Antifungal activity of compounds from Gordonia sp. WA8-44 isolated from the gut of Periplaneta americana and molecular docking studies.
Invasive fungal infections are on the rise, leading to a continuous demand for antifungal antibiotics. Rare actinomycetes have been shown to contain a variety of interesting compounds worth exploring. In this study, 15 strains of rare actinobacterium Gordonia were isolated from the gut of Periplaneta americana and screened for their anti-fungal activity against four human pathogenic fungi. Strain WA8-44 was found to exhibit significant anti-fungal activity and was selected for bioactive compound production, separation, purification, and characterization. Three anti-fungal compounds, Collismycin A, Actinomycin D, and Actinomycin X2, were isolated from the fermentation broth of Gordonia strain WA8-44. Of these, Collismycin A was isolated and purified from the secondary metabolites of Gordonia for the first time, and its anti-filamentous fungi activity was firstly identified in this study. Molecular docking was carried out to determine their hypothetical binding affinities against nine target proteins of Candida albicans. Chitin Synthase 2 was found to be the most preferred antimicrobial protein target for Collismycin A, while 1,3-Beta-Glucanase was the most preferred anti-fungal protein target for Actinomycin D and Actinomycin X2. ADMET prediction revealed that Collismycin A has favorable oral bioavailability and little toxicity, making it a potential candidate for development as an orally active medication.


Development of two search strategies for literature in MEDLINE-PubMed: nursing diagnoses in the context of evidence-based nursing.
To develop and validate search filters for MEDLINE via PubMed according to two categories of the NLINKS-EBN matrix. The search results of the search filters were compared to a gold standard. The usage of nursing classification terms for the literature search in evidence-based nursing (EBN) is still limited because taxonomies are neither widely used in nursing literature nor applied for indexing by MEDLINE. The proposed filters achieved a sensitivity of 96% and a specificity of 94% for "secondary data" and a sensitivity of 87% and a specificity of 73% for "diagnostic tests." The usage of database-specific search filters are a reliable and valid method to search for nursing classification terms in medical databases.


Acinar ventilation heterogeneity in COPD relates to diffusion capacity, resistance and reactance.
The aim of this study was to investigate heterogenic ventilation in the acinar (Sacin) and conductive (Scond) airways of patients with varying chronic obstructive pulmonary disease (COPD) severity and how these relates to advanced lung function parameters, primarily measured by impulse oscillometry (IOS). A secondary aim was to investigate the effects of a short acting beta2-agonist and a muscarinic antagonist on the heterogenic ventilation. Eleven never smoking controls, 12 smoking controls, and 57 COPD patients (7 GOLD 1, 25 GOLD 2, 14 GOLD 3 and 11 GOLD 4) performed flow-volume spirometry, IOS, body plethysmography, single breath carbon monoxide diffusion, and N2-multiple breath washout. Six smoking controls and 13 of the COPD patients also performed double reversibility test by using salbutamol and its combination with ipratropium. Sacin was significantly higher in GOLD 2-4 compared to never smoking controls and smoking controls, but showed similar levels in GOLD 3 and 4. A factor analysis identified 4 components consisting of; 1) IOS parameters, 2) volume parameters, 3) diffusion parameters, Sacin and some IOS parameters and 4) Scond with central obstruction/air trapping. Salbutamol and its combination with ipratropium had no effect on Sacin and Scond. Increased Sacin in COPD was strongly related to diffusion capacity and lung volumes, but also weakly to resistance and reactance, showing a link between ventilation heterogeneity in the acinar airways and parameters measured by IOS.


Partial trisomy 18q in a newborn with typical 18 trisomy phenotype.
This paper describes a case of partial trisomy of almost the entire long arm of chromosome 18 in a newborn with classic trisomy-18 phenotype, resulting from a de novo unbalanced 181/21p translocation: karyotype: 46,XX,-21,t(18;21)(18qter leads to 18q11 ::21p12 leads to 21qter). A review of the other reported cases of partial trisomy 18 suggests that a critical segment in chromosome 18, corresponding to bands q11-q12, might be responsible for most of the signs of trisomy 18, including failure to thrive and early death.


Identification of tyrosine phosphatase 2(256-760) construct as a new, sensitive marker for the detection of islet autoimmunity in type 2 diabetic patients: the non-insulin requiring autoimmune diabetes (NIRAD) study 2.
The presence of autoantibodies to islet antigens GAD and/or tyrosine phosphatase 2 (IA-2) in type 2 diabetic patients (latent autoimmune diabetes in adults [LADA]) identifies subjects at high risk to develop insulin dependency. The aim of this study was to dissect humoral anti-IA-2 immune response in Caucasian LADA patients, identifying the most sensitive construct to evaluate IA-2 immunoreactivity and comparing LADA IA-2 epitope specificities to those found in type 1 diabetes. We analyzed 177 LADA and 978 type 2 diabetic patients with different disease duration, collected in a nationwide Italian survey, the Non-Insulin Requiring Autoimmune Diabetes (NIRAD) study aimed at assessing prevalence and characteristics of autoimmune diabetes in type 2 diabetic patients and 106 newly diagnosed type 1 diabetic patients (53 children, 53 adults). By radioimmunoassay, we analyzed humoral immunoreactivity to seven IA-2 constructs: IA-2(PTP (687-979)), IA-2((761-964)), IA-2((256-760)), IA-2(JM (601-630)), IA-2(IC (605-979)), IA-2(BDC (256-556:630-979)), and IA-2(FL (1-979)). IA-2((256-760)) fragment was identified as the marker with the highest sensitivity for detection of humoral IA-2 immunoreactivity in LADA patients, identifying IA-2 autoantibodies in approximately 30% of GAD antibody (GADA)-positive LADA patients and in 3.4% of GADA-negative type 2 diabetic patients. LADA IA-2((256-760))A positivity was associated with an increased frequency of autoimmune diabetes HLA-susceptible genotypes and with a higher risk for developing thyroid autoimmunity compared with autoantibody-negative type 2 diabetic patients. At disease diagnosis, adult-onset type 1 diabetic and LADA patients showed a lower IA-2 COOH-terminal immunoreactivity compared with childhood-onset type 1 diabetic patients. IA-2 immunoreactivity in LADA patients has thus far been underestimated, and IA-2((256-760)) autoantibody detection may represent a novel diagnostic tool for the identification of islet autoimmunity in these patients.


Event-related slow potential (ERSP) correlates of thyroid gland function level.
This study shows an association between thyroid gland function level and event-related slow brain potential (ERSP) parameters (peak amplitude and area under the curve), obtained during "classical" and "operant" reaction-time paradigms. A significant positive correlation between ERSP parameters and 24-hr I131 uptake and a negative nonsignificant one between them and ankle jerk reflex were found. Organismic factors related to thyroid function had greater influence upon ERSP amplitude and area than situational ones, for no significant effect of task was evidenced and no interaction between them was found under the conditions employed. Hyper- and hypothyroids showed also a tendency to present longer reaction times than euthyroids. These results are discussed within the framework of the arousal-distraction coupling hypothesis as proposed by Tecce and Cole (1976) and compared to those previously obtained in high-neuroticism anxiety-prone indivuduals. Although these and hyperthyroids do show indications of similar behavioral manifestations (excessive reactive arousal), both groups are considered to differ regarding empirical referennts of anticipatory arousal (ERSP parameters). A major difference seems to be the absence of a "ceiling effect" in hyperthyroids. This hypothetical phenomenon can be expected on the basis of the inverted U-shaped relation between ERSP amplitude and arousal level. A stronger "distraction" effect associated with increased arousal in anxiety neurotics is postulated and tentatively attributed to covert verbalizations of worry and feelings added to increased awareness of autonomic input. The contention is advanced that similar behavioral manifestations could be distinguishable at the physiological level employed and this might add further insights to diagnostic typologies (e.g., "psychosomatic" vs. "psychoneurotic" patients).


Safety and tolerability of hydroxychloroquine in health care workers and first responders for the prevention of COVID-19: WHIP COVID-19 Study.
Health care workers (HCW) are among the highest risk groups for acquisition of COVID-19 because of occupational exposures. The WHIP COVID-19 Study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) as chemoprophylaxis for SARS-CoV-2 infection in this population. HCW, first responders, and other occupationally high-risk participants were enrolled in a randomized, placebo-controlled clinical study of HCQ from April to October 2020. The trial compared daily versus weekly HCQ with placebo and with a prospective cohort on HCQ for autoimmune diseases. Participants were followed for 8 weeks. Serology or a positive polymerase chain reaction test was used to determine laboratory confirmed clinical cases. A total of 624 participants were randomized to placebo (n = 200), weekly HCQ (n = 201), daily HCQ (n = 197). For the primary safety end point, 279 (44.7%) participants experienced adverse event (AE) level II or lower (total AEs n = 589), similar rates in all randomized groups (P = .188) with no hospitalizations or interventions required. Only 4 laboratory confirmed COVID-19 cases occurred, with 2 in the placebo arm and one in each HCQ randomized arm. This randomized placebo-controlled trial was able to demonstrate the safety of HCQ outpatient chemoprophylaxis in high-risk groups against COVID-19. Future studies of chemoprophylaxis for SARS-CoV-2 are needed as the epidemic continues worldwide.


Determination of Optimal Vitamin D Dosage in Children with Cholestasis.
Vitamin D deficiency in patients with cholestasis is due to impaired intestinal vitamin D absorption, which results from decreased intestinal bile acid concentration. Patients with cholestasis usually do not achieve optimal vitamin D status when a treatment regimen for children without cholestasis is used. However, data on high-dose vitamin D treatment in patients with cholestasis are limited. This study is a prospective study that included pediatric patients with cholestasis (serum direct bilirubin > 1 mg/dL) who had vitamin D deficiency (serum 25-hydroxyvitamin D, 25-OHD, < 20 ng/mL). In Phase 1, single-day oral loading of 300,000 IU (or 600,000 IU if weight ≥ 20 kg) of vitamin D2 was administered, followed by an additional loading if serum 25-OHD < 30 ng/mL, and 4-week continuation of treatment using a vitamin D2 dose calculated based on the increment of 25-OHD after first loading. In Phase 2, oral vitamin D2 (200,000 IU/day) was administered for 12 days, followed by 400,000 IU/day of vitamin D2 orally for another 8 weeks if serum 25-OHD < 30 ng/mL. Phase 1: Seven patients were enrolled. Three out of seven patients had a moderate increase in serum 25-OHD after loading (up to 20.3-27.2 ng/mL). These patients had conditions with partially preserved bile flow. The remaining four patients, who had biliary atresia with failed or no Kasai operation, had low increments of serum 25-OHD. Phase 2: Eleven patients were enrolled. Eight out of 11 patients had a moderate increase in serum 25-OHD after 200,000 IU/day of vitamin D2 for 12 days. Serum 25-OHD continued increasing after administering 400,000 IU/day of vitamin D2 for another 8 weeks, with maximal serum 25-OHD of 15.7-22.8 ng/mL. Very high doses of vitamin D2 (200,000 and 400,000 IU/day) partly overcame poor intestinal vitamin D absorption and resulted in moderate increases in serum 25-OHD in pediatric patients with cholestasis, particularly when cholestasis was caused by uncorrectable bile duct obstruction.


Identification and characterization of a novel bat polyomavirus in Japan.
A novel polyomavirus (PyV) was identified in the intestinal contents of Japanese eastern bent-wing bats (Miniopterus fuliginosus) via metagenomic analysis. We subsequently sequenced the full genome of the virus, which has been tentatively named Miniopterus fuliginosus polyomavirus (MfPyV). The nucleotide sequence identity of the genome with those of other bat PyVs was less than 80%. Phylogenetic analysis revealed that MfPyV belonged to the same cluster as PyVs detected in Miniopterus schreibersii. This study has identified the presence of a novel PyV in Japanese bats and provided genetic information about the virus.


"Acquired" adrenal hyperplasia with 21-hydroxylase deficiency is not the same genetic disorders as congenital adrenal hyperplasia.
Hormonal studies and HLA genotyping were performed on the family of a patient with "acquired" adrenal hyperplasia (AAH) due to 21-hydroxylase deficiency. The results of these studies suggest that "AAH", is not the same genetic disease as CAH.


[Influence of femoral catheter stimulation intensity on post-surgical analgesia after total knee replacement].
Stimulating catheters allow the catheter point to be positioned near the nerve, thus reducing the amount of local anaesthetic required for a successful block. There is currently a debate on what is the stimulation intensity required to provide adequate analgesia, although it does seem that if it is obtained with 1mAmp or less the block is more effective. The objective of the study was to demonstrate whether different neurostimulation intensities with the stimulating catheter at femoral nerve level, had an influence on the adequacy of post-surgical analgesia during the 48h after total knee arthroplasty. A comparative, prospective and randomised study was conducted on patients subjected to total knee replacement. After surgery with subarachnoid anaesthesia, a continuous femoral block was performed with a stimulating catheter at a neurostimulation intensity 0.2 and 0.5mAmp in Group 1, between 0.6 and 1mAmp in Group 2, equal or higher than 1.1mAmp in Group 3, and in Group 4 the catheter was introduced between 3-5cm without looking for a motor response. A dose of 0.2% ropivacaine 0.4mL/kg and an infusion at 5mL/h, with boluses of 10mL/30min, was administered via the catheter. Sciatic nerve block was also performed on all patients with 20ml of 0.5% ropivacaine. The patient demographics were recorded, as well as, post-surgical analgesia details, sensory and motor block in each area, boluses requested, rescue analgesia, and undesirable effects at 8, 16, 24, 36 and 48h. A total of 124 patients were included, 32 in Group 1 (25.8%), 21 in Group 2 (16.9%), 31 in Group 3 (25%), and 40 in group 4 (32.3%). The 4 groups were homogeneous as regards age, height, weight and ASA. There were no statistically significant differences found in the post-operative pain, except during movement in the femoral area at 36 hours (p=.032). There were also no statistically significant differences found in the sensory block in the femoral area at 48 hours (p=.019) and in the femoral cutaneous nerve block at 8 hours (p=.049) or at 24 hours (p=.045). As regards motor block, differences were only found in the obturator nerve at 24 hours (p=.016). There were no differences in rescue analgesia, patient controlled analgesia (PCA) boluses requested or administered, except that the number of boluses requested at 16 hours was less in Group 3 (p=.049). There were also no significant differences in undesirable effects or in the level of satisfaction of the patients between the four groups. In our study, no influence was found on the level of analgesia provided after knee replacement surgery with the neurostimulation intensity to which the neuromuscular system involved responded when a stimulating catheter is inserted at femoral level.


Intussusception following jejunoileal bypass for morbid obesity: report of a case.
A man who had undergone jejunoileal bypass for morbid obesity had cramping abdominal pains for which no cause could be found, despite repeated clinical examinations and numerous investigations. Only during anesthesia could the large mass formed by the intussusception be palpated. Following reduction of the intussusception and refixing to the anterior abdominal wall, all symptoms abated.


Pre-operative Hepatic Artery Resistive Index is a Non-invasive Predictive Indicator of Prognosis in Biliary Atresia.
The aim of this study is to evaluate hepatic artery resistive index (HARI) as a noninvasive prognostic predictor by correlating it with peripheral blood nitric oxide (NO) levels, portal pressure (PP) and histopathological changes in the liver in patients of biliary atresia (BA). Twenty-five patients were included in the study prospectively from November 2012 to June 2014. All patients underwent Doppler sonography to calculate the HARI preoperatively. Peripheral blood NO was also measured preoperatively. Biochemical liver function tests (LFTs) were measured preoperatively and at 1, 3, and 6 months postoperatively. The PP was measured intraoperatively, and a liver biopsy was taken in all patients. Disappearance of jaundice defined successful surgical treatment. Postoperatively, a hepatobiliary IminoDiacetic Acid scan (HIDA) was done to demonstrate a patent bilio-enteric pathway. The mean preoperative HARI was 0.78 ± 0.105, and the median was 0.80 (range 0.60-1.0). The median HARI was used to correlate the other parameters; 13 (52%) patients had HARI ≥0.8. The mean PP was 24.96 ± 6.54 mmHg. The HARI had a strong correlation with PP (P = 0.0001) and (NO) (P = 0.0001); with every 0.1 increase in HARI, there was 5.2 mmHg increase in PP and 3.8 μmol/L increase in NO. The histological parameters which reached significance in relation to HARI were hepatocellular damage, bile duct inflammation, portal inflammation, and portal fibrosis. The postoperative improvement in LFT was significantly better in patients with HARI <0.8. All four patients who died during or after the study period had HARI >0.8, elevated PP, and NO levels. Preoperative HARI was found to have a direct correlation with PP and peripheral blood NO as a measure of portal hypertension. A preoperative HARI ≥0.8 should be considered as a risk factor for poor outcomes in BA.


[Injuries of the thoracolumbar spine in children].
Injuries of the thoracolumbar spine in children are rare and challenging for the treating physician. Besides knowledge of fracture treatment, the anatomical particularities of the spine in children are of great importance. The article gives an overview of the diagnosis and therapy with the most common classification of injuries of the thoracolumbar spine. Taking into account the children's age and the fracture morphology most cases can be treated conservatively, especially because the young spine has great potential for remodelling. The older the child becomes, the more smoothly the transition to adult treatment occurs; thus, unstable fractures should be treated with surgery. The difficult indication and the specific characteristics of surgery necessitate treatment in a spine centre with experience with surgery on children.


Computerised tomography and the liver.
Computerised tomography produces an excellent image of the liver. The author discusses the relevant technical factors such as the use of window levels and window widths, tissue attenuation values and filtering. The importance of the applied anatomy and the use of contrast agents are discussed and then the findings on computed tomography in clinical practice are presented. The lesions that can be visualised include cysts, abscesses, primary tumours, metastases, fatty liver, subphrenic abscess, dilated bile ducts and cholelithiasis as well as surrounding ascites. These appearances are described and illustrated.


Regression of atheroma in the rabbit.
Ten studies in the literature concerning regression of rabbit atheroma were re-examined. In studies where cholesterol content was referred to weight, a degree of regression was noted in 3/4 studies. Such regression might at least partly have resulted from the dilution effect of the atheroma contents when results were expressed on a weight basis. By contrast, when results were referred to length or protein, partial regression was seen in only 1/4 studies. Mild atheroma induced by short-term cholesterol feeding did seem to regress in 2/2 studies.


Lower initial red blood cell count in cerebrospinal fluid predicts good functional outcome in patients with spontaneous subarachnoid haemorrhage.
Red blood cell (RBC) degradation after subarachnoid haemorrhage (SAH) negatively affects functional outcome. Although the detection of RBCs in the cerebrospinal fluid (CSF) is a widely available part of neurological routine diagnostics, the prognostic value as a biomarker remains unclear. This study was undertaken to investigate whether CSF RBC count correlates with established radiological markers of SAH volume and whether the CSF RBC count can predict functional outcome in SAH patients. A total of 121 consecutive spontaneous SAH patients were retrospectively analyzed. CSF was collected from external ventricular drain as part of routine diagnostic procedures. We used multivariable binary logistic regression to investigate associations between CSF RBC counts and functional outcome 3 months after SAH or hospital survival. Good functional outcome was defined as modified Rankin Scale ≤ 2. Patients' age was 60 ± 14 years, and the median admission Hunt & Hess grade (H&H) was 4. CSF samples were collected 2 days after intensive care unit admission. High CSF RBC counts positively correlated with radiological measurements for SAH volume, for example, modified Fisher score (p = 0.002) and Hijdra ventricle score (p = 0.016). Multivariable regression analysis adjusted for age, H&H grade, modified Fisher and Hijdra scores showed that low CSF RBC counts predicted hospital survival (per 100,000 CSF RBCs: adjusted odds ratio [adjOR] = 0.74, 95% confidence interval [CI] = 0.61-0.89, p = 0.001) and good functional outcome after 3 months (per 100,000 CSF RBC: adjOR = 0.76, 95% CI = 0.60-0.96, p = 0.020). CSF RBC counts correlate with radiographic scores quantifying SAH volume and may serve as an early independent biomarker for hospital survival and good functional 3-month outcome in patients requiring ventriculostomy after SAH.


Correction: Frequent Mobile Electronic Medical Records Users Respond More Quickly to Emergency Department Consultation Requests: Retrospective Quantitative Study.
[This corrects the article DOI: 10.2196/14487.].


Synthesis and evaluation of Janus type nucleosides as potential HCV NS5B polymerase inhibitors.
The synthesis of new ribo and 2'-β-C-methyl ribo Janus type nucleosides J-AA, J-AG and J-AU is reported along with their ability to block HCV and HIV replication. Their toxicity was also assessed in Huh7, human lymphocytes, CEM and Vero cells.


Spanish version of the self-care self-efficacy scale: A validation study in community-dwelling older adults with chronic multimorbidity.
To test the psychometric properties of the Spanish version of the Self-Care Self-Efficacy Scale (SCSES-Sp) in community-dwelling older adults with chronic multimorbidity. A sample of 1013 community-dwelling older adults with chronic multimorbidity participated in an observational cross-sectional study that was carried out in 3 phases. Confirmatory factor analysis showed that the SCSES-Sp has 4 dimensions: "self-efficacy in self-care behaviours based on clinical knowledge", "self-efficacy in self-care maintenance", "self-efficacy in self-care monitoring", and "self-efficacy in self-care management". A panel of independent experts considered the content of the SCSES-Sp valid. Convergent validity analysis showed moderate-strong correlations between all of the SCSES-Sp's dimensions and the reference criteria chosen. Reliability was good for the SCSES-Sp and all its dimensions. Test-retest reliability analysis showed that the SCSES-Sp was temporally stable. The SCSES-Sp is a valid and reliable tool to assess self-efficacy in self-care in Spanish-speaking, community-dwelling older adults with chronic multimorbidity.


Photodynamic therapy activated STAT3 associated pathways: Targeting intrinsic apoptotic pathways to increase PDT efficacy in human squamous carcinoma cells.
5-Aminolaevulinic acid-based photodynamic therapy (ALA-PDT) has been used for part of squamous cell carcinoma (premalignant conditions or in situ cutaneous SCC-Bowen disease). However, mechanism of ALA-PDT is not fully understood yet on the cell apoptosis pathway. The aim of this study was to further investigate the effect and mechanism of 5-ALA-PDT on human squamous carcinoma A431cells. Apoptosis and cell viability after PDT were evaluated using Annexin V-FITC apoptosis detection kit and MTT assay. The mRNA and protein levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Our data showed that 5-ALA-PDT significantly inhibited cell proliferation (p<0.05), but there was no significant difference when the photosensitizer reached to 4.8mM. The inhibition in cell proliferation after 5-ALA-PDT treatment was correlated to more cells being arrested in the G0/G1 phase of the cell cycle (p<0.01). Immunocytochemical observations using anti-active caspase-3 antibodies showed active caspase-3 was translocated from cytoplasm to nuclear during apoptosis. STAT3 and its downstream gene Bax and BCL-2 were changed after 5-ALA-PDT treatment for the mRNA and protein expression. Our studies confirmed that 5-ALA-PDT might be an effective treatment for human squamous carcinoma by inhibiting the tumor cell A431growth and for the first time demonstrated that the expression of STAT3 was significantly reduced at 24h after 5-ALA-PDT treatment.


Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis.
The lysosomal aspartic protease cathepsin D (cath-D) is over-expressed and hyper-secreted by epithelial breast cancer cells. This protease is an independent marker of poor prognosis in breast cancer being correlated with the incidence of clinical metastasis. Cath-D over-expression stimulates tumorigenicity and metastasis. Indeed it plays an essential role in the multiple steps of tumor progression, in stimulating cancer cell proliferation, fibroblast outgrowth and angiogenesis, as well as in inhibiting tumor apoptosis. A mutated cath-D devoid of catalytic activity still proved mitogenic for cancer, endothelial and fibroblastic cells, suggesting an extra-cellular mode of action of cath-D involving a triggering, either directly or indirectly, of an as yet unidentified cell surface receptor. Cath-D is also a key mediator of induced-apoptosis and its proteolytic activity has been involved generally in this event. During apoptosis, mature lysosomal cath-D is translocated to the cytosol. Since cath-D is one of the lysosomal enzymes which requires a more acidic pH to be proteolytically-active relative to the cysteine lysosomal enzymes, such as cath-B and -L, it is open to question whether cytosolic cath-D might be able to cleave substrate(s) implicated in the apoptotic cascade. This review summarises our current knowledge on cath-D action in cancer progression and metastasis, as well as its dual function in apoptosis.


Optimization of conventional therapy in patients with IBD.
The majority of patients with IBD use conventional therapy (namely, aminosalicylates, antibiotics, corticosteroids and immunomodulatory agents) for prolonged periods of time, to both induce and maintain remission. Treatment paradigms in IBD have evolved towards a rapid escalation of therapy to achieve stringent goals, including mucosal healing and a reduction in the need for hospital admission and surgery. In this context, the failure to optimize conventional therapy can lead to a potentially effective treatment being abandoned too early, which is undesirable when only a limited number of drugs are effective in the management of IBD, and could also lead to patients being unnecessarily exposed to potentially toxic and/or expensive biologic drugs. This Review provides an overview of the many ways in which conventional therapy can be optimized, and describes strategies to improve adherence to drug regimens, such as simplifying the dosing regimen, optimizing drug delivery and dose, and tailoring medication on the basis of metabolite levels.


Statistical process control for the analysis of quality control in urodynamics: A potential new approach for quality review of urodynamics.
To analyze quality control in urodynamic studies, using a proportion control chart (p-chart) for statistical process control. This single-center study was conducted at the Urodynamic Center of West China Hospital, Sichuan University. We randomly selected 15 samples from each month in 2020, and 180 urodynamic traces were finally enrolled. We used the p-chart of statistical process control for analysis. We calculated the proportion of the incidence of a selected set of artefacts in the monthly urodynamic study process, including non-standard zero setting, no cough test, incomplete records of all measurements by urodynamicists, catheter displacement, and baseline drift. Through the specific calculation formula of statistical process control, we obtained the values of the center line, lower control limit, and upper control limit. All data points of each artefact were within zone A. However, one outlier was found in the p-chart of all artefacts in October, which might have been caused by inexperienced operators. Statistical process control may play an important role in the process control of urodynamic studies and guide us in identifying the cause of poor quality in process management.


Correction to: Two-stage Bayesian hierarchical modeling for blinded and unblinded safety monitoring in randomized clinical trials.
An amendment to this paper has been published and can be accessed via the original article.


Study of the interaction between bovine serum albumin and ZnS quantum dots with spectroscopic techniques.
The interaction between bovine serum albumin (BSA) and ZnS quantum dots (QDs) was studied by fluorescence, UV-vis spectroscopic techniques. The results showed that the fluorescence of BSA was strongly quenched by ZnS QDs and the quenching mechanism was discussed to be a static quenching procedure, which was proved by quenching rate constant K(q.) The recorded UV-vis data and the fluorescence data quenching by the QDs demonstrated that the interaction between them leads to the formation of QDs-BSA complex. Furthermore, the temperature effects on the structural and spectroscopic properties of individual QDs and protein and their bioconjugates (QDs-BSA) were also researched. It was found that, compared to the monotonically decrease of the individual QDs fluorescence intensity, the temperature dependence of the QDs-BSA emission had a much more complex behavior, highly sensitive to the conformational changes of the protein.


Differential accuracy of physical activity self-report by body mass index.
To examine whether agreement between self-reported and accelerometer-measured physical activity varies by BMI category in a low-income black sample. Participants completed a questionnaire and wore an accelerometer for 4-6 days. Using one- and 10-minute bouts, accelerometers measured light, moderate, and vigorous physical activity time. Correlations varied by obesity (nonobese: one-minute r=0.41; 10-minute r=0.47; obese: one-minute r=0.21; 10-minute r=0 .14). Agreement was highest among nonobese persons (one-minute kappa = 0.48, 10-minute kappa = 0.023; obese: one-minute kappa = -0.024, 10- minute kappa = -0.020). We found compromised questionnaire performance among obese participants.


Investigations on indoor Radon in Austria, part 2: Geological classes as categorical external drift for spatial modelling of the Radon potential.
Geological classes are used to model the deterministic (drift or trend) component of the Radon potential (Friedmann's RP) in Austria. It is shown that the RP can be grouped according to geological classes, but also according to individual geological units belonging to the same class. Geological classes can thus serve as predictors for mean RP within the classes. Variability of the RP within classes or units is interpreted as the stochastic part of the regionalized variable RP; however, there does not seem to exist a smallest unit which would naturally divide the RP into a deterministic and a stochastic part. Rather, this depends on the scale of the geological maps used, down to which size of geological units is used for modelling the trend. In practice, there must be a sufficient number of data points (measurements) distributed as uniformly as possible within one unit to allow reasonable determination of the trend component.


A real-time biomonitoring system to detect arsenic toxicity by valve movement in freshwater clam Corbicula fluminea.
Arsenic (As) is the element of greatest ecotoxicological concern in aquatic environments. Effective monitoring and diagnosis of As pollution via a biological early warning system is a great challenge for As-affected regions. The purpose of this study was to synthesize water chemistry-based bioavailability and valve daily rhythm in Corbicula fluminea to design a biomonitoring system for detecting waterborne As. We integrated valve daily rhythm dynamic patterns and water chemistry-based Hill dose-response model to build into a programmatic mechanism of inductance-based valvometry technique for providing a rapid and cost-effective dynamic detection system. A LabVIEW graphic control program in a personal computer was employed to demonstrate completely the functional presentation of the present dynamic system. We verified the simulated dissolved As concentrations based on the valve daily rhythm behavior with published experimental data. Generally, the performance of this proposed biomonitoring system demonstrates fairly good applicability to detect waterborne As concentrations when the field As concentrations are less than 1 mg L(-1). We also revealed that the detection times were dependent on As exposure concentrations. This biomonitoring system could particularly provide real-time transmitted information on the waterborne As activity under various aquatic environments. This parsimonious C. fluminea valve rhythm behavior-based real-time biomonitoring system presents a valuable effort to promote the automated biomonitoring and offers early warnings on potential ecotoxicological risks in regions with elevated As exposure concentrations.


MicroCT assessment of bone microarchitecture in implant sites reconstructed with autogenous and xenogenous grafts: a pilot study.
To assess bone microarchitecture in maxillary sites grafted with autogenous or xenogenous grafts as well as to demonstrate the usefulness of microCT in dental implant research. Samples (n = 12) consisting of titanium fixation screws covered by at least 0.5-1 mm of human bone were obtained from 17 sites grafted with autogenous or xenogenous materials and prepared for microCT scanning and conventional histology. Bone histomorphometric parameters were evaluated in three distinct regions (graft region, transitional region, and native bone region). Three-dimensional (3D) bone-to-implant contact (BIC) calculation was performed using microCT data. Histological sections were used to calculate two-dimensional (2D) BIC percentages, which were compared with values obtained from 2D microCT images. Histomorphometric parameters varied according to the type of graft used, but sites reconstructed with autogenous bone showed higher mean values in general. In autograft samples, indices for parameters such as Tb.Th and Tb.Sp were significantly different when the native bone region was compared to the graft region. While a higher mean 3D BIC was found in the native bone region for both graft materials, significant BIC differences were absent when graft types were compared. The 2D BIC percentages obtained from histological and microCT images were similar. Autografts outperformed the xenogenous material used in this study concerning the histomorphometric parameters assessed. While graft type did not seem to influence 3D BIC, the native bone region showed the highest BIC percentages when compared to the other regions in both graft groups. In addition, 2D BIC ratios were similar regardless of graft material or image source (histological sections x microCT slices). Taken together, our findings suggest that microCT is an effective tool for 2D and 3D histomorphometric and BIC assessments in dental implant research.


The "Long-arm" of chronic conditions in childhood: Evidence from Canada using linked survey-administrative data.
The objective of this study was to investigate the relationship between health conditions in childhood (ages 4-11), and health and socioeconomic outcomes in adulthood (ages 21-33). This study takes advantage of a new linkage between the National Longitudinal Survey of Children and Youth (NLSCY) and administrative tax data from the T1 Family File (T1FF) from Statistics Canada. The NLSCY includes rich longitudinal information on child development, while the T1FF includes administrative tax information on each child in adulthood (e.g., income, social assistance). The primary measures of child health relate to the diagnosis of a chronic condition, affecting the child's physical or mental/developmental health. The results suggest that mental/developmental health conditions in childhood more negatively influence adult health and socioeconomic conditions, compared to physical health conditions. Interaction models reveal modest heterogenous effects; for example, there is some evidence of a cushioning effect from higher household income in childhood, as well as an exacerbating negative effect from lower birth weight for mental/developmental health conditions. Using a covariate decomposition approach to explore underlying pathways, the results reveal that associations between health in early life and outcomes in adulthood are partially explained by differences in cognitive skills (i.e., mathematics test scores) in adolescence (ages 16-17). Results may encourage policy investments to mitigate the occurrence of health conditions in childhood and to ensure timely access to educational supports and health services for children with chronic conditions.


Spectrum of unrecognized posterior urethral valves in the adult.
The spectrum of symptoms and findings associated with posterior urethral valves can vary and mimic other conditions. Three cases of congenital posterior urethral valves in adult males are presented. Two patients were on dialysis with end-stage renal failure at the time of diagnosis after many earlier urologic evaluations. One patient subsequently received two cadaver renal transplants. The remaining patient presented with typical symptoms of prostatitis and was found to have posterior valves with a dilated posterior urethra and intraprostatic reflux on voiding cystourethrography.


A mycological and bacteriological survey on feed ingredients and mixed poultry feeds in Reunion island.
A survey was carried out in Reunion island to obtain data on the occurrence of fungi, aflatoxigenic strains of Aspergillus flavus, aflatoxins, total aerobic bacteria and salmonellae of 150 samples of mixed poultry feeds and raw materials. These were collected at five farms over a 3-month period during the warm rainy season. White corn and Braizlian soybean meal seemed to present a better microbiological quality than yellow corn and US soybean meal. Mixed poultry feeds presented a high total mold count reflecting the mold flora of raw materials. The most frequent and abundant fungi were Aspergillus flavus. A. glaucus group, Fusarium spp., Penicillium spp., A. candidus, Mucor spp., A. restrictus, Scopulariopsis spp., Cladosporium spp. and A. versicolor. Of the 118 A. flavus strains screened, 42 (35.6%) were aflatoxigenic. Yellow corn samples were the most frequently contaminated with aflatoxigenic strains (54.5%), followed by mixed feeds (44%). Of the 66 samples tested, 24 (36%) contained aflatoxins (traces to 22 ng/g). A good correlation seemed to exist between presence of at least one aflatoxigenic strain per sample and presence of aflatoxins.


Are early myoclonic encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other?
Early myoclonic encephalopathy (EME) and the Ohtahara syndrome are currently listed as two separate syndromes in the classification of epilepsies. The most prominent differentiating points are the observations that patients with Ohtahara syndrome experience predominantly tonic seizures; their seizures evolve to infantile spasms and the prognosis is often worse than patients with EME. We performed a literature review of published cases. Although syndromes may have distinct courses, the differentiation early on may be impossible as both myoclonus and tonic seizures may coexist. There is also an overlap in the etiologies. Tonic seizures are considered a manifestation of brainstem dysfunction and it is possible that this is more prominent in Ohtahara syndrome. To date, there are 17 autopsy cases (12 presumed to be Ohtahara cases and 5 EME). Evidence of hindbrain pathology was present in all. Tonic seizures or tonic posturing was a feature of all cases. We suggest that the two syndromes may represent a continuum and that the prominence of tonic seizures in the Ohtahara syndrome may be an indication of brainstem dysfunction which may play an important role in the subsequent transition to infantile spasms.


Screening for bacteriuria of schoolchildren by the nitrite reaction.
The author is conducting systematic screening surveys for bacteriuria among the pupils in the primary schools (6-14 years) of a provincial town and environments. He applies the nitrite reaction for the detection of bacteriuria. Over the past 5 years 16,621 children, 7982 girls and 8639 boys, were screened, part of them repeatedly. Four bacteriuric cases were diagnosed among the boys and 130 among the girls. In a single screening the prevalence rate of bacteriuria proved to be 1.23% among the girls. In repeated screenings the incidence rate was 0.44% on the average per annum. Fifty-six of the 130 bacteriuric girls were subjected to general examination; radiological abnormalities were found in 26 of them. The author considers the systematic screening of schoolchildren as reasonable. The nitrite reaction is the most appropriate for mass screening, since it is simple, immediate, inexpensive, specific and sufficiently sensitive.


Quantitative measures of the resting EEG in stroke: a systematic review on clinical correlation and prognostic value.
Quantitative electroencephalography (qEEG) has shown promising results as a predictor of clinical impairment in stroke. We systematically reviewed published papers that focus on qEEG metrics in the resting EEG of patients with mono-hemispheric stroke, to summarize current knowledge and pave the way for future research. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched the literature for papers that fitted our inclusion criteria. Rayyan QCRR was used to allow deduplication and collaborative blinded paper review. Due to multiple outcomes and non-homogeneous literature, a scoping review approach was used to address the topic. Or initial search (PubMed, Embase, Google scholar) yielded 3200 papers. After proper screening, we selected 71 papers that fitted our inclusion criteria and we developed a scoping review thar describes the current state of the art of qEEG in stroke. Notably, among selected papers 53 (74.3%) focused on spectral power; 11 (15.7%) focused on symmetry indexes, 17 (24.3%) on connectivity metrics, while 5 (7.1%) were about other metrics (e.g. detrended fluctuation analysis). Moreover, 42 (58.6%) studies were performed with standard 19 electrodes EEG caps and only a minority used high-definition EEG. We systematically assessed major findings on qEEG and stroke, evidencing strengths and potential pitfalls of this promising branch of research.


Investigation of association between hip osteoarthritis susceptibility loci and radiographic proximal femur shape.
To test whether previously reported hip morphology or osteoarthritis (OA) susceptibility loci are associated with proximal femur shape as represented by statistical shape model (SSM) modes and as univariate or multivariate quantitative traits. We used pelvic radiographs and genotype data from 929 subjects with unilateral hip OA who had been recruited previously for the Arthritis Research UK Osteoarthritis Genetics Consortium genome-wide association study. We built 3 SSMs capturing the shape variation of the OA-unaffected proximal femur in the entire mixed-sex cohort and for male/female-stratified cohorts. We selected 41 candidate single-nucleotide polymorphisms (SNPs) previously reported as being associated with hip morphology (for replication analysis) or OA (for discovery analysis) and for which genotype data were available. We performed 2 types of analysis for genotype-phenotype associations between these SNPs and the modes of the SSMs: 1) a univariate analysis using individual SSM modes and 2) a multivariate analysis using combinations of SSM modes. The univariate analysis identified association between rs4836732 (within the ASTN2 gene) and mode 5 of the female SSM (P = 0.0016) and between rs6976 (within the GLT8D1 gene) and mode 7 of the mixed-sex SSM (P = 0.0003). The multivariate analysis identified association between rs5009270 (near the IFRD1 gene) and a combination of modes 3, 4, and 9 of the mixed-sex SSM (P = 0.0004). Evidence of associations remained significant following adjustment for multiple testing. All 3 SNPs had previously been associated with hip OA. These de novo findings suggest that rs4836732, rs6976, and rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape.


Effects of kirenol on bovine type II collagen-induced rat lymphocytes in vivo and in vitro.
To investigate the effect of kirenol on bovine type II collagen (CII)-specific lymphocytes in vivo and in vitro, and explore the mechanism of kirenol-induced immunosuppression in antigen-specific lymphocytes. Twenty-four Wistar rats were randomized into control group, collagen-induced arthritis (CIA) model group, kirenol group (2 mg/kg), and prednisolone group (2 mg/kg). After CII injection, the rats in the latter two groups received intragastric administration of kirenol and prednisolone for 30 days, and the spleens and draining lymph nodes of the rats were harvested to prepare single cell suspensions for measurement of the cytokine levels using ELISA. In the in vitro experiment, the lymphocytes from the control rats, with or without 20 µg/ml CII treatment in the presence of 0-80 µg/ml kirenol, were evaluated for cell proliferation and apoptosis using [(3)H]-thymidine incorporation and flow cytometry, respectively. Compared with those in CIA group, IFN-γ and TNF-α production was significantly reduced in splenocyte culture supernatant of kirenol group (P<0.05 and P<0.01, respectively), and the level of IL-10 and IL-4 was up-regulated (P<0.05 and P<0.01, respectively); IFN-γ and TNF-α secretion by the cultured lymph node cells (LNCs) significantly decreased (P<0.05 and P<0.001, respectively) and IL-10 and IL-4 production increased (P<0.05, P<0.001) in kirenol group. In the in vitro experiment, kirenol treatment caused obvious suppression of CII-induced LNC proliferation and dose-dependently induced antigen-specific apoptosis of the splenocytes and LNCs. Kirenol treatment reduces pro-inflammatory cytokine secretion, increases anti-inflammatory cytokine production, inhibits cell proliferation and induces apoptosis of CII-specific lymphocytes in vitro, suggesting the potential of kirenol as an immunosuppressant.


Acute non-lymphocytic leukemia is not a major type of childhood leukemia in Japan.
The distribution of acute leukemia according to type was examined in Japanese children by three surveys: (1) a review of bone marrow slides of 81 cases diagnosed as acute myelogenous leukemia between 1964 and 1976; (2) a prospective study of 97 cases observed since 1977, and (3) a study of 8108 cases registered with the Children's Cancer Registry of Japan from 1969 to 1984. The results indicate that the ratio of acute lymphocytic leukemia to non-lymphocytic leukemia in Japan is not different from that in other countries.


Phenol amplifies complement-fixing activity and induces IgG-precipitating activity in grain-dust extract.
The use of phenol as a preservative in extracts of grain dust was found to be associated with an amplification of complement-fixing activity and the appearance of IgG-precipitating activity. Both activities were absorbed by IgG, suggesting that they were due to a single material. Phenol itself neither fixed complement nor formed a precipitate with IgG. 14C-labeled phenol was incorporated into the IgG precipitating material. Both the amplification of complement-fixing activity and the appearance of IgG-precipitating activity in phenol-containing grain-dust extract were dependent on the presence of air and were inhibited by heating the extract before phenol addition. One interpretation of these results is that a component of grain-dust extract, possibly an enzyme, oxidatively modifies phenol to a form that fixes complement and precipitates IgG. The modified material demonstrates properties of a polyphenol (tannin).


The relationship between religious attendance and blood pressure: the HUNT Study, Norway.
Research from the United States shows a possible relationship between religious attendance (RA) and blood pressure (BP). The religious context in the United States differs widely from Scandinavia. The aim was, therefore, to test whether the relationship between RA and BP is specific to the religious culture in the United States or whether a similar relationship exists between RA and BP in a Norwegian context. Data from the Nord-Trøndelag Health Study's third wave, HUNT 3 (2006-08), was used. The associations between RA and diastolic (DBP) and systolic (SBP) blood pressure in women (n = 20,066) and men (n = 15,898) were investigated in a cross-sectional study using multiple regression analyses. Mean DBP for women/men was 71.0 mmHg/76.7 mmHg. Mean SBP was 128.5 mmHg/134.0 mmHg; 39.1%/42.8% of women/men never attended religious services, 3.8%/3.4% attended more than 3x/month. The bivariate associations were statistically significant between RA and SBP in both genders and women's DBP but not men's DBP. After adjustment, inverse associations between RA and DBP/SBP for both genders were found. The RA-DBP relationship (p < 0.001) demonstrated a gradient in effect for both genders, with increasing RA associated with decreasing DBP, with 1.50/1.67 mmHg lower in women/men respectively in those attending more than 3x/month, 0.87/1.16 mmHg lower in those attending 1-3x/month, and 0.49/0.10 mmHg less in those attending 1-6x/6 months. Differences in RA-SBP (p < 0.05) were 2.12/1.71 mmHg, 0.30/0.11 mmHg, and 0.58/0.63 mmHg, respectively. In a large population-based survey in Norway, RA was associated with lower DBP and SBP after adjusting for relevant variables.


Binding and internalization of ricin labelled with fluorescein isothiocyanate.
The toxic lectin ricin has been covalently labelled with fluorescein isothiocyanate on the enzymatically active A chain. The fluorescein reacted toxin maintains its biological activity. The lateral diffusion coefficient of cell surface bound ricin, studied in two cell lines by fluorescence photobleaching recovery, is D = 1 - 2 x 10(-10) cm2/s. Fluorescence microscopy provides preliminary evidence for secondary endosomes in the cytoplasm.


Classification and evaluation of prolapse.
Pelvic organ prolapse is prevalent among older women. Milder stages of prolapse, cranial to the hymen, are common and usually symptomless. A specific symptom is a bulge outside the vagina. Functional symptoms from the bladder, bowel and sexual life frequently coexist without a known cause/effect relationship to prolapse. Prolapse should be measured by the validated internationally approved pelvic organ prolapse quantification (POPQ) system that can measure prolapse in the three compartments and three levels of the vagina. We should work on a common classification system and agreement in which symptoms should be recorded as related to prolapse and expected to improve by prolapse surgery.


Positron emission tomography: new analytic tool for vascular disease.
Positron emission tomography (PET) is a noninvasive technique that allows the quantification of regional physiologic and biochemical function in vivo. Biochemically active compounds, labeled with positron-emitting isotopes, are administered and the subsequent distribution of radioactivity measured. Although images are produced, they are of secondary importance to the ability to measure cellular metabolic function. The capability of PET to measure regional blood flow, oxygen, and substrate metabolism make it particularly useful in conditions of vascular compromise. Brain and heart have been studied extensively during normal function and while ischemic. PET is able to distinguish ischemic tissue from normal and reversibly from irreversibly injured tissue. PET has been used to document the need for and the metabolic response to vascular surgery. Although PET is complex and expensive, it may offer a means for establishing a more scientific basis for the therapy of vascular disease.


Defective phosphatidic acid-phospholipase C signaling in diabetic cardiomyopathy.
The effects of exogenous phosphatidic acid (PA) on Ca2+ transients and contractile activity were studied in cardiomyocytes isolated from chronic streptozotocin-induced diabetic rats. In control cells, 25 microM PA induced a significant increase in active cell shortening and Ca2+ transients. PA increased IP3 generation in the control cardiomyocytes and its inotropic effects were blocked by a phospholipase C inhibitor. In cardiomyocytes from diabetic rats, PA induced a 25% decrease in active cell shortening and no significant effect on Ca2+ transients. Basal and PA-induced IP3 generation in diabetic rat cardiomyocytes was 3-fold lower as compared to control cells. Sarcolemmal membrane PLC activity was impaired. Insulin treatment of the diabetic animals resulted in a partial recovery of PA responses. Our results, therefore, identify an important defect in the PA-PLC signaling pathway in diabetic rat cardiomyocytes, which may have significant implications for heart dysfunction during diabetes.


A change in membrane microviscosity of mouse neuroblastoma cells in association with morphological differentiation.
Changes in membrane microviscosity as well as in membrane constituents of mouse neuroblastoma clone N-18 were studied in association with neurite formation. The membrane microviscosity studied by fluorescence technique increased with the formation of neurites. The concomitant increase increase in the ratio of cholesterol to phospholipids was also observed.


Unusual venous thrombosis associated with protein C deficiency.
A patient in whom massive puerperal thrombophlebitis developed had protein C deficiency. In patients who initially have thrombosis that is unusual either in its nature or extent, investigation may, as in this case, reveal the presence of a hypercoagulable state.


Mirror-like aneurysms of proximal anterior cerebral artery: report of a case and review of literature.
'Mirror-like' or 'twin' aneurysms, which are located bilaterally on corresponding arteries, constitute less than 5% of overall aneurysms and mirror aneurysms on proximal anterior cerebral artery (A1) have never been reported in the past. We report a case of bilateral proximal A1 segment aneurysms (mirror). The approach to this patient is being described and the literature reviewed. The proximal A1 segment aneurysm is more approachable from the contralateral side. In case of mirror A1 aneurysms, the approach may be better from contralateral side of the larger aneurysm.


Effect of age, pubertal stage and season on testosterone concentration in male dromedary camel.
The present study was conducted in the Laboratory of Animal Physiology and Biotechnology, Department of Animal Production, Faculty of Agriculture, Mansoura University, Egypt. The present investigation aimed at studying effects of ages, pubertal stages and seasons of the year on testosterone concentrations in blood plasma and tissue homogenate of the testes. The testes used in the current study were collected from a total of 104 one-humped male camels (Camelus dromedarius). Samples were taken from pre (1-3.5 years) and post (3.5-13 years) pubertal camels. Testes were studied for a two consecutive seasons. The freshly prepared homogenate of the testicular tissue and blood plasma were used for determining the concentrations of testosterone in plasma and testicular extract. The concentrations of testosterone in blood plasma and testicular tissue were significantly increased during the breeding season compared with that of non-breeding season; the concentration of testosterone was higher in testicular tissue than in blood plasma. Testosterone concentrations in plasma and testicular tissue were increased in breeding than in non-breeding season. In addition, the testosterone concentrations were closely related with seasonal changes, stage of puberty and advancing age.


Modification by indomethacin of the blood pressure lowering effect of pindolol and propranolol in conscious rabbits.
In conscious rabbits, the intravenous administration of pindolol (0.125 mg/kg) and propranolol (1 mg/kg) induced a highly significant (p less than 0.001) decrease of mean arterial blood pressure and with propranolol, a significant (p less than 0.01) bradycardia. In the same model the intravenous administrtion of saline (1 ml/kg) and of indomethacin (1 mg/kg) did not affect mean arterial blood pressure or heart rate (p greater than 0.3). Pretreatment of the animals with indomethacin (1 mg/kg) abolished the effect of both beta-blockers on mean arterial blood pressure (p greater than 0.05) and had no significant effect on heart rate.


Breathing some new life into an old topic: chalcogen-nitrogen π-heterocycles as electron acceptors.
Recent progress in the design, synthesis and characterization of chalcogen-nitrogen π-heterocycles, mostly 1,2,5-chalcogenadiazoles (chalcogen: S, Se and Te) and their fused derivatives, possessing positive electron affinity is discussed together with their use in preparation of charge-transfer complexes and radical-anion salts-candidate building blocks of molecule-based electrical and magnetic functional materials.


Frequent mutations in the amino-terminal domain of BCL7A impair its tumor suppressor role in DLBCL.
Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex are frequently found in different human cancers. While the tumor suppressor function of this complex is widely established in solid tumors, its role in hematologic malignancies is largely unknown. Recurrent point mutations in BCL7A gene, encoding a subunit of the SWI/SNF complex, have been reported in diffuse large B-cell lymphoma (DLBCL), but their functional impact remains to be elucidated. Here we show that BCL7A often undergoes biallelic inactivation, including a previously unnoticed mutational hotspot in the splice donor site of intron one. The splice site mutations render a truncated BCL7A protein, lacking a portion of the amino-terminal domain. Moreover, restoration of wild-type BCL7A expression elicits a tumor suppressor-like phenotype in vitro and in vivo. In contrast, splice site mutations block the tumor suppressor function of BCL7A by preventing its binding to the SWI/SNF complex. We also show that BCL7A restoration induces transcriptomic changes in genes involved in B-cell activation. In addition, we report that SWI/SNF complex subunits harbor mutations in more than half of patients with germinal center B-cell (GCB)-DLBCL. Overall, this work demonstrates the tumor suppressor function of BCL7A in DLBCL, and highlights that the SWI/SNF complex plays a relevant role in DLBCL pathogenesis.


Indirect X-ray detectors with single-photon sensitivity.
The new generation of synchrotron light sources are pushing X-ray detectors to their limits. Very demanding conditions with unprecedented flux and higher operating energies now require high-performance X-ray detectors combining sensitivity, efficiency and scalability. Over the years, hybrid pixel detectors have supplemented indirect detectors based on scintillation, with undeniable advantages. Such detectors based on silicon are, however, rather expensive to produce and are no more satisfying in terms of X-ray stopping power when targeting energies above 20 keV. An indirect detector with single X-ray photon sensitivity therefore offers promising opportunities for applications operating over a wide range of energies and fluxes. In this work, the performances of such an approach are investigated with state-of-the-art elements: a commercial sCMOS camera with fiber-optics plate coupling and a Gd2O2S:Tb powder-based scintillator. A simple method is presented for evaluation of the single X-ray photon detection limit and single X-ray sensitivity is demonstrated with the studied detector above 20 keV. Geant4 simulations also provide insight to better define the limiting factors. Finally, guidelines are provided for future R&D in the design and assembly of an innovative detector combining advantages of direct and indirect detection schemes.


Comparison of mortality rate and septic and aseptic revisions in total hip arthroplasties for osteoarthritis and femoral neck fracture: an analysis of the German Arthroplasty Registry.
Indications for total hip arthroplasties (THA) differ from primary osteoarthritis (OA), which allows elective surgery through femoral neck fractures (FNF), which require timely surgical care. The aim of this investigation was to compare mortality and revisions in THA for primary OA and FNF. Data collection for this study was performed using the German Arthroplasty Registry (EPRD) with analysis THA for the treatment of FNF and OA. Cases were matched 1:1 according to age, sex, body mass index (BMI), cementation, and the Elixhauser score using Mahalanobis distance matching. Overall 43,436 cases of THA for the treatment of OA and FNF were analyzed in this study. Mortality was significantly increased in FNF, with 12.6% after 1 year and 36.5% after 5 years compared with 3.0% and 18.7% in OA, respectively (p < 0.0001). The proportion for septic and aseptic revisions was significantly increased in FNF (p < 0.0001). Main causes for an aseptic failure were mechanical complications (OA: 1.1%; FNF: 2.4%; p < 0.0001) and periprosthetic fractures (OA: 0.2%; FNF: 0.4%; p = 0.021). As influencing factors for male patients with septic failure (p < 0.002), increased BMI and Elixhauser comorbidity score and diagnosis of fracture (all p < 0.0001) were identified. For aseptic revision surgeries, BMI, Elixhauser score, and FNF were influencing factors (p < 0.0001), while all cemented and hybrid cemented THA were associated with a risk reduction for aseptic failure within 90 days after surgery (p < 0.0001). In femoral neck fractures treated with THA, a significant higher mortality, as well as septic and aseptic failure rate, was demonstrated compared with prosthesis for the therapy of osteoarthritis. Increased Elixhauser comorbidity score and BMI are the main influencing factors for development of septic or aseptic failure and can represent a potential approach for prevention measures. Level III, Prognostic.


Predispositions to Lymphoma: A Practical Review for Genetic Counselors.
This review provides a synopsis for genetic counselors of the major concepts of lymphoma predisposition: genomic instability, immune deficiency, inappropriate lymphoproliferation, and chronic antigen stimulation. We discuss syndromes typifying each of these mechanisms. Importantly, our review of the genetic counseling literature reveals sparse discussion of genetically-based immune-mediated lymphoma predisposition, which we address in depth here. We aim to increase awareness among genetic counselors and colleagues in oncology about familial susceptibility and facilitate critical thinking about lymphoma risk assessment. Clinical application of this knowledge is aided by recommendations for collection of personal and family history to guide risk assessment and testing. Lastly, we include a special discussion of genetic counseling issues including perceptions of the context, nature, and magnitude of lymphoma risk, as well as coping with awareness of susceptibility to lymphoma.


Naturalistic, multimethod exploratory study of sleep duration and quality as predictors of dysregulated eating in youth with overweight and obesity.
Although poor sleep has been found to adversely impact eating and weight regulation in youth, past research is limited by retrospective reporting and/or non-naturalistic designs. We investigated the feasibility of combining three momentary, ecologically valid approaches to assessing sleep and eating behavior, and associations between these constructs, among youth (aged 8-14y) with overweight/obesity (n = 40). Participants completed 14 overlapping days of actigraphy assessment and smartphone-based ecological momentary assessment (EMA) of eating behavior, of which 3 days also included computerized, self-guided 24-h dietary recall. Feasibility of completing measures concurrently was evaluated by generating frequencies of compliance. Associations between sleep indices and next-day eating behavior were examined via generalized estimating equations. Of 29 participants who provided EMA and 24-h recall data that aligned with previous night actigraphy data, both EMA and sleep data were available on an average of 8.6 out of 14 possible days, and both 24-h recall and sleep data on an average of 2.7 out of 3 possible days. Each additional hour of sleep was associated with consuming fewer calories from solid fats, alcohol, and added sugars (b = 0.70; p = .04). Combining naturalistic, momentary assessments of sleep and eating behavior appears to be acceptable in youth. Larger experimental studies are needed to further understand associations between sleep parameters and eating behavior.


Magnesium Ion-Driven Folding and Conformational Switching Kinetics of Tetracycline Binding Aptamer: Implications for in vivo Riboswitch Engineering.
Engineering in vitro selected RNA aptamers into in vivo functional riboswitches represents a long-standing challenge in molecular biology. The highly specific aptamer domain of the riboswitch undergoes a conformational adjustment in response to ligand sensing, which in turn exerts the regulatory function. Besides essential factors like structural complexity and ligand binding kinetics, the active role of magnesium ions in stabilizing RNA tertiary structures and assisting in ligand binding can be a vital criterion. We present spectroscopic studies on the magnesium ion-driven folding of the Tetracycline binding aptamer. Using fluorescent labels, the aptamer pre-folding and subsequent ligand binding is monitored by magnesium titration experiments and time-resolved stopped-flow measurements. A minimum concentration of 0.5 mM magnesium is required to fold into a magnesium ion-stabilized binding-competent state with a preformed binding pocket. Tetracycline binding causes a pronounced conformational change that results in the establishment of the triple helix core motif, and that further propagates towards the closing stem. By a dynamic acquisition of magnesium ions, a kink motif is formed at the intersection of the triple helix and closing stem regions. This ultimately entails a stabilization of the closing stem which is discussed as a key element in the regulatory function of the Tetracycline aptamer.


The influence of snow on lynx and coyote movements: does morphology affect behavior?
We studied sympatric lynx (Lynx canadensis) and coyotes (Canis latrans) to assess how morphological disadvantages to locomotion over snow affected movement patterns. Both species are of similar size and mass, but the feet of lynx are much larger, and coyotes were found to have 4.1-8.8 times the foot-load (ratio of body mass to foot area) of lynx. This resulted in greater mean sinking depths of coyote limbs, although the magnitude of the difference was less than that in foot-load. Coyotes exhibited stronger use of behavioral patterns that reduced negative effects of snow on movements. Coyotes were most abundant at low elevations where snow was shallow, whereas lynx were mostly at higher elevations. Coyotes also used areas at both elevations where snow was shallower than average, while lynx used areas where snow was deeper. further, both species used travel routes where snow was shallower than it was near the track. Coyotes traveled on harder snow and used trails more frequently, thereby tending to reduce sinking depths to those similar to lynx. The behavioral repertoire of coyotes reduced the morphological advantage of large feet possessed by lynx; however, overall sinking depths were still greater in coyotes. Snowshoe hares (Lepus americanus) were the main prey of both species, and their foot-load was less than that of either predator. Hare kills by coyotes occurred after fewer bounds than did those by lynx, and the large difference between foot-loads of both species of predators may have forced coyotes to ambush rather than chase hares, as did lynx.


Optimization of EDX performance in Tecnai TEMs.
The quality of X-ray spectra from FEGTEMs has been improved by three different means: the use of beryllium shields, improved collimation and improved specimen holder geometry. The improvements lead to a significant increase in peak-to-background ratios and a reduction in spurious peaks in the EDX spectra. A double-tilt, low-background specimen holder was designed to allow EDX analysis at 0 degrees of tilt without shadowing.


Antihypertensive, antioxidant, antidyslipidemic and endothelial modulating activities of a polyherbal formulation (POL-10).
The present investigation was aimed at providing the pharmacological basis for the medicinal use of a polyherbal formulation (POL-10) in hypertension and dyslipidemia. In spontaneously hypertensive rats, POL-10 significantly (p<0.05) reduced blood pressure to 183.2+/-2.97 vs 198.1+/-5.2 mmHg (Mean+/-S.E.M; n=7-10), improved endothelial dysfunction (p<0.01) by increasing acetylcholine-induced relaxation up to 46.0+/-6.7% vs 24.6+/-3.8% (n=5-10) and decreased serum triglycerides (TG) to 54.5+/-3.3 vs. 93.84+/-5.7 mg/dl (p<0.001). In high fat diet-induced hypercholesterolemia, POL-10 caused reduction in total cholesterol (TC), low density lipoproteins (LDL) levels and the atherogic index (TC-HDL/HDL). It decreased TG levels in tyloxapol-induced hyperlipidemia and increased high-density lipoprotein cholesterol (HDL-C) and reduced atherogenic index in normotensive rats. It exhibited strong antioxidant activity in different in vitro assays. In isolated smooth muscle preparation, POL-10 exhibited calcium channel blocking (CCB) activity by inhibition of high K(+)- induced contractions and rightward shift of Ca(++) concentration-response curves similar to that of verapamil. In conclusion, these findings rationalize the medicinal use of POL-10 in cardiovascular disorders which are mediated through multiple pathways such as, antioxidant, CCB, inhibition of lipid biosynthesis and absorption.


Translation and validation of the Korean version of the Sarcopenia Quality of Life (SarQoL-K®) questionnaire and applicability with the SARC-F screening tool.
The purpose of this paper was to translate and validate into the Korea language and setting the Sarcopenia Quality of Life (SarQoL®) questionnaire. The participants consisted of 450 individuals in Namgaram-2 cohort who were followed up in 2019-2020. The study participants were divided into four groups: (1) SARC-F < 4, (2) SARC-F ≥ 4 and robust grip strength, (3) SARC-F ≥ 4, low grip strength, robust muscle mass, (4) SARC-F ≥ 4, low grip strength, and low muscle mass. To assess construct validity, population with sarcopenia-associated symptoms (SARC-F ≥ 4) apart from the Korean SarQoL (SarQoL-K®) completed the Korean versions of two generic questionnaires, the Short Form-36 and the EuroQoL 5-dimension. To validate the Korean SarQoL®, we assessed its validity (discriminative power, construct validity), reliability (internal consistency, test-retest reliability), and floor/ceiling effects. The SarQoL-K® questionnaire was translated without major difficulties. The mean SarQoL-K scores were 72.9 (95%, CI; 71.2-74.6) in SARC-F < 4, 54.6 (95%, CI; 50.7-58.3) in SARC-F ≥ 4 and robust grip strength, 47.0 (95%, CI; 43.8-50.1) in SARC-F ≥ 4, low grip strength, robust muscle mass, 46.6 (95%, CI; 43.0-50.1) in SARC-F ≥ 4, low grip strength, and low muscle mass. The results indicated good discriminative power across each four groups (p < 0.001), high internal consistency (Cronbach's alpha of 0.866), and excellent test-retest reliability (ICC = 0.977, 95% CI 0.975-0.979). No floor- or ceiling-effects were observed. This is the first study to confirm the reliability and validity of the Korean version of the SarQoL®. We demonstrated that the population with sarcopenia-associated symptoms (determined using the SARC-F questionnaire) has a lower quality of life.


Becker and limb-girdle muscular dystrophy associated with pituitary dwarfism.
In 1981 a report appeared of a patient with Duchenne muscular dystrophy associated with dwarfism caused by growth hormone deficiency, in whom the muscular disease was unusually benign. The authors suggested that the benign course might be related to the growth hormone deficiency and dwarfism. Other authors later supported this idea, having observed that in dystrophic mice and hamsters with congenital and experimentally induced pituitary dwarfism, respectively, pathological expressions of the dystrophy were markedly reduced. In this paper one case of Becker and one of limb-girdle dystrophy, each associated with short stature and growth hormone deficiency are described. In these cases the disease did not have a particularly benign course. It is concluded that caution is necessary, at least in certain cases, before an association between reduced muscular growth and the dystrophic process can be assumed.


The mechanical effects of femoral shaft perforation at total hip replacement.
Perforation of the femoral shaft at total hip arthroplasty is a complication which is being reported more frequently. It has been suggested that the presence of bone cement in the perforation decreases the weakening effect of the perforation, but the mechanical basis for this belief is dubious. The anatomy of perforation was studied by cadaver dissection and its mechanical consequences were assessed in two models using Pedilen, a polyurethane foam, and pig femora. It was found that cement in a hole in bone decreased the weakening effect of the hole to tensile stress.


Treatment of bifurcation in-stent restenotic lesions with beta radiation using strontium 90 and sequential positioning pullback technique: procedural details and clinical outcomes.
In-stent restenotic lesions have been problematic for many patients with the need for multiple repeat percutaneous coronary interventions (PCI). The need for repeat PCI has been significantly reduced in patients since the advent of vascular brachytherapy. In-stent restenosis resulting in bifurcation presents even more of a challenge. The use of radiation therapy for the treatment of this kind of lesion has not yet been reported. The purpose of this paper is to present five cases of radiation therapy in bifurcation in-stent restenotic lesions using the intraluminal beta radiation catheter delivery system (Beta-Cath System, Novoste Corporation, Norcross, Georgia). We reviewed the database of patients enrolled in our Compassionate Use Registry between August 1999 and April 2002. The data is reported for 5 patients who received radiation in both branches of bifurcation lesions with the Beta-Cath catheter system. The mean diameter of the vessels was 3.1 mm 0.5 mm. The dose administered was from 18.3 to 23 Gy, with an overlap of 3.3 to 10.3 mm; the hinge angle between the branches went from 43.3 to 65.4 . Angiographic follow-up was obtained at 6 months in 4 patients, with a single patient showing a focal (< 5 mm) edge lesion treated by balloon angioplasty (TVR no TLR). No aneurysms or zones of ectasia were noted. Beta radiation with the Beta-Cath catheter system appears to be safe, secure and clinically useful in in-stent restenotic bifurcation lesions.


Targeted insertion and reporter transgene activity at a gene safe harbor of the human blood fluke, Schistosoma mansoni.
The identification and characterization of genomic safe harbor sites (GSHs) can facilitate consistent transgene activity with minimal disruption to the host cell genome. We combined computational genome annotation and chromatin structure analysis to predict the location of four GSHs in the human blood fluke, Schistosoma mansoni, a major infectious pathogen of the tropics. A transgene was introduced via CRISPR-Cas-assisted homology-directed repair into one of the GSHs in the egg of the parasite. Gene editing efficiencies of 24% and transgene-encoded fluorescence of 75% of gene-edited schistosome eggs were observed. The approach advances functional genomics for schistosomes by providing a tractable path for generating transgenics using homology-directed, repair-catalyzed transgene insertion. We also suggest that this work will serve as a roadmap for the development of similar approaches in helminths more broadly.


Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma.
Tertiary lymphoid structures (TLSs) provide a local and critical microenvironment for generating anti-tumor cellular and humoral immune responses. TLSs are associated with improved clinical outcomes in most solid tumors investigated to date. However, their role in hepatocellular carcinoma (HCC) is debated, as they have recently been shown to promote the growth of malignant hepatocyte progenitors in the non-tumoral liver. We aimed to determine, by pathological review, the prognostic significance of both intra-tumoral and non-tumoral TLSs in a series of 273 patients with HCC treated by surgical resection in Henri Mondor University Hospital. Findings were further validated by gene expression profiling using a public data set (LCI cohort). TLSs were identified in 47% of the tumors, by pathological review, with lymphoid aggregates, primary and secondary follicles in 26%, 16% and 5% of the cases, respectively. Univariate and multivariate analyses showed that intra-tumoral TLSs significantly correlated with a lower risk of early relapse (<2 years after surgery, hazard ratio 0.46, p = 0.005). Interestingly, the risk of recurrence was also related to the degree of TLS maturation (primary or secondary follicles vs. lymphoid aggregates, p = 0.01). A gene expression signature associated with the presence of intra-tumoral TLS was also independently associated with a lower risk of early relapse in the LCI cohort. No association between the density of TLSs located in the adjacent non-tumoral liver and early or late recurrence was observed. We have shown that intra-tumoral TLSs are associated with a lower risk of early relapse in 2 independent cohorts of patients with HCC treated by surgical resection. Thus, intra-tumoral TLSs may reflect the existence of ongoing, effective anti-tumor immunity. Tertiary lymphoid structures provide a critical microenvironment for generating anti-tumor immune responses, and are associated with improved clinical outcome in most cancers investigated. Their role in hepatocellular carcinoma is however debated. We show in the present study that intra-tumoral tertiary lymphoid structures are associated with a low risk of early relapse after surgical resection, suggesting that they reflect the existence of in situ, effective anti-tumor immunity.


Radial nerve injury during double plating of a displaced intercondylar fracture.
Double-plate fixation is a popular treatment method for intercondylar humeral fractures. Ulnar nerve complications are emphasized, but radial nerve complications are rarely mentioned. We present a case of iatrogenic radial nerve palsy following open reduction and double plating of a supracondylar/intercondylar fracture of the humerus. Before surgery, only a sensory deficit in the radial nerve territory was present, but after surgery, there was a complete motor deficit of the wrist and finger extensors. On exploration, a segment of nerve was found crushed within the reduced lateral condyle fracture site, with a screw from the posteroradial plate going through the nerve. Although rare, radial nerve injury can occur with posteriorly displaced supracondylar/intercondylar humerus fractures. When preoperative signs of radial nerve injury are present, we recommend that the radial nerve be identified and protected during double-plate fixation.


Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.
Statins have been widely prescribed to treat hyperlipidemia, and can be used for primary and secondary prevention of cardiovascular diseases. Several studies have shown that statins have antiinflammatory effects in addition to cholesterol-lowering properties. There is new evidence suggesting that statins have beneficial effects on patients with chronic obstructive pulmonary disease (COPD), which is characterized by a persistent inflammatory response. The aim of this study was to determine the association between statins and COPD by using the Taiwan National Health Insurance database. This was a nationwide population-based cohort study. A total of 6252 newly diagnosed COPD patients (median age, 64 years; 50.3% male) who received statins for hyperlipidemia treatment were identified from the 1 million sampling cohort dataset between January 2000 and December 2007. Another 12,469 newly diagnosed COPD patients (median age, 64 years; 50.3% male) who were matched for age, gender, and medication for COPD treatment, except for statin use, were enrolled as the control group. The end point of the study was hospitalization due to COPD. During an average of 4.58 (2.36) years' follow-up period, there were 1832 patients who experienced hospitalization for COPD exacerbation (statin vs control = 508 [8.1%] vs 1324 [10.6%]; P = 0.001). Statin use was independently associated with the decreased risk of COPD hospitalization (hazard ratio, 0.66; 95% CI, 0.60-0.74; P < 0.001). In the selected Taiwanese population, statins were associated with reduced hospitalization due to COPD in patients newly diagnosed with COPD, suggesting a potential beneficial effect of statins in patients with COPD.


Acute effects of troglitazone on in vivo insulin action in normal rats.
Troglitazone is a newly developed antidiabetic agent that shows hypoglycemic effects in insulin-resistant animal models and non-insulin-dependent diabetic humans. To determine whether this drug could affect in vivo insulin action acutely, insulin-stimulated glucose utilization was measured with the euglycemic glucose clamp technique before, during, and after troglitazone infusion (20 micrograms/min) in normal rats. Hepatic glucose production (HGP) was measured with a tracer-dilution technique (D-[3-3H]-glucose). At 18-pmol/kg/min insulin infusion rate, steady-state glucose disposal rate (GDR) was significantly increased during troglitazone infusion versus control vehicle infusion (162 +/- 6.1 v 142.3 +/- 4.4 mumol/kg/min, P < .02). The glucose infusion rate (GIR) required to maintain euglycemia increased shortly (10 to 20 minutes) after initiation of troglitazone infusion and was significantly greater until 30 minutes after cessation of the drug versus the vehicle infusion. At 9-pmol/kg/min insulin infusion rate, HGP was significantly decreased during troglitazone infusion as compared with control vehicle infusion (21.7 +/- 3.5 v 39.5 +/- 3.7 mumol/kg/min, P < .02). These results indicate that troglitazone can acutely increase in vivo insulin action in normal rats, and some possible mechanisms are discussed.


Development of a model for predicting reaction rate constants of organic chemicals with ozone at different temperatures.
To assess the persistence and fate of volatile organic compounds in the troposphere, the rate constants for the reaction with ozone (kO3) are needed. As kO3 values are only available for hundreds of compounds, and experimental determination of kO3 is costly and time-consuming, it is of importance to develop predictive models on kO3. In this study, a total of 379 logkO3 values at different temperatures were used to develop and validate a model for the prediction of kO3, based on quantum chemical descriptors, Dragon descriptors and structural fragments. Molecular descriptors were screened by stepwise multiple linear regression, and the model was constructed by partial least-squares regression. The cross validation coefficient QCUM(2) of the model is 0.836, and the external validation coefficient Qext(2) is 0.811, indicating that the model has high robustness and good predictive performance. The most significant descriptor explaining logkO3 is the BELm2 descriptor with connectivity information weighted atomic masses. kO3 increases with increasing BELm2, and decreases with increasing ionization potential. The applicability domain of the proposed model was visualized by the Williams plot. The developed model can be used to predict kO3 at different temperatures for a wide range of organic chemicals, including alkenes, cycloalkenes, haloalkenes, alkynes, oxygen-containing compounds, nitrogen-containing compounds (except primary amines) and aromatic compounds.


Dynamical ventral tegmental area circuit mechanisms of alcohol-dependent dopamine release.
A large body of data has identified numerous molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms interact to result in dysregulated dopamine (DA) release under the influence of alcohol in vivo remains unclear. In this manuscript, we delineate potential circuit-level mechanisms responsible for EtOH-dependent dysregulation of DA release from the ventral tegmental area (VTA) into its projection areas. For this purpose, we constructed a circuit model of the VTA that integrates realistic Glutamatergic (Glu) inputs and reproduces DA release observed experimentally. We modelled the concentration-dependent effects of EtOH on its principal VTA targets. We calibrated the model to reproduce the inverted U-shape dose dependence of DA neuron activity on EtOH concentration. The model suggests a primary role of EtOH-induced boost in the Ih and AMPA currents in the DA firing-rate/bursting increase. This is counteracted by potentiated GABA transmission that decreases DA neuron activity at higher EtOH concentrations. Thus, the model connects well-established in vitro pharmacological EtOH targets with its in vivo influence on neuronal activity. Furthermore, we predict that increases in VTA activity produced by moderate EtOH doses require partial synchrony and relatively low rates of the Glu afferents. We propose that the increased frequency of transient (phasic) DA peaks evoked by EtOH results from synchronous population bursts in VTA DA neurons. Our model predicts that the impact of acute ETOH on dopamine release is critically shaped by the structure of the cortical inputs to the VTA.


Densitometric study of developing vertebral bodies.
To define the quantitative aspects of ossification of human fetal spine, we performed a high resolution densitometric study by lateral and postero-anterior scanning of five fetal spines (18-36 weeks of conceptual age) and one spine of a 4-month-old infant. The data were plotted against developmental age for each spine and vertebra. Bone mineral content increased with developmental age, with a peak at the upper lumbar level, in agreement with the ossification pattern of the spine, reported in embryological literature. Bone mineral density (BMD) was unrelated to developmental age, and showed similar trends for each vertebra in all the vertebral columns examined. The changes of BMD seems to be a phenomenon related to individual variability. This study also demonstrates that densitometric techniques may provide useful and interesting information in studies on skeletal development.


Comparative analyses and structural insights of new class glutathione transferases in Cryptosporidium species.
Cryptosporidiosis, caused by protozoan parasites of the genus Cryptosporidium, is estimated to rank as a leading cause in the global burden of neglected zoonotic parasitic diseases. This diarrheal disease is the second leading cause of death in children under 5 years of age. Based on the C. parvum transcriptome data, glutathione transferase (GST) has been suggested as a drug target against this pathogen. GSTs are diverse multifunctional proteins involved in cellular defense and detoxification in organisms and help pathogens to alleviate chemical and environmental stress. In this study, we performed genome-wide data mining, identification, classification and in silico structural analysis of GSTs in fifteen Cryptosporidium species. The study revealed the presence three GSTs in each of the Cryptosporidium species analyzed in the study. Based on the percentage identity and comprehensive comparative phylogenetic analysis, we assigned Cryptosporidium species GSTs to three new GST classes, named Vega (ϑ), Gamma (γ) and Psi (ψ). The study also revealed an atypical thioredoxin-like fold in the C. parvum GST1 of the Vega class, whereas C. parvum GST2 of the Gamma class and C. melagridis GST3 of the Psi class has a typical thioredoxin-like fold in the N-terminal region. This study reports the first comparative analysis of GSTs in Cryptosporidium species.


Dose-related alterations in growth and mineral disposition by chronic oral cadmium administration in the male rat.
The effect of cadmium (1, 10, or 100 ppm) administered to male rats in drinking water for 13 weeks on body weight and mineral disposition (Cd, Mg, P and Zn) in several body tissues was examined. Most alterations observed in these parameters occurred only at the 100 ppm dose of Cd. Terminal body weight was decreased by 10% in rats ingesting Cd at 100 ppm resulting from decreased food intake since weight gain/food consumption ratio was the same for all treatment groups. In serum, cadmium ingestion resulted in an inhibition of alkaline phosphatase activity at all concentrations and phosphorous was elevated only in animals receiving 100 ppm Cd. No changes were observed in Ca in urea. In bone, Cd decreased zinc content, increased Ca content, but did not influence bone ash, Mg or P and roentgenographic examination revealed no bone abnormalities. In both liver and kidney, cadmium ingestion did not influence intestinal absorption of Ca, Mg, P, or Zn or the renal excretion of Ca, P, or urea. The results of this study indicate that alterations in body weight and tissue mineral disposition resulting from chronic Cd ingestion are dose-related.


Risk factors for carbapenem-resistant Gram-negative bacteremia in intensive care unit patients.
Carbapenem-resistant (CR) Gram-negative pathogens have increased substantially. This study was performed to identify the risk factors for development of CR Gram-negative bacteremia (GNB) in intensive care unit (ICU) patients. Prospective study; risk factors for development of CR-GNB were investigated using two groups of case patients: the first group consisted of patients who acquired carbapenem susceptible (CS) GNB and the second group included patients with CR-GNB. Both case groups were compared to a shared control group defined as patients without bacteremia, hospitalized in the ICU during the same period. Eighty-five patients with CR- and 84 patients with CS-GNB were compared to 630 control patients, without bacteremia. Presence of VAP (OR 7.59, 95 % CI 4.54-12.69, p < 0.001) and additional intravascular devices (OR 3.69, 95 % CI 2.20-6.20, p < 0.001) were independently associated with CR-GNB. Presence of VAP (OR 2.93, 95 % CI 1.74-4.93, p < 0.001), presence of additional intravascular devices (OR 2.10, 95 % CI 1.23-3.60, p = 0.007) and SOFA score on ICU admission (OR 1.11, 95 % CI 1.03-1.20, p = 0.006) were independently associated with CS-GNB. The duration of exposure to carbapenems (OR 1.079, 95 % CI 1.022-1.139, p = 0.006) and colistin (OR 1.113, 95 % CI 1.046-1.184, p = 0.001) were independent risk factors for acquisition of CR-GNB. When the source of bacteremia was other than VAP, previous administration of carbapenems was the only factor related with the development of CR-GNB (OR 1.086, 95 % CI 1.003-1.177, p = 0.042). Among ICU patients, VAP development and the presence of additional intravascular devices were the major risk factors for CR-GNB. In the absence of VAP, prior use of carbapenems was the only factor independently related to carbapenem resistance.


Dietary L-tryptophan modulates agonistic behavior and brain serotonin in male dyadic contests of a cichlid fish.
Although some studies have investigated the effects of dietary L-tryptophan on agonistic behavior, research on adult fish specimens is still lacking. Moreover, submissive behaviors have been generally overlooked. We focused on agonistic behavior between males of the cichlid fish Cichlasoma dimerus, in dyadic encounters held in a novel context after being fed or not with an L-tryptophan enriched diet (TRP) for 2 weeks. We arranged three different dyads: control/control (control conditions: not TRP enriched), control/TRP, and TRP/TRP. We also registered the response of the brain serotonergic system in four brain regions. TRP/TRP dyads showed higher latencies to first attack, lower overall aggression, and lower proportions of bites and passive copings (submissive display) compared to control/control. TRP dominant males performed fewer bites with respect to controls, and subordinate males opposed to TRP males showed fewer passive copings. Higher serotonergic activities were found in subordinates' optic tectum and in the telencephalon and preoptic area/hypothalamus of TRP males. Altogether, results point out that dietary L-tryptophan reduced males' motivation to attack and dominant aggression, which consequently influenced subordinate agonistic repertory. In addition, males within TRP/TRP dyads showed a switch in their behavioral agonistic repertory. These behavioral outcomes were probably due to modifications at brain serotonergic functioning.


Antiemetics: american society of clinical oncology clinical practice guideline update.
ASCO's update to its antiemetics guideline now includes an evaluation of evidence on complementary antiemetic therapy.


Esterase D enhances type I interferon signal transduction to suppress foot-and-mouth disease virus replication.
The enzymatic activities of esterase D (ESD) are involved in many human diseases. However, no antiviral property of ESD has been described to date. Foot-and-mouth disease virus (FMDV) is the etiological agent of foot-and-mouth disease. In this study, we showed that FMDV infection triggered ESD expression. Overexpression of ESD significantly suppressed FMDV replication and knockdown of ESD expression enhanced virus replication, showing an essential antiviral role of ESD. Furthermore, we found that Sendai-virus-induced interferon (IFN) signaling was enhanced by upregulation of ESD, and ESD promoted activation of the IFN-β promoter simulated by IFN regulatory factor (IRF)3 or its upstream molecules (retinoic acid-inducible gene-I, melanoma differentiation-associated protein 5, virus-induced signaling adaptor and TANK binding kinase 1). Detailed analysis revealed that ESD protein enhanced IRF3 phosphorylation during FMDV infection. Overexpression of ESD also promoted the expression of various antiviral interferon-stimulated genes (ISGs) and knockdown of ESD impaired the expression of these antiviral genes during FMDV infection. Our findings demonstrate a new mechanism evolved by ESD to enhance type I IFN signal transduction and suppress viral replication during FMDV infection.


Seizure Prophylaxis in Unruptured Aneurysm Repair: A Randomized Controlled Trial.
Prophylactic antiepileptic drugs (pAEDs) are often prescribed for seizure prophylaxis in patients undergoing surgical treatment of unruptured intracranial aneurysms (UIAs). We aimed to evaluate the benefit of pAEDs in patients undergoing surgical repair of UIAs. We randomly assigned eligible patients undergoing surgical repair of UIAs to receive levetiracetam for seven days post-operatively or standard care alone. The primary outcome was the evaluation of seizures in the perioperative period (within 4 weeks). We also evaluated seizure occurrence throughout follow-up and assessed functional outcomes using the modified Rankin scale score (mRS). 35 patients were randomized to the "no-levetiracetam" group and 41 patients were randomized to receive levetiracetam. The two study groups had similar overall baseline characteristics and the surgical complication rate was similar for both groups (p = 0.8). One patient in the "no-levetiracetam" group had a seizure in the perioperative period versus 2 patients in the group randomized to receive levetiracetam (2.9% vs 4.9%, respectively, p = 1.00). No patients in the "no-levetiracetam" group had any additional late seizures (mean follow-up of 20.4 months), but three patients in the levetiracetam group had late seizures during follow-up (mean follow-up of 19.1 months) (0% vs 7.3%, p = 0.2). mRS score of 0-2 at 90 days and at the latest follow-up were similar between the two groups (p = 1.00). Perioperative seizure prophylaxis with levetiracetam does not reduce the rate of seizures as compared to controls in patients undergoing surgical repair of UIAs.