Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery.
We sought to characterize patterns of clopidogrel use before coronary artery bypass grafting (CABG) and examine the drug's impact on risks for postoperative transfusions among patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). Adherence in community practice to American College of Cardiology/American Heart Association guidelines for clopidogrel use among NSTE ACS patients has not been previously characterized. We evaluated 2,858 NSTE ACS patients undergoing CABG at 264 hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Initiative. We examined the patterns of acute clopidogrel therapy and its association with bleeding risks among those having "early" CABG < or =5 days and again among those having "late" surgery >5 days after catheterization. Within 24 h of admission, 852 patients (30%) received clopidogrel. In contrast to national guidelines, 87% of clopidogrel-treated patients underwent CABG < or =5 days after treatment. Among those receiving CABG within < or =5 days of last treatment, the use of clopidogrel was associated with a significant increase in blood transfusions (65.0% vs. 56.9%, adjusted odds ratio [OR] 1.36, 95% confidence interval [CI] 1.10 to 1.68) as well as the need for transfusion of > or =4 U of blood (27.7% vs. 18.4%, OR 1.70, 95% CI 1.32 to 2.19). In contrast, acute clopidogrel therapy was not associated with higher bleeding risks if CABG was delayed >5 days (adjusted OR 1.18, 95% CI 0.54 to 2.58). Despite guideline recommendations, the overwhelming majority of NSTE ACS patients treated with acute clopidogrel needing CABG have their surgery within < or =5 days of treatment. A failure to delay surgery is associated with increased blood transfusion requirements that must be weighed against the potential clinical and economic impacts of such delays.


Modeling fitness changes in wild Atlantic salmon populations faced by spawning intrusion of domesticated escapees.
Genetic interaction between domesticated escapees and wild conspecifics represents a persistent challenge to an environmentally sustainable Atlantic salmon aquaculture industry. We used a recently developed eco-genetic model (IBSEM) to investigate potential changes in a wild salmon population subject to spawning intrusion from domesticated escapees. At low intrusion levels (5%-10% escapees), phenotypic and demographic characteristics of the recipient wild population only displayed weak changes over 50 years and only at high intrusion levels (30%-50% escapees) were clear changes visible in this period. Our modeling also revealed that genetic changes in phenotypic and demographic characteristics were greater in situations where strayers originating from a neighboring wild population were domestication-admixed and changed in parallel with the focal wild population, as opposed to nonadmixed. While recovery in the phenotypic and demographic characteristics was observed in many instances after domesticated salmon intrusion was halted, in the most extreme intrusion scenario, the population went extinct. Based upon results from these simulations, together with existing knowledge, we suggest that a combination of reduced spawning success of domesticated escapees, natural selection purging maladapted phenotypes/genotypes from the wild population, and phenotypic plasticity, buffer the rate and magnitude of change in phenotypic and demographic characteristics of wild populations subject to spawning intrusion of domesticated escapees. The results of our simulations also suggest that under specific conditions, natural straying among wild populations may buffer genetic changes in phenotypic and demographic characteristics resulting from introgression of domesticated escapees and that variation in straying in time and space may contribute to observed differences in domestication-driven introgression among native populations.


Physiological Indirect Response Model to Omics-Powered Quantitative Systems Pharmacology Model.
Over the past several decades, mathematical modeling has been applied to increasingly wider scopes of questions in drug development. Accordingly, the range of modeling tools has also been evolving, as showcased by contributions of Jusko and colleagues: from basic pharmacokinetics/pharmacodynamics (PK/PD) modeling to today's platform-based approach of quantitative systems pharmacology (QSP) modeling. Aimed at understanding the mechanism of action of investigational drugs, QSP models characterize systemic effects by incorporating information about cellular signaling networks, which is often represented by omics data. In this perspective, we share a few examples illustrating approaches for the integration of omics into mechanistic QSP modeling. We briefly overview how the evolution of PK/PD modeling into QSP has been accompanied by an increase in available data and the complexity of mathematical methods that integrate it. We discuss current gaps and challenges of integrating omics data into QSP models and propose several potential areas where integrated QSP and omics modeling may benefit drug development.


Validation of a novel biomarker for acute axonal injury in experimental autoimmune encephalomyelitis.
In multiple sclerosis, inflammatory axonal injury is a key pathological mechanism responsible for the development of progressive neurological dysfunction. The injured axon represents a therapeutic target in this disease; however, therapeutic trials of neuroprotective candidates will initially require preclinical testing in an animal model of inflammatory axonal injury and subsequently the development of a reliable paraclinical measure of axonal degeneration in humans. In the present study, we demonstrate the validity of serum phosphorylated neurofilament H (pNF-H) as a marker of axonal injury in murine experimental autoimmune encephalomyelitis (EAE). At the time of maximum disease severity (EAE day 22), the average serum pNF-H level reached 5.7 ng/ml, correlating significantly with the EAE paraplegia score (r = 0.75, P < 0.001). On average, 40% of axons in the spinal cord were lost in EAE, and serum pNF-H levels were highly correlated with axon loss (r = 0.8, P < 0.001). Axonal injury was a severe and acute event, insofar as serum pNF-H levels were not significantly elevated at early (EAE day 12) or late (EAE days 35 and 50) disease time points. Our results demonstrate that acute inflammatory axonal injury is a pathological feature of murine MOG(35-55) EAE, indicating that this model may mirror the acute pathological events in active multiple sclerosis lesions. Furthermore, we have validated the serum pNF-H assay as an unbiased measurement of axonal injury in EAE, facilitating rapid screening of potential neuroprotective therapies in this model.


Diarrhea prevalence in a randomized, controlled prospective trial of point-of-use water filters in homes and schools in the Dominican Republic.
Lack of sustainable access to clean drinking water continues to be an issue of paramount global importance, leading to millions of preventable deaths annually. Best practices for providing sustainable access to clean drinking water, however, remain unclear. Widespread installation of low-cost, in-home, point of use water filtration systems is a promising strategy. We conducted a prospective, randomized, controlled trial whereby 16 villages were selected and randomly assigned to one of four treatment arms based on the installation location of Sawyer® PointONE™ filters (filter in both home and school; filter in home only; filter in school only; control group). Water samples and self-reported information on diarrhea were collected at multiple times throughout the study. Self-reported household prevalence of diarrhea decreased from 25.6 to 9.76% from installation to follow-up (at least 7 days, and up to 200 days post-filter installation). These declines were also observed in diarrhea with economic or educational consequences (diarrhea which led to medical treatment and/or missing school or work) with baseline prevalence of 9.64% declining to 1.57%. Decreases in diarrhea prevalence were observed across age groups. There was no evidence of a loss of efficacy of filters up to 200 days post-filter installation. Installation of filters in schools was not associated with decreases in diarrhea prevalence in school-aged children or family members. Unfiltered water samples both at schools and homes contained potential waterborne bacterial pathogens, dissolved heavy metals and metals associated with particulates. All dissolved metals were detected at levels below World Health Organization action guidelines. This controlled trial provides strong evidence of the effectiveness of point-of-use, hollow fiber membrane filters at reducing diarrhea from bacterial sources up to 200 days post-installation when installed in homes. No statistically significant reduction in diarrhea was found when filters were installed in schools. Further research is needed in order to explore filter efficacy and utilization after 200 days post-installation. ClinicalTrials.gov, NCT03972618 . Registered 3 June 2019-retrospectively registered.


Professional roles of female urologists: A webinar-based survey of perceptions and obstacles to career development.
Urology, traditionally a maledominated specialty, keeping pace with the quickly changing gender landscape, has been characterized by waves of feminization. This study aims to understand the perspectives of women urologists on the obstacles to their career development, and the impact of such hurdles on their professional roles in urological education, practice, and leadership. 119 female urology residents/consultants were surveyed via a webinar-based platform, covering relevant questions on domains of Academia, Mentorship, Leadership, Parenting, and Charity. Statistical analysis was done using frequency distribution based on the responses. 46.8% of the respondents felt that there is an under-representation of women in academia. 'Having a good mentor' was the most important factor for a novice to succeed in academia (68%). The most important trait in becoming a good leader was 'good communication skills' (35%), followed by 'visionary' (20%). The greatest challenge faced by leaders in the medical field was considered as 'time management' (31.9%). Only 21.2% of the participants felt difficulty in having a work-personal life balance, whereas 63.8% of them found it difficult only 'sometimes'. As a working parent, 'the guilt that they are not available all the time' was considered the most difficult aspect (59.5%), and 'more flexible schedule' was needed to make their lives as a working parent easier (46.8%). 34% of the respondents were affiliated with some charitable organizations. The biggest drive to do charity was their satisfaction with a noble cause (72.3%). Need for increased encouragement and recruitment of females into urology, and to support and nurture them in their career aspirations.


Innovative mechanisms for precision assembly and actuation of arrays of nanowire oscillators.
Bottom-up assembling of Micro/Nano Electromechanical System (MEMS/NEMS) devices from nanoscale building blocks is highly desirable but extremely difficult to achieve. In this work, we report innovative mechanisms for precision assembly and actuation of arrays of nanowire NEMS devices that can synchronously oscillate between two designated positions for over 4000 cycles. The assembly and actuation mechanisms are based on unique magnetic interactions between nanoentities with perpendicular magnetic anisotropy (PMA) and electric-tweezer manipulation, our recent invention. Quantitative analysis of the dynamics of torques involved in the nano-oscillators reveals that the induced electrostatic torques due to the external electric fields between metallic NEMS components play a significant role in the mechanical actuation. These new findings are expected to inspire new in situ assembly and actuation strategies in the general field of NEMS devices such as nanomechanical switches for toggling on/off circuits and nanoresonators for biochemical sensors and radio frequency communication.


High-throughput micropatterning platform reveals Nodal-dependent bisection of peri-gastrulation-associated versus preneurulation-associated fate patterning.
In vitro models of postimplantation human development are valuable to the fields of regenerative medicine and developmental biology. Here, we report characterization of a robust in vitro platform that enabled high-content screening of multiple human pluripotent stem cell (hPSC) lines for their ability to undergo peri-gastrulation-like fate patterning upon bone morphogenetic protein 4 (BMP4) treatment of geometrically confined colonies and observed significant heterogeneity in their differentiation propensities along a gastrulation associable and neuralization associable axis. This cell line-associated heterogeneity was found to be attributable to endogenous Nodal expression, with up-regulation of Nodal correlated with expression of a gastrulation-associated gene profile, and Nodal down-regulation correlated with a preneurulation-associated gene profile expression. We harness this knowledge to establish a platform of preneurulation-like fate patterning in geometrically confined hPSC colonies in which fates arise because of a BMPs signalling gradient conveying positional information. Our work identifies a Nodal signalling-dependent switch in peri-gastrulation versus preneurulation-associated fate patterning in hPSC cells, provides a technology to robustly assay hPSC differentiation outcomes, and suggests conserved mechanisms of organized fate specification in differentiating epiblast and ectodermal tissues.


Retrospective investigation of the 2019 African swine fever epidemic within smallholder pig farms in Oudomxay province, Lao PDR.
The 2019 African swine fever (ASF) outbreak in the Lao People's Democratic Republic (Lao PDR or Laos) represented a major epidemiologic event where a transitioning lower-middle income nation (LMIC) experienced a viral epidemic in a naïve pig population. The diversity of pig management styles creates challenges for local and regional policymakers when formulating recommendations to control an ASF outbreak. The aim of this study were to investigate the management of pigs in villages of Oudomxay province that were affected by ASF in 2019, as a case study in a smallholder pig-rasing system in northern Laos. The frequencies of well known risk factors were measured in the affected villages and the timelines and household level stock losses due to the outbreak were investigated. These findings were compared to data available from a similar outbreak in the southern province of Savannakhet. Disease control implications of these findings are discussed. Mean losses were 3.0-23.3 pigs per household, with a mean lost herd value of USD 349, 95% CI (294-415). These pig losses reflect those estimated in Savannakhet (6.7 pigs per household). However, the financial loss estimated per household was higher, USD 349 versus USD 215, possibly due to higher pig values and a higher input/output management approach in Oudomxay. The investigation revealed the presence of numerous ASF risk factors, such as swill-feeding and free-ranging. In addition, poor biosecurity practices - such as inappropriate garbage disposal and slaughtering - that could contaminate the environment were present. ASF cases occurred across all villages between June and December 2019, with outbreak periods ranging from 22-103 days. These values are consistent with the outbreak in Savannakhet; however, notable differences in management styles were observed. These findings demonstrate the need for more disease control resources from the village to the Governmental level. Villages need support in enacting context appropriate biosecurity measures, whilst the ongoing surveillance and investigation of ASF require investment in logistical and veterinary resources at the Governmental level.


A comparison of physostigmine and soman using taste aversion and nociception.
The effects of a reversible (physostigmine) and an irreversible (soman) acetylcholinesterase inhibitor were compared in terms of nociception using the rat tail flick (TF), and hot plate (HP) tests. The conditioned taste aversion (CTA) procedure was employed to evaluate the stimulus properties of these drugs. In all procedures physostigmine salicylate was administered at doses of 0.20, 0.32, 0.45, or 0.65 mg/kg, IM. Soman was administered at doses ranging from 40 to 80 microgram/kg, IM. Using either TF or HP, physostigmine and soman were evaluated at 40 min following injection. Both physostigmine and soman produced dose-related effects on each measure of nociception. The median effective dose of physostigmine was 0.27 mg/kg on TF and 0.55 mg/kg on HP. For soman, the median effective dose was 54 micrograms/kg on TF and 52 micrograms/kg on HP. In the CTA procedure, a novel, saccharin sweetened solution was paired with either physostigmine or soman. Three days later rats were offered a choice of saccharin or tap water. Both soman and physostigmine produced dose-related CTAs over the range of doses studied. Whereas the ED50 for soman was 59 micrograms/kg with significant effects at doses of 60 micrograms/kg or more, physostigmine produced effects at doses of 0.45 mg/kg or greater (ED50 = 0.05 mg/kg) with no additional changes in saccharin preference beyond 0.45 mg/kg. The data suggest that these experimental procedures, TF, HP, and conditioned taste aversion may be employed to evaluate the behavioral toxicity of physostigmine and soman.


Bioelectric effects of ions microinjected into the giant axon of Loligo.
1. A technique is described for recording the bioelectric activity of the squid giant axon during and following alteration of the internal axonal composition with respect to ions or other substances. 2. Experimental evidence indicates that the technique as described is capable of measuring changes in local bioelectric activity with an accuracy of 10 to 15 per cent or higher. 3. Alterations of the internal K(+) or Cl(-) concentrations do not cause the change in resting potential expected on the basis of a Donnan mechanism. 4. The general effect of microinjection of K(+) Rb(+), Na(+), Li(+), Ba(++), Ca(++), Mg(++), or Sr(++) is to cause decrease in spike amplitude, followed by propagation block. 5. The resting potential decreases when the amplitude of the spike becomes low and block is incipient. 6. The decrease in resting potential and spike amplitude may be confined to the immediate vicinity of the injection. 7. At block, the resting potential decreases up to 50 per cent, but injection of small quantities of divalent cations may cause much larger localized depolarization. 8. The blocking effectiveness of K(+), Na(+), and Ca(++) expressed as reciprocals of the relative amounts needed to cause block is approximately 1:5:100. Rb(+) has the same low effectiveness as does K(+). Li(+) resembles Na(+). Ba(++) and Mg(++) are approximately as effective as Ca(++). 9. Microinjection of Na(+) may cause marked prolongation of the spike at the injection site as well as decrease in its amplitude. 10. The anions used (Cl(-), HCO(3) (-), NO(3) (-), SO(4) (-), aspartate, and glutamate) do not seem to exert specific effects. 11. A tentative explanation is offered for the insensitivity of the resting potential to changes in the axonal ionic composition. 12. New data are presented on the range of variation, in a large sample, of the magnitude of the resting potential and spike amplitude.


Factors related to tooth loss among community-dwelling middle-aged and elderly Japanese men.
Using data from a large-scale community-based Japanese population, we attempted to identify factors associated with tooth loss in middle-aged and elderly men. A total of 8352 men aged 40 to 79 years who lived in the north of the main island of Japan and underwent health checkups were enrolled between 2002 and 2005. Number of teeth was assessed by the question, "How many teeth do you have (0, 1-9, 10-19, or ≥20)?". On the basis of the answer to this question, participants were classified into 2 groups (≤19 teeth or ≥20 teeth). Using multivariate logistic regression, factors related to having 19 or fewer teeth were estimated. The numbers (percentages) of participants who had 0, 1 to 9, 10 to 19, and 20 or more teeth were 1764 (21.1%), 1779 (21.3%), 1836 (22.0%), and 2973 (35.6%), respectively. Among the participants overall and those aged 65 to 79 years, having 19 or fewer teeth was significantly associated with older age, smoking status (current smoking and ex-smoking), and low education level. In addition, men with 19 or fewer teeth were more likely to have a low body mass index and low serum albumin level and less likely to be current alcohol drinkers. Among men aged 40 to 64 years, but not men aged 65 to 79 years, those with 19 or fewer teeth were more likely to have a low serum high-density lipoprotein cholesterol level and high glycosylated hemoglobin (HbA1c) level. Smoking, low education level, and poor nutritional status were associated with tooth loss among middle-aged and elderly Japanese men.


Nutraceutical Supplements in the Thyroid Setting: Health Benefits beyond Basic Nutrition.
In recent years, there has been a growing interest in nutraceuticals, which may be considered as an efficient, preventive, and therapeutic tool in facing different pathological conditions, including thyroid diseases. Although iodine remains the major nutrient required for the functioning of the thyroid gland, other dietary components play important roles in clinical thyroidology-these include selenium, l-carnitine, myo-inositol, melatonin, and resveratrol-some of which have antioxidant properties. The main concern regarding the appropriate and effective use of nutraceuticals in prevention and treatment is due to the lack of clinical data supporting their efficacy. Another limitation is the discrepancy between the concentration claimed by the label and the real concentration. This paper provides a detailed critical review on the health benefits, beyond basic nutrition, of some popular nutraceutical supplements, with a special focus on their effects on thyroid pathophysiology and aims to distinguish between the truths and myths surrounding the clinical use of such nutraceuticals.


Immobilization of functional light antenna structures derived from the filamentous green bacterium Chloroflexus aurantiacus.
The integration of highly efficient, natural photosynthetic light antenna structures into engineered systems while their biophotonic capabilities are maintained has been an elusive goal in the design of biohybrid photonic devices. In this study, we report a novel technique to covalently immobilize nanoscaled bacterial light antenna structures known as chlorosomes from Chloroflexus aurantiacus on both conductive and nonconductive glass while their energy transducing functionality was maintained. Chlorosomes without their reaction centers (RCs) were covalently immobilized on 3-aminoproyltriethoxysilane (APTES) treated surfaces using a glutaraldehyde linker. AFM techniques verified that the chlorosomes maintained their native ellipsoidal ultrastructure upon immobilization. Results from absorbance and fluorescence spectral analysis (where the Stokes shift to 808/810 nm was observed upon 470 nm blue light excitation) in conjunction with confocal microscopy confirm that the functional integrity of immobilized chlorosomes was also preserved. In addition, experiments with electrochemical impedance spectroscopy (EIS) suggested that the presence of chlorosomes in the electrical double layer of the electrode enhanced the electron transfer capacity of the electrochemical cell. Further, chronoamperometric studies suggested that the reduced form of the Bchl- c pigments found within the chlorosome modulate the conduction properties of the electrochemical cell, where the oxidized form of Bchl- c pigments impeded any current transduction at a bias of 0.4 V within the electrochemical cell. The results therefore demonstrate that the intact chlorosomes can be successfully immobilized while their biophotonic transduction capabilities are preserved through the immobilization process. These findings indicate that it is feasible to design biophotonic devices incorporating fully functional light antenna structures, which may offer significant performance enhancements to current silicon-based photonic devices for diverse technological applications ranging from CCD devices used in retinal implants to terrestrial and space fuel cell applications.


BCR-ABL1 RT-qPCR for monitoring the molecular response to tyrosine kinase inhibitors in chronic myeloid leukemia.
The pathognomonic genetic alteration in chronic myeloid leukemia is the formation of the BCR-ABL1 fusion gene, which produces a constitutively active tyrosine kinase that drives leukemic transformation. Targeted tyrosine kinase inhibitor treatment with imatinib, nilotinib, dasatinib, bosutinib, and ponatinib is the cornerstone of modern therapy for this hematologic malignancy. Real-time quantitative RT-PCR (RT-qPCR, also RQ-PCR) of BCR-ABL1 RNA is a necessary laboratory technique for monitoring the efficacy of tyrosine kinase inhibitor therapy and quantitatively assessing minimal residual disease. The molecular response measured by BCR-ABL1 RT-qPCR assists in identifying suboptimal responses and can help inform the decision to switch to alternative therapies that may be more efficacious (or to pursue more stringent monitoring). Furthermore, the tyrosine kinase inhibitor-mediated molecular response provides valuable risk stratification and prognostic information on long-term outcomes. Despite these attributes, informed, universal, practical utilization of this well-established monitoring test will require heightened efforts by the molecular diagnostics laboratory community to adopt the standardized reporting units of the International Scale. Without widespread adoption of the International Scale, the consensus major molecular response and early molecular response treatment thresholds will not be definable, and optimal clinical outcomes for patients with chronic myeloid leukemia may not be achieved.


Molecular epidemiology of the citrus bacterial pathogen Xanthomonas citri pv. citri from the Arabian Peninsula reveals a complex structure of specialist and generalist strains.
Molecular epidemiology studies are essential to refine our understanding of migrations of phytopathogenic bacteria, the major determining factor in their emergence, and to understand the factors that shape their population structure. Microsatellite and minisatellite typing are useful techniques for deciphering the population structure of Xanthomonas citri pv. citri, the causal agent of Asiatic citrus canker. This paper presents a molecular epidemiology study, which has improved our understanding of the history of the pathogen's introductions into the Arabian Peninsula, since it was first reported in the 1980s. An unexpectedly high genetic diversity of the pathogen was revealed. The four distinct genetic lineages within X. citri pv. citri, which have been reported throughout the world, were identified in the Arabian Peninsula, most likely as the result of multiple introductions. No copper-resistant X. citri pv. citri strains were identified. The pathogen's population structure on Mexican lime (their shared host species) was closely examined in two countries, Saudi Arabia and Yemen. We highlighted the marked prevalence of specialist pathotype A* strains in both countries, which suggests that specialist strains of X. citri pv. citri may perform better than generalist strains when they occur concomitantly in this environment. Subclade 4.2 was the prevailing lineage identified. Several analyses (genetic structure deciphered by discriminant analysis of principal components, RST-based genetic differentiation, geographic structure) congruently suggested the role of human activities in the pathogen's spread. We discuss the implications of these results on the management of Asiatic citrus canker in the region.


Structure and bioactivity of the polysaccharides in medicinal plant Dendrobium huoshanense.
Detailed structures of the active polysaccharides extracted from the leaf and stem cell walls and mucilage of Dendrobium huoshanense are determined by using various techniques, including chromatographic, spectroscopic, chemical, and enzymatic methods. The mucilage polysaccharide exhibits specific functions in activating murine splenocytes to produce several cytokines including IFN-gamma, IL-10, IL-6, and IL-1alpha, as well as hematopoietic growth factors GM-CSF and G-CSF. However, the deacetylated mucilage obtained from an alkaline treatment fails to induce cytokine production. The structure and bioactivity of mucilage components are validated by further fractionation. This is the first study that provides clear evidence for the structure and activity relationship of the polysaccharide in D. huoshanense.


Colloquium--is there a surgical cure for pain?
We have heard today that psychological factors are extremely important in pain problems and that careful psychiatric assessment should delineate patients who have the potential of achieving good pain relief with interventional procedures. The bulwarks of the neurosurgical management of pain have been peripheral neurectomy, rhizotomy, sympathectomy, and cordotomy. We have heard each of these discussed. Peripheral neurectomy and rhizotomies are not highly successful in the treatment of pain, but are useful in carefully chosen patients. Cordotomy remains an excellent technique for the management of many patients with chronic pain or malignancy, and sympathectomy can be one of the most gratifying operations performed, as long as the patients are well chosen. The major lesson we have learned today is that there is no cure for pain at the present time. Nevertheless, neurosurgical procedures remain an important part of pain management. They should be applied after an adequate diagnosis is made, after psychiatric characterization of the entire pain problem is complete, and only when there is only a definitive pain generator which can be relieved by an interventional procedure. Perhaps the most important message we have heard is the categorization of pain patients given us by Doctor Hendler. It is important that we all identify those patients with affective or exaggerated pain behavior so that interventional procedures are carried out only on those patients who have a real possibility of benefiting from them. I believe if we all do this, we will see a significant increase in the effectiveness of surgical procedures for pain.


Drug-induced gastrointestinal disorders.
Drug-induced gastrointestinal disorders can mimic conditions, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and, hence, recognition can prevent unnecessary investigations and treatment. While the knowledge and awareness relating to the adverse gastrointestinal effects of some medications, such as non-steroidal anti-inflammatory drugs are well established, other commonly prescribed drugs, such as antipsychotics, antidepressants and metformin are less well understood and warrant further study. This review attempts to integrate recent information regarding adverse drug reactions and place this in a useful clinical context.


Getting Creative: Pilot Study of a Coached Writing Intervention in Patients with Advanced Cancer at a Rural Academic Medical Center.
Background: Unfacilitated writing activities, such as expressive writing, have not shown benefit in people with advanced cancer, but facilitated writing activities have yet to be fully explored. Objectives: To assess the feasibility and acceptability of facilitated writing activities determined by a writing coach in people with advanced incurable cancer. Design: This is a single-arm pilot study. Settings/Subjects: Adult patients with advanced incurable solid malignancies from a U.S. rural comprehensive cancer program met with a writing coach monthly for at least three months for facilitated writing activities. Measurements: Feasibility was assessed by enrollment and postinclusion attrition rate. Acceptability was assessed by (1) <15% drop out rate due to the intervention, (2) <15% elevated anxiety or depression due to the intervention, and (3) patient qualitative comments. Results: In total, 22 out of 63 patients consented (35%). Postinclusion attrition rate was 18% (n = 4) at three months with 82% completing at least three months of the writing coach intervention. No participants dropped out or had elevated anxiety/depression due to the intervention. The majority of patients wanted the whole intervention continued. Conclusions: A writing coach using facilitated writing activities was feasible and acceptable in patients with advanced incurable cancer, but further studies are needed to assess impact. Clinical Trial Registration Number NCT 025 75898.


Comparisons of Self-reported Glaucoma Medication Adherence With a New Wireless Device: A Pilot Study.
To compare use of topical medications between a wireless monitoring device and validated self-reported measures of glaucoma medication adherence. This study involved adults from a group ophthalmology practice diagnosed with and being medicinally treated for glaucoma who were not scheduled for a surgery during the study period. Subjects were required to use a new wireless device to dispense their glaucoma medication for 2 months, and were surveyed at baseline and immediately following the study to assess mobile phone use, glaucoma-related self-efficacy, and medication adherence. Complete data (survey and accurate device recordings) were available for 23 subjects at both baseline and endpoint. Median adherence, as measured by the device, was 82% and dropped slightly between 30-day periods, from 83% to 77%. Similarly, the percent adherent (dosing at least 75% of the time) dropped significantly between months according to both the device (78.3% and 52.2%) and a self-reported measure (63% and 56%). Kappa statistics indicated low agreement between the device and self-report when classifying adherent status. A majority of subjects interviewed found the device easy to use, indicated that it did not interfere with medication-taking or normal activities, and were not bothered by their physician knowing when medication was dispensed. In this pilot, nearly all Kali Drop devices performed as expected, providing real-time data on medication use over a 60-day period. Data suggested that self-reported and electronic estimates of glaucoma medication use differ, but additional testing of this new device is needed to corroborate the data observed.


Detection and enumeration of Leishmania in sand flies using agar-based media.
An agar plating technique was used to determine the number of amastigotes ingested by Lutzomyia longipalpis fed on papules on Mesocricetus auratus caused by Leishmania mexicana amazonensis and on lesions on Mystromys albicaudatus caused by Leishmania braziliensis panamensis. The technique involved homogenizing sand flies after bloodfeeding on the infected animals and spreading the homogenate over the surface of agar plates. A great variation in the number of amastigotes ingested by individual sand flies was demonstrated. Not all amastigotes ingested developed anterior stomodeal infections.


Nicotinic binding sites in rat and mouse brain: comparison of acetylcholine, nicotine, and alpha-bungarotoxin.
The properties of the binding sites for radiolabeled acetylcholine (measured in the presence of atropine), nicotine, and alpha-bungarotoxin were compared in brain tissue prepared from both rat and mouse. These three binding sites were tested for the following properties: affinity and density of ligand binding, effects of competitive inhibitors, regional distribution, effects of treatment with dithiothreitol and the reversal of these effects by treatment with 5,5'-dithiobis(2-nitrobenzoic acid), thermal lability, effects of protease treatment, and response to chronic administration of nicotine in vivo. The binding sites for acetylcholine and nicotine were affected identically for all measurements, whereas the binding site for alpha-bungarotoxin was affected in a manner different from that for the other two ligands. Although the regional distribution of nicotine and acetylcholine binding differed between rat and mouse brain, other properties of this binding site were very similar between the two species. The results are consistent with the proposal that acetylcholine and nicotine bind to the same sites in both rat and mouse brain, whereas alpha-bungarotoxin binds to different sites.


The investigation and assessment of characteristics of waste activated sludge after ultrasound pretreatment.
In this study, the characteristics of sonicated waste activated sludge (WAS) originating from a nutrient-removal wastewater treatment plant were investigated and evaluated. Different combinations of power inputs, sonication durations and volumes were used for optimization of the sonication conditions. Ultrasound density levels ranged between 0.32 and 3.2 W/mL. Optimal conditions based on soluble COD concentrations (SCOD) after sonication at different ultrasound density levels and sonication durations (1, 5, 10 and 30 min) were determined. An ultrasonic density of 1.6 W/mL and a sonication time of 30 min were identified as optimal sonication conditions in terms of SCOD concentration. The sludge sonicated under these optimal conditions was further investigated to determine the effect of ultrasound treatment on solubilization of organic matter and volatile solids, particle size and biodegradability. Disruption of the sludge structure was confirmed by the increase in the SCOD by 35.5%, reduction in volatile suspended solids by 26% and reduction in particle size by 85%. The availability of COD fractions of sonicated sludge was also tested with oxygen uptake rate and phosphate release data indicating that using sonicated sludge for both subsequent biological treatment and sludge treatment is promising.


What we know about ST13, a co-factor of heat shock protein, or a tumor suppressor?
This article is to summarize the molecular and functional analysis of the gene "suppression of tumorigenicity 13" (ST13). ST13 is in fact the gene encoding Hsp70 interacting protein (Hip), a co-factor (co-chaperone) of the 70-kDa heat shock proteins (Hsc/Hsp70). By collaborating with other positive co-factors such as Hsp40 and the Hsp70-Hsp90 organizing protein (Hop), or competing with negative co-factors such as Bcl2-associated athanogen 1 (Bag1), Hip facilitates may facilitate the chaperone function of Hsc/Hsp70 in protein folding and repair, and in controlling the activity of regulatory proteins such as steroid receptors and regulators of proliferation or apoptosis. Although the nomenclature of ST13 implies a role in the suppression of tumorigenicity (ST), to date available experimental data are not sufficient to support its role in cancer development, except for the possible down-regulation of ST13 in gastric and colorectal cancers. Further investigation of this gene at the physiological level would benefit our understanding of diseases such as endocrinological disorders, cancer, and neurodegeneration commonly associated with protein misfolding.


Distribution of plasma cells and other cells containing immunoglobulin in the respiratory tract of normal man and class of immunoglobulin contained therein.
The anatomical distribution of plasma cells and other cells containing immunoglobulin in the respiratory tract, and the relative proportions of the immunoglobulin classes have been estimated on necropsy tissues from nine adult human subjects without respiratory disease, five non-smokers and four smokers, none of whom had cough or sputum. Cell counts on multiple sections stained by immunofluorescent methods for the presence of immunoglobulin were carried out on the upper trachea, main bronchus, and lower lobe bronchus. Cells containing immunoglobulin were found mostly in the submucous glands but were also present in the lamina propria of the tracheal and bronchial epithelium. These cells were present in the greatest concentration in the main bronchus and were always present in the lobar bronchus and, in most subjects, in the upper trachea. The cells were not always present round small bronchi and bronchioles and were virtually absent from alveolar walls. Cells containing IgA were much more numerous than those containing other immunoglobulin classes in all subjects except one, in whom IgG and IgE cells were equally numerous. Two subjects appeared to be significantly different from the rest. One non-smoking subject had a marked deficiency of IgA cells at all sampling sites, and one smoker had a marked excess of IgA cells. In spite of these two subjects there was no significant difference between smokers and non-smokers except in the lobar bronchus where the smokers had significantly more IgA cells than the non-smokers.


Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia.
We present a novel tauopathy in a patient with a 10-yr history of progressive frontal lobe dementia and a negative family history. Autopsy revealed mild atrophy of frontal and parietal lobes and severe atrophy of the temporal lobes. There were occasional filamentous tau-positive inclusions, but more interesting were numerous distinctive globular neuronal and glial tau-positive inclusions in both gray and white matter of the neocortex. Affected subcortical regions included substantia nigra, globus pallidus, subthalamic nucleus, and cerebellar dentate nucleus, in a distribution similar to progressive supranuclear palsy (PSP), but without significant accompanying neuronal loss or gliosis. Predominantly straight filaments were detected by electron microscopy (EM), while other inclusions were similar to fingerprint bodies. No twisted ribbons were detected. Immuno-EM studies revealed that only the filamentous inclusions were composed of tau. Immunoblotting of sarkosyl-insoluble tau revealed 2 major bands of 64 and 68 kDa. Blotting analysis after dephosphorylation revealed predominantly 4-repeat tau. Sequence analysis of tau revealed that there were no mutations in either exons 9-13 or the adjacent intronic sequences. The unique cortical tau pathology in this case of sporadic multiple system tauopathy with dementia adds a new pathologic profile to the spectrum of tauopathies.


Lipid management in people with peripheral artery disease.
To summarize recent data on the role of dyslipidaemia and the benefit from managing this in people with disease of the abdominal aorta and its peripheral branches (peripheral artery disease, PAD). Findings from the Further Cardiovascular Outcomes Research with Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition in Subjects with Elevated Risk (FOURIER) trial demonstrate the benefit of intensely lowering low-density lipoprotein-cholesterol (LDL-c) in people with PAD to substantially reduce the incidence of major cardiovascular events (MACE; myocardial infarction, stroke or cardiovascular death) and major adverse limb events (MALE). Despite the evidence of substantial benefits from lowering LDL-c, the uptake of drug therapies to lower LDL-c remains sub-optimal in people with PAD. Effective methods to educate physicians and patients on best medical management are needed. Further research is needed to examine the benefit of LDL-c lowering and other lipid therapies for PAD-specific problems like abdominal aortic aneurysm progression and walking impairment. Other novel lipid therapies, such as those that lower lipoprotein (a), maybe particularly beneficial to people with PAD given the evidence indicating high concentrations in this population and the high incidence of MACE in these individuals.


Loganin Attenuates Osteoarthritis in Rats by Inhibiting IL-1β-Induced Catabolism and Apoptosis in Chondrocytes Via Regulation of Phosphatidylinositol 3-Kinases (PI3K)/Akt.
BACKGROUND Chondrocyte apoptosis and catabolism are 2 major factors that contribute to the progression of osteoarthritis (OA). Loganin, an iridoid glycoside present in several herbs, including Flos lonicerae, Cornus mas L, and Strychnos nux vomica, is a valuable medication with anti-inflammatory and anti-apoptotic effects. Our study examines these effects and explores the potential benefits of loganin in the OA treatment. MATERIAL AND METHODS To clarify the roles of loganin in OA and its specific signaling pathway, chondrocytes were administrated with IL-1ß and supplemented with or without LY294002 (a classic PI3K/Akt inhibitor). The apoptotic level, catabolic factors (MMP-3 and MMP-13 and ADAMTS-4 and ADAMTS-5), extracellular matrix (ECM) degradation, and activation of the PI3K/Akt pathway were evaluated using western blotting, PCR, and an immunofluorescent assay. The degenerative condition of the cartilage was evaluated using the Safranin O assay in vivo. The expression of cleaved-caspase-3 (C-caspase-3) was measured using immunochemistry. RESULTS The data suggested that loganin suppressed the apoptotic level, reduced the release of catabolic enzymes, and decreased the ECM degradation of IL-1ß-induced chondrocytes. However, suppressing PI3K/Akt signaling using LY294002 alleviated the therapeutic effects of loganin in chondrocytes. Our in vivo experiment showed that loganin partially attenuated cartilage degradation while inhibiting the apoptotic level. CONCLUSIONS This work revealed that loganin treatment attenuated IL-1ß-treated apoptosis and ECM catabolism in rat chondrocytes via regulation of the PI3K/Akt signaling, revealing that loganin is a potentially useful treatment for OA.


Weight variability and mortality: the Iowa Women's Health Study.
To evaluate the association between weight variability and risk of mortality in women. Prospective cohort study, 1986-1991. Participants were a population-based sample of 33,760 Iowa women aged 55-69 y, free of cancer and heart disease, who completed a mailed questionnaire including self-reported weight at ages 18, 30, 40, 50 y, and currently. Weight variability was defined by (1) a measure of deviation from the linear regression of each woman's five weights on age (the root mean squared error, RMSE) and (2) categories of weight gain or loss. All-cause (n = 1068) and cause-specific mortality. After adjustment for age and the regression slope of weight on age, women who displayed higher weight variability (RMSE) over their adult years had an increased subsequent 6-y mortality. The relative risks of death for increasing quartiles of RMSE were 1.00 (referent), 1.17, 1.45 and 1.82 (ptrend < 0.001). Positive linear trends were seen across quartiles of RMSE for cardiovascular disease, cancer, and for non-cancer/non-cardiovascular deaths. These associations were attenuated increasingly with (1) statistical adjustment for body mass index, waist-to-hip ratio, smoking, education level, physical activity, alcohol intake, marital status and hormone replacement therapy; (2) further adjustment for diabetes and hypertension; and (3) exclusion of women in poor or fair health in 1986. Even so, with all adjustments, relative risks of coronary heart disease mortality for increasing quartiles of RMSE were 1.00 (referent), 1.22, 1.63 and 1.67 (ptrend = 0.049). Using the categorical approach, age-adjusted risks of death were highest in women who had a large weight loss (> 10%) or a large cycle of weight change (> or = 10% loss-gain or gain-loss), compared with women who had a stable weight (within 5%). Adjustment for covariates attenuated these relative risks. Women who displayed greater weight variability in adulthood had an increased risk of dying in later life, especially from coronary heart disease. However, to a considerable degree this association seems to be due to other unhealthy characteristics and pre-existing disease among those displaying increased weight variability.


Adversarial-residual-coarse-graining: Applying machine learning theory to systematic molecular coarse-graining.
We utilize connections between molecular coarse-graining (CG) approaches and implicit generative models in machine learning to describe a new framework for systematic molecular CG. Focus is placed on the formalism encompassing generative adversarial networks. The resulting method enables a variety of model parameterization strategies, some of which show similarity to previous CG methods. We demonstrate that the resulting framework can rigorously parameterize CG models containing CG sites with no prescribed connection to the reference atomistic system (termed virtual sites); however, this advantage is offset by the lack of a closed-form expression for the CG Hamiltonian at the resolution obtained after integration over the virtual CG sites. Computational examples are provided for cases in which these methods ideally return identical parameters as relative entropy minimization CG but where traditional relative entropy minimization CG optimization equations are not applicable.


Migrating existing clinical content from ICD-9 to SNOMED.
To identify challenges in mapping internal International Classification of Disease, 9th edition, Clinical Modification (ICD-9-CM) encoded legacy data to Systematic Nomenclature of Medicine (SNOMED), using SNOMED-prescribed compositional approaches where appropriate, and to explore the mapping coverage provided by the US National Library of Medicine (NLM)'s SNOMED clinical core subset. This study selected ICD-CM codes that occurred at least 100 times in the organization's problem list or diagnosis data in 2008. After eliminating codes whose exact mappings were already available in UMLS, the remainder were mapped manually with software assistance. Of the 2194 codes, 784 (35.7%) required manual mapping. 435 of these represented concept types documented in SNOMED as deprecated: these included the qualifying phrases such as 'not elsewhere classified'. A third of the codes were composite, requiring multiple SNOMED code to map. Representing 45 composite concepts required introducing disjunction ('or') or set-difference ('without') operators, which are not currently defined in SNOMED. Only 47% of the concepts required for composition were present in the clinical core subset. Search of SNOMED for the correct concepts often required extensive application of knowledge of both English and medical synonymy. Strategies to deal with legacy ICD data must address the issue of codes created by non-taxonomist users. The NLM core subset possibly needs augmentation with concepts from certain SNOMED hierarchies, notably qualifiers, body structures, substances/products and organisms. Concept-matching software needs to utilize query expansion strategies, but these may be effective in production settings only if a large but non-redundant SNOMED subset that minimizes the proportion of extensively pre-coordinated concepts is also available.


[Work-related accidents in traditional fishermen from the Medium Araguaia River region, Tocantins, Brazil].
This is a cross-sectional study of work-related accidents among traditional fishermen in the Medium Araguaia River region of Tocantins, Brazil. From June to August 2002, fishermen from the Municipality of Araguacema were interviewed about the organization of their work activities and work-related accidents during the previous six months. Of the 92 participating fishermen, 56 reported having suffered a work-related accident (annual incidence was 82.6%). Some 95.7% of those interviewed did not regularly pay social security insurance as self-employed workers and were not aware of their social rights and duties. For fishermen reporting accidents, this proportion was 98.2%. Approximately 23.0% had another work activity, mainly as construction workers (47.6%) or sport-fishing guides (23.9%). Injuries inflicted by aquatic animals were the main form of accidents (about 86.0%). From these results, it is apparent that accidents from aquatic animals are an important health hazard, in some cases causing temporary work incapacity.


A polymorphism in the gene for microsomal epoxide hydrolase is associated with pre-eclampsia.
Microsomal epoxide hydrolase is an important enzyme involved in the metabolism of endogenous and exogenous toxicants. Polymorphic variants of the human epoxide hydrolase gene vary in enzyme activity. We determined whether genetic variability in the gene encoding for microsomal epoxide hydrolase contributes to individual differences in susceptibility to the development of pre-eclampsia with or without the syndrome of Haemolysis, Elevated Liver enzymes, and Low Platelets (HELLP). A total of 183 non-pregnant women with a history of pre-eclampsia, 96 of whom had concurrently developed the HELLP syndrome, and 151 healthy female controls were genotyped for the 113Tyr-->His polymorphism in exon 3 and the 139His-->Arg polymorphism in exon 4 of the epoxide hydrolase gene by a polymerase chain reaction-restriction fragment length polymorphism assay. Chi-square analysis was used for statistical evaluation of differences in polymorphic rates. In pre-eclampsia a higher frequency (29%) of the high activity genotype Tyr113 Tyr113 in exon 3 was found as compared to controls (16%, OR 2.0, 95% CI 1.2-3.7). There was no difference between groups for the 139His-->Arg polymorphism. In women with a history of pre-eclampsia, no difference in epoxide hydrolase genotypes was found between women who either did or did not develop the HELLP syndrome. In addition, a significant association was found between predicted EPHX activity and pre-eclampsia. Women with the high activity genotype in exon 3, which could reflect differences in metabolic activation of endogenous or exogenous toxic compounds, may have enhanced susceptibility to pre-eclampsia. However, polymorphisms in the epoxide hydrolase gene do not seem to influence the risk for concurrent development of the HELLP syndrome.


A Ugandan Parenting Programme to Prevent Gender-Based Violence: Description and Formative Evaluation.
Purpose: To develop a culturally-sensitive intervention for the early prevention of gender-based violence (GBV) in Uganda. Methods: Programme design followed the 6SQuID model of intervention development and multi-sectorial advice. A formative evaluation was conducted in two communities with six groups and 138 participants. Findings: Four familial predictors of GBV were identified as potentially malleable: poor parent-child attachment, harsh parenting, inequitable gendered socialization and parental conflict. A community-based parenting programme was developed to address them. Its programme theory incorporates Attachment Theory, the concept that positive behavioural control develops emotional control, and Social Learning Theory. Its rationale, structure and content are presented using the TIDieR checklist. A formative evaluation showed the programme to be widely acceptable, culturally appropriate, and perceived to be effective, but also identified challenges. Conclusion: The careful development of this community-based parenting programme shows promise for the early prevention of GBV.


The cardiac K+ channel KCNQ1 is essential for gastric acid secretion.
Gastric H+ secretion via the H+/K+-adenosine triphosphatase is coupled to the uptake of K+. However, the molecular identity of luminal K+ channels enabling K+ recycling in parietal cells is unknown. This study was aimed to investigate these luminal K+ channels. Acid secretion was measured in vivo and in vitro; KCNQ1 protein localization was assessed by immunofluorescence, and acid-sensitivity of KCNQ1 by patch-clamp. We identified KCNQ1, which is mutated in cardiac long QT syndrome, as a K+ channel located in tubulovesicles and apical membrane of parietal cells, where it colocalized with H+/K+-adenosine triphosphatase. Blockade of KCNQ1 current by 293B led to complete inhibition of acid secretion. The putative KCNQ1 subunits, KCNE2 and KCNE3, were abundant in human stomach; KCNE1, however, was absent. Coexpression of KCNE3/KCNQ1 in COS cells led to an acid-insensitive current; KCNE2/KCNQ1 was activated by low extracellular pH. We identified KCNQ1 as the missing luminal K+ channel in parietal cells and characterized its crucial role in acid secretion. Because KCNE3 and KCNE2 are expressed in human stomach, one or both are candidates to coassemble with KCNQ1 in parietal cells. Thus, stomach- and subunit-specific inhibitors of KCNQ1 might offer new therapeutical perspectives for peptic ulcer disease.


The Philadelphia Brief Assessment of Cognition (PBAC): a validated screening measure for dementia.
The Philadelphia Brief Assessment of the Cognition (PBAC) is a brief dementia-screening instrument. The PBAC assesses five cognitive domains: working memory/executive control; lexical retrieval/language; visuospatial/visuoconstructional operations; verbal/visual episodic memory; and behavior/social comportment. A revised version of the PBAC was administered to 198 participants including patients with Alzheimer's disease (AD) (n=46) and four groups of patients with frontotemporal dementia (FTD) syndromes: behavioral-variant FTD (bvFTD; n=65), semantic-variant primary progressive aphasia (PPA) (svPPA; n=22), non-fluent/agrammatic-variant PPA (nfaPPA; n=23), and corticobasal syndrome (CBS; n=42), and a group of normal controls (n=15). The total PBAC score was highly correlated with the MMSE. The criterion validity of the PBAC was assessed relative to standard neuropsychological test performance. Using standard neuropsychological test performance as a criterion, the total PBAC score accurately identified the presence and severity of dementia. Intra-class correlations between PBAC subscales and standard neuropsychological tests were highly significant. PBAC subscales demonstrated good clinical utility in distinguishing AD and FTD subtypes using receiver operating characteristic analysis and standard diagnostic performance statistics to determine optimal subscale cut scores. The PBAC is a valid tool and able to assesses differential patterns neuropsychological/behavioral impairment in a broad range of neurodegenerative conditions.


Lysophosphatidic acid receptor type 2 activation contributes to secondary damage after spinal cord injury in mice.
Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions by signaling through six known G-protein-coupled receptors (LPA1-LPA6). In the central nervous system (CNS), LPA mediates a wide range of effects, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and contributions to pain, schizophrenia and hydrocephalus. We recently reported that LPA-LPA1 signaling mediates functional deficits and myelin loss after spinal cord injury (SCI). Here, we provide clear evidence on the deleterious contribution of another LPA receptor, LPA2, to myelin loss after SCI. We found that LPA2 is constitutively expressed in the spinal cord parenchyma and its transcripts were up-regulated after contusion injury, in part, by microglial cells. We also found that the demyelinating lesion triggered by intraspinal injection of LPA into the undamaged spinal cord was markedly reduced in the lack of LPA2. Similarly, LPA2 deficient mice showed enhanced motor skills and myelin sparing after SCI. To gain insights into the detrimental actions of LPA2 in spinal cord we performed cell culture studies. These experiments revealed that, similar to LPA1, activation of microglia LPA2 led to oligodendrocyte cell death. Moreover, we also found that the cytotoxic effects underlaying microglial LPA-LPA2 axis were mediated by the release of purines by microglia and the activation of P2X7 receptor on oligodendrocytes. Overall, this study provides new mechanistic insights into how LPA contributes to SCI physiopathology, and suggest that targeting LPA2 could be a novel therapeutic approach for the treatment of acute SCI.


[Postura de la Academia Nacional de Medicina de México en relación con las decisiones sobre el final de la vida].
There are decisions at the end of life that currently are relevant as humanistic values. Respect for human life and dignity are part of human rights. The National Academy of Medicine of Mexico declares its posture about end-of-life decisions that include treatment refusal, limitation of the therapeutic effort, advance directives and palliative sedation, among others, with the purpose to favor a peaceful death.


[Study of carbohydrate metabolism in rats after administration of myocardium-damaging doses of adrenaline].
The investigation included a study of the content of glycogen, of the activity of the enzymes of its decay (phosphorylase and hydrolytic enzymes), of the content of lactic acid, and glucose in rats following the administration of myocardium damaging doses of adrenalin, as well as in animals who had died after the administration of adrenalin or were agonizing. The analysis of the carbohydrate metabolism parameters in animals who had died due to the adrenalin administration, or who had been sacrificed in an agonizing state (sharp fall of the glycogen content in the heart, increased activity of hydrolytic enzymes in the heart during the agonizing phase) indicated that the temporary elevation of the glycogen content in the heart after the administration of 300microng/100g of adrenalin was a compensatory reaction of the body. It is suggested that a certain relationship exists between the markedness of this compensatory reaction, i.e. the glycogen level in the heart muscle, and the severity of necrotic lesions.


Latex test for serodiagnosis of infectious mononucleosis.
A glycoprotein was isolated from bovine erythrocytes which has 20% carbohydrate and migrates on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a single band. This glycoprotein carries the reactivity of bovine erythrocytes with Paul-Bunnell heterophile antibody of infectious mononucleosis. This bovine glycoprotein was coupled to carboxyl-modified latex particles with water-soluble carbodiimide. The resulting reagent was then used to develop a new test for the detection of infectious mononucleosis antibody. The bovine erythrocyte glycoprotein-latex reagent is more stable than sheep or horse erythrocytes, the traditional reagents for detection of infectious mononucleosis antibody. This new reagent is used in a direct slide test; no preabsorption of the sera is necessary. In the present study the glycoprotein-latex reagent compared favorably in terms of sensitivity and specificity with two standard tests for infectious mononucleosis antibody. Ninety-nine serum samples were tested. Agreement of the latex test with a stabilized horse erythrocyte spot test was 90%. Ten samples were weakly positive with the latex test and negative with the horse cell test. Only one of these was also positive with an enzyme-treated sheep cell test. This latter test was somewhate more sensitive than the latex test.


Physical characterization of a novel wireless DRX Plus 3543C using both a carbon nano tube (CNT) mobile x-ray system and a traditional x-ray system.
This work aims to characterize the novel DRX Plus 3543C detector in terms of detective quantum efficiency (DQE) using both a mobile x-ray system called Carestream DRX Revolution Nano and a traditional x-ray system (Carestream DRX Evolution). We used the commercial system DRX Revolution Nano, equipped with a new x-ray source based on CNT technology and field emission (FE) as the electron emitter (cathode). An innovative aspect of this device is its intrinsic selection of the focal spot size. We tested the system using three IEC-specified beam qualities (RQA3, 5 and 7) in terms of modulation transfer function (MTF), normalized noise power spectra (NNPS) and DQE as defined in the IEC 62220-1-1:2015. We compared the results obtained using DRX Revolution Nano and DRX Evolution with correlation and with Bland-Altman plots to study their agreement. RQA3 MTF is slightly lower than the RQA5 and 7 curves between 0.5 and 2.5 cycles mm-1. We measured MTF values of about 0.6 at 1 lp mm-1 and about 0.28 lp mm-1 at 2 lp mm-1. The NNPS curves show a decreasing trend with the energy regarding the DRX Revolution Nano. On the other hand, the DRX Evolution NNPS curve at RQA3 is greater than the one at RQA5, but the one at RQA5 is less than the one at RQA7. The DQE(0) ranged between about 0.82 (DRX Evolution at RQA3) and 0.54 (DRX Evolution at RQA7). As expected, the squared Pearson's correlation coefficients between the two x-ray tubes were always in an optimal agreement, and Bland-Altman plots confirmed a substantial equivalence between the two physical characterizations of the wireless detector. In conclusion, we can show that the dynamic focal selection of the system equipped with CNT does not play a substantial role in image quality compared to a traditional system in terms of physical characterisation of the detector in our measurement conditions.


Stereotactic gamma radiosurgery for intracranial vascular malformations and tumors: report of the initial North American experience in 331 patients.
We reviewed the initial experience with 331 consecutive patients treated during the first 2 years of operation of the University of Pittsburgh Gamma Unit. Among 178 patients with vascular malformations, 161 had angiographically demonstrable arteriovenous malformations, and 17 had angiographically occult malformations. Patients with tumors included 123 with histologically benign, predominantly extra-axial neoplasms and 30 with malignant, predominantly intra-axial neoplasms. When the arteriovenous malformation nidus could be covered with at least the 50% isodose line and a dose to the margin greater than or equal to 20 Gy, 60% were obliterated within 1 year. Patients with benign tumors and well-circumscribed malignant tumors did not experience tumor growth within the radiosurgical treatment volume. The role of radiosurgery is expanding to include primary treatment of larger lesions than was formerly possible and adjunctive treatment of more complex arteriovenous malformation and tumors.


A three-dimensional biomechanical evaluation of quadriceps and hamstrings function using electrical stimulation.
Neurological disorders such as stroke impair locomotor control and result in abnormal 3-D gait kinematics. Establishment of effective rehabilitation strategies requires an understanding of how individual muscles contribute to pathological movement. Forward dynamic simulations account for complexities of interjoint coupling and can be used to predict dynamic muscle function. However to date, limited experimental validations of dynamic models have been performed. Our objective was to measure 3-D movement induced by the biceps femoris (BF), rectus femoris (RF), and vastus lateralis (VL) in limb configurations corresponding to the swing phase of gait, and to assess the biomechanical factors that affect dynamic function. Subjects were positioned in a robotic gait orthosis that included a compliant interface. Electrical stimulation was introduced into individual muscles while induced hip and knee joint movements were recorded. Measured hip to knee sagittal plane acceleration ratios were consistent with dynamic musculoskeletal model simulations. However RF and VL induced substantially larger frontal plane hip movements than model-based predictions. Sensitivity analyses on musculoskeletal model parameters revealed that muscle function depends primarily on moment arm assumptions. Though generic musculoskeletal models are suitable for predicting sagittal plane muscle function, improvements in moment arm accuracy are essential for investigation of 3-D pathological gait.


A norwalk-like virus waterborne community outbreak in a Swedish village during peak holiday season.
An outbreak of gastroenteritis due to Norwalk-like virus (NLV) affecting approximately 500 people occurred in a Swedish ski resort during February-March 2002. Epidemiological investigations were performed on cohorts of schoolchildren, permanent residents and skiers visiting the area. Attack rates were respectively 39.7, 29.9 and 38.5%. Drinking un-boiled water originating from one of the three communal water systems was a significant risk factor for all groups. For schoolchildren, the risk of illness increased with increasing amount of water consumed. Nine of 12 stool samples of patients analysed tested positive for NLV. The water tested negative for indicator bacteria and results of NLV tests were inconclusive. In the absence of microbiological findings, the environmental authorities were reluctant to act based on the epidemiological analysis alone, and intervention was delayed until mid-April, following the discovery of a crack in a sewage pipe 10 m from the well.


Biochemical aspects of bupivacaine-induced acute muscle degradation.
A single injection of a local anaesthetic, bupivacaine, into the soleus muscle of adult rat has a severe mytoxic effect, i.e. rapid dissolution of myofilaments and degradation of myofibrillar proteins shortly after injection. Increased lysosomal enzymes were observed in homogenates of affected muscle. The activity of potent proteolytic enzyme, cathepsins B and L (assayed against a new synthetic substrate succinyl-Tyr-Met-naphthylamide), gradually increased and reached a plateau value that was 11-fold greater than the control 48 h after bupivacaine injection. The chronological change in the activity of cathepsins B and L was reflected in the myofibrillar protein pattern in bupivacaine-treated muscle. To determine whether the increase in lysosomal peptide hydrolases is due to activation of muscle lysosomes or not, mononuclear cells were separated from both injected and control muscles. The activity of cathepsins B and L in the lysate from injured muscle was 180-fold higher than the control. Affinity-purified antibody was used to study the intracellular localization of cathepsin B by immunohistochemical procedures. The results were consistent with the biochemical observation that the main source of cathepsin B in muscle homogenates was infiltrated mononuclear cells. Therefore, we conclude that the increased lysosomal enzymes may be derived mainly from mononuclear cells (macrophages), not from muscle lysosomes, in bupivacaine-induced acute muscle degeneration.


Inhibition of mitochondrial oxidative metabolism attenuates EMCV replication and protects β-cells from virally mediated lysis.
Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide-dependent manner.


HLA and epidermolysis bullosa. Association between the HLA complex and recessive dystrophic epidermolysis bullosa.
--Epidermolysis bullosa refers to a group of genetic diseases characterized by marked skin fragility and blister formation following minor mechanical trauma. The patients with recessive dystrophic epidermolysis bullosa (RDEB) are the most severely affected with marked internal and external blistering, scarring, and death at an early age, secondary to malnutrition, septicemia, and/or metastatic squamous cell carcinoma. An association between RDEB and HLA antigens was explored in 28 patients with RDEB and their family members. --Our data demonstrate that susceptibility to develop RDEB may be associated with the HLA complex. The gene frequencies of DR4 and DQw3 were much higher in the patients than expected. These increases were likely due to statistically significant excess of DR4 and DQw3 homozygotes in the patients. In addition, the observed frequencies of two HLA haplotypes: Bw62, DR4, DQw3 and Bw60, DR4, DQw3 were significantly higher than expected. --If these observations are confirmed in the larger series of patients, the association between RDEB and HLA complex may have clinical utility in genetic counseling of siblings of child-bearing age who are at risk of being carriers of RDEB.


Silencing of KCNQ1OT1 Decreases Oxidative Stress and Pyroptosis of Renal Tubular Epithelial Cells.
Long noncoding RNAs (lncRNAs) can regulate the progression of DN. This research aimed to study the effect of lncRNA KCNQ1OT1 on the oxidative stress and pyroptosis of the renal tubular epithelial cells induced by high glucose (HG). RT-qPCR analysis detected the KCNQ1OT1 expression in serum with DN and HG-induced HK-2 cells, detect the expression of NLRP3, cleaved-caspase1, P-caspase1, IL-1β, p-IL-1β and GSDMD-N in HG-induced HK-2 cells, and confirm the transfection effects. The expression of NLRP3, cleaved-caspase1, P-caspase1, IL-1β, p-IL-1β and GSDMD-N in HG-induced HK-2 cells was also analyzed by Western blot analysis. ELISA assay detected the levels of TNF-α, IL-6 and MCP-1. The levels of ROS, MDA and SOD were determined by respective ELISA kits and ROS was also detected by the ROS assay kit (containing DCFH-DA). We found that KCNQ1OT1 was increased in the plasma of patients with DN and HG-induced HK-2 cells and KCNQ1OT1 interference could decrease the inflammation, oxidative stress and pyroptosis of HG-induced HK-2 cells. In addition, KCNQ1OT1 directly targets miR-506-3p. MiR-506-3p was downregulated in the plasma of patients with DN and HG-induced HK-2 cells and KCNQ1OT1 interference promoted the expression of miR-506-3p. MiR-506-3p overexpression suppressed the inflammation, oxidative stress and pyroptosis of HG-induced HK-2 cells. This study demonstrated that downregulation of KCNQ1OT1 inhibited the inflammation, oxidative stress and pyroptosis of HG-induced HK-2 cells by up-regulating the expression of miR-506-3p, which provide new insights into the treatment of DN.


Phase diagram of colloid-rod system.
The semigrand ensemble theory [H. N. W. Lekkerkerker, W. C. K. Poon, P. N. Pusey, A. Stroobants, and P. B. Warren, Europhys. Lett. 20, 559 (1992)] in conjunction with the fundamental measure density functional theory [V. B. Warshavsky and X. Song, Phys. Rev. E 69, 061113 (2004)] are used to construct the Helmholtz free energy densities of a mixture of uncharged colloidal hard spheres and colloidal rods in its solid and liquid phases. Given these free energy density functions, we apply the free energy density minimization method [G. F. Wang and S. K. Lai, Phys. Rev. E 70, 051402 (2004)] to crosshatch the system's regions of phases in coexistence. The calculated results show that the triangular area bounded by gas-liquid, gas-solid, and liquid-solid coexisting two phases which has been called the coexistence region of gas-liquid-solid corresponds in fact to sets of two phases in coexistence. The phase boundaries which define our calculated coexistence domains compare very well with previous theoretical calculations. The relevance of the phase-diagram domains to three phases in coexistence will be discussed.


The childhood executive functioning inventory (CHEXI): a new rating instrument for parents and teachers.
Poor executive functioning has been shown to be of central importance in disruptive behavior disorders such as attention deficit hyperactivity disorder (ADHD), and a large number of laboratory measures of executive functioning have been developed. There are, however, few available questionnaires tapping executive functioning and those that exist also include items focused directly on the symptom criteria for ADHD, which makes it difficult to draw conclusions regarding executive functioning per se. In the present study, a new rating instrument, the Childhood Executive Functioning Inventory (CHEXI) was therefore introduced. This instrument was shown to have good test-retest reliability. Using factor analysis, two factors tapping working memory and inhibition emerged using parent ratings and these two factors were replicated using teacher ratings. Modest, yet mostly significant, relations to laboratory measures of working memory and inhibition were found. Ratings on the CHEXI were also found to be significantly related to ADHD symptoms as well as early academic achievement. Interestingly, ratings on the CHEXI and laboratory measures of working memory and inhibition were shown to explain independent variance in ADHD symptoms and academic achievement, which point to the importance of using a multi-assessment strategy when studying executive functioning.


Post-modern valence bond theory for strongly correlated electron spins.
We give a pedagogical overview of our recently introduced electronic-structure method, Coupled Cluster Valence Bond (CCVB). We show that CCVB can be viewed as an approximation to the accurate, yet very expensive, Spin Coupled Valence Bond model (SCVB). Both of these models are intended for use on strongly correlated molecular systems, especially when the strong correlations are due to electron spin coupling. Using familiar ideas from electronic-structure theory, we provide definitions for these strong-correlation concepts. We show that CCVB and SCVB generally produce similar results, with more substantial discrepancies occurring for systems displaying electronic resonance. We conclude that CCVB is a useful, inexpensive alternative to SCVB.


Cutting edge: pulmonary Legionella pneumophila is controlled by plasmacytoid dendritic cells but not type I IFN.
Plasmacytoid dendritic cells (pDCs) are well known as the major cell type that secretes type I IFN in response to viral infections. Their role in combating other classes of infectious organisms, including bacteria, and their mechanisms of action are poorly understood. We have found that pDCs play a significant role in the acute response to the intracellular bacterial pathogen Legionella pneumophila. pDCs were rapidly recruited to the lungs of L. pneumophila-infected mice, and depletion of pDCs resulted in increased bacterial load. The ability of pDCs to combat infection did not require type I IFN. This study points to an unappreciated role for pDCs in combating bacterial infections and indicates a novel mechanism of action for this cell type.


A test of enhancing model accuracy in high-throughput crystallography.
The high throughput of structure determination pipelines relies on increased automation and, consequently, a reduction of time spent on interactive quality control. In order to meet and exceed current standards in model accuracy, new approaches are needed for the facile identification and correction of model errors during refinement. One such approach is provided by the validation and structure-improvement tools of the MOL: PROBITY: web service. To test their effectiveness in high-throughput mode, a large subset of the crystal structures from the SouthEast Collaboratory for Structural Genomics (SECSG) has used protocols based on the MOL: PROBITY: tools. Comparison of 29 working-set and 19 control-set SECSG structures shows that working-set outlier scores for updated Ramachandran-plot, sidechain rotamer, and all-atom steric criteria have been improved by factors of 5- to 10-fold (relative to the control set or to a Protein Data Bank sample), while quality of covalent geometry, R(work), R(free), electron density and difference density are maintained or improved. Some parts of this correction process are already fully automated; other parts involve manual rebuilding of conformations flagged by the tests as trapped in the wrong local minimum, often altering features of functional significance. The ease and effectiveness of this technique shows that macromolecular crystal structures from either traditional or high-throughput determinations can feasibly reach a new level of excellence in conformational accuracy and reliability.


Digital Image Analysis of Heterogeneous Tuberculosis Pulmonary Pathology in Non-Clinical Animal Models using Deep Convolutional Neural Networks.
Efforts to develop effective and safe drugs for treatment of tuberculosis require preclinical evaluation in animal models. Alongside efficacy testing of novel therapies, effects on pulmonary pathology and disease progression are monitored by using histopathology images from these infected animals. To compare the severity of disease across treatment cohorts, pathologists have historically assigned a semi-quantitative histopathology score that may be subjective in terms of their training, experience, and personal bias. Manual histopathology therefore has limitations regarding reproducibility between studies and pathologists, potentially masking successful treatments. This report describes a pathologist-assistive software tool that reduces these user limitations, while providing a rapid, quantitative scoring system for digital histopathology image analysis. The software, called 'Lesion Image Recognition and Analysis' (LIRA), employs convolutional neural networks to classify seven different pathology features, including three different lesion types from pulmonary tissues of the C3HeB/FeJ tuberculosis mouse model. LIRA was developed to improve the efficiency of histopathology analysis for mouse tuberculosis infection models, this approach has also broader applications to other disease models and tissues. The full source code and documentation is available from https://Github.com/TB-imaging/LIRA.


Flexible and Biocompatible Antifouling Polyurethane Surfaces Incorporating Tethered Antimicrobial Peptides through Click Reactions.
Efficient, simple antibacterial materials to combat implant-associated infections are much in demand. Herein, the development of polyurethanes, both cross-linked thermoset and flexible and versatile thermoplastic, suitable for "click on demand" attachment of antibacterial compounds enabled via incorporation of an alkyne-containing diol monomer in the polymer backbone, is described. By employing different polyolic polytetrahydrofurans, isocyanates, and chain extenders, a robust and flexible material comparable to commercial thermoplastic polyurethane is prepared. A series of short synthetic antimicrobial peptides are designed, synthesized, and covalently attached in a single coupling step to generate a homogenous coating. The lead material is shown to be biocompatible and does not display any toxicity against either mouse fibroblasts or reconstructed human epidermis according to ISO and OECD guidelines. The repelling performance of the peptide-coated materials is illustrated against colonization and biofilm formation by Staphylococcus aureus and Staphylococcus epidermidis on coated plastic films and finally, on coated commercial central venous catheters employing LIVE/DEAD staining, confocal laser scanning microscopy, and bacterial counts. This study presents the successful development of a versatile and scalable polyurethane with the potential for use in the medical field to reduce the impact of bacterial biofilms.


[Pregnancy and fetal development in epileptic women].
Epilepsy affects almost 1% of all pregnant women. Epileptic women marry more often than epileptic men. Married epileptic women have a lower socio-economic status and are more severely ill than married male epileptics.--Several reasons are discussed--poor compliance being probably the most essential one--for an explanation of an occasional increase in the rate of attacks and a frequently observed tendency to a drop in plasma concentrations of anti-epileptics during pregnancy. Pregnancy and parturition are not more complicated in epileptic women than in non-epileptics women. Nevertheless, abortions are performed, and delivery by surgery is initiated, more often with epileptics, although there are no convincing arguments in favour of such procedures. For unknown reasons, perinatal lethality is up to twice as high than with controls.--Children of mothers treated with anti-epileptics have a tendency to intrauterine dystrophia, which is manifested mainly by a reduced size of the head which is not made up completely during the first few years of life, contrary to other body dimensions. We do not know as yet whether there are any links between dystrophia of the body, malformations and inhibited psychomotoric development.--Depending on the type of anti-epileptics given to the mothers who are breast-feeding their children, and on the concentration of these drugs in the plasma or in the mother's milk, breast-fed children may display signs of withdrawal or sedation. This must not be overlooked when considering the problem of breast-feeding.--The slightly enhanced risk of malformations appears to be less intimately connected, with intrauterine exposition of anti-epileptics than with the underlying disease itself.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of CA125, physical and radiological findings in follow-up of ovarian cancer patients.
The majority of ovarian cancer patients will suffer from intraabdominal relapse within the first five years after surgery. Today various diagnostic tools, including ultrasound or CT, are available to detect an ovarian cancer recurrence. Radiological examinations at regular time-intervals may lead to the detection of tumor relapse, however these procedures have limited sensitivity and specificity. Moreover, imaging procedures are costly. CA125 is a tumor marker with high sensitivity in ovarian cancer patients. Tumor marker determination is a simple, reproducible technique, and may therefore be useful in routine follow-up in ovarian cancer patients, supplemented with additional imaging procedures. In a retrospective analysis of 58 patients with recurrent ovarian cancer, the sensitivity of clinical examination and tumor marker analysis was compared to radiological findings. Physical interview and physical examination were performed for all patients. CA125 levels were determined in 54 out of 58 patients at the time of diagnosis of recurrence. Forty-seven out of 58 patients received a vaginal ultrasound and 42 were examined by CT scan. In 45 out of 54 (83%) patients, CA 125 was elevated at the time of recurrence. In 45 out of the 58 (78%) patients, a tumor was detected by physical examination. Forty-two out of the 58 patients had CT scans. Pathological findings were seen in 33 out of these patients (80%) Ultrasound revealed tumor recurrence in 33 out of 47 patients (70%). By a follow-up based on physical examination and CA125 determination, 53 out of 54 (98%) patients with recurrences could be identified. In patients with a pelvic recurrence, vaginal examination had the highest sensitivity in comparison to vaginal ultrasound and CT scan. Imaging techniques did not add clinically relevant information during follow-up and should therefore only be performed prior to surgical or therapeutical intervention.


Factors Associated with Serum 25-Hydroxyvitamin D Concentration in Two Cohorts of Pregnant Women in Southern Ontario, Canada.
Vitamin D deficiency in pregnancy is widely reported, but whether this applies in North America is unclear since no population-based surveys of vitamin D status in pregnancy exist in Canada or the United States. The objectives were to assess (i) the intake and sources of vitamin D, (ii) vitamin D status, and (iii) factors associated with serum 25-hydroxyvitamin D (25-OHD) concentration in two cohorts of pregnant women from Southern Ontario, Canada, studied over a span of 14 years. Maternal characteristics, physical measurements, fasting blood samples and nutrient intake were obtained at enrolment in 332 pregnant women from the Family Atherosclerosis Monitoring In early Life (FAMILY) study and 191 from the Be Healthy in Pregnancy (BHIP) study. Serum 25-OHD was measured by LC/MS-MS. The median (Q1, Q3) total vitamin D intake was 383 IU/day (327, 551) in the FAMILY study and 554 IU/day (437, 796) in the BHIP study. Supplemental vitamin D represented 64% of total intake in participants in FAMILY and 78% in BHIP. The mean (SD) serum 25-OHD was 76.5 (32.9) nmol/L in FAMILY and 79.7 (22.3) nmol/L in BHIP. Being of European descent and blood sampling in the summer season were significantly associated with a higher maternal serum 25-OHD concentration. In summary, health care practitioners should be aware that vitamin D status is sufficient in the majority of pregnant Canadian women of European ancestry, likely due to sun exposure.


The COPD assessment test (CAT) assists prediction of COPD exacerbations in high-risk patients.
We evaluated the predictive value of the COPD assessment test (CAT™) for exacerbation in the following six months or time to first exacerbation among COPD patients with previous exacerbations. COPD outpatients with a history of exacerbation from 19 hospitals completed the CAT questionnaire and spirometry over six months. Exacerbation events were prospectively collected using a structured questionnaire. The baseline CAT score categorised into four groups (0-9, 10-19, 20-29, and 30-40) showed strong prediction for time to first exacerbation and modest prediction for any exacerbation or moderate-severe exacerbation (AUC 0.83, 0.64, and 0.63 respectively). In multivariate analyses, the categorised CAT score independently predicted all three outcomes (p = 0.001 or p < 0.001). Compared with the lowest CAT score category, the higher categories were associated with significantly shorter time to first exacerbation and higher exacerbation risks. The corresponding adjusted median time was >24, 14, 9, and 5 weeks and the adjusted RR was 1.00, 1.30, 1.37, and 1.50 in the category of 0-9, 10-19, 20-29, and 30-40 respectively. Exacerbation history (≥2 vs. 1 event in the past year) was related to time to first exacerbation (adjusted HR 1.35; p = 0.023) and any exacerbation during the study period (adjusted RR 1.15; p = 0.016). The results of this study support the use of the CAT as a simple tool to assist in the identification of patients at increased risk of exacerbations. This could facilitate timely and cost-effective implementation of preventive interventions, and improve health resource allocation. Clinicaltrials.gov: NCT01254032.


Introduction of a normal human chromosome 11 into a Wilms' tumor cell line controls its tumorigenic expression.
The development of Wilms' tumor, a pediatric nephroblastoma, has been associated with a deletion in the p13 region of chromosome 11. The structure and function or functions of this deleted genetic material are unknown. The role of this deletion in the process of malignant transformation was investigated by introducing a normal human chromosome 11 into a Wilms' tumor cell line by means of the microcell transfer technique. These variant cells, derived by microcell hybridization, expressed similar transformed traits in culture as the parental cell line. Furthermore, expression of several proto-oncogenes by the parental cells was unaffected by the introduction of this chromosome. However, the ability of these cells to form tumors in nude mice was completely suppressed. Transfer of other chromosomes, namely X and 13, had no effect on the tumorigenicity of the Wilms' tumor cells. These studies provide support for the existence of genetic information on chromosome 11 which can control the malignant expression of Wilms' tumor cells.


Recent Patent Advances for Neurodegenerative Disorders and its Treatment.
Neurodegenerative disorders are among the most common challenging diseases that affect the population with extreme medical and financial burdens. Widely seen neurodegeneration affects population of all ages, as it progresses with age, affecting a large proportion of elderly population including patients, caregivers, and immensely increasing the financial load of the country. These diseases have a very complex nature that frequently results from combined genetic, environmental and pathological factors. Various challenges are faced by the researchers working on the pathogenesis and the possible treatment of neurodegenerative disorder. The review has analysed for recent patent documents and treatment approaches for neurodegenerative disorders. This review does not relate to potential targets such as ( i.e. protein where modulation could be predicted to impact on pathophysiology), rather it mainly focuses on various available patented approaches for neurodegenerative disorders. The study design is based on updating the international and national literatures and an exhaustive patent search, compiling various patented documents for the treatment of neurodegenerative disorders (EP2282779A1, US20110229555A1) to provide information in the state of technological innovation in terms of research and development. In the present review, the authors described various neurodegenerative diseases, there treatment strategies and emphasized on various patented approaches for age-related neurodegenerative disorders such as novel therapeutic methods for treating Alzheimer's and associated disorders via modulated cell stress response EP2282779A1, through combined therapies that modulate angiogenesis US20120058992A1. The review will attract the interest of academics, researchers, students and pharmaceutical companies with regard to the recent on-going activities in neurodegenerative disorders.


Real-time analysis of G protein-coupled receptor reconstitution in a solubilized system.
Receptor based signaling mechanisms are the primary source of cellular regulation. The superfamily of G protein-coupled receptors is the largest and most ubiquitous of the receptor mediated processes. We describe here the analysis in real-time of the assembly and disassembly of soluble G protein-coupled receptor-G protein complexes. A fluorometric method was utilized to determine the dissociation of a fluorescent ligand from the receptor solubilized in detergent. The ligand dissociation rate differs between a receptor coupled to a G protein and the receptor alone. By observing the sensitivity of the dissociation of a fluorescent ligand to the presence of guanine nucleotide, we have shown a time- and concentration-dependent reconstitution of the N-formyl peptide receptor with endogenous G proteins. Furthermore, after the clearing of endogenous G proteins, purified Galpha subunits premixed with bovine brain Gbetagamma subunits were also able to reconstitute with the solubilized receptors. The solubilized N-formyl peptide receptor and Galpha(i3) protein interacted with an affinity of approximately 10(-6) m with other alpha subunits exhibiting lower affinities (Galpha(i3) > Galpha(i2) > Galpha(i1) Galpha(o)). The N-formyl peptide receptor-G protein interactions were inhibited by peptides corresponding to the Galpha(i) C-terminal regions, by Galpha(i) mAbs, and by a truncated form of arrestin-3. This system should prove useful for the analysis of the specificity of receptor-G protein interactions, as well as for the elucidation and characterization of receptor molecular assemblies and signal transduction complexes.


Arrival of Imidazo[2,1-b]thiazole-5-carboxamides: Potent Anti-tuberculosis Agents That Target QcrB.
Increasing interest in the potent anti-tuberculosis activity and the novel target (QcrB) of imidazo[1,2-a]pyridine-3-carboxamides encouraged extended structure-activity relationship studies of additional scaffolds. This study reports on the in vitro profiling of the imidazo[2,1-b]thiazole-5-carboxamides as a new promising class of anti-tuberculosis compounds endowed with nanomolar potency against replicating and drug-resistant Mycobacterium tuberculosis (Mtb) as well as low toxicity to VERO cells. Compounds 6, 16, and 17 had MIC values <10 nM and toxicity >100 μM. On-target selectivity of this series was confirmed by cross-resistance of specific QcrB mutants as well as the hypersusceptibility of a mutant with a functional gene deletion of the alternative cytochrome bd oxidase. Additionally, to demonstrate selectivity, three analogues (6, 15, 17) were broadly screened against a diverse set of eight strains of bacteria, including both Gram-positive and Gram-negative as well as six disease-causing non-tuberculosis mycobacteria. Finally, compounds 16 and 17 were found to be active in macrophages infected with Mtb.


Regions of broad-host-range plasmid RK2 involved in replication and stable maintenance in nine species of gram-negative bacteria.
The replication and maintenance properties of the broad-host-range plasmid RK2 and its derivatives were examined in nine gram-negative bacterial species. Two regions of RK2, the origin of replication (oriV) and a segment that encodes for a replication protein (trfA delta kilD, designated trfA*), are sufficient for replication in all nine species tested. However, stable maintenance of this minimal replicon (less than 0.3% loss per generation under nonselection conditions) is observed only in Escherichia coli, Pseudomonas aeruginosa, Pseudomonas putida, and Azotobacter vinelandii. Maintenance of this minimal replicon is unstable in Rhizobium meliloti, Agrobacterium tumefaciens, Caulobacter crescentus, Acinetobacter calcoaceticus, and Rhodopseudomonas sphaeroides. A maintenance function has been localized to a 3.1-kilobase (kb) region of RK2 encoding three previously described functions: korA (trfB korB1 korD), incP1-(II), and korB. The 3.1-kb maintenance region can increase or decrease the stability of maintenance of RK2 derivatives dependent on the host species and the presence or absence of the RK2 origin of conjugal transfer (oriT). In the case of A. calcoaceticus, stable maintenance requires an RK2 segment that includes the promoter and the kilD (kilB1) functions of the trfA operon in addition to the 3.1-kb maintenance region. The broad-host-range maintenance requirements of plasmid RK2, therefore, are encoded by multiple functions, and the requirement for one or more of these functions varies among gram-negative bacterial species.