Pemphigus vulgaris presenting as a gingival lesion. A case report.
A 26-year-old hispanic male presented with a nonspecific gingival lesion initially presumed to be of infectious etiology. During continued follow-up over several weeks, the lesion evolved into one typical of desquamative gingivitis. Direct immunofluorescent testing and routine histopathology resulted in a diagnosis of pemphigus vulgaris, which was confirmed by indirect immunofluorescence. Although it is unusual for pemphigus vulgaris to present with the gingiva as the sole primary site of involvement, this case serves to enhance our awareness of the gingiva as a site at which systemic disease can be manifested.


[A study on clinical application of a novel reagent detecting toxigenic strains of Clostridium difficile].
Objective: To evaluate the performances of a "ready-to-use" liquid chromogenic medium for detecting toxigenic strains of C. difficile from stool specimens, by comparing with the reference method of combined GeneXpert detection with MALDI-TOF MS identification. Methods: This study was a clinical application research. A total of 322 stool specimens from patients with diarrhea in Henan Provincial People's Hospital were detected by using this liquid chromogenic mediumor by combination of GeneXpert and MALDI-TOF MS identification after CCFA culture from March to November 2017. The reference method was combined GeneXpert detection with MALDI-TOF MS identification. Data were analyzed with kappa analysis by use of SPSS 13.0. In this study, the limit of detection and anti-interference capability of chromogenic medium were determined with standard strains. Results: This assay had a sensitivity of 92.86% (52/56), a specificity of 96.99% (258/266), a positive predictive value of 86.67% (52/60), and a negative predictive value of 98.47% (258/262). Furthermore, this assay was well consistent with the reference method (kappa=0.874, P<0.01). The limit of detection of this assay was 10(3) CFU/ml for toxigenic strain of ATCC9689, and there was no interference by non-toxigenic strain of ATCC43593 or Clostridium perfringens (ATCC13124) even.When the concentration of ATCC9689 was as low as 0.5 McFarland. Conclusions: It is worth expanding clinical research for this "ready-to-use" chromogenic medium and preparing for its popularization in primary medical institutions, due to its similar performance to the reference method for detecting toxigenic strains of C. difficile, simple operation and no need of anaerobic condition.


The p38 and JNK pathways cooperate to trans-activate vitamin D receptor via c-Jun/AP-1 and sensitize human breast cancer cells to vitamin D(3)-induced growth inhibition.
The signaling connection between mitogen-activated protein kinases(MAPKs) and nuclear steroid receptors is complex and remains mostly unexplored. Here we report that stress-activated protein kinases p38 and JNK trans-activate nuclear steroid vitamin D receptor (VDR) gene and increase vitamin D(3)-dependent growth inhibition in human breast cancer cells. Activation of p38 and JNK by an active MAPK kinase 6 stimulates VDR promoter activity independently of the ligand vitamin D(3) and estrogen receptor expression. Moreover, stimulation of the endogenous stress pathways by adenovirus-mediated delivery of recombinant MAPK kinase 6 also activates VDR and sensitizes MCF-7 cells to vitamin D(3)-dependent growth inhibition. Both the p38 and JNK MAPK pathways and the downstream transcription factor c-Jun/AP-1 are required for the VDR stimulation, as revealed by application of their dominant negatives, the specific p38 inhibitor SB203580, and site-directed mutagenesis of the AP-1 element in the VDR promoter. The essential role of the p38 and JNK stress pathways in up-regulation of VDR expression is further confirmed by using the chemical stimulator arsenite. These results establish a signaling connection between the stress MAPK pathways and steroid hormone receptor VDR expression and thereby offer new insights into regulation of cell growth by the MAPK pathways through regulation of vitamin D(3)/VDR activity.


Characteristics of hepatitis B virus isolates of genotype G and their phylogenetic differences from the other six genotypes (A through F).
Eight hepatitis B virus (HBV) isolates of genotype G were recovered from patients and sequenced over the entire genome. Six of them had a genomic length of 3,248 bp and two had genomic lengths of 3,239 bp (USG15) and 3,113 bp (USG18) due to deletions. The 10 HBV/G isolates, including the 8 sequenced isolates as well as the original isolate (AF160501) and another isolate (B1-89), had a close sequence homology of 99.3 to 99.8% among themselves (excluding USG18 with a long deletion) but of <88.7% to any of the 68 HBV isolates of the other six genotypes with the full-length sequence known. The eight HBV/G isolates possessed an insertion of 36 bp in the core gene and two stop codons in the precore region, as did the AF160501 and B1-89 isolates. The 10 HBV/G isolates clustered on a branch separate from those bearing the other six genotypes (A through F [A-F]) in the phylogenetic tree constructed from full-length sequences of 78 HBV isolates as well as in those constructed from the core, polymerase, X, and envelope genes. Despite two stop codons in the precore region that prohibited the translation of the HBV e antigen (HBeAg), all of the eight patients with HBV/G infection possessed the HBeAg in serum. By restriction fragment length polymorphism of the surface gene, all of the eight patients were found to be coinfected with HBV of genotype A (HBV/A), which would be responsible for the expression of HBeAg in them. It is worthy of examination to determine how coinfection occurs and whether HBV/G needs HBV/A for replication.


Member Input: The Challenge of Staffing in Ambulatory Infusion Settings
The Oncology Nursing Society (ONS) has conducted several member surveys that included questions about staffing but has not established nurse-patient ratios, given the number and complexity of variables that must be considered. The 2016 ONS member survey showed that staffing was the most frequently cited challenge in the practice setting. With the implementation of ONS Communities in 2017, members have the opportunity to network and connect about issues. Staffing in chemotherapy infusion centers has been a frequent topic.


Efficiency enhancements in solid-state hybrid solar cells via reduced charge recombination and increased light capture.
We compare a series of molecular sensitizers in dye-sensitized solar cells containing the organic hole transporter 2,2',7,7'-tetrakis(N,N-di-p-methoxypheny-amine)-9,9'-spirobifluorene (spiro-MeOTAD). Charge recombination is reduced by the presence of "ion-coordinating" moieties on the dye, with the longest electron lifetime and highest solar cell efficiency achieved using a novel sensitizer with diblock alkoxy-alkane pendent groups. By further increasing the optical path length in the active layer, we achieve a power conversion efficiency of over 5% under simulated sun light.


Parkin- and PINK1-Dependent Mitophagy in Neurons: Will the Real Pathway Please Stand Up?
Parkinson's disease (PD) is characterized by massive degeneration of dopaminergic neurons in the substantia nigra. Whereas the majority of PD cases are sporadic, about 5-10% of cases are familial and associated with genetic factors. The loss of parkin or PINK1, two such factors, leads to an early onset form of PD. Importantly, recent studies have shown that parkin functions downstream of PINK1 in a common genetic pathway affecting mitochondrial homeostasis. More precisely, parkin has been shown to mediate the autophagy of damaged mitochondria (mitophagy) in a PINK1-dependent manner. However, much of the work characterizing this pathway has been carried out in immortalized cell lines overexpressing high levels of parkin. In contrast, whether or how endogenous parkin and PINK1 contribute to mitophagy in neurons is much less clear. Here we review recent work addressing the role of parkin/PINK1-dependent mitophagy in neurons. Clearly, it appears that mitophagy pathways differ spatially and kinetically in neurons and immortalized cells, and therefore might diverge in their ultimate outcome and function. While evidence suggests that parkin can translocate to mitochondria in neurons, the function and mechanism of mitophagy downstream of parkin recruitment in neurons remains to be clarified. Moreover, it is noteworthy that most work has focused on the downstream signaling events in parkin/PINK1 mitophagy, whereas the upstream signaling pathways remain comparatively poorly characterized. Identifying the upstream signaling mechanisms that trigger parkin/PINK1 mitophagy will help to explain the nature of the insults affecting mitochondrial function in PD, and a better understanding of these pathways in neurons will be the key in identifying new therapeutic targets in PD.


[Analysis of NIPBL gene mutation in a patient with Cornelia de Lange syndrome].
To analyze the genotype-phenotype correlation in a case with Cornelia de Lange syndrome (CdLS). Genetic testing was carried out for a baby girl born by Cesarean section. The patient had clinical features including peculiar face, long bushy eyebrows, hypertelorism, wide sagittal suture, low-set ears, retrognathia, polydactyly and polysyndactyly of first toes, weak cry, poor suck and slow response, and was suspected as CdLS. Sequencing of CdLS-related genes including NIPBL, SMC1A, SMC3, RAD21 and HDAC8A has identified a novel heterozygous deletional mutation of the NIPBL gene. The deletion region has encompassed exon 46 and part of exon 47. The frameshift caused by the mutation has led to significant alteration of its protein sequence. A novel deletional mutation of the NIPBL gene has been identified, which has enriched its mutational spectrum and may facilitate further research into the genotype-phenotype correlation of CdLS.


Levetiracetam reduces anesthetic-induced hyperalgesia in rats.
As part of an increase in excitability, small doses of pentobarbital, propofol, and midazolam induce an increased sensitivity to pain. Specific therapy to prevent or reduce this excitability may offer advantages over current clinical management with analgesics and sedatives. The pharmacological profile of the novel antiepileptic drug, levetiracetam, suggests that it may reduce the intensity of the excitatory stages of anesthesia. We examined the influence of levetiracetam on the reduction of the nociceptive reflex threshold in rats by sedative doses of pentobarbital, propofol, and midazolam. Measurements of nociceptive reflex threshold to pressure and heat were made and then repeated after intraperitoneal injection of saline or one of three doses of levetiracetam (100, 200, 500 mg/kg). Pentobarbital (30 mg/kg), propofol (30 mg/kg), or midazolam (1.9 mg/kg) were then administered. The reflex threshold was measured every 10 min, starting at 5 min after the sedative injection, until 65 min had elapsed. Levetiracetam did not alter nociceptive reflex threshold in nonsedated animals (P = 0.11) or influence the degree or duration of sedation. The three anesthetic/sedative drugs reduced the nociceptive reflex threshold by 20%-30% of control values. Levetiracetam reduced the hyperreflexia associated with pentobarbital and midazolam (P < 0.05), but not propofol. These findings support further investigation into the role of levetiracetam in the prevention of anesthetic-induced excitability.


"Staircase" saccadic intrusions plus transient yoking and neural integrator failure associated with cerebellar hypoplasia: a model simulation.
We present hypothesized ocular motor mechanisms of unique "staircase-like" sequences of saccadic intrusions in one direction that we have named, "staircase saccadic intrusions (SSI)," square-wave jerks/oscillations (SWJ/SWO), and transient failures of yoking and neural integrators in a patient with severe hypotonia, ataxic speech, motor and language developmental delays, and torticollis (Joubert syndrome). Brain magnetic resonance imaging showed hypoplasia of the cerebellar vermis and inferior cerebellar peduncles, abnormal superior cerebellar peduncles with deepening of the interpeduncular fossa, and enlargement of the fourth ventricle. During far and near fixation and smooth pursuit (rightward markedly better than leftward), the subject exhibited conjugate SSI (rightward more than leftward, with intersaccadic intervals equivalent to the normal 250 msec visual latency), SWJ, SWO, and uniocular, convergent and divergent saccades (including double saccades). Simulations using a behavioral ocular motor system model identified hypothetical mechanisms for SWJ, SWO, and SSI and ruled out the loss of efference copy as the cause. SSI may result from simultaneous dysfunctions: 1) a transient loss of accurate retinal-error information and/or sampled, reconstructed error; plus 2) a constant sampled, reconstructed retinal error that drives saccades.


Understanding the roles of central and autonomic activity during sleep in the improvement of working memory and episodic memory.
The last decade has seen significant progress in identifying sleep mechanisms that support cognition. Most of these studies focus on the link between electrophysiological events of the central nervous system during sleep and improvements in different cognitive domains, while the dynamic shifts of the autonomic nervous system across sleep have been largely overlooked. Recent studies, however, have identified significant contributions of autonomic inputs during sleep to cognition. Yet, there remain considerable gaps in understanding how central and autonomic systems work together during sleep to facilitate cognitive improvement. In this article we examine the evidence for the independent and interactive roles of central and autonomic activities during sleep and wake in cognitive processing. We specifically focus on the prefrontal-subcortical structures supporting working memory and mechanisms underlying the formation of hippocampal-dependent episodic memory. Our Slow Oscillation Switch Model identifies separate and competing underlying mechanisms supporting the two memory domains at the synaptic, systems, and behavioral levels. We propose that sleep is a competitive arena in which both memory domains vie for limited resources, experimentally demonstrated when boosting one system leads to a functional trade-off in electrophysiological and behavioral outcomes. As these findings inevitably lead to further questions, we suggest areas of future research to better understand how the brain and body interact to support a wide range of cognitive domains during a single sleep episode.


Complementary medicine use in US adults with a history of colorectal cancer: a nationally representative survey.
In the USA, colorectal cancer is among the top diagnosed cancers. The current study specifically targets the US adult population that have a history of colorectal cancer. We used the 2017 National Health Interview Survey (NHIS) to investigate the prevalence and predictors of colorectal cancer survivors using complementary medicine in the past 12 months in a representative sample of the US population (N = 26,742). We descriptively analyzed the 12-month prevalence of any complementary medicine use separately for individuals with a prior diagnosis of colorectal cancer and those without. Using chi-squared tests and backward stepwise multiple logistic regression analyses, we identified predictors of complementary medicine use in the past 12 months. A weighted total of 1,501,481 US adults (0.6%) had a history of colorectal cancer. More individuals without (weighted n = 76,550,503; 31.2%) than those with a history of colorectal cancer (weighted n = 410,086; 27.3%) had used complementary medicine. The most commonly used complementary medicine among colorectal cancer patients was mind-body medicine, followed by chiropractic. A higher prevalence of complementary medicine use was associated with being female, higher educated and/or living in the US Midwest or South. In this study, over one fourth of the US colorectal cancer survivors had used complementary medicine. Mind-body medicine was found to be the most commonly used. With evidence supporting the effectiveness and safety of mind-body medicine use among colorectal cancer patients, promoting the use of evidence-based mind-body medicine for colorectal cancer management could be considered.


Granulosa and theca cell tumors in children: a report of 17 cases and literature review.
The files of the Emil Novak Ovarian Tumor Registry (ENOTR) were searched for granulosa and theca cell tumors in children aged 12 years and less. In addition, an extensive literature search was done for English publications on children with these tumors aged 10 years or less. Of the 17 children from the ENOTR, 5 had adult-type granulosa cell tumors, 6 had juvenile granulosa cell tumors, and 1 had a luteinized granulosa cell tumor. In addition, there were three cases with gonadal stomal tumors, one theca cell tumor, and one granulosa-theca cell tumor. Precocious pseudopuberty was present in 70 percent of the children, abdominal pain in 24 percent, and ascites in 18 percent. The literature review revealed a tumor-related mortality rate of 9 percent (based on 163 cases with granulosa cell tumors, including the juvenile type). Some of these tumors are large with acute pain, but nevertheless, the prognosis is good, particularly in cases with precocious puberty. Treatment can be conservative.


Socio-demographic and clinical characterization of patients with Bipolar Disorder I vs II: a Nationwide Italian Study.
Bipolar disorders (BDs) are prevalent, comorbid and disabling conditions, associated with the highest suicide risk among psychiatric illnesses. In the last few years, new efforts to better characterize the socio-demographic and clinical profiles of BD type I vs II have been documented by several reports, with novel and insightful findings in the field. The present multicenter study aimed to provide a comprehensive and reliable representation of the Italian reality, through the analysis of the largest national sample of bipolar patients collected so far. A total of 1500 patients (BD I n = 963 and BD II n = 537) from different psychiatric departments, participating in the Italian Chapter of the "International Society of Bipolar Disorders" (ISBD), were assessed and divided into two groups on the basis of their diagnostic subtype, and different socio-demographic and clinical variables were compared between the two subgroups. Chi-squared tests for categorical variables and t tests for continuous variables were performed for group comparison. Furthermore, a multivariable logistic regression was performed, considering diagnostic bipolar subtype (type I or II) as dependent variable, and socio-demographic/clinical characteristics as independent variables. BD I vs II patients showed an overall less favorable socio-demographic and clinical profile. In addition, the multivariable logistic regression showed that BD II vs BD I was predicted by the absence of lifetime suicide attempts (OR = 1.58, p = 0.01), a later age of diagnosis (OR = 1.03, p < 0.01), less hypomanic episodes in the last year (OR = 2.29, p < 0.0001) and absence of psycho-educational interventions in the last year (OR = 0.51, p < 0.01). BD I and II patients were found to significantly differ in relation to specific clinical variables, which should be considered within updated diagnostic-therapeutic algorithms.


Immunologic and molecular characterizations of T cell-derived T cell activating factor.
Culture supernatants from several subclones of a human T hybrid line (24A) stimulated with PMA showed co-stimulatory activity in the proliferation of Con A-stimulated murine thymocytes, but did not show any IL 2 activity. Some subclones did not show co-stimulatory activity even when stimulated with PMA, excluding the possibility of a carry-over effect. The factor found in the culture supernatants increased IL 2 production in normal T cells stimulated with a suboptimal concentration of PHA. The factor also induced IL 2 production in a T hybrid clone, T-394.1, when the latter was stimulated with a suboptimal concentration of mitogens, indicating a direct effect by this T cell-derived factor on mitogen-stimulated T cells inducing IL 2 production. This factor also induced the generation of other lymphokines such as BCDF and IFN-gamma. Northern blot analysis showed that the factor induced an increase in mRNA for IL 2 as well as IL 2 receptor. These results indicated that T cells could secrete a factor with IL 1-like activity. However, Northern blot analysis showed that mRNA from a T hybrid clone does not cross-react with cDNA for IL 1 (beta) derived from human monocytes.


Synthetic genistein glycosides inhibiting EGFR phosphorylation enhance the effect of radiation in HCT 116 colon cancer cells.
The need to find new EGFR inhibitors for use in combination with radiotherapy in the treatment of solid tumors has drawn our attention to compounds derived from genistein, a natural isoflavonoid. The antiproliferative potential of synthetic genistein derivatives used alone or in combination with ionizing radiation was evaluated in cancer cell lines using clonogenic assay. EGFR phosphorylation was assessed with western blotting. Genistein derivatives inhibited clonogenic growth of HCT 116 cancer cells additively or synergistically when used in combination with ionizing radiation, and decreased EGFR activation. Our preclinical evaluation of genistein-derived EGFR inhibitors suggests that these compounds are much more potent sensitizers of cells to radiation than the parent isoflavonoid, genistein and indicate that these compounds may be useful in the treatment of colon cancer with radiation therapy.


Early Relapsing Multiple Sclerosis.
This article provides an evidence-based approach to the management of patients with early relapsing multiple sclerosis (MS). Numerous clinical trials have shown the role of disease-modifying therapies in reducing relapses and new MRI lesions in patients with relapsing MS. Many of these trials also show the ability of these agents to delay disability progression, and a few suggest that disease-modifying therapies may slow brain atrophy in relapsing MS; however, very few suggest that disease-modifying therapies can improve symptoms or disability. The therapeutic armamentarium of disease-modifying therapies includes five interferon formulations, two versions of glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, and alemtuzumab. Although multiple disease-modifying therapies exist, the risks of these vary markedly, head-to-head comparator trials are limited, and no prospective biomarkers for treatment efficacy exist; therefore, choosing a disease-modifying therapy for an individual patient with MS is a difficult decision. This difficulty is compounded by limitations in predicting a patient's disease course, and the risk tolerance of the patient and opinions of the care partner need to be factored into the decision analysis as well. After a disease-modifying therapy is chosen, vigilance for clinical or radiographic breakthrough disease is very important, as this may suggest a suboptimal response to the chosen therapy. Furthermore, the role of symptom management and wellness should always remain part of the approach to the patient with MS.


Control of breathing at elevated lung volumes in anesthetized cats.
We monitored the steady-state ventilatory responses of anesthetized cats to increases in lung volume produced by expiratory threshold loads (ETL) to study the roles of peripheral and central neural mechanisms in controlling respiration at elevated lung volumes. Application of an ETL of 5 cmH2O produced a significant decrease in respiratory frequency (-18%) but no change in minute ventilation (VE) due to a significant increase in tidal volume (VT) (19.3%). The drop in frequency was due solely to an increase in expiratory duration. ETL of 10 cmH2O significantly reduced VE (-17.5%) for the same reason. VT was maintained or increased at elevated lung volumes due to both an increase in the rate of rise of phrenic activity and a maintenance of inspiratory duration (TI) despite increases in both chemical drive and pulmonary stretch receptor (PSR) activity. No PSR adapted completely to the maintained change in lung volume. The sensitivity of the inspiratory off-switch mechanism to increases in lung volume, given by the reciprocal of the VT-TI relationship, decreased significantly during breathing on ETL. The results are consistent with the hypothesis that central habituation, not just peripheral adaptation of PSR, determines breathing pattern at elevated lung volumes.


Time-resolved resonance Raman spectroscopy and density functional study of 2-fluorenylnitrene and its dehydroazepine products.
We report time-resolved resonance Raman spectra for 2-fluorenylnitrene and its dehydroazepine products acquired after photolysis of 2-fluorenylnitrene in acetonitrile. The experimental Raman band frequencies exhibit good agreement with the calculated vibrational frequencies from UBPW91/cc-PVDZ density functional calculations for the singlet and triplet states of the 2-fluorenylnitrene as well as BPW91/cc-PVDZ calculations for the two dehydroazepine ring-expansion product species. The decay of the 2-fluorenylnitrene Raman signal and the appearance of the dehydroazepine products suggest the presence of an intermediate species (probably an azirine) that does not absorb very much at the 416 nm probe wavelength used in the time-resolved resonance Raman experiments. Comparison of the singlet 2-fluorenylnitrene species with the singlet 2-fluorenylnitrenium ion species indicates that protonation of the nitrene to give the nitrenium ion leads to a significant enhancement of the cyclohexadienyl character of the phenyl rings without much change of the C-N bond length.


Nebivolol Alleviates Vascular Endothelial Insulin Resistance by Inhibiting Endoplasmic Reticulum Stress.
Vascular endothelial insulin resistance (IR) is an important risk factor in the development of vascular complications in diabetes. Prolonged endoplasmic reticulum stress (ERS) contributes to the development and progression of endothelial IR. The current study assessed the effects and mechanism of nebivolol on vascular IR in Goto-Kakizaki (GK) rats and endothelial IR induced by high glucose (33.3 mmol/L) associated with high insulin (10-7 mol/L) in human aortic endothelial cells (HAECs). Rats were divided into Wistar, Wistar + Neb (Wistar rats treated with nebivolol, 10 mg/kg, ig), GK, and GK + Neb (GK rats treated with nebivolol, 10 mg/kg, ig). GK rats showed hyperglycemia, dyslipidemia, impaired glucose homeostasis, metabolic IR, reduced relaxation to insulin, and lower serum nitric oxide (NO) level. Treatment with nebivolol for 4 months ameliorated insulin's vasorelaxation and NO production, and relieved dyslipidemia in GK rats. Additionally, nebivolol increased glucose uptake and NO level in the endothelial IR group in vitro. Nebivolol increased aortic expressions of IRS-1/PI3K/Akt/eNOS relative proteins and GLUT4 and reduced expressions of ERS markers (ATF6, GRP78, and CHOP, p-JNK/JNK). Furthermore, both nebivolol and TUDCA (ERS inhibitor) alleviated the attenuated IRS-1PI3K/Akt/eNOS pathway and enhanced ERS in HAECs IR. Tunicamycin (ERS inducer) not only induced endothelial IR but also blocked nebivolol's alleviation on the IRS-1PI3K/Akt/eNOS pathway and ERS. Nebivolol ameliorated endothelial IR partially by inhibiting ERS and then regulating the IRS-1/PI3K/Akt/eNOS signal.


Parental exposures to occupational asthmagens and risk of autism spectrum disorder in a Danish population-based case-control study.
Environmental exposures and immune conditions during pregnancy could influence development of autism spectrum disorder (ASD) in offspring. However, few studies have examined immune-triggering exposures in relation to ASD. We evaluated the association between parental workplace exposures to risk factors for asthma ("asthmagens") and ASD. We conducted a population-based case-control study in the Danish population using register linkage. Our study population consisted of 11,869 ASD cases and 48,046 controls born from 1993 through 2007. Cases were identified by ICD-10 codes in the Danish Psychiatric Central Register. ASD cases and controls were linked to parental Danish International Standard Classification of Occupations (DISCO-88) job codes. Parental occupational asthmagen exposure was estimated by linking DISCO-88 codes to an asthma-specific job-exposure matrix. Our maternal analyses included 6706 case mothers and 29,359 control mothers employed during the pregnancy period. We found a weak inverse association between ASD and any maternal occupational asthmagen exposure, adjusting for sociodemographic covariates (adjusted OR: 0.92, 95% CI: 0.86-0.99). In adjusted analyses, including 7647 cases and 31,947 controls with employed fathers, paternal occupational asthmagen exposure was not associated with ASD (adjusted OR: 0.98, 95% CI: 0.92-1.05). We found a weak inverse association between maternal occupational asthmagen exposure and ASD, and a null association between paternal occupational exposure and ASD. We suggest that unmeasured confounding negatively biased the estimate, but that this unmeasured confounding is likely not strong enough to bring the effect above the null. Overall, our results were consistent with no positive association between parental asthmagen exposure and ASD in the children.


Gross and radiographic appearance of porotic hyperostosis and cribra orbitalia in thalassemia affected skulls.
Porotic hyperostosis (PH) is the expansion of the cranial diploë, generating 'hair-on-end' appearance on X-rays. This condition is extremely rare and had a prevalence of 0.08%. It is alternatively known as cribra orbitalia (CO) when the orbital roof is affected. In this study, we describe the gross morphology of two skulls affected by PH and CO. The first skull belonged to a 41-year-old female previously diagnosed with beta thalassemia. The skull was affected by excessive PH and CO. The second skull, belonging to a 35-year-old male diagnosed with unspecified thalassemia, showed PH without CO. The etiology of PH and CO is discussed. In conclusion, PH and CO are extremely rare, and are of significant importance for radiologists and anatomists when interpreting radiographs or encountering unusual gross morphology of the skull.


Use of traditional Chinese medicine as an adjunctive treatment for COVID-19: A systematic review and meta-analysis.
This review aims to evaluate the supportive effects of frequently used traditional Chinese medicine (TCM) for the treatment of coronavirus disease 2019 (COVID-19). Five databases were searched through July 7, 2020. Randomized controlled trials investigating the efficacy of TCM for use in the treatment of COVID-19 were included. Newcastle-Ottawa Scale (NOS) and modified Jadad score were used for the evaluation of the methodological quality of the included studies. Weighted mean difference, odds ratio (OR), and 95% confidence interval (95% CI) were calculated for pooling out results. Data were extracted for conducting a meta-analysis using STATA version 12.0. Eight studies with a total of 750 patients were included in this meta-analysis. All included trial groups involved treatment with TCM and Western medicine, while the control groups were treated only with Western medicine. The intervention therapy significantly improved the overall effective rate (n = 346, OR = 2.5, 95% CIs = 1.46-4.29), fever symptom disappearance rate (n = 436; OR = 3.6; 95% CIs = 2.13-6.08), fatigue symptom disappearance rate (n = 436; OR = 3.04; 95% CIs = 1.76-5.26), cough symptom disappearance rate (n = 436; OR = 2.91; 95% CIs = 1.36-6.19), and sputum production reduction (n = 436; OR = 5.51; 95% CIs = 1.94-15.64). Based on the Newcastle-Ottawa Scale assessment, 6 studies received a score of 4, and 1 study achieved a score of 5. One study was assessed using the modified Jadad score, achieving a score of 6. The integration of TCM with Western medicine has significantly improved the treatment for COVID-19 patients compared to Western medicine treatment alone. Combined therapy using TCM and Western medicine revealed the potential adjunctive role of TCM in treating COVID-19. However, high-quality clinical studies are still required to further evaluate the efficacy and safety of TCM in the treatment of COVID-19.


Landscape composition and local floral resources influence foraging behavior but not the size of Bombus impatiens Cresson (Hymenoptera: Apidae) workers.
Bumble bee communities are strongly disrupted worldwide through the population decline of many species; a phenomenon that has been generally attributed to landscape modification, pesticide use, pathogens, and climate change. The mechanisms by which these causes act on bumble bee colonies are, however, likely to be complex and to involve many levels of organization spanning from the community down to the least understood individual level. Here, we assessed how the morphology, weight and foraging behavior of individual workers are affected by their surrounding landscape. We hypothesized that colonies established in landscapes showing high cover of intensive crops and low cover of flowering crops, as well as low amounts of local floral resources, would produce smaller workers, which would perform fewer foraging trips and collect pollen loads less constant in species composition. We tested these predictions with 80 colonies of commercially reared Bombus impatiens Cresson placed in 20 landscapes spanning a gradient of agricultural intensification in southern Québec, Canada. We estimated weekly rate at which workers entered and exited colonies and captured eight workers per colony over a period of 14 weeks during the spring and summer of 2016. Captured workers had their wing, thorax, head, tibia, and dry weight measured, as well as their pollen load extracted and identified to the lowest possible taxonomic level. We did not detect any effect of landscape habitat composition on worker morphology or body weight, but found that foraging activity decreased with intensive crops. Moreover, higher diversity of local floral resources led to lower pollen constancy in intensively cultivated landscapes. Finally, we found a negative correlation between the size of workers and the diversity of their pollen load. Our results provide additional evidence that conservation actions regarding pollinators in arable landscapes should be made at the landscape rather than at the farm level.


A novel mechanism of SRRM4 in promoting neuroendocrine prostate cancer development via a pluripotency gene network.
Prostate adenocarcinoma (AdPC) cells can undergo lineage switching to neuroendocrine cells and develop into therapy-resistant neuroendocrine prostate cancer (NEPC). While genomic/epigenetic alterations are shown to induce neuroendocrine differentiation via an intermediate stem-like state, RNA splicing factor SRRM4 can transform AdPC cells into NEPC xenografts through a direct neuroendocrine transdifferentiation mechanism. Whether SRRM4 can also regulate a stem-cell gene network for NEPC development remains unclear. Multiple AdPC cell models were transduced by lentiviral vectors encoding SRRM4. SRRM4-mediated RNA splicing and neuroendocrine differentiation of cells and xenografts were determined by qPCR, immunoblotting, and immunohistochemistry. Cell morphology, proliferation, and colony formation rates were also studied. SRRM4 transcriptome in the DU145 cell model was profiled by AmpliSeq and analyzed by gene enrichment studies. SRRM4 induces an overall NEPC-specific RNA splicing program in multiple cell models but creates heterogeneous transcriptomes. SRRM4-transduced DU145 cells present the most dramatic neuronal morphological changes, accelerated cell proliferation, and enhanced resistance to apoptosis. The derived xenografts show classic phenotypes similar to clinical NEPC. Whole transcriptome analyses further reveal that SRRM4 induces a pluripotency gene network consisting of the stem-cell differentiation gene, SOX2. While SRRM4 overexpression enhances SOX2 expression in both time- and dose-dependent manners in DU145 cells, RNA depletion of SOX2 compromises SRRM4-mediated stimulation of pluripotency genes. More importantly, this SRRM4-SOX2 axis is present in a subset of NEPC patient cohorts, patient-derived xenografts, and clinically relevant transgenic mouse models. We report a novel mechanism by which SRRM4 drives NEPC progression via a pluripotency gene network. FUND: Canadian Institutes of Health Research, National Nature Science Foundation of China, and China Scholar Council.


Interaction between antibodies and hapten-protein conjugates of different composition: theoretical predictions and experimental data.
Mathematical models of competitive ELISAs with labelled antibody and with labelled antigen taking into account bivalent interactions between antibodies and hapten-protein conjugates were developed and analyzed. It was shown that in the kinetic model of the immunochemical reaction the conjugate composition influenced the amplitude of detected signal but not ELISA sensitivity. In the equilibrium model decreased sensitivity correlated with bivalent complexes formation. The predictions were tested experimentally using 2,4-dichlorophenoxyacetic acid (2,4-D) and testosterone as haptens. It was confirmed that increasing of the hapten : protein ratio resulted in formation of bivalent complexes with antibodies. The equilibrium binding constants for these complexes were two orders of magnitude higher than for monovalent ones. Optimal conjugate compositions have been chosen for ELISA of these haptens.


Comparing Magnetic Resonance Fingerprinting (MRF) and the MAGiC Sequence for Simultaneous T1 and T2 Quantitative Measurements in the Female Pelvis: A Prospective Study.
The aim of this study was to explore the potential of magnetic resonance fingerprinting (MRF), an emerging quantitative MRI technique, in measuring relaxation values of female pelvic tissues compared to the conventional magnetic resonance image compilation (MAGiC) sequence. The study included 32 female patients who underwent routine pelvic MRI exams using anterior and posterior array coils on a 3T clinical scanner. Our findings demonstrated significant correlations between MRF and MAGiC measured T1 and T2 values (p < 0.0001) for various pelvic tissues, including ilium, femoral head, gluteus, obturator, iliopsoas, erector spinae, uterus, cervix, and cutaneous fat. The tissue contrasts generated from conventional MRI and synthetic MRF also showed agreement in bone, muscle, and uterus for both T1-weighted and T2-weighted images. This study highlights the strengths of MRF in providing simultaneous T1 and T2 mapping. MRF offers distinct tissue contrast and has the potential for accurate diagnosis of female pelvic diseases, including tumors, fibroids, endometriosis, and pelvic inflammatory disease. Additionally, MRF shows promise in monitoring disease progression or treatment response. Overall, the study demonstrates the potential of MRF in the field of female pelvic organ imaging and suggests that it could be a valuable addition to the clinical practice of pelvic MRI exams. Further research is needed to establish the clinical utility of MRF and to develop standardized protocols for its implementation in clinical practice.


Association of human papillomavirus type 16 with neoplastic lesions of the vulva and other genital sites by in situ hybridization.
The authors examined paraffin sections from 85 genital tract tissues from 49 cases for the presence of human papillomavirus (HPV) Types 6/11, 16, and 18 by stringent in situ hybridization using 35S-labeled viral DNA probes, and for viral capsid antigen by the immunoperoxidase test. The cases, selected mostly on the basis of vulvar pathology, were distributed as follows: early neoplasia (Group I, 6 cases); early neoplasia with viral cytopathic effect (CE) (Group II, 24 cases); and papillomavirus infection (PVI) (Group III, 19 cases). Available tissues from all affected sites were examined when the disease was multicentric. One or more viral DNAs were identified in 58% of 77 tissues from Groups II and III and in 2 of 8 tissues from Group I. HPV-6/11, HPV-16 and HPV-18 DNAs were detected, respectively, in 25, 24, and 2 tissues; 3 tissues were infected simultaneously with either two or three viruses. Viral DNA was identified at more than one site in 14 of 30 DNA-positive patients; in 10 of these, a single type was detected at all sites in the same patient. The viral DNA was localized mostly in areas showing viral cytopathology. The presence of HPV-16 correlated with neoplasia. HPV-16 DNA was identified in the 2 virus-positive tissues showing neoplasia, in 17 of 20 (85%) of the DNA-positive tissues showing neoplasia with CE, and in 5 of 25 (20%) of the DNA-positive tissues showing PVI. Conversely, HPV-6/11 was found in 25% of the DNA-positive tissues showing neoplasia with CE and in 80% of the cases of PVI. An HPV genome was identified in neoplastic cells in 14 instances; in all but 1 case, the genome was HPV-16. The association of HPV-16 with neoplasia was seen for both vulvar and cervical lesions. Viral antigen was detected in 83% of lesions associated with HPV 6/11 and in 62% of lesions associated with HPV-16.


Hepatocellular carcinoma developed on noncirrhotic livers. Sinusoids in hepatocellular carcinoma.
In hepatocellular carcinoma, there is modification of cell-to-cell and cell-to-extracellular matrix interactions. Two cases of well-differentiated hepatocellular carcinoma that developed in noncirrhotic livers were explored by light and electron microscopy on perfusion-fixed liver biopsy specimens. In addition, immunocytolocalization of collagen types I, III, and IV, laminin, and fibronectin was assessed. The main features included the following: absence of collagen staining inside the tumor with Sirius red; decrease of collagen types I and III and the increase of collagen type IV, laminin, and fibronectin; widening of Disse's spaces containing numerous, discontinuous, and thick fragments of basement membrane-like material piled up beneath endothelial cells and around perisinusoidal cells; transformation of perisinusoidal cells into cells with the characteristics of fibroblasts and myofibroblasts; decreased numbers of fenestrae for endothelial cells with processes often overlapping and attached with tight junctions; and rarefaction of Kupffer's cells. Expression of cellular and extracellular material abnormalities are related to the tumor differentiation. The study of these abnormalities may have implications in prognosis.


A wafer-like apparatus for two-dimensional measurement of plasma parameters and temperature distribution in low-temperature plasmas.
A wafer-type monitoring apparatus that can simultaneously measure the two-dimensional (2D) distributions of substrate temperature and plasma parameters is developed. To measure the temperature of the substrate, a platinum resistance temperature detector is used. The plasma density and electron temperature are obtained using the floating harmonics method, and incoming heat fluxes from the plasma to the substrate are obtained from the plasma density and electron temperature. In this paper, 2D distributions of the substrate temperature, plasma density, and electron temperature are obtained simultaneously for the first time in inductively coupled plasma. The shapes of the 2D distributions of the substrate temperature and incoming heat flux are similar to each other, but some differences are found. To understand that, an energy balance equation for the substrate is established, which shows good agreement with the experimental results. This apparatus will promote the understanding of surface reactions, which are very sensitive to the temperatures and plasma densities in plasma processing.


Phlebotomus argentipes seasonal patterns in India and Nepal.
The current control of Phebotomus argentipes (Annandale and Brunetti), the vector of Leishmania donovani (Laveran and Mesnil), on the Indian subcontinent is base on indoor residual spraying. The efficacy of this method depends, among other factors, on the timing and number of spraying rounds, which depend on the P. argentipes seasonality. To describe P. argentipes' seasonal patterns, six visceral leishmaniasis (VL) endemic villages, three in Muzaffarpur and three in Sunsari districts in India and Nepal, respectively, were selected based on accessibility and VL incidence. Ten houses per cluster with the highest P. argentipes density were monitored monthly for 15-16 mo using Center for Disease Control and Prevention light traps. Minimum and maximum temperature and rainfall data for the months January 2006 through December 2007 were collected from the nearest available weather stations. Backwards stepwise regression was used to generate the minimal adequate model for explaining the monthly variation in P. argentipes populations. The seasonality of P. argentipes is similar in India and Nepal, with two annual density peaks around May and October. Monthly P. argentipes density is positively associated with temperature and negatively associated with rainfall in both study sites. The multivariate climate model explained 57% of the monthly vectorial abundance. Vector control programs against P. argentipes (i.e., indoor residual spraying) should take into account the seasonal described here when implementing and monitoring interventions. Monitoring simple meteorological variables (i.e., temperature, rainfall) may allow prediction of VL epidemics on the Indian subcontinent.


Use of fresh-frozen plasma in 2012 at the Fondazione Ca' Granda Hospital of Milan: assessment of appropriateness using record linkage techniques applied to data routinely recorded in various hospital information systems.
The Quality Unit of a research and teaching hospital in Milan assessed the increased clinical use of fresh-frozen plasma in patients treated during 2012 in order to evaluate the appropriateness of this use. For each patient in the study, a pathology profile was generated by means of record linkage techniques involving data collected through different information systems. Patients' information was combined using the patient identifier key generating pathology profiles exported to an Excel file. The profiles were reviewed by two haematologists who identified 101 potentially inappropriate treatments for which the medical records had to be reviewed manually. In 2012, 490 patients were transfused and for 473 cases the automatic record linkage provided a complete profile. The information relating to the remaining patients did not match, mainly because the patients underwent outpatient procedures for which clinical information is not automatically recorded. In the overall audit only 13 treatments were judged inappropriate. Our study supports the view that record linkage techniques applied to data routinely recorded in different hospital information systems could be potentially extended to support clinical audits, enabling the generation of automated patient profiles that can be easily evaluated, relegating manual checks on medical records to doubtful cases only. Moreover, the method applied in this study allows the analysis of a full set of cases instead of sample surveys, increasing the robustness of the audit results.


Fluorangiographic study of the ocular fundus in normal horses.
To describe the protocol and appearance of fluorescein angiography (FA) in normal horses. A total of 25 healthy horses aged between 5 and 15 years. The horses were sedated with 15 microg/kg detomidine and 50 microg/kg butorphanol and dilated with topical tropicamide 1%. All angiograms were recorded after intravenous bolus injection of 10 mg/kg of fluorescein sodium solution. Two successive angiographic phases could be discerned: the choriopapillary phase, starting at 46.95 +/- 9.48 s, and the retinal vascular phase, starting at 47.79 +/- 10.38 s. The retinal vascular phase was divided in three parts: filling phase, maximum fluorescence point, and fading phase. During the filling phase, the dye progressed into the retinal vessels, obtaining maximum fluorescence at 59.79 +/- 10.39 s, termed the maximum fluorescence point. The fading phase started immediately following the maximum fluorescence point. During this phase, vascular fluorescence decreased to complete reduction at 74.76 +/- 9.81 s. Also, areas of delayed choroidal filling, the presence of short retinal vessels in the ventral region of the optic disc, and a particular filling of the optic disc were also observed. The normal angiographic sequence was described in horses. FA may be a useful method for studying the integrity of the blood-retinal barriers in horses.


The effect of L-dopa in Parkinson's disease as revealed by neurophysiological studies of motor and sensory functions.
This review will first discuss evidence of motor and sensory abnormalities as yielded by neurophysiological techniques in patients with PD. It will then go on to describe the effects of L-dopa replacement on motor and sensory abnormalities in PD as assessed by neurophysiological studies. Areas covered: We analyzed papers in English using Pubmed with the following keywords: L-dopa, dopamine, bradykinesia, basal ganglia, kinematic analysis, TMS, motor cortex plasticity, motor cortex excitability, somatosensory discrimination threshold, pain Expert commentary: L-dopa improves the amplitude and speed of upper limb voluntary movements, but it does not restore abnormalities in the sequence effect or voluntary facial movements. L-dopa only partially normalizes changes in motor cortex excitability and plasticity and has also contrasting effects on the sensory system and on sensory-motor integration. The neurophysiological studies reviewed here show that PD is more than a hypo-dopaminergic disease, and non-dopaminergic mechanisms should also be considered.


Corticospinal and peripheral responses to heat-induced hypo-hydration: potential physiological mechanisms and implications for neuromuscular function.
Heat-induced hypo-hydration (hyperosmotic hypovolemia) can reduce prolonged skeletal muscle performance; however, the mechanisms are less well understood and the reported effects on all aspects of neuromuscular function and brief maximal contractions are inconsistent. Historically, a 4-6% reduction of body mass has not been considered to impair muscle function in humans, as determined by muscle torque, membrane excitability and peak power production. With the development of magnetic resonance imaging and neurophysiological techniques, such as electromyography, peripheral nerve, and transcranial magnetic stimulation (TMS), the integrity of the brain-to-muscle pathway can be further investigated. The findings of this review demonstrate that heat-induced hypo-hydration impairs neuromuscular function, particularly during repeated and sustained contractions. Additionally, the mechanisms are separate to those of hyperthermia-induced fatigue and are likely a result of modulations to corticospinal inhibition, increased fibre conduction velocity, pain perception and impaired contractile function. This review also sheds light on the view that hypo-hydration has 'no effect' on neuromuscular function during brief maximal voluntary contractions. It is hypothesised that irrespective of unchanged force, compensatory reductions in cortical inhibition are likely to occur, in the attempt of achieving adequate force production. Studies using single-pulse TMS have shown that hypo-hydration can reduce maximal isometric and eccentric force, despite a reduction in cortical inhibition, but the cause of this is currently unclear. Future work should investigate the intracortical inhibitory and excitatory pathways within the brain, to elucidate the role of the central nervous system in force output, following heat-induced hypo-hydration.


The safety of sublingual immunotherapy with one or multiple pollen allergens in children.
Since the majority of allergic patients are polysensitized, it is often necessary to prescribe immunotherapy with multiple allergens. It is crucial to know if the administration of multiple allergens with sublingual immunotherapy (SLIT) increases the risk of side-effects in children. Consecutive children with respiratory allergy because of pollens, receiving SLIT for multiple or single allergens were followed-up in a postmarketing survey. Inclusion criteria were those for prescribing SLIT according to guidelines. Parents recorded in a diary card the side-effects (eye symptoms, rhinitis/ear itching, asthma, oral itching/swelling, nausea, vomiting, abdominal pain, diarrhoea, urticaria, angioedema and anaphylaxis). The side-effects were graded as mild, moderate and severe. Four hundred and thirty-three children (285 male, age range 3-18 years) receiving SLIT were surveyed. Of them, 179 received a single extract, and 254 multiple allergens. The total number of doses given was 40 169 (17 143 with single allergen). Overall, 178 episodes were reported. Of them, 76 occurred with the single allergen (42.46% patients, 4.43/1000 doses) and 102 (40.3% patients, 4.42/1000 doses) with multiple allergens (P = NS). 165 episodes (92.5%) were mild and self-resolving and were equally distributed in the two groups. In 13 cases, the events were judged of moderate severity and medical advice was required. Three patients discontinued SLIT, despite the local side-effects being mild. No emergency treatment was required at all. The use of multiple allergens for SLIT does not increase the rate of side-effects in children.


ORGANIZATION OF PREDATOR-PREY COMMUNITIES AS AN EVOLUTIONARY GAME.
We consider a simple predator-prey model of coevolution. By allowing coevolution both within and between trophic levels the model breaks the traditional dichotomy between coevolution among competitors and coevolution between a prey and its predator. By allowing the diversity of prey and predator species to emerge as a property of the evolutionarily stable strategies (ESS), the model breaks another constraint of most approaches to coevolution that consider as fixed the number of coevolving species. The number of species comprising the ESS is influenced by a parameter that determines the predator's niche breadth. Depending upon the parameter's value the ESS may contain: 1) one prey and one predator species, 2) two prey and one predator, 3) two prey and two predators, 4) three prey and two predators, 5) three prey and three predators, etc. Evolutionarily, these different ESSs all emerge from the same model. Ecologically, however, these ESSs result in very different patterns of community organization. In some communities the predator species are ecologically keystone in that their removal results in extinctions among the prey species. In others, the removal of a predator species has no significant impact on the prey community. These varied ecological roles for the predator species contrasts sharply with the essential evolutionary role of the predators in promoting prey species diversity. The ghost of predation past in which a predator's insignificant ecological role obscures its essential evolutionary role may be a frequent property of communities of predator and prey.


A rare report of Rothia dentocariosa endocarditis.
Rothia species are gram positive, round to rod-shaped bacteria that are normally oral and respiratory tract flora. They were first isolated in 1967 from dental caries. We present a 69-year-old male with no risk factors for aforementioned bacteria however was found to have thickened anterior leaflet of the mitral valve with a small isoechoic lesion consistent with vegetation on Transthoracic echocardiogram. Blood cultures grew pan sensitive Rothia dentocariosa. Patient was treated with long-term antibiotics. This case adds to the limited number of cases of Rothia dentocariosa Endocarditis.


Ex vivo Quantitative Proteomic Analysis of Serotonin Transporter Interactome: Network Impact of the SERT Ala56 Coding Variant.
Altered serotonin (5-HT) signaling is associated with multiple brain disorders, including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD). The presynaptic, high-affinity 5-HT transporter (SERT) tightly regulates 5-HT clearance after release from serotonergic neurons in the brain and enteric nervous systems, among other sites. Accumulating evidence suggests that SERT is dynamically regulated in distinct activity states as a result of environmental and intracellular stimuli, with regulation perturbed by disease-associated coding variants. Our lab identified a rare, hypermorphic SERT coding substitution, Gly56Ala, in subjects with ASD, finding that the Ala56 variant stabilizes a high-affinity outward-facing conformation (SERT∗) that leads to elevated 5-HT uptake in vitro and in vivo. Hyperactive SERT Ala56 appears to preclude further activity enhancements by p38α mitogen-activated protein kinase (MAPK) and can be normalized by pharmacological p38α MAPK inhibition, consistent with SERT Ala56 mimicking, constitutively, a high-activity conformation entered into transiently by p38α MAPK activation. We hypothesize that changes in SERT-interacting proteins (SIPs) support the shift of SERT into the SERT∗ state which may be captured by comparing the composition of SERT Ala56 protein complexes with those of wildtype (WT) SERT, defining specific interactions through comparisons of protein complexes recovered using preparations from SERT-/- (knockout; KO) mice. Using quantitative proteomic-based approaches, we identify a total of 459 SIPs, that demonstrate both SERT specificity and sensitivity to the Gly56Ala substitution, with a striking bias being a loss of SIP interactions with SERT Ala56 compared to WT SERT. Among this group are previously validated SIPs, such as flotillin-1 (FLOT1) and protein phosphatase 2A (PP2A), whose functions are believed to contribute to SERT microdomain localization and regulation. Interestingly, our studies nominate a number of novel SIPs implicated in ASD, including fragile X mental retardation 1 protein (FMR1) and SH3 and multiple ankyrin repeat domains protein 3 (SHANK3), of potential relevance to long-standing evidence of serotonergic contributions to ASD. Further investigation of these SIPs, and the broader networks they engage, may afford a greater understanding of ASD as well as other brain and peripheral disorders associated with perturbed 5-HT signaling.


Human Exoproteome in Acute Apical Abscesses.
An acute apical abscess is a severe response of the host to massive invasion of the periapical tissues by bacteria from infected root canals. Although many studies have investigated the microbiota involved in the process, information on the host factors released during abscess formation is scarce. The purpose of this study was to describe the human exoproteome in samples from acute apical abscesses. Fourteen pus samples were obtained by aspiration from patients with an acute apical abscess. Samples were subjected to protein digestion, and the tryptic peptides were analyzed using a mass spectrometer and ion trap instrument. The human proteins identified in this analysis were classified into different functional categories. A total of 303 proteins were identified. Most of these proteins were involved in cellular and metabolic processes. Immune system proteins were also very frequent and included immunoglobulins, S100 proteins, complement proteins, and heat shock proteins. Polymorphonuclear neutrophil proteins were also commonly detected, including myeloperoxidases, defensins, elastases, and gelatinases. Iron-sequestering proteins including transferrin and lactoferrin/lactotransferrin were found in many samples. The human exoproteome included a wide variety of proteins related to cellular processes, metabolism, and immune response. Proteins involved in different mechanisms against infection, tissue damage, and protection against tissue damage were identified. Knowledge of the presence and function of these proteins using proteomics provides an insight into the complex host-pathogen relationship, the host antimicrobial strategies to fight infections, and the disease pathogenesis.


Effects of body weight on responses of serum prolactin to metoclopramide and thyrotrophin-releasing hormone in secondary amenorrhoeic women.
The present study was designed to investigate the influence of body weight on the prolactin responsiveness to metoclopramide and thyrotrophin-releasing hormone (TRH) in secondary amenorrhoeic women. The responses of serum prolactin to metoclopramide and TRH were assessed in relation to body mass index (BMI). Doses of 10 mg of metoclopramide hydrochloride and 500 micrograms of TRH were administered i.v. to 42 secondary amenorrhoeic women and six women with primary ovarian failure. The increment of serum prolactin at 30 min after the administration of metoclopramide was significantly lower (P < 0.01, respectively) in amenorrhoeic women with a BMI of > or = 30 or < 19 than in amenorrhoeic women with a BMI of 19-24. A significant correlation ration (eta = 0.63; P < 0.01) was found between the BMI and the increment of serum prolactin at 30 min after metoclopramide administration in amenorrhoeic women. The increment of serum prolactin at 15 min after TRH administration was slightly lower in amenorrhoeic women with a BMI of > or = 30 or < 19 than in amenorrhoeic women with a BMI of 19-24, but these differences were not statistically significant. These results indicate that the body weight influences the responsiveness of serum prolactin to metoclopramide in secondary amenorrhoeic women.


Analysis of 121 fatal passenger car-adult pedestrian accidents in China.
To study the characteristics of fatal vehicle-pedestrian accidents in China,a team was established and passenger car-pedestrian crash cases occurring between 2006 and 2011 in Beijing and Chongqing, China were collected. A total of 121 fatal passenger car-adult pedestrian collisions were sampled and analyzed. The pedestrian injuries were scored according to Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS). The demographical distributions of fatal pedestrian accidents differed from other pedestrian accidents. Among the victims, no significant discrepancy in the distribution of ISS and AIS in head, thorax, abdomen, and extremities by pedestrian age was found, while pedestrian behaviors prior to the crashes may affect the ISS. The distributions of AIS in head, thorax, and abdomen among the fatalities did not show any association with impact speeds or vehicle types, whereas there was a strong relationship between the ISS and impact speeds. Whether pedestrians died in the accident field or not was not associated with the ISS or AIS. The present results may be useful for not only forensic experts but also vehicle safety researchers. More investigations regarding fatal pedestrian accidents need be conducted in great detail.


Transcriptional activation of Hedgehog pathway components in aggressive haemangioma.
Infantile hemangioma is a vascular neoplasm and is one of the most common tumors diagnosed in young children. Although most hemangiomas are harmless and involute spontaneously, some show severe progression, leading to serious complications, such as high-output cardiac failure, ulcerations, compression of the trachea or deprivation amblyopia, depending on their size and localization. However, the pathogenesis and cause of hemangioma are largely unknown to date. The goal of this study was to identify markers that could predict hemangiomas with aggressive growth and severe progression that would benefit from early intervention. By using a PCR-based screening approach, we first confirmed that previously known markers of hemangioma, namely FGF2 and GLUT1, are highly expressed in hemangioma. Nevertheless, these genes did not show any differential expression between severely progressing tumors and mild tumors. However, transcriptional upregulation of several Hedgehog signalling components, comprising the ligand Sonic Hedgehog (SHH), the transcription factor GLI2 and its target gene FOXA2 were detected in extremely aggressive hemangioma specimens during the proliferation phase. Notably, GLI2 was even overexpressed in involuting hemangiomas if they showed an aggressive growth pattern. In conclusion, our data suggest that overexpression of the Hedgehog components SHH, GLI2 and FOXA2 might be used as markers of an aggressive hemangioma that would benefit from too early intervention, while FGF2 and GLUT1 are more general markers of hemangiomas.


Clinical Statistical Analysis with Comparison between Pelvic and Non-pelvic Chondrosarcoma.
Chondrosarcomas are rare tumors with a variable biological characteristic. Their treatment clinically and surgically is controversial. Analysis of the clinical statistics and prognostic factors of pelvic chondrosarcoma provides a reference for clinical diagnosis and treatment. A total of 73 cases of chondrosarcoma were collected, including 24 pelvic samples, from 2008 to 2017 from the hospital database and divided into two groups: pelvic chondrosarcoma and non-pelvic chondrosarcoma. The clinical characteristics and prognostic factors of pelvic chondrosarcoma were analyzed using different statistical methods. Among the 24 pelvic chondrosarcoma patients, the ratio of male to female was 1.4:1, and the median age was 43.5 years. According to the classification proposed by Enneking, there were five grade I, 14 grade II, and five grade III. Histological grading of chondrosarcoma was grade I in one case, II in 15 cases, and III in eight cases. The histological type was 17 conventional, three dedifferentiated, two secondary, one myxoid, and one mesenchymal. The overall survival rates for 24 cases at three, five, and 10 years were 82.2±8.1%, 77.3±8.9%, and 52.4±12.1%, respectively. The local recurrence rate of pelvic chondrosarcoma after surgical resection (83.3%) was significantly higher than that of other sites (34.7%), and the difference was statistically significant (p < 0.001). The final proportion of amputation rate (50.0%) was also higher than other parts (20.4%), with a statistically significant difference (p = 0.010). The total survival of the two groups was not significantly different (p = 0.216). Chondrosarcoma of bone generally has an excellent prognosis when optimally diagnosed and treated by an experienced team of specialists. Pelvic chondrosarcoma has a higher local recurrence rate than the other sites and tends to result in amputation. Early local recurrence after surgery indicates a poor prognosis.


Sudden death caused by parasites: postmortem cerebral malaria discoveries in the african endemic zone.
This survey presents several cases of sudden deaths in Africa, specifically in Cote d'Ivoire, where the postmortem diagnosis of human cerebral malaria was determined after autopsy followed by pathologic examination of the brain. It is thought that cerebral malaria may be the primary cause of sudden death in nonimmunized persons during or after traveling in such endemic areas of Africa. The target population is composed of tourists, business travelers, and sailors. Because death caused by cerebral malaria occurs so suddenly, it can lead to forensic issues. Therefore, in any cases involving sudden death, it is very important for the forensic scientist to do a systematic evaluation, including pathologic examination of brain tissue, to rule in or exclude cerebral malaria. This practice will reinforce and aid research in progress directed at developing a vaccine and elucidating the role of tumor necrosis factor in this disease. Furthermore, this study will alert the physician to the importance of an effective and well-followed prophylaxis.


Identification of risk factors for hearing impairment in newborns: a hospital based study.
Aim To identify risk factors for hearing impairment presented in neonates born in Cantonal Hospital Zenica (CHZ) and to estimate their influence on outcome of hearing tests in Newborn Hearing Screening (NHS). Methods Retrospective-prospective study was done at the Department of Gynaecology and Maternity. The NHS was performed with transitory evoked otoacoustic emissions (TEOAE) during a six-month period using "Titan" device (Interacoustics, Denmark). The questionnaire was written for the purpose of getting more structured basic information about every newborn and to identify risk factors for hearing impairment. Chi-square test was used to investigate the difference between experimental and control group refer incidence. Results A total of 1217 newborns was screened for hearing impairment of which 259 (21.28%) with one or more known risk factors for hearing impairment. The following risk factors for hearing impairment were identified during the study period: family history of permanent childhood hearing impairment in 42 (3.45%) newborns, prematurity in 39 (3.21%), low APGAR scores in 29 (2.40%), asphyxia in 31 (2.55%), hyperbilirubinemia in 41 (3.37%), admission of ototoxic medication (aminoglycosides) after birth in 155 (12.74%). Conclusion There were many serious risk factors for hearing loss identified in this study. Identification of risk factors for hearing impairment in neonates is necessary because a follow up of the children with risk factors is very important.


[Functional state of the myocardium during stenocardia induced by isoproterenol].
Hemodynamic changes in healthy subjects versus patients with chronic coronary heart disease are compared. In cases of isoproterenol caused tachycardia, the patients developing angina showed a less prominent beneficial inotropic effect as compared with healthy subjects and angina-free patients. The initiation of drug infusion led to a marked increase in the rheographic index of myocardial contractility; however, already in the initial stages of ST segment depression, this parameter was characterized by a reversed time-course which progressed with the increasing electrocardiographic signs of myocardial ischemia. The degree of the observed impairments of the patients' inotropic response correlated with the severity of myocardial ischemia and the nature of the disease course.


Use of rK39 for diagnosis of post kala-azar dermal leishmaniasis in Nepal.
A recently developed nitrocellulose-based dipstick test, rK39, has been widely used for the diagnosis of kala-azar. In this study, we evaluated its use for the diagnosis of post kala-azar dermal leishmaniasis (PKDL). We also investigated the time taken by patients to develop PKDL after apparent cure of kala-azar (visceral leishmaniasis, VL) and the time taken by patients to come to the hospital after the appearance of symptoms of PKDL. A majority of patients developed the disease within three years after the apparent cure of kala-azar (KA). A majority of patients sought treatment within five years after the onset of PKDL. The amastigotes of Leishmania donovani bodies (LDBs) were demonstrated in 70, 20, and 20% of slit-skin smears (SSS) prepared, respectively, from nodular, papular, and macular forms. The presence of highest density (6+) LDBs in the SSS of 20% of nodular PKDL patients indicated that they may have acted as reservoir in the community. Other reservoirs are not known in Nepal. Only 8% cases were detected by aldehyde test. Although this test is obsolete it is still used in rural parts of Nepal. The dipstick (rK39) was 96% sensitive and 100% specific to diagnose PKDL. Its positive predictive value, negative predictive value, and diagnostic efficacy were 100, 91, and 97% respectively. Due to the advantage of cost compared with the direct agglutination test (DAT), and being easy to use and store in field conditions, rK39 is a good tool to diagnose PKDL in rural situations. All the PKDL patients were cured of the disease after treatment by SAG.


QT-RR relationship in healthy subjects exhibits substantial intersubject variability and high intrasubject stability.
Recently, it was demonstrated that the QT-RR relationship pattern varies significantly among healthy individuals. We compared the intra- and interindividual variations of the QT-RR relationship. Twenty-four-hour 12-lead digital electrocardiograms (ECGs; SEER MC, GE Marquette; 10-s ECG recorded every 30 s) were obtained at baseline and after 24 h, 1 wk, and 1 mo in 75 healthy subjects (42 women, 33 men, age 27.9 +/- 9.6 vs. 26.8 +/- 7.5 yr, P = not significant). QT interval was measured automatically in each ECG by six different algorithms, and the mean of the six measurements was analyzed. In each recording of each individual, QT-RR relationship was assessed by 10 different regression models including linear (QT = beta + alpha x RR) and parabolic (QT = beta x RR(alpha)) models. Standard deviations (SDs) of regression parameters alpha and beta of consecutive recordings of each individual were compared with SD of the individual means. Intrasubject stability and interindividual variability were further tested by ANOVA. With all models, intraindividual SDs of the regression parameters were highly significantly smaller than SD of individual means (P < 10(-5)-10(-9)). The intrasubject stability was further confirmed by ANOVA (P < 10(-19)-10(-30)). The QT-RR relationship exhibits substantial intersubject variability as well as a high intrasubject stability. This has practical implications for a precise estimation of the heart rate-corrected QT interval in which optimized subject-specific rate correction formulas should be used.


Health-related quality of life in carers of patients with dementia.
Carers of patients with dementia experience high levels of stress that can adversely affect their health and well-being. Our aim was to assess the health-related quality of life of carers of patients with dementia compared with an age- and gender-matched sample from the general population. A cross-sectional study was conducted in 37 primary health care centres in Catalonia, Spain. Carers (n = 181; 78% females, mean age 63 years) of patients with dementia together with a random sample of 543 individuals from the general population, matched for age and gender, were assessed with the SF-36 questionnaire, which is a generic measure of health status. With the exception of physical function category, seven of the scales showed lower scores for females in the carer group. The most important differences were observed in the emotional role [95% confidence interval (CI) -37.7 to -3.6], mental health (95% CI -21.0 to -1.6) and bodily pain (95% CI -37.7 to -8.6) categories. In contrast, male carers had higher scores in the physical function category (95% CI 2.2-19.4), and no differences were observed on the other scales. Female carers of patients with dementia experienced a seriously decreased quality of life level compared with their contemporaries in the general population.


Effects of the synthetic pyrethroid insecticide, permethrin, on two estuarine fish species.
Limited toxicity data are available for estuarine and marine species and the widely used pyrethroid insecticide, permethrin. This study determined acute effects of permethrin on survival, lipid peroxidation, acetylcholinesterase activity, and splenocyte proliferation for two fish species found in South Carolina estuaries; juvenile red drum (Sciaenops ocellatus) and adult mummichog (Fundulus heteroclitus). Juvenile S. ocellatus were significantly more sensitive than adult F. heteroclitus to permethrin exposure, with a 96-h LC50 value of 8 μg/L determined for red drum compared to 23 μg/L for mummichog. Lipid peroxidation activity of the liver increased in permethrin-treated fish compared to control animals after 24 h and decreased after 96 h. Permethrin had no effect on acetylcholinesterase activity of the brain at the concentrations tested. Permethrin exposure significantly inhibited splenocyte proliferation, indicating an immunosuppressive effect. Most of the effects of permethrin on fish cellular stress enzymes and survival occurred at concentrations much higher than those typically measured in the environment. However, inhibition of splenocyte proliferation in juvenile red drum occurred at approximately twice that of measured permethrin concentrations in surface water. These findings may prove useful to the future management and regulation of pyrethroid insecticide use near estuarine habitats.


Optimizing Ozone Disinfection in Water Reuse: Controlling Bromate Formation and Enhancing Trace Organic Contaminant Oxidation.
The use of ozone/biofiltration advanced treatment has become more prevalent in recent years, with many utilities seeking an alternative to membrane/RO based treatment for water reuse. Ensuring efficient pathogen reduction while controlling disinfection byproducts and maximizing oxidation of trace organic contaminants remains a major barrier to implementing ozone in reuse applications. Navigating these challenges is imperative in order to allow for the more widespread application of ozonation. Here, we demonstrate the effectiveness of ozone for virus, coliform bacteria, and spore forming bacteria inactivation in unfiltered secondary effluent, all the while controlling the disinfection byproduct bromate. A greater than 6-log reduction of both male specific and somatic coliphages was seen at specific ozone doses as low as 0.75 O3:TOC. This study compared monochloramine and hydrogen peroxide as chemical bromate control measures in high bromide water (Br- = 0.35 ± 0.07 mg/L). On average, monochloramine and hydrogen peroxide resulted in an 80% and 36% decrease of bromate formation, respectively. Neither bromate control method had any appreciable impact on virus or coliform bacteria disinfection by ozone; however, the use of hydrogen peroxide would require a non-Ct disinfection framework. Maintaining ozone residual was shown to be critical for achieving disinfection of more resilient microorganisms, such as spore forming bacteria. While extremely effective at controlling bromate, monochloramine was shown to inhibit TrOC oxidation, whereas hydrogen peroxide enhanced TrOC oxidation.


Association of donor and recipient SUMO4 rs237025 genetic variant with new-onset diabetes mellitus after liver transplantation in a Chinese population.
New-onset diabetes mellitus (NODM) is a common complication after liver transplantation (LT). The small ubiquitin-like modifier 4 (SUMO4) rs237025 polymorphism has been reported to be associated with type 2 diabetes mellitus (T2DM). In this study, we aimed to evaluate the association of donor and recipient SUMO4 rs237025 polymorphisms with NODM and the long-term consequences of NODM after LT. A total of 126 liver transplant patients were enrolled in the study. One single nucleotide polymorphism, SUMO4 rs237025, was genotyped in both donors and recipients. Both donor and recipient SUMO4 rs237025 polymorphisms were found to be significantly associated with NODM after LT. In multivariate analysis, recipient age>50 years, tacrolimus trough concentrations>10ng/mL at 1month after LT, donor and recipient rs237025 genetic variant, and the combined donor and recipient rs237025 genetic variant were independent predictive factors of NODM. Area under the receiver operating characteristic curve (AUROC) analysis indicated the higher predictive ability of the model containing combined donor and recipient rs237025 polymorphisms than the clinical model (p=0.046). Furthermore, Kaplan-Meier survival analysis demonstrated that NODM was related to significantly poorer patient survival in comparison with non-NODM patients (p=0.041). Both donor and recipient SUMO4 rs237025 polymorphisms contribute to the development of NODM after LT and NODM is a frequent complication that negatively affects patient survival.


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Use of Zeolite with Alum and Polyaluminum Chloride Amendments to Mitigate Runoff Losses of Phosphorus, Nitrogen, and Suspended Solids from Agricultural Wastes Applied to Grassed Soils.
Diffuse pollutant losses containing phosphorus (P), nitrogen (N), and suspended solids (SS) can occur when agricultural wastes are applied to soil. This study aimed to mitigate P, N, and SS losses in runoff from grassed soils, onto which three types of agricultural wastes (dairy slurry, pig slurry, and dairy-soiled water [DSW]), were applied by combining amendments of either zeolite and polyaluminum chloride (PAC) with dairy and pig slurries or zeolite and alum with DSW. Four treatments were investigated in rainfall simulation studies: (i) control soil, (ii) agricultural wastes, (iii) dairy and pig slurries amended with PAC and DSW amended with alum, and (iv) dairy and pig slurries amended with zeolite and PAC and DSW amended with zeolite and alum. Our data showed that combined amendments of zeolite and PAC applied to dairy and pig slurries reduced total P (TP) in runoff by 87 and 81%, respectively, compared with unamended slurries. A combined amendment of zeolite and alum applied to DSW reduced TP in runoff by 50% compared with unamended DSW. The corresponding reductions in total N (TN) were 56% for dairy slurry and 45% for both pig slurry and DSW. Use of combined amendments reduced SS in runoff by 73 and 44% for dairy and pig slurries and 25% for DSW compared with unamended controls, but these results were not significantly different from those using chemical amendments only. The findings of this study are that combined amendments of zeolite and either PAC or alum reduce TP and TN losses in runoff to a greater extent than the use of single PAC or alum amendments and are most effective when used with dairy slurry and pig slurry but less effective when used with DSW.


Lateral Flow Rapid Test for Accurate and Early Diagnosis of Scrub Typhus: A Febrile Illness of Historically Military Importance in the Pacific Rim.
Scrub typhus (ST) is an infection caused by Orientia tsutsugamushi. Historically, ST was ranked as the second most important arthropod-borne medical problem only behind malaria during World War II and the Vietnam War. The disease occurs mainly in Southeast Asia and has been shown to emerge and reemerge in new areas, implying the increased risk for U.S. military and civilian personnel deployed to these regions. ST can effectively be treated by doxycycline provided the diagnosis is made early, before the development of severe complications. Scrub Typhus Detect is a lateral flow rapid test based on a mixture of recombinant 56-kDa antigens with broad reactivity. The performance of this prototype product was evaluated against indirect immunofluorescence assay, the serological gold standard. Using 249 prospectively collected samples from Thailand, the sensitivity and specificity for IgM was found to be 100% and 92%, respectively, suggesting a high potential of this product for clinical use. This product will provide a user friendly, rapid, and accurate diagnosis of ST for clinicians to provide timely and accurate treatments of deployed personnel.


Relaxation to equilibrium can be hindered by transient dissipative structures.
Relaxation processes in a closed chemical reaction-diffusion system which can potentially form Turing-like patterns during the transient are investigated to address the question given by the title. We find that when certain conditions are fulfilled the relaxation process is indeed drastically hindered, once the pattern is formed. This slowing down is shown to be due to stepwise relaxation, where each plateau in the relaxation process corresponds to residence at a certain spatial pattern. Mechanism and universality of the phenomena are discussed.


Differential inhibitory effects of various flavonoids on the activities of reverse transcriptase and cellular DNA and RNA polymerases.
Four flavonoids, 5,6,7-trihydroxyflavone (baicalein), 3,3',4',5,7-pentahydroxyflavone (quercetin), 3,3',4',5,6,7-hexahydroxyflavone (quercetagetin) and 3,3',4',5,5',7-hexahydroxyflavone (myricetin), were found to be potent inhibitors of reverse transcriptases from Rauscher murine leukemia virus (RLV) and human immunodeficiency virus (HIV). Under the reaction conditions employed, any one of these flavonoids almost completely inhibited the activity of RLV reverse transcriptase at a concentration of 1 microgram/ml. HIV reverse transcriptase was inhibited by 100%, 100%, 90% and 70% in the presence of 2 micrograms/ml quercetin, myricetin, quercetagetin and baicalein, respectively. The mode of inhibition of these flavonoids was competitive (RLV reverse transcriptase) or partially competitive (HIV reverse transcriptase) with respect to the template.primer complex, (rA)n.(dT), and noncompetitive with respect to the triphosphate substrate, dTTP. The Ki values for RLV reverse transcriptase were found to be 0.37 microM and 0.08 microM for baicalein and quercetin, respectively and those for HIV reverse transcriptase were 2.52 microM, 0.52 microM, 0.46 microM and 0.08 microM for baicalein, quercetin, quercetagetin and myricetin, respectively. Comparative studies with other flavonoids (hydroxyflavones, dihydroxyflavones and polyhydroxyflavones and flavanones) carried out to clarify the structure/activity relationships, revealed that the presence of both the unsaturated double bond between positions 2 and 3 of the flavonoid pyrone ring, and the three hydroxyl groups introduced on positions 5, 6 and 7, (i.e. baicalein) were a prerequisite for the inhibition of reverse transcriptase activity. Removal of the 6-hydroxyl group of baicalein required the introduction of three additional hydroxyl groups at positions 3, 3' and 4' (quercetin), to afford a compound still capable of inhibiting the reverse transcriptase activity. Quercetagetin which contains the structures of both baicalein and quercetin, and myricetin which has the structure of quercetin with an additional hydroxyl group on the 5' position also proved strong inhibitors of reverse transcriptase activity. The inhibition by baicalein of reverse transcriptase is highly specific, whereas quercetin and quercetagetin were also strong inhibitors of DNA polymerase beta and DNA polymerase I, respectively. Myricetin was also a potent inhibitor of both DNA polymerase alpha and DNA polymerase I.


Diagnostic and treatment workup for IgG4-related disease.
IgG4-Related Disease is a newly recognized condition which is increasingly diagnosed by practitioners due to improvement in clinical awareness. Men and women have been found to be affected by this disease in various organs, more commonly with involvement of the salivary and lacrimal glands as well as pancreas and liver. Areas covered: The diagnosis and management of this condition remain challenging as biomarkers and therapies are being investigated. Hallmark features on histology are still the gold standard for confirmation of diagnosis, whereas serum IgG4 level has been shown to be neither necessary nor sufficient for the diagnosis. Glucocorticoids remain the most effective initial management for this condition while there are limited clinical trials on the effectiveness of maintenance therapy. Expert commentary: This review serves as an update on approaches for diagnosis and management of IgG4-RD. Most of the known data in this field comes from retrospective cohort studies and expert consensus guidelines but new ongoing prospective studies, clinical trials and better understanding of the pathogenesis of this condition are promising.


Enhanced efficiency through nuclear localization signal fusion on phage PhiC31-integrase: activity comparison with Cre and FLPe recombinase in mammalian cells.
The integrase of the phage PhiC31 recombines an attP site in the phage genome with a chromosomal attB site of its Streptomyces host. We have utilized the integrase-mediated reaction to achieve episomal and genomic deletion of a reporter gene in mammalian cells, and provide the first comparison of its efficiency with other recombinases in a new assay system. This assay demonstrated that the efficiency of PhiC31-integrase is significantly enhanced by the C-terminal, but not the N-terminal, addition of a nuclear localization signal and becomes comparable with that of the widely used Cre/loxP system. Furthermore, we found that the improved FLP recombinase, FLPe, exhibits only 10% recombination activity on chromosomal targets as compared with Cre, whereas the Anabaena derived XisA recombinase is essentially inactive in mammalian cells. These results provide the first demonstration that a nuclear localisation signal and its position within a recombinase can be important for its efficiency in mammalian cells and establish the improved PhiC31-integrase as a new tool for genome engineering.


Regulation of peroxiredoxin I activity by Cdc2-mediated phosphorylation.
Hydrogen peroxide is implicated as an intracellular messenger in various cellular responses such as proliferation and differentiation. Peroxiredoxin (Prx) I is a member of the peroxiredoxin family of peroxidases and contains a consensus site (Thr(90)-Pro-Lys-Lys) for phosphorylation by cyclin-dependent kinases (CDKs). This protein has now been shown to be phosphorylated specifically on Thr(90) by several CDKs, including Cdc2, in vitro. Phosphorylation of Prx I on Thr(90) reduced the peroxidase activity of this protein by 80%. The phosphorylation of Prx I in HeLa cells was monitored with the use of antibodies specific for Prx I phosphorylated on Thr(90). Immunoblot analysis with these antibodies of HeLa cells arrested at various stages of the cell cycle revealed that Prx I phosphorylation occurs in parallel with the activation of Cdc2; Prx I phosphorylation was thus marked during mitosis but virtually undetectable during interphase. Furthermore, when Cdc2 expression was reduced by RNA interference with cognate small interfering RNAs, Prx I phosphorylation was not observed in the cells synchronized in mitotic phase. The cytosolic location of Prx I likely prevents its interaction with activated CDKs until after the breakdown of the nuclear envelope during mitosis, when Cdc2 is the CDK that is most active. Phosphorylation of Prx I on Thr(90) both in vitro and in vivo was blocked by roscovitine, an inhibitor of CDKs. These results suggest that Cdc2-mediated phosphorylation and inactivation of Prx I and the resulting intracellular accumulation of H(2)O(2) might be important for progression of the cell cycle.


Kawasaki Disease Presenting with Bloody Diarrhea and Acute Renal Failure: First Case.
Kawasaki disease (KD) is an acute febrile vasculitis of an unknown cause. It affects children <5 year of age, even if cases over 5 years old have been also reported. It is the commonest cause of acquired heart diseases in children which may lead to serious morbidity and mortality. The complications and mortality increase when the diagnosis is delayed. One of the main reasons leading to delayed diagnosis and consequent delayed treatment is the unusual presentation of KD. Its unusual manifestations have been increasingly reported to jeopardize the timely diagnosis and proper treatment. As there is not yet available blood test to diagnose it, low threshold should be taken into account for considering KD, when the clinical criteria are not typical. KD with renal manifestations is infrequently described. We present and discuss a case of an unusual presentation of KD presenting as bloody diarrhea and acute renal failure.


Clinical potential of lurasidone in the management of schizophrenia.
Lurasidone is a new second-generation antipsychotic approved in October 2010 by the Food and Drug Administration for the treatment of schizophrenia. Like other second-generation antipsychotics, lurasidone is a powerful antagonist of D(2) dopamine and 5HT(2A) serotonin receptors, but differs from the other second-generation antipsychotics in its action profile for certain receptors. Lurasidone is the second-generation antipsychotic with the greatest affinity for 5HT(7) receptors and has a high affinity for 5HT(1A) serotonin receptors, compatible with favorable effects on cognitive function and an antidepressant action. By contrast, lurasidone has a low affinity for and α(1) α(2C)-adrenergic and 5HT(2C) serotonin receptors, and no affinity for histaminergic H(1) or muscarinic M(1) receptors, suggesting a better tolerability profile than the other second-generation antipsychotics. Lurasidone has demonstrated its efficacy in several short-term trials in acute schizophrenia, promptly and significantly reducing total Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores compared with placebo. Several long-term studies are in progress to assess its efficacy in the maintenance treatment of schizophrenic patients. The efficacy of lurasidone with regard to cognitive functions and depressive symptoms seems good, but requires further work. Lurasidone differs from the other second-generation antipsychotics by having a good tolerability profile, in particular for cardiometabolic tolerability. However, it seems to have a significant although moderate link with the occurrence of akathisia, extrapyramidal symptoms, and hyperprolactinemia at the start of treatment. This tolerance profile greatly broadens the scope of second-generation antipsychotics and so supports the view of some authors that the term "second-generation antipsychotic" is now outdated. Other therapeutic perspectives of lurasidone are assessed here, in particular bipolar depression.


Estimating synchronous demographic changes across populations using hABC and its application for a herpetological community from northeastern Brazil.
Many studies propose that Quaternary climatic cycles contracted and/or expanded the ranges of species and biomes. Strong expansion-contraction dynamics of biomes presume concerted demographic changes of associated fauna. The analysis of temporal concordance of demographic changes can be used to test the influence of Quaternary climate on diversification processes. Hierarchical approximate Bayesian computation (hABC) is a powerful and flexible approach that models genetic data from multiple species, and can be used to estimate the temporal concordance of demographic processes. Using available single-locus data, we can now perform large-scale analyses, both in terms of number of species and geographic scope. Here, we first compared the power of four alternative hABC models for a collection of single-locus data. We found that the model incorporating an a priori hypothesis about the timing of simultaneous demographic change had the best performance. Second, we applied the hABC models to a data set of seven squamate and four amphibian species occurring in the Seasonally Dry Tropical Forests (Caatinga) in northeastern Brazil, which, according to paleoclimatic evidence, experienced an increase in aridity during the Pleistocene. If this increase was important for the diversification of associated xeric-adapted species, simultaneous population expansions should be evident at the community level. We found a strong signal of synchronous population expansion in the Late Pleistocene, supporting the increase of the Caatinga during this time. This expansion likely enhanced the formation of communities adapted to high aridity and seasonality and caused regional extirpation of taxa adapted to wet forest.


SLAP Lesion with Supraglenoid Labral Cyst causing Suprascapular Nerve Compression: A case report.
We present a case of left suprascapular nerve palsy in a 39- year-old female secondary to compression from a large ganglion cyst. She presented with a two month history of left posterior shoulder pain which affected her work and disturbed her sleep. Clinical examination revealed a positive O'Brien's test. Supraspinatus and infraspinatus strength was mildly weakened. A magnetic resonance imaging (MRI) scan of the left shoulder revealed a superior labral anterior to posterior (SLAP) lesion with a large supraglenoid labral cyst extending posteriorly to the spinoglenoid notch, resulting in compression of the suprascapular nerve. Arthroscopy revealed the SLAP lesion with a haemorrhagic labral cyst at the posterosuperior aspect. Arthroscopic decompression of the cyst and SLAP repair with two suture anchors was performed. At 22 months postoperative follow-up, the patient's left shoulder remained asymptomatic with full range of motion and full strength. SLAP lesion; Supraglenoid Labral Cyst; Suprascapular Nerve Compression.


Knowledge, attitude, and practices of front line health workers after receiving a COVID-19 vaccine: a cross-sectional study in Pakistan.
Globally, there is an increased risk of COVID-19 infection among front-line health workers (FHW). This study aimed to evaluate the knowledge, attitude, and practices of FHW of Pakistan after receiving the COVID-19 vaccine. A population web-based survey on COVID-19 vaccine was conducted on 635 FHW in Pakistan between April 15, 2021, and July 15, 2021. The survey focused on four main sections consisting of socio-demographic data, knowledge, attitude, and practices after receiving the COVID-19 vaccine. The data was analyzed on SPSS. p < 0.05 was considered significant. Overall, 60% of FHW were nervous before getting vaccinated, with the leading reason to get vaccinated being their concern to protect themselves and their community (53.4%). A majority of FHW had fear about the unseen side effects of the COVID-19 vaccine (59.7%) used in Pakistan, with the most common side effect reported as soreness at the injection site (39%). It has been noted that almost all of the FHW observed preventive practices after getting vaccinated. The results showed that married respondents had favorable practices towards COVID-19 vaccines (B = 0.53, p < 0.01) (B, unstandardized regression coefficient). It was also found that more informational sources (B = 0.19, p < 0.01), higher knowledge of vaccination (B = 0.15, p < 0.001), and favorable attitude toward vaccine (B = 0.12, p < 0.001) significantly predicted favorable practices toward COVID-19 vaccination. The findings reflect that FHW, though they were worried about its side effects, have good knowledge and a positive attitude after getting the COVID-19 vaccine. This study is significant as the FHWs are a symbol for guidance, a reliable source of information, and an encouraging means of receiving COVID-19 vaccine for the general public. This study also reported that post-vaccination side effects were mild which will aid in reducing the vaccine hesitancy among the general Pakistani population.