ligand under hydrothermal conditions. These compounds show a variety of structural topologies, reflecting the variable coordination geometries of the alkaline-earth ions as well as the key role of the metal precursor salts. Ca, Sr, and Ba give porous three-dimensional compounds, namely [Ca(2,5-pzdc)(H2O)2]·H2O (1), [Sr(2,5-pzdc)(H2O)4]·H2O (3), [Ba(2,5-pzdc)(H2O)4]·2H2O (4) and [Ba(2,5pzdc)(H2O)2] (5), that feature one-dimensional hydrophilic channels which are filled with water molecules. The Sr compound retains its structure when the lattice water molecules are removed, while the other compounds undergo a structural rearrangement. The hydrophilicity of the Sr compound combined with its high stability even in the absence of guest molecules are the key characteristics that determine its good water adsorption and proton conductivity properties.


Effect of water storage in silver container on the viability of enteric bacterial pathogens.
Silver is one of the heavy metals traditionally played major role in the human life. It is used in the form of ornaments or as containers to store or drink water and other consumable liquids. The study was designed to observe the effect of water storage in silver containers on enteric pathogens. Three sets of sterile silver, stainless steel and glass metal screw capped containers were filled with non-chlorinated sterilized well water. One each of the three sets was inoculated with enteric pathogens viz. Shigella dysenteriae, Vibrio cholerae O1 and Salmonella typhi cultures drawn from the laboratory stock and incubated at 37 degrees C for varying periods. Preliminary findings of this study indicated that silver is bactericidal within an hour to Shigella dysenteriae, Vibrio cholerae O1 and Salmonella typhi which cause life-threatening enteric human diseases. The quantity of silver needed to eliminate these bacteria was found to be less than 2.5 ug/dl at pH 6.5. This study reveals the potential for silver containers to be used to disinfect natural water in areas of poor hygiene and sanitation where groundwater is the main source of drinking water.


Residential proximity to high-density poultry operations associated with campylobacteriosis and infectious diarrhea.
Poultry carry zoonotic bacteria that can cause gastroenteritis in humans. Environmental transmission of pathogens from poultry operations may increase gastrointestinal infection risk in surrounding communities. To evaluate associations between residential proximity to high-density poultry operations and individual-level diarrheal illnesses, we conducted a nested case-control study among 514,488 patients in Pennsylvania (2006-2015). Using electronic health records, we identified cases of five gastrointestinal outcomes: three pathogen-specific infections, including Escherichia coli (n = 1425), Campylobacter (n = 567), and Salmonella (n = 781); infectious diarrhea (n = 781); and non-specific diarrhea (2012-2015; n = 28,201). We estimated an inverse-distance squared activity metric for poultry operations based on farm and patient addresses. Patients in the second and fourth (versus first) quartiles of the poultry operation activity metric had increased odds of Campylobacter (AOR [CI], Q2: 1.36 [1.01, 1.82]; Q3: 1.38 [0.98, 1.96]; Q4: 1.75 [1.31, 2.33]). Patients in the second, third, and fourth quartiles had increased odds of infectious diarrhea (Q2: 1.76 [1.29, 2.39]; Q3: 1.76 [1.09, 2.85]; Q4: 1.60 [1.12, 2.30]). Stratification revealed stronger relations of fourth quartile and both Campylobacter and infectious diarrhea in townships, the most rural community type in the study geography. Increasing extreme rainfall in the week prior to diagnosis strengthened fourth quartile Campylobacter associations. The poultry operation activity metric was largely unassociated with E. coli, Salmonella, and non-specific diarrhea. Findings suggest high-density poultry operations may be associated with campylobacteriosis and infectious diarrhea in nearby communities, highlighting additional public health concerns of industrial agriculture.


Use of a New High Resolution Melting Method for Genotyping Pathogenic Leptospira spp.
Leptospirosis is a worldwide zoonosis that is endemic in tropical areas, such as Reunion Island. The species Leptospira interrogans is the primary agent in human infections, but other pathogenic species, such as L. kirschner and L. borgpetersenii, are also associated with human leptospirosis. In this study, a melting curve analysis of the products that were amplified with the primer pairs lfb1 F/R and G1/G2 facilitated an accurate species classification of Leptospira reference strains. Next, we combined an unsupervised high resolution melting (HRM) method with a new statistical approach using primers to amplify a two variable-number tandem-repeat (VNTR) for typing at the subspecies level. The HRM analysis, which was performed with ScreenClust Software, enabled the identification of genotypes at the serovar level with high resolution power (Hunter-Gaston index 0.984). This method was also applied to Leptospira DNA from blood samples that were obtained from Reunion Island after 1998. We were able to identify a unique genotype that is identical to that of the L. interrogans serovars Copenhageni and Icterohaemorrhagiae, suggesting that this genotype is the major cause of leptospirosis on Reunion Island. Our simple, rapid, and robust genotyping method enables the identification of Leptospira strains at the species and subspecies levels and supports the direct genotyping of Leptospira in biological samples without requiring cultures.


Assessment of a holistic wellness program for persons with spinal cord injury.
To test the effectiveness of a holistic (comprehensive and integrated) wellness program for adults with spinal cord injury. A total of 43 adults with spinal cord injury were randomly assigned to intervention or control groups. The intervention group attended six half-day wellness workshops during 3 mos, covering physical activity, nutrition, lifestyle management, and prevention of secondary conditions. Outcome measures included several physical measures and standard psychosocial measures. Statistical analyses included paired t tests, used to determine within-group differences, and multiple regression conducted to assess between-group differences. When comparing within-group baseline and final results, the intervention group reported fewer and less severe secondary conditions by the end of the study. Similarly, significant improvements were found in health-related self-efficacy and health behaviors. No significant changes in physiologic variables were observed. Although no significant between-group differences were observed, regression analyses suggested participation in the wellness program may be associated with improved health behaviors. Within-group comparisons suggest improvements in several areas of the participants' overall health behaviors. These findings, although preliminary, emphasize the potential role of health behaviors in positively influencing long-term health outcomes and quality of life.


Hypoxia inducible factor (HIF) as a model for studying inhibition of protein-protein interactions.
The modulation of protein-protein interactions (PPIs) represents a major challenge in modern chemical biology. Current approaches (e.g. high-throughput screening, computer aided ligand design) are recognised as having limitations in terms of identification of hit matter. Considerable success has been achieved in terms of developing new approaches to PPI modulator discovery using the p53/hDM2 and Bcl-2 family of PPIs. However these important targets in oncology might be considered as "low-hanging-fruit". Hypoxia inducible factor (HIF) is an emerging, but not yet fully validated target for cancer chemotherapy. Its role is to regulate the hypoxic response and it does so through a plethora of protein-protein interactions of varying topology, topography and complexity: its modulation represents an attractive approach to prevent development of new vasculature by hypoxic tumours.


Disruption of Visc-2, a Brain-Expressed Conserved Long Noncoding RNA, Does Not Elicit an Overt Anatomical or Behavioral Phenotype.
Although long noncoding RNAs (lncRNAs) are proposed to play essential roles in mammalian neurodevelopment, we know little of their functions from their disruption in vivo. Combining evidence for evolutionary constraint and conserved expression data, we previously identified candidate lncRNAs that might play important and conserved roles in brain function. Here, we demonstrate that the sequence and neuronal transcription of lncRNAs transcribed from the previously uncharacterized Visc locus are conserved across diverse mammals. Consequently, one of these lncRNAs, Visc-2, was selected for targeted deletion in the mouse, and knockout animals were subjected to an extremely detailed anatomical and behavioral characterization. Despite a neurodevelopmental expression pattern of Visc-2 that is highly localized to the cortex and sites of neurogenesis, anomalies in neither cytoarchitecture nor neuroproliferation were identified in knockout mice. In addition, no abnormal motor, sensory, anxiety, or cognitive behavioral phenotypes were observed. These results are important because they contribute to a growing body of evidence that lncRNA loci contribute on average far less to brain and biological functions than protein-coding loci. A high-throughput knockout program focussing on lncRNAs, similar to that currently underway for protein-coding genes, will be required to establish the distribution of their organismal functions.


Interdisciplinary lifestyle intervention for weight management in a community population (HealthTrack study): Study design and baseline sample characteristics.
Integrating professional expertise in diet, exercise and behavioural support may provide more effective preventive health services but this needs testing. We describe the design and baseline results of a trial in the Illawarra region of New South Wales, Australia. The HealthTrack study is a 12 month randomised controlled trial testing effects of a novel interdisciplinary lifestyle intervention versus usual care. The study recruited overweight and obese adults 25-54 years resident in the Illawarra. Primary outcomes were weight, and secondary outcomes were disease risk factors (lipids, glucose, blood pressure), and behaviour (diet, activity, and psychological factors). Protocols, recruitment and baseline characteristics are reported. Between May 2014 and April 2015, 377 participants were recruited and randomised. The median age (IQR) of the mostly female sample (74%) was 45 (37-51) years. The sample comprised obese (BMI 32 (29-35) kg/m(2)) well educated (79% post school qualifications) non-smokers (96%). A high proportion reported suffering from anxiety (26.8%) and depression (33.7%). Metabolic syndrome was identified in 34.9% of the sample. The HealthTrack study sample was recruited to test the effectiveness of an interdisciplinary approach to preventive healthcare in self-identified overweight adults in the Illawarra region. The profile of participants gives some indication of those likely to use services similar to the trial design.


Cell surface vitamin D-binding protein (GC-globulin) is acquired from plasma.
Vitamin D-binding protein (DBP) is an abundant plasma protein. The observation of immunodetectable, cell-associated DBP on peripheral blood mononuclear cells and placental cytotrophoblasts had presented the question of the origin, function, and precise subcellular localization of cell-associated DBP. Using anti-human DBP F(ab')2 with fluorescence-activated cytometric analysis and immunogold electron microscopy, we detected DBP on the plasmalemma of U937 cells, a monoblastic, histiocytic cell line grown in media supplemented with fetal calf serum (FCS). DBP was then removed from FCS by actin affinity chromatography followed by anti-DBP immunoaffinity chromatography. U937 cells in this DBP-free medium exhibited nearly identical growth rates to cells grown in medium containing native FCS. However, in contrast to cells grown with native FCS, those grown for seven to eight generations with DBP-free FCS exhibited less cell-surface DBP as quantified by fluorescence-activated cytometric analysis (73% decrease) and immunoelectron microscopy (88% decrease). DBP mRNA could not be detected in U937 cells, placental tissues, freshly prepared resting and stimulated B and T lymphocytes, or lymphocyte-derived cell lines by Northern analysis. In addition, using the sensitive reverse transcriptase/polymerase chain reaction assay no DBP fragments were detectable in U937 cells. We conclude that U937 cell-associated DBP is exogenously derived from plasma and is located on the plasmalemma. Based upon this conclusion, we postulate that specific binding sites for DBP may exist on the plasma membranes of certain cell types.


MsrR contributes to cell surface characteristics and virulence in Staphylococcus aureus.
MsrR, a factor contributing to methicillin resistance in Staphylococcus aureus, belongs to the LytR-CpsA-Psr family of cell envelope-associated proteins. Deletion of msrR increased cell size and aggregation, and altered envelope properties, leading to a temporary reduction in cell surface hydrophobicity, diminished colony-spreading ability, and an increased susceptibility to Congo red. The reduced phosphorus content of purified cell walls of the msrR mutant suggested a reduction in wall teichoic acids, which may explain some of the observed phenotypes. Microarray analysis of the msrR deletion mutant revealed only minor changes in the global transcriptome, suggesting that MsrR has structural rather than regulatory functions. Importantly, virulence of the msrR mutant was decreased in a nematode-killing assay as well as in rat experimental endocarditis. MsrR is therefore likely to play a role in cell envelope maintenance, cell separation, and pathogenicity of S. aureus.


Tobacco use: prevention, cessation, and control.
The RTI International-University of North Carolina at Chapel Hill Evidence-based Practice Center (RTI-UNC EPC) systematically reviewed the evidence on (a) the effectiveness of community- and population-based interventions to prevent tobacco use and to increase consumer demand for and implementation of effective cessation interventions; (b) the impacts of smokeless tobacco marketing on smoking, use of those products, and population harm; and (c) the directions for future research. We searched MEDLINE, Cumulative Index to Nursing and Applied Health (CINAHL), Cochrane libraries, Cochrane Clinical Trials Register, Psychological Abstracts, and Sociological Abstracts from January 1980 through June 10, 2005. We included English-language randomized controlled trials, other trials, and observational studies, with sample size and follow-up restrictions. We used 13 Cochrane Collaboration systematic reviews, 5 prior systematic reviews, and 2 meta-analyses as the foundation for this report. Trained reviewers abstracted detailed data from included articles into evidence tables and completed quality assessments; other senior reviewers confirmed accuracy and resolved disagreements. We identified 1,288 unique abstracts; 642 did not meet inclusion criteria, 156 overlapped with prior reviews, and 2 were not published articles. Of 488 full-text articles retrieved and reviewed, we excluded 298 for several reasons, marked 88 as background, and retained 102. Evidence (consistent with previous reviews) showed that (a) school-based prevention interventions have short-term (but not long-term) effects on adolescents; (b) multicomponent approaches, including telephone counseling, increase the number of users who attempt to quit; (c) self-help strategies alone are ineffective, but counseling and pharmacotherapy used either alone or in combination can improve success rates of quit attempts; and (d) provider training and academic detailing improve provider delivery of cessation treatments, but evidence is insufficient to show that these approaches yield higher quit rates. New evidence was insufficient to address the following: (a) effectiveness of population-based prevention interventions; (b) effectiveness of provider-based interventions to reduce tobacco initiation; (c) effectiveness of community- and provider-based interventions to increase use of proven cessation strategies; (d) effectiveness of marketing campaigns to switch tobacco users from smoking to smokeless tobacco products; and (e) effectiveness of interventions in populations with comorbidities and risk behaviors (e.g., depression, substance and alcohol abuse). No evidence was available on the way in which smokeless tobacco product marketing affects population harm. The evidence base has notable gaps and numerous study deficiencies. We found little information to address some of the issues that previous authoritative reviews had not covered, some information to substantiate earlier conclusions and recommendations from those reviews, and no evidence that would overturn any previous recommendations.


Cachectin/tumor necrosis factor mediates changes of skeletal muscle plasma membrane potential.
Lethal infections are associated with cellular dysfunction as evidenced by a decrease in the resting transmembrane potential difference (Em) of skeletal muscle fibers. Endotoxin stimulation of macrophages evokes production of cachectin, a protein that has been implicated as a mediator of the lethal effects of endotoxemia. In the present study, rat skeletal muscle fiber Em decreased when incubated with recombinant human cachectin. The reduction of Em induced by cachectin occurred in a dose-related fashion and was inhibited by mAb against the monokine. Infusion of cachectin induced a decline of skeletal muscle Em in vivo, and suggests that cachectin may acutely mediate alterations of skeletal muscle membrane function after infection.


Sorting of actin isoforms in chicken auditory hair cells.
Most nonmuscle cells of higher vertebrates contain two different actin isoforms, beta- and gamma-cytoplasmic actin. The beta-isoform is with few exceptions the predominant isoform in nonmuscle cells and tissues. Perturbation of the beta:gamma ratio has been shown to affect the organization of bundled actin filaments indicating that the beta- and gamma-genes encode functionally distinct cytoarchitectural information. In the present study we localized by immunostaining beta- and gamma-actin in chicken auditory hair cells. These highly specialized cells serve as model system for studying certain developmental and structural aspects of a complex actin filament system with high architectural precision. We show that gamma-actin is the predominant actin isoform in auditory hair cells with an apparent beta:gamma ratio of approximately 1:2. gamma-Actin is not sorted and occurs in all three actin assemblies of the hair border, i.e. the cores of sensory hairs (stereocilia), the subjacent gel-like actin filament meshwork (cuticular plate) and the zonula adherens ring. In contrast to gamma-actin, the beta-isoform is specifically sorted to the actin filament core bundle of stereocilia that is extensively crosslinked by fimbrin. In view of recent studies showing that L-plastin, the leukocyte homolog of fimbrin, has a higher binding affinity for beta-actin than for gamma-actin, a mechanism is proposed for how hair cells might restrict formation of actin filament bundles to a single cellular site (i.e. the stereocilia). The limited level of expression of beta-actin in hair cells may help to prevent ectopic bundle formation in other cellular compartments.


Low-grade inflammation predicts persistence of depressive symptoms.
Evidence suggests that depression is cross-sectionally and longitudinally associated with activation of inflammatory response system. A few studies, however, have investigated the longitudinal relationship between raised inflammatory biomarkers and persistence of depressive symptoms. We examined the temporal relationship between serum levels of inflammatory biomarkers and persistence of depressive symptoms among older participants. Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms at baseline and at 5-year follow-up in 656 participants (233 men, 423 women) aged >60 years of the Rotterdam Study. Markers of inflammation interleukin (IL)-6, alpha-1-antichymotrypsin (ACT) and C-reactive protein (CRP) were assessed at baseline, and all participants taking antidepressant medications were excluded from the analysis. No cross-sectional association was found between IL-6, ACT and CRP with depressive symptoms at baseline. However, higher levels of IL-6 and CRP predicted depressive symptoms at 5-year follow-up. Adjustment for confounding variables had no impact on the observed associations. Similarly, a positive association was found between baseline levels of IL-6 (OR = 2.44, p = 0.030) and CRP (OR = 1.81, p = 0.052) and persistence of depressive symptoms over 5 years. Our data suggest that dysregulation of the inflammatory response system is associated with a more severe form of depression more likely to re-occur.


Novel approaches to the treatment of obesity and type 2 diabetes mellitus: bioactive leptin-related synthetic peptide analogs.
Leptin, the protein product of the ob gene, is primarily an adipocyte-secreted hormone, whose functional significance is rapidly expanding. Although early research efforts were focused on defining leptin's role in reversing obesity in rodents, there is now substantial evidence indicating that its influence extends to a number of hypothalamic-pituitaryendocrine axes, including adrenal, gonadal, growth hormone, pancreatic islets, and thyroid. The pleiotropic nature of leptin has been confirmed by demonstration of a role for leptin in hematopoiesis, angiogenesis, immune function, osteogenesis, reproduction, and wound healing. Unfortunately, the results of the majority of clinical trials with recombinant human leptin indicated that its effectiveness in restoring energy balance and correcting obesity-related endocrinopathies in genetically obese rodent models extended only to the management of those rare forms of human obesity caused by mutation in the ob gene. Failure of leptin in the clinic, and withdrawal of phentermine from Europe, and fenfluramine and sibutrimine from clinical use in the United States, have stimulated new approaches in the development of anti-obesity and anti-diabetes pharmacophores. These efforts are focused on utilizing leptin-related synthetic peptides as leptin receptor antagonists or leptin-related synthetic peptide analogs or mimetics. This review summarizes patents on leptin-related peptide analogs, antagonists and mimetics.


Effect of Yoga on Blood Pressure in Prehypertension: A Systematic Review and Meta-Analysis.
Prehypertension is a precursor for developing hypertension and is a risk factor for cardiovascular diseases. Yoga therapy may have a role in lowering the blood pressures in prehypertension and hypertension. This systematic review aims to synthesize the available literature for the same. Methodology. Databases such as PubMed, Embase, Scopus, and Web of Science were searched for randomised control trials only in the time duration of 2010-2021. The main outcome of interest was systolic and diastolic blood pressures. Articles were screened based on the inclusion criteria, and 8 articles were recruited for the review. Meta-analysis was done for suitable articles. RevMan 5.4 by Cochrane was used for meta-analysis and forest plot construction. Risk of bias was determined using the Downs and Black checklist by three independent authors. The meta-analysis of the articles favoured yoga intervention over the control intervention. Yoga therapy had significantly reduced the systolic pressure (-0.62 standard mean difference, at IV fixed 95% CI: -0.83, -0.41) and diastolic pressure (-0.81 standard mean difference, at IV random 95% CI: -1.39, -0.22). Secondary outcome measures studied were heart rate, weight, BMI, waist circumference, and lipid profile. The main protocol of yoga therapy included postures, breathing exercises, and different meditation techniques. A significant reduction in secondary outcomes was observed, except for HDL values in lipid profile which showed a gradual increase in yoga group in comparison with alternative therapy. Yoga therapy has shown to be significant in the reduction of systolic and diastolic pressure in prehypertensive population. Supporting evidence lacks in providing a proper structured dosage of yoga asanas and breathing techniques. Considering the existing literature and evidence, Yoga therapy can be used and recommended in prehypertensive population and can be beneficial in reducing the chances of developing hypertension or cardiovascular diseases.


Acidic pH-responsive nanogels as smart cargo systems for the simultaneous loading and release of short oligonucleotides and magnetic nanoparticles.
Smart materials able to sense environmental stimuli can be exploited as intelligent carrier systems. Acidic pH-responsive polymers, for instance, exhibit a variation in the ionization state upon lowering the pH, which leads to their swelling. The different permeability of these polymers as a function of the pH could be exploited for the incorporation and subsequent release of previously trapped payload molecules/nanoparticles. We provide here a proof of concept of a novel use of pH-responsive polymer nanostructures based on 2-vinylpyridine and divinylbenzene, having an overall size below 200 nm, as cargo system for magnetic nanoparticles, for oligonucleotide sequences, as well as for their simultaneous loading and controlled release mediated by the pH.


The IASLC Lung Cancer Staging Project: Analysis of Resection Margin Status and Proposals for Residual Tumor Descriptors for Non-Small Cell Lung Cancer.
Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un). A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact. In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobe-specific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for R0, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between R0 and R(un) in pN0 cases. R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies.


Genetic reversion in an acute myelogenous leukemia cell line from a Fanconi anemia patient with biallelic mutations in BRCA2.
A 2-year old boy was diagnosed with Fanconi anemia (FA) and acute myeloid leukemia (AML). A cell line (termed FA-AML1) was established from blast cells obtained after a second relapse after a successful bone marrow transplant. Histochemical and surface marker analysis confirmed that the cells were derived from the myeloid lineage. Cytogenetic analysis revealed multiple chromosomal aberrations, including a ring 7. Stable proliferation of the cultured cells was absolutely dependent on the presence of granulocyte macrophage colony-stimulating factor or interleukin 3. This is the first AML cell line successfully established from a FA patient. Remarkably, FA-AML1 cells appeared to lack the characteristic cellular FA phenotype, i.e., a hypersensitivity to growth inhibition and chromosomal breakage by the cross-linking agent mitomycin C. Genomic DNA from the patient showed biallelic mutations [8415G>T (K2729N)and 8732C>A (S2835STOP)] in the breast cancer susceptibility gene FANCD1/BRCA2 [N. Howlett et al., Science (Wash. DC), 297: 606-609, 2002]. In the AML cells, however, the 8732C>A nonsense mutation was changed into a missense mutation by a secondary alteration, 8731T>G, resulting in 2835E, which restored the open-reading frame of the gene and could explain the reverted phenotype of these cells. Loss of the FA phenotype by genetic correction of a FA gene mutation during AML progression may be a common late event in the pathogenesis of AML in FA patients, which may be treatment related. This finding suggests a novel mechanistic principle of tumor progression based on the genetic correction of an early caretaker gene defect.


54-fs, 10-GHz soliton generation from a polarization-maintaining dispersion-flattened dispersion-decreasing fiber pulse compressor.
A 10-GHz train of nearly transform-limited 54-fs soliton pulses was generated by adiabatic compression of the output of a mode-locked fiber laser with a polarization-maintaining dispersion-flattened dispersion-decreasing fiber. The peak-to-pedestal ratio exceeded 23 dB. At high input powers, the pulse width was reduced to as short as 43 fs, although the wings of the pulse were degraded and the jitter increased. The compression properties are different for the two polarization axes, owing to their different dispersion characteristics. The output polarization exhibits no drift.


Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis.
Congenital tufting enteropathy (CTE) is a severe autosomal recessive human diarrheal disorder with characteristic intestinal epithelial dysplasia. CTE can be caused by mutations in genes encoding EpCAM, a putative adhesion molecule, and HAI-2, a cell surface protease inhibitor. A similar phenotype occurs in mice whose intestinal epithelial cells (IECs) fail to express the tight junction-associated protein claudin-7. EpCAM stabilizes claudin-7 in IECs, and HAI-2 regulates the cell surface serine protease matriptase, a known modifier of intestinal epithelial physiology. Therefore, we hypothesized that HAI-2, matriptase, EpCAM, and claudin-7 were functionally linked. Herein we have demonstrated that active matriptase cleaves EpCAM after Arg80 and that loss of HAI-2 in IECs led to unrestrained matriptase activity and efficient cleavage of EpCAM. Cleavage of EpCAM decreased its ability to associate with claudin-7 and targeted it for internalization and lysosomal degradation in conjunction with claudin-7. CTE-associated HAI-2 mutant proteins exhibited reduced ability to inhibit matriptase and also failed to efficiently stabilize claudin-7 in IECs. These results identify EpCAM as a substrate of matriptase and link HAI-2, matriptase, EpCAM, and claudin-7 in a functionally important pathway that causes disease when it is dysregulated.


Inflammatory bowel disease and tobacco smoke--a case-control study.
A case-control study was carried out in Stockholm, Sweden between 1984 and 1987 to evaluate the association of cigarette smoking and exposure to environmental tobacco smoke during childhood and the subsequent development of inflammatory bowel disease. Information on smoking was obtained by a postal questionnaire. The relative risk of Crohn's disease in current smokers compared with those who had never smoked was 1.33 (95% confidence limits 0.7; 2.6) in men and 4.99 (2.7; 9.2) in women; the corresponding results for ulcerative colitis were 0.96 (0.5; 1.8) and 0.72 (0.4; 1.4). The relative risk of ulcerative colitis in recent exsmokers compared with those who had never smoked was 2.18 (0.9; 5.0). Furthermore, an increase in the risk of Crohn's disease was found in those who were exposed to environmental tobacco smoke during childhood, the relative risk being 1.50 (1.0; 2.3). The corresponding relative risk of ulcerative colitis was 0.98 (0.6; 1.5).


Molecular population genetics and phenotypic sensitivity to ethanol for a globally diverse sample of the nematode Caenorhabditis briggsae.
New genomic resources and genetic tools of the past few years have advanced the nematode genus Caenorhabditis as a model for comparative biology. However, understanding of natural genetic variation at molecular and phenotypic levels remains rudimentary for most species in this genus, and for C. briggsae in particular. Here we characterize phenotypic variation in C. briggsae's sensitivity to the potentially important and variable environmental toxin, ethanol, for globally diverse strains. We also quantify nucleotide variation in a new sample of 32 strains from four continents, including small islands, and for the closest-known relative of this species (C. sp. 9). We demonstrate that C. briggsae exhibits little heritable variation for the effects of ethanol on the norm of reaction for survival and reproduction. Moreover, C. briggsae does not differ significantly from C. elegans in our assays of its response to this substance that both species likely encounter regularly in habitats of rotting fruit and vegetation. However, we uncover drastically more molecular genetic variation than was known previously for this species, despite most strains, including all island strains, conforming to the broad biogeographic patterns described previously. Using patterns of sequence divergence between populations and between species, we estimate that the self-fertilizing mode of reproduction by hermaphrodites in C. briggsae likely evolved sometime between 0.9 and 10 million generations ago. These insights into C. briggsae's natural history and natural genetic variation greatly expand the potential of this organism as an emerging model for studies in molecular and quantitative genetics, the evolution of development, and ecological genetics.


Emergency carotid endarterectomy.
A retrospective review of carotid endarterectomies performed by the Neurosurgical Service at Massachusetts General Hospital from July, 1976, through December, 1985, disclosed 64 procedures that were performed on an emergency basis. The patients included 40 men and 24 women, with a mean age of 64 years (range 32 to 87 years). Correlation of angiographic findings with outcome revealed that of the 27 patients with severe stenosis, usually with delay in blood flow, 25 (93%) were the same or improved postoperatively; of the 11 patients with stenosis and an intraluminal filling defect (six of whom had an intraluminal clot), eight (73%) were the same or improved after surgery; of the 16 patients with complete occlusion, 14 (88%) were the same or improved (backflow was established in all cases); and of the 10 patients with moderate to severe stenosis and/or severe ulceration (including three with transient ischemic attacks who were receiving heparin), eight (80%) were the same or improved. Pre- and postoperative clinical status were graded into five categories: intact; mild deficit; moderate deficit (significant impairment but able to perform activities of daily living); severe deficit (requiring assistance for daily activities); and death. Of the 36 patients who preoperatively were intact or had mild deficits, 33 (92%) were the same or improved postoperatively, three were worse, and there were no deaths. Among 15 patients presenting with moderate deficits, 12 (80%) were the same or improved, two were worse, and one died. Of the 13 patients with severe deficits, 10 (77%) were the same or improved and three died. Two patients with sudden severe deficits associated with loss of contralateral bruit were operated on without angiography and were intact postoperatively. Of the four deaths in the total series, two were attributed to cardiac causes and two to unrelated disease processes. The indications for emergency carotid endarterectomy are discussed.


Crosstalk between endoplasmic reticulum stress and anti-viral activities: A novel therapeutic target for COVID-19.
The outbreak of COVID-19 caused by 2019-nCov/SARS-CoV-2 has become a pandemic with an urgent need for understanding the mechanisms and identifying a treatment. Viral infections including SARS-CoV are associated with increased levels of reactive oxygen species, disturbances of Ca++ caused by unfolded protein response (UPR) mediated by endoplasmic reticulum (ER) stress and is due to the exploitation of virus's own protein i.e., viroporins into the host cells. Several clinical trials are on-going including testing Remdesivir (anti-viral), Chloroquine and Hydroxychloroquine derivatives (anti-malarial drugs) etc. Unfortunately, each drug has specific limitations. Herein, we review the viral protein involvement to activate ER stress transducers (IRE-1, PERK, ATF-6) and their downstream signals; and evaluate combination therapies for COVID-19 mediated ER stress alterations. Melatonin is an immunoregulator, anti-pyretic, antioxidant, anti-inflammatory and ER stress modulator during viral infections. It enhances protective mechanisms for respiratory tract disorders. Andrographolide, isolated from Andrographis paniculata, has versatile biological activities including immunomodulation and determining SARS-CoV-2 binding site. Considering the properties of both compounds in terms of anti-inflammatory, antioxidant, anti-pyrogenic, anti-viral and ER stress modulation and computational approaches revealing andrographolide docks with the SARS-CoV2 binding site, we predict that this combination therapy may have potential utility against COVID-19.


Ebolavirus VP35 suppresses IFN production from conventional but not plasmacytoid dendritic cells.
Ebolaviruses naturally infect a wide variety of cells including macrophages and dendritic cells (DCs), and the resulting cytokine and interferon-α/β (IFN) responses of infected cells are thought to influence viral pathogenesis. The VP35 protein impairs RIG-I-like receptor-dependent signaling to inhibit IFN production, and this function has been suggested to promote the ineffective host immune response characteristic of ebolavirus infection. To assess the impact of VP35 on innate immunity in biologically relevant primary cells, we used a recombinant Newcastle disease virus encoding VP35 (NDV/VP35) to infect macrophages and conventional DCs, which primarily respond to RNA virus infection via RIG-I-like pathways. VP35 suppressed not only IFN but also tumor necrosis factor (TNF)-α secretion, which are normally produced from these cells upon NDV infection. Additionally, in cells susceptible to the activity of VP35, IRF7 activation is impaired. In contrast, NDV/VP35 infection of plasmacytoid DCs, which activate IRF7 and produce IFN through TLR-dependent signaling, leads to robust IFN production. When plasmacytoid DCs deficient for TLR signaling were infected, NDV/VP35 was able to inhibit IFN production. Consistent with this, VP35 was less able to inhibit TLR-dependent versus RIG-I-dependent signaling in vitro. These data demonstrate that ebolavirus VP35 suppresses both IFN and cytokine production in multiple primary human cell types. However, cells that utilize the TLR pathway can circumvent this inhibition, suggesting that the presence of multiple viral sensors enables the host to overcome viral immune evasion mechanisms.


Is action execution part of the decision-making process? An investigation of the embodied choice hypothesis.
In this study, we aimed to explore whether action execution is an inherent part of the decision-making process. According to the hypothesis of embodied choice, the decision-making process is bidirectional as action dynamics exert their backward influence on decision processes through changing the cost and value of the potential options. This influence takes place as moving toward one option increases the commitment to and, therefore, the likelihood of choosing that option. This commitment effect can be the result of either (a) the continuous act of getting closer to this option or (b) the increased movement cost associated with changing the movement direction to select a different option. To disentangle the potential influence of these two factors, we developed the Guided Movement Task, a choice task designed to bias participant's computer-mouse movements by constraining the allowed movement space by a corridor. Using this task, we created different conditions in which the participants' mouse cursor, after being guided toward one of the options, either had equal or unequal distances to the choice options. By this manipulation, we could test whether the continuous act of getting closer to an option in itself is sufficient to influence people's decisions-a claim of "strong embodiment." In two experiments, we found that the likelihood of choosing an option only increased when the distances between the two options were unequal after the initial movement but not when they were equal. These results disagree with the hypothesis that action execution is an inherent part of the decision-making process. (PsycINFO Database Record


Risk aversion and religious behaviour: Analysis using a sample of Danish twins.
Economics offers an analytical framework to consider human behaviour including religious behaviour. Within the realm of Expected Utility Theory, religious belief and activity could be interpreted as an insurance both for current life events and for afterlife rewards. Based on that framework, we would expect that risk averse individuals would demand a more generous protection plan which they may do by devoting more effort and resources into religious activities such as church attendance and prayer, which seems to be in accordance with previous empirical results. However, a general concern regards the problems of spurious correlations due to underlying omitted or unobservable characteristics shaping both religious activities and risk attitudes. This paper examines empirically the demand for religion by analysing the association between risk attitudes on the one hand, and church attandance and prayer frequency on the other controlling for unobservable variables using survey data of Danish same-sex twin pairs. We verify the correlation between risk preferences and religion found previously by carrying out cross-sectional analyses. We also show that the association between risk attitudes and religious behaviour is driven by the subgroup of individuals who believe in an afterlife. In addition, when re-analysing our results using panel data analyses which cancel out shared factors among twin pairs, we find that the correlation found between risk aversion and religious behaviour is no longer significant indicating that other factors might explain differences in religious behaviour. Caution is needed in the interpretation of our results as the insignificant association between risk aversion and religious behaviour in the panel data analyses potentially might be due to measurement error causing attenuation bias or lack of variation within twin pairs rather than the actual absence of an association.