Observation of normal appearance and wall thickness of esophagus on CT images.
This study sought to observe the appearance of normal esophagus, measure and record the thickness of esophageal wall in order to offer reference for estimating esophageal wall abnormalities and delineating gross tumor target of esophageal carcinomas on CT images. From September 2006 to February 2007, 110 consecutive CT films from adult patients without esophageal diseases were collected and studied. On CT images the entire esophagus was divided into cervical, thoracic, retrocardiac and intraabdominal segments. The appearance of esophagus was described when the esophagus contracted or dilated. Thickness of esophageal wall and diameters of esophageal cavities were measured by hard-copy reading with a magnifying glass. Age, sex and the thickness of subcutaneous fat of each patient were recorded. It was observed that the esophagus presented both contracted and dilated status on CT images. In each segment there were certain portions of esophagus in complete contraction or dilatation. 47 images (42.7%) showed contracted esophagus in each segment available for measurement. The largest wall thickness when esophagus was in contraction and dilatation was 4.70 (95%CI: 4.44-4.95)mm and 2.11 (95%CI: 2.00-2.23)mm, respectively. When contracting, the intraabdominal esophagus was thicker than the cervical, thoracic and retrocardiac parts, and the average thickness was 5.68 (95%CI: 5.28-6.09)mm, 4.67 (95%CI: 4.36-4.86)mm, 4.56 (95%CI: 4.31-4.87)mm, and 4.05 (95%CI: 3.71-4.21)mm, respectively. When the esophagus was dilating, the average esophageal wall thickness was between 1.87 and 2.70 mm. The thickest part was cervical esophagus. Thickness of esophageal wall was larger in males than that of females (5.26 mm vs. 4.34 mm p<0.001). Age and the thickness of subcutaneous fat had no significant impact on the thickness of esophageal wall (p-value was 0.056 and 0.173, respectively). The Observation of normal appearance and wall thickness of esophagus helps us to identify thickened esophageal wall on CT images using new CT scan technologies. Thus it is probably helpful in judging esophageal diseases and delineating gross tumor target of esophageal carcinomas in modern radiotherapy.


Trends in phenology of Betula pubescens across the boreal zone in Finland.
Timing of plant phenophases is a useful biological indicator which shows how nature responds to the variation in climate. Thus, long phenological observation series help to estimate the impact of changing climate on forest plants. We investigated whether phenological patterns of downy birch Betula pubescens respond to warming climate and whether the intensity of the responses varies among phytogeographical zones. We studied data collected by the Finnish National Phenological Network from 30 observation sites across Finland during 1997-2006. The advancement in the timing of the earliest phenophase, bud burst, ranged from 0.7 days/year in southern boreal zone to 1.4 days/year in middle and northern boreal zones. Timing of bud burst was most clearly dependent on mean May temperatures. The intensity of the response to temperature increased from south to north. The advancement of bud burst resulted into a significant lengthening of the growth period by 1.2-1.6 days per year in northern and middle boreal zones, respectively, whereas the lengthening was not significant in the southern boreal zone. No trend was observed in the timing of autumn phenophases.


The effect of cytochalasin B on the endosteal lining cells of mammalian bone. A scanning electron microscopic study.
The lining osteoblasts of the rat tibial endosteum were treated for various times (between 1 and 60 min) and increasing doses (3.87-38.7 microgram/ml) with the macrolide fungal metabolite cytochalasin B (CB). Dimethylsulfoxide (DMSO) served as the vehicle for CB and was administered to control tissues. An in vitro incubation system and scanning electron microscopy (SEM) were used to evaluate the effects of CB. The drug initiated cell rounding (contraction), nuclear protrusion, bleb formation, and the subsequent clustering of blebs and microvilli into aggregates. All CB-induced aberrations of the surface structure were readily reversible when tissues were washed with CB-free media. DMSO had no significant effect on cell surface morphology. The reversible structural changes brought about by CB are explained in terms of alterations of the subplasmalemmal cortical microfilament system of osteoblasts. The potential use of CB in evaluating the bone cell cytoskeleton and its relationship to the physiology of the cellular functional membrane (endosteum) of bone is discussed.


Brachial plexus injury: a survey of incidence and referral pattern.
The aim of this study was to establish the incidence and the pattern of referral of injuries to the brachial plexus for a single calendar year: 1987. A questionnaire was sent to every orthopaedic consultant and referral centre in the United Kingdom. Replies were received from 402 surgeons. It is estimated that in 1987 there were at least 336 patients with traumatic injuries and 137 patients with other problems related to the plexus. Only 145 patients were seen at a referral centre. The anatomical nature, mode of injury and methods of treatment were analysed for both the referred and unreferred patients. We found that injuries to the brachial plexus are far more common than is generally appreciated, but only a minority of patients are referred for specialist evaluation and treatment.


Prevalence of malnutrition comparing NRS2002, MUST, and PG-SGA with the GLIM criteria in adults with cancer: A multi-center study.
This study aimed to evaluate the diagnostic capacity of the Nutritional Risk Screening 2002 (NRS2002), Malnutrition Universal Screening Tool (MUST), and Patient-generated Subjective Global Assessment (PG-SGA) in light of the Global Leader Initiative on Malnutrition (GLIM) criteria in adult patients with cancer. A multicenter observational study was conducted. Nutritional screening and assessment were performed at the time of admission to hospitals with the NRS2002, MUST, PG-SGA, and GLIM criteria. Sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratio, and Kappa (K) values were used to evaluate the performance of these tools. Of the 637 included patients, 24.8% and 15.4% of patients were at moderate and high risk of malnutrition, respectively, using the NRS2002 and MUST. The NRS2002 was better correlated to the GLIM criteria with a higher value of Kappa (K = 0.823 vs. 0.596) and area under the receiver operating characteristic curve (K = 0.896 vs. 0.757) than the MUST. Meanwhile, 28.3% of patients were diagnosed as malnourished at the time of admission per the GLIM criteria, and 43.3% were malnourished per the PG-SGA. The PG-SGA had a fair agreement with the GLIM criteria (K = 0.453), revealing a positive predictive value of 52.9% and negative predictive value of 90.6%. The NRS2002 was better correlated with the GLIM diagnostic criteria of malnutrition than the MUST. The PG-SGA was too sensitive to detect nutrition-related deteriorations, leading to a low positive predictive value in the malnutrition diagnosis. Thus, the GLIM criteria could be used to confirm the presence of malnutrition identified by the PG-SGA in adults with cancer.


Increased in vitro labeling of stable RNA within the rat nodose ganglion following abdominal vagotomy.
An in vitro procedure for labeling of RNA in the excised rat nodose ganglion was used to evaluate the changes in incorporation of [3H]uridine into ganglionic RNA following transection of the abdominal vagus nerves. Significant increases in the incorporation into 28S, 18S and 4S RNA were observed at 1 day after injury, which were maximal at 4 days before returning to unoperated control level by 7 days. A second transient increase in the labelling of these RNA species occurred between 9 and 11 days after injury. Comparison of the time course of these increases with those seen previously following cervical vagus nerve crush injury indicate that the time of onset of the increase in incorporation in independent of the site of injury, but that the maximal response is delayed by 1 day with the more distal lesion. These data are consistent with the existence of separate signals for initiating and modulating the cell body response to axon injury, which are transported retrogradely from the site of injury at rates exceeding the slow component of axoplasmic transport.


Rotenone mediated developmental toxicity in Drosophila melanogaster.
Rotenone (ROT) is a widely used natural pesticide, and its effect on growth and developmental toxicity remain unclear. In the present study, the effects of ROT exposure on the reproductive structure and function of the female Drosophila melanogaster and third instar larvae were investigated. ROT exposure on female Drosophila melanogaster resulted in developmental inhibition and ovarian abnormality, which were evident from the disruptive growth of border cells as well as morphological changes in the orientation of nurse cells during the 9th-10th stage of developing egg chamber of in the Drosophila ovary. Other abnormalities, such as, altered developmental gene expression (Osk, Grk, Nos, Bic-d), inhibition in the kinesin motor protein level (KIF-5B), increased caspases activities (Caspase 3, 8, & 9) and apoptosis were also observed. Subsequently, ROT treated larvae exhibited behavioral deficits and delay in developmental time. The above findings demonstrate that the exposure of ROT causes developmental toxicity in Drosophila melanogaster.


[Treatment of opiate weaning by clonidine in prison (evaluation based on 36 patients)].
The authors have used Clonidine for withdrawal from opiates of prisoners. About detoxification of 36 men entering into prison and published studies, they show that Clonidine is an efficacy and safe treatment. Clonidine induced hypotensia is not considered problematic.


Facts, myths and legends on the prime industrial microorganism.
Archaic speculations and firmly established legends regarding the origin of the yeast Saccharomyces cerevisiae and related species are revisited in light of past and recent ecological evidence pointing to a strict association with artificial, man-made environments such as wineries and fermentation plants. The nomenclature within this industrially important group is also discussed in view of the modifications imposed from application of molecular techniques to classification.


Latifolians A and B, novel JNK3 kinase inhibitors from the Papua New Guinean plant Gnetum latifolium.
As part of our search for natural products active against the JNK3 kinase, two novel, charged benzylisoquinolines, latifolian A (1) and latifolian B (2), were isolated from the stem bark of the Papua New Guinean vine Gnetum latifolium. The planar structures were determined through detailed 2D NMR analysis. The relative configurations were assigned after examination of the ROESY data and through detailed molecular modeling studies.


Targeting the programmed axon degeneration pathway as a potential therapeutic for Charcot-Marie-Tooth disease.
The programmed axon degeneration pathway has emerged as an important process contributing to the pathogenesis of several neurological diseases. The most crucial events in this pathway include activation of the central executioner SARM1 and NAD+ depletion, which leads to an energetic failure and ultimately axon destruction. Given the prevalence of this pathway, it is not surprising that inhibitory therapies are currently being developed in order to treat multiple neurological diseases with the same therapy. Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of neurological diseases that may also benefit from this therapeutic approach. To evaluate the appropriateness of this strategy, the contribution of the programmed axon degeneration pathway to the pathogenesis of different CMT subtypes is being actively investigated. The subtypes CMT1A, CMT1B and CMT2D are the first to have been examined. Based on the results from these studies and advances in developing therapies to block the programmed axon degeneration pathway, promising therapeutics for CMT are now on the horizon.


Long-term exposure to cyprodinil causes abnormal zebrafish aggressive and antipredator behavior through the hypothalamic-pituitary-interrenal axis.
Cyprodinil, one of the main pyrimidinamine fungicides, has been used to control fungal diseases in plants and vegetables worldwide. Previous studies have investigated the influences of cyprodinil on the developmental and reproductive toxicity of fish. However, it remains unknown whether it affects fish behaviors and the underlying mechanisms. In our current study, zebrafish, an ideal model animal for behavioral studies, were exposed to cyprodinil from fertilization to 240 days postfertilization at 0.1 μg/L (environmentally relevant concentration) and 1, 10 μg/L. Firstly, we observed that aggressive behavior of zebrafish was significantly enhanced after exposure to 0.1-10 μg/L cyprodinil and antipredator behavior was decreased after exposure. Cyprodinil exposure altered the adrenocorticotropic hormone and cortisol levels, which regulate cortisol homeostasis and were significantly reduced in all exposure groups (0.1-10 μg/L). In addition, most of the key genes in the hypothalamic-pituitary-interrenal gland axis, such as corticotropin-releasing hormone and melanocortin 2 receptor, were downregulated significantly in all exposure groups, which was consistent with the hormone levels. In addition, in the hypothalamus, the number of apoptotic cells increased in a dose-dependent manner in the cyprodinil exposure groups. Moreover, these changes were potentially responsible for the increased aggression of zebrafish during the mirror-like aggressive test and for the reduced antipredator behavior during the predator avoidance test. Overall, the data provided herein further our understanding of cyprodinil toxicity and can be used to assess the ecological effects of cyprodinil on the induction of abnormal behaviors at the environmental level.


Purification and characterisation of a fructosyltransferase from Rhodotorula sp.
The present work was devoted to investigations concerning the purification and characterisation of the fructooligosaccharide (FOS)-producing extracellular enzyme of Rhodotorula sp. LEB-V10. FOS are functional food ingredients showing prebiotic properties, meaning that it could stimulate selectively the growth and/or activity of probiotic bacteria in the gut. The purification of the enzyme was carried out according to the following sequential procedure: cell separation by centrifugation, recovering by ethanol precipitation and purification by anion exchange chromatography. The molecular weight was estimated to be 170 kDa by preparative gel filtration and 77 kDa by sodium dodecyl sulphate-polyacrylamide gel electrophoresis, signifying that the native enzyme exists as a dimer. With sucrose as substrate, the data failed to fit the Michaelis-Menten behaviour, rather showing a sigmoid shape similar to that of the allosteric enzymes (cooperative behaviour), requiring high sucrose concentrations to obtain high reaction rates. The enzyme showed both fructofuranosidase (FA) and fructosyl-transferase (FTA) activities. The optimum pH and temperature for FA activity were found to be around 4.0 and 72-75 degrees C, respectively, while FTA showed optimum activity at pH 4.5 and 65-70 degrees C. Both activities were very stable at temperatures below 66 degrees C, while for FA, the enzyme was more stable at pH 4.0 and for FTA at pH 5.0.


Skin testing with ultra-heat-treated (UHT) cow's milk in children with cow's milk allergy.
A large proportion of cow's milk (CM)-allergic children are able to tolerate extensively heated forms of CM such as baked goods. Little is known about whether ultra-heat-treated (UHT) forms of cow's milk are immunologically similar to extensively heated cow's milk and therefore may be tolerated by these children. To determine whether skin test wheal size using UHT CM was significantly different from other forms of CM and CM extracts. Children presenting for oral food challenges with either extensively heated or unheated cow's milk underwent skin prick test (SPT) to commercial CM, UHT CM, evaporated CM, and fresh whole CM. The results were compared between groups of children. At study exit, only 14% of children were avoiding all forms of CM, compared with 70% at study entry. No difference was seen in the mean SPT results for UHT CM between those children that could tolerate heated CM compared with those that could not. The mean SPT result for casein was significantly lower in those that could tolerate heated CM. However, within the group of heated milk-tolerant children, the mean SPT for UHT CM was significantly lower than the SPT for fresh whole CM. Ultra-heat-treated CM does not behave significantly differently from other forms of CM when evaluated by SPT in heated milk-allergic vs heated milk-tolerant children. This suggests that UHT CM is not sufficiently immunologically different from unheated CM to be tolerated by heated CM-tolerant children.


Evaluation of a high-velocity flame-spraying technique for hydroxyapatite.
Titanium alloy sprayed with hydroxyapatite (HA) was developed by a high-velocity flame-spraying technique (HVFST). Biocompatible responses of bony tissues to high-velocity flame-sprayed HA (HVFS-HA) implanted into tibias of adult male rabbits was investigated 4 and 18 months after implantation by light and electron microscopy. Both light and electron microscope features in histological sections showed that inflammatory responses of tissues in situ were completely cleared and the interface between the bone and the implant was filled with newly formed bony substrate. This suggests that the HVFS-HA was sufficiently biocompatible to be adapted to the bone in situ.


High amount of visceral fat mass is associated with multiple metabolic changes in offspring of type 2 diabetic patients.
To investigate the relative contribution of total body fat mass (TFM) and intra-abdominal fat mass (IAFM) to metabolic consequences of obesity in offspring of type 2 diabetic parents. Cross-sectional study of 129 nondiabetic offspring of diabetic parents (59 men, 70 women, age 35.7 +/- 6.3 y, body mass index 26.2 +/- 4.6 kg/m2). Study subjects were grouped according to TFM (assessed with bioelectrical impedance) and IAFM (assessed with CT). Insulin sensitivity was assessed with the euglycemic hyperinsulinemic clamp, insulin secretion with the intravenous glucose tolerance test and energy expenditure with indirect calorimetry. Furthermore, C-reactive protein (CRP) and adiponectin levels were measured. Insulin resistance, low rates of oxidative and nonoxidative glucose disposal, high rates of lipid oxidation and reduced energy expenditure during hyperinsulinemia were associated with high IAFM, independently of TFM. Adiponectin level was reduced and CRP level increased in subjects with high IAFM. The metabolic changes relating to obesity are largely attributable to high IAFM, and are present even in normal weight subjects with high IAFM.


[Right ventricular inflow tract obstruction in primary non-Hodgkin lymphoma of the heart].
An unusual case of non-Hodgkin lymphoma (centroblastic B-cell type) is described presenting with severe tricuspid stenosis due to a large right atrial intracavitary tumor mass obstructing the tricuspid orifice. The clinical picture of cardiogenic shock was relieved by surgical removal of the greater part of the tumor mass from the right atrium.


Precision medicine applied to metastatic colorectal cancer using tumor-derived organoids and in-vitro sensitivity testing: a phase 2, single-center, open-label, and non-comparative study.
Patients with colorectal metastatic disease have a poor prognosis, limited therapeutic options, and frequent development of resistance. Strategies based on tumor-derived organoids are a powerful tool to assess drug sensitivity at an individual level and to suggest new treatment options or re-challenge. Here, we evaluated the method's feasibility and clinical outcome as applied to patients with no satisfactory treatment options. In this phase 2, single-center, open-label, non-comparative study (ClinicalTrials.gov, register NCT03251612), we enrolled 90 patients with metastatic colorectal cancer following progression on or after standard therapy. Participants were 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, adequate organ function, and metastasis available for biopsy. Biopsies from the metastatic site were cultured using organoids model. Sensitivity testing was performed with a panel of drugs with proven activity in phase II or III trials. At the discretion of the investigator considering toxicity, the drug with the highest relative activity was offered. The primary endpoint was the proportion of patients alive without disease progression at two months per local assessment. Biopsies available from 82 to 90 patients were processed for cell culture, of which 44 successfully generated organoids with at least one treatment suggested. The precision cohort of 34 patients started treatment and the primary endpoint, progression-free survival (PFS) at two months was met in 17 patients (50%, 95% CI 32-68), exceeding the pre-defined level (14 of 45; 31%). The median PFS was 67 days (95% CI 51-108), and the median overall survival was 189 days (95% CI 103-277). Patient-derived organoids and in-vitro sensitivity testing were feasible in a cohort of metastatic colorectal cancer. The primary endpoint was met, as half of the patients were without progression at two months. Cancer patients may benefit from functional testing using tumor-derived organoids. ClinicalTrials.gov, register NCT03251612.


Non-steroidal anti-inflammatory drugs that cause relatively little gastric damage.
Gastrointestinal damage by non-steroidal anti-inflammatory drugs (NSAID), which is common and sometimes fatal, involves inhibition of prostaglandin (PG) synthesis. The damage is less with NSAID that inhibit inflammatory cyclo-oxygenase (COX)-2 but not gastroprotective COX-1. We have compared nimesulide and acemetacin, two NSAID that cause relatively little gastric damage, with indomethacin for effects on purified COX-1 and COX-2. The results are related to findings on human gastric mucosa and leucocytes. With purified COX-1, inhibition was absent with nimesulide, weak with acemetacin (inhibitory concentration of 50% [IC50 ] 85 m̈mol/L), and potent with indomethacin (IC50 0.6 m̈mol/L). Inhibition of purified COX-2 occurred with nimesulide and indomethacin (IC50 values 90 and 4.1 m̈mol/L, respectively) but not acemetacin. All results with nimesulide are consistent with a preferential block of COX-2 that contributes to relatively little gastric damage in patients. However, our previous report on acemetacin needs re-evaluation. Acemetacin did not inhibit sheep COX-2 and only weakly inhibited COX-1. Our previous leucocyte (COX-2) experiments required 24 h incubation, and hydrolysis of acemetacin to indomethacin presumably accounted for the COX-2 inhibition. In the few minutes of enzyme incubation, virtually no hydrolysis would be expected. Acemetacin itself presumably causes relatively little gastric damage mainly because it only weakly inhibits COX-1.


Grey matter abnormalities within cortico-limbic-striatal circuits in acute and weight-restored anorexia nervosa patients.
Functional disturbances within cortico-striatal control systems have been implicated in the psychobiology (i.e. impaired cognitive-behavioral flexibility, perfectionist personality) of anorexia nervosa. The aim of the present study was to investigate the morphometry of brain regions within cortico-striatal networks in acute anorexia nervosa (AN) as well as long-term weight-restored anorexia nervosa (AN-WR) patients. A total of 39 participants: 12 AN, 13 AN-WR patients, and 14 healthy controls (HC) underwent high-resolution, T1-weighted magnetic resonance imaging (MRI), a cognitive-behavioral flexibility task, and a psychometric assessment. Group differences in local grey matter volume (GMV) were analyzed using whole brain voxel-based morphometry (VBM) and brain-atlas based automatic volumetry computation (IBASPM). Individual differences in total GMV were considered as a covariate in all analyses. In the regional brain morphometry, AN patients, as compared to HC, showed decreased GMVs (VBM and volumetry) in the anterior cingulate cortex (ACC), the supplementary motor area (SMA), and in subcortical regions (amygdala, putamen: VBM only). AN-WR compared to HC showed decreased GMV (VBM and volumetry) in the ACC and SMA, whereas GMV of the subcortical region showed no differences. The findings of the study suggest that structural abnormalities of the ACC and SMA were independent of the disease stage, whereas subcortical limbic-striatal changes were state dependent.


Incontinence during intercourse: myths unravelled.
This study aimed to establish the prevalence of urinary leakage during intercourse, the extent to which urinary leakage impacts on sex life and the correlation between different urodynamic diagnosis and coital leakage. Four hundred eighty women attending between 1 January 2006 and December 2010 with urinary incontinence and subsequently undergoing urodynamic assessment were included. Data were collected as part of routine clinical care using the electronic Pelvic floor Assessment Questionnaire and correlated with urodynamic findings. Sixty percent of women with urinary incontinence reported leakage during intercourse. Overall quality of life in women with urinary incontinence was strongly correlated to the impact of urinary symptoms on sex life. Parameters of sexual function were no different in women with different urodynamic diagnosis. Worsening urinary incontinence has a deleterious effect on sexual function. Urodynamic diagnosis does not correlate with the nature of underlying sexual problems, orgasm or penetration incontinence.


Studies into the occurrence of soluble antigen-antibody complexes in disease. VIII. Fractionation of rheumatoid samples containing immune complex-like material.
Fractionation studies were performed of an immune complex-like material measured in rheumatoid synovial fluid using a biological assay based on histamine release from guinea pig lung. This material was eluted from Sepharose 6B in the excluded fraction, from DEAE cellulose predominantly in the third buffer, and from polyacrylamide electrophoresis in a cathodal position. Heterogeneity of the complexes was evident on iso-electric focussing, with one peak of activity at a pH of 4.2--5.6 and the other at pH 6.8--8.6. Purification of the material was limited by a loss of activity which occurred on using three fractionation procedure in sequence. This instability was avoided in the case of Sepharose 6B by adding 0.1% bovine or rabbit albumin to the elution buffer.


Acute hepatitis with periportal confluent necrosis associated with human herpesvirus 6 infection in liver transplant patients.
To correlate human herpesvirus 6 (HHV-6) viral load with pathologic features in graft acute hepatitis of unknown origin. Liver frozen samples from 26 patients with graft hepatitis of unknown origin were available for HHV-6 DNA quantification. In 10 (38.5%) of 26 liver samples, HHV-6 DNA was detectable, with a median viral load of 3.84 log10 copies/10⁶ cells. Confluent periportal necrosis was observed in 4 of 10 patients and associated with high viral load. These 4 patients responded to antiviral therapy. Mild unspecific hepatitis was observed in 4 patients with low intragraft viral load and in 2 patients with high viral load in a context of deep immunosuppression. Patients with HHV-6-negative graft hepatitis disclosed lobular necrotico-inflammatory activity without periportal necrosis. Our study provides data supporting the pathogenic role of HHV-6 for liver allografts. The presence of confluent periportal necrosis could be a clue for prompt diagnosis of HHV-6-induced graft hepatitis.


Inhibition of Ras-mediated signaling pathways in CML stem cells.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of the BCR-ABL1 oncoprotein in cells with a hematopoietic stem cell (HSC) origin. BCR-ABL1 tyrosine kinase activity leads to constitutive activation of Ras, which in turn acts as a branch point to initiate multiple downstream signaling pathways governing proliferation, self-renewal, differentiation and apoptosis. As aberrant regulation of these cellular processes causes transformation and disease progression particularly in advanced stages of CML, investigation of these signaling pathways may uncover new therapeutic targets for the selective eradication of CML stem cells. Transcription factors play a crucial role in unbalancing the Ras signaling network and have recently been investigated as potential modulators in this regard. In this review, we first briefly summarize the Ras-associated molecular pathways that are involved in the regulation of CML stem cell properties. Next we discuss the relevance of Ras-associated transcription factors as nuclear targets in combination treatment strategies for CML. A closer investigation of the influence of Ras-mediated signaling pathways on CML progression to blast crisis is warranted to uncover new directions for targeted therapies, particularly in cases that are resistant to current tyrosine kinase inhibitors.


Atrial Fibrillation as an Ischemic Stroke Clinical and Economic Burden Modifier: A 15-Year Nationwide Study.
Atrial fibrillation (AF) is a major risk factor for ischemic stroke (IS). Patients with AF may undergo preventive therapy. Although the AF impact in the clinical burden of IS has been studied, information is lacking in Southern Europe and there are no studies about the impact in potential years of life lost. Moreover, no nationwide or long-term study analyzed the economic burden of IS stratified by AF. To study the impact of AF in the clinical and economic burden of IS. We conducted a retrospective study using nationwide administrative data for all public hospitalizations in mainland Portugal from 2000 to 2014. We considered IS hospitalizations stratified by the presence of AF as secondary diagnosis. Of the total 275,173 IS hospitalizations, 22.6% reported AF. The total number of IS hospitalizations increased from 14,836 in 2000 to 19,561 in 2014 (32% increase), with an increase of 138% in the AF group (from 2,411 to 5,727). In-hospital mortality decreased from 13.6% to 11.5% and was consistently higher in the AF group (17.3% vs. 11.1%). Mean charges were also higher in the AF group (€2297 vs. €2191). Age-adjusted potential years of life lost rate was higher in the group without AF (39.6 vs. 7.5). AF-associated IS hospitalizations more than doubled in the studied 15-year period. Also, AF was responsible for higher in-hospital mortality and hospitalization charges. These facts highlight the need for early detection of AF and preventive treatment to limit IS occurrence, its associated burden, and poorer health outcomes.


Poor Outcomes After Emergency Department Discharge of the Elderly: A Case-Control Study.
The emergency department (ED) is an inherently high-risk setting. Our objective is to identify the factors associated with the combined poor outcome of either death or an ICU admission shortly after ED discharge in older adults. We conducted chart review of 600 ED visit records among adults older than 65 years that resulted in discharge from any of 13 hospitals within an integrated health system in 2009 to 2010. We randomly chose 300 patients who experienced the combined outcome within 7 days of discharge and matched case patients to controls who did not experience the outcome. Two emergency physicians blinded to the outcome reviewed the records and identified whether a number of characteristics were present. Predictors of the outcome were identified with conditional logistic regression. Of 1,442,594 ED visits to Kaiser Permanente Southern California in 2009 to 2010, 300 unique cases and 300 unique control records were randomly abstracted. Characteristics associated with the combined poor outcome included cognitive impairment (adjusted odds ratio [AOR] 2.10; 95% confidence interval [CI] 1.19 to 3.56), disposition plan change (AOR 2.71; 95% CI 1.50 to 4.89), systolic blood pressure less than 120 mm Hg (AOR 1.48; 95% CI 1.00 to 2.20), and pulse rate greater than 90 beats/min (AOR 1.66; 95% CI 1.02 to 2.71). We found that older patients discharged from the ED with a change in disposition from "admit" to "discharge," cognitive impairment, systolic blood pressure less than 120 mm Hg, and pulse rate greater than 90 beats/min were at increased risk of death or ICU admission shortly after discharge. Increased awareness of these high-risk characteristics may improve ED disposition decisionmaking.


Stability of treatments for recurrent temporomandibular joint luxation: a systematic review.
Temporomandibular joint luxation (TMJ) is the excessive anterior translation of the mandibular condyle out of its normal range of movement and away from the glenoid fossa. Once dislocation occurs, the abnormal condylar position generates reflex contractions of the masticatory muscles, which in turn hinder movement of the condyle back to its resting position. Frequent luxation episodes characterize a condition referred to as recurrent TMJ luxation. While there are several surgical and conservative therapeutic options available for recurrent TMJ luxation, a robust, evidence-based rationale for choosing one technique over another is missing. Thus, a systematic review based on the PRISMA statement was proposed in an attempt to determine which therapeutic option results in the longest time to relapse. There is no good quality evidence on which treatment options guarantee the long-term elimination of recurrent TMJ luxation. In cases of post-surgical relapse, eminectomy has often been used as a 'rescue procedure', which may mean that surgeons empirically consider this treatment to be the 'gold standard' for addressing recurrent TMJ luxation.


Gold nanoparticles-decorated peptide hydrogel for antifouling electrochemical dopamine determination.
A reliable and brief ultralow fouling electrochemical sensing system capable of monitoring targets in complex biological media was constructed and validated based on gold nanoparticles-peptide hydrogel-modified screen-printed electrode. The self-assembled zwitterionic peptide hydrogel was prepared by a newly designed peptide sequence of Phe-Phe-Cys-Cys-(Glu-Lys)3 with the N-terminal modified with a fluorene methoxycarbonyl group. The thiol groups on cysteine of the designed peptide are able to self-assemble with AuNPs to form a three-dimensional nanonetwork structure, which showed satisfactory antifouling capability in complex biological media (human serum). The developed gold nanoparticles-peptide hydrogel-based electrochemical sensing platform displayed notably sensing properties for dopamine determination, with a wide linear range (from 0.2 nM to 1.9 μM), a low limit of detection (0.12 nM), and an excellent selectivity. This highly sensitive and ultralow fouling electrochemical sensor was fabricated via simple preparation with concise components that avoid the accumulation of layers with single functional material and complex activation processes. This ultralow fouling and highly sensitive strategy based on the gold nanoparticles-peptide hydrogel with a three-dimensional nanonetwork offers a solution to the current situation of various low-fouling sensing systems facing impaired sensitivity and provides a potential path for the practical application of electrochemical sensors.


Induction of macrophage growth by the lipid moiety of lipoprotein and its augmentation by denaturation of the lipoproteins.
Lipoprotein (d less than 1.21) isolated from mouse tumor ascitic fluid or mouse-serum induced growth of peritoneal macrophages in vitro. Lipoprotein fractions that stimulated macrophage growth were the chylomicron, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL), whereas the high-density lipoprotein (HDL) fraction did not. Lipids extracted from total lipoprotein also showed significant macrophage-growth-stimulating activity and lost this activity when hydrolyzed. The macrophage-growth-stimulating activity of the lipoprotein (d less than 1.21) was increased about ten times by heat treatment of the lipoprotein (100 degrees C, 30 min). The HDL fraction that had no activity in the native form also showed activity after heat treatment. Lipoprotein-depleted ascitic fluid and simple proteins such as bovine serum albumin (BSA) had no activity even after heat treatment. These results show that the lipid moiety of lipoproteins caused proliferation of macrophages and that denatured lipoproteins were more effective than native ones.


Communication attitudes in children who stutter: A meta-analytic review.
This article presents a meta-analytic review of differences in communication attitudes between children who stutter (CWS) and children who do not stutter (CWNS). To be included in this review, the studies had to include a group of CWS and CWNS between the ages of 3-18 years and a measurement of communication attitudes. The journal articles were identified by using the key words stutter*, speech disfluenc*, fluency disorder*, and stammer* cross-referenced to awareness*, reaction*, attitude*, KiddyCAT, CAT, A-19 Scale, PASS and OASES. A total of 18 studies met the inclusion criteria for this meta-analysis. The results showed that CWS exhibit more negative communication attitudes than CWNS from the preschool years. The differences between the groups increased with age, but were not influenced by gender. The results indicate that negative communication attitudes can be an effect of stuttering. Key issues requiring further investigation are whether communication attitudes differ as a function of age at stuttering onset and whether communication attitudes influence the development of stuttering. After reading this article, the reader will be able to: (a) summarise empirical findings with regard to the relationship between communication attitudes and childhood stuttering; (b) describe the different instruments used to measure communication attitudes; (c) discuss the relationship between communication attitudes, age and gender.


The stimulatory effect of human PMNI lysosomes on lymphocytes in vitro and in vivo.
The proteins isolated from human PMNL lysosome granules have activated the lymphocytes in vitro. It was found that T cells undergo transformation in response to lysosome mitogens but no LIF production was observed. Transformation induced by PHA, PWM and Con A was depressed in the presence of lysosome mitogens. The in vivo response to T-dependent antigens is amplified by lysosome mitogens. The above experiments demonstrate that lysosome mitogens stimulate T lymphocytes.


Anti-inflammatory properties of the protein kinase C inhibitor, 3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H- pyrrole-2,5-dione monohydrochloride (GF109203X) in the PMA-mouse ear edema model.
Protein kinase C (PKC) mediates a number of intracellular signal transduction pathways implicated in the pathogenesis of inflammation, including phospholipase A2-dependent arachidonic acid release and eicosanoid production. Recent studies demonstrate that the PKC inhibitor GF109203X significantly reduces a number of inflammatory processes resulting from PKC activation by the topical application of phorbol myristate acetate (PMA) to mouse ears. In this model, GF109203X significantly reduced edema at doses similar to the PKC inhibitor staurosporine, and more effectively than indomethacin, zileuton, or sodium meclofenamate. Histological and biochemical analysis of biopsies from control and drug-treated ears revealed a marked reduction in edema, infiltrating neutrophils, and levels of the neutrophil-specific marker, myeloperoxidase, in GF109203X-treated mice. Prostaglandin E2 levels were also reduced in ears treated with GF109203X. These data suggest that GF109203X is an effective antiinflammatory agent as evaluated in the PMA model of edema, and implicates PKC as a potential target in the development of novel anti-inflammatory agents.


Flow and geochemical modeling of drainage from Tomitaka mine, Miyazaki, Japan.
The chemistry and flow of water in the abandoned Tomitaka mine of Miyazaki, western Japan were investigated. This mine is located in a non-ferrous metal deposit and acid mine drainage issues from it. The study was undertaken to estimate the quantities of mine drainage that needs to be treated in order to avoid acidification of local rivers, taking into account seasonal variations in rainfall. Numerical models aimed to reproduce observed water levels and fluxes and chemical variations of groundwater and mine drainage. Rock-water interactions that may explain the observed variations in water chemistry are proposed. The results show that: (1) rain water infiltrates into the deeper bedrock through a highly permeable zone formed largely by stopes that are partially filled with spoil from excavations (ore minerals and host rocks); (2) the water becomes acidic (pH from 3 to 4) as dissolved oxygen oxidizes pyrite; (3) along the flow path through the rocks, the redox potential of the water becomes reducing, such that pyrite becomes stable and pH of the mine drainage becomes neutral; and (4) upon leaving the mine, the drainage becomes acidic again due to oxidation of pyrite in the rocks. The present numerical model with considering of the geochemical characteristics can simulate the main variations in groundwater flow and water levels in and around the Tomitaka mine, and apply to the future treatment of the mine drainage.


Plasma, urinary and biliary residues in cattle following intramuscular injection of nortestosterone laurate.
The synthetic androgen 19-nortestosterone (beta-NT) has been used illegally as a growth promoter in cattle production in the European Union. Elimination of beta-NT and its metabolites in plasma, urine and bile was studied in three cattle with cannulated gallbladders following intramuscular injection at a single site of 500 mg of the laurate ester (NTL) containing 300.5 mg beta-NT. Using enzyme immunoassay quantification, plasma Cmax of free beta-NT was 0.5 +/- 0.15 microgram/L (mean +/- SEM). Concentrations of free beta-NT in plasma were consistently greater than the assay limit of quantification (0.12 microgram/L) for 32.7 +/- 13.42 days. Mean residence time for the beta-NT in plasma was 68.5 +/- 20.75 days. Following sample preparation by immunoaffinity chromatography, high-resolution GC-MS was used to quantify beta-NT and alpha-NT in urine and bile. beta-NT was detected irregularly in urine from two of the three animals post injection. The principal metabolite present in the urine, alpha-NT, was detected for 160.3 +/- 22.67 days post injection. Cmax for alpha-NT in urine was 13.7 +/- 5.14 micrograms/L. Mean urinary AUC0-183 days for alpha-NT was 845.7 +/- 400.90 (microgram h)/L. In bile, alpha-NT was the only metabolite detected for 174.3 +/- 8.67 days post treatment. Cmax for alpha-NT in bile was 40.8 +/- 12.70 micrograms/L and mean biliary AUC0-183 days for alpha-NT was 1982.6 +/- 373.81 (microgram h)/L. Concentrations of alpha-NT in bile samples were greater than those in urine samples taken at the same time. The mean ratio of biliary:urinary AUC0-183 days was 3.0 +/- 0.72. It is concluded that bile is a superior fluid for detection of alpha-NT following injection of NTL, owing to the longer period during which residues may be detected after administration.


Effects of enhancing mitochondrial oxidative phosphorylation with reducing equivalents and ubiquinone on 1-methyl-4-phenylpyridinium toxicity and complex I-IV damage in neuroblastoma cells.
The effects of increasing mitochondrial oxidative phosphorylation (OXPHOS), by enhancing electron transport chain components, were evaluated on 1-methyl-4-phenylpyridinium (MPP+) toxicity in brain neuroblastoma cells. Although glucose is a direct energy source, ultimately nicotinamide and flavin reducing equivalents fuel ATP produced through OXPHOS. The findings indicate that cell respiration/mitochondrial O(2) consumption (MOC) (in cells not treated with MPP+) is not controlled by the supply of glucose, coenzyme Q(10) (Co-Q(10)), NADH+, NAD or nicotinic acid. In contrast, MOC in whole cells is highly regulated by the supply of flavins: riboflavin, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), where cell respiration reached up to 410% of controls. In isolated mitochondria, FAD and FMN drastically increased complex I rate of reaction (1300%) and (450%), respectively, having no effects on complex II or III. MPP+ reduced MOC in whole cells in a dose-dependent manner. In isolated mitochondria, MPP+ exerted mild inhibition at complex I, negligible effects on complexes II-III, and extensive inhibition of complex IV. Kinetic analysis of complex I revealed that MPP+ was competitive with NADH, and partially reversible by FAD and FMN. Co-Q(10) potentiated complex II ( approximately 200%), but not complex I or III. Despite positive influence of flavins and Co-Q(10) on complexes I-II function, neither protected against MPP+ toxicity, indicating inhibition of complex IV as the predominant target. The nicotinamides and glucose prevented MPP+ toxicity by fueling anaerobic glycolysis, evident by accumulation of lactate in the absence of MOC. The data also define a clear anomaly of neuroblastoma, indicating a preference for anaerobic conditions, and an adverse response to aerobic. An increase in CO(2), CO(2)/O(2) ratio, mitochondrial inhibition or O(2) deprivation was not directly toxic, but activated metabolism through glycolysis prompting depletion of glucose and starvation. In conclusion, the results of this study indicate that the mechanism of action for MPP+, involves the inhibition of complex I and and more specifically complex IV, leading to impaired OXPHOS and MOC. Moreover, flavin dervatives control the rate of complex I/cellular respiration and Co-Q10 augments complex II [corrected].


Pediatric functional endonasal sinus surgery.
Functional endoscopic sinus surgery has been used to treat children in whom medical and traditional surgical therapy have failed. Special approaches are necessary in children because of the small size of the paranasal sinuses. Modifications of the techniques used in adults that are appropriate for use in children are fully explained.


Changes in religious beliefs following trauma.
Information processing theorists propose that traumatic events can lead to disruptions in the processing of information and to changes in beliefs. This study examined the relationships among trauma, posttraumatic stress disorder (PTSD), and religious beliefs. Participants included 120 individuals from community and clinical samples who participated in the DSM-IV Field Trial Study on PTSD. Results indicated that the PTSD group was more likely to report changes in religious beliefs following the first/only traumatic event, generally becoming less religious. PTSD status was not related to change in religious beliefs following the most recent event. Intrinsic religiosity was related to multiple victimization, but not PTSD. Results are discussed in terms of understanding the function of religiosity in participants' lives and future directions for research.


Surgical relief of causalgia with an artificial nerve guide tube: Successful surgical treatment of causalgia (Complex Regional Pain Syndrome Type II) by in situ tissue engineering with a polyglycolic acid-collagen tube.
Two patients with causalgia associated with allodynia and finger contracture were treated surgically with a bioresorbable nerve guide tube made from polygycolic acid and collagen: the injured segment of the digital nerve was resected and the resulting gap (25 and 36mm) was bridged with the tube. In both cases, a neuroma was found on the injured nerve and many sprouting branches were. After reconstruction, the causalgia and allodynia disappeared and movement of the fingers recovered during the following 6 months. Functional recovery was objectively identified for 1 year and 9 months. Both patients regained full use of their finger and were free of discomfort for up to 24 and 18 months, respectively. Since the first description of causalgia in 1864, there has been no definitive treatment for this intractable burning pain. Our experience shows that at least some types of causalgia can be resolved successfully by surgery.


Synchronous bilateral primary germ cell tumors in patient receiving estrogen therapy.
The present report concerns the occurrence of bilateral synchronous germ cell tumors in a sixty-eight-year-old man who received estrogen therapy for eleven months. Although there are previous reports on Leydig cell tumors developing in mice and man receiving estrogens, we have not found any connection between germ cell tumors and estrogen medication reported in the literature.


Pituitary and bilateral adrenal enlargement: an unusual presentation of hepatocellular carcinoma.
Pituitary metastases account for about 1% of operated pituitary lesions. Most derive from primaries in the breast or lung. Pituitary metastases from hepatocellular carcinoma (HCC) have rarely been reported. We describe a patient in whom headache and left external ophthalmoplegia were the only presenting signs of a clinically silent and radiographically undetectable HCC, that had metastasized to the pituitary and both adrenal glands. Pituitary histology and adrenal needle biopsy failed to establish the final diagnosis, which was reached only after surgical exploration of the abdomen. This case illustrates the difficulties encountered in the histopathological diagnosis of pituitary metastasis and the need for good clinical judgment when confronting pituitary tumors with atypical features.


Unusual vascular complications of dissecting thoracic aortic aneurysms.
Nondissecting, chronic, thoracic aortic aneurysms (TAA) may be associated with such vascular complications as aorto-cardiac, aorto-superior vena caval (SVC) and aorto-pulmonary arterial (PA) fistual formation, and/or SVC or PA compression. Dissecting TAA have been associated with these lesions far less often. This report summarizes the occurence and outcome of the following complications of dissecting TTA: (1) SVC obstruction; (2) aorto-right and -left atrial, aorta-right ventricular and aorto-PA fistula formation; (3) compression of the PA and (4) hematoma of the interatrial septum. Two patients are described with aortic dessection complicated by: (1) SVC obstruction and aorto-left atrial fistula; and (2) aorto-PA fistula. These complications are rarer with aortic dissection, because of the acute, catastrophic nature of this lesion. When dissection is chronic, however, arteriovenous fistulae are often well tolerated, and urgent surgical intervention seems to be unnecessary.


Risk of Cardiovascular Events Among Patients With Head and Neck Cancer.
Cardiovascular (CV) disease is a substantial cause of morbidity and mortality in cancer due to shared risk factors and exposure to potentially cardiotoxic cancer therapy. However, our understanding of CV risk in patients with head and neck squamous cell carcinoma (HNSCC) is limited. To define CV risk profiles, incident stroke, myocardial infarction (MI), and mortality in patients with HNSCC. This retrospective, population-based cohort study included 35 897 US veterans with newly diagnosed HNSCC from January 1, 2000, to December 31, 2020. Data were analyzed from May 2022 to January 2023. Demographic, cancer-specific, and treatment characteristics. Prevalence of CV risk factors, medication use, and control at HNSCC diagnosis; cumulative incidence of stroke and MI; and all-cause death. Of 35 857 US veterans with HNSCC (median [IQR] age, 63 [58-69] years; 176 [0.5%] American Indian or Alaska Native, 57 [0.2%] Asian, 5321 [16.6%] Black, 207 [0.6%] Native Hawaiian or Other Pacific Islander, and 26 277 [82.0%] White individuals), there were high rates of former or current smoking (16 341 [83%]), hypertension (24 023 [67%]), diabetes (7988 [22%]), and hyperlipidemia (18 421 [51%]). Although most patients were taking risk-lowering medications, 15 941 (47%) had at least 1 uncontrolled CV risk factor. Black race was associated with increased risk of having uncontrolled CV risk factor(s) (relative risk, 1.06; 95% CI, 1.03-1.09), and patients with larynx cancer had higher rates of prevalent and uncontrolled risk factors compared with other cancer subsites. Considering death as a competing risk, the 10-year cumulative incidence of stroke and MI was 12.5% and 8.3%, respectively. In cause-specific hazards models, hypertension, diabetes, carotid artery stenosis, coronary artery disease, and presence of uncontrolled CV risk factor(s) were significantly associated with stroke and MI. In extended Cox models, incident stroke and MI were associated with a 47% (95% CI, 41%-54%) and 71% (95% CI, 63%-81%) increased risk of all-cause death, respectively. The results of this cohort study suggest that in HNSCC, the burden of suboptimally controlled CV risk factors and incident risk of stroke and MI are substantial. Modifiable CV risk factors are associated with risk of adverse CV events, and these events are associated with a higher risk of death. These findings identify populations at risk and potentially underscore the importance of modifiable CV risk factor control and motivate strategies to reduce CV risk in HNSCC survivorship care.


ATP-evoked arachidonic acid mobilization in astrocytes is via a P2Y-purinergic receptor.
To reveal more of the mechanism whereby ATP induces arachidonic acid (AA) mobilization in astrocytes, primary cell cultures prelabeled with [3H]AA were exposed to ATP and various analogs. Release of 3H was dose and time dependent and was inhibited by blocking ATP binding. The potencies of a range of ATP analogs in mobilizing AA were consistent with that predicted for the involvement of a P2Y-purinergic receptor. Mobilization of AA was not due to non-specific cell permeabilization, as assessed by leakage of cytoplasmic lactate dehydrogenase. AA mobilization by ATP was reduced when mobilization of intracellular calcium was inhibited and in the absence of extracellular calcium. Thapsigargin, which induces release of intracellular calcium, evoked mobilization of AA and thromboxane formation, findings similar to the effects of ATP. These results suggest that ATP stimulates AA mobilization via a P2Y-purinergic receptor and that, although extracellular calcium is involved, mobilization of intracellular calcium activates phospholipase A2.


Adaptive innovation of green plants by horizontal gene transfer.
Horizontal gene transfer (HGT) refers to the movement of genetic material between distinct species by means other than sexual reproduction. HGT has contributed tremendously to the genome plasticity and adaptive evolution of prokaryotes and certain unicellular eukaryotes. The evolution of green plants from chlorophyte algae to angiosperms and from water to land represents a process of adaptation to diverse environments, which has been facilitated by acquisition of genetic material from other organisms. In this article, we review the occurrence of HGT in major lineages of green plants, including chlorophyte and charophyte green algae, bryophytes, lycophytes, ferns, and seed plants. In addition, we discuss the significance of horizontally acquired genes in the adaptive innovations of green plants and their potential applications to crop breeding and improvement.


Immunogenicity of RNA-protein fraction isolated from axenic Entamoeba histolytica (NIH:200).
The immunogenicity of Entamoeba histolytica RNA (EhRNA) was studied in guinea-pigs. Animals immunized with a single dose of EhRNA and Freund's complete adjuvant (FCA) showed a high level of cell-mediated immune response (CMIR) as assessed by percent leucocyte migration inhibition (74.8 +/- 2.9) after 1 week of immunization. This response faded away gradually and by week 5 after immunization the percent leucocyte migration inhibition was 27.1 +/- 8.27, which is quite close to control values. The immunogenic activity of EhRNA was found to be specific, since yeast RNA failed to elicit immunological responses, and was RNase-sensitive. The CMIR could be maintained at its high level by giving boosters or multiple doses. Anti-EhRNA antibodies (haemagglutinins or precipitins) could not be demonstrated at any stage.


Single-cell sequencing of a novel model of neonatal bile duct ligation in mice identifies macrophage heterogeneity in obstructive cholestasis.
Macrophages (MΦ) play a role in neonatal etiologies of obstructive cholestasis, however, the role for precise MΦ subsets remains poorly defined. We developed a neonatal murine model of bile duct ligation (BDL) to characterize etiology-specific differences in neonatal cholestatic MΦ polarization. Neonatal BDL surgery was performed on female BALB/c mice at 10 days of life (DOL) with sham laparotomy as controls. Comparison was made to the Rhesus Rotavirus (RRV)-induced murine model of biliary atresia (BA). Evaluation of changes at day 7 after surgery (BDL and sham groups) and murine BA (DOL14) included laboratory data, histology (H&E, anti-CD45 and anti-CK19 staining), flow cytometry of MΦ subsets by MHCII and Ly6c expression, and single cell RNA-sequencing (scRNA-seq) analysis. Neonatal BDL achieved a 90% survival rate; mice had elevated bile acids, bilirubin, and alanine aminotransferase (ALT) versus controls (p < 0.05 for all). Histology demonstrated hepatocellular injury, CD45+ portal infiltrate, and CK19+ bile duct proliferation in neonatal BDL. Comparison to murine BA showed increased ALT in neonatal BDL despite no difference in histology Ishak score. Neonatal BDL had significantly lower MHCII-Ly6c+ MΦ versus murine BA, however, scRNA-seq identified greater etiology-specific MΦ heterogeneity with increased endocytosis in neonatal BDL MΦ versus cellular killing in murine BA MΦ. We generated an innovative murine model of neonatal obstructive cholestasis with low mortality. This model enabled comparison to murine BA to define etiology-specific cholestatic MΦ function. Further comparisons to human data may enable development of immune modulatory therapies to improve patient outcomes.


Enhanced Acid Tolerance in Bifidobacterium longum by Adaptive Evolution: Comparison of the Genes between the Acid-Resistant Variant and Wild-Type Strain.
Acid stress can affect the viability of probiotics, especially Bifidobacterium. This study aimed to improve the acid tolerance of Bifidobacterium longum BBMN68 using adaptive evolution. The stress response, and genomic differences of the parental strain and the variant strain were compared by acid stress. The highest acid-resistant mutant strain (BBMN68m) was isolated from more than 100 asexual lines, which were adaptive to the acid stress for 10(th), 20(th), 30(th), 40(th), and 50(th) repeats, respectively. The variant strain showed a significant increase in acid tolerance under conditions of pH 2.5 for 2 h (from 7.92 to 4.44 log CFU/ml) compared with the wildtype strain (WT, from 7.87 to 0 log CFU/ml). The surface of the variant strain was also smoother. Comparative whole-genome analysis showed that the galactosyl transferase D gene (cpsD, bbmn68_1012), a key gene involved in exopolysaccharide (EPS) synthesis, was altered by two nucleotides in the mutant, causing alteration in amino acids, pI (from 8.94 to 9.19), and predicted protein structure. Meanwhile, cpsD expression and EPS production were also reduced in the variant strain (p < 0.05) compared with WT, and the exogenous WT-EPS in the variant strain reduced its acid-resistant ability. These results suggested EPS was related to acid responses of BBMN68.


Role of RAD51AP1 in homologous recombination DNA repair and carcinogenesis.
Homologous recombination (HR) serves to repair DNA double-strand breaks and damaged replication forks and is essential for maintaining genome stability and tumor suppression. HR capacity also determines the efficacy of anticancer therapy. Hence, there is an urgent need to better understand all HR proteins and sub-pathways. An emerging protein that is critical for RAD51-mediated HR is RAD51-associated protein 1 (RAD51AP1). Although much has been learned about its biochemical attributes, the precise molecular role of RAD51AP1 in the HR reaction is not yet fully understood. The available literature also suggests that RAD51AP1 expression may be relevant for cancer development and progression. Here, we review the efforts that led to the discovery of RAD51AP1 and elaborate on our current understanding of its biochemical profile and biological function. We also discuss how RAD51AP1 may help to promote cancer development and why it could potentially represent a promising new target for therapeutic intervention.


Molecular identification, polymorphism, and expression analysis of major histocompatibility complex class IIA and B genes of turbot (Scophthalmus maximus).
Major histocompatibility complex (MHC) class II has a central role in the adaptive immune system by presenting foreign peptides to the T-cell receptor. The full lengths of MHC class II A and B cDNA were cloned from turbot by homology cloning and rapid amplification of cDNA ends polymerase chain reaction (RACE PCR), and genomic organization, molecular polymorphism, and expression of turbot class IIB gene were examined to study the function of class IIB gene in fish. The deduced amino acid sequence of turbot class II A (GenBank accession no.DQ001730) and turbot class IIB (GenBank accession no. DQ094170) had 69.8%, 67.6%, 65.5%, 59.2%, 54.5%, 52.8%, 46.2%, 46.6%, 28.3%, 28.5%, 22.2% identity and 71.5%, 70.7%, 67.1%, 68.4%, 46.7%, 53.5%, 46.7%, 50.0%, 25.2%, 29.2%, 27.6% identity with those of Japanese flounder, striped sea bass, red sea bream, cichlid, rainbow trout, Atlantic salmon, carp, zebrafish, nurse shark, mouse and human, respectively. Eleven class IIB alleles were identified from three turbot individuals. The amino acid sequence of turbot class IIB designated as Scma-DAB*0101 had 86.9%, 88.6%, 88.6%, 89.4%, 87.8%, 86.9%, 84.1%, 86.5%, 87.3%, 77.1%, and 86.9% identity with those of turbot class IIB 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (Scma-DAB*0201- Scma-DAB*1201), respectively. Six different class IIB alleles observed in a single individual may infer the existence of three loci at least. Semiquantitative reverse transcriptase PCR (RT-PCR) demonstrated that turbot class IIA and B were ubiquitously expressed in normal tissues. Challenge of turbot with pathogenic bacteria, Vibrio anguillarum, resulted in a significant decrease in the expression of MHC class IIB mRNA from 24 h to 48 h after infection in liver and head kidney, and a significant decrease from 24 h to 72 h after infection in spleen, followed by an increase after 96 h, respectively.


Transfusion knowledge of medical and surgical specialty board residents: a cohort study.
This study was conducted to assess transfusion knowledge between different specialty board residents and to identify areas of need for further education. Physicians' knowledge of transfusion medicine (TM) is critical for patients' safety. Many clinicians who are involved in day-to-day transfusion practice have little or no formal training in TM. There are no studies to assess physician's TM knowledge locally. A comprehensive anonymous survey was developed to assess baseline TM knowledge of all the residents. The survey is composed of different sections, including a questionnaire on resident's demographics, resident's self-reflection on their TM knowledge and 30 multiple choice questions addressing basic and clinical TM knowledge in two major domains: component selection and transfusion practice and transfusion safety and transfusion reactions. Finally, the residents' opinion on educational needs was assessed. A total of 130 residents were surveyed. The lowest score obtained among the two major domains assessed was in the transfusion safety and transfusion reaction domain, with a mean score of 4·34 of 15 (SD ± 3·27). The mean score obtained on component selection and transfusion practice was 7·1 of 15 (SD ± 3·74). A substantial proportion of the residents (74·7%) admitted minimal baseline knowledge in the field of TM. Finally, 94·5% of the residents admitted the need for more education during residency, whereas 49·5% thought additional education is required during the first year of practice. This survey shows serious TM knowledge deficiency and indicates the need for additional education among all physicians during training.


Comparison of clinical outcomes of implantable collamer lens implantation with and without use of an ophthalmic viscosurgical device.
To compare the clinical efficacy of posterior chamber phakic implantable collamer lens (ICL) implantation with and without the use of an ophthalmic viscosurgical device (OVD). Onnuri Eye Hospital, Jeonju, Jeollabuk-do, South Korea. Retrospective case series. Included were patients who underwent ICL implantation with the use of an OVD (OVD group) and patients who underwent ICL implantation without the use of an OVD (hydro group). Refractive error, endothelial cell density (ECD), intraocular pressure (IOP), vault, and adverse events were evaluated at 1 day, 1 week, 1 month, and 3 months postoperatively. The IOP and vault were checked 1 hour postoperatively, and the surgical time was recorded. The OVD group comprised 54 eyes of 27 patients and the hydro group 49 eyes of 25 patients. There were no significant preoperative differences between the 2 groups. At 1 hour postoperatively, the IOP was significantly higher in the OVD group (P < .001); however, there was no significant difference in IOP between the 2 groups at other follow-up timepoints. Surgical time was significantly shorter for the hydro group (P = .032). There was no statistically significant difference in vault, ECD, or refractive error between the 2 groups during the 3-month follow-up period. No adverse events were observed. ICL implantation without the use of an OVD was safe and effective. The advantages of this technique included a short surgical time, prevention of early postoperative IOP spikes, and cost savings due to OVD elimination.


c-Jun Amino-Terminal Kinase is Involved in Valproic Acid-Mediated Neuronal Differentiation of Mouse Embryonic NSCs and Neurite Outgrowth of NSC-Derived Neurons.
Valproic acid (VPA), an anticonvulsant and mood-stabilizing drug, can induce neuronal differentiation, promote neurite extension and exert a neuroprotective effect in central nervous system (CNS) injuries; however, comparatively little is known regarding its action on mouse embryonic neural stem cells (NSCs) and the underlying molecular mechanism. Recent studies suggested that c-Jun N-terminal kinase (JNK) is required for neurite outgrowth and neuronal differentiation during neuronal development. In the present study, we cultured mouse embryonic NSCs and treated the cells with 1 mM VPA for up to 7 days. The results indicate that VPA promotes the neuronal differentiation of mouse embryonic NSCs and neurite outgrowth of NSC-derived neurons; moreover, VPA induces the phosphorylation of c-Jun by JNK. In contrast, the specific JNK inhibitor SP600125 decreased the VPA-stimulated increase in neuronal differentiation of mouse embryonic NSCs and neurite outgrowth of NSC-derived neurons. Taken together, these results suggest that VPA promotes neuronal differentiation of mouse embryonic NSCs and neurite outgrowth of NSC-derived neurons. Moreover, JNK activation is involved in the effects of VPA stimulation.


Extra-abdominal desmoid fibromatosis: An evaluation of clinical factors affecting local recurrence rates.
The aim of this study was to determine the prognostic factors for recurrence in patients with extra-abdominal desmoid tumors (EDTs) treated surgically. This single-institution, retrospective study included patients with a histologically-proven extra-abdominal desmoid tumor between 2007 and 2018. The demographic characteristics (age, sex) of the patients, tumor characteristics (region, size, proximity to neurovascular structures, margins), treatment management (surgery and/or adjuvant radiotherapy), and clinical results were analyzed. The effects of these possible prognostic factors on overall and disease-free survival rates and the risk of local recurrence were evaluated. Evaluation was made of 22 patients (16 females, 6 males) with a mean age at diagnosis of 34.7 years (range = 22-76 years). The mean follow-up was 104 months (range = 4.8-168). Tumor localization was in the upper extremity in 4 patients (18.1%), the lower extremity in 11 (50.0%), and the trunk in 7 (31.8%). The mean tumor size (maximum diameter) was 5.2 cm (range = 0.6-13 cm; median = 5.8 cm), and the mean tumor volume was 181.3 ± 531.4 ml. All the 22 patients were treated surgically along with adjuvant radiotherapy (RT) administered to 8 in addition to surgery for the primary treatment of the tumor. Following primary surgery, resection margins were R0 in 11 patients, R1 in 9 and R2 in 2. Local recurrence (LR) developed in 6 patients (27.2%) during the follow-up period. Recurrence-free survival rate (RFS) was 90.9% at one year, 74.1% at 5 years, and 61.7% at 10 years. During the follow-up, no patient died, and distant metastasis was not detected. Tumor length, resection margins, and adjuvant RT were observed to influence the risk of local recurrence (P < 0.05). The results of this study have demonstrated that tumor size ≥ 5 cm and the presence of microscopic or macroscopic positive surgical margins can increase the risk of LR, and adjuvant RT can reduce the development of LR in the management of EDT.


beta-alanine and alpha-fluoro-beta-alanine concentrative transport in rat hepatocytes is mediated by GABA transporter GAT-2.
Studies on the compartmentalization of uridine catabolic metabolism in liver have indicated accumulation of beta-alanine as well as alpha-fluoro-beta-alanine (FbetaAL) for 5-fluorouracil in the hepatocytes. Using preparations of rat hepatocytes we were able to identify a Na+-dependent transport with high affinity for beta-alanine and GABA with Michaelis constant (Km) of 35.3 and 22.5 microM, respectively. A second Na+-dependent kinetic component with Km >1 mM was also identified. The sigmoidal profile of beta-alanine uptake with respect to Na+ shows the involvement of multiple ions of sodium in the transport process. A Hill coefficient of 2.6 +/- 0.4 indicates that at least two sodium ions are cotransported with beta-alanine. The flux of beta-alanine was also shown to be chlorine dependent. The substitution of this anion with gluconate, even in the presence of Na+, reduced the intracellular concentrative accumulation of beta-alanine to passive diffusion level, indicating that both Na+ and Cl- are essential for the activity of this transporter. The transport of beta-alanine was inhibited by GABA, hypotaurine, beta-aminoisobutyric acid, and FbetaAL in a competitive manner. However, concentrations up to 1 mM of L- and D-alanine, taurine, and alpha-aminoisobutyric acid did not affect beta-alanine uptake. Considering the similarities in substrate specificity with the rat GAT-2 transporter, extracts of hepatocytes were probed with the anti-GABA transporter antibody R-22. A 80-kDa band corresponding to GAT-2 was present in the hepatocyte and in the GAT-2 transfected Madin-Darby canine kidney cell extract, confirming the extraneural localization of this transporter. In view of these results, the neurotoxic effects related to the administration of uridine and 5-fluorouracil could be explained with the formation of beta-alanine and FbetaAL and their effect on the cellular reuptake of GABA.


Silver-based intermetallic heterostructures in Sb2Te3 thick films with enhanced thermoelectric power factors.
In this work, Ag(x)Te(y)-Sb(2)Te(3) heterostructured films are prepared by ligand exchange using hydrazine soluble metal chalcogenide. Because of the created interfacial barrier, cold carriers are more strongly scattered than hot ones and thereby an over 50% enhanced thermoelectric power factor (~2 μW/(cm·K(2))) is obtained at 150 °C. This shows the possibility of engineering multiphases to further improve thermoelectric performance beyond phonon scattering through a low-temperature solution processed route.


Localization of CAI and CAII isoenzymes in normal term human placenta by immunofluorescence techniques.
The carbonic anhydrase isoenzymes, low activity CAI and high activity CAII, were localized in normal term human placenta by immunocytochemical techniques. Both CAI and CAII isoenzymes were present in the syncytial trophoblasts. Fetal erythrocytes in the placental capillaries also showed positive staining for both CAI and CAII isoenzymes. The possible physiological roles of CA in human placenta are also discussed.


A novel K509I mutation of KIT identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy.
KIT mutation has been implicated in sporadic mastocytosis, yet clusters in only a few sites in the molecule. For those malignancies associated with KIT mutation or over-expression, imatinib offers a specific therapeutic option, yet it has no effect on D816V mutation commonly seen in sporadic mastocytosis. The majority of cases of familial mastocytosis seem to lack KIT mutation. We report a kindred with mastocytosis in whom in vitro and in vivo sensitivity to imatinib was demonstrated. Mutation analysis of the KIT coding region in this family identified a novel A>T mutation at nucleotide 1547 [K509I] in exon 9 in both of the affected patients.


Improvement of a two-stage carcinogenesis model to detect modifying effects of endocrine disrupting chemicals on thyroid carcinogenesis in rats.
In order to improve the sensitivity of our previously established thyroid carcinogenesis model and to clarify whether endocrine disrupting chemicals with weak estrogenic activity have any modifying effects on the development of thyroid proliferative lesions, 6-week-old female castrated F344 rats were first given a single subcutaneous injection of 2000 mg/kg body weight of N-bis(2-hydroxypropyl)nitrosamine. From 1 week later, they received diets with: no supplement (basal diet (BD) group); cholesterol pellets containing 0.5 mg 17 beta-estradiol 3-benzoate (EB); or diet admixed with 1000 ppm methoxychlor (MXC) or 10,000 ppm bisphenol A (BPA) for 20 weeks. Furthermore, additional groups were administered 200 ppm sulfadimethoxine (SDM) in the drinking water simultaneously with the BD, EB, MXC or BPA treatments. Thyroid follicular cell hyperplasias, adenomas and/or carcinomas were induced only in the EB+SDM group, the incidences of non-malignant lesions being significantly increased, as compared with the BD+SDM group values. Furthermore, the serum level of thyroid stimulating hormone (TSH) was significantly increased in this group. No significant variation in quantitative values for thyroid proliferative lesions or TSH levels were observed in the other treated groups. The results of the present study convincingly indicate that EB, with strong estrogenic activity, but not MXC and BPA, with weak estrogenic activities, exerts promoting effects on thyroid carcinogenesis in rats. The present modified rat two-stage thyroid carcinogenesis model appears to have advantages over our previous model for screening purposes.


Electrokinetic flow in a capillary with a charge-regulating surface polymer layer.
An analytical study of the steady electrokinetic flow in a long uniform capillary tube or slit is presented. The inside wall of the capillary is covered by a layer of adsorbed or covalently bound charge-regulating polymer in equilibrium with the ambient electrolyte solution. In this solvent-permeable and ion-penetrable surface polyelectrolyte layer, ionogenic functional groups and frictional segments are assumed to distribute at uniform densities. The electrical potential and space charge density distributions in the cross section of the capillary are obtained by solving the linearized Poisson-Boltzmann equation. The fluid velocity profile due to the application of an electric field and a pressure gradient through the capillary is obtained from the analytical solution of a modified Navier-Stokes/Brinkman equation. Explicit formulas for the electroosmotic velocity, the average fluid velocity and electric current density on the cross section, and the streaming potential in the capillary are also derived. The results demonstrate that the direction of the electroosmotic flow and the magnitudes of the fluid velocity and electric current density are dominated by the fixed charge density inside the surface polymer layer, which is determined by the regulation characteristics such as the dissociation equilibrium constants of the ionogenic functional groups in the surface layer and the concentration of the potential-determining ions in the bulk solution.


Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis.
Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA+ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA+ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.


Impact of the COVID-19 pandemic on the stage and the type of surgical treatment of laryngeal cancer.
Changes in the entire health care system during COVID-19 epidemic have affected the management of patients with head and neck cancer and posed several clinical challenges for ENT surgeons. Therefore, the present study aimed to investigate the effect of COVID-19 on the stage and the type of surgical treatments used in laryngeal cancer (including total laryngectomy, supracricoid partial laryngectomy (SCPL) and transoral laser microsurgery (TLM)) and also to compare the results of April 2020 to April 2021 with the previous year. This cross-sectional study was performed on all patients with a diagnosis of laryngeal cancer who underwent surgery in the tertiary care center from April 2020 to April 2021 and the year before the pandemic in the same time. Demographic, cancer stage, and treatment data of all patients were recorded and analysis in two groups. Patients referred at the time of the virus outbreak; 111 were male and 5 were female, and in the group of patients referred before COVID-19, 90 were male and 12 were female. The type of surgical treatment of laryngeal cancer, mean time elapsed from sampling to surgery, stage of disease and mean tumor volume was statistically significant differences in patients before and during the outbreak. Patients who referred for diagnosis and treatment at the time of COVID-19 outbreak had more advanced stages of the disease and also the tumor volume was higher in them than patients who had referred before the outbreak. It is necessary to provide new solutions, education and treatment management for patients with laryngeal cancer in such pandemics.


Synthesis, crystal structure and Hirshfeld surface analysis of bis-{2-[(pyridin-2-yl)amino]-pyridinium} tetra-cyano-nickelate(II).
In the title mol-ecular salt, (C10H10N3)2[Ni(CN)4], the dihedral angle between the pyridine rings in the cation is 1.92 (13)° and the complete anion is generated by a crystallographic centre of symmetry. An intra-molecular N-H⋯N hydrogen bond occurs in the cation, which closes an S(6) ring. In the crystal, the components are linked by N-H⋯N and weak C-H⋯N hydrogen bonds, which generate chains propagating in the [101] direction. Weak aromatic π-π stacking inter-actions are also observed. A Hirshfeld surface analysis and two-dimensional fingerprint plots indicate that the most important contact types in the crystal packing are N⋯H/H⋯N, C⋯H/H⋯C and H⋯H with contributions of 37.2, 28.3 and 21.9%, respectively.


Proteome metabolome and transcriptome data for three Symbiodiniaceae under ambient and heat stress conditions.
The Symbiodiniaceae are a taxonomically and functionally diverse family of marine dinoflagellates. Their symbiotic relationship with invertebrates such as scleractinian corals has made them the focus of decades of research to resolve the underlying biology regulating their sensitivity to stressors, particularly thermal stress. Research to-date suggests that Symbiodiniaceae stress sensitivity is governed by a complex interplay between phylogenetic dependent and independent traits (diversity of characteristics of a species). Consequently, there is a need for datasets that simultaneously broadly resolve molecular and physiological processes under stressed and non-stressed conditions. Therefore, we provide a dataset simultaneously generating transcriptome, metabolome, and proteome data for three ecologically important Symbiodiniaceae isolates under nutrient replete growth conditions and two temperature treatments (ca. 26 °C and 32 °C). Elevated sea surface temperature is primarily responsible for coral bleaching events that occur when the coral-Symbiodiniaceae relationship has been disrupted. Symbiodiniaceae can strongly influence their host's response to thermal stress and consequently it is necessary to resolve drivers of Symbiodiniaceae heat stress tolerance. We anticipate these datasets to expand our understanding on the key genotypic and functional properties that influence the sensitivities of Symbiodiniaceae to thermal stress.


Sorbitol dehydrogenase is a cytosolic protein required for sorbitol metabolism in Arabidopsis thaliana.
Sorbitol is converted to fructose in Rosaceae species by SORBITOL DEHYDROGENASE (SDH, EC 184.108.40.206), especially in sink organs. SDH has also been found in non-Rosaceae species and here we show that the protein encoded by At5g51970 in Arabidopsis thaliana (L.) Heynh. possesses the molecular characteristics of an SDH. Using a green fluorescent protein-tagged version and anti-SDH antisera, we determined that SDH is cytosolically localized, consistent with bioinformatic predictions. We also show that SDH is widely expressed, and that SDH protein accumulates in both source and sink organs. In the presence of NAD+, recombinant SDH exhibited greatest oxidative activity with sorbitol, ribitol and xylitol as substrates; other sugar alcohols were oxidized to a lesser extent. Under standard growth conditions, three independent sdh- mutants developed as wild-type. Nevertheless, all three exhibited reduced dry weight and primary root length compared to wild-type when grown in the presence of sorbitol. Additionally, under short-day conditions, the mutants were more resistant to dehydration stress, as shown by a reduced loss of leaf water content when watering was withheld, and a greater survival rate on re-watering. This evidence suggests that limitations in the metabolism of sugar alcohols alter the growth of Arabidopsis and its response to drought.


An inclusive study on cytokine gene expression in Parkinson's disease: Advanced analysis using Bayesian regression model.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease throughout the globe whose specific pathophysiology is unknown. Researchers believe that inflammation and oxidative stress contribute to PD development. Also, alterations in cytokines production appear to have a key role in the pathogenesis of PD. The aim of the current study was to evaluate gene expression levels of nine cytokines in the peripheral blood of PD patients compared to a healthy control group. Real-time PCR was used to analyze cytokines gene expression followed by advanced statistical analysis performed using Bayesian regression model in R (version 4.1.0) statistical software. TNF-α, IL-1β, IL-2, IL-4, IFN-γ, IL-17 and IL-6 transcript levels were upregulated in patients compared to healthy controls. However, CXCL8 expression was downregulated in patients compared to controls and IFN-β expression was not statistically different between the two groups. While we found no significant difference between the groups based on gender and age regarding TNF-α, IL-1β, CXCL8, IL-2, IL-4, IFN-γ and IFN-β gene expression, IL-6 and IL-17 transcript levels showed significant upregulations in older subjects and in females, respectively. In addition, we found that the interaction effects between gender and group on gene expression levels were not significant. In this way, the subgroup analysis within gender revealed that in each gender, expression levels of TNF-α, IL-2, IL-4, IL-6, IFN-γ and IL-17 were significantly higher in patients than controls. However, IFN-β expression level did not show any significant difference between groups and subgroups. The present study provides evidence on significant alterations in cytokine expression with different patterns and points to immune system dysregulation in PD.


Localization of axonally transported label in chick retinal ganglion cell axons after intravitreal injections of wheat germ agglutinin conjugated to horseradish peroxidase.
We have studied the subcellular localization of peroxidase-labeled organelles after anterograde axonal transport by chick retinal ganglion cells that had been exposed 23-25 h earlier to wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). After intravitreal injection of WGA-HRP, we found in the optic tectum that 82% of labeled organelles were located within axons and axon terminals. The organelles included: tubules and cisternae of the smooth endoplasmic reticulum, hypolemmal cisternae, vesicles, dense bodies and multivesticular bodies. We also measured the distances between the centers of the labeled organelles and the plasma membrane of these profiles. The density of organelles (number of organelles/micron 2) was plotted as a function of distance from the plasma membrane. Irrespective of the dose of lectin-peroxidase injected, labeled organelles were most densely concentrated in a 30 nm wide annular zone centered 75 nm in from the plasma membrane. In axon terminals the labeled organelles were most concentrated 75-90 nm in from the plasma membrane. Assuming that the peroxidase label indicates the presence of WGA-HRP, we conclude that after anterograde axonal transport the lectin accumulates in lysosomal organelles and elements of the smooth endoplasmic reticulum. Therefore, in contrast to the more restricted localization of [125I]WGA as inferred from electron microscopic autoradiography after uptake and transport by the same cell type, WGA-HRP-labeled organelles are found more diffusely within the axoplasm, particularly in axon terminals. Furthermore, peroxidase-labeled organelles in dendritic, glial or neuronal cell bodies in the tectum were seen less frequently than expected based on evidence of frequent transfer to second cells after intravitreal injections of [125I]WGA. Thus, we infer that at these concentrations WGA labeled with HRP may not be transferred intercellularly as efficiently as even lower concentrations of iodinated WGA are apparently transferred.


Dynamics of uptake and elimination of 17α-ethinylestradiol in male goldfish (Carassius auratus).
We used male goldfish (Carassius auratus) as a model species to determine the uptake, elimination, and bioaccumulation of 17α-ethinylestradiol (EE2). Goldfish were exposed to EE2 via two different routes: water (135ng/L±12.8 standard deviation) for 72h, and food (231ng/g±42 SD) for 120h. We observed a rapid uptake of EE2 in goldfish, reaching 8.4ng/g±1.2 dry weight (dw) after the first hour of exposure with an uptake rate coefficient (k1) of 45h(-1). The elimination rate coefficient (k2) was determined by a depuration experiment to be 0.0786h(-1). In the feeding experiment, EE2 concentrations increased rapidly, reaching an average of 1.4ng/g after 3h following the first dietary exposure with an estimated absorption efficiency (α) of 0.106. An average of 2.66ng/g±0.87 (n=8) was determined in the 24-72h samples, whereas EE2 concentrations in fish fell below our method detection limits (0.67ng/g) for all samples after 72h, suggesting efficient elimination over time. The bioconcentration factor (BCF) for EE2 reached a maximum of 377, similar to BCFs measured for other pharmaceuticals like fluoxetine and sertraline. Our kinetic data were also used to model various scenarios of EE2 uptake in the aquatic environment. To our knowledge, this is the first report to describe aqueous and dietary EE2 uptake and elimination in fish, as well as providing important data to model EE2 kinetics in fish.


Perceived skills in palliative medicine of newly qualified doctors in the U.K.
To ascertain the perceived skills of students at U.K. medical schools in palliative medicine. A validated questionnaire survey. Newly qualified U.K. pre-registration house officers (PRHOs). A Likert scale from 0 to 5 for respondents to rate their perceived skills in four clinical scenarios, and their anxiety in caring for the dying. Mean confidence rating in breaking bad news was 2.9, in ability to empathize was 3.2, in discussing prognosis was 3.3, and in providing symptom control was 2.8. Mean anxiety rating in caring for a dying patient was 2.9. Of the comments, 24% wished for more "hands on" experience and 23% suggested further curriculum recommendations. Teaching of palliative medicine is still inadequate for the needs of recently qualified doctors. Although PRHOs have identified a need for further instruction there is also acknowledgment that it is a difficult subject to teach. Recommendations are made for coordination of current interdepartmental teaching programs.


Molecular cloning, characterization and regulation of the cockroach vitellogenin receptor during oogenesis.
The vitellogenin receptor (VgR) belongs to the low density lipoprotein receptor (LDLR) superfamily, and mediates the uptake of vitellogenin (Vg) into developing oocytes of all oviparous species. We cloned and characterized a VgR from previtellogenic ovaries of the cockroach, Periplaneta americana (Pa). This is the first report on a VgR from a hemimetabolous insect. The cDNA, comprising 5722 bp, encoded a 1790-residue mature protein with a predicted molecular mass of 200.5 kDa. We next characterized the ovarian expression pattern, developmental regulation and cellular distribution of the VgR mRNA and protein. Northern blot analysis confirmed that a approximately 7.2 kb transcript was specifically expressed in ovarian tissues at high levels throughout ovarian development, especially in previtellogenic ovaries and in ovaries before adult emergence. RNA in situ hybridization and immunocytochemistry localized the VgR mRNA and protein to germ-line derived cells, the oocytes, and revealed that VgR gene transcription and translation begin very early during oocyte differentiation in the germarium. Immunoblot analysis detected an ovary-specific VgR protein of approximately 210 kDa that was present in previtellogenic ovaries on the day of female emergence. The VgR protein signal strengthened every day and was intense after initiation of vitellogenesis and onset of Vg uptake. The immunoblotting of vitellins demonstrated that Vg uptake occurred on day 5, one day after Vg first appeared in the haemolymph, indicating that the receptor-endocytotic machinery starts functioning soon after the ligand becomes available.


Concomitant disseminated herpes simplex virus type 2 infection and varicella zoster virus primoinfection in a pregnant woman.
We report the first case of a HSV and VZV coinfection during pregnancy. VZV infection was diagnosed by a seroconversion and PCR. HSV 2 infection was diagnosed by cell culture. The mother and the newborn received no treatment and did not develop any complication. This case report highlights the need for increased surveillance of pregnant women with herpes virus infections.


Psychological distress and related factors among caregivers of children with attention-deficit/hyperactivity disorder during the COVID-19 pandemic.
The present study examined the relationships of caregiver factors (including caregivers' age, sex and educational year), child-family interactions (caregivers' difficulties in managing children's protective behaviors against COVID-19, learning and daily performance, children's conflict with elders and siblings, and parenting styles), and children's factors (attention-deficit/hyperactivity disorder [ADHD] and oppositional defiant disorder [ODD] symptoms) with psychological distress of the caregivers of children with ADHD in the COVID-19 pandemic. This study recruited 252 caregivers of children with ADHD to participate and complete a questionnaire collecting their psychological distress in the COVID-19 pandemic, demographics, difficulties in managing children's protective behaviors against COVID-19, learning and daily performance, and parenting styles as well as children's conflict with elders and siblings, and the ADHD and ODD symptoms. Hierarchical regression models were constructed to examine the factors related to psychological distress among caregivers. Factors across caregiver, child, and child-family interaction dimensions, including children's conflict levels with elders and siblings, inattention symptoms, and caregivers' difficulties in managing children's protective behaviors against COVID-19, learning and daily performance, female sex, and younger age were significantly associated with psychological distress among caregivers in various hierarchical regression models. Health professionals should take the relevant factors identified in this study when developing an intervention to relieve caregivers' psychological distress in the COVID-19 pandemic.


Mifepristone potentiates etoposide toxicity in Hep G2 cells by modulating drug transport.
Etoposide is a well-known and widely used anticancer drug that displays several side effects. In addition, tumors often acquire resistance to this drug. Our aim is to develop a combination therapy that would augment toxicity of etoposide in malignant cells. Based on literature and our experiments, we selected mifepristone (RU486) as a potential supporting molecule that is able to enhance etoposide toxicity against cancer cells. All experiments were performed with Hep G2 cells, a well-known and described human hepatocellular carcinoma cell line. By using xCELLigence system, we demonstrated that mifepristone enhances toxicity of etoposide in a dose dependent manner with concomitant caspase-3 activity. We evaluated upregulation of Bax because mifepristone was demonstrated to modulate proapoptotic Bax protein expression. Our data show only weak and not statistically significant increase of Bax expression. On the other hand, we show that mifepristone increases etoposide toxicity via inhibition of ABC transporters, coupled with significant increase of intracellular etoposide concentration. In conclusion, we demonstrate that mifepristone has a synergistic effect with etoposide treatment in the Hep G2 cells and that the effect is related to ABC transporters inhibition.


Fusion based on attention mechanism and context constraint for multi-modal brain tumor segmentation.
This paper presents a 3D brain tumor segmentation network from multi-sequence MRI datasets based on deep learning. We propose a three-stage network: generating constraints, fusion under constraints and final segmentation. In the first stage, an initial 3D U-Net segmentation network is introduced to produce an additional context constraint for each tumor region. Under the obtained constraint, multi-sequence MRI are then fused using an attention mechanism to achieve three single tumor region segmentations. Considering the location relationship of the tumor regions, a new loss function is introduced to deal with the multiple class segmentation problem. Finally, a second 3D U-Net network is applied to combine and refine the three single prediction results. In each stage, only 8 initial filters are used, allowing to decrease significantly the number of parameters to be estimated. We evaluated our method on BraTS 2017 dataset. The results are promising in terms of dice score, hausdorff distance, and the amount of memory required for training.


The Nrf2 pathway is required for intracellular replication of Toxoplasma gondii in activated macrophages.
Reactive oxygen species (ROS) produced by oxidases and nonenzymatic sources are important for host defence against intracellular pathogens. In this study, we knocked out the Nrf2 gene in RAW264.7 cells using the CRISPR/Cas9 system and investigated the antioxidant effects of the Nrf2 pathway in the cells stimulated by IFN-γ and TNF-α. The results indicated that the Nrf2 signalling pathway is necessary for maintaining redox homeostasis in activated RAW264.7 cells. Inactivation of Nrf2 impaired parasite growth. We also found that p62 contributes to Nrf2-mediated pathways involved in T gondii infection. These findings suggest that the Nrf2/Keap1 pathway may be targeted to prevent and treat toxoplasmosis.


Cyclooxygenase and lipoxygenase inhibitors--induced changes in the distribution of glycosaminoglycans in the pregnant rat uterine cervix.
In order to study the hormonal control mechanisms of cervical maturation, we investigated cyclooxygenase and 5-lipoxygenase inhibitors-induced changes in the distribution of glycosaminoglycans (GAG) in pregnant Wistar rat uterine cervices at term. The GAG were measured in a control (n = 11), in a Diclofenac (cyclooxygenase inhibitor) treated group (n = 8), in a BW 755C (dual inhibitor of cyclooxygenase and 5-lipoxygenase) treated group (n = 6), and a L 651392 (5-lipoxygenase inhibitor) treated group (n = 9). The results of these studies suggest, that cervical hyaluronic acid metabolism and cervical hydration are controlled in association by prostaglandins and leukotrienes (and perhaps by other phospholipids metabolites), whereas heparan sulphate metabolism is obviously controlled by prostaglandins. Nevertheless complete and normal cervical maturation is probably controlled in association by arachidonic acid metabolites and other factors (steroids and peptides).