Wireless and Wearable Auditory EEG Acquisition Hardware Using Around-The-Ear cEEGrid Electrodes.
Aside from a clinical interest in electroencephalography (EEG) measurements of real-time data with a high temporal resolution, there is a demand for acquisition systems that are operable outside the laboratory environment. In this study, we designed a wearable and low-power EEG system for multichannel EEG acquisition beyond the lab doors. Around-the-ear cEEGrid electrodes are used to capture 8 biopotential channels which are amplified by low-power precision instrumentation amplifiers and passed on to an analog-to-digital converter (ADC). An ESP32 micro-controller captures the data from the ADC and stores it on an external SD card. The proposed system is compared to a state-of-the-art EEG acquisition system (BioSemi) to assess its diagnostic power for auditory brainstem responses (ABRs). The recordings with our portable system match, and even outperform, the baseline method's specifications. Our hardware opens up new avenues for fast sampling-rate auditory EEG recordings that can be used in hearing diagnostics, damage prevention and treatment follow up.


Envelope-chimeric entry-targeted measles virus escapes neutralization and achieves oncolysis.
Measles virus (MV) is a promising vector for cancer therapy and multivalent vaccination, but high prevalence of pre-existing neutralizing antibodies may reduce therapeutic efficacy, particularly following systemic administration. MV has only one serotype, but here we show that its envelope glycoproteins can be exchanged with those of the closely related canine distemper virus (CDV), generating a chimeric virus capable of escaping neutralization. To target its entry, we displayed on the CDV attachment protein a single-chain antibody specific for a designated receptor. To enhance oncolytic efficacy we armed the virus with a prodrug convertase gene capable of locally activating chemotherapeutic prodrugs. The new virus achieved high titers, was genetically stable, and was resistant to neutralization by sera from both MV-immunized mice and MV-immune humans. The new virus targeted syngeneic murine tumor cells expressing the designated receptor implanted in immunocompetent mice, and synergized with a chemotherapeutic prodrug in a model of oncolysis. Importantly, the chimeric MV remained oncolytic when administered systemically even in the presence of anti-MV antibodies capable of abrogating the therapeutic efficacy of the parental, nonshielded MV. This work shows that targeting, arming, and shielding can be combined to generate a tumor-specific, neutralization-resistant virus that can synergize with chemotherapeutics.


[Role of physico-chemical and biochemical composition of urine in the genesis of combined nephrolithiasis and cholelithiasis].
Enzymuria, principal fractions of phospholipids, crystal-inhibiting urine activity were measured in 120 patients with nephrolithiasis combined with cholelithiasis. The patients were divided into two groups: group 1-80 patients with symptoms of nephrolithiasis and latent cholelithiasis; group 2-40 patients with symptoms of cholelithiasis and latent nephrolithiasis. It is shown that hyperenzymuria/microproteinuria, high excretion of phospholipids and cholesterol with urine in patients with nephrolithiasis and its complications not only affect physico-chemical properties of urine promoting atypical salt crystallization with stone formation but also determine characteristics of phasic urine conditions. High urine concentration of phospholipid (acyl derivatives) degradation products and cholesterol in patients with combination of nephrolithiasis with cholelithiasis changes solubilizing and micello-forming ability of urine and can directly stimulate crystal formation and development of aseptic inflammation in renal parenchyma. Low total crystal-inhibiting urine activity, altered surface-free energy due to surface-active substances, high calcium ionization and low urine magnesium ionization are not only pathognomonic criteria of nephrolithiasis but also parameters reflecting high risk of oxalate-calcium formation in patients with nephrolithiasis combination with cholelithiasis.


Vibrio vulnificus rpoS expression is repressed by direct binding of cAMP-cAMP receptor protein complex to its two promoter regions.
Vibrio vulnificus, a septicemia-causing pathogenic bacterium, acquires resistance against various stresses and expresses virulence factors via an rpoS gene product. In this study, we investigated the transcriptional characteristics of this global regulator. Two distinct transcriptional initiation sites for the rpoS gene, the proximal promoter (P(p)) and the distal promoter (P(d)), were defined by primer extension experiments. Various rpoS::luxAB transcriptional fusions indicated that P(d) is a major promoter of rpoS expression. Western blot analysis showed that RpoS levels were inversely correlated with intracellular levels of 3',5'-cyclic AMP (cAMP). The expressions of both P(d) and P(p) were increased in cya and crp mutants. The exogenous addition of cAMP to the cya mutant resulted in repressed expression of rpoS. In addition, rpoS expression was significantly lowered in the cpdA mutant, in which the level of cAMP was elevated because of the absence of 3',5'-cAMP phosphodiesterase. In vitro transcription assays using the V. vulnificus RNA polymerase showed that the transcripts from both promoters were reduced by addition of the cAMP-cAMP receptor protein (CRP). The cAMP-CRP was shown to bind to two rpoS promoters by electrophoretic mobility shift assays. The alteration of the putative CRP-binding site on each rpoS promoter, via site-directed mutagenesis, abolished the binding of cAMP-CRP as well as regulation by cAMP-CRP. Therefore, this study shows a relationship between the level of intracellular cAMP and the degree of rpoS expression and further demonstrates, for the first time, the direct binding of the cAMP-CRP complex to rpoS upstream regions, which results in repression of rpoS gene expression.


Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes: A potential interferon-γ-dependent mechanism contributing to HIV neuropathogenesis.
Induction of the detoxifying enzyme heme oxygenase-1 (HO-1) is a critical protective host response to cellular injury associated with inflammation and oxidative stress. We previously found that HO-1 protein expression is reduced in brains of HIV-infected individuals with HIV-associated neurocognitive disorders (HAND) and in HIV-infected macrophages, where this reduction associates with enhanced glutamate release and neurotoxicity. Because HIV-infected macrophages are a small component of the cellular content of the brain, the reduction of macrophage HO-1 expression likely accounts for a small portion of brain HO-1 loss in HIV infection. We therefore investigated the contribution of astrocytes, the major pool of brain HO-1. We identified immunoproteasome-mediated HO-1 degradation in astrocytes as a second possible mechanism of brain HO-1 loss in HIV infection. We demonstrate that prolonged exposure of human fetal astrocytes to interferon-gamma (IFNγ), an HIV-associated CNS immune activator, selectively reduces expression of HO-1 protein without a concomitant reduction in HO-1 RNA, increases expression of immunoproteasome subunits, and decreases expression of constitutive proteasome subunits, consistent with a shift towards increased immunoproteasome activity. In HIV-infected brain HO-1 protein reduction also associates with increased HO-1 RNA expression and increased immunoproteasome expression. Finally, we show that IFNγ treatment of astrocytic cells reduces HO-1 protein half-life in a proteasome-dependent manner. Our data thus suggest unique causal links among HIV infection, IFNγ-mediated immunoproteasome induction, and enhanced HO-1 degradation, which likely contribute to neurocognitive impairment in HAND. Such IFNγ-mediated HO-1 degradation should be further investigated for a role in neurodegeneration in inflammatory brain conditions. Kovacsics et al. identify immunoproteasome degradation of heme oxygenase-1 (HO-1) in interferon gamma-stimulated astrocytes as a plausible mechanism for the observed loss of HO-1 protein expression in the brains of HIV-infected individuals, which likely contributes to the neurocognitive impairment in HIV-associated neurocognitive disorders.


Characterization of nonspecific esterase activity in macrophages and intestinal epithelium of the rat.
We determined the histochemical characteristics of nonspecific esterase in different populations of rat macrophages. The cells included alveolar and peritoneal macrophages recovered by lavage and a mixed cell population obtained by collagenase digestion of the small intestine. The histochemically localized enzyme activity of alveolar and peritoneal macrophages was cytoplasmic, diffuse, and inhibited by sodium fluoride. Both populations were effectively stained using alpha-naphthyl acetate and alpha-naphthyl butyrate as the esterase substrate. When the intestinal cells were examined for activity, a greater percentage of cells showed positive nonspecific esterase than would be predicted by differential counts for macrophages on the basis of morphological criteria. We confirmed, using cell smears and tissue sections, that rat intestinal epithelial cells, a prominent component of the isolated cell population, possessed esterases that react similarly to macrophage esterases with histochemical procedures.


Increased spontaneous unit discharge rates following electrical kindling in the rat.
Changes in neuronal excitability that persist after seizures may play a key role in epilepsy. In this study, extracellular single unit recording techniques were used to investigate the changes in cell discharge patterns that result from kindling in vivo. The spontaneous activity of piriform and perirhinal cortical units in chronically implanted adult rats was recorded before, during and after kindling the amygdala. We observed that kindling-induced seizures resulted in a prolonged and dramatic increase in the rate of spontaneous background neuronal discharge in both the piriform and perirhinal regions.


Primary total hip arthroplasty versus hemiarthroplasty for displaced intracapsular hip fractures in older patients: systematic review.
To determine whether total hip arthroplasty is associated with lower reoperation rates, mortality, and complications, and better function and quality of life than hemiarthroplasty for displaced fractures of the femoral neck in older patients. Systematic review and meta-analysis of randomised trials, quasirandomised trials, and cohort studies. Medline, Embase, Cochrane register of controlled trials, publishers' databases, and manual search of bibliographies. Randomised controlled trials, quasirandomised trials, and cohort studies (retrospective and prospective) comparing hemiarthroplasty with total hip arthroplasty for treating displaced femoral neck fractures in patients aged more than 60 years. Relative risks, risk differences, and mean differences from each trial, aggregated using random effects models. Analyses were stratified for experimental and non-experimental designs, and two way sensitivity analyses and tests for interaction were done to assess the influence of various criteria of methodological quality on pooled estimates. 3821 references were identified. Of the 202 full papers inspected, 15 were included (four randomised controlled trials, three quasirandomised trials, and eight retrospective cohort studies, totalling 1890 patients). Meta-analysis of 14 studies showed a lower risk of reoperation after total hip arthroplasty compared with hemiarthroplasty (relative risk 0.57, 95% confidence interval 0.34 to 0.96, risk difference 4.4%, 95% confidence interval 0.2% to 8.5%), although this effect was mainly driven by investigations without concealed treatment allocation. Total hip arthroplasty consistently showed better ratings in the Harris hip score (three studies, 246 patients, weighted mean difference 5.4, 95% confidence interval 2.7 to 8.2) after follow-up periods of 12 to 48 months. The standardised mean difference of different scores from five studies was 0.42 (95% confidence interval 0.24 to 0.61), indicating a medium functional advantage of total hip arthroplasty over hemiarthroplasty. Total hip arthroplasty was associated with a slightly higher risk of dislocation (relative risk 1.48, 95% confidence interval 0.89 to 2.46) and general complications (1.14, 0.87 to 1.48). Single stage total hip arthroplasty may lead to lower reoperation rates and better functional outcomes compared with hemiarthroplasty in older patients with displaced femoral neck fractures. However, heterogeneity across the available trials and distinct subgroup effects preclude definitive statements and require further research in this area.


Rectal Administration of Ibuprofen: Comparison of Enema and Suppository Form.
Ibuprofen is a widely used and well-tolerated analgesic and antipyretic. It is desirable to have a formulation with a rapid rate of absorption because it is required for rapid pain relief and temperature reduction. Previous studies have described the pharmacokinetic profiles of ibuprofen suppository and the mean peak times of ibuprofen suppository were around 1.8 hours, indicating a slower rate of absorption. The aim of this study is to compare the pharmacokinetic parameters of rectal administration of ibuprofen between enema and suppository form in order to provide evidence for the faster absorption rates of ibuprofen enema. This study was a phase-1 clinical study, open-label, randomized and two-way crossover with one-week washout period comparing the absorption profile of equal dose of ibuprofen administered rectally in two treatment phases: ibuprofen suppository and enema. Blood samples were collected post dose for pharmacokinetic analyses. Tmax was analyzed using a Wilcoxon matched paired test. A standard ANOVA model, appropriate for bioequivalence studies was used and ratios of 90% confidence intervals were calculated. This study showed that Tmax for ibuprofen enema was less than half that of ibuprofen suppository (median 40 min vs. 90 min, respectively; p-value=0.0003). Cmax and AUC0-12 for ibuprofen enema were bioequivalent to ibuprofen suppository, as the ratio of test/reference=104.52%, 90% CI 93.41-116.95% and the ratio of test/reference=98.12%, 90%CI 93.34-103.16%, respectively, which fell within 80-125% bioequivalence limit. The overall extent of absorption was similar to the both, which were all well tolerated. In terms of Tmax, Ibuprofen enema was absorbed twice as quickly as from ibuprofen suppository. Therefore it is expected that an ibuprofen enema may provide faster onset of analgesic and antipyretic benefit.


[Comparative study between sodium stibogluconate BP 88 and meglumine antimoniate in cutaneous leishmaniasis treatment. II. Biochemical and cardiac toxicity].
Toxicity of two antimonial pentavalents were evaluated in 111 patients with cutaneous leishmaniasis. Forty-seven patients received meglumine antimoniate (Group I) and 64 patients, sodium stibogluconate BP 88 (Group II), 20 mg Sbv/kg/day for 20 days. Evaluation of aminotransferases, alkaline phosphatase, amilase, creatinine, urea, urine analysis and electrocardiogram were performed at baseline, on the tenth and twentieth day of treatment. Greater frequency of aminotransferase abnormal levels were observed on the tenth and twentieth days in group II (p < 0.001) and a greater proportion of amilase abnormal levels at the tenth day in the same group (p < 0.001). There was a greater variation of aminotransferases, alkaline phosphatase and amilase in the first ten days of treatment in group II (p < 0.01). On the twentieth day there was a greater variation of aminotransferase levels in group II (p = 0.02 and p = 0.03, respectively). Forty-three percent of group I and 54% of group II showed electrocardiographic abnormalities (p = 0.30).


Serum 25 hydroxyvitamin D, bone mineral density and fracture risk across the menopause.
Low levels of serum 25 Hydroxyvitamin D [25(OH)D] have been linked to greater fracture risk in older women. This study aimed to determine whether higher 25(OH)D is associated with slower loss of bone mineral density (BMD) and lower fracture risk during the menopausal transition. This was a prospective cohort study at five clinical centers in the United States. Mean age was 48.5 ± 2.7 years. The fracture analysis included 124 women with an incident traumatic fracture, 88 with incident nontraumatic fracture, and 1532 women without incident fractures; average followup was 9.5 years. BMD analysis included 922 women with a documented final menstrual period. Serum 25(OH)D was measured by liquid chromatography tandem mass spectrometry at the third annual clinic visit. BMD was measured and incident fractures ascertained at each annual visit. The mean 25(OH)D was 21.8 ng/mL; seven-hundred two (43%) of the women had 25(OH)D values <20 ng/mL. There was no significant association between 25(OH)D and traumatic fractures. In multivariate adjusted hazards models, the hazard ratio (HR) for nontraumatic fractures (95% confidence interval [CI]) was 0.72 (0.54-0.96) for each 10-ng/mL increase in 25(OH)D. Comparing women whose 25(OH)D was ≥20 vs <20 ng/mL, the HR (95% CI) for fracture was 0.54 (0.32-0.89). Changes in lumbar spine and femoral neck bone mineral density across menopause were not significantly associated with serum 25(OH)D level. Serum 25(OH)D levels are inversely associated with nontraumatic fracture in mid-life women. Vitamin D supplementation is warranted in midlife women with 25(OH)D levels <20 ng/mL.


An evaluation of tuberculosis contact investigations against national standards.
Contact tracing is a key element in England's 2015 collaborative TB strategy, although proposed indicators of successful contact tracing remain undescribed. We conducted descriptive and multivariable analyses of contact tracing of TB cases in London between 1 July 2012 and 31 December 2015 using cohort review data from London's TB Register, identifying characteristics associated with improved indicators and yield. Of the pulmonary TB cases notified, 60% (2716/4561) had sufficient information for inclusion. Of these, 91% (2481/2716) had at least 1 contact (median: 4/case (IQR: 2-6)) identified, with 86% (10 251/11 981) of these contacts evaluated. 4.1% (177/4328), 1.3% (45/3421) and 0.70% (51/7264) of evaluated contacts of pulmonary smear-positive, pulmonary smear-negative and non-pulmonary cases, respectively, had active disease. Cases who were former prisoners or male were less likely to have at least one contact identified than those never imprisoned or female, respectively. Cases diagnosed at clinics with more directly observed therapy or social workers were more likely to have one or more contacts identified. Contacts screened at a different clinic to their index case or of male index cases were less likely to be evaluated than those screened at the same clinic or of women, respectively; yield of active disease was similar by sex. 10% (490/4850) of evaluated child contacts had latent TB infection. These are the first London-wide estimates of TB contact tracing indicators which are important for monitoring the strategy's success and informing risk assessment of index cases. Understanding why differences in indicators occur between groups could improve contact tracing outcomes.


Prolonged sitting leg vasculopathy: contributing factors and clinical implications.
Atherosclerotic peripheral artery disease primarily manifests in the medium- to large-sized conduit arteries of the lower extremities. However, the factors underlying this increased vulnerability of leg macrovasculature to disease are largely unidentified. On the basis of recent studies, we propose that excessive time spent in the sitting position and the ensuing reduction in leg blood flow-induced shear stress cause endothelial cell dysfunction, a key predisposing factor to peripheral artery disease. In particular, this review summarizes the findings from laboratory-based sitting studies revealing acute leg vascular dysfunction with prolonged sitting in young healthy subjects, discusses the primary physiological mechanisms and the potential long-term implications of such leg vasculopathy with repeated exposure to prolonged sitting, as well as identifies strategies that may be effective at evading it.


The growth hormone response to insulin induced hypoglycaemia in anorexia nervosa and control underweight or normal subjects.
Hypoglycaemic stimulation of growth hormone (GH) secretion has been measured in 12 anorexia nervosa patients, 11 adolescents approximately matched for weight and age, 14 underweight adults with no history of anorexia nervosa and 27 normal patients. The results showed a high proportion of blunted growth hormone responses among the anorexia nervosa patients as compared to normal subjects, underweight adolescents or adults. In the group of underweight adults, diminshed growth hormone responses were most frequently seen in patients with depressive illness. The complex pathogenesis of the diminshed growth hormone response in anorexia nervosa involves many factors; undernutrition itself, possible hypothalamic insufficiency related to the psychopathological background and other endocrine abnormalities like hypogonadism, relative hypercorticism and hypothyroidism. The interference of the nutritional, psychological and endocrine factors could not be dissociated in our investigation or from the review of the literature on this subject. It is suggested that hypothalamic insufficiency plays a prominent role in the growth hormone hyporesponsiveness in anorexia nervosa. Although diminished, the stimulated growth hormone response remains higher in anorexia nervosa than in true hypopituitarism. This phenomenon coupled to a preserved or even increased suprarenal function enables one to differentiate cachexia resulting from anorexia nervosa and hypopituitarism leading eventually to cachexia.


[Changes in general hemostasis in patients with diabetic retinopathy].
The hemostasis system was analyzed in 106 patients with diabetes mellitus, including 86 patients with diabetic retinopathy. Parameters of coagulogram and thromboelastogram as well as platelets aggregation, stimulated by collagen, were examined in all patients. Besides, the fibrinolytic activity of blood plasma as well as the concentration of plasminogen, fibrinogen and of fibrin-degradation products were evaluated. Essential changes were detected, which correlated with an intensity of diabetic changes in the eye fundus, i.e. generalized hypercoagulation caused by a lower activity of the system antithrombin III-heparin, a higher activity of fibrinogen and activation of the fibrinolytic system. The obtained data denote an important role of impaired hemostasis in the pathogenesis of diabetic retinopathy.


Dynamic, contrast-enhanced CT of human brain tumors: quantitative assessment of blood volume, blood flow, and microvascular permeability: report of two cases.
We present two patients with metastatic brain tumors who underwent dynamic contrast-enhanced CT that yielded estimates of blood volume, blood flow, and microvascular permeability. For one patient, these CT-based quantifications were compared with contrast-enhanced MR-based assessments of fractional blood volume and permeability. Regional blood volume heterogeneity patterns were consistent between both CT- and MR imaging-based mapping. Permeability variations across the tumor, however, were less consistent, perhaps because of differences between ionic and non-ionic contrast agents. The advantages of dynamic contrast-enhanced CT in comparison with dynamic, contrast-enhanced MR imaging for microvascular quantifications are its availability and lower costs, applicability in the presence of MR imaging contraindications, and potentially more accurate analyses. The disadvantages are its limited anatomic coverage, radiation exposure, and the need for injection of a contrast agent.


Psychiatric morbidity in epilepsy: a case controlled study of adults receiving disability benefits.
To compare the prevalence of non-organic psychiatric disorders among disabled patients of normal intelligence with epilepsy with the prevalence of similar psychiatric disorders among age and sex matched disabled patients with other somatic diseases. A case-control study was carried out in Iceland among people receiving disability benefits using information available at the State Social Security Institute. There were 344 patients with epilepsy in Iceland 16 to 66 years of age (inclusive) receiving disability benefits in 1995. By excluding mentally retarded patients, autistic patients, and patients with organic psychoses, 241 index cases with epilepsy qualified for the study. For each case two age and sex matched controls were selected from all patients receiving disability benefits who had cardiovascular diseases, respiratory diseases, or arthropathies. The same exclusion criteria were applied to the controls as the index cases. In both patient groups psychiatric diagnoses were classified into one of the four following categories: (1) psychotic illness; (2) neurotic illness or personality disorders; (3) alcohol or drug dependence or misuse; and (4) other mental disorders. Psychiatric diagnosis was present among 35% (85/241) of the cases compared with 30% (143/482) of the controls (p=0.15). There was a difference in the distribution of the two groups into different psychiatric categories (p=0.02). This was mainly due to an excess of men in the index group with psychosis, particularly schizophrenia or paranoid states. The results suggest that there is not a difference in the prevalence of non-organic psychiatric disorders among disabled patients of normal intelligence with epilepsy compared with patients with other disabling somatic diseases. However, the data indicate that when psychopathology is present disabled patients with epilepsy are more likely to have psychotic illness than the other disabled patients.


Comprehensive analysis of the impact of procedure time and the 'golden hour' in subpopulations of stroke thrombectomy patients.
To evaluate the effect of procedure time on thrombectomy outcomes in different subpopulations of patients undergoing endovascular thrombectomy (EVT), given the recently expanded indications for EVT. This multicenter study included patients undergoing EVT for acute ischemic stroke at 35 centers globally. Procedure time was defined as time from groin puncture to successful recanalization (Thrombolysis in Cerebral Infarction score ≥2b) or abortion of procedure. Patients were stratified based on stroke location, use of IV tissue plasminogen activator (tPA), Alberta Stroke Program Early CT score, age group, and onset-to-groin time. Primary outcome was the 90-day modified Rankin Scale (mRS) score, with scores 0-2 designating good outcome. Secondary outcome was postprocedural symptomatic intracranial hemorrhage (sICH). Multivariate analyses were performed using generalized linear models to study the impact of procedure time on outcomes in each subpopulation. Among 8961 patients included in the study, a longer procedure time was associated with higher odds of poor outcome (mRS score 3-6), with 10% increase in odds for each 10 min increment. When procedure time exceeded the 'golden hour', poor outcome was twice as likely. The golden hour effect was consistent in patients with anterior and posterior circulation strokes, proximal or distal occlusions, in patients with large core infarcts, with or without IV tPA treatment, and across age groups. Procedures exceeding 1 hour were associated with a 40% higher sICH rate. Posterior circulation strokes, delayed presentation, and old age were the variables most sensitive to procedure time. In this work we demonstrate the universality of the golden hour effect, in which procedures lasting more than 1 hour are associated with worse clinical outcomes and higher rates of sICH across different subpopulations of patients undergoing EVT.


Retinoic acid modulates rat Ito cell proliferation, collagen, and transforming growth factor beta production.
Recent studies suggest that vitamin A plays an inhibitory role with respect to "activation" of the hepatic Ito cell, a likely effector of hepatic fibrogenesis. Ito cell "activation" during fibrogenesis is characterized by a decrease in intracellular vitamin A and an increase in cellular proliferation and collagen production. To explore the hypothesis that retinoids have the capacity to diminish Ito cell activation, cultured Ito cells were exposed to retinoic acid and its effects assessed on three key features: cell proliferation, collagen protein production and mRNA abundance, and transforming growth factor beta protein production. Retinoic acid was 100-1,000X more potent than retinol with respect to inhibition of Ito cell proliferation. Interstitial collagen and transforming growth factor beta production were also reduced by 10(-6) M retinoic acid. The relative abundance of type I collagen mRNA however, was not significantly altered. By contrast, retinoic acid administration to rats caused a marked reduction in the abundance of type I collagen mRNA in both total hepatic and purified Ito cell RNA. The relative abundance of rat hepatic fibronectin or apolipoprotein E mRNA was not significantly altered. These studies demonstrate that retinoic acid can differentially modulate several key features of hepatic fibrogenesis in vitro and in vivo.


Development of a Larval Zebrafish Infection Model for Clostridioides difficile.
Clostridioides difficile infection (CDI) is considered to be one of the most common healthcare-associated gastrointestinal infections in the United States. The innate immune response against C. difficile has been described, but the exact roles of neutrophils and macrophages in CDI are less understood. In the current study, Danio rerio (zebrafish) larvae are used to establish a C. difficile infection model for imaging the behavior and cooperation of these innate immune cells in vivo. To monitor C. difficile, a labeling protocol using a fluorescent dye has been established. A localized infection is achieved by microinjecting labeled C. difficile, which actively grows in the zebrafish intestinal tract and mimics the intestinal epithelial damage in CDI. However, this direct infection protocol is invasive and causes microscopic wounds, which can affect experimental results. Hence, a more noninvasive microgavage protocol is described here. The method involves delivery of C. difficile cells directly into the intestine of zebrafish larvae by intubation through the open mouth. This infection method closely mimics the natural infection route of C. difficile.


Limb and hip morphology of two African colobine monkeys and its relationship to the mechanics of leaping and bounding locomotion.
Although a bounding gait is practiced by a diversity of animals, the morphological characteristics, kinematics, and energetics associated with this locomotor form remain poorly understood. This study focuses on the locomotor anatomy of two species of African colobine monkeys (Piliocolobus badius, a leaper, and Colobus polykomos, a leaper-bounder) in an effort to assess if bounding should be considered a unique primate locomotor category or is better viewed as a behavior on a leaping continuum. A total of 53 femora, 28 humeri, and 45 ossa coxae from the two species provide comparative morphological data. Free-body models of bounding and leaping are presented to characterize loading conditions. Species differences in morphometric traits are evaluated via parametric and nonparametric tests (i.e., analysis of variance, resampling). C. polykomos exhibits traits that align more closely with putative leaping specializations when compared to P. badius (e.g., large femoral head, long femur, low femoral neck angle), while also possessing certain traits that are not (e.g., long femoral neck and reduced relative femoral robusticity). Consequently, C. polykomos likely experiences absolutely greater joint forces at the hip and higher bending at the femoral neck both when it leaps and bounds, given equivalent accelerations in bounding and leaping. Bounding is best described as a form of low-acceleration leaping. If bounding has lower acceleration requirements relative to leaping, C. polykomos achieves locomotor competence with less energy, relatively smaller bending moments, and reduced joint forces.


Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992.
In 1982 the European Neuroblastoma Study Group (ENSG) established a prospective registry for patients with newly diagnosed neuroblastoma ('The ENSG Survey'). Clinical information was collected primarily to: (a) establish an ENSG database; and (b) investigate prognostic factors in neuroblastoma. This paper summarises the results of the survey. By 1992, 1277 patients with a median age of 26 months (range: 0-289 months), gender ratio of 1.19 M:F had been registered from 30 centres. The median follow-up of survivors is 9.7 years (range: 1-14 years). Overall 5-year survival (S) is 45% (95% CI 42-48%), and event-free survival (EFS) is 43% (95% CI 40-45%). For both survival and EFS the key established prognostic factors, stage and age, are highly significant (P<0.001). In particular, patients under 1 year of age at diagnosis, whatever the disease stage, had a more favourable prognosis than older patients; stage 2 (EFS 93% (95% (CI 85-97) versus 76% (95% CI 67-86), P=0.02), stage 3 (EFS 91% (95% CI 82-96) versus 52% (95% CI 44-60), P<0.001) and stage 4 (EFS 59% (95% CI 48-69) versus 16% (95% CI 13-19), P<0.001). Multivariate analysis established that the anatomical location of the primary tumour (i.e. abdominal versus other sites) and primary tumour volume also conferred a statistically significant difference. In stage 4 disease the 20% of patients without demonstrable bone marrow involvement had a more favourable prognosis than those with infiltrated marrow (EFS 36% (95% CI 13-19) versus 16% (95% CI 29-45), P<0.001). Urine catecholamine metabolite levels (raised versus normal), histology (ganglioneuroblastoma versus neuroblastoma) and gender had no significant effect on outcome after stage and age were accounted for. 5-year survival following first relapse is only 5.6% (95% CI 2.8-8.4). This ENSG Survey provides secure data for future comparisons with new prognostic factors and treatment programmes.


Gender-specific profiles of adverse childhood experiences, past year mental and substance use disorders, and their associations among a national sample of adults in the United States.
This study examined profiles of adverse childhood experiences (ACEs) and mental and substance use disorders (MSUDs), and associations between distinct profiles of ACEs and MSUDs. Participants were adults (N = 34, 652) involved in the National Epidemiologic Survey on Alcohol and Related Conditions. Latent class analysis was used to examine both profiles of ten ACEs and ten past year MSUDs. Dual latent class analysis regression was used to examine associations between profiles of ACEs and MSUDs. Given gender differences in ACEs and MSUDs, analyses were conducted separately for females and males. Four profiles of ACEs and three profiles of MSUDs were selected for both genders. The four profiles of ACEs were characterized by the following probabilities: high multiple ACEs, high parental substance abuse, high childhood physical abuse, and low ACEs. The three profiles of MSUDs were characterized by the following probabilities: high multiple MSUDs for females and low MSUDs except alcohol use disorders for males, moderate-to-high major depressive episode, and low MSUDs. When compared to the low ACEs and MSUDs profiles, members in the higher ACEs profiles had 3.71-89.75 times greater odds of also being members in the higher MSUDs profiles. However, more than one-third of members in the high multiple ACEs profiles were also in the low MSUDs profiles. Study findings suggest four profiles of the ACEs widely studied as part of the Adverse Childhood Experiences study and risk and resilience for recent MSUDs among men and women nationally affected by ACEs.


Dysbiotic Lesional Microbiome With Filaggrin Missense Variants Associate With Atopic Dermatitis in India.
Background: Atopic Dermatitis (AD) has been associated with the loss of function (LoF) mutations in Filaggrin (FLG) gene and increase in relative abundance of specific microbes in the lesional skin, predominantly in Caucasians. Our study aims to determine, in Indian AD patients, (a) the prevalence of FLG LoF and missense mutations, and (b) the nature and extent of dysbiosis and altered microbial pathways with and without mutations in FLG. AD patients (n = 34) and healthy controls (n = 54) were recruited from India in this study and shotgun sequencing was carried out in a subset of samples with adequate microbiome DNA concentration. Host DNA from the same subset of samples was subjected to FLG coding region sequencing and host-microbiome association was estimated. Results: The prevalence of FLG LoFs that are associated with AD globally were significantly lesser in our cases and controls (8.6%, 0%) than those reported in Europeans (27%, 2.6%). Staphylococcus aureus was present only on AD skin [abundance in Pediatric AD: 32.86%; Adult AD: 22.17%], but not on healthy skin on which Staphylococcus hominis (Adult controls: 16.43%, Adult AD: 0.20%; p = 0.002), Cutibacterium acnes (Adult controls:10.84%, Adult AD: 0.90%; p = 0.02), and Malassezia globosa (Adult controls: 8.89%, Adult AD: 0.005%; p = 0.001) were significantly more abundant. Microbial pathways mostly associated with skin barrier permeability, ammonia production and inflammation (Arginine and Proline metabolism, Histidine Metabolism and Staphylococcus aureus infection) were significantly enriched on AD skin metagenome. These pathways are also reported to impair antimicrobial peptide activity. Among AD patients with missense single nucleotide polymorphisms harboring "potentially damaging" alleles in FLG gene, damaging allele dosage was significantly (p < 0.02) positively correlated with relative abundance of phylum_Proteobacteria up to order_Pseudomonadales and negatively correlated with phylum_Firmicutes up to species_Staphylococcus aureus. Conclusion: Our study has provided evidence that host DNA profile is significantly associated with microbiome composition in the development of AD. Species and strain level analysis showed that the microbial pathways enriched in AD cases were mostly found in MRSA strains. These evidences can be harnessed to control AD by modulating the microbiome using a personalized strategy. Our findings on the association of FLG genotypes with the microbiome dysbiosis may pave the way for a personalized strategy to provide a more effective control of AD.


Experience with irinotecan for the treatment of malignant glioma.
Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course. Chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival. Novel agents and new approaches to therapy are required to improve clinical outcomes. Irinotecan, a first-line treatment for metastatic colorectal cancer and an agent with high activity against solid tumors of the gastrointestinal tract, is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription. Irinotecan crosses the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts. Its antitumor activity has also been demonstrated against glioblastoma cells with multidrug resistance. Studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Studies of irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results. Irinotecan monotherapy has demonstrated efficacy; however, its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents. When administered concurrently with enzyme-inducing antiepileptic drugs, the dosage must be increased to compensate for enhanced cytochrome CY3A4/5 enzyme activity. Toxicities associated with irinotecan have been manageable; the most important dose-limiting toxicities are neutropenia and diarrhea. Irinotecan-based chemotherapy of malignant glioma merits further study.


Parallel and nonparallel behavioural evolution in response to parasitism and predation in Trinidadian guppies.
Natural enemies such as predators and parasites are known to shape intraspecific variability of behaviour and personality in natural populations, yet several key questions remain: (i) What is the relative importance of predation vs. parasitism in shaping intraspecific variation of behaviour across generations? (ii) What are the contributions of genetic and plastic effects to this behavioural divergence? (iii) And to what extent are responses to predation and parasitism repeatable across independent evolutionary lineages? We addressed these questions using Trinidadian guppies (Poecilia reticulata) (i) varying in their exposure to dangerous fish predators and Gyrodactylus ectoparasites for (ii) both wild-caught F0 and laboratory-reared F2 individuals and coming from (iii) multiple independent evolutionary lineages (i.e. independent drainages). Several key findings emerged. First, a population's history of predation and parasitism influenced behavioural profiles, but to different extent depending on the behaviour considered (activity, shoaling or boldness). Second, we had evidence for some genetic effects of predation regime on behaviour, with differences in activity of F2 laboratory-reared individuals, but not for parasitism, which had only plastic effects on the boldness of wild-caught F0 individuals. Third, the two lineages showed a mixture of parallel and nonparallel responses to predation/parasitism, with parallel responses being stronger for predation than for parasitism and for activity and boldness than for shoaling. These findings suggest that different sets of behaviours provide different pay-offs in alternative predation/parasitism environments and that parasitism has more transient effects in shaping intraspecific variation of behaviour than does predation.


Antidepressant Effect of the VA Weight Management Program (MOVE) Among Veterans With Severe Obesity.
Obesity is prevalent among users of Veteran's Health Administration services, where it is comorbid with depression, post-traumatic stress disorder, type 2 diabetes, cardiovascular disease, colon, and breast cancer. Among obese subjects, severe obesity represents a subpopulation with the highest risk of depression. We investigate the antidepressant effect of a local VA weight management program (Managing Overweight Veterans Everywhere - MOVE) among depressed veterans with severe obesity. In a 10-week prospective pilot study, 14 clinically depressed veterans with severe obesity were recruited from: (1) the 2-week residential based intense MOVE program (IMP) (N = 7) and (2) the 10-week educational module of self-management MOVE program (SMP) (N = 7). Subjects had a Beck Depression Inventory, 2nd edition (BDI-II) score > 12 and BMI > 40 or BMI > 35 with associated to comorbid conditions. Concurrent treatment for depression such as medications or psychotherapy was excluded. The primary efficacy endpoint was the change in BDI-II score form baseline to week 10. Analysis consisted of linear mixed model with baseline BDI-II score as a covariate, and level of MOVE intervention (IMP vs. SMP), time, and time by treatment interaction as fixed effects, and random patient effect. Pearson's correlation examined the relationships between clinical and demographic variables and change in severity of depression by BDI-II scores. Secondary outcomes include weight loss and energy expenditure. The sample was composed by 14 subjects (IMP = 7; SMP = 7) mostly unemployed (N = 9), married (N = 10), mid-aged (mean = 58.2, SD = 8.4), Caucasian (N = 13), male (N = 12), with recurrent depression (N = 11), and a mean overall duration of current depressive episode of 13.5 months (SD = 10.2). Out of 14 participants; seven had a family history of mood disorder, two had previous psychiatric hospitalization, three had a previous suicidal attempt, and eight had a history of substance use disorder. There was a significant decrease in severity of depression among all 14 (F3,36.77 = 5.28; P < 0.01); antidepressant effect favored the IMP compared to SMP at day 12 (F1,15.10 = 9.37, P = 0.01) and week 6 (F2,27.34 = 4.26, P = 0.03), but effect fell short of significance at week 10. The change in severity of depression measured by BDI-II score significantly correlated with total weight loss (r = -0.60; P = 0.04) and daily energy expenditure at 12 days (r = -0.67; P = 0.01), week 6 (r = -0.59; P = 0.03), and week 10 (r = -0.71; P = 0.01). Depressed veterans with severe obesity improved their depressive symptoms by participating in the MOVE program. Veterans in the IMP had greater but short-term antidepressant effect as compared to educational intervention for obesity. Future studies with larger sample size may elucidate the underlying mechanisms of weight reduction to improve depression and, more importantly, sustain response among veterans with severe obesity.


Chemical modulation of airway epithelial permeability.
The mucosal surface of the conducting airways has specialized structures for respiratory defense. Glands secret mucus that may act as a barrier to particle penetration and participate in particle clearance. Intraepithelial irritant receptors aid in particle clearance through airway constriction and cough. The epithelium acts as a barrier to the penetration of inhaled material into the airway wall. Morphologic studies have identified the tight junctions adjoining respiratory epithelial cells as the principal barrier to passive solute translocation across the airway. New approaches have been used to study airway epithelial function. Use of excised canine trachea mounted in Ussing chambers has permitted quantitative estimates of probe molecule permeation, the correlation of permeability with bioelectric properties, and estimation of equivalent pore radii. Probe molecule diffusion across canine trachea [mean transmucosal electric potential difference (PD) = 33 mV, lumen negative] is directly related to conductance (2.9 mS/cm2) and is compatible with an equivalent pore radius of 7.5 nm. Direct measurement of tracheal PD in vivo (-29 mV) facilitates study of the genesis of the biopotential in intact animals. Measurement of the movement of HRP by radioimmunoassay has allowed correlation of the rate of probe flow across airway walls in vivo with ultrastructure. These approaches lend themselves to the study of pharmacologic and toxicologic effects on epithelial function. Antigen challenge, diethyl ether, and unfractionated cigarette smoke have been shown to increase epithelial permeability to HRP accompanied by ultrastructural evidence of tight junctional damage. Application of pharmacologic agents, e.g. amphotericin, ouabain, onto the respiratory epithelium induces similar changes in in vitro and in vivo PD. We conclude that techniques that have been used to measure permeability and transport in other epithelia may help elucidate modes of action of environmental agents on airways.


Effects of carbamazepine on muscle tone in the decerebrate cat.
Previous studies, which have demonstrated that carbamazepine (CBZ) possesses direct muscle spindle suppressant activity, suggest that CBZ may have therapeutic value in the treatment of hypertonic disorders characterized by high fusimotor drive. The effects of CBZ on motor tone in the midcollicular decerebrate cat were therefore examined. CBZ, in a concentration-dependent manner, reduced muscle tone, as measured by the force necessary to overcome hyperextension. Significant depression was first observed at a serum concentration of about 25 micrograms/ml, whereas 50% depression occurred at about 40 micrograms/ml. These effects could not be attributed to the hypotensive effect of the drug. CBZ produced little or no effect on spontaneous gamma motoneuron activity recorded in teased ventral roots of segmentally deafferented spinal cords of decerebrate animals; chlorpromazine, however, was effective in suppressing such activity. In the same preparations, CBZ reduced polysynaptic but had little effect on monosynaptic spinal reflexes evoked by dorsal root stimulation. The drug also shortened the duration of the pause in spontaneous gamma motoneuron activity after dorsal root stimulation. Serum concentrations which diminished extensor rigidity in decerebrate cats induced mild to moderate intoxication in intact unanesthetized cats. This was characterized by ataxic gait, sedation and hypotonia. These experiments indicate that CBZ may be of value alone or adjunctively in the reduction of some forms of muscle hypertonicity.


Tongue piercing and associated oral and dental complications.
The insertion of metal objects into intraoral and perioral sites is growing in popularity. However, there are numerous oral and dental complications associated with tongue piercing. Fifteen patients with tongue piercings (pierced in the body of the tongue, anterior to the lingual frenum) attending the dental office of the authors, with and without complaints, were clinically and radiographically examined. The most common dental problem registered was chipping of teeth. Furthermore, two cracked teeth and four teeth with cusp fractures were also seen. One case of selective dental abrasion was registered. Trauma to the lingual anterior gingiva was the most common gingival problem. A salivary flow stimulating effect was only reported by 2 of the 15 individuals. None of the patients complained of interference with speech, mastication and swallowing. One case of galvanic currents produced by the appliance was registered. On the basis of the registered data, we concluded that patients need to be better informed of the potential complications associated with tongue and oral piercings, and that the dental profession can serve this role.


Effective removal of 137Cs ions from radioactive wastewater by Melamine-Styrene based Polymer (MSP).
Cesium (Cs) is a major product of uranium fission, which is one of the most existed radionuclides in radioactive wastes. Removal of Cs-137 has a critical role in the decontamination of liquid radioactive waste due to its half-life of 30.17 years. Concordantly, melamine styrene based conjugated polymer (MSP) was designed, synthesized, and characterized with FTIR, TGA, SEM and BET measurements. The novelty of the study is that the MSP adsorbent is designed as a highly conjugated structure to have better interaction with Cs over the Cs-π bond of the benzene groups of the adsorbent. In this work, the adsorption behavior and rate of MSP were investigated as parameters of adsorbent amount, pH, contact time, particle size, initial Cs+ concentration, and temperature. Besides, the adsorption efficiency of Cs-137 was examined by Gamma Spectroscopy. Adsorption results were fitted to three different isotherms which were Freundlich, Langmuir and Dubinin-Radushkevich (D-R). The maximum adsorption capacity of polymer for Cs+ ion was found from Langmuir isotherm as 78 mg g-1. As a part of kinetic parameters, pseudo first and second orders were investigated and in terms of the correlation coefficient pseudo second order was much more appropriate for adsorption of Cs-137 onto MSP.


Influential Factors in Pursuit of Pediatric Urology Fellowship Training.
We investigated factors that helped recent fellows achieve a successful match and sought to understand the influences in pursuing a career in pediatric urology. Selecting to continue training after urology residency entails much consideration. However, there are few tangible resources available to help residents understand the process. A 20-item web based survey was e-mailed to second year fellows and recent graduates of pediatric urology fellowships (103) from the graduating classes of 2013 to 2015. The survey explored factors that affected the decision to pursue this field along with the influence of mentors, fellows and other residents who applied to pediatric urology. We assessed the key factors that helped applicants achieve a successful match. Descriptive statistics and univariate logistic regression analysis were used to determine relationships between program characteristics and respondents' decisions to apply and interview at various programs. In total, 59 of 103 individuals surveyed (57.3%) responded to the survey. Faculty, program reputation and clinical volume had key roles in ranking programs, while satisfaction with the match result was contingent upon accurately assessing programs based on key factors such as family considerations, location, program reputation, faculty, clinical year volume and gut feeling. In addition, our survey demonstrated that having a pediatric urology fellow at one's institution had little impact on a resident's decision to pursue pediatric urology. As the subspecialty of pediatric urology continues to grow, we identified key elements that help shape and influence choices to participate in the future of this ever evolving field.


Enteral omega-3 in acute respiratory distress syndrome.
The acute respiratory distress syndrome (ARDS) is a severe illness that is often the cause of death in ICU patients. A safe and effective intervention for this condition is lacking. Fish oil-based enteral nutrition [rich in n-3 polyunsaturated fatty acids (PUFAs) and antioxidants] improved clinical outcomes in a previous trial on ARDS patients but was ineffective, or even harmful in other studies utilizing different fish oil formulae (rich in n-3 PUFAs and arginine) in severely ill ICU patients. Until most recently, consistent evidence that enteral n-3 PUFA is therapeutic in ARDS was lacking. In ARDS, an overwhelming inflammatory response damages the endothelial-alveolar units, reducing oxygen diffusion and increasing pulmonary workload. n-3 PUFA targets this inflammatory response. In two recent randomized, controlled studies, the fish oil formula that was previously shown to be effective was administered to patients with ARDS/acute lung injury (in which hypoxia is less severe) and to patients with severe sepsis and hypoxia, respectively. n-3 PUFA feeding improved oxygenation, and a meta-analysis of the three studies demonstrated that enteral fish oil reduces mortality, complications and length of ICU stay. Enteral administration of fish oil, antioxidants and physiologic amounts of arginine improve oxygenation and clinical outcomes in ICU patients with impaired oxygenation. Whether n-3 PUFA per se produces such benefit is the subject of an ongoing clinical study.


Caffeine Use Disorder: A Comprehensive Review and Research Agenda.
Caffeine is the most commonly used drug in the world. Although consumption of low to moderate doses of caffeine is generally safe, an increasing number of clinical studies are showing that some caffeine users become dependent on the drug and are unable to reduce consumption despite knowledge of recurrent health problems associated with continued use. Thus, the World Health Organization and some health care professionals recognize caffeine dependence as a clinical disorder. In this comprehensive literature review, we summarize published research on the biological evidence for caffeine dependence; we provide a systematic review of the prevalence of caffeine dependence and rates of endorsement of clinically meaningful indicators of distress and functional impairment among habitual caffeine users; we discuss the diagnostic criteria for Caffeine Use Disorder-a condition for further study included in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.); and we outline a research agenda to help guide future clinical, epidemiological, and genetic investigations of caffeine dependence. Numerous controlled laboratory investigations reviewed in this article show that caffeine produces behavioral and physiological effects similar to other drugs of dependence. Moreover, several recent clinical studies indicate that caffeine dependence is a clinically meaningful disorder that affects a nontrivial proportion of caffeine users. Nevertheless, more research is needed to determine the reliability, validity, and prevalence of this clinically important health problem.


Light-scattering studies on deoxyribonucleic acid flexibility. The solution properties of a small circular deoxyribonucleic acid molecule.
Previous investigations on the persistence length of DNA in solution have revealed large discrepancies between hydrodynamic results and those from light-scattering techniques which have potentially a greater resolving power. The information obtained from experiments on a small circular DNA molecule has resolved these discrepancies. The non-superhelical circular double-stranded DNA molecule from bacteriophage [unk]X174-infected cells is small enough to permit accurate light-scattering extrapolations, and its solutions have negligible anisotropy. The persistence length obtained from experimental investigations on this molecule is comparable with that obtained by hydrodynamic techniques, even with variation of the excluded-volume factor.


First early hominin from central Africa (Ishango, Democratic Republic of Congo).
Despite uncontested evidence for fossils belonging to the early hominin genus Australopithecus in East Africa from at least 4.2 million years ago (Ma), and from Chad by 3.5 Ma, thus far there has been no convincing evidence of Australopithecus, Paranthropus or early Homo from the western (Albertine) branch of the Rift Valley. Here we report the discovery of an isolated upper molar (#Ish25) from the Western Rift Valley site of Ishango in Central Africa in a derived context, overlying beds dated to between ca. 2.6 to 2.0 Ma. We used µCT imaging to compare its external and internal macro-morphology to upper molars of australopiths, and fossil and recent Homo. We show that the size and shape of the enamel-dentine junction (EDJ) surface discriminate between Plio-Pleistocene and post-Lower Pleistocene hominins, and that the Ishango molar clusters with australopiths and early Homo from East and southern Africa. A reassessment of the archaeological context of the specimen is consistent with the morphological evidence and suggest that early hominins were occupying this region by at least 2 Ma.


Are We Ready for NGS HIV Drug Resistance Testing? The Second "Winnipeg Consensus" Symposium.
HIV drug resistance is a major global challenge to successful and sustainable antiretroviral therapy. Next-generation sequencing (NGS)-based HIV drug resistance (HIVDR) assays enable more sensitive and quantitative detection of drug-resistance-associated mutations (DRMs) and outperform Sanger sequencing approaches in detecting lower abundance resistance mutations. While NGS is likely to become the new standard for routine HIVDR testing, many technical and knowledge gaps remain to be resolved before its generalized adoption in regular clinical care, public health, and research. Recognizing this, we conceived and launched an international symposium series on NGS HIVDR, to bring together leading experts in the field to address these issues through in-depth discussions and brainstorming. Following the first symposium in 2018 (Winnipeg, MB Canada, 21-22 February, 2018), a second "Winnipeg Consensus" symposium was held in September 2019 in Winnipeg, Canada, and was focused on external quality assurance strategies for NGS HIVDR assays. In this paper, we summarize this second symposium's goals and highlights.


Assessing Mental Healthcare Worker Experiences of Workplace Fairness and Organizational Value: A National Survey of Peer-Support Specialists.
Peer-support specialists-individuals with diagnosed mental illnesses who provide support services to other adults with diagnosed mental health issues-often feel stigmatized and undervalued at work, leading to negative personal- and job-related outcomes. Given their important link to positive service user outcomes, this study assessed how peer-support specialists perceive fairness and feel valued in the workplace. Peer-support specialists (N = 274) were recruited online from peer-support specialist listservs, social media groups, and patient-run organizations to take a cross-sectional survey that included a 14-item scale on how workplace fairness relates to job satisfaction and four questions on how valued they felt by administrators, clinicians, the people they serve, and fellow peer-support specialists. Descriptive and bivariate statistics were used to assess total scores and differences by gender and race. Ranging in age from 20 to 77 years and identifying predominantly as White (81.0%) and female (62.9%), respondents noted that fair practices in the workplace would increase their job satisfaction, with no significant differences observed by gender or race. Most peer-support specialists felt valued by the people they serve (97.1%) and fellow peer-support specialists (92.7%). However, fewer reported feeling valued by administrators (64.6%) and clinicians (60.6%). Peer-support specialists value fairness at the workplace and feel undervalued by some staff. This study highlights peer-support specialists' important role in behavioral health services and suggests that healthcare professionals, including occupational health specialists, are important stakeholders in creating fairer workplaces and increasing peer-support specialists' sense of being valued, leading to improved personal and organizational outcomes.


Localization of metabotropic glutamate receptor 7 mRNA and mGluR7a protein in the rat basal ganglia.
Metabotropic glutamate receptors (mGluRs) coupled to G-proteins have important roles in the regulation of basal ganglia function. We have examined the localization of the mGluR7 mRNA and mGluR7a protein in the basal ganglia of the rat. Strong mGluR7 hybridization signals are found in cerebral cortex and striatum, but much less intense signals are present in other components of the basal ganglia. Abundant mGluR7a immunoreactivity was found in striatum, globus pallidus (GP), and substantia nigra pars reticulata (SNr). Examination using confocal microscopy together with dendritic and presynaptic markers as well as studies in lesion models provided evidence for the presence of mGluR7a on presynaptic terminals in all three structures. Electron microscopic studies confirmed the presence of mGluR7a in axon terminals in both the striatum and the GP and also revealed the presence of mGluR7a at postsynaptic sites in both of these regions. Our data demonstrate that mGluR7a is located not only on presynaptic glutamatergic terminals of the corticostriatal pathway, where it may serve as an autoreceptor, but also on terminals of striatopallidal and striatonigral projections, where it may modulate the release of gamma-aminobutyric acid (GABA). The presence of mGluR7 at these multiple sites in the basal ganglia suggests that this receptor has a particularly crucial role in modulating neurotransmitter release in major basal ganglia pathways.


Fatherhood alters gene expression within the MPOA.
Female parenting is obligate in mammals, but fathering behavior among mammals is rare. Only 3-5% of mammalian species exhibit biparental care, including humans, and mechanisms of fathering behavior remain sparsely studied. However, in species where it does exist, paternal care is often crucial to the survivorship of offspring. The present study is the first to identify new gene targets linked to the experience of fathering behavior in a biparental species using RNA sequencing. In order to determine the pattern of gene expression within the medial preoptic area that is specifically associated with fathering behavior, we identified genes in male prairie voles (Microtus ochrogaster) that experienced one of three social conditions: virgin males, pair bonded males, and males with fathering experience. A list of genes exhibiting different expression patterns in each comparison (i.e. Virgin vs Paired, Virgin vs Fathers, and Paired vs Fathers) was evaluated using the gene ontology enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes pathways analysis to reveal metabolic pathways associated with specific genes. Using these tools, we generated a filtered list of genes that exhibited altered patterns of expression in voles with different amounts of social experience. Finally, we used NanoString to quantify differences in the expression of these selected genes. These genes are involved in a variety of processes, with enrichment in genes associated with immune function, metabolism, synaptic plasticity, and the remodeling of dendritic spines. The identification of these genes and processes will lead to novel insights into the biological basis of fathering behavior.


Three Drosophila beta-tubulin sequences: a developmentally regulated isoform (beta 3), the testis-specific isoform (beta 2), and an assembly-defective mutation of the testis-specific isoform (B2t8) reveal both an ancient divergence in metazoan isotypes and structural constraints for beta-tubulin function.
The genomic DNA sequence and deduced amino acid sequence are presented for three Drosophila melanogaster beta-tubulins: a developmentally regulated isoform beta 3-tubulin, the wild-type testis-specific isoform beta 2-tubulin, and an ethyl methanesulfonate-induced assembly-defective mutation of the testis isoform, B2t8. The testis-specific beta 2-tubulin is highly homologous to the major vertebrate beta-tubulins, but beta 3-tubulin is considerably diverged. Comparison of the amino acid sequences of the two Drosophila isoforms to those of other beta-tubulins indicates that these two proteins are representative of an ancient sequence divergence event which at least preceded the split between lines leading to vertebrates and invertebrates. The intron/exon structures of the genes for beta 2- and beta 3-tubulin are not the same. The structure of the gene for the variant beta 3-tubulin isoform, but not that of the testis-specific beta 2-tubulin gene, is similar to that of vertebrate beta-tubulins. The mutation B2t8 in the gene for the testis-specific beta 2-tubulin defines a single amino acid residue required for normal assembly function of beta-tubulin. The sequence of the B2t8 gene is identical to that of the wild-type gene except for a single nucleotide change resulting in the substitution of lysine for glutamic acid at residue 288. This position falls at the junction between two major structural domains of the beta-tubulin molecule. Although this hinge region is relatively variable in sequence among different beta-tubulins, the residue corresponding to glu 288 of Drosophila beta 2-tubulin is highly conserved as an acidic amino acid not only in all other beta-tubulins but in alpha-tubulins as well.


Developing market class specific InDel markers from next generation sequence data in Phaseolus vulgaris L.
Next generation sequence data provides valuable information and tools for genetic and genomic research and offers new insights useful for marker development. This data is useful for the design of accurate and user-friendly molecular tools. Common bean (Phaseolus vulgaris L.) is a diverse crop in which separate domestication events happened in each gene pool followed by race and market class diversification that has resulted in different morphological characteristics in each commercial market class. This has led to essentially independent breeding programs within each market class which in turn has resulted in limited within market class sequence variation. Sequence data from selected genotypes of five bean market classes (pinto, black, navy, and light and dark red kidney) were used to develop InDel-based markers specific to each market class. Design of the InDel markers was conducted through a combination of assembly, alignment and primer design software using 1.6× to 5.1× coverage of Illumina GAII sequence data for each of the selected genotypes. The procedure we developed for primer design is fast, accurate, less error prone, and higher throughput than when they are designed manually. All InDel markers are easy to run and score with no need for PCR optimization. A total of 2687 InDel markers distributed across the genome were developed. To highlight their usefulness, they were employed to construct a phylogenetic tree and a genetic map, showing that InDel markers are reliable, simple, and accurate.


Depression in primary care: detection, diagnosis, and treatment. US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research.
1. About 15% of the general public will suffer from major depressive disorder sometime in their life, but fewer than one in three will be accurately diagnosed and treated. 2. About 10% to 15% or more of major depressive conditions are caused by general medical illnesses or other conditions. Generally, treat the associated condition first. If the depression persists after treatment, major depressive disorder should be diagnosed and treated. 3. In over 50% of depressed outpatients, antidepressant medication caused marked improvement or complete remission of their depressive symptoms. Several forms of short-term psychotherapy are effective for mild or moderate depression; combined treatment should be considered in certain situations.


[Roentgenological-endovascular occlusion and ligation of internal iliac arteries in bleeding tumors of the bladder].
A comparative estimation of the effectiveness of hemostasis by means of ligation of the internal iliac arteries and roentgen-endovascular occlusion of these vessels was carried out in 30 patients with a bleeding carcinoma of the urinary bladder and prostate growing into its wall. For the occlusion of the internal iliac artery metallic spirals were used in 15 patients, in 4 of them they were used in combination with a gelatine sponge. The roentgen-endovascular occlusion is thought by the authors to be the method of choice.


Fluid-structure interaction simulation of tissue degradation and its effects on intra-aneurysm hemodynamics.
Tissue degradation plays a crucial role in vascular diseases such as atherosclerosis and aneurysms. Computational modeling of vascular hemodynamics incorporating both arterial wall mechanics and tissue degradation has been a challenging task. In this study, we propose a novel finite element method-based approach to model the microscopic degradation of arterial walls and its interaction with blood flow. The model is applied to study the combined effects of pulsatile flow and tissue degradation on the deformation and intra-aneurysm hemodynamics. Our computational analysis reveals that tissue degradation leads to a weakening of the aneurysmal wall, which manifests itself in a larger deformation and a smaller von Mises stress. Moreover, simulation results for different heart rates, blood pressures and aneurysm geometries indicate consistently that, upon tissue degradation, wall shear stress increases near the flow-impingement region and decreases away from it. These findings are discussed in the context of recent reports regarding the role of both high and low wall shear stress for the progression and rupture of aneurysms.


Sample type is crucial to the diagnosis of Mycoplasma pneumoniae pneumonia by PCR.
Sensitive and specific methods for rapid laboratory diagnosis of Mycoplasma pneumoniae were not available until nucleic acid amplification methods were developed. The choice of sample type and method of sampling are crucial to optimal diagnostic efficacy. Three types of respiratory samples from 32 young military conscripts with pneumonia were collected during an outbreak of M. pneumoniae infection. Sputum, nasopharyngeal aspirate and throat swab specimens were tested by 16S rRNA gene-based PCR with liquid-phase probe hybridization, and the results were compared with serology. The PCR result was positive for 22 (69 %) of the sputa, 16 (50 %) of the aspirates and 12 (37.5 %) of the swabs. Serology with increasing or high titres supported the positive findings in all instances. Sputum, when available, is clearly the best sample type for young adults with pneumonia.


Thromboembolic Events Following Atrial Fibrillation Cardioversion and Ablation: What's the Culprit?
Stroke is a rare but possible complication after atrial fibrillation (AF) ablation. However, its etiopathogenesis is far from being completely characterized. Here we report a case of stroke, with recurrent peripheral embolism after AF ablation procedure. In our patient, an in situ femoral vein thrombosis and iatrogenic atrial septal defect were simultaneously detected. A comprehensive review of multiple pathophysiological mechanisms of stroke in this context is provided. The case underlines the importance of a global evaluation of patients undergoing AF ablation.


Outcome in critically ill patients with candidal fungaemia: Candida albicans vs. Candida glabrata.
In a retrospective study (1 January 1992-12 December 1998), we investigated population characteristics and outcome in critically ill patients with fungaemia involving C. albicans (n=41) and C. glabrata (n=15). Patients with C. glabrata fungaemia were significantly older compared with patients in the C. albicans group (P=0.024). There were no other differences in population characteristics or severity of illness. Logistic regression analysis showed age (P=0.021), the presence of a polymicrobial blood stream infection (P=0.039), and renal failure (P=0.044) to be independent predictors of mortality. There was no significant difference in in-hospital mortality between the C. glabrata and C. albicans groups (60.0% vs. 41.5%; P=0.24). Since age was an independent predictor of mortality, the trend towards a higher mortality in patients with C. glabrata can be explained by this population being significantly older. In conclusion, we found no difference in mortality between patients with fungaemia involving C. albicans and C. glabrata.


Transcriptome Profile Analysis Reveals an Estrogen Induced LncRNA Associated with Lipid Metabolism and Carcass Traits in Chickens (Gallus Gallus).
Accumulating evidences have demonstrated that long noncoding RNAs (lncRNA) play important roles in hepatic lipid metabolism in mammals. However, no systematic screening of the potential lncRNAs in the livers of laying hens has been performed, and few studies have been reported concerning the effects of the lncRNAs on lipid metabolism in the livers of chickens during egg-laying period. The purpose of this study was to compare the difference in lncRNA expression in the livers of pre-laying and peak-laying hens at the age of 20 and 30 weeks old by transcriptome sequencing and to investigate the interaction networks among lncRNAs, mRNAs and miRNAs. Moreover, the regulatory mechanism and biological function of lncLTR, a significantly differentially expressed lncRNA in the liver between pre- and peak-laying hens, was explored in vitro and in vivo. Bioinformatics analyses were conducted to identify the differentially expressed (DE) lncRNAs between the two groups of hens. The target genes of the DE lncRNA were predicated for further functional enrichment. An integrated analysis was performed among the DE lncRNA datasets, DE mRNAs and DE miRNA datasets obtained from the same samples to predict the interaction relationship. In addition, in vivo and in vitro trials were carried out to determine the expression regulation of lncLTR, and polymorphism association analysis was conducted to detect the biological role of ncLTR. A total of 124 DE lncRNAs with a P-value ≤ 0.05 were identified. Among them, 44 lncRNAs including 30 known and 14 novel lncRNAs were significant differentially expressed (SDE) with FDR ≤ 0.05. Thirty-two lncRNAs were upregulated and 12 were downregulated in peak-laying group compared with pre-laying group. The functional enrichment results revealed that target genes of some lncRNAs are involved in the lipid metabolism process. Integrated analysis suggested that some of the genes involved in lipid metabolism might be regulated by both the lncRNA and the miRNA. In addition, an upregulated lncRNA, designated lncLTR, was demonstrated to be induced by estrogen via ERβ signaling. The c242. G>A SNP in lncLTR was significantly associated with chicken carcass weight, evisceration weight, semi-evisceration weight, head weight, double-wing weight, claw weight traits, and blood biochemical index, especially for the blood triglyceride content. A series of lncRNAs associated with lipid metabolism in the livers of chickens were identified by transcriptome sequencing and functional analysis, providing a valuable data resource for further studies on chicken hepatic metabolism activities. LncLTR was regulated by estrogen via ERβ signaling and associated with chicken carcass trait and blood triglyceride content.


Color modulation by selective excitation activated defects and complex cation distribution in Zn1-xMgxAl2O4 nanocrystals.
Complex cation distribution in spinel solid solution, fosters defect generation and permutates the optical properties. To scrutinize the effect on structural properties, viz. the cation distribution and defect states upon substitution of Zn with Mg; and to tune the emission properties, Zn1-xMgxAl2O4 (0.01 ≤ x ≤ 0.30) nanocrystals are synthesized. The nanocrystals show increased inversion and generation of multiple defects, namely zinc vacancies, zinc interstitials, oxygen vacancies and antisite defects with increasing Mg content, which thereby impacts the optical band gap. Pentahedral coordination in addition to tetra- and octahedral coordination of Al has been observed, which infers the presence of oxygen vacancies and dangling bonds. Moire fringes formation has intimated the presence of two or more crystal lattices with higher Mg substitution. Band-to-band and defect-assisted photoluminescence shows the role of multiple defects, especially defect clusters, in deciphering the properties of the resulting crystals. Color change from bluish-white to pink has been achieved depending upon the excitation wavelength and emission mechanism, as proposed through a band model schematic. The presented study may be beneficial for designing the Zn1-xMgxAl2O4 nanocrystals with optimized emission properties.


Mms1 binds to G-rich regions in Saccharomyces cerevisiae and influences replication and genome stability.
The regulation of replication is essential to preserve genome integrity. Mms1 is part of the E3 ubiquitin ligase complex that is linked to replication fork progression. By identifying Mms1 binding sites genome-wide in Saccharomyces cerevisiae we connected Mms1 function to genome integrity and replication fork progression at particular G-rich motifs. This motif can form G-quadruplex (G4) structures in vitro. G4 are stable DNA structures that are known to impede replication fork progression. In the absence of Mms1, genome stability is at risk at these G-rich/G4 regions as demonstrated by gross chromosomal rearrangement assays. Mms1 binds throughout the cell cycle to these G-rich/G4 regions and supports the binding of Pif1 DNA helicase. Based on these data we propose a mechanistic model in which Mms1 binds to specific G-rich/G4 motif located on the lagging strand template for DNA replication and supports Pif1 function, DNA replication and genome integrity.


Survival Outcomes of De Novo vs Inverted Papilloma-Associated Sinonasal Squamous Cell Carcinoma: A Systematic Review and Meta-analysis.
Overall, the prognosis of sinonasal squamous cell carcinoma (SCC) is poor. This malignancy can arise de novo or from inverted papillomas, but it is unclear whether survival differences between the 2 pathologies exist. To assess for survival differences between patients with sinonasal de novo SCC (dnSCC) and those with inverted papilloma-associated SCC (IPSCC). A search of Ovid MEDLINE, Embase, Scopus, and the Cochrane Library from inception to January 23, 2020, with cross-referencing of retrieved studies, was performed. Additional data were requested from authors. Inclusion and exclusion criteria were designed to capture studies with survival outcomes of adults with sinonasal SCC who underwent regular treatment. Clinical trials, cohort studies, case-control studies, and case series with more than 10 adults aged 18 years or older with sinonasal SCC were included. Exclusion criteria were studies on non-SCC sinonasal neoplasms, studies without histopathologic diagnoses, non-English language articles, nonhuman animal studies, and abstract-only articles. Two blinded investigators (J.J.L., A.M.P., T.W.E., or N.S.W.) screened each abstract and full text, and a third investigator (J.J.L. or P.P.) adjudicated discrepancies. Of 729 unique citations, 26 studies of 1194 total patients were included. Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. The Methodological Index for Nonrandomized Studies (MINORS) criteria were used to assess study quality. Two blinded investigators (J.J.L., A.M.P., T.W.E., or N.S.W.) independently extracted data from each study. Data were pooled using a random-effects model. The primary outcome was overall survival, and secondary outcomes were disease-free and disease-specific survival. Before data collection, it was hypothesized that the dnSCC cohort would have worse survival outcomes than the IPSCC cohort. One study of patients with dnSCC, 12 studies of patients with IPSCC, and 5 studies with both cohorts were included in the meta-analysis of overall survival. The pooled 5-year overall survival rate for 255 patients with dnSCC was 56% (95% CI, 41%-71%; I2 = 83.8%) and for 475 patients with IPSCC was 65% (95% CI, 56%-73%; I2 = 75.7%). Five comparative studies of both cohorts totaling 240 patients with dnSCC and 155 patients with IPSCC were included in another meta-analysis. The pooled overall survival hazard ratio was 1.87 (95% CI, 1.24-2.84; I2 = 0%). This systematic review and meta-analysis found that patients with dnSCC had almost a 2-fold increased risk of mortality compared with those with IPSCC. Large, multicenter studies are necessary to validate these findings before considering treatment alterations such as de-escalation based on histopathology.


Living on the edge: a review of the literature.
A comprehensive review of the literature of the universal experience of living on the edge is discussed. Literature was reviewed from biology, criminology, ecology, economics, ethics, finance, fine arts, historical biography, medicine, nursing, philosophy, physiology, psychology, sociology, and theology. Three themes emerged with this literature review: living on the edge as a sacred place one travels to or where one lives, living on the edge as a choice in taking risks and surviving danger, and living on the edge as engaging with health experiences in which persons and nurses coparticipate. Living on the edge is a visionary quest into a new frontier that holds illimitable possibilities that transform the world. The literature is discussed according to theoretical and research findings.


Noninvasive evaluation of mucosal healing in inflammatory bowel diseases.
Current opinions increasingly cite the need to achieve not only clinical response but also endoscopic mucosal healing in the treatment of both types of inflammatory bowel disease: ulcerative colitis (UC) and Crohn's disease (CD). Although endoscopic procedures are necessary for confirmation of mucosal healing, undergoing colonoscopy is invasive and burdensome to patients. Therefore, alternative noninvasive methods of evaluating or predicting mucosal status have been eagerly desired. For this purpose, blood, fecal, and radiologic modalities have been suggested and examined. C-reactive protein and fecal markers such as fecal calprotectin can evaluate active inflammation to some extent in both UC and CD. However, their predictive values for mucosal healing have not yet been fully evaluated and current knowledge indicates that the values were rather insufficient. Radiologic modalities such as computed tomography, magnetic resonance, and ultrasound can also evaluate mucosal inflammation but are currently not suitable for detection of healing. Capsule endoscopy may be optimal for evaluating mucosal status of the small bowel in CD patients, but sufficient data are not yet available, particularly for mucosal healing. Thus, these candidates for the surrogate modality are currently imperfect for evaluation of mucosal healing, but the changes in values/findings of these modalities after initiation of therapy appear to be rather promising as a marker of efficacy of the therapy. Finally, our recent data showed that a fecal immunochemical test for evaluation of mucosal healing in UC was very promising and this method should be further evaluated in CD also.


Role of routine imaging in lymphoma.
Patients with lymphoma commonly undergo routine imaging studies after treatment completion, yet the appropriate interval, duration, and modality of follow-up, and the overall efficacy of various approaches is unclear. Existing guidelines are vague and not evidence-based, and consequently, practice patterns are varied. Most surveillance approaches in lymphoma have focused on early detection of recurrence, with the hope of prolonged survival and potential cure. Concerns regarding the prognostic value of frequent scanning, cost-effectiveness, and long-term risks associated with prolonged radiation exposure have led many to question the role of routine imaging in this setting. Given the multiple lymphoma subtypes and the clinical heterogeneity of these entities, a single approach to follow-up may not be reasonable. Much of the available literature focuses on Hodgkin lymphoma, and may not be generalizable. Retrospective series show that most relapses are detected by signs and symptoms regardless of the imaging schedule. In summary, clinicians are still left with "expert opinion" to guide them. This article examines the available data outlining the role of surveillance imaging in lymphoma.


Arginase is upregulated in healthy women infected by oncogenic HPV types.
The implication of arginase enzyme in Human Papillomavirus (HPV) infections has not been clearly elucidated. The present study investigates whether HPV infection is correlated with changes in plasmatic arginase activity and cervical ARG1 and ARG2 mRNA expression among infected women negative for intraepithelial lesions (NIL). The present study included 300 women. The plasmatic arginase activity was evaluated by a colorimetric assay. Cervical HPV was detected by real-time PCR. The circulating viral load and ARG1 and ARG2 mRNA expression quantification were performed by quantitative real-time PCR. A significant increase in plasma arginase activity and ARG1 and ARG2 mRNA expression levels in cervical cells was observed among HPV-positive women compared to the HPV-negative group. The highest levels were significantly associated with oncogenic HPV, and increased arginase activity was associated with a high HPV circulating viral load. Moreover, the highest levels of arginase activity were observed in oncogenic HPV-positive inflammatory smears. These data suggest that HPV could modulate arginase activity and expression, which may restrict arginine bioavailability and inhibit this amino acid's antiviral properties. Our findings revealed that arginase activity and isoform gene expression were upregulated in women with HPV infection, particularly the oncogenic HPV types.


Effect of thallium impurities in the DAMA experiment on the allowed parameter space for inelastic dark matter.
The inelastic dark matter scenario was proposed to reconcile the DAMA annual modulation with null results from other experiments. In this scenario, weakly interacting massive particles (WIMPs) scatter into an excited state, split from the ground state by an energy δ comparable to the available kinetic energy of a galactic WIMP. We note that for large splittings δ the dominant scattering at DAMA can occur off of thallium nuclei, with A∼205, which are present as a dopant at the 10(-3) level in NaI(Tl) crystals. For a WIMP mass mχ≈100 GeV/c2 and δ≈200 keV, we find a region in δ-mχ-parameter space which is consistent with all experiments. These parameters, in particular, can be probed in experiments with thallium in their targets, such as KIMS, but are inaccessible to lighter target experiments. Depending on the tail of the WIMP velocity distribution, a highly modulated signal may or may not appear at CRESST-II.


Mechanistic insights into plasmonic photocatalysts in utilizing visible light.
The utilisation of sunlight as an abundant and renewable resource has motivated the development of sustainable photocatalysts that can collectively harvest visible light. However, the bottleneck in utilising the low energy photons has led to the discovery of plasmonic photocatalysts. The presence of noble metal on the plasmonic photocatalyst enables the harvesting of visible light through the unique characteristic features of the noble metal nanomaterials. Moreover, the formation of interfaces between noble metal particles and semiconductor materials further results in the formation of a Schottky junction. Thereby, the plasmonic characteristics have opened up a new direction in promoting an alternative path that can be of value to the society through sustainable development derived through energy available for all for diverse applications. We have comprehensively prepared this review to specifically focus on fundamental insights into plasmonic photocatalysts, various synthesis routes, together with their strengths and weaknesses, and the interaction of the plasmonic photocatalyst with pollutants as well as the role of active radical generation and identification. The review ends with a pinnacle insight into future perspectives regarding realistic applications of plasmonic photocatalysts.


Establishing the flow cytometric assessment of myeloid cells in kidney ischemia/reperfusion injury.
Polychromatic flow cytometry is a powerful tool for assessing populations of cells in the kidney through times of homeostasis, disease and tissue remodeling. In particular, macrophages have been identified as having central roles in these three settings. However, because of the plasticity of myeloid cells it has been difficult to define a specific immunophenotype for these cells in the kidney. This study developed a gating strategy for identifying and assessing monocyte and macrophage subpopulations, along with neutrophils and epithelial cells in the healthy kidney and following ischemia/reperfusion (IR) injury in mice, using antibodies against CD45, CD11b, CD11c, Ly6C, Ly6G, F4/80, CSF-1R (CD115), MHC class II, mannose receptor (MR or CD206), an alternatively activated macrophage marker, and the epithelial cell adhesion marker (EpCAM or CD326). Backgating analysis and assessment of autofluorescence was used to extend the knowledge of various cell types and the changes that occur in the kidney at various time-points post-IR injury. In addition, the impact of enzymatic digestion of kidneys on cell surface markers and cell viability was assessed. Comparisons of kidney myeloid populations were also made with those in the spleen. These results provide a useful reference for future analyses of therapies aimed at modulating inflammation and enhancing endogenous remodeling following kidney injury.


Effects of topical flurbiprofen on the intraocular pressure lowering effects of apraclonidine and timolol.
We performed a prospective study that evaluated whether pretreatment with topical flurbiprofen alters the intraocular pressure (IOP) lowering effects of either topical 1% apraclonidine hydrochloride or 0.5% timolol maleate. Eighteen normal volunteers participated in this six-armed, randomized, double-masked, crossover study. All subjects received the first study medication, either bilateral 0.3% flurbiprofen or placebo (its vehicle), every 30 minutes for four applications. They next received the second study medication: either 0.5% timolol maleate (Timoptic), 1% apraclonidine hydrochloride, or placebo in both eyes. We measured IOP before the instillation of the first study medication and the second study medication (baseline), and then at 1, 3, and 6 hours later. All subjects underwent all six treatment arms. Flurbiprofen alone had no effect on IOP. Maximum IOP lowering occurred between 3 and 6 hours after timolol and apraclonidine administration. There was no difference in IOP lowering between timolol- and apraclonidine-treated eyes. Pretreatment with flurbiprofen did not affect the IOP lowering that was obtained with timolol or apraclonidine administration.


Nanolayered hybrid mediates synergistic co-delivery of ligand and ligation activator for inducing stem cell differentiation and tissue healing.
Cellular behaviors, such as differentiation, are regulated by complex ligation processes involving cell surface receptors, which can be activated by various divalent metal cations. The design of nanoparticle for co-delivery of ligand and ligation activator can offer a novel strategy to synergistically stimulate ligation processes in vivo. Here, we present a novel layered double hydroxide (LDH)-based nanohybrid (MgFe-Ado-LDH), composed of layered MgFe hydroxide nanocarriers sandwiching the adenosine cargo molecule, maintained through an electrostatic balance, to co-deliver the adenosine (Ado) ligand from the interlayer spacing and the Mg2+ ion (ligation activator) through the dissolution of the MgFe nanocarrier itself. Our findings demonstrate that the MgFe-Ado-LDH nanohybrid promoted osteogenic differentiation of stem cells through the synergistic activation of adenosine A2b receptor (A2bR) by the dual delivery of adenosine and Mg2+ ions, outperforming direct supplementation of adenosine alone. Furthermore, the injection of the MgFe-Ado-LDH nanohybrid and stem cells embedded within hydrogels promoted the healing of rat tibial bone defects through the rapid formation of fully integrated neo-bone tissue through the activation of A2bR. The newly formed bone tissue displayed the key features of native bone, including calcification, mature tissue morphology, and vascularization. This study demonstrates a novel and effective strategy of bifunctional nanocarrier-mediated delivery of ligand (cargo molecule) and activation of its ligation to receptor by the nanocarrier itself for synergistically inducing stem cell differentiation and tissue healing in vivo, thus offering novel design of biomaterials for regenerative medicine.


Identification of HLA-A24-restricted novel T Cell epitope peptides derived from P-cadherin and kinesin family member 20A.
We here identified human leukocyte antigen-(HLA-)A(∗)2402-restricted epitope peptides from Cadherin 3, type 1, P-cadherin (CDH3) and kinesin family member 20A (KIF20A) that were found to be specifically expressed in cancer cells through genome-wide expression profile analysis. CDH3-10-807 peptide and KIF20A-10-66 peptide successfully induced specific CTL clones, and these selectively responded to COS7 cells expressing both HLA-A(∗)2402 and respective protein while did not respond to parental cells or COS7 cells expressing either HLA-A(∗)2402 or respective protein. Furthermore, CTL clones responded to cancer cells that endogenously express HLA-A(∗)2402 and respective protein, suggesting that CDH3-10-807 peptide and KIF20A-10-66 peptide are naturally presented on HLA-A(∗)2402 molecule of human cancer cells. Our results demonstrated that CDH3-10-807 peptide and KIF20A-10-66 peptide are novel HLA-A24-restricted tumor-associated antigens and would be applicable for CTL-inducing cancer therapies.


Molecular cloning and characterization of rat ST1B1 and human ST1B2 cDNAs, encoding thyroid hormone sulfotransferases.
Human and rat cDNAs encoding thyroid hormone sulfotransferases have been isolated from their liver cDNA libraries. The isolated sulfotransferases, termed rat ST1B1 and human ST1B2, share 77 and 74% homologies at nucleotide and deduced amino acid levels. These forms showed less than 36 and 56% homologies to hydroxysteroid and aryl sulfotransferases, indicating that they constitute a new gene subfamily of aryl sulfotransferase. Expression of ST1B1 and ST1B2 in COS-1 cells resulted in the appearance of 33.0 and 32.5 kDa proteins, respectively, whose mobilities were identical with proteins detected in rat and human livers in Western blots using antibodies raised against ST1B1 and ST1B2 produced in Escherichia coli. The recombinant forms catalyzed sulfation of p-nitrophenol, 3,3',5-triiodothyronine (T3) and dopamine, but not of beta-estradiol and dehydroepiandrosterone. ST1B1 and ST1B2 showed higher affinities for formation of T3 sulfate (apparent Km 40.2 and 63.5 microM, respectively) than did thermostable phenol sulfotransferase ST1A3 (apparent Km 413 microM) or thermolabile phenol sulfotransferase ST1A5 (apparent Km 180 microM). These data indicate that the newly characterized sulfotransferases constitute a distinct ST1 subfamily of enzymes catalyzing the sulfation of T3 as a typical endogenous substrate in rats and humans.