Liquidity effects on oil volatility forecasting: From fintech perspective.
Fin-tech is an emerging field, inspiring revolutionary innovations in the financial field. It may initiate the evolutionary episode of the financial research, where volatility forecasting is a crucial topic in finance. For forecasting volatility, GARCH model is a prevailing model, however, further improvement of the GARCH model is still challenging. In this paper, we demonstrate how Fintech can play a part in volatility forecasting by employing a metaheuristic procedure called Genetic Programming. On the basis, we are able to develop a new volatility forecasting model, which can beat GARCH family models (including GARCH, IGARCH and TGARCH models) in a significant way. Since genetic programming is an evolutionary algorithm based on the principles of natural selection, this innovative work will be a breakthrough point in the financial area. The innovation of this paper demonstrates how GP technology can be applied in the financial field, attempting to explore the volatility forecasting area from the combination of new technology and finance, known as fintech. More importantly, when the formula of volatility forecasting is unknown as we introduce a new factor, namely, the liquidity factor, we unveil that how GP method can be helpful in determining the specific volatility forecasting model format. We thereby exhibit the liquidity effects on volatility forecasting filed from the fintech perspective.


Multiparametric MR Index for the Diagnosis of Non-Alcoholic Steatohepatitis in Patients with Non-Alcoholic Fatty Liver Disease.
Non-alcoholic steatohepatitis (NASH) is a complex disease consisting of various components including steatosis, lobular inflammation, and ballooning degeneration, with or without fibrosis. Therefore, it is difficult to diagnose NASH with only one imaging modality. This study was aimed to evaluate the feasibility of magnetic resonance imaging (MRI) for predicting NASH and to develop a non-invasive multiparametric MR index for the detection of NASH in non-alcoholic fatty liver disease (NAFLD) patients. This prospective study included 47 NAFLD patients who were scheduled to undergo or underwent ultrasound-guided liver biopsy within 2 months. Biopsy specimens were graded as NASH or non-NASH. All patients underwent non-enhanced MRI including MR spectroscopy (MRS), MR elastography (MRE), and T1 mapping. Diagnostic performances of MRS, MRE, and T1 mapping for grading steatosis, activity, and fibrosis were evaluated. A multiparametric MR index combining fat fraction (FF), liver stiffness (LS) value, and T1 relaxation time was developed using linear regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of the newly devised MR index. Twenty NASH patients and 27 non-NASH patients were included. Using MRS, MRE, and T1 mapping, the mean areas under the curve (AUCs) for grading steatosis, fibrosis, and activity were 0.870, 0.951, and 0.664, respectively. The multiparametric MR index was determined as 0.037 × FF (%) + 1.4 × LS value (kPa) + 0.004 × T1 relaxation time (msec) -3.819. ROC curve analysis of the MR index revealed an AUC of 0.883. The cut-off value of 6 had a sensitivity of 80.0% and specificity of 85.2%. The multiparametric MR index combining FF, LS value, and T1 relaxation time showed high diagnostic performance for detecting NASH in NAFLD patients.


Silver Nanoparticles for Waste Water Management.
Rapidly increasing industrialisation has human needs, but the consequences have added to the environmental harm. The pollution caused by several industries, including the dye industries, generates a large volume of wastewater containing dyes and hazardous chemicals that drains industrial effluents. The growing demand for readily available water, as well as the problem of polluted organic waste in reservoirs and streams, is a critical challenge for proper and sustainable development. Remediation has resulted in the need for an appropriate alternative to clear up the implications. Nanotechnology is an efficient and effective path to improve wastewater treatment/remediation. The effective surface properties and chemical activity of nanoparticles give them a better chance to remove or degrade the dye material from wastewater treatment. AgNPs (silver nanoparticles) are an efficient nanoparticle for the treatment of dye effluent that have been explored in many studies. The antimicrobial activity of AgNPs against several pathogens is well-recognised in the health and agriculture sectors. This review article summarises the applications of nanosilver-based particles in the dye removal/degradation process, effective water management strategies, and the field of agriculture.


Transcriptional Read-Through Induction Treatment Trial in Intestinal Failure Induced by an EpCAM Nonsense Mutation.
Congenital tufting enteropathy (CTE) is a rare autosomal recessive diarrheal disorder where epithelial tufts can be present from the duodenum to the large intestine. CTE has been linked to mutations in the epithelial cell adhesion molecule gene (EpCAM) Sivagnanam et al. (2008). We recently reported the first case with a nonsense mutation in EpCAM Sivagnanam et al. (2010). Here, we explored the clinical and molecular effects of enterally administered gentamicin in this CTE patient. Altogether, our findings indicate that the therapy employed was insufficient to produce notable read-through induction of the EpCAM premature termination codon. This report highlights the utility of genetic testing not only in respect of diagnostics, prognostics, and family planning, but potential mutation-specific therapeutic considerations as well.


Keepsakes at the End of Life.
Keepsakes are a relatively unexplored form of bereavement support that is frequently provided as part of the 3 Wishes Project (3WP). The 3WP is a palliative care intervention in which individualized wishes are implemented in the adult intensive care unit for dying patients and their families. We aimed to characterize and enumerate the keepsakes that were created as part of the 3WP and to understand their value from the perspective of bereaved family members. We performed a secondary analysis of family interviews during a multicenter study on the 3WP and characterized all wishes that involved keepsakes. Sixty interviews with family members regarding the 3WP were reanalyzed using qualitative analysis to identify substantive themes related to keepsakes. Of 730 patients, 345 (47%) received keepsakes as part of their participation in 3WP. Most keepsakes were either tangible items that served as reminders of the patient's presence (thumbprints and locks of hair) or technology-assisted items (photographs and word clouds). The median cost per keepsake wish was $8.50 (interquartile range $2.00-$25.00). Qualitative analysis revealed two major themes: keepsakes are tangible items that are highly valued by family members; and the creation of the keepsake with clinical staff is valued and viewed as a gesture of compassion. Keepsakes are common wishes that clinicians in the intensive care unit are able to provide and sometimes cocreate with families when patients are dying. Both the offering to create the keepsake and receipt of the final product are perceived by family members as helpful.


Adrenal neutral cholesteryl ester hydrolase: identification, subcellular distribution, and sex differences.
Adrenals express a high level of neutral cholesteryl ester hydrolase (CEH) activity, and male rats have greater activity than females; however, the identity of the enzyme(s) responsible for this activity and the basis for the sex differences are unknown. Using mice in which hormone-sensitive lipase (HSL) was inactivated by homologous recombination (HSL -/-), neutral CEH activity was reduced more than 98% compared with controls. Female HSL -/- mice showed a reduction in stimulated corticosterone values. Mechanical separation of rat adrenals revealed less HSL in the outer than the inner cortex. Examination of subfractions of rat adrenals showed that immunoreactive HSL was prominently expressed in microsomes, with lesser amounts in the cytosol and little to no HSL in mitochondrial and nuclear fractions or the lipid droplet. Four- to 10-fold more neutral CEH activity was in the microsomal fraction than any other fraction. No sex differences in the expression or subcellular distribution of HSL protein were found; however, neutral CEH activity was lower in the microsomal fraction of females, and female adrenals contained more cholesteryl esters. Thus, HSL appears to be responsible for most, if not all, of adrenal neutral CEH activity, is prominently expressed in microsomes, and its activity is influenced by sex.


Effects of Cable Sway, Electrode Surface Area, and Electrode Mass on Electroencephalography Signal Quality during Motion.
More neuroscience researchers are using scalp electroencephalography (EEG) to measure electrocortical dynamics during human locomotion and other types of movement. Motion artifacts corrupt the EEG and mask underlying neural signals of interest. The cause of motion artifacts in EEG is often attributed to electrode motion relative to the skin, but few studies have examined EEG signals under head motion. In the current study, we tested how motion artifacts are affected by the overall mass and surface area of commercially available electrodes, as well as how cable sway contributes to motion artifacts. To provide a ground-truth signal, we used a gelatin head phantom with embedded antennas broadcasting electrical signals, and recorded EEG with a commercially available electrode system. A robotic platform moved the phantom head through sinusoidal displacements at different frequencies (0-2 Hz). Results showed that a larger electrode surface area can have a small but significant effect on improving EEG signal quality during motion and that cable sway is a major contributor to motion artifacts. These results have implications in the development of future hardware for mobile brain imaging with EEG.


Chinese midlife women's perceptions and attitudes about menopause.
The purpose of this research was to discover and describe the meaning of and attitudes toward menopause in midlife Chinese women in Taiwan. How these women learned about menopause was also explored. Questionnaires were distributed to a convenience sample of 208 Chinese women aged 35 to 55 living in Taiwan; 168 responded. Qualitative data were analyzed using content analysis. Percentage and chi-square were used to examine the quantitative data. The findings revealed that 154 (91.7%) women perceived menopause as a natural phenomenon. No statistically significant differences in attitude toward menopause were found between women grouped by different menopausal levels, by use or not use of hormones, or by religious preference. Some women described menopause as, "no longer young, getting old." Others described menopause as, "wisdom and maturation," "a symbol of achievement," and "a time to start enjoying life." Sixty-eight (40.5%) of the sample indicated they obtained menopausal information from friends and printed materials such as books, newspapers, and magazines. Study findings indicate that Chinese women in Taiwan perceive menopause in a positive and holistic way. Culturally sensitized Western practitioners can utilize this study's findings to more appropriately individualize care for Chinese midlife women.


Increased production of fatty acids and triglycerides in Aspergillus oryzae by enhancing expressions of fatty acid synthesis-related genes.
Microbial production of fats and oils is being developed as a means of converting biomass to biofuels. Here we investigate enhancing expression of enzymes involved in the production of fatty acids and triglycerides as a means to increase production of these compounds in Aspergillus oryzae. Examination of the A. oryzae genome demonstrates that it contains two fatty acid synthases and several other genes that are predicted to be part of this biosynthetic pathway. We enhanced the expression of fatty acid synthesis-related genes by replacing their promoters with the promoter from the constitutively highly expressed gene tef1. We demonstrate that by simply increasing the expression of the fatty acid synthase genes we successfully increased the production of fatty acids and triglycerides by more than two-fold. Enhancement of expression of the fatty acid pathway genes ATP-citrate lyase and palmitoyl-ACP thioesterase increased productivity to a lesser extent. Increasing expression of acetyl-CoA carboxylase caused no detectable change in fatty acid levels. Increases in message level for each gene were monitored using quantitative real-time reverse transcription polymerase chain reaction. Our data demonstrate that a simple increase in the abundance of fatty acid synthase genes can increase the detectable amount of fatty acids.


A systematic review of the evidence for the treatment of acute depression in bipolar I disorder.
In this article, we examined evidence for the acute treatment of depression in bipolar I disorder, focusing on double-blind, placebo-controlled studies with a definite primary outcome measure and published in peer review journals. Quetiapine and olanzapine/fluoxetine are currently approved by the FDA for the treatment of bipolar depression, and a number of additional agents (including other atypical antipsychotics, mood stabilizers, antidepressants, and novel compounds) have been studied with varying degrees of efficacy. The medication with the most evidence for efficacy in bipolar depression is quetiapine, with five studies showing positive efficacy compared to placebo. In contrast, five studies of lamotrigine were negative, although meta-analyses of the pooled have found some treatment effects. Two studies of olanzapine and olanzapine/fluoxetine and three small studies of divalproex showed significant efficacy in treating bipolar depression. Two studies of aripiprazole found no differences compared to placebo. Early research on lithium in bipolar depression had significant methodological flaws, and only one study of lithium met our primary search criteria. To better understand the role of antidepressants, we also examined studies of antidepressants as adjunctive treatment of bipolar depression in participants taking mood stabilizers or atypical antipsychotics. These studies reported mixed results for a variety of antidepressants, but the majority found no differences compared to placebo. Other studies of adjunctive treatment were also discussed. There has been one positive adjunctive study each of lamotrigine, omega-3 fatty acids, modafinil, and armodafinil, while there was one negative trial each of omega-3 fatty acids, ziprasidone, and levetiracetam.


Encephalitogenic T cell clones specific for myelin basic protein. An unusual bias in antigen recognition.
Class II-restricted T cell clones specific for myelin basic protein (MBP) have been generated from PL/J and (PL/J X SJL/J)F1 [((PLSJ)F1] mice following sensitization to rat MBP. Of 17 T cell clones generated from (PLSJ)F1 mice, 5 are I-Au(A alpha uA beta u) restricted, one is restricted to I-As(A alpha sA beta s), 10 are restricted to hybrid I-A(u X s)F1 (A alpha sA beta u) determinants, and one clone is restricted to hybrid I-E(u X s) (E alpha uE beta s) molecules. Thus, of 16 I-A-restricted T cell clones generated from (PLSJ)F1 mice, only one is I-As-restricted, reflecting a lack of priming to MBP in association with I-As. T cell clones restricted to I-Au and to I-E (E alpha u E beta s) molecules recognize mouse (self) MBP. Furthermore, only the five T cell clones restricted to I-Au molecules recognize a determinant in common with mouse (self) MBP within the encephalitogenic N-terminal peptide. Three such I-Au restricted T cell clones, derived independently, cause paralysis in 100% of (PL/J X SJL/J)F1 mice tested. Acute, chronic unremitting, and chronic relapsing paralysis are all induced following injection of these clones. Administration of greater numbers of cloned T cells causes acute and fatal experimental allergic encephalomyelitis, while administration of lower numbers of cloned T cells is associated with chronic unremitting and relapsing paralysis. Paralysis induced with T cell clones shares many clinical, immunologic, and histologic aspects with human demyelinating diseases such as multiple sclerosis. Histopathology reveals perivascular lymphocytic infiltration, demyelination, and remyelination. These studies demonstrate the utility of T cell clones for analyzing the association between class II major histocompatibility complex molecules and disease susceptibility.


Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma.
Loss of heterozygosity (LOH) studies have suggested that somatic mutations of a tumour suppressor gene or genes on chromosome 3p are a critical event in the pathogenesis of non-familial renal cell carcinoma (RCC). Germline mutations of the von Hippel-Lindau (VHL) disease gene predispose to early onset and multifocal clear cell renal cell carcinoma, and the mechanism of tumorigenesis in VHL disease is consistent with a one-hit mutation model. To investigate the role of somatic VHL gene mutations in non-familial RCC, we analysed 99 primary RCC for VHL gene mutations by SSCP and heteroduplex analysis. Somatic VHL gene mutations were identified in 30 of 65 (46%) sporadic RCC with chromosome 3p allele loss and one of 34 (3%) tumours with no LOH for chromosome 3p. The VHL gene mutations were heterogeneous (17 frameshift deletions, eight missense mutations, four frameshift insertions, one nonsense and one splice site mutation), but no mutations were detected in the first 120 codons of cloned coding sequence. Most RCCs with somatic VHL mutations (23 of 27 (85%) informative cases) had chromosome 3p25 allele loss in the region of the VHL gene so that both alleles of the VHL gene had been inactivated as expected from a two-hit model of tumorigenesis. Detailed histopathology was available for 59 of the tumours investigated: 18 of 43 (42%) RCC with a clear cell appearance had a somatic VHL gene mutation but none of 16 non-clear cell RCC (eight chromophilic, three chromophobe and five oncocytoma) (chi2 = 7.77, P < 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)


Teaching hip surgery to orthopaedic residents: what's new?
The purpose of this study is to provide an overview of the published literature on the existing educational methods used to teach surgical skills, with a specific focus on hip surgery, to orthopaedic residents. A total of 31 articles were selected from a PubMed literature search on the topic of teaching surgical skills to orthopaedic residents, and 9 articles on hip surgery are included in this review. Although several methods are included in the published literature to teach orthopaedic residents, only arthroscopy of the knee and shoulder joint is well described. Hip arthroscopy has a steeper learning curve and thus the use of simulation training as a complementary teaching method is even more important. Currently, open surgery skills for joint arthroplasty are largely acquired by apprenticeship learning. Simulation training in the form of virtual reality could contribute to better performance of residents, decreasing operation time and improving patient safety.


Cloning, phenotypic expression, and DNA sequence of the gene for lactacin F, an antimicrobial peptide produced by Lactobacillus spp.
Lactacin F is a heat-stable bacteriocin produced by Lactobacillus acidophilus 11088. A 63-mer oligonucleotide probe deduced from the N-terminal lactacin F amino acid sequence was used to clone the putative laf structural gene from plasmid DNA of a lactacin F-producing transconjugant, L. acidophilus T143. One clone, NCK360, harbored a recombinant plasmid, pTRK160, which contained a 2.2-kb EcoRI fragment of the size expected from hybridization experiments. An Escherichia coli-L. acidophilus shuttle vector was constructed, and a subclone (pTRK162) containing the 2.2-kb EcoRI fragment was introduced by electroporation into two lactacin F-negative strains, L. acidophilus 89 and 88-C. Lactobacillus transformants containing pTRK162 expressed lactacin F activity and immunity. Bacteriocin produced by the transformants exhibited an inhibitory spectrum and heat stability identical to those of the wild-type bacteriocin. An 873-bp region of the 2.2-kb fragment was sequenced by using a 20-mer degenerate lactacin F-specific primer to initiate sequencing from within the lactacin F structural gene. Analysis of the resulting sequence identified an open reading frame which could encode a protein of 75 amino acids. The 25 N-terminal amino acids for lactacin F were identified within the open reading frame along with an N-terminal extension, possibly a signal sequence. The lactacin F N-terminal sequence, through the remainder of the open reading frame (57 amino acids; 6.3 kDa), correlated extremely well with composition analyses of purified lactacin F which also predicted a size of 51 to 56 amino acid residues. Molecular characterization of lactacin F identified a small hydrophobic peptide that may be representative of a common bacteriocin class in lactic acid bacteria.


Restoration of High Frequency Auditory Perception After Robot-Assisted or Manual Cochlear Implantation in Profoundly Deaf Adults Improves Speech Recognition.
Background and Purpose: Robot-assisted cochlear implantation has recently been implemented in clinical practice; however, its effect on hearing outcomes is unknown. The aim of this preliminary study was to evaluate hearing performance 1 year post-implantation whether the electrode array was inserted manually or assisted by a robot. Methods: Forty-two profoundly deaf adults were implanted either manually (n = 21) or assisted by a robot (RobOtol®, Collin, Bagneux, France) with three different electrode array types. Participants were paired by age, and electrode array type. The scalar position of the electrode array in the cochlea was assessed by 3D reconstruction from the pre- and post-implantation computed tomography. Pure-tone audiometry and speech perception in silence (percentage of disyllabic words at 60 dB) were tested on the implanted ear 1 year post-implantation in free-field conditions. The pure-tone average was calculated at 250-500-750 Hz, 500-1,000-2,000-3,000 Hz, and 3,000-4,000-8,000 Hz for low, mid, and high frequencies, respectively. Results: One year after cochlear implantation, restoration of the high-frequency thresholds was associated with better speech perception in silence, but not with low or mid frequencies (p < 0.0001; Adjusted R 2 = 0.64, polynomial non-linear regression). Although array translocation was similar using either technique, the number of translocated electrodes was lower when the electrode arrays had been inserted with the assistance of the robot compared with manual insertion (p = 0.018; Fisher's exact test). Conclusion: The restoration of high-frequency thresholds (3,000-4,000-8,000 Hz) by cochlear implantation was associated with good speech perception in silence. The numbers of translocated electrodes were reduced after a robot-assisted insertion.


[Regularities of organ-specific expression of enzyme systems in cattle].
The organ specificity of creatine kinase, esterase, isocitrate dehydrogenase lactate dehydrogenase, nucleoside phosphorylase, adenylate kinase, hexokinase, malate dehydrogenase, malic enzyme, glucose-6-phosphate dehydrogenase of black-white cattle has been studied. Esterases, creatine kinase, adenylate kinase, hexokinase and glucose-6-phosphate dehydrogenase have a very wide spectrum of the organ variabilities. Liver and heart have the largest specificity of enzymes activity. Some peculiarities of isozyme spectrum are found in ovaries and spleen.


Differential Development of Facial and Hind Paw Allodynia in a Nitroglycerin-Induced Mouse Model of Chronic Migraine: Role of Capsaicin Sensitive Primary Afferents.
Despite the relatively high prevalence of migraine or headache, the pathophysiological mechanisms triggering headache-associated peripheral hypersensitivities, are unknown. Since nitric oxide (NO) is well known as a causative factor in the pathogenesis of migraine or migraine-associated hypersensitivities, a mouse model has been established using systemic administration of the NO donor, nitroglycerin (NTG). Here we tried to investigate the time course development of facial or hindpaw hypersensitivity after repetitive NTG injection. NTG (10 mg/kg) was administrated to mice every other day for nine days. Two hours post-injection, NTG produced acute mechanical and heat hypersensitivity in the hind paws. By contrast, cold allodynia, but not mechanical hypersensitivity, occurred in the facial region. Moreover, this hindpaws mechanical hypersensitivity and the facial cold allodynia was progressive and long-lasting. We subsequently examined whether the depletion of capsaicin-sensitive primary afferents (CSPAs) with resiniferatoxin (RTX, 0.02 mg/kg) altered these peripheral hypersensitivities in NTG-treated mice. RTX pretreatment did not affect the NTG-induced mechanical allodynia in the hind paws nor the cold allodynia in the facial region, but it did inhibit the development of hind paw heat hyperalgesia. Similarly, NTG injection produced significant hindpaw mechanical allodynia or facial cold allodynia, but not heat hyperalgesia in transient receptor potential type V1 (TRPV1) knockout mice. These findings demonstrate that different peripheral hypersensitivities develop in the face versus hindpaw regions in a mouse model of repetitive NTG-induced migraine, and that these hindpaw mechanical hypersensitivity and facial cold allodynia are not mediated by the activation of CSPAs.


Long-term survival after urinary diversion. A reappraisal of ureterosigmoidostomy.
Long-term survival occurs following both ureterosigmoid and ileal diversions. Both manoeuvres carry a significant complication rate but where patients have good rectal continence, ureterosigmoid diversion offers the advantage of appliance free life. Success depends on initial good renal function and successful implantation of the ureters into bowel avoiding both reflux and stenosis. Where there is a likelihood of long survival as in such conditions as ectopia vesicae, this technique will provide very satisfactory management and three patients surviving more than a total of 100 years illustrate this approach.


The Top 100 Cited Articles in Clinical Orthopedic Sports Medicine.
Orthopedic sports medicine continues to evolve, owing much of its clinical management and practice to rigorous academic research. In this review, we identify and describe the top 100 cited articles in clinical sports medicine and recognize the authors and institutions driving the research. We collected articles (excluding basic science, animal, and cadaveric studies) from the 25 highest-impact sports medicine journals and analyzed them by number of citations, journal, publication date, institution, country, topic, and author. Mean number of citations was 408 (range, 229-1629). The articles were published in 7 journals, most in the 1980s to 2000s, and represented 15 countries. Thirty topics were addressed, with a heavy emphasis on anterior cruciate ligament injury and reconstruction, knee rating systems, rotator cuff reconstruction, and chondrocyte transplantation. The 3 most cited articles, by Insall and colleagues, Constant and Murley, and Tegner and Lysholm, addressed a knee, a shoulder, and another knee rating system, respectively. Several authors contributed multiple articles. The Hospital for Special Surgery and the University of Bern contributed the most articles (5 each). This study provides a comprehensive list of the past century's major academic contributions to sports medicine. Residents and fellows may use this list to guide their scholarly investigations.


Increased risk of functional gastrointestinal sequelae after Clostridium difficile infection among active duty United States military personnel (1998-2010).
Some acute enteric infections are associated with the development of functional gastrointestinal disorders, most commonly irritable bowel syndrome but also other functional and organic gastrointestinal sequelae. Clostridium difficile infection has increased in incidence and severity, however, few studies have evaluated functional disorders after this infection. We evaluated the epidemiology and sequelae of C difficile in the US military population by using the US Department of Defense's Armed Forces Health Surveillance Center Defense Medical Ecounter Database. We then performed a retrospective cohort study of 891 active-duty US military personnel who developed C difficile from 1998 to 2010 and 3231 matched subjects who had not been exposed to C difficile. Subjects were identified based on International Classification of Diseases, 9th revision, Clinical Modification codes for C difficile disease. C difficile was associated independently with increased rate ratios (RRs) for incident irritable bowel syndrome (RR, 6.1; 95% confidence interval [CI], 2.9-12.9), gastroesophageal reflux disease (GERD) (RR, 1.9; 95% CI, 1.4-2.6), dyspepsia (RR, 3.3; 95%, 1.4-7.7), and constipation (RR, 2.2; 95% CI, 1.3-3.7). Approximately 14.1% of subjects with C difficile later were identified with one of these functional gastrointestinal disorders (FGDs), compared with 6% of controls. Community- and health care-associated C difficile were associated at similar rates with these sequelae. Patients were at increased risk for FGDs within 3 months of a C difficile episode, with one additional case of FGD developing for every 12 diagnoses of C difficile. The incidence of community- and health care-associated C difficile has increased in the US military population from 1998 through 2010. As for other gastrointestinal infections, C difficile disease is associated with clinically relevant functional sequelae in this military population.


Effects of subanesthetic doses of inert gases on behavioral thermoregulation in mice.
Mice exposed to subanesthetic partial pressures of N2O (0.25 to 0.75 atm) or N2 (5.7 or 11.33 atm) and allowed to choose between a warm and a cool environment showed a marked preference for the cooler environment. This behavior was associated with the onset of hypothermia, with deep body temperature falling by up to about 3 degrees C, usually to a new, steady level. Both the length of time spent in the cooler environment and the degree of the hypothermia produced increased with the partial pressure of N2O or N2 used. The effects of N2O on behavioral thermoregulation and body temperature were reversible. There was a correlation between anesthetic potency and the ability of both gases to alter thermoregulation, suggesting that the effect of these agents on thermoregulation was caused by the same molecular interactions as those which underlie anesthesia. Since both gases elicited changes in behavioral thermoregulation promoting rather than opposing the onset of hypothermia, it is concluded that they may have acted to lower the level at which deep body temperature was being regulated.


Survey of hepatitis B viral markers at a public day school and a residential institution sharing mentally handicapped students.
The prevalence of hepatitis B virus markers was studied among employees and clients at a nonresidential public school for the mentally handicapped and at a privately operated residential facility. In the residential institution, 73 (80%) of 91 clients and 15 (16%) of 92 workers had positive tests for hepatitis B virus markers. Twenty-three clients, including six carriers of hepatitis B surface antigen (subtype ayw), received their education their education at the public school. Only two students (4%) who did not live at the residential institution and one employee (2%) had positive tests for hepatitis B virus markers. One of these students had acute hepatitis B infection, with hepatitis B surface antigen subtype ayw; the subtyping suggested that he had acquired the infection from one of the six carriers from the residential institution. Testing for IgM antibody to hepatitis B core antigen in single serum samples facilitated the identification of acute and chronic hepatitis B infection in children and staff of both facilities. The results show hepatitis B can be transmitted in this setting, and vaccination may be warranted for susceptible students and staff.


Expression of human beta-defensin-3 in gingival epithelia.
This study aimed to investigate the expression patterns of the newly discovered human beta-defensin-3 (hBD-3) in human gingiva. Human beta-defensins (hBDs) are a group of small, broad-spectrum, cationic antimicrobial peptides. Our recent study showed that the expression levels of hBD-1 and 2 peptides were associated with periodontal conditions. A total of 49 gingival biopsies were collected, including 33 samples from 21 patients with chronic periodontitis and 16 samples from 16 periodontally healthy subjects. The expression of hBD-3 was detected by immunohistochemistry and in situ hybridization. Double staining was undertaken to identify hBD-3 peptide-positive cells, using CD-1a and cytokeratin 20 as markers for Langerhans cells and Merkel cells, respectively. hBD-3 peptide was detected in 88% of the samples, which was confined to the gingival epithelia. In healthy control subjects, hBD-3 peptide was more frequently detected in the basal layer as compared to the patients (53% vs. 18%, p < 0.05). In patients, hBD-3 expression extended from the basal layer to the spinous layers (82%), in which hBD-3 was confined to the basal and deep spinous layers in clinically healthy tissues from patients, whereas it extended to the superficial spinous layers in pocket tissues from patients (0% vs. 50%, p < 0.05). In both groups, hBD-3 peptide was expressed not only in gingival keratinocytes, but also in Langerhans cells and Merkel cells. hBD-3 transcripts were detected in 90% of the samples and they were confined to the basal and/or suprabasal layers of gingival epithelia. This study shows that hBD-3 is frequently expressed in gingival epithelia. The appropriate expression of hBD-3 peptide may contribute to the maintenance of periodontal homeostasis, possibly through its antimicrobial effect and promotion of adaptive immune responses.


Oxidation of ammonia and hydroxylamine to nitrate in the rat.
We have demonstrated that ammonia is oxidized to nitrate in the rat. Male Sprague-Dawley rats gavaged with 1 000 mumol 15N-ammonium chloride each day for five days were found to excrete low, but significant, amounts of excess 15N-nitrate in their urines on the five days of treatment and on the five subsequent days. We recovered a total of 0.28 +/- 0.03 mumol excess 15N-nitrate (mean +/- SE) per rat, which indicates that ammonia is converted to nitrate with a yield of about 0.0080%. 15N-Hydroxylamine was oxidized in the rat to 15N-nitrate with a yield of 4.7%, but oxidation of 15N-labeled glycine and L-glutamic acid to 15N-nitrate could not be detected. These results suggest that hydroxylamine, but not glycine or L-glutamic acid, may be an intermediate in the ammonia oxidation process. The injection of rats with Arochlor 1254 failed to stimulate nitrate synthesis, which indicates that the cytochrome P-450 drug metabolizing system is probably not involved in ammonia oxidation. Carbon tetrachloride, which causes hepatic lipid peroxidation, produced a small, but significant, increase in nitrate synthesis. Our results are consistent with the hypothesis that ammonia is oxidized in vivo by a non-enzymatic process involving reactive oxygen species. We estimate that a 215 g rat produces 3.0 mumol of nitrate per day by this process. The significance of our results to the problem of endogenous N-nitroso compound formation in man is discussed.


Sleep after arousal from hibernation is not homeostatically regulated.
Electroencephalographic slow-wave activity (SWA) in non-rapid eye movement (NREM) sleep is directly related to prior sleep/wake history, with high levels of SWA following extended periods of wake. Therefore, SWA has been thought to reflect the level of accumulated sleep need. The discovery that euthermic intervals between hibernation bouts are spent primarily in sleep and that this sleep is characterized by high and monotonically declining SWA has led to speculation that sleep homeostasis may play a fundamental role in the regulation of the timing of bouts of hibernation and periodic arousals to euthermia. It was proposed that because the SWA profile seen after arousal from hibernation is strikingly similar to what is seen in nonhibernating mammals after extended periods of wakefulness, that hibernating mammals may arouse from hibernation with significant accumulated sleep need. This sleep need may accumulate during hibernation because the low brain temperatures during hibernation may not be compatible with sleep restorative processes. In the present study, golden-mantled ground squirrels were sleep deprived during the first 4 h of interbout euthermia by injection of caffeine (20 mg/kg ip). We predicted that if the SWA peaks after bouts of hibernation reflected a homeostatic response to an accumulated sleep need, sleep deprivation should simply have displaced and possibly augmented the SWA to subsequent recovery sleep. Instead we found that after caffeine-induced sleep deprivation of animals just aroused from hibernation, the anticipated high SWA typical of recovery sleep did not occur. Similar results were found in a study that induced sleep deprivation by gentle handling (19). These findings indicate that the SWA peak immediately after hibernation does not represent homeostatic regulation of NREM sleep, as it normally does after prolonged wakefulness during euthermia, but instead may reflect some other neurological process in the recovery of brain function from an extended period at low temperature.


Freeze-fracture studies of nexuses between smooth muscle cells. Close relationship to sarcoplasmic reticulum.
The freeze-fracture appearance of the nexus was compared in the smooth muscle of guinea pig sphincter pupillac, portal vein, pulmonary artery, taenia coli, uretzr, and vas diferens, mouse vas deferens, chicken gizzard and anterior mesenteric artery, and toad stomach. Nexuses are particularly numerous in the guinea pig sphincter pupillae; they are usually oval and their average area is 0.15 mum2, although some as large as 0.6 mum2 were seen. Small aggregations of particles were observed which would not be recognizable as nexuses in thin section. What constitutes the minimum size of a nexus is discussed. It is estimated that the number of nexuses per cell in this preparation is of the order of tens rather than hundreds. All nexuses examined had 6-9-nm particles in the PF face, with corresponding 3-4-nm pits on the EF face forming a polygonal tending towards a hexagonal lattice. The nexuses are arranged in rows parallel to the main axis of the cell, usually alternating with longitudinal rows of plasmalemmal vesicles. Many nexuses in the guinea pig sphincter pupillae, chicken gizzard, and toad stomach show a close relationship with sarcoplasmic reticulum. The possibility that this may have some role in current flow across this specialized junction is discussed.


Orbitrap mass spectrometry.
Orbitrap is the newest addition to the family of high-resolution mass spectrometry analyzers. With its revolutionarily new, miniature design, Orbitrap combines high speed with excellent quantification properties, ranking favorably in many analytical applications.


Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation.
Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration.


Monoclonal antibody studies of alpha-keratin low-sulfur proteins.
Monoclonal antibodies to the two families of low-sulfur proteins from wool were produced. Selection was applied to identify those hybridomas secreting antibody that was effective in the Electro-blot system. The specificities of eight different monoclonal antibodies were investigated by their binding to alpha-keratin low-sulfur proteins which had been subjected to electrophoresis from wool, goat hair, porcupine quill, rat hair and echidna quill, using the Electro-blot procedure. Considerable cross-reactivity was found both within the low-sulfur protein components of individual keratins from a particular species, and also between the keratins of the different species. Some antibodies were found to bind selectively to components of one family of low-sulfur proteins in wool, while others recognized determinants in both families, indicating some homology between the two families.


A multilingual evaluation of current health information on the Internet for the treatments of benign prostatic hyperplasia.
To compare the quality of current Internet information on benign prostatic hyperplasia (BPH) and its surgical and medical managements across four Western languages and a comparative analysis of website sponsors. BPH Internet information quality is particularly relevant in an era of expanding, minimally invasive and surgical therapies. However, no comprehensive analysis exists. World Health Organization Health on the Net (HON) principles may be applied to websites using an automated toolbar function. Using a search engine (www.google.com), 9,000 websites were assessed using keywords related to BPH and its medical and surgical treatment in English, French, German, and Spanish. The first 150 websites in each language had HON principles measured whilst a further analysis of site sponsorship was undertaken. Very few BPH websites had greater than ten per cent HON accredited with significant differences (P<0.001) based on terms used for BPH, its medical and surgical management. Tertiles (thirds) of the first 150 websites returned differences in accredited websites (P<0.0001). English language had most accredited websites. Odds ratios for different terms returning accredited websites also were significantly different across terms (P<0.001). Websites were largely commercially sponsored. A lack of validation of most BPH sites should be appreciated with discrepancies in quality and number of websites across diseases, languages and also between medical and alternate terms. Physicians should participate in and encourage the development of informative, ethical and reliable health websites on the Internet and direct patients to them.


The effects of extending cognitive-behavioral therapy for binge eating disorder among initial treatment nonresponders.
The study was designed with the aim of determining whether extending group cognitive-behavioral therapy (CBT) would enhance outcome among individuals with binge eating disorder (BED) who failed to stop binge eating after an initial 12-week CBT intervention. Forty-six participants who met diagnostic criteria for BED were randomly allocated to either a 12-week group CBT intervention or a waiting list control condition. At the end of 12 weeks, treated participants who met clinical criteria for improvement subsequently received 12 sessions of behavioral weight loss. Remaining participants received 12 additional sessions of CBT for binge eating. Fifty percent of treated participants improved with the initial 12-week course of CBT. There was a strong trend for the extension of CBT to affect improvement in binge eating among initial nonresponders (6 of 14 subjects no longer met diagnostic criteria for BED). Overall, extending CBT led to clinical improvement in 66.7% of all treated participants, with treatment gains occurring through session 20. The results suggest that an extended course of CBT (i.e., longer than 12 weeks) will likely maximize the number of potential responders to treatment.


The generation of hybrid electrospun nanofiber layer with extracellular matrix derived from human pluripotent stem cells, for regenerative medicine applications.
Extracellular matrix (ECM) has been utilized as a biological scaffold for tissue engineering applications in a variety of body systems, due to its bioactivity and biocompatibility. In the current study we developed a modified protocol for the efficient and reproducible derivation of mesenchymal progenitor cells (MPCs) from human embryonic stem cells as well as human induced pluripotent stem cells (hiPSCs) originating from hair follicle keratinocytes (HFKTs). ECM was produced from these MPCs and characterized in comparison to adipose mesenchymal stem cell ECM, demonstrating robust ECM generation by the excised HFKT-iPSC-MPCs. Exploiting the advantages of electrospinning we generated two types of electrospun biodegradable nanofiber layers (NFLs), fabricated from polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA), which provide mechanical support for cell seeding and ECM generation. Elucidating the optimized decellularization treatment we were able to generate an available "off-the-shelf" implantable product (NFL-ECM). Using rat subcutaneous transplantation model we demonstrate that this stem-cell-derived construct is biocompatible and biodegradable and holds great potential for tissue regeneration applications.


A Comparison of Personal Sound Amplification Products and Hearing Aids in Ecologically Relevant Test Environments.
The aim of this study was to compare the benefit of self-adjusted personal sound amplification products (PSAPs) to audiologist-fitted hearing aids based on speech recognition, listening effort, and sound quality in ecologically relevant test conditions to estimate real-world effectiveness. Twenty-five older adults with bilateral mild-to-moderate hearing loss completed the single-blinded, crossover study. Participants underwent aided testing using 3 PSAPs and a traditional hearing aid, as well as unaided testing. PSAPs were adjusted based on participant preference, whereas the hearing aid was configured using best-practice verification protocols. Audibility provided by the devices was quantified using the Speech Intelligibility Index (American National Standards Institute, 2012). Outcome measures assessing speech recognition, listening effort, and sound quality were administered in ecologically relevant laboratory conditions designed to represent real-world speech listening situations. All devices significantly improved Speech Intelligibility Index compared to unaided listening, with the hearing aid providing more audibility than all PSAPs. Results further revealed that, in general, the hearing aid improved speech recognition performance and reduced listening effort significantly more than all PSAPs. Few differences in sound quality were observed between devices. All PSAPs improved speech recognition and listening effort compared to unaided testing. Hearing aids fitted using best-practice verification protocols were capable of providing more aided audibility, better speech recognition performance, and lower listening effort compared to the PSAPs tested in the current study. Differences in sound quality between the devices were minimal. However, because all PSAPs tested in the study significantly improved participants' speech recognition performance and reduced listening effort compared to unaided listening, PSAPs could serve as a budget-friendly option for those who cannot afford traditional amplification.


Mechanistic Insights into Hsp104 Potentiation.
Potentiated variants of Hsp104, a protein disaggregase from yeast, can dissolve protein aggregates connected to neurodegenerative diseases such as Parkinson disease and amyotrophic lateral sclerosis. However, the mechanisms underlying Hsp104 potentiation remain incompletely defined. Here, we establish that 2-3 subunits of the Hsp104 hexamer must bear an A503V potentiating mutation to elicit enhanced disaggregase activity in the absence of Hsp70. We also define the ATPase and substrate-binding modalities needed for potentiated Hsp104(A503V) activity in vitro and in vivo. Hsp104(A503V) disaggregase activity is strongly inhibited by the Y257A mutation that disrupts substrate binding to the nucleotide-binding domain 1 (NBD1) pore loop and is abolished by the Y662A mutation that disrupts substrate binding to the NBD2 pore loop. Intriguingly, Hsp104(A503V) disaggregase activity responds to mixtures of ATP and adenosine 5'-(γ-thio)-triphosphate (a slowly hydrolyzable ATP analogue) differently from Hsp104. Indeed, an altered pattern of ATP hydrolysis and altered allosteric signaling between NBD1 and NBD2 are likely critical for potentiation. Hsp104(A503V) variants bearing inactivating Walker A or Walker B mutations in both NBDs are inoperative. Unexpectedly, however, Hsp104(A503V) retains potentiated activity upon introduction of sensor-1 mutations that reduce ATP hydrolysis at NBD1 (T317A) or NBD2 (N728A). Hsp104(T317A/A503V) and Hsp104(A503V/N728A) rescue TDP-43 (TAR DNA-binding protein 43), FUS (fused in sarcoma), and α-synuclein toxicity in yeast. Thus, Hsp104(A503V) displays a more robust activity that is unperturbed by sensor-1 mutations that greatly reduce Hsp104 activity in vivo. Indeed, ATPase activity at NBD1 or NBD2 is sufficient for Hsp104 potentiation. Our findings will empower design of ameliorated therapeutic disaggregases for various neurodegenerative diseases.


Entomotoxicology. A new area for forensic investigation.
Insects and other arthropods can be valuable tools in death investigations. In addition to their use in the estimation of postmortem intervals, insects may serve as reliable alternate specimens for toxicological analyses in the absence of tissues and fluids normally taken for such purposes. Recent research has also demonstrated that the presence of drugs and/or toxins in decomposing tissues may alter the rate and patterns of development in arthropods using such tissues as food, thus potentially altering estimates of the postmortem interval. Current advances in the use of arthropods as alternate toxicological specimens and the effects of various drugs and toxins on arthropod development are reviewed here.


Circumferential torsoplasty.
The abdominal deformities remaining after massive weight loss of 30% or more body weight often are not satisfactorily corrected by standard abdominoplasty techniques. Redundant lateral flank and hip rolls may in fact be accentuated by the operation. Accordingly, a circumferential torso excision was designed by the senior author and utilized for 7 patients during the past two years. This technique dramatically reduces the lateral flank and posterior tissue rolls to improve the operative results. Contour improvement of the buttocks and lateral thighs is produced as well. We employ a four blade propeller pattern of fascial plication centered on the umbilicus which tightens the abdominal fascia in both vertical and horizontal dimensions. Details of patient selection, operative technique, post-operative management and results are presented. Complications have been minimal and satisfaction of both patients and surgeons significantly enhanced.


Oxidative stress and transferrin receptor recycling.
Perturbation of the oxidative balance in biological systems plays an important role in numerous pathological states as well as in many physiological processes such as receptor activity. In order to evaluate if oxidative stress induced by menadione influences membrane receptor processes, a study was conducted on the transferrin receptor. Consequently, biochemical, biophysical and ultrastructural studies were carried out on different cell lines. The results obtained seem to indicate that oxidative stress is able of inducing a rapid and specific down-modulation of membrane transferrin receptor due to a block of receptor recycling on the cell surface without affecting binding affinity.


Prevention of thrombus growth by antithrombin III-dependent and two direct thrombin inhibitors in rabbits: implications for antithrombotic therapy.
We compared the abilities of heparin and two direct thrombin inhibitors to prevent fibrin accretion onto pre-existing thrombi in rabbits. Inhibition of thrombus growth was measured as the ability of each test compound to inhibit the accretion of 125I-fibrin onto thrombi pre-formed in jugular veins of rabbits. When administered as a continuous infusion, the two direct (i.e. antithrombin III-independent) thrombin inhibitors, r-hirudin and a tripeptide, Ac(D)-Phe-Pro-bor-Arg (P-8714) inhibited fibrin accretion as effectively as heparin, but did so in doses which generated little systemic anticoagulation, as compared to the marked anticoagulation associated with the heparin effect. However, both r-hirudin and P-8714 were more effective when they were administered as a single bolus injection than as a continuous infusion. Under the former conditions, there was only a transient systemic anticoagulant effect. We conclude that direct or antithrombin III-independent thrombin inhibitors are more effective than heparin in preventing thrombus growth. The limited effect of heparin is likely due to fibrin impairing the ability of heparin/antithrombin III to inactivate thrombin.


Mercury and Cadmium Concentrations in Muscle Tissue of the Blue Shark (Prionace glauca) in the Central Eastern Pacific Ocean.
Blue sharks (Prionace glauca) are an important resource in Ecuador's fisheries; however, biological and ecological information of this species in the area is scarce. The goal of this study was to determine Hg and Cd concentration levels in muscle tissue, as well as its relationship with size, sex, and sexual maturity stages. A total of 80 specimens (34 females and 46 males) collected from the Ecuadorian longline fishing fleet between June and December 2012 were examined. Sizes for females ranged from 97 to 280 cm total length, with values of Hg between 0.20 to 2.38 mg kg-1 wet weight (x̄ = 0.71, ± 0.61) and values of Cd between 0.01 and 0.12 mg kg-1 (x̄ = 0.04, ± 0.02). Sizes for males ranged from 137 to 290 cm TL with values of Hg between 0.17 and 2.94 mg kg-1 (x̄ = 0.81, ± 0.68) and Cd concentrations between 0.01 and 0.12 mg kg-1 (x̄ = 0.04, ± 0.03). A Spearman's rank correlation showed a medium positive association between TL and Hg concentrations (ρ = 0.66; p < 0.05), but there was no correlation between TL and Cd concentrations (ρ = 0.00, p < 0.05). Of the analyzed sharks, 46% and 20% had Hg and Cd concentrations, respectively, greater than the limit established by authorities for fishes consumed by humans.


Cell-mediated immune responses in tuberculosis.
Tuberculosis is primarily a disease of the lung, and dissemination of the disease depends on productive infection of this critical organ. Upon aerosol infection with Mycobacterium tuberculosis (Mtb), the acquired cellular immune response is slow to be induced and to be expressed within the lung. This slowness allows infection to become well established; thus, the acquired response is expressed in an inflammatory site that has been initiated and modulated by the bacterium. Mtb has a variety of surface molecules that interact with the innate response, and this interaction along with the autoregulation of the immune response by several mechanisms results in less-than-optimal control of bacterial growth. To improve current vaccine strategies, we must understand the factors that mediate induction, expression, and regulation of the immune response in the lung. We must also determine how to induce both known and novel immunoprotective responses without inducing immunopathologic consequences.


Effectiveness of a Motivational Smoking Reduction Strategy Across Socioeconomic Status and Stress Levels.
Smoking consequences are seen disproportionately among low-SES smokers. We examine the self-regulatory strategy of mental contrasting with implementation intentions (MCII) as a smoking reduction tool and whether its effectiveness depends on subjective-SES. This pre-registered online experiment comprised a pre-screening, baseline survey, and follow-up. Participants reported past-week smoking, subjective-SES, perceived stress, and were randomized to an active control (n = 161) or MCII condition (n = 164). Data were collected via MTurk, during the U.S.' initial wave of COVID-19. Participants were moderate-to-heavy smokers open to reducing or quitting. The primary outcome was self-reported smoking reduction, computed as the difference between recent smoking at baseline and follow-up. The secondary outcome was cessation, operationalized as self-reported 7-day point-prevalence abstinence at follow-up. Among those low-but not high-in subjective-SES, MCII (vs. control) improved smoking reduction by an average of 1.09 fewer cigarettes smoked per day, though this effect was not conclusive (p = 0.11). Similarly, quitting was descriptively more likely for those in the MCII than control condition, but the effect was non-significant (p = 0.11). Per an exploratory analysis, we observed that stress significantly moderated the condition effect (p = 0.01), such that MCII (vs. control) facilitated reduction among those experiencing high (p = 0.03), but not low stress (p = 0.15). Consistent with prior findings that MCII works best in vulnerable populations, MCII may be more effective for smoking reduction among high-stress than low-stress individuals. These findings contribute to growing research on income-related health disparities and smoking behavior change tools.


Accurate detection of typical absence seizures in adults and children using a two-channel electroencephalographic wearable behind the ears.
Patients with absence epilepsy sensitivity <10% of their absences. The clinical gold standard to assess absence epilepsy is a 24-h electroencephalographic (EEG) recording, which is expensive, obtrusive, and time-consuming to review. We aimed to (1) investigate the performance of an unobtrusive, two-channel behind-the-ear EEG-based wearable, the Sensor Dot (SD), to detect typical absences in adults and children; and (2) develop a sensitive patient-specific absence seizure detection algorithm to reduce the review time of the recordings. We recruited 12 patients (median age = 21 years, range = 8-50; seven female) who were admitted to the epilepsy monitoring units of University Hospitals Leuven for a 24-h 25-channel video-EEG recording to assess their refractory typical absences. Four additional behind-the-ear electrodes were attached for concomitant recording with the SD. Typical absences were defined as 3-Hz spike-and-wave discharges on EEG, lasting 3 s or longer. Seizures on SD were blindly annotated on the full recording and on the algorithm-labeled file and consequently compared to 25-channel EEG annotations. Patients or caregivers were asked to keep a seizure diary. Performance of the SD and seizure diary were measured using the F1 score. We concomitantly recorded 284 absences on video-EEG and SD. Our absence detection algorithm had a sensitivity of .983 and false positives per hour rate of .9138. Blind reading of full SD data resulted in sensitivity of .81, precision of .89, and F1 score of .73, whereas review of the algorithm-labeled files resulted in scores of .83, .89, and .87, respectively. Patient self-reporting gave sensitivity of .08, precision of 1.00, and F1 score of .15. Using the wearable SD, epileptologists were able to reliably detect typical absence seizures. Our automated absence detection algorithm reduced the review time of a 24-h recording from 1-2 h to around 5-10 min.


Ultrasound characteristics of soft tissues near sacroiliac joints and in the lumbar region of patients with ankylosing spondylitis.
To investigate the musculoskeletal morphomechanical properties (i.e., the thickness and elastic modulus) and the total count of power Doppler signals near the sacroiliac joints in patients with ankylosing spondylitis (AS) and non-AS individuals. Twenty participants with AS [median age (interquartile range): 31.7 (11.04) years] and 19 controls [36.3 (10.5) years] with no AS history were recruited. Bilateral ultrasound image acquisition was performed, including the short posterior sacroiliac ligament, interosseous sacroiliac ligament, long posterior sacroiliac ligament, iliolumbar ligament, proximal piriformis muscle, and sacrotuberous ligament. The intraclass correlation coefficients (ICC) of ultrasound parameters, laboratory test results of human leukocyte antigen B27, C-reactive protein, and erythrocyte sedimentation rate, and self-reported physical and disease activity scores were also obtained. The ligaments and piriformis muscle were thicker and stiffer (greater elastic modulus) in participants with AS than in non-AS participants (all p<0.01). The measurements showed good or excellent reliability (all ICC(3,1) >0.85). The numbers of power Doppler signals detected in the iliolumbar ligament, proximal piriformis muscle, and sacrotuberous ligament were higher in participants with AS than in non-AS participants (all p<0.001). A correlation was identified between disease duration and the elastic modulus of the piriformis muscle (r=0.640, p=0.003). We conclude that the ligaments and proximal piriformis muscle of AS participants have increased thickness, elastic modulus, and power Doppler signal than those of non-AS individuals. These reliable findings may serve as potential markers for the early diagnosis of AS and for assessing medication effects.


Refolding hydrogels self-assembled from N-(2-hydroxypropyl)methacrylamide graft copolymers by antiparallel coiled-coil formation.
A novel hybrid hydrogel system based on N-(2-hydroxypropyl)methacrylamide copolymers was proposed. It consisted of the hydrophilic polymer backbone and a pair of oppositely charged peptide grafts. Two distinct pentaheptad peptides (CCE and CCK) were anticipated to create a dimerization motif and serve as physical cross-linkers. Consequently, the graft copolymers CCE-P and CCK-P self-assembled into hybrid hydrogels in situ; the process was modulated by the formation of antiparallel heterodimeric coiled-coils. This approach possesses an advantage to decrease the steric hindrance of the polymer backbone on the "in-register" alignment of peptide grafts. Indeed, equimolar mixtures of the graft copolymers, CCE-P/CCK-P, have been observed to self-assemble into hydrogels in PBS solution at neutral pH at concentrations as low as 0.1 wt %. Circular dichroism spectroscopy, sedimentation equilibrium experiments, and microrheology revealed that the self-assembly process corresponded to the two-stranded alpha-helical coiled-coil formation between CCE and CCK. Moreover, the formation of hybrid hydrogels was reversible. Denaturation of the coiled-coil domains with guanidine hydrochloride (GdnHCl) solutions resulted in disassembly of the hydrogels. Removal of GdnHCl by dialysis caused coiled-coil refolding and hydrogel reassembly. Scanning electron microscopy results demonstrated that the concentration of the graft copolymers had a significant impact on the structure and morphology of self-assembled hydrogels.


Effect of diabetes mellitus on walking distance parameters after supervised exercise therapy for intermittent claudication: A systematic review.
Some believe that certain patients with intermittent claudication may be unsuitable for supervised exercise therapy (SET), based on the presence of comorbidities and the possibly increased risks. We conducted a systematic review (MEDLINE, EMBASE and CENTRAL) to summarize evidence on the potential influence of diabetes mellitus (DM) on the response to SET. Randomized and nonrandomized studies that investigated the effect of DM on walking distance after SET in patients with IC were included. Considered outcome measures were maximal, pain-free and functional walking distance (MWD, PFWD and FWD). Three articles met the inclusion criteria ( n = 845). In one study, MWD was 111 meters (128%) longer in the non-DM group compared to the DM group after 3 months of follow-up ( p = 0.056). In a second study, the non-DM group demonstrated a significant increase in PFWD (114 meters, p ⩽ 0.05) after 3 months of follow-up, whereas there was no statistically significant increase for the DM group (54 meters). On the contrary, the largest study of this review did not demonstrate any adverse effect of DM on MWD and FWD after SET. In conclusion, the data evaluating the effects of DM on SET were inadequate to determine if DM impairs the exercise response. While trends in the data do not suggest an impairment, they are not conclusive. Practitioners should consider this limitation when making clinical decisions.


Removal of Organic Micropollutants from Water by Macrocycle-Containing Covalent Polymer Networks.
Access to clean drinking water is a recognized societal need that touches on the health and livelihood of millions of people worldwide. This is providing an incentive to develop new water-treatment technologies. Traditional technologies, while widespread, are usually inefficient at removing organic pollutants from sewage or so-called grey water. Macrocycle-containing covalent polymer networks have begun to attract attention in the context of water treatment owing to the inherent stability provided by the polymer backbones and their ability to capture micropollutant guests as the result of tunable macrocycle-based host-guest interactions. In this Minireview, we summarize recent advances (from 2016 to mid-2020) involving the removal of organic micropollutants from water using macrocycle-containing covalent polymer networks. An overview of future challenges within this subfield is also provided.


Trace element concentrations in feathers from three seabird species breeding in the Timor Sea.
Mobile marine predators, such as seabirds, are frequently used as broad samplers of contaminants that are widespread in the marine environment. The Timor Sea off remote Western Australia is a poorly studied, yet rapidly expanding area of offshore development. To provide much needed data on contamination in this region, we quantified trace element concentrations in breast feathers of three seabird species breeding on Bedout Island. While adult Masked Boobies Sula dactylatra exhibited some of the highest concentrations, values for all species were below toxicology thresholds for seabirds and were comparable to those reported in other closely related species. The low concentrations detected in the birds provide a valuable baseline and suggest that the local marine environment around Bedout is in relatively good condition. However, careful monitoring is warranted in light increasing anthropogenic activity in this region.


Volume imaging by tracking sparse topological features in electron micrograph tilt series.
The sensitive coherent interference of electron waves arising from a specimen is useful for revealing subtle structural information in electron micrographs, which can be important for minimising dose and for rapid imaging. In general, dynamical diffraction is expected due to the useful strong interactions of electrons with matter, which can create phase contrast that violates the requisite Radon projection assumption for tomography. It is for these reasons that incoherent imaging modalities such as high angle annular dark field have been favoured to date in electron tomography of crystalline specimens, to access a monotonic relationship between specimen thickness and micrograph intensity. Here we use a geometric approach to track topological features that are robust to perturbation of the imaging conditions, to enable 3D reconstructions from electron microscope tilt series under imaging conditions that violate the Radon projection assumption, with an emphasis on phase contrast. Invoking a sparsity assumption, we demonstrate that topological features can be reliably tracked in 3D using a differential geometric form of stereoscopy, to circumvent departures from the projection approximation and reduce noise by effecting segmentation of interest points from the outset. We demonstrate this approach on a variety of different specimen and data types, from polyhedral nanoparticles, to steel dislocation networks, cryo-EM cellular structures and 3D diffuse diffraction of a relaxor ferroelectric.


Structural and functional insight into the Mycobacterium tuberculosis protein PrpR reveals a novel type of transcription factor.
The pathogenicity of Mycobacterium tuberculosis depends upon its ability to catabolize host cholesterol. Upregulation of the methylcitrate cycle (MCC) is required to assimilate and detoxify propionyl-CoA, a cholesterol degradation product. The transcription of key genes prpC and prpD in MCC is activated by MtPrpR, a member of a family of prokaryotic transcription factors whose structures and modes of action have not been clearly defined. We show that MtPrpR has a novel overall structure and directly binds to CoA or short-chain acyl-CoA derivatives to form a homotetramer that covers the binding cavity and locks CoA tightly inside the protein. The regulation of this process involves a [4Fe4S] cluster located close to the CoA-binding cavity on a neighboring chain. Mutations in the [4Fe4S] cluster binding residues rendered MtPrpR incapable of regulating MCC gene transcription. The structure of MtPrpR without the [4Fe4S] cluster-binding region shows a conformational change that prohibits CoA binding. The stability of this cluster means it is unlikely a redox sensor but may function by sensing ambient iron levels. These results provide mechanistic insights into this family of critical transcription factors who share similar structures and regulate gene transcription using a combination of acyl-CoAs and [4Fe4S] cluster.


Performance of a loop-mediated isothermal amplification assay (Isoplex CRE-ART) to detect common carbapenemase-encoding genes in Gram-negative bacteria.
Carbapenem-resistant Gram-negative bacteria (CR-GNB) are a major source of nosocomial infections worldwide. In this study, the ability of a loop-mediated isothermal amplification (LAMP)-based method (Isoplex CRE-ART) to rapidly detect carbapenemase-encoding genes bla OXA-48-like, bla OXA-23-like, bla OXA-24-like, bla KPC, bla VIM, bla NDM and bla IMP in 231 carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii isolates was investigated. The accuracy of the LAMP test was compared to results of molecular isolate characterization using a Laboratory Developed Test multiplex carbapenemase PCR assay. The LAMP test correctly identified the presence of on-panel carbapenemases with a sensitivity of 99.16 % [95 % confidence interval (CI): 95.39-99.96 %] and a specificity of 98.21 % (95 % CI: 93.72-99.68 %) in 60 min. Our findings suggest that the Isoplex CRE-ART assay is able to rapidly identify carbapenemase genes in CR-GNB and improves options for pathogen characterization in the context of clinical microbiological and infection control diagnostics.


Looking in the mouth for Crohn's disease.
It is widely acknowledged among gastroenterologists that the oral cavity may be involved in Crohn's disease (CD). However, the specific manifestations are poorly appreciated. Although oral aphthous ulceration is probably not diagnostically useful in patients with suspected CD, disease-specific manifestations do occur and are particularly common in children presenting with CD. These manifestations can be subtle, often are subclinical, yet commonly harbor diagnostically useful material (granulomas). Orofacial granulomatosis (OFG) is conventionally used to describe patients with overt oral disease without obvious involvement of the gastrointestinal tract. However, many patients with OFG have subclinical intestinal CD or will progress to develop overt intestinal CD with time. The management of severe oral disease is challenging and lacks a clear evidence base.


Gas6 Ameliorates Inflammatory Response and Apoptosis in Bleomycin-Induced Acute Lung Injury.
Acute lung injury (ALI) is characterized by alveolar damage, lung edema, and exacerbated inflammatory response. Growth arrest-specific protein 6 (Gas6) mediates many different functions, including cell survival, proliferation, inflammatory signaling, and apoptotic cell clearance (efferocytosis). The role of Gas6 in bleomycin (BLM)-induced ALI is unknown. We investigated whether exogenous administration of mouse recombinant Gas6 (rGas6) has anti-inflammatory and anti-apoptotic effects on BLM-induced ALI. Compared to mice treated with only BLM, the administration of rGas6 reduced the secretion of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2, and increased the secretion of hepatocyte growth factor in bronchoalveolar lavage (BAL) fluid. rGas6 administration also reduced BLM-induced inflammation and apoptosis as evidenced by reduced neutrophil recruitment into the lungs, total protein levels in BAL fluid, caspase-3 activity, and TUNEL-positive lung cells in lung tissue. Apoptotic cell clearance by alveolar macrophages was also enhanced in mice treated with both BLM and rGas6 compared with mice treated with only BLM. rGas6 also had pro-resolving and anti-apoptotic effects in mouse bone marrow-derived macrophages and alveolar epithelial cell lines stimulated with BLM in vitro. These findings indicate that rGas6 may play a protective role in BLM-induced ALI.


[(11)C]UCB-A, a novel PET tracer for synaptic vesicle protein 2A.
Development of a selective and specific high affinity PET tracer, [(11)C]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine VT. A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. 3-5GBq of [(11)C]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65GBq/μmol. In vitro binding showed high selective binding towards SV2A. [(11)C]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the VT could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [(11)C]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. We have developed the novel PET tracer, [(11)C]UCB-A, that can be used to measure SV2A expression in vivo. The dosimetry allows up to 5 administrations of 400MBq of [(11)C]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline VT values. This will have to be further validated in human studies.


Effects of strong physical exercise on blood glutamate and its metabolite 2-ketoglutarate levels in healthy volunteers.
Excessive concentrations of L-glutamate (glutamate) have been found to posses neurotoxic properties. This study investigates how stress induced by strong physical exercise effects blood glutamate, 2-ketoglutarate, Alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST) levels. The relationship between muscle damage caused by strong physical exercise and blood glutamate levels was also examined. Twenty-two healthy volunteers engaged in intense veloergometry ("spinning") for a duration of 60 minutes. Two 10 minute peaks of extremely intense exercise were performed at 10 minutes and 50 minutes after the start of exercise. After 60 minutes of exercise, volunteers were monitored for an additional 180 minutes in resting conditions. Blood samples for determination of glutamate and 2-ketoglutarate levels were collected prior to exercise and then every 30 min for entire experiment. Blood samples were also taken at those time points to measure glutamate, 2-ketoglutarate, AST, ALT, creatine phosphokinase (CPK), myoglobin, lactate and venous blood gas levels. Blood glutamate levels were significantly elevated throughout the exercise session (P less than 0.001) and then returned to baseline levels at the cessation of exercise. 2-ketoglutarate, a product of glutamate metabolism, reached significantly elevated levels at 30 minutes (P less than 0.01) from the start of exercise and remained elevated up to 240 minutes post exercise initiation (P less than 0.001). AST and ALT levels were elevated at 60 minutes when compared to baseline. AST levels remained elevated at 240 minutes, unlike ALT levels which returned to baseline values at 240 minutes. Strong physical exercise leads to a significant elevation in blood glutamate, most likely as a result of skeletal muscle damage. 2-ketoglutarate was also found to be elevated for long periods of time, reflecting an ongoing process of glutamate breakdown. Elevated concentrations of AST and ALT in plasma reflect the importance of these enzymes in the maintenance of stable blood glutamate concentrations.


The role of coiled-coil alpha-helices and disulfide bonds in the assembly and stabilization of cartilage matrix protein subunits. A mutational analysis.
Cartilage matrix protein (CMP) exists as a disulfide-bonded homotrimer in the matrix of cartilage. Each monomer consists of two CMP-A domains that are separated by an epidermal growth factor-like domain. A heptad repeat-containing tail makes up the carboxyl-terminal domain of the protein. The secreted form of CMP contains 12 cysteine residues numbered C1 through C12. Two of these are in each of the CMP-A domains, six are in the epidermal growth factor-like domain, and two are in the heptad repeat-containing tail. Two major categories of mutant CMPs were generated to analyze the oligomerization process of CMP: a mini-CMP and a heptadless full-length CMP. The mini-CMP consists of the CMP-A2 domain and the heptad repeat-containing tail. In addition, a number of mutations affecting C9 through C12 were generated within the full-length, the mini-, and the heptad-less CMPs. The mutational analysis indicates that the heptad repeats are necessary for the initiation of CMP trimerization and that the two cysteines in the heptad repeat-containing tail are both necessary and sufficient to form intermolecular disulfide bonds in either full-length or mini-CMP. The two cysteines within a CMP-A domain form an intradomain disulfide bond.


Physiologically Difficult Airway in the Patient with Severe Hypotension and Metabolic Acidosis.
The expertise to recognize and manage the difficult airway is essential in anesthesiology. Conventionally, this refers to anatomical concerns causing difficulties with facemask ventilation and/or with tracheal intubation. Severe derangements in patients' physiology can make induction and intubation likewise difficult, and approximately 30% of critically ill patients had cardiovascular collapse subsequently to intubation. We present the case of a 58-year-old male with a past medical history of type II diabetes and hypertension who presented with altered mental status due to severe metabolic acidosis with a pH of 6.8 on admission to the intensive care unit. The anesthesia team was called to urgently intubate the patient. Upon arrival, the patient was localizing to pain and was hypocapnic, tachycardic, and hypotensive despite ongoing therapy with norepinephrine, vasopressin, and bicarbonate drips. Bedside point-of-care ultrasound showed hyperdynamic left ventricle with no other abnormalities. The patient was induced with IV ketamine, and dissociation occurred with maintenance of spontaneous respirations, which was followed by laryngoscopy and intubation causing only minimal hemodynamic changes. The patient was subsequently dialyzed and treated supportively. He was discharged from the hospital two weeks later-neurologically intact and at his baseline. Combination of hypotension and severe metabolic acidosis is particularly a challenging setting for airway management and a major risk factor for adverse events, including cardiopulmonary arrest. Hemodynamically stable induction agents should be preferred. In addition, sustaining spontaneous ventilation and avoiding periods of apnea in the peri-intubation period is paramount-any buildup of CO2 could push a critically low pH even lower and cause cardiovascular collapse. Sympathomimetic properties of ketamine make this induction agent a particularly appealing choice in this setting. This case report further supports the concept that severe physiologic perturbations-in which conventional induction techniques are not feasible-should be included in the current definition of a difficult airway.


Cross-orientation inhibition in cat is GABA mediated.
Visual evoked potentials (VEPs) were recorded from cat cortex (area 17) before, during and after application of the GABA blocker bicuculline (iontophoretic or topical). The stimuli comprised a test sinusoidal grating, and a mask grating oriented either parallel or orthogonal to the test. Both test and mask alternated in contrast at different temporal frequencies. VEPs were averaged in synchrony with the test contrast reversal, so the mask did not contribute directly to the averaged VEP response. Before application of bicuculline, both parallel and orthogonal masks attenuated the amplitude of VEPs and changed the phase response, but in different ways. Orthogonal masks lowered the slope of the contrast response curve without affecting extrapolated threshold, while parallel masks caused the curve to shift to the right. Orthogonal masks increased the phase advance, while parallel masks eliminated it. During application of bicuculline, neither parallel nor the orthogonal masks attenuated VEP amplitudes. The results suggest that although the mechanisms for the action of parallel and orthogonal masks are clearly distinct, both are mediated by the GABA-ergic inhibitory system. Given this evidence, measurement of VEP contrast response curves may provide a simple non-invasive technique for monitoring visual inhibition in humans.


Effectiveness of a program to improve hypertension screening in primary care.
To evaluate the effectiveness of a program to improve hypertension screening practices in primary care. Retrospective quasi-experimental study. Two hospital-based family medicine centres (FMCs). In the study FMC, two study groups of randomly selected adult patients: 425 who visited the FMC before implementation of the screening improvement program (from Apr. 1, 1983, to Mar. 31, 1984) and 418 who visited it afterward (from Apr. 1, 1986, to Mar. 31, 1987). These patients were matched with 392 and 442 control patients respectively seen during the same time frames at the second FMC. Educational sessions for physicians to standardize blood pressure measurement and knowledge of the recommendations from the Canadian Hypertension Society on hypertension screening and diagnosis, and specific operational incentives to improve hypertension screening, including a reference guide placed in each physician's office, a coloured form for recording blood pressure measurements placed in every patient's chart and a follow-up and recall card file. Frequency of blood pressure measurements recorded in patient charts. The hypertension screening rate was 60% per year in the study group before program implementation and 79% in the study group afterward; the corresponding rates in the two control groups were 72% and 59% (p < 0.0001). Patients were more likely to be screened if they visited the physician for a periodic health examination than for other problems (e.g., psychosocial or dermatologic) and if they had a scheduled appointment rather than no appointment. Physician characteristics that were positive predictors of screening were low age, female sex and payment on a salary basis. Physician education and incentives are effective in improving hypertension screening practices in hospital-based FMCs without incurring additional costs or other use of resources. Further evaluation of such a program should be undertaken in other primary care settings.


PI3-kinase γ promotes Rap1a-mediated activation of myeloid cell integrin α4β1, leading to tumor inflammation and growth.
Tumor inflammation, the recruitment of myeloid lineage cells into the tumor microenvironment, promotes angiogenesis, immunosuppression and metastasis. CD11b+Gr1lo monocytic lineage cells and CD11b+Gr1hi granulocytic lineage cells are recruited from the circulation by tumor-derived chemoattractants, which stimulate PI3-kinase γ (PI3Kγ)-mediated integrin α4 activation and extravasation. We show here that PI3Kγ activates PLCγ, leading to RasGrp/CalDAG-GEF-I&II mediated, Rap1a-dependent activation of integrin α4β1, extravasation of monocytes and granulocytes, and inflammation-associated tumor progression. Genetic depletion of PLCγ, CalDAG-GEFI or II, Rap1a, or the Rap1 effector RIAM was sufficient to prevent integrin α4 activation by chemoattractants or activated PI3Kγ (p110γCAAX), while activated Rap (RapV12) promoted constitutive integrin activation and cell adhesion that could only be blocked by inhibition of RIAM or integrin α4β1. Similar to blockade of PI3Kγ or integrin α4β1, blockade of Rap1a suppressed both the recruitment of monocytes and granulocytes to tumors and tumor progression. These results demonstrate critical roles for a PI3Kγ-Rap1a-dependent pathway in integrin activation during tumor inflammation and suggest novel avenues for cancer therapy.


Enzootic icterus--a form of chronic copper poisoning.
The findings of a recent investigation into the epizootiology, course, symptomatology, gross pathology, chemical pathology and prevention of Enzootic Icterus are presented and the findings of previous investigations on these and other aspects are reevaluated. Enzootic Icterus and chronic copper poisoning are shown to be identical in all fundamental features. Both diseases are characterised by sudden onset, high mortality, icterus, anaemia, haemoglobinaemia, methaemoglobinaemia, haemoglobinuria and deeply pigmented kidneys. There are no described microscopic features on which the diseases can be differentiated. Very high levels of copper in the blood, liver and kidneys are found in both diseases. In the present work 36 liver specimens had a mean copper concentration of 701 microgram/g. Of 31 kidney specimens no values under 10 microgram/g were found while the mean was 107 microgram/g. Prevention of Enzootic Icterus by salts of molybdenum given orally confirms the identity. No close relationship with Geeldikkop is found other than the probability that the two diseases may act synergistically. Interpretation of existing knowledge of mineral levels of natural grazing in the enzootic region shows that the levels can account for the presence of chronic copper poisoning, although more investigation is required.


Population structuring of the invasive mosquito Aedes albopictus (Diptera: Culicidae) on a microgeographic scale.
Aedes albopictus is an invasive mosquito species that has spread globally and can transmit several arboviruses, including dengue, chikungunya and yellow fever. The species was first reported in Brazil in 1986 and since then has been found in 24 of the 27 Brazilian states, often in peri-urban environments close to highly urbanized areas. To date, population genetics of this important mosquito in areas in the city of São Paulo has not been investigated. In this study, we used 12 microsatellite loci to investigate the microgeographic population genetics of Ae. albopictus, which is present throughout the city of São Paulo. All the analyses revealed structuring of the populations studied, divided into two groups with restricted gene flow between them and without evidence of isolation by distance. We propose two hypotheses to explain the results: (i) low dispersal capability-limited gene flow between populations is due to the low dispersal capability inherent to Ae. albopictus; and (ii) multiple introductions-the structure identified here results from multiple introductions, which led to different dispersal patterns within the city and more genetic heterogeneity. The ability of Ae. albopictus to invade new areas and expand may explain why these mosquito populations appear to be well established and thriving in the city of São Paulo.


IL-1 beta-converting enzyme (ICE) is present and functional in human alveolar macrophages: macrophage IL-1 beta release limitation is ICE independent.
Tissue macrophages readily produce intracellular pro-IL-1beta in response to stimuli such as LPS, but are limited in mature IL-1beta release compared with blood monocytes. The mechanism of this IL-1beta control may provide important insights into the physiology of IL-1beta at the tissue level. Since it has been hypothesized that IL-1beta processing by the IL-1beta-converting enzyme (ICE) regulates IL-1beta release, we compared human alveolar macrophages and human blood monocytes for relative ICE expression and activation. Using immunoblots and enzyme-linked immunoassay for ICE, we demonstrate that alveolar macrophages do not differ from blood monocytes in antigenic p45 ICE. Furthermore, an indirect assay for functional ICE documents similar ICE activities in both monocytes and alveolar macrophages, i.e., similar concentrations of soluble synthetic ICE inhibitor (IC50 values of 0.3 +/- 0.01 and 0.6 +/- 0.2 microM, respectively) are required to block mature IL-1beta generation. However, as has been reported for THP-1 myelomonocytic cells, neither alveolar macrophages nor blood monocytes contain directly quantifiable levels of functional ICE forms (p22/p20 and p10) when assayed by immunoblots or by a sensitive capture ELISA that uses an irreversible, biotinylated ICE inhibitor. These findings document that the macrophage limitation in mature IL-1beta release is not due to a lack of ICE or to an inability to activate ICE. Finally, using a staged release assay, the time to half-maximum mature IL-1beta release is significantly depressed in macrophages compared with that in monocytes. Taken together, these findings suggest that macrophage IL-1beta export is regulated independently of ICE activation.


Upstream domains of the Xenopus laevis rDNA promoter are revealed in microinjected oocytes.
The DNA sequences involved in promoting transcription of the Xenopus laevis rRNA genes were determined by microinjecting a series of deletion mutants into oocyte nuclei. A very small promoter region is sufficient to direct efficient transcription when templates are microinjected at high rDNA concentration, since 5'delta- 9 and 3'delta +6 templates are fully active. However, as the concentration of injected template is decreased, an increasing requirement for upstream domains, extending to nucleotide approximately -170, is observed. The major downstream border of the required region does not change. This apparently expanding 5' promoter border results from the fact that, as the rDNA concentration is decreased, transcription from templates lacking the upstream promoter domain falls off much more sharply than does transcription from a complete promoter. In fact, the deleted promoters are virtually inactive below a threshold rDNA concentration. It is indeed the rDNA concentration that is important, for coinjected vector DNA does not increase the level of transcription obtained from low concentrations of the 5' deletions. From these data we conclude that polymerase I transcription factors can recognize and initiate transcription from a small core promoter domain, but that sequences extending upstream to nucleotide approximately -170 increase the efficiency of initiation. A model is presented that could account for these results.


Perioperative THR-184 and AKI after Cardiac Surgery.
AKI after cardiac surgery is associated with mortality, prolonged hospital length of stay, use of dialysis, and subsequent CKD. We evaluated the effects of THR-184, a bone morphogenetic protein-7 agonist, in patients at high risk for AKI after cardiac surgery. We conducted a randomized, double-blind, placebo-controlled, multidose comparison of the safety and efficacy of perioperative THR-184 using a two-stage seamless adaptive design in 452 patients between 18 and 85 years of age who were scheduled for nonemergent cardiac surgery requiring cardiopulmonary bypass and had recognized risk factors for AKI. The primary efficacy end point was the proportion of patients who developed AKI according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. The proportion of patients who developed AKI within 7 days of surgery was similar in THR-184 treatment groups and placebo groups (range, 74%-79%; P=0.43). Prespecified secondary end point analysis did not show significant differences in the severity of AKI stage (P=0.53) or the total duration of AKI (P=0.44). A composite of death, dialysis, or sustained impaired renal function by day 30 after surgery did not differ between groups (range, 11%-20%; P=0.46). Safety-related outcomes were similar across all treatment groups. In conclusion, compared with placebo, administration of perioperative THR-184 through a range of dose exposures failed to reduce the incidence, severity, or duration of AKI after cardiac surgery in high-risk patients.


Prospective multicenter non-interventional real-world study to assess the patterns of use, effectiveness and safety of follitropin delta in routine clinical practice (the PROFILE study).
To observe the real-world utilization patterns, effectiveness and safety profile of follitropin delta in women ≥18 years naïve to ovarian stimulation undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Prospective, multinational, multicenter, observational study. All IVF/ICSI treatment protocols were conducted according to routine clinical practice, including undertaking fresh/frozen transfers. Outcomes included use of dosing algorithm, follitropin delta dosing patterns, ovarian response, pregnancy rates and adverse drug reactions (ADRs). The first ovarian stimulation cycle using follitropin delta was initiated in 944 women. Mean baseline demographics were: age, 33.5 ± 4.7 years; bodyweight, 67.1 ± 13.6 kg; anti-Müllerian hormone, 20.3 ± 16.1 pmol/L (2.84 ± 2.25 ng/mL). The dosing algorithm was used to calculate the follitropin delta daily starting dose in 893/944 women (94.5%). The mean difference between the calculated and prescribed daily dose was small (0.2 ± 1.40 µg). The mean daily starting follitropin delta dose was 10.4 ± 2.72 µg and the mean total dose administered was 104 µg. Follitropin delta dose adjustments were reported for 57/944 (6.0%) women. The mean number of retrieved oocytes was 10.1 ± 7.03. Ongoing pregnancy at 10-11 weeks was reported for 255 women (27.0% per initiated cycle and 43.1% per fresh transfer [n=592]). Cumulative ongoing pregnancy rate after fresh and/or frozen transfer was 36.4% (344/944). Four women discontinued follitropin delta due to ADRs. Ovarian hyperstimulation syndrome (OHSS) was the most frequently reported ADR (n=37 [3.9%]); most cases of OHSS were of mild or moderate intensity (n=30 [3.2%]). This large real-world study of follitropin delta utilization patterns confirms its good pregnancy rates while minimizing OHSS risk during first ovarian stimulation cycle.


Serum 7 alpha-hydroxycholesterol as a new parameter of liver function in patients with chronic liver diseases.
To examine bile acid synthesis in chronic liver diseases, serum total 7 alpha-hydroxycholesterol level was measured by gas-liquid chromatography-mass spectrometry in patients with cirrhosis (n = 23), patients with chronic hepatitis (n = 21), and control subjects (n = 18). The serum 7 alpha-hydroxycholesterol levels were significantly lower in patients with cirrhosis than the controls (78 +/- 59 pmol/mL vs. 237 +/- 97 pmol/mL; mean +/- SD). However, in patients with chronic hepatitis, the level was fully retained (262 +/- 102 pmol/mL). Serum 7 alpha-hydroxycholesterol levels of 17 patients with cirrhosis classified as Child B and C ranged from 33 to 69 pmol/mL, and all were less than the normal range (between 104 and 466 pmol/mL), however, those levels of some patients classified as Child A were within the normal range. Serum 7 alpha-hydroxycholesterol levels significantly correlated with serum albumin, cholinesterase, total bile acid, direct bilirubin, alkaline phosphatase, indocyanine green (ICG) retention rate, hepaplastin test, and lecithin-cholesterol acyltransferase activities. We conclude that bile acid synthesis is well preserved in patients with chronic hepatitis and that it is decreased in most patients with cirrhosis. Serum 7 alpha-hydroxycholesterol may be a new parameter of liver function testing to assess hepatic bile acid synthesis in patients with chronic liver diseases.