Crizotinib for Untreated Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.
As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal process, the manufacturer of crizotinib submitted evidence on the clinical and cost effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell lung cancer (NSCLC). Crizotinib has previously been assessed by NICE for patients with previously treated ALK-positive NSCLC (TA 296). It was not approved in this previous appraisal, but had been made available through the cancer drugs fund. As part of this new appraisal, the company included a price discount patient access scheme (PAS). The Centre for Reviews and Dissemination and Centre for Health Economics Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company's submission and the ERG's review and summarises the resulting NICE guidance issued in August 2016. The main clinical-effectiveness data were derived from a multicentre randomised controlled trial-PROFILE 1014-that compared crizotinib with pemetrexed chemotherapy in combination with carboplatin or cisplatin in patients with untreated non-squamous ALK-positive NSCLC. In the trial, crizotinib demonstrated improvements in progression-free survival (PFS) and overall survival (OS). The company's economic model was a three-state 'area under the curve' Markov model. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be greater than £50,000 per quality-adjusted life-year (QALY) gained (excluding the PAS discount). The ERG assessment of the evidence submitted by the company raised a number of concerns. In terms of the clinical evidence, the OS benefit was highly uncertain due to the cross-over permitted in the trial and the immaturity of the data; only 26% of events had occurred by the data cut-off point. In the economic modelling, the most significant concerns related to the analysis of OS and assumptions made regarding the duration of therapy. The ERG exploratory re-analysis of the OS data relaxed the assumption of proportional hazards made in the company submission, which demonstrated significant uncertainty regarding the OS gains from crizotinib. The ERG reconfigured the economic model so that duration of therapy was based on the area under the curve analysis of the PROFILE 1014 trial, dramatically increasing the cost associated with implementing crizotinib and consequently, substantially increasing the ICER. At the first appraisal meeting, the NICE Appraisal Committee concluded that crizotinib, while clinically effective, was not sufficiently cost effective for use in the UK NHS. Following the consultation, the company offered a revised PAS and conducted extensive re-analysis, resulting in a revised base-case ICER of £47,291 per QALY gained. The NICE Appraisal Committee concluded that crizotinib was likely to be a cost-effective use of NHS resources, despite the uncertainty that persisted around a number of factors, namely the long-term survival benefit of crizotinib. Crizotinib was therefore recommended as an option for untreated ALK-positive advanced NSCLC in adults.


Modulation of regional dispersion of repolarization and T-peak to T-end interval by the right and left stellate ganglia.
Left stellate or right stellate ganglion stimulation (LGSG or RSGS, respectively) is associated with ventricular tachyarrhythmias; however, the electrophysiological mechanisms remain unclear. We assessed 1) regional dispersion of myocardial repolarization during RSGS and LSGS and 2) regional electrophysiological mechanisms underlying T-wave changes, including T-peak to T-end (Tp-e) interval, which are associated with ventricular tachyarrhythmia/ventricular fibrillation. In 10 pigs, a 56-electrode sock was placed around the heart, and both stellate ganglia were exposed. Unipolar electrograms, to asses activation recovery interval (ARI) and repolarization time (RT), and 12-lead ECG were recorded before and during RSGS and LSGS. Both LSGS and RSGS increased dispersion of repolarization; with LSGS, the greatest regional dispersion occurred on the left ventricular (LV) anterior wall and LV apex, whereas with RSGS, the greatest regional dispersion occurred on the right ventricular posterior wall. Baseline, LSGS, and RSGS dispersion correlated with Tp-e. The increase in RT dispersion, which was due to an increase in ARI dispersion, correlated with the increase in Tp-e intervals (R(2) = 0.92 LSGS; and R(2) = 0.96 RSGS). During LSGS, the ARIs and RTs on the lateral and posterior walls were shorter than the anterior LV wall (P < 0.01) and on the apex versus base (P < 0.05), explaining the T-wave vector shift posteriorly/inferiorly. RSGS caused greater ARI and RT shortening on anterior versus lateral or posterior walls (P < 0.01) and on base versus apex (P < 0.05), explaining the T-wave vector shift anteriorly/superiorly. LSGS and RSGS cause differential effects on regional myocardial repolarization, explaining the ECG T-wave morphology. Sympathetic stimulation, in line with its proarrhythmic effects, increases Tp-e interval, which correlates with increases in myocardial dispersion of repolarization.


[Relationship between the cause of admission and the cause of death in patients admitted to an internal medicine departament].
When patients are admitted to an internal medicine ward, they and their relatives believe that they will leave the internal medicine service in a better health condition or, if they die, their cause of death will be the same that motivated the hospital admission. Sometimes, patients die due to a different disease than the cause of admission or due to complications of diagnostic or therapeutic procedures. To assess the proportion of deaths that occurred in internal medicine wards for causes that differ from the cause for admission and the proportion of deaths related to complications of diagnostic or therapeutic procedures. Three hundred and three consecutive patients were studied during 28 months. Their cause qf death was classified n four groups: A. If it was the same illness of admission; B. Afrecuent or expected complication of the illness that motivated the admission; C. A complication of one of their chronic diseases and not the one of admission; D. If it was not related to an already present chronic illness or the cause for admission. Sixty nine percent of deaths corresponded to group A, 7.9% to group B, 11.2%96 to group C and 11.9% to group D. Diagnostic or therapeutic procedures were the cause of death in 0. 7 and 3.6% of cases respectively. Twenty three percent of patients died due to causes that differ from the cause of admission. A low percentage of deaths were related to procedures and most of them were due to complications of therapeutic measures.


Capillary density and caliber as assessed by optical coherence tomography angiography may be significant predictors of diabetic retinopathy severity.
To validate retinal capillary density and caliber associations with diabetic retinopathy (DR) severity in different clinical settings. This cross-sectional study assessed retinal capillary density and caliber in the superficial retinal layer of 3-mm OCTA scans centered on the fovea. Images were collected from non-diabetic controls and subjects with mild or referable DR (defined DR worse than mild DR) between February 2016 and December 2019 at secondary and tertiary eye care centers. Vessel Skeleton Density (VSD), a measure of capillary density, and Vessel Diameter Index (VDI), a measure of vascular caliber, were calculated from these images. Discriminatory performance of VSD and VDI was evaluated using multivariable logistic regression models predicting DR severity with adjustments for sex, hypertension, and hyperlipidemia. Area under the curve (AUC) was estimated. Model performance was evaluated in two different cohorts. This study included 594 eyes from 385 subjects. Cohort 1 was a training cohort of 509 eyes including 159 control, 155 mild non-proliferative DR (NPDR) and 195 referable DR eyes. Cohort 2 was a validation cohort consisting of 85 eyes including 16 mild NPDR and 69 referable DR eyes. In Cohort 1, addition of VSD and VDI to a model using only demographic data significantly improved the model's AUC for discrimination of eyes with any DR severity from controls (0.91 [95% CI, 0.88-0.93] versus 0.80 [95% CI, 0.76-0.83], p < 0.001) and eyes with referable DR from mild NPDR (0.90 [95% CI, 0.86-0.93] versus 0.69 [95% CI, 0.64-0.75], p < 0.001). The transportability of this regression model was excellent when implemented in Cohort 2 for the referable DR versus mild NPDR comparison. The odds ratio of having any DR compared to control subjects, and referable DR compared to mild DR decreased by 15% (95% CI: 12-18%), and 13% (95% CI: 10-15%), respectively, for every 0.001 unit increase in VSD after adjusting for comorbidities. OCTA-derived capillary density has real world clinical value for rapidly assessing DR severity.


Public health partnerships in medical toxicology education and practice.
In December 2002, the medical toxicology sub-board, which consists of representatives from emergency medicine, preventive medicine, and pediatrics, released revised core content for medical toxicology, aiming to better meet the academic challenges imposed by the continually expanding knowledge base of medical toxicology. These challenges included the addition of relatively new areas of interest in medical toxicology, including population health, while simultaneously ensuring that a structural framework existed to accommodate future areas of interest. There is no evidence readily available to assess how well the educational curricula of existing fellowship programs are meeting these needs. In an effort to address this, the authors describe a medical toxicology fellowship program that consists of a partnership among the Emory University School of Medicine, the Georgia Poison Control Center, and the CDC, as well as the results of a reorganization of its academic curriculum that occurred in 2006. To the best of the authors' knowledge, this is the first published report describing such a curriculum redesign. Suggestions and potential resources proposed as enhancements for the public health-associated education of medical toxicology fellows are discussed. The authors also seek to initiate a discussion among programs about how to optimally meet the new challenges developed by the medical toxicology sub-board.


Eligibility criteria for biologic disease-modifying antirheumatic drugs in axial spondyloarthritis: going beyond BASDAI.
To compare definitions of high disease activity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in selecting patients for treatment with biologic disease-modifying antirheumatic drugs (bDMARDs). Patients from Rheumatic Diseases Portuguese Register (Reuma.pt) with a clinical diagnosis of axial spondyloarthritis (axSpA) were included. Four subgroups (cross-tabulation between ASDAS (≥2.1) and BASDAI (≥4) definitions of high disease activity) were compared regarding baseline characteristics and response to bDMARDs at 3 and 6 months estimated in multivariable regression models. Of the 594 patients included, the majority (82%) had both BASDAI≥4 and ASDAS ≥2.1. The frequency of ASDAS ≥2.1, if BASDAI<4 was much larger than the opposite (ie, ASDAS <2.1, if BASDAI≥4): 62% vs 0.8%. Compared to patients fulfilling both definitions, those with ASDAS ≥2.1 only were more likely to be male (77% vs 51%), human leucocyte antigen B27 positive (79% vs 65%) and have a higher C reactive protein (2.9 (SD 3.5) vs 2.1 (2.9)). Among bDMARD-treated patients (n=359), responses across subgroups were globally overlapping, except for the most 'stringent' outcomes. Patients captured only by ASDAS responded better compared to patients fulfilling both definitions (eg, ASDAS inactive disease at 3 months: 61% vs 25% and at 6 months: 42% vs 25%). The ASDAS definition of high disease activity is more inclusive than the BASDAI definition in selecting patients with axSpA for bDMARD treatment. The additionally 'captured' patients respond better and have higher likelihood of predictors thereof. These results support using ASDAS≥2.1 as a criterion for treatment decisions.


Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators.
Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo. In a chemical program we aimed to improve the affinity, physicochemical properties and metabolic stability exploring three regions of the hit. Systematic variation of different amines at position 4 (region I) led to the identification of 4-methyl-piperidinyl analogues. Substituents of the quinoline core (region II) and the phenylsulfonyl moiety (region III) were mapped by parallel synthesis. Evaluation of both morpholino- and 4-methyl-piperidinyl-sulfoquinoline libraries of about 270 derivatives revealed beneficial substituent combinations in regions II and III. Blood levels of optimized 4-methyl-piperidinyl-sulfoquinolines, however, were still insufficient for robust in vivo efficacy. Finally, introducing 4-hydoxymethyl-piperidinyl substituent to region I resulted in new sulfoquinolines with greatly improved solubility and reasonable affinity coupled with affordable metabolic stability. The most promising analogues (24 and 25) showed high blood levels and demonstrated significant efficacy in the experimental model of anxiety.


Continent-based systematic review of the short-term health impacts of wildfire emissions.
This review systematically gathers and provides an analysis of pollutants levels emitted from wildfire (WF) and their impact on short-term health effects of affected populations. The available literature was searched according to Population, Exposure, Comparator, Outcome, and Study design (PECOS) database defined by the World Health Organization (WHO) and a meta-analysis was conducted whenever possible. Data obtained through PECOS characterized information from the USA, Europe, Australia, and some Asian countries; South American countries were seldom characterized, and no data were available for Africa and Russia. Extremely high levels of pollutants, mostly of fine fraction of particulate matter (PM) and ozone, were associated with intense WF emissions in North America, Oceania, and Asia and reported to exceed several-fold the WHO guidelines. Adverse health outcomes include emergency department visits and hospital admissions for cardiorespiratory diseases as well as mortality. Despite the heterogeneity among exposure and health assessment methods, all-cause mortality, and specific-cause mortality were significantly associated with WF emissions in most of the reports. Globally, a significant association was found for all-cause respiratory outcomes including asthma, but mixed results were noted for cardiovascular-related effects. For the latter, estimates were only significant several days after WF emissions, suggesting a more delayed impact on the heart. Different research gaps are presented, including the need for the application of standardized protocols for assessment of both exposure and adverse health risks. Mitigation actions also need to be strengthened, including dedicated efforts to communicate with the affected populations, to engage them for adoption of protective behaviors and measures.


Fibulin-3 promotes glioma growth and resistance through a novel paracrine regulation of Notch signaling.
Malignant gliomas are highly invasive and chemoresistant brain tumors with extremely poor prognosis. Targeting of the soluble factors that trigger invasion and resistance, therefore, could have a significant impact against the infiltrative glioma cells that are a major source of recurrence. Fibulin-3 is a matrix protein that is absent in normal brain but upregulated in gliomas and promotes tumor invasion by unknown mechanisms. Here, we show that fibulin-3 is a novel soluble activator of Notch signaling that antagonizes DLL3, an autocrine inhibitor or Notch, and promotes tumor cell survival and invasion in a Notch-dependent manner. Using a strategy for inducible knockdown, we found that controlled downregulation of fibulin-3 reduced Notch signaling and led to increased apoptosis, reduced self-renewal of glioblastoma-initiating cells, and impaired growth and dispersion of intracranial tumors. In addition, fibulin-3 expression correlated with expression levels of Notch-dependent genes and was a marker of Notch activation in patient-derived glioma samples. These findings underscore a major role for the tumor extracellular matrix in regulating glioma invasion and resistance to apoptosis via activation of the key Notch pathway. More importantly, this work describes a noncanonical, soluble activator of Notch in a cancer model and shows how Notch signaling can be reduced by targeting tumor-specific accessible molecules in the tumor microenvironment.


Plants Grown in Parafilm-Wrapped Petri Dishes Are Stressed and Possess Altered Gene Expression Profile.
Arabidopsis is used as a model species in numerous physiological and genetic studies. Most of them employ parafilm-wrapped sterile culture. Here we demonstrate that this method is prone to potential artifacts and can lead to erroneous conclusions. We compared the effect of different sealing methods including air-permeable paper tape and traditional parafilm on Arabidopsis seedling growth, root development and gene expression network. Although seedlings grown in Petri dishes after 1 week sealed with paper tape showed a similar growth phenotype to that of parafilm-sealed seedlings, more than 700 differentially expressed genes (DEG) were found, including stress and nutrition-responsive genes. In addition, more H2O2 was accumulated in the tissues of parafilm-sealed plants. After 14 days of growth, paper tape-sealed plants grew much better than parafilm-sealed ones and accumulated higher chlorophyll content, with 490 DEGs found. After 3 weeks of growth, paper tape-sealed plants had higher chlorophyll and better growth compared to parafilm-sealed ones; and only 10 DEGs were found at this stage. Thus, the obvious phenotype observed at the latter stage was a result of differential gene expression at earlier time points, mostly of defense, abiotic stress, nutrition, and phytohormone-responsive genes. More O2 content was detected inside paper tape-sealed Petri dishes at early growth stage (7 days), and distinct difference in the CO2 content was observed between parafilm-sealed and paper tape-sealed Petri dishes. Furthermore, the carbon source also influenced seedlings growth with different sealing methods. In conclusion, conventional sealing using parafilm was not the optimal choice, most likely because of the limited gas exchange and a consequent stress caused to plants.


The postprandial chylomicron triacylglycerol response to dietary fat in healthy male adults is significantly explained by a combination of single nucleotide polymorphisms in genes involved in triacylglycerol metabolism.
The postprandial chylomicron (CM) triacylglycerol (TG) response to dietary fat, which is positively associated with atherosclerosis and cardiovascular disease risk, displays a high interindividual variability. This is assumed to be due, at least partly, to polymorphisms in genes involved in lipid metabolism. Existing studies have focused on single nucleotide polymorphisms (SNPs), resulting in only a low explained variability. We aimed to identify a combination of SNPs associated with the postprandial CM TG response. Thirty-three healthy male volunteers were subjected to 4 standardized fat tolerance test meals (to correct for intraindividual variability) and genotyped using whole-genome microarrays. The plasma CM TG concentration was measured at regular interval times after each meal. The association of SNPs in or near candidate genes (126 genes representing 6225 SNPs) with the postprandial CM TG concentration (0-8 h areas under the curve averaged for the 4 test meals) was assessed by partial least squares regression, a multivariate statistical approach. Data obtained allowed us to generate a validated significant model (P = 1.3 × 10(-7)) that included 42 SNPs in 23 genes (ABCA1, APOA1, APOA5, APOB, BET1, CD36, COBLL1, ELOVL5, FRMD5, GPAM, INSIG2, IRS1, LDLR, LIPC, LPL, LYPLAL1, MC4R, NAT2, PARK2, SLC27A5, SLC27A6, TCF7L2, and ZNF664) and explained 88% of the variance. In 39 of these SNPs, univariate analysis showed that subjects with different genotypes exhibited significantly different (q < .05) postprandial CM TG responses. Using a multivariate approach, we report a combination of SNPs that explains a significant part of the variability in the postprandial CM TG response.


Raman scattering boson peak and differential scanning calorimetry studies of the glass transition in tellurium-zinc oxide glasses.
Raman scattering and differential scanning calorimetry (DSC) measurements have been carried out on four mixed tellurium-zinc oxide (TeO(2))(1 - x)(ZnO)(x) (x = 0.1, 0.2, 0.3, 0.4) glasses under variable temperature, with particular attention being given to the respective glass transition region. From the DSC measurements, the glass transition temperature T(g) has been determined for each glass, showing a monotonous decrease of T(g) with increasing ZnO content. The Raman study is focused on the low-frequency band of the glasses, the so-called boson peak (BP), whose frequency undergoes an abrupt decrease at a temperature T(d) very close to the respective T(g) values obtained by DSC. These results show that the BP is highly sensitive to dynamical effects over the glass transition and provides a means for an equally reliable (to DSC) determination of T(g) in tellurite glasses and other network glasses. The discontinuous temperature dependence of the BP frequency at the glass transition, along with the absence of such a behaviour by the high-frequency Raman bands (due to local atomic vibrations), indicates that marked changes of the medium range order (MRO) occur at T(g) and confirms the correlation between the BP and the MRO of glasses.


Isoproterenol-induced myocardial dysfunction in dogs with coronary stenosis.
Stress-induced regional myocardial ischemia in the presence of mild coronary stenosis was studied in five dogs 2-4 wk after implantation of pairs of ultrasonic crystals to measure left ventricular wall thickening (% delta WT) and subendocardial segmental shortening (% delta L). Isoproterenol (0.2 micrograms.kg-1.min-1) was infused before and after production of coronary stenosis, which produced no resting dysfunction. During isoproterenol infusion with coronary stenosis % delta WT and subendocardial % delta L were significantly decreased although blood flow was comparable to conditions at rest, indicating that the demand for blood flow exceeded supply. Linear regression analysis of mean transmural blood flow versus % delta WT during isoproterenol demonstrated that wall thickening was significantly related to changes in mean blood flow: y (percentage wall thickening) = 27.5 X (transmural blood flow) -8.2 (r = 0.83); likewise % delta L was significantly related to subendocardial blood flow during isoproterenol infusion: y (percentage shortening) = 17.1 X (subendocardial blood flow) -0.4 (r = 0.85). These results indicate that both regional % delta WT and % delta L sensitively reflect the adequacy of myocardial perfusion even during stress-induced changes in myocardial O2 demands and blood flow.


Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock.
Lactate clearance, a surrogate for the magnitude and duration of global tissue hypoxia, is used diagnostically, therapeutically and prognostically. This study examined the association of early lactate clearance with selected inflammatory, coagulation, apoptosis response biomarkers and organ dysfunction scores in severe sepsis and septic shock. Measurements of serum arterial lactate, biomarkers (interleukin-1 receptor antagonist, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, intercellular adhesion molecule-1, high mobility group box-1, D-Dimer and caspase-3), and organ dysfunction scores (Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Multiple Organ Dysfunction Score, and Sequential Organ Failure Assessment) were obtained in conjunction with a prospective, randomized study examining early goal-directed therapy in severe sepsis and septic shock patients presenting to the emergency department (ED). Lactate clearance was defined as the percent change in lactate levels after six hours from a baseline measurement in the ED. Two-hundred and twenty patients, age 65.0 +/- 17.1 years, were examined, with an overall lactate clearance of 35.5 +/- 43.1% and in-hospital mortality rate of 35.0%. Patients were divided into four quartiles of lactate clearance, -24.3 +/- 42.3, 30.1 +/- 7.5, 53.4 +/- 6.6, and 75.1 +/- 7.1%, respectively (p < 0.01). The mean levels of all biomarkers and organ dysfunction scores over 72 hours were significantly lower with higher lactate clearance quartiles (p < 0.01). There was a significant decreased in-hospital, 28-day, and 60-day mortality in the higher lactate clearance quartiles (p < 0.01). Early lactate clearance as a surrogate for the resolution of global tissue hypoxia is significantly associated with decreased levels of biomarkers, improvement in organ dysfunction and outcome in severe sepsis and septic shock.


The mechanics of prey prehension in chameleons.
Iguanian lizards generally use their tongue to capture prey. Because lingual prehension is based on surface phenomena (wet adhesion, interlocking), the maximal prey size that can be captured is small. However, published records show that prey items eaten by chameleons include small vertebrates such as lizards and birds, indicating that these lizards are using a different prey prehension mechanism. Using high-speed video recordings, cineradiography, electromyography, nerve transection and stimulation experiments, we investigated the function of the tongue during prey capture. The results of these experiments indicate that chameleons have modified the primitive iguanian system by including a suction component in their prehension mechanism. Suction is generated by the activity of two modified intrinsic tongue muscles that pull the tongue pad inwards. Moreover, we demonstrate that the mechanism described here is a prerequisite for successful feeding.


Exopolysaccharide-Derived Carbon Dots for Microbial Viability Assessment.
Fluorescent dye staining combined with fluorescence microscopy or flow cytometry is becoming a routine way to monitor microorganism viability that is necessary for food safety, antibiotic development, and human health. However, the conventional live/dead assay dyes suffer from high cost, inconvenient staining steps, and high cytotoxicity, which is urgently needed to overcome. Herein, cheap carbon dots, CDs-EPS605, were reported to successfully assess microbial viability in a convenient way with neglectable cytotoxicity. The fluorescent N-doped CDs-EPS605 could be facilely prepared from bacterial amino exopolysaccharide (EPS) by one-step hydrothermal carbonization, which is cost-effective and sustainable. The negatively charged CDs-EPS605 consisted of C, H, O, N, P, and S, and featured various functional groups, including -COOH, -OH, -CONH-, and -NH2. CDs-EPS605 were observed to sensitively and selectively stain dead microorganisms instead of live ones to enable discrimination of live/dead microorganisms. The labeling method with CDs-EPS605 did not require protection from light, or washing, which is convenient. Additionally, CDs-EPS605 displayed better photostability and much less cytotoxicity compared to the commercial counterpart. Altogether, CDs-EPS605 represent a simple, yet powerful staining agent for microbial viability assessment, and at the same time enrich the current applications of microbial EPS.


RNAi screening comes of age: improved techniques and complementary approaches.
Gene silencing through sequence-specific targeting of mRNAs by RNAi has enabled genome-wide functional screens in cultured cells and in vivo in model organisms. These screens have resulted in the identification of new cellular pathways and potential drug targets. Considerable progress has been made to improve the quality of RNAi screen data through the development of new experimental and bioinformatics approaches. The recent availability of genome-editing strategies, such as the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system, when combined with RNAi, could lead to further improvements in screen data quality and follow-up experiments, thus promoting our understanding of gene function and gene regulatory networks.


Trends in baseline patient characteristics during the years 1995-2008: observations from Riks-Stroke, the Swedish Stroke Register.
Reported improvements in outcome in stroke patients treated in hospital are often attributed to advances in stroke care. However, secular trends in patient characteristics that are present already on admission to hospital may also contribute to improved outcome. Time trends for baseline data (289,854 stroke admittances) in Riks-Stroke, the Swedish national quality register for stroke care, were analyzed for the years 1995 through 2008. The following data were included: number of strokes for each year, age, sex, risk factors, stroke subtype, stroke severity, functional status and need of external home service before the stroke. The number of annually reported strokes increased until 2005. The proportion of recurrent strokes decreased from 28.0 to 25.9%. The mean age at first-ever stroke increased in women, but not in men. The proportion of smokers dropped, and the proportion of patients who had treated hypertension increased. The stroke severity decreased in men. The prestroke functional status (walking, dressing, toileting) improved in both sexes over these years. More patients lived alone in 2008 than in 1995, and more had home help service. Many baseline parameters in Riks-Stroke have changed over the years. This has consequences for the interpretation of outcome data. Some changes may be due to inclusion bias, others due to alterations in general health, evolution of vascular risk factors or demographics.


Remote sensing of atmospheric optical depth using a smartphone sun photometer.
In recent years, smart phones have been explored for making a variety of mobile measurements. Smart phones feature many advanced sensors such as cameras, GPS capability, and accelerometers within a handheld device that is portable, inexpensive, and consistently located with an end user. In this work, a smartphone was used as a sun photometer for the remote sensing of atmospheric optical depth. The top-of-the-atmosphere (TOA) irradiance was estimated through the construction of Langley plots on days when the sky was cloudless and clear. Changes in optical depth were monitored on a different day when clouds intermittently blocked the sun. The device demonstrated a measurement precision of 1.2% relative standard deviation for replicate photograph measurements (38 trials, 134 datum). However, when the accuracy of the method was assessed through using optical filters of known transmittance, a more substantial uncertainty was apparent in the data. Roughly 95% of replicate smart phone measured transmittances are expected to lie within ±11.6% of the true transmittance value. This uncertainty in transmission corresponds to an optical depth of approx. ±0.12-0.13 suggesting the smartphone sun photometer would be useful only in polluted areas that experience significant optical depths. The device can be used as a tool in the classroom to present how aerosols and gases effect atmospheric transmission. If improvements in measurement precision can be achieved, future work may allow monitoring networks to be developed in which citizen scientists submit acquired data from a variety of locations.


Electrogenicity of microbial biofilms of medically relevant microorganisms: potentiometric, amperometric and wireless detection.
Since the progression of biofilm formation is related to the success of infection treatment, detecting microbial biofilms is of great interest. Biofilms of Gram-positive Staphylococcus aureus and Streptococcus gordonii bacteria, Gram-negative Pseudomonas aeruginosa and Escherichia coli bacteria, and Candida albicans yeast were examined using potentiometric, amperometric, and wireless readout modes in this study. As a biofilm formed, the open circuit potential (OCP) of biofilm hosting electrode (bioanode) became increasingly negative. Depending on the microorganism, the OCP ranged from -70 to -250 mV. The co-culture generated the most negative OCP (-300 mV vs Ag/AgCl), while the single-species biofilm formed by E. coli developed the least negative (-70 mV). The OCP of a fungal biofilm formed by C. albicans was -100 mV. The difference in electrode currents generated by biofilms was more pronounced. The current density of the S. aureus biofilm was 0.9‧10-7 A cm-2, while the value of the P. aeruginosa biofilm was 1.3‧10-6 A cm-2. Importantly, a biofilm formed by a co-culture of S. aureus and P. aeruginosa had a slightly higher negative OCP value and current density than the most electrogenic P. aeruginosa single-species biofilm. We present evidence that bacteria can share redox mediators found in multi-species biofilms. This synergy, enabling higher current and OCP values of multi-species biofilm hosting electrodes, could be beneficial for electrochemical detection of infectious biofilms in clinics. We demonstrate that the electrogenic biofilm can provide basis to construct novel wireless, chip-free, and battery-free biofilm detection method.


Scalable Multiplexed Drug-Combination Screening Platforms Using 3D Microtumor Model for Precision Medicine.
Cancer heterogeneity is a notorious hallmark of this disease, and it is desirable to tailor effective treatments for each individual patient. Drug combinations have been widely accepted in cancer treatment for better therapeutic efficacy as compared to a single compound. However, experimental complexity and cost grow exponentially with more target compounds under investigation. The primary challenge remains to efficiently perform a large-scale drug combination screening using a small number of patient primary samples for testing. Here, a scalable, easy-to-use, high-throughput drug combination screening scheme is reported, which has the potential of screening all possible pairwise drug combinations for arbitrary number of drugs with multiple logarithmic mixing ratios. A "Christmas tree mixer" structure is introduced to generate a logarithmic concentration mixing ratio between drug pairs, providing a large drug concentration range for screening. A three-layer structure design and special inlets arrangement facilitate simple drug loading process. As a proof of concept, an 8-drug combination chip is implemented, which is capable of screening 172 different treatment conditions over 1032 3D cancer spheroids on a single chip. Using both cancer cell lines and patient-derived cancer cells, effective drug combination screening is demonstrated for precision medicine.


[Distribution of subfractions of high-density lipoproteins during their separation according to hydrated density and particle size].
Distribution of high density lipoprotein (HDL) subfractions was studied by means of gradient ultracentrifugation depending on their hydration density and using electrophoresis in gradient polyacrylamide gel according to the particles size. 53 men were examined, where 43 patients were impaired with ischemic heart disease and with atherosclerosis of coronary arteries documented by angiography. In all the patients with ischemic heart disease and dislipoproteinemias distribution of the HDL particles was altered towards a decrease in amount of HDL2b particles; at the same time, loading with cholesterol of the HDL3 subfraction was lowered. The alterations in the subfraction spectrum and composition of HDL observed in the patients with the ischemia and coronary atherosclerosis appear to exhibit the atherogenous impairments in cholesterol elimination from arterial wall.


Trends and ethnic differences in hospital admissions and mortality for congestive heart failure in the elderly in Singapore, 1991 to 1998.
To describe trends in hospital admissions and mortality from congestive heart failure in the elderly population aged 65 years and over in Singapore, 1991 to 1998. Analysis of trends and population subgroup differences in rates of hospital admission and mortality for a primary diagnosis of congestive heart failure, classified as ICD-9, codes 428, 402.0, 402.11, and 402.91. The state of Singapore (multiethnic population of three million: Chinese 77%, Malay 14%, Indian 8%). Congestive heart failure accounted for 4.5% of all hospital admissions and 2.5% of overall mortality in this age group. Age adjusted hospital admission rates for congestive heart failure increased by 38% (from 85.4 per 10 000 in 1991 to 110.3 per 10 000 in 1998), while mortality decreased by 20% (from 7.3 per 10 000 in 1991 to 6.1 per 10 000 in 1998). The decline in mortality was greater in women than in men. There were no sex differences in the rates of hospital admission, but there were significant ethnic differences in admissions and mortality. Thus hospital admissions for congestive heart failure were about 35% higher in both Malays and Indians than in Chinese; and mortality was 3.5 times higher in Malays, but was about the same in Indians and Chinese. Over the period studied, mortality from congestive heart failure declined in both Chinese and Indians, but rose in Malays. The increases in hospital admissions were similar in both sexes and all ethnic groups. An increasing rate of hospital admission accompanied by declining mortality from congestive heart failure is occurring in elderly people in this Asian multiethnic population. However, there are pronounced ethnic differences, with both Malays and Indians showing higher hospital admission rates than Chinese, and Malays showing a rising mortality as opposed to the falling mortality in the other ethnic groups.


Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients.
The efficacy of tenofovir disoproxil fumarate (TDF) as part of combination antiretroviral treatment (ART) has been demonstrated in several randomized, controlled trials. However, an increasing number of case reports suggest that TDF use may be associated with significant nephrotoxicity. Our objective was to determine the renal safety of TDF-containing ART regimens for HIV-infected individuals. MEDLINE, EMBASE, Global Health, Scopus, Biosis Previews, Cochrane Library, Web of Science, and existing systematic reviews were searched. Prospective studies comparing TDF-containing with non-TDF containing ART regimens were selected for inclusion. We extracted data on study characteristics, participant characteristics, therapeutic interventions, renal function, bone density, and fracture rates. A total of 17 studies (including 9 randomized, controlled trials) met the selection criteria. Median sample size was 517 participants. Constituent ART regimens were diverse. There was a significantly greater loss of kidney function among the TDF recipients, compared with control subjects (mean difference in calculated creatinine clearance, 3.92 mL/min; 95% confidence interval [CI], 2.13-5.70 mL/min), as well as a greater risk of acute renal failure (risk difference, 0.7%; 95% CI, 0.2-1.2). There was no evidence that TDF use led to increased risk of severe proteinuria, hypophosphatemia, or fractures. Although TDF use was associated with a statistically significant loss of renal function, the clinical magnitude of this effect was modest. Our findings do not support the need to restrict TDF use in jurisdictions where regular monitoring of renal function and serum phosphate levels is impractical.


KIFC1: a promising chemotherapy target for cancer treatment?
The kinesin motor KIFC1 has been suggested as a potential chemotherapy target due to its critical role in clustering of the multiple centrosomes found in cancer cells. In this regard, KIFC1 seems to be non-essential in normal somatic cells which usually possess only two centrosomes. Moreover, KIFC1 is also found to initiatively drive tumor malignancy and metastasis by stabilizing a certain degree of genetic instability, delaying cell cycle and protecting cancer cell surviving signals. However, that KIFC1 also plays roles in other specific cell types complicates the question of whether it is a promising chemotherapy target for cancer treatment. For example, KIFC1 is found functionally significant in vesicular and organelle trafficking, spermiogenesis, oocyte development, embryo gestation and double-strand DNA transportation. In this review we summarize a recent collection of information so as to provide a generalized picture of ideas and mechanisms against and in favor of KIFC1 as a chemotherapy target. And we also drew the conclusion that KIFC1 is a promising chemotherapy target for some types of cancers, because the side-effects of inhibiting KIFC1 mentioned in this review are theoretically easy to avoid, while KIFC1 is functionally indispensable during mitosis and malignancy of multi-centrosome cancer cells. Further investigations of how KIFC1 is regulated throughout the mitosis in cancer cells are needed for the understanding of the pathways where KIFC1 is involved and for further exploitation of indirect KIFC1 inhibitors.


Shame reactions after suicide attempt.
Shame reactions were spontaneously described by 13 of 18 patients interviewed in a qualitative study investigating experiences of care following a suicide attempt. The shame data from the interview study were extracted, analysed separately, and are reported in this article. The shame reactions often occurred in conjunction with the suicide attempt. Feelings of shame were accompanied by impulses to hide or flee, i.e., fear of seeking help or impulses to leave the hospital. The attempted suicide patients often experienced the initial encounter at the hospital as difficult. Having attempted suicide and survived was often perceived as yet another failure, in addition to the problems leading to the attempt. The attempted suicide patients were sensitive to the attitudes and behaviours of the personnel. Experiencing the personnel as kind, respectful, and nonjudgemental seemed to contribute to a relief from shame for some patients. Some respondents expressed that a tolerant and flexible atmosphere in the psychiatric ward, with low demands on the attempted suicide patient, helped them accept treatment and made them feel less ashamed for not living up to the expectations of everyday life. On the other hand, feeling too exposed to others or experiencing negative attitudes from the personnel seemed to contribute to an exacerbation of shame for some patients. Being aware of possible shame reactions after a suicide attempt might help caring personnel to understand and interact with attempted suicide patients in a way that could make it easier for these patients to accept and benefit from psychiatric care after a suicide attempt.


Optimal reordering of measurements for photonic quantum tomography.
Quantum tomography is an essential method of the photonic technology toolbox and is routinely used for evaluation of experimentally prepared states of light and characterization of devices transforming such states. The tomography procedure consists of many different sequentially performed measurements. We present considerable tomography speedup by optimally arranging the individual constituent measurements, which is equivalent to solving an instance of the traveling salesman problem. As an example, we obtain solutions for photonic systems of up to five qubits, and conclude that already for systems of three or more qubits, the total duration of the tomography procedure can be halved. The reported speedup has been verified experimentally for quantum state tomography and also for full quantum process characterization up to six qubits, without resorting to any complexity reduction or simplification of the system of interest. Our approach is versatile and reduces the time of an input-output characterization of optical devices and various scattering processes as well.


[Identification of small RNA in polyhedra of Bombyx mori nuclear polyhedrosis virus].
It has been shown by bioinformatic methods that regions of the Bombyx mori viral nuclear polyhedrosis genome encoded two small RNA--snc RNA-1 and snc RNA-2, which could perform a structural function in polyhedra crystals formation. The aim of this work was identification of the nucleotide sequence of small non-coding RNAs, predicted by bioinformatic methods in B. mori polyhedra. The following methods have been used: polymerase chain reaction, agarose gel electrophoresis, the cloning of PCR products, sequencing. There were first determined nucleotide sequences of snc RNA-1 and snc RNA-2 ofpolyhedrin mRNA complementary regions which are included in B. mori polyhedra. These RNAs have 100% identity with bioinformatic predicted sequences. These results confirmed our bioinformatic approach to the search for small RNAs encoded in B. mori nuclear polyhedrosis virus genome.


3D assessment of cortical bone porosity and tissue mineral density using high-resolution µCT: effects of resolution and threshold method.
Current micro-computed tomography (µCT) systems allow scanning bone at resolutions capable of three-dimensional (3D) characterization of intracortical vascular porosity and osteocyte lacunae. However, the scanning and reconstruction parameters along with the image segmentation method affect the accuracy of the measurements. In this study, the effects of scanning resolution and image threshold method in quantifying small features of cortical bone (vascular porosity, vascular canal diameter and separation, lacunar porosity and density, and tissue mineral density) were analyzed. Cortical bone from the tibia of Sprague-Dawley rats was scanned at 1-µm and 4-µm resolution, reconstructions were density-calibrated, and volumes of interest were segmented using approaches based on edge-detection or histogram analysis. In 1-µm resolution scans, the osteocyte lacunar spaces could be visualized, and it was possible to separate the lacunar porosity from the vascular porosity. At 4-µm resolution, the vascular porosity and vascular canal diameter were underestimated, and osteocyte lacunae were not effectively detected, whereas the vascular canal separation and tissue mineral density were overestimated compared to 1-µm resolution. Resolution had a much greater effect on the measurements than did threshold method, showing partial volume effects at resolutions coarser than 2 µm in two separate analyses, one of which assessed the effect of resolution on an object of known size with similar architecture to a vascular pore. Although there was little difference when using the edge-detection versus histogram-based threshold approaches, edge-detection was somewhat more effective in delineating canal architecture at finer resolutions (1-2 µm). In addition, use of a high-resolution (1 µm) density-based threshold on lower resolution (4 µm) density-calibrated images was not effective in improving the lower-resolution measurements. In conclusion, if measuring cortical vascular microarchitecture, especially in small animals, a µCT resolution of 1 to 2 µm is appropriate, whereas a resolution of at least 1 µm is necessary when assessing osteocyte lacunar porosity.


PCR for detection of cdt-III and the relative frequencies of cytolethal distending toxin variant-producing Escherichia coli isolates from humans and cattle.
A PCR assay that uses primers whose sequences were obtained from the published sequence of the cdt-III gene was developed to determine the frequencies of the cdt-I, cdt-II, and cdt-III genes in Escherichia coli isolates from humans and animals. E. coli isolates producing cytolethal distending toxin (CDT) were infrequently detected. The cdt-I gene was preferentially detected in strains with the cnf1 gene, while the cdt-III gene was found in strains carrying the cnf2 gene. The cdt-III genotype was more prevalent in animal isolates, while the cdt-I and cdt-II genotypes were more evident in human isolates. The presence of further cdt gene variants was indicated by the presence of toxin activity in cell culture in the absence of PCR amplification of the cdt-I, cdt-II, or cdt-III gene.


Dispersion and colonization of Triatoma ryckmani (Hemiptera: Reduviidae) in artificial environments in a semiarid region of a Chagas disease endemic area in Guatemala.
The colonization capacity and dispersal of sylvatic populations of Triatoma ryckmani Zeledón and Ponce were investigated by means of experimental chicken coops installed within the semiarid region in the Department of El Progreso, Guatemala. In the four artificial habitats a total of 672 T. ryckmani was found as well as two males of T. dimidiata (Latreille). Triatomine densities were not the same in the four chicken coops. From one chicken coop 53.4% (359) of the triatomines were collected. Full colonization, i.e. all stages from egg to adult found at the same time, took place in the fourth month after the first female's arrival. High dispersal and colonization capacity of T. ryckmani was evident; adult dispersal occurs mainly during the dry and coolest season (November-February). The overall female/male sex ratio was 2:1; more females than males were found throughout the year. Most of the triatomines in the shelter inside the chicken coops were found on the northern (43%; with less heat and sunlight) and eastern side (35%; more windy). This is the first report on the colonization capacity and population dynamics of T. ryckmani in artificial habitats in a Chagas disease endemic area of Central America.


A population-based study of intracranial arachnoid cysts: clinical and neuroimaging outcomes following surgical cyst decompression in children.
If, when, and how children with arachnoid cysts should undergo surgery has been a matter of debate. In the present study the authors describe long-term clinical and neuroimaging results in children with intracranial arachnoid cysts, treated in accordance with the authors' policy of performing surgery in most of these cases. The study included 48 pediatric patients (age < 16 years of age) who underwent surgery for treatment of an arachnoid cyst at Haukeland University Hospital between January 1987 and September 2004. Forty-one patients underwent cyst fenestration to the basal cisterns and posterior fossa. Long-term results were assessed retrospectively on the basis of medical and neuroimaging records. Additional information was obtained by means of a check-box questionnaire completed by the patients and their parents. At their follow-up examinations, 82% of the patients had no or insignificant complaints, 14% reported no improvement, and 4% noted a worsening of symptoms. In 56% of the patients with appropriate imaging for analysis, the cyst was no longer visible on neuroimaging studies. In 23%, the postoperative fluid volume was reduced to less than 50% of the original cyst volume, and in another 19%, the volume was reduced but was larger than 50% of the original. The cyst was unchanged in only 2%. There was a significant association between a volume reduction greater than 50% and clinical improvement. Three patients (6%), all with temporal cysts, had minor complications that led to additional surgery in one patient. No complications caused permanent disability. Eight patients (17%) underwent additional surgery due to suspected or demonstrated treatment failure. Most children who underwent cyst fenestration via a craniotomy experienced a good long-term outcome with no severe complications.


MR-based attenuation correction for cardiac FDG PET on a hybrid PET/MRI scanner: comparison with standard CT attenuation correction.
The aim of this study was to evaluate the feasibility of attenuation correction (AC) for cardiac (18)F-labelled fluorodeoxyglucose (FDG) positron emission tomography (PET) using MR-based attenuation maps. We included 23 patients with no known cardiac history undergoing whole-body FDG PET/CT imaging for oncological indications on a PET/CT scanner using time-of-flight (TOF) and subsequent whole-body PET/MR imaging on an investigational hybrid PET/MRI scanner. Data sets from PET/MRI (with and without TOF) were reconstructed using MR AC and semi-quantitative segmental (20-segment model) myocardial tracer uptake (per cent of maximum) and compared to PET/CT which was reconstructed using CT AC and served as standard of reference. Excellent correlations were found for regional uptake values between PET/CT and PET/MRI with TOF (n = 460 segments in 23 patients; r = 0.913; p < 0.0001) with narrow Bland-Altman limits of agreement (-8.5 to +12.6 %). Correlation coefficients were slightly lower between PET/CT and PET/MRI without TOF (n = 460 segments in 23 patients; r = 0.851; p < 0.0001) with broader Bland-Altman limits of agreement (-12.5 to +15.0 %). PET/MRI with and without TOF showed minimal underestimation of tracer uptake (-2.08 and -1.29 %, respectively), compared to PET/CT. Relative myocardial FDG uptake obtained from MR-based attenuation corrected FDG PET is highly comparable to standard CT-based attenuation corrected FDG PET, suggesting interchangeability of both AC techniques.


Influences of spatial practices on pressure ulcer management in the context of spinal cord injury.
Nursing practice is significantly influenced by the type and use of space in which nursing is practised. While investigating current patterns of service delivery for the management of pressure ulcers from the perspective of people with spinal cord injuries and their families, the space in which care was delivered was identified as a central determinant of care. Qualitative methods were used to investigate consumer perspectives among patients residing in both metropolitan and rural communities who had been hospitalized for the management of pressure ulcers. Issues related to the spatial practices of the hospital are discussed, demonstrating a link between well-being and the creation of an appropriate caring milieu. It is concluded that service could be improved markedly if health-care professionals placed more consideration on the impact of space on their service delivery.


Further observations on Bulinus (Bulinus) truncatus rohlfsi (Clessin) in Ghana: Seasonal population fluctuations and biology.
Bulinus (B.) truncatus rohlfsi is an important snail host of Schistosoma haematobium in Ghana and probably elsewhere in West Africa. Study of this snail in natural habitats in Northern Ghana has shown that the pronounced population fluctuations can be broadly related to the alternating wet and dry seasons and to any marked changes in the aquatic vegetation. An increase in snail density and reproductive activity begins during the rainy season, reaching a peak in the dry season. The onset of the contraction phase in the snail population is often abrupt, although it may be preceded by intense oviposition; during this phase there are but a few widely scattered snails and little reproductive activity with a low level of survival, particularly of juvenile snails. The factors which favour the survival of young specimens are clearly critical in the evolution of the snail population.The findings are related to snail population studies carried out elsewhere in Africa, and to the application as well as limitations of molluscicides in bilharziasis control programmes.


Nephroblastoma in an ovotestis of a true hermaphrodite: a case report.
We describe a patient who presented with a painful mass in the left inguinoscrotal region, gynecomastia, perineal hypospadias with chordee and a bifid scrotum with a small gonad in the right hemiscrotum. At operation the left mass was found to be an ovotestis with hemorrhage in a corpus luteum cyst. A rudimentary uterus and fallopian tube were situated next to the ovotestis. The right gonad also was an ovotestis with a tiny focus of small cell malignancy that was suggestive of nephroblastoma.


Clinical comparison of two new minimally invasive techniques in the treatment of benign prostatic hyperplasia: Twister™ Diode Laser System vs. BiVap (Richard Wolf®) saline vaporization of the prostate.
The aim of this study was to evaluate complications and postoperative follow-up outcomes of the recently developing endoscopic techniques of BiVap (Richard Wolf®) and Twister™ system in patients with benign prostatic obstruction (BPO). Eighty patients treated with BiVap (Richard Wolf®) (N.=46) and Twister™ system (N.=34) were included in the study. Operation, hospitalization and catheter removal time were noted. Postoperative complications including urinary tract infection, transient hematuria, severe dysuria, and fever >38° C, urinary incontinence and urethral stricture were also noted. All patients were evaluated at the postoperative 1st, 3rd, 6th and 12th month and preoperative and postoperative values of IPSS score, QoL score, total PSA, IIEF 15, PVR, Qmax and Qave were compared. Statistical analyses were performed with SPSS version 18. A P-value<0.05 was considered significant. Mean age of the patients was 64.1 ± 7.1 years. Significant improvement was observed for IPSS, Qmax, Qave, PVR, and QoL score by the postoperative first month compared to the preoperative values in both groups. In group 1 maximum improvement in the IPSS, Qmax, Qave, QoL score and PVR were achieved at postoperative 3, 3, 12, 3 and 12th months, respectively. In group 2 maximum improvement in the IPSS, Qmax, Qave, QoL score and PVR were achieved at postoperative 6, 3, 6, 6 and 3rd months, respectively. There was no significant difference between the two groups in terms of IPSS, Qmax, Qave, QoL, PSA, PVR, IIEF (Total), IIEF-EF, IIEF-IS, IIEF-OF, IIEF-SD and IIEF-OS during the 1 year follow-up period. Total IIEF and subgroup scores improved to their preoperative levels by the postoperative 3rd month in both groups. Both BiVap (Richard Wolf®) and Twister™ systems are safe and highly effective minimal invasive techniques, which can be used in the surgical treatment of BPO.


Trans-osseous Biopsy CT Guided: Experience Report on 24 Patients.
The objective of this study is to assess the effectiveness of computed tomography-guided trans-osseous biopsies in deep-seated lesions and report encountered complications. A retrospective cohort study was performed which included twenty-four patients with pathologic medical history and lesions non-accessible by common approaches. Exclusion criteria include patients who could be biopsied without trans-osseous access, as for example procedures aided with hydro- or pneumo-dissection. The population studied included 13 females (54.2%) and the overall average age was 64.5 (IIQ 43-69). The procedures were carried out through the following bones: sternum (n = 6), vertebral (n = 5), iliac (n = 5), scapula (n = 3), rib (n = 2), sacral (n = 2), and pubis (n = 1). The efficiency for these procedures was 87.5%, while 8.33% of them were non-diagnostic and 4.17% were inconclusive due to vital risk during the procedure. Computed tomography-guided trans-osseous biopsy resulted in a safe and effective technique for those lesions blocked by vital structures or apparently directly inaccessible.


Pressure-Measuring Devices for Compression Therapy in Venous Leg Ulcers: A Comprehensive Review.
To investigate the evolution of pressure-measuring devices used in compression treatment for venous leg ulcers and assess the most practical and effective devices to determine optimal pressure in compression therapy. Relevant information was retrieved from databases including Google Scholar, PubMed, Wiley Online, and ScienceDirect without publication date restrictions. The keywords included venous leg ulcer, compression therapy, pressure measuring device, pressure sensor, and wireless system. Studies included in the review had to be published in English and discuss or compare pressure-measuring devices/sensors for compression therapy, the development of alternative sensors, and the applications of wireless technologies. Veterinary studies, conference proceedings, and unpublished articles were excluded. Applicable studies and articles were critically evaluated and synthesized. After abstract review, 39 studies were identified. During full-text review, study details were collected using a data extraction form and organized into tables. Device attributes, accuracy, price, and limitations were categorized and analyzed. Studies disagree on the effectiveness and user-friendliness of existing pressure-measuring devices. These devices often impact user comfort and convenience, which are crucial factors in the adoption and use of wearable devices. Potential solutions for pressure-measuring devices with promising technologies were proposed: four feasible alternative sensors are described that could improve comfort and facilitate prolonged use under bandages. Advanced communication technologies may provide more convenience for users and practitioners. Conventional pressure-measuring devices used in compression therapy are not designed for the user's comfort and convenience. The use of flexible and stretchy pressure sensors (e-skin) provides good biocompatibility, conformability, and comfort and when integrated with near-field communication technology could address the drawbacks of current pressure-measuring devices.


Retrospective serological investigation of bovine tuberculosis in two gemsbok (Oryx gazelle gazelle) and an onager (Equus hemionus onager).
In 1997 a 26-yr-old gemsbok (Oryx gazelle gazelle) died of bovine tuberculosis in a zoo. Three remaining gemsbok were administered the comparative tuberculin skin test repeatedly over a period of 5 mo. Two animals showed inconclusive results on the second test. All three gemsbok were euthanatized. Mycobacterium bovis was isolated from one of those with an inconclusive skin test result, whereas Mycobacterium fortuitum was detected in the other gemsbok. Eight years later, an onager (Equus hemionus onager) died of bovine tuberculosis. This animal had been kept in the same building as the gemsbok. Three herd mates were culled after administering the comparative tuberculin skin test. They were all nonreactors and produced no evidence of tuberculosis at postmortem examination. Retrospectively, using plasma samples collected from the gemsbok and onagers, three antibody tests, Elephant TB STAT-PAK, multiantigen print immunoassay (MAPIA), and dual-path platform (DPP) VetTB (Chembio Diagnostic Systems Inc., Medford, New York, 11763, USA), were used to assess their diagnostic value for these species. The M. bovis-infected gemsbok tested strongly positive by Elephant TB STAT-PAK at the time of euthanasia and 5 mo earlier when the skin test was negative. This animal was not antibody reactive in MAPIA and DPP VetTB. No M. bovis-specific antibody was detected in the other two gemsboks by any of the immunoassays. Among the onagers, Elephant TB STAT-PAK, MAPIA, and DPP VetTB revealed gradually increasing antibody response in the animal that died of bovine tuberculosis, but not in the three disease-free herd mates euthanatized. Seroconversion in the M. bovis-infected onager was first noticed 5 yr before death when the tuberculin skin test was negative.


Identifying regional cardiac abnormalities from myocardial strains using nontracking-based strain estimation and spatio-temporal tensor analysis.
Myocardial strain is a critical indicator of many cardiac diseases and dysfunctions. The goal of this paper is to extract and use the myocardial strain pattern from tagged magnetic resonance imaging (MRI) to identify and localize regional abnormal cardiac function in human subjects. In order to extract the myocardial strains from the tagged images, we developed a novel nontracking-based strain estimation method for tagged MRI. This method is based on the direct extraction of tag deformation, and therefore avoids some limitations of conventional displacement or tracking-based strain estimators. Based on the extracted spatio-temporal strain patterns, we have also developed a novel tensor-based classification framework that better conserves the spatio-temporal structure of the myocardial strain pattern than conventional vector-based classification algorithms. In addition, the tensor-based projection function keeps more of the information of the original feature space, so that abnormal tensors in the subspace can be back-projected to reveal the regional cardiac abnormality in a more physically meaningful way. We have tested our novel methods on 41 human image sequences, and achieved a classification rate of 87.80%. The regional abnormalities recovered from our algorithm agree well with the patient's pathology and clinical image interpretation, and provide a promising avenue for regional cardiac function analysis.


New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.
The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.


5-HT3-receptor antagonists: a review of pharmacology and clinical efficacy.
To review the role of serotonin in chemotherapy-induced emesis and the mechanism by which 5-hydroxytryptamine3 (5-HT3)-receptor antagonists block the action of serotonin; to review the pharmacology and clinical efficacy of the 5-HT3-receptor antagonists in controlling nausea and vomiting induced by highly emetogenic chemotherapy regimens, including a comparison of agents in this class. Journal articles and proceedings of clinical oncology conferences. Prior to the availability of 5-HT3-receptor antagonists, metoclopramide was the therapy of choice for prevention of cisplatin-associated emesis. Several randomized, double-blind, comparative trials have established that a 5-HT3-receptor antagonist used alone is more effective than metoclopramide and equal to or better than the combination of metoclopramide and dexamethasone. 5-HT3-receptor antagonists contribute significantly to the current armamentarium of antiemetic agents. Clinical trials consistently have demonstrated a benefit with these agents that exceeds the previously established antiemetic standards. 5-HT3-receptor antagonists have had a profound impact on the clinical management of acute chemotherapy-induced nausea and vomiting. Based on their unique mechanism of action and low toxicity profile, the 5-HT3-receptor antagonists offer a relatively new approach to controlling nausea and vomiting associated with highly emetogenic chemotherapy.


[Intestinal polyp of the umbilical cord].
The morphology, pathogenesis, complications and differential diagnosis of an intestinal polyp of the umbilical cord are presented. The polyp were detected postnatal on the umbilical cord in an healthy male newborn. The presents of intestinal tissue upon the umbilical cord ist possible about the persistence from remnants of the ductus omphalomesentericus with prolapse and differentiation of the intestinal cells. The ductus omphalomesentericus is a tubular structure, a communication between the developing embryonic gut and the yolk sac, forming during the early embryonic life. Obliteration of the omphalomesenteric duct is usually complete by the 10(th) week of gestation. Various portions of the duct may persist, however, giving rise to polyps, fistulas or cysts of the umbilical cord with potentially dangerous clinical consequences. Other tumors of the umbilical cord are myxoma, angioma and teratoma are differential diagnosis.


Contribution of Th17 cells to tissue injury in hypertension.
Hypertension has been demonstrated to be a chief contributor to morbidity and mortality throughout the world. Although the cause of hypertension is multifactorial, emerging evidence, obtained in experimental studies, as well as observational studies in humans, points to the role of inflammation and immunity. Many aspects of immune function have now been implicated in hypertension and end-organ injury; this review will focus upon the recently-described role of Th17 cells in this pathophysiological response. Studies in animal models and human genetic studies point to a role in the adaptive immune system as playing a contributory role in hypertension and renal tissue damage. Th17 cells, which produce the cytokine IL17, are strongly pro-inflammatory cells, which may contribute to tissue damage if expressed in chronic disease conditions. The activity of these cells may be enhanced by physiological factors associated with hypertension such as dietary salt or Ang II. This activity may culminate in the increased sodium retaining activity and exacerbation of inflammation and renal fibrosis via multiple cellular mechanisms. Th17 cells are a distinct component of the adaptive immune system that may strongly enhance pathways leading to increased sodium reabsorption, elevated vascular tone and end-organ damage. Moreover, this pathway may lend itself towards specific targeting for treatment of kidney disease and hypertension.


Exercise and coronary heart disease risk markers in South Asian and European men.
South Asians have a higher-than-average risk of CHD. The reasons for this are unclear, but physical inactivity and/or poor responsiveness to exercise may play a role. This study compared the effect of prior exercise on postprandial triacylglycerol (TAG), glucose, insulin, interleukin-6, and soluble intercellular adhesion molecule-1 concentrations in South Asian and European men. Ten healthy South Asian men (i.e., nine Indian men and one Pakistani man) and 10 healthy European men age 20 to 28 yr completed two 2-d trials (exercise and control) in a randomized crossover design. On the afternoon of day 1 of the exercise trial, participants ran on a treadmill for 60 min at approximately 70% of maximal oxygen uptake. Participants rested on day 1 of the control trial. On day 2 of both trials, participants rested and consumed high-fat (57% of energy content) test meals for breakfast (0 h) and lunch (4 h). Fourteen venous blood samples were collected from a cannula between 0 and 9 h for metabolic measurements. Three-way ANOVA identified higher (P < 0.05) postprandial TAG and insulin concentrations in South Asian versus European men. Exercise lowered postprandial TAG and interleukin-6 and elevated soluble intercellular adhesion molecule-1 concentrations. An interaction effect indicated a greater decrease (22% vs 10%) in TAG area under the concentration versus time curve after exercise in South Asian than in European men. Postprandial TAG and insulin responses to high-fat meals were elevated in these South Asian men, but acute exercise was equally, if not more, effective for reducing postprandial lipemia in South Asian than in European men.


Concentration and seasonal variations of purine bases, nucleotides and nucleotide-sugars in liver of Bufo arenarum. Comparison with early embryogenesis.
A comparative study of the bases, nucleotides and nucleotide-sugars was performed in liver of Bufo arenarum. Samples were obtained at different seasons of the year, according to the periods of active (December-March) and passive metabolism (April-July). It was found that guanine and hypoxanthine increase significantly in spring. A remarkable decrease in the levels of the nucleosides triphosphates adenosine 5'-triphosphate (ATP) and guanosine 5'-triphosphate (GTP) was found in spring; correlatively, an increase in the levels of adenosine 5'-monophosphate (AMP) and guanosine 5'-monophosphate (GMP) and adenosine 5'-pyrophosphate (ADP) and guanosine 5'-pyrophosphate (GDP was observed. A notable increase in the amounts of uridine 5'-diphosphate- D - glucose (UDP-glucose) was detected at the end of the period of low metabolism, which is coincident wtih a decrease in the level of glycogen, observed by other authors.


Calling long distance: Cell cycle-dependent Ca2+ flows connect stem cells across regeneration tissues.
How adult stem cells signal in vivo over time to coordinate their fate and behavior across self-renewing tissues remains a challenging question. In this issue, Moore et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202302095) combine high-resolution live imaging in mice with machine learning tools to reveal temporally regulated tissue-scale patterns of Ca2+ signaling orchestrated by cycling basal stem cells of the skin epidermis.


Solid Dispersion Matrix Tablet Comprising Indomethacin-PEG-HPMC Fabricated with Fusion and Mold Technique.
The purpose of this study is to fabricate the polyethylene glycol matrix tablet by mold technique. Indomethacin and hydroxypropylmethylcellulose were used as model drug and polymer, respectively, in PEG matrix system. The physical and drug release characteristics of developed matrix tablet were studied. This inert carrier system comprising 7:3 polyethylene glycol 4000: polyethylene glycol 400 could effectively enhance the solubility of indomethacin and an addition of hydroxypropylmethylcellulose could sustain the drug release. Scanning electron microscope photomicrograph indicated the drug diffusion outward through the porous network of this developed matrix tablet into the dissolution fluid. Least square fitting the experimental dissolution data to the mathematical expressions (power law, first-order, Higuchi's and zero-order) indicated the drug release kinetics primarily as Fickian diffusion. Both the enhancement of drug dissolution and the prolongation of the drug release could be achieved for aqueous insoluble drug such as, indomethacin, by using polyethylene glycol-hydroxypropylmethylcellulose matrix system prepared with melting and mold technique.


High Temperature Deformation Mechanisms in a DLD Nickel Superalloy.
The realisation of employing Additive Layer Manufacturing (ALM) technologies to produce components in the aerospace industry is significantly increasing. This can be attributed to their ability to offer the near-net shape fabrication of fully dense components with a high potential for geometrical optimisation, all of which contribute to subsequent reductions in material wastage and component weight. However, the influence of this manufacturing route on the properties of aerospace alloys must first be fully understood before being actively applied in-service. Specimens from the nickel superalloy C263 have been manufactured using Powder Bed Direct Laser Deposition (PB-DLD), each with unique post-processing conditions. These variables include two build orientations, vertical and horizontal, and two different heat treatments. The effects of build orientation and post-process heat treatments on the materials' mechanical properties have been assessed with the Small Punch Tensile (SPT) test technique, a practical test method given the limited availability of PB-DLD consolidated material. SPT testing was also conducted on a cast C263 variant to compare with PB-DLD derivatives. At both room and elevated temperature conditions, differences in mechanical performances arose between each material variant. This was found to be instigated by microstructural variations exposed through microscopic and Energy Dispersive X-ray Spectroscopy (EDS) analysis. SPT results were also compared with available uniaxial tensile data in terms of SPT peak and yield load against uniaxial ultimate tensile and yield strength.


Multiple residues contribute to the inability of murine CCR-5 to function as a coreceptor for macrophage-tropic human immunodeficiency virus type 1 isolates.
Infection of CD4-positive cells by human immunodeficiency virus type 1 (HIV-1) requires functional interaction of the viral envelope protein with a coreceptor belonging to the chemokine receptor family of seven-membrane-spanning receptors. For the majority of macrophage-tropic HIV-1 isolates, the physiologically relevant coreceptor is the human CCR-5 (hCCR-5) receptor. Although the murine homolog of CCR-5 (mCCR-5) is unable to mediate HIV-1 infection, chimeric hCCR-5/mCCR-5 molecules containing single extracellular domains derived from hCCR-5 are effective coreceptors for certain macrophage-tropic HIV-1 isolates. Here, we have sought to identify residues in hCCR-5 critical for HIV-1 infection by substitution of mCCR-5-derived residues into the context of functional chimeric hCCR-5/mCCR-5 receptor molecules. Using this strategy, we demonstrate that residues 7, 13, and 15 in the first extracellular domain and residue 180 in the third extracellular domain of CCR-5 are important for HIV-1 envelope-mediated membrane fusion. Of interest, certain substitutions, for example, at residues 184 and 185 in the third extracellular domain, have no phenotype when introduced individually but strongly inhibit hCCR-5 coreceptor function when present together. We hypothesize that these changes, which do not preclude chemokine receptor function, may inhibit a conformational transition in hCCR-5 that contributes to HIV-1 infection. Finally, we report that substitution of glycine for valine at residue 5 in CCR-5 can significantly enhance the level of envelope-dependent cell fusion by expressing cells. The diversity of the mutant phenotypes observed in this mutational analysis, combined with their wide distribution across the extracellular regions of CCR-5, emphasizes the complexity of the interaction between HIV-1 envelope and coreceptor.


Femoropopliteal versus femorotibial bypass grafting for lower extremity revascularization.
Thirty-nine femoropopliteal revascularization procedures were compared with 35 femorotibial revascularization and one brachioradial revascularization over a follow-up period of six months to six years. Preoperative study, operative technique, results and complications are described. Living patency is compared with closure rates. The living patency rates are 49 per cent and 51 per bent for the femoropopliteal and femorotibial group. The complication rate was higher in the femorotibial group by four times (37% compared to 10%). Four reoperations were done because of progression of the patient's disease in the femorotibial group. Femorotibial revascularization is at least as effective as femoropopliteal revascularization, and produces a comparable live patency record, but with a higher incidence of postoperative complications.


Population genetics and geographic variation of alcohol dehydrogenase (Adh) paralogs and glucose-6-phosphate dehydrogenase (G6pd) in Drosophila mojavensis.
Populations of Drosophila mojavensis from the deserts of the Baja California peninsula and mainland Mexico utilize different cactus hosts with different alcohol contents. The enzyme alcohol dehydrogenase (ADH) has been proposed to play an important role in the adaptation of Drosophila species to their environment. This study investigates the role of ADH in the adaptation of the cactophilic D. mojavensis to its cactus host. In D. mojavensis and its sibling species, D. arizonae, the Adh gene has duplicated, giving rise to a larval/ovarian form (Adh-1) and an adult form (Adh-2). Studies of sequence variation presented here indicate that the Adh paralogs have followed different evolutionary trajectories. Adh-1 exhibits an excess of fixed amino acid replacements, suggesting adaptive evolution, which could have been a result of several host shifts that occurred during the divergence of D. mojavensis. A 17-bp intron haplotype polymorphism segregates in Adh-2 and has markedly different frequencies in the Baja and mainland populations. The presence of the intron polymorphism suggests possible selection for the maintenance of pre-mRNA structure. Finally, this study supports the proposed Baja California origination of D. mojavensis and subsequent colonization of the mainland accompanied by a host shift.


Properties of an R factor from Pseudomonas aeruginosa.
An R factor from Pseudomonas aeruginosa, which confers resistance to penicillins, kanamycin, and tetracycline, was studied in Escherichia coli K-12. The R factor could coexist with F-like or I-like plasmids and therefore constituted a novel compatibility group. The R factor was transferable from E. coli to bacterial genera outside the Enterobacteriaceae (Pseudomonas and members of the Rhizobiaceae) to which transfer of F-like and I-like plasmids could not be demonstrated.


Deregulation of microtubule organization and RNA metabolism in Arx models for lissencephaly and developmental epileptic encephalopathy.
X-linked lissencephaly with abnormal genitalia (XLAG) and developmental epileptic encephalopathy-1 (DEE1) are caused by mutations in the Aristaless-related homeobox (ARX) gene, which encodes a transcription factor responsible for brain development. It has been unknown whether the phenotypically diverse XLAG and DEE1 phenotypes may converge on shared pathways. To address this question, a label-free quantitative proteomic approach was applied to the neonatal brain of Arx knockout (ArxKO/Y) and knock-in polyalanine (Arx(GCG)7/Y) mice that are respectively models for XLAG and DEE1. Gene ontology and protein-protein interaction analysis revealed that cytoskeleton, protein synthesis and splicing control are deregulated in an allelic-dependent manner. Decreased α-tubulin content was observed both in Arx mice and Arx/alr-1(KO) Caenorhabditis elegans ,and a disorganized neurite network in murine primary neurons was consistent with an allelic-dependent secondary tubulinopathy. As distinct features of Arx(GCG)7/Y mice, we detected eIF4A2 overexpression and translational suppression in cortex and primary neurons. Allelic-dependent differences were also established in alternative splicing (AS) regulated by PUF60 and SAM68. Abnormal AS repertoires in Neurexin-1, a gene encoding multiple pre-synaptic organizers implicated in synaptic remodelling, were detected in Arx/alr-1(KO) animals and in Arx(GCG)7/Y epileptogenic brain areas and depolarized cortical neurons. Consistent with a conserved role of ARX in modulating AS, we propose that the allelic-dependent secondary synaptopathy results from an aberrant Neurexin-1 repertoire. Overall, our data reveal alterations mirroring the overlapping and variant effects caused by null and polyalanine expanded mutations in ARX. The identification of these effects can aid in the design of pathway-guided therapy for ARX endophenotypes and NDDs with overlapping comorbidities.


Contrast gain control in the cat's visual system.
We have examined the idea that the adaptation of cortical neurons to local contrast levels in a visual stimulus is functionally advantageous. Specifically, cortical cells may have large differential contrast sensitivity as a result of adjustments that center a limited response range around a mean level of contrast. To evaluate this notion, we measured contrast-response functions of cells in striate cortex while systematically adapting them to different contrast levels of stimulus gratings. For the majority of cortical neurons tested, the results of this basic experiment show that contrast-response functions shift laterally along a log-contrast axis so that response functions match mean contrast levels in the stimulus. This implies a contrast-dependent change in the gain of the cell's contrast-response relationship. We define this process as contrast gain control. The degree to which this contrast adjustment occurs varies considerably from cell to cell. There are no obvious differences regarding cell type (simple vs. complex) or laminar distribution. Contrast gain control is almost certainly a cortical function, since lateral geniculate cells and fibers exhibit only minimal effects. Tests presented in the accompanying paper (37) provide additional evidence on the cortical origin of the process. In another series of experiments, the effect of contrast adaptation on physiological estimates of contrast sensitivity was evaluated. Sustained adaptation to contrast levels as low as 3% was capable of nearly doubling the thresholds of most of the cells tested. Adaptation may therefore be an important factor in determinations of the contrast sensitivity of cortical neurons. We tested the spatial extent of the mechanisms responsible for these gain-control effects by attempting to adapt cells using both a large grating and a grating patch limited to that portion of a cell's receptive field from which excitatory discharges could be elicited directly (the central discharge region). Adaptation was found to be an exclusive property of the central region. This held even in the case of hypercomplex cells, which received strong influences from surrounding regions of the visual field. Finally, we measured the time course of contrast adaptation. We found the process to be rather slow, with a mean time constant of approximately 6 s. Once again, there was considerable variability in this value from cell to cell.


Psilocybin in Finnish Psilocybe semilanceata.
The use of a hallucinogenic mushroom, PSILOCYBE SEMILANCEATA, has been occasionally reported in Finland, where the species is widely distributed. We have determined, by HPLC, the content of psilocybin and psilocin in P. SEMILANCEATA samples collected from different parts of Finland; the psilocybin content was found to be high (0.62-2.37%, mean 1.42% of dry weight), some samples also contained low concentrations (0.01-0.02% dry weight) of psilocin.


Gray matter volume in schizophrenia and bipolar disorder with psychotic features.
There is growing evidence that schizophrenia (SZ) and bipolar disorder (BD) overlap significantly in risk factors, neurobiological features, clinical presentations, and outcomes. SZ is characterized by well documented gray matter (GM) abnormalities in multiple frontal, temporal and subcortical structures. Recent voxel-based morphometry (VBM) studies and meta-analyses in BD also report GM reductions in overlapping, albeit less widespread, brain regions. Psychosis, a hallmark of SZ, is also experienced by a significant proportion of BD patients and there is evidence that psychotic BD may be characterized by specific clinical and pathophysiological features. However, there are few studies comparing GM between SZ and psychotic BD. In this study we compared GM volumes in a sample of 58 SZ patients, 28 BD patients experiencing psychotic symptoms and 43 healthy controls using whole-brain voxel-based morphometry. SZ patients had GM reductions in multiple frontal and temporal regions compared to healthy controls and in the subgenual cortex compared to psychotic BD patients. GM volume was increased in the right posterior cerebellum in SZ patients compared to controls. However, psychotic BD patients did not show significant GM deficits compared to healthy controls or SZ patients. We conclude that GM abnormality as measured by VBM analysis is less pronounced in psychotic BD compared to SZ. This may be due to disease-specific factors or medications used more commonly in BD.


Response of 1,2-dichloroethane-adapted microbial communities to ex-situ biostimulation of polluted groundwater.
The microbial community of a groundwater system contaminated by 1,2-dichloroethane (1,2-DCA), a toxic and persistent chlorinated hydrocarbon, has been investigated for its response to biostimulation finalized to 1,2-DCA removal by reductive dehalogenation. The microbial population profile of samples from different wells in the aquifer and from microcosms enriched in the laboratory with different organic electron donors was analyzed by ARISA (Amplified Ribosomal Intergenic Spacer Analysis) and DGGE (Denaturing Gradient Gel Electrophoresis) of 16S rRNA genes. 1,2-DCA was completely removed with release of ethene from most of the microcosms supplemented with lactate, acetate plus formate, while cheese whey supported 1,2-DCA dehalogenation only after a lag period. Microbial species richness deduced from ARISA profiles of the microbial community before and after electron donor amendments indicated that the response of the community to biostimulation was heterogeneous and depended on the well from which groundwater was sampled. Sequencing of 16S rRNA genes separated by DGGE indicated the presence of bacteria previously associated with soils and groundwater polluted by halogenated hydrocarbons or present in consortia active in the removal of these compounds. A PCR assay specific for Desulfitobacterium sp. showed the enrichment of this genus in some of the microcosms. The dehalogenation potential of the microbial community was confirmed by the amplification of dehalogenase-related sequences from the most active microcosms. Cloning and sequencing of PCR products indicated the presence in the metagenome of the bacterial community of a new dehalogenase potentially involved in 1,2-DCA reductive dechlorination.


Using community-based participatory research methods to reach women with health messages: results from the North Carolina BEAUTY and Health Pilot Project.
This pilot study used a community-based participatory research approach to recruit and train five licensed cosmetologists from two beauty salons to deliver health promotion messages to their customers. Stylists attended a 4-hr workshop to develop skills for delivering targeted health messages. Educational displays in the salons reinforced these messages. Qualitative and quantitative methods assessed satisfaction, readiness to change, and self-reported health behavior changes in customers immediately postintervention and at 12 months. Trained stylists reported they would continue delivering health messages after the 7-week pilot was completed; 81% of customers read the educational displays, and 86% of customers talked with their cosmetologist about the Bringing Education and Understanding to You Project. At 12 months, 55% of customers reported making changes in their health because of the conversations they had with their cosmetologist. Customers who spoke more often with their cosmetologists about health also reported a higher percentage of self-reported behavior changes. It appears that trained licensed cosmetologists are effective in promoting health messages to their customers.


Unresolved or Contradictory Issues About Management of Patients With Patent Foramen Ovale and Previous Cryptogenic Stroke: Additional Randomized Controlled Trials Are Eagerly Awaited.
Stating a well-codified and widely accepted therapeutic conduct for patients with patent foramen ovale (PFO) and previous cryptogenic stroke is made difficult and somewhat controversial by several issues remained unresolved so far. In this short review, some aspects of the possible role played by the PFO in the pathogenesis of cryptogenic stroke are succinctly analyzed. First, some aspects of cardiovascular anatomy of the human fetus and the adult are outlined. Subsequently, the three randomized controlled trials (RCTs) that have been accomplished so far to compare the implant of a transeptal occluding device with a simple medical therapy in patients with PFO and history of cryptogenic stroke are briefly examined. These RCTs, when assessed using the "intention to treat" method, do not show a greater protective effect of therapy with transeptal device as regards the recurrences of stroke. Afterwards, there is a brief presentation of the findings of several meta-analyses that have been derived from the three above mentioned RCTs, whose results are strikingly discordant with each other. In fact, some of them come to the conclusion that the transcatheter closure of PFO does not offer significant advantages compared to antithrombotic therapy for the secondary prevention of cryptogenic stroke, while others based on subgroup analyses argue that the transcatheter closure of PFO with Amplatzer device, differently from the one performed using the STARFlex device, would be associated with significantly lower incidence of cerebrovascular events compared with medical therapy alone. Finally, the authors argue the need to adhere to the current scientific guidelines. They substantially deny an alleged superior efficacy of transcatheter PFO occlusion compared to medical therapy with antithrombotic agents (anticoagulants or antiplatelet agents), except for selected cases of patients with documented PFO and concomitant clinical-instrumental picture of deep venous thrombosis.


Trion Emission Dominates the Low-Temperature Photoluminescence of CdSe Nanoplatelets.
Colloidal nanoplatelets (NPLs) are atomically flat, quasi-two-dimensional particles of a semiconductor. Despite intense interest in their optical properties, several observations concerning the emission of CdSe NPLs remain puzzling. While their ensemble photoluminescence spectrum consists of a single narrow peak at room temperature, two distinct emission features appear at temperatures below ∼160 K. Several competing explanations for the origin of this two-color emission have been proposed. Here, we present temperature- and time-dependent experiments demonstrating that the two emission colors are due to two subpopulations of uncharged and charged NPLs. We study dilute films of isolated NPLs, thus excluding any explanation relying on collective effects due to NPL stacking. Temperature-dependent measurements explain that trion emission from charged NPLs is bright at cryogenic temperatures, while temperature activation of nonradiative Auger recombination quenches the trion emission above 160 K. Our findings clarify many of the questions surrounding the photoluminescence of CdSe NPLs.


Duration and pattern of asymptomatic rotavirus shedding by hospitalized children.
Fecal shedding of rotaviruses by infants and children without gastrointestinal symptoms has recently been recognized, but little is known about the duration or frequency of virus shedding in such patients. We therefore evaluated rotavirus shedding by 16 infants and children during the course of their prolonged hospitalizations. Repeated fecal specimens were obtained from these patients and examined for the presence of rotavirus by means of immunoassay, electron microscopy and polyacrylamide gel electrophoresis. Asymptomatic rotavirus shedding was observed in each of the 16 patients, and more than 1 episode of virus excretion was detected in 15 of these. Electropherotype analysis indicated that some of these episodes were probably the result of reinfection with different strains of rotavirus. Asymptomatic shedding may be important in transmission of rotaviruses. Its role should be taken into consideration in future investigations of the epidemiology and control of this nosocomial pathogen.


The efficacy and safety of chemotherapy with or without anti-PD-1 for the first-line treatment of advanced urothelial carcinoma.
To compare the efficacy and safety of first-line anti-PD-1 combined with chemotherapy versus chemotherapy alone in patients with advanced urothelial carcinoma (UC). Patients with advanced UC who received first-line treatment of chemotherapy (n = 51, gemcitabine/paclitaxel [albumin-bound] combined with platinum) or immunochemotherapy (n = 50, PD-1 inhibitors plus chemotherapy) were enrolled. The efficacy and safety were analyzed between the two groups. This study included data from 101 patients, including 51 patients in the chemotherapy group and 50 patients in the immunochemotherapy group. The median progression-free survival of the immunochemotherapy group was significantly longer than that of the chemotherapy group (11.5 vs. 7.17 m, HR = 0.56, p = 0.009). The two groups' overall survival showed no significant difference (20.3 vs. 17.8 m, p = 0.204). The objective response rates and the disease control rates of the two groups were 38.0% versus 49.0% (p = 0.26) and 88.0% versus 80.4% (p = 0.29). The incidence of adverse reactions (AEs) in the immunochemotherapy group and chemotherapy group were 90.0% and 84.3% (p = 0.394), respectively, and the incidence of Grade III-IV AEs were 32.0% and 35.3% (p = 0.726), respectively. In the first-line treatment of patients with advanced UC, anti-PD-1 therapy combined with chemotherapy might have better efficacy than chemotherapy alone, and AEs are similar between the two groups.