The effects of topical application of metronidazole for treatment of chronic anal fissure: A randomized, controlled pilot study.
Chronic anal fissures (CAFs) rarely heal with conservative management. Because they are associated with strong anal sphincter tone, most treatment aim to reduce anal pressure. Although infections can cause fissures, as can traumatic injury to the anal canal, antimicrobial treatment is not recommended. In a previous study, we reported identifying a wide spectrum of pathogenic microorganisms in the bases of CAFs, anaerobic bacteria being present in half the cases. We postulated that microbial colonization delays healing of CAF and aimed to determine whether decreasing the bacterial load with topical antibacterial treatment accelerates fissure healing. We cultured fecal samples and swabs from the bases of CAFs in 103 patients. Patients in whose samples anaerobic bacteria were identified (47 patients) were then invited to participate in a prospective randomized clinical trial comparing topical metronidazole with conventional treatment. The primary endpoint was fissure healing confirmed on anoscopy. Secondary endpoints of maximum pain on defecation assessed by visual analog scale, maximum anal resting pressure, and rectal pH were recorded on entry and at 10, 21, and 28 days. The CAFs were colonized by mixtures of gram-positive/gram-negative anaerobic bacteria or gram-negative aerobic monocultures. Patients with anaerobic bacteria in their swabs who received topical metronidazole treatment experienced rapid relief of pain and anal sphincter spasm along with enhanced fissure healing (95.6 % healing rate compared with 70.8 % in the control group, p = 0.048). Topical antimicrobial treatment can be effective in patients with CAF provided the relevant microorganisms are correctly identified.


Relationship of Q angle and joint hypermobility and Q angle values in different positions.
Patellar malalignment is the most important reason for anterior knee pain. Patellar alignment is commonly determined by the measurement of the quadriceps (Q) angle. In this study, our primary aim was to investigate the Q angle difference between healthy individuals with and without joint hypermobility. The other objectives were to compare the Q angle values, which were measured in supine and upright positions, to determine hypermobility frequency among healthy males in a certain population, and to investigate the correlation between the existent skeletal deformities and Beighton score levels. Two hundred fifty-three healthy male college students were examined for hypermobility and skeletal deformities. According to the Beighton scoring system, three groups (n=20) were formed, and Q angle measurements were performed on the 60 individuals in both supine and upright positions. In the comparison of the groups, the mean Q angle values in healthy hypermobile individuals were found to be significantly higher than that of the nonhypermobile ones (p<0.05). No statistical difference was found between Q angle values in supine and upright positions (p>0.05). The frequency of joint hypermobility (Beighton score 4 or more) was found to be 29.25% in this population. No correlation was determined between existent skeletal deformities and Beighton score values (p>0.05). In conclusion, the Q angle evaluation among healthy hypermobile individuals may have a prognostic value for probable knee pathologies that may appear in the future.


Effects of acoustic trauma on dorsal cochlear nucleus neuron activity in slices.
Previous studies found increased multi-unit spontaneous activity in the dorsal cochlear nucleus (DCN) of animals that had been exposed to intense sound. Such activity may be related to tinnitus. Our study examined effects of previous exposure to intense sound on single neurons in the DCN, by measuring spontaneous activities and sensitivities to acetylcholine, an important neurotransmitter of centrifugal pathways to the cochlear nucleus, in brain slices. Spontaneous discharges were recorded extracellularly in the DCN portion of brain slices from control and intense-tone-exposed rats. Slices from exposed rats showed increased prevalence of bursting and decreased regular spontaneous activity. Since regular neurons include fusiform cells, and bursting neurons include cartwheel cells, intense tone exposure may lead to increased activity of DCN cartwheel cells and decreased activity of fusiform cells. Alternatively, the activity of some fusiform cells might change to bursting. Intense tone exposure also appeared to increase bursting neuron sensitivity to carbachol. This suggests that changes in DCN cartwheel cell spontaneous activity may reflect changes in effects of cholinergic centrifugal pathways following intense tone exposure. We conclude that acoustic trauma may lead to changes in the physiology and pharmacology of DCN neurons. These changes may be related to underlying mechanisms of central tinnitus.


Molecular Modeling, Synthesis and Biological Evaluation of N-Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents.
The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (1H and 13C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds 8 (IC50 Caco-2 = 98 µM, IC50 HCT-116 = 337 µM) and 16 (IC50 Caco-2 = 13 µM, IC50 HCT-116 = 240.2 µM). Results showed that compound 16 significantly affected the gene encoding AKT, BAD, and PI3K. The induced-fit docking (IFD) studies against PI3Kα demonstrated that the scaffold accommodates the kinase domains and forms H-bonds with significant binding residues.


Simple and rapid field tests for brucellosis in livestock.
Four simple and rapid field tests for the serodiagnosis of brucellosis in cattle, goat, sheep and swine were developed. The performance of the assays was investigated using serum samples collected in Portugal from animals originating from herds with a defined sanitary status with respect to the presence of brucellosis. The sensitivity calculated for the bovine, caprine, ovine and swine Brucella lateral flow assays based on results obtained for samples collected from animals with culture confirmed brucellosis was 90%, 100%, 90% and 73%, respectively. None of the samples from animals from herds free of brucellosis reacted in the flow assays indicating a high specificity. However, as expected, some degree of reactivity was observed when testing selected serum samples that reacted non-specific in reference tests for brucellosis.


A novel naphthalimide that selectively targets breast cancer via the arylhydrocarbon receptor pathway.
We report that the naphthalimide analogue 2-(2-aminophenyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (NAP-6) is a highly potent and selective breast cancer targeting molecule. These effects are mediated via the aryl hydrocarbon receptor (AHR) pathway and the subsequent induction of CYP1 metabolising monooxygenases in breast cancer cell line models. Indeed the triple negative breast cancer cell line MDA-MB-468 with a GI50 value of 100 nM is greater than 500-fold more sensitive to NAP-6 compared with other tumour derived cell models. Within 1 h exposure of these cells to NAP-6, CYP1A1 expression increases 25-fold, rising to 250-fold by 24 h. A smaller concurrent increase in CYP1A2 and CYP1B1 is also observed. Within 24 h these cells present with DNA damage as evident by enhanced H2AXγ expression, cell cycle checkpoint activation via increased CHK2 expression, S-phase cell cycle arrest and cell death. Specific small molecule inhibitors of the AHR and CYP1 family ameliorate these events. A positive luciferase reporter assay for NAP-6 induced XRE binding further confirms the role of the AHR in this phenomenon. Non-sensitive cell lines fail to show these biological effects. For the first time we identify 2-(2-aminophenyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione as a new AHR ligand that selectively targets breast cancer.


Major open abdominal surgery is associated with increased levels of endothelial damage and interleukin-6.
To examine changes in biomarkers of endothelial glycocalyx shedding, endothelial damage, and surgical stress following major open abdominal surgery and the correlation to postoperative morbidity. Major abdominal surgery is associated with high levels of postoperative morbidity. Two possible reasons are the surgical stress response and the impairment of the glycocalyx and endothelial cells. Further, the degree of these responses may correlate with postoperative morbidity and complications. A secondary data analysis of prospectively collected data from two cohorts of patients undergoing open liver surgery, gastrectomy, esophagectomy, or Whipple procedure (n = 112). Hemodynamics and blood samples were collected at predefined timestamps and analyzed for biomarkers of glycocalyx shedding (Syndecan-1), endothelial activation (sVEGFR1), endothelial damage (sThrombomodulin (sTM)), and surgical stress (IL6). Major abdominal surgery led to increased levels of IL6 (0 to 85 pg/mL), Syndecan-1 (17.2 to 46.4 ng/mL), and sVEGFR1 (382.8 to 526.5 pg/mL), peaking at the end of the surgery. In contrast, sTM, did not increase during surgery, but increased significantly following surgery (5.9 to 6.9 ng/mL), peaking at 18 h following the end of surgery. Patients characterized with high postoperative morbidity had higher levels of IL6 (132 vs. 78 pg/mL, p = 0.007) and sVEGFR1 (563.1 vs. 509.4 pg/mL, p = 0.045) at the end of the surgery, and of sTM (8.2 vs. 6.4 ng/mL, p = 0.038) 18 h following surgery. Major abdominal surgery leads to significantly increased levels of biomarkers of endothelial glycocalyx shedding, endothelial damage, and surgical stress, with the highest levels seen in patients developing high postoperative morbidity.


Furosemide pharmacokinetics and pharmacodynamics in renal transplantation.
Furosemide was administered intravenously to four patients who had undergone renal transplantation in the past and four creatinine clearance--matched control subjects. Both patients who had undergone renal transplant and control subjects displayed similar pharmacokinetic and pharmacodynamic behavior, as assessed by drug delivery to the urine and sodium excretion, respectively. Despite similar degrees of natriuresis, patients who had undergone renal transplantation demonstrated a clear defect in urine potassium excretion. This defect in potassium excretion was not related to altered responsiveness of the renin-angiotensin-aldosterone axis because plasma renin activity increased in a normal fashion after furosemide in both control and transplant subjects. Although the plasma aldosterone response to increases in plasma renin activity was sluggish in patients undergoing renal transplantation, normal increases in plasma aldosterone levels were achieved in both groups, suggesting that there may be an intrinsic defect in distal tubular potassium secretion that can be unmasked by furosemide.


Cost effectiveness of paclitaxel-eluting stents for patients undergoing percutaneous coronary revascularization: results from the TAXUS-IV Trial.
This study sought to compare aggregate medical care costs for patients undergoing percutaneous coronary intervention with paclitaxel-eluting stents (PES) and bare-metal stents (BMS) and to formally evaluate the incremental cost effectiveness of PES for patients undergoing single-vessel percutaneous coronary intervention. Although the cost effectiveness of SES has been studied in both clinical trials and decision-analytic models, few data exist on the cost effectiveness of alternative drug-eluting stent (DES) designs. In addition, no clinical trials have specifically examined the cost effectiveness of DES among patients managed without mandatory angiographic follow-up. We performed a prospective economic evaluation among 1,314 patients undergoing percutaneous coronary revascularization randomized to either PES (N = 662) or BMS (N = 652) in the TAXUS-IV trial. Clinical outcomes, resource use, and costs (from a societal perspective) were assessed prospectively for all patients over a 1-year follow-up period. Cost effectiveness was defined as the incremental cost per target vessel revascularization (TVR) event avoided and was analyzed separately among cohorts assigned to mandatory angiographic follow-up (n = 732) or clinical follow-up alone (n = 582). The PES reduced TVR by 12.2 events per 100 patients treated, resulting in a 1-year cost difference of 572 dollars per patient with incremental cost-effectiveness ratios of 4,678 dollars per TVR avoided and 47,798 dollars/quality-adjusted life year (QALY) gained. Among patients assigned to clinical follow-up alone, the net 1-year cost difference was 97 dollars per patient with cost-effectiveness ratios of 760 dollars per TVR event avoided and $5,105/QALY gained. In the TAXUS-IV trial, treatment with PES led to substantial reductions in the need for repeat revascularization while increasing 1-year costs only modestly. The cost-effectiveness ratio for PES in the study population compares reasonably with that for other treatments that reduce coronary restenosis, including alternative drug-eluting stent platforms.


[Sodium restriction prevents cardiovascular remodeling associated with insulin-resistance in the rat].
In the present work, the objective was to evaluate the influence of a dietary sodium restriction on cardiovascular morphology changes associated with insulin-resistance. At 8 weeks of age, rats were fed for 12 weeks a 60%-fructose diet containing a regular sodium content (0.64%) or totally lacking in sodium chloride (<0.01%). A group of rats fed a wheat starch-based diet with regular sodium content served as control group. Elevated HOMA index and plasma insulin confirm the presence of insulin-resistance in fructose-fed rats. Concomitantly, an increase in cardiac mass and in cardiac collagen (Sirius red staining) was detected without obvious change in arterial pressure or cardiac aldosterone synthase mRNA expression. In addition, cross-sectional area of the carotid artery was higher in fructose-fed rats. Production of superoxide anion, equated with dihydroethidium (DHE) staining, was enhanced in cardiac tissue of rats with insulin-resistance. Withdrawal of sodium from the fructose diet prevented all the cardiovascular effects of fructose consumption, including DHE staining. These results are in favor of the participation of oxidative stress normalization in the beneficial influence of dietary sodium deprivation on cardiovascular remodeling in this model of insulin-resistance in rats.


Efficacy and Safety of Panax notoginseng Saponins in the Treatment of Adults With Ischemic Stroke in China: A Randomized Clinical Trial.
Preclinical and clinical studies have suggested the neuroprotective effect of Panax notoginseng saponins (Xuesaitong soft capsules). However, robust evidence in patients with ischemic stroke is lacking. To assess the efficacy and safety of Xuesaitong soft capsules in patients with ischemic stroke. This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 67 tertiary health centers in China from July 1, 2018, to June 30, 2020. Included patients were aged 18 to 75 years with a diagnosis of ischemic stroke and a National Institutes of Health Stroke Scale score between 4 and 15. Eligible patients were randomly assigned within 14 days after symptom onset to receive either treatment with Xuesaitong soft capsules (120 mg orally twice daily) or placebo (120 mg orally twice daily) for 3 months. The primary outcome was functional independence at 3 months, defined as a modified Rankin Scale score of 0 to 2. Among 3072 eligible patients with ischemic stroke who were randomized, 2966 (96.5%) were included in the modified intention-to-treat cohort (median [IQR] age, 62 [55-68] years; 1982 male [66.8%]). The number of patients who achieved functional independence at 3 months was 1328 (89.3%) in the Xuesaitong group and 1218 (82.4%) in the control group (odds ratio, 1.95; 95% CI, 1.56-2.44; P < .001). In the safety cohort, serious adverse events occurred in 15 of 1488 patients (1.0%) in the Xuesaitong group and 16 of 1482 (1.1%) in the control group (P = .85). In this randomized clinical trial, Xuesaitong soft capsules significantly increased the likelihood of functional independence at 3 months in patients with ischemic stroke, indicating that this may be a safe and effective alternative therapy to improve prognosis in this population. Chinese Clinical Trial Registry Identifier: ChiCTR1800016363.


Methodology for detecting swallowing sounds.
The use of cervical auscultation in the evaluation of the pharyngeal swallow may become a part of the clinical evaluation of dysphagic patients. Though its use is based on subjective evaluation, an acoustic analysis of swallowing sounds might establish more objective criteria in the detection of swallowing disorders. The present study sought to investigate three aspects of the methodology for detecting swallowing sounds: (1) the type of acoustic detector unit suited to an acoustic analysis of the pharyngeal swallow, (2) the type of adhesive suited for the attachment of the detector, and (3) the optimal site for sound detection of the pharyngeal swallow. An accelerometer with double-sided paper tape was selected as the appropriate detector unit because of its wide range of frequency response and small attenuation level. Using this detector unit, swallowing sounds and noise associated with simulated laryngeal elevation and the carotid pulse were acquired at 24 sites on the neck in 14 normal subjects; these signals were acoustically analyzed. The determination of the optimal site for detecting swallowing sounds was based on the signal-to-noise ratio. The site over the lateral border of the trachea immediately inferior to the cricoid cartilage is the optimal site for detection of swallowing sounds because this site showed the greatest signal-to-noise ratio with the smallest variance. The site over the center of the cricoid cartilage and the midpoint between the site over the center of the cricoid cartilage and the site immediately superior to the jugular notch were also considered to be the most appropriate sites.


Chronic pain: illusion or pathology? A case report of a vascular leiomyoma in the leg.
Patients with chronic pain constitute a major problem for the surgeon as the cause of their pain is often difficult to diagnose and is only rarely a well circumscribed lesion which is amenable to surgical or other treatment. We report a case of chronic pain due to a vascular leiomyoma beneath the deep fascia of the leg. Angioleiomyomas are rare tumours that are usually found in the subcutaneous tissue.


The role of Trp-82 in the folding of intestinal fatty acid binding protein.
Multiple phases have been observed during the folding and unfolding of intestinal fatty acid binding protein (WT-IFABP) by stopped-flow fluorescence. Site-directed mutagenesis has been used to examine the role of each of the two tryptophans of this protein in these processes. The unfolding and refolding kinetics of the mutant protein containing only tryptophan 82 (W6Y-IFABP) showed that the tryptophan at this location was critical to the fluorescence signal changes observed throughout the unfolding reaction and early in the refolding reaction. However, the kinetic patterns of the mutant protein containing only tryptophan 6 (W82Y-IFABP) indicated that the tryptophan at this location participated in the fluorescence signal changes observed early in the unfolding reaction and late in the refolding reaction. Together, these data suggest that native-like structure was formed first in the vicinity of tryptophan 82, near the center of the hydrophobic core of this beta-sheet protein, prior to formation of native-like structure in the periphery of the protein.


Potent inhibitors of farnesyltransferase and geranylgeranyltransferase-I.
Compound 1 has been shown to be a dual prenylation inhibitor with FPTase (IC50=2 nM) and GGPTase-I (IC50=95 nM). Analogues of 1, which replaced the cyanophenyl group with various biaryls, led to the discovery of highly potent dual FPTase/GGPTase-I inhibitors. 4-trifluoromethylphenyl, trifluoropentynyl, and trifluoropentyl were identified as good p-cyano replacements.


Secretion of antileucoprotease from a human lung tumor cell line.
Two human tumor cell lines were analyzed for the production of human antileucoprotease (ALP). One of them, a human squamous lung carcinoma cell line (HS-24) synthesized, as confirmed by Western blot analysis, high amounts of ALP in serum-free medium. The supernatant inhibited elastase, chymotrypsin and trypsin. Northern blot analysis with an 18-mer radiolabelled oligonucleotide, derived from an ALP specific cDNA clone, revealed a specific mRNA of about 700-800 nucleotides in HS-24 tumor cells. In contrast, a secondary human lung tumor cell line (SB-3), derived from the adrenal cortex, did not synthesize ALP when assayed under identical conditions. The supernatant inhibited only trypsin and chymotrypsin.


Longitudinal assessment of parotid function in patients receiving tomotherapy for head-and-neck cancer.
Conventional radiotherapy is associated with high doses to the salivary glands which causes xerostomia and adverse effects on quality of life. The study aims to investigate the potential of helical tomotherapy (Hi-Art Tomotherapy) to preserve parotid function in head-and-neck cancer patients. Seven consecutive patients treated with helical tomotherapy at the UZ Brussel, Belgium, were included. During planning, priority was attributed to planning target volume (PTV) coverage: > or =95% of the dose must be delivered to > or =95% of the PTV. Elective nodal regions received 54 Gy (1.8 Gy/fraction). A dose of 70.5 Gy (2.35 Gy/fraction) was prescribed to the primary tumor and pathologic lymph nodes = simultaneous integrated boost scheme. If possible, the mean parotid dose was kept below 26 Gy. Salivary gland function was assessed by technetium scintigraphy. There was a significant dose-response relationship between mean parotid dose and functional recuperation. If the mean dose was kept <31 Gy, a recuperation of 75% can be expected at 12 months. The authors equally observed a significant correlation between salivary excretion (SE) and the percentage of parotid gland receiving a dose <26 Gy (V26%). In order to preserve 75% of SE, 46% of the parotid volume should receive a dose <26 Gy. With the use of heLical tomography the parotid gland function can largely be preserved since the mean dose to the entire gland as well as glandular volume receiving >26 Gy can be reduced.


Bioconversion of municipal solid waste into bio-based products: A review on valorisation and sustainable approach for circular bioeconomy.
Municipal solid waste management is one of the major issues throughout the world. Inappropriate management of municipal solid waste (MSW) can pose a major hazard. Anaerobic processing of MSW followed by methane and biogas generation is one of the numerous sustainable energy source options. Compared with other technologies applicable for the treatment of MSW, factors like economic aspects, energy savings, and ecological advantages make anaerobic processing an attractive choice. This review discusses the framework for evaluating conversion of municipal solid waste to energy and waste derived bioeconomy in order to address the sustainable development goals. Further, this review will provide an innovative work foundation to improve the accuracy of structuring, quality control, and pre-treatment for the ideal treatment of different segments of MSW to achieve a sustainable circular bioeconomy. The increasing advancements in three essential conversion pathways, in particular the thermochemical, biochemical, and physiochemical conversion methods, are assessed. Generation of wastes should be limited and resource utilization must be minimised to make total progress in a circular bioeconomy.


Exploring the impact of temporal heat stress on skeletal muscle hypertrophy in bovine myocytes.
The primary aim of this investigation was to explore the impact of different temporal stress conditions on the regulators associated with skeletal muscle hypertrophy in bovine myocytes. Bovine satellite cells (BSCs) were extracted from three-month-old Holstein bull calves and subjected to myogenic differentiation under three thermal treatments: 38 °C (control; CON), 39.5 °C (moderate heat stress; MHS), and 41 °C (extreme heat stress; EHS) for a duration of 3 or 48 h. Exposure to EHS resulted in elevated (P < 0.01) expression levels of heat shock protein (HSP)20, HSP27, HSP70, and HSP90, along with increased (P < 0.01) protein levels. Moreover, cells exposed to MHS and EHS exhibited enhanced (P < 0.01) gene expression of myoblast determination protein 1 (MyoD), while myogenin (MyoG) was overexpressed (P < 0.01) in cells exposed to EHS. These findings suggest that heat exposure can potentially induce myogenic differentiation through the modulation of myogenic regulatory factors. Furthermore, our investigations revealed that exposure to EHS upregulated (P < 0.01) myosin heavy chain (MHC) I expression, whereas MHC IIA (P < 0.01) and IIX (P < 0.01) expression were increased; P < 0.01) under MHS conditions. These observations suggest that the temperature of the muscle may alter the proportion of muscle fiber types. Additionally, our data indicated that EHS activated (P < 0.01) the expression of insulin-like growth factor 1 (IGF-1) and triggered the activation of the Akt/mTOR/S6KB1 pathway, a known anabolic pathway associated with cellular protein synthesis. Consequently, these altered signaling pathways contributed to enhanced protein synthesis and increased myotube size. Overall, the results obtained from our current study revealed that extreme heat exposure (41 °C) may promote skeletal muscle hypertrophy by regulating myogenic regulatory factors and IGF-1-mediated mTOR pathway in bovine myocytes.


Risk factors, diagnosis and management of venous thromboembolic disease in pregnancy.
Venous thromboembolism (VTE) in pregnancy is a leading cause of maternal morbidity and mortality. However, despite the significant associated clinical burden and potentially devastating societal impact, there is still a paucity of data surrounding its prevention and management. Consequently, international guideline recommendations vary widely. Exclusion of pregnant women from clinical trials in the past has contributed to knowledge gaps. However, recently published and ongoing studies demonstrate that excellent clinical trials in pregnancy are achievable. This review will discuss prevention, diagnosis and treatment of VTE in pregnancy, and will also explore priorities for future research. To gain an understanding of current knowledge on risk factors for pregnancy-associated venous thromboembolism (PA-VTE).To gain an understanding of the diagnosis of PA-VTE.To review up-to-date approaches to preventing and treating PA-VTE.To discuss possible limitations in current research and areas which require improvement.


Attachment of mitochondria to intermediate filaments in adrenal cells: relevance to the regulation of steroid synthesis.
The rate of steroid synthesis is regulated by the rate of transport of cholesterol from lipid droplets to mitochondria. We have previously demonstrated that lipid droplets in adrenal cells are tightly attached to intermediate filaments. Here we now show that mitochondria colocalize with intermediate filaments in modified double indirect immunofluorescence and by electron microscopy of extracted adrenal cells. Direct contact between mitochondria and intermediate filaments was established by examination of stereo pairs of electron micrographs from extracted cells. The attachment of both droplets and mitochondria to intermediate filaments suggests possible mechanisms for this form of intracellular transport of cholesterol to mitochondria and hence for the regulation of steroid synthesis.


An unusual suspect: coconut bezoar after laparoscopic Roux-en-Y gastric bypass.
Nausea and vomiting after gastric bypass are common, but some of the underlying causes may be life threatening or, in some cases, unusual. This case report describes a patient who underwent laparoscopic Roux-en-Y gastric bypass and whose postoperative course was complicated by a bezoar in the gastric pouch. To our knowledge, this is the first published report addressing a coconut bezoar in the gastric pouch after gastric bypass surgery. Coconut (cocos nucifera) is known to form emulsions and suspensions, properties likely to have contributed to this patient's condition. Nutritional counseling should be an ongoing process in the postoperative care of gastric bypass patients in an effort to prevent serious complications that may arise from dietary indiscretions.


Treatable Traits in Misdiagnosed Chronic Obstructive Pulmonary Disease: Data from the Akershus Cardiac Examination 1950 Study.
Chronic obstructive pulmonary disease (COPD) is often misdiagnosed. We aimed to estimate the prevalence of misdiagnosed COPD in middle-aged Norwegians, and to assess potentially treatable clinical traits in over- and undiagnosed individuals. The Akershus Cardiac Examination (ACE) 1950 Study is a population-based study of the 1950 birth cohort of Akershus county including 3706 participants aged 62-65 years at baseline. COPD was defined as a forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio < lower limit of normal (LLN). Misdiagnosed COPD was defined according to self-reported COPD. A total of 259 (7.1%) participants had spirometry confirmed COPD. Of these, only 72 (28%) reported having COPD, thus 187 (72%) were undiagnosed. A total of 92 (2.5%) of the 164 particpants who reported having COPD had an FEV1/FVC ratio ≥ LLN and were overdiagnosed. They had lower lung function, and more respiratory symptoms, self-reported asthma, eosinophils, and sleep apnea than other non-COPD participants . The main predictor of being overdiagnosed was overweight. Spirometry in participants reporting wheezing or cough and current smokers or participants with ≥20 tobacco pack-year history would have identified 85% of the undiagnosed cases. Both over- and underdiagnosis of COPD is frequent. Undiagnosed individuals have better lung function and less symptoms, but similar prevalence of comorbidities and systemic inflammation. Overdiagnosed individuals have treatable traits including asthma, eosinophilic inflammation, and sleep apnea. The main predictor of being overdiagnosed was being overweight.


Detection of Mycobacterium tuberculosis Rifampicin Resistance Conferred by Borderline rpoB Mutations: Xpert MTB/RIF is Superior to Phenotypic Drug Susceptibility Testing.
To compare the ability of detection of borderline rifampicin resistance in Mycobacterium tuberculosis between molecular assay and phenotypic drug susceptibility tests. Fifty-seven isolates with His445Leu, Asp435Tyr, Leu452Pro, Leu430Pro, His445Asn, Ile491Phe, and His445Ser mutations in rpoB gene identified by whole-genome sequencing conferring borderline rifampicin resistance were included. Molecular-based Xpert MTB/RIF, phenotypic Löwenstein-Jensen (L-J) medium-based drug susceptibility test (DST) with a critical concentration of 40.0μg/mL and minimal inhibitory concentration (MIC) assay were performed to detect borderline rifampicin resistance. When using Xpert MTB/RIF, 48/57 (84.2%) isolates exhibited resistance to rifampicin. 25/57 (43.9%) and 33/57 (57.9%) isolates showed rifampicin resistance by L-J medium-based DST with 4 and 6 weeks of incubation, respectively. 30/57 (52.6%) and 40/57 (70.2%) strains were resistant to rifampicin by MIC method at cutoff values of 1.0 and 0.5μg/mL, respectively. The detection rate of rifampicin resistance of Xpert MTB/RIF was significantly higher than that of phenotypic methods (p < 0.001). Of the 57 isolates with borderline rpoB mutations, 5 (8.8%) had MICs of 0.25 or 0.12μg/mL, 22 (38.6%) had MICs of 0.5μg/mL or 1.0μg/mL, and 30 (52.6%) other isolates showed MICs ≥2.0μg/mL. Molecular-based Xpert MTB/RIF showed superior ability to detect borderline rifampicin resistance over phenotypic DST methods. Extending the incubation time of L-J DST or lowering the cutoff value of the MIC method can improve borderline rifampicin resistance detection.


Impact of time to surgery in the outcome of patients with liver resection for BCLC 0-A stage hepatocellular carcinoma.
The Barcelona Clinic Liver Cancer (BCLC) guidelines recommend resection for very early and early single hepatocellular carcinoma (HCC) patients. It is not known whether a delay in resection from the time of diagnosis (the time to surgery [TTS], i.e. the elapsed time from diagnosis to surgery) affects outcomes. We aim to evaluate the impact of TTS on recurrence and survival outcomes in patients with HCC. All patients resected for BCLC stage 0-A single HCC from 2006 to 2016 were studied to evaluate the impact of TTS on recurrence rate, recurrence-free survival (RFS), transplantability following recurrence, and intention-to-treat overall survival (ITT-OS). Propensity score matching (PSM) was further performed to ensure comparability. The study population included 100 patients. Surgery was performed between 0.6 and 77 months after diagnosis (median TTS: three months; interquartile range: 1.8-4.6 months). There was no post-operative mortality. Compared to those with TTS <3 months, patients with TTS ≥3 months (70% of these patients had TTS 3-6 months) had a higher post-operative morbidity (36% vs. 16%, p = 0.02), a similar tumor recurrence rate (32% vs. 32%, p = 1.00), RFS (37% vs. 48%, p = 0.42), transplantability following tumor recurrence (63% vs. 50%, p = 0.48), and five-year ITT-OS (82% vs. 80%, p = 0.20). Similar results were observed after PSM. Patients with BCLC stage 0-A single HCC can undergo surgery with TTS ≥3 months without impaired oncologic outcomes. An increase in the TTS within a safe range could allow time for proper evaluation before surgery, and ethical testing of new neoadjuvant treatments, aiming to reduce the high rate of tumor recurrence despite curative resection. A delay of ≥3 months in time to resection after diagnosis in HCC patients meeting the European Association for the Study of Liver Disease/American Association for the Study of Liver Disease criteria for resection does not affect oncological and long-term outcomes compared to those with a delay to surgery of <3 months.


Pilot study to determine the interaction of oxiracetam with antiepileptic drugs.
Oxiracetam, a nootropic drug, could be of potential use in the treatment of memory disturbances in patients with epilepsy who are using antiepileptic drugs. The half-life of oxiracetam appears to be influenced by the concomitant use of carbamazepine or valproic acid, necessitating more frequent administration of oxiracetam than is recommended for other conditions. No effect was observed on the serum concentrations of these antiepileptic drugs by oxiracetam. Long term concurrent use of oxiracetam and antiepileptic agents does not appear to be contraindicated.


The risk of HIV drug resistance following implementation of pre-exposure prophylaxis.
Results of trials determining if pre-exposure prophylaxis (PrEP) with antiretroviral drugs prevents transmission of HIV are expected soon. Tenofovir and emtricitabine--currently evaluated as PrEP--are popular in treatment of HIV. Drug resistance could, therefore, be critical in the use of PrEP. We review the literature regarding risks associated with drug resistance owing to PrEP. Few studies addressed the issue of drug resistance to tenofovir and/or emtricitabine. Studies in HIV-1-infected individuals followed small numbers of patients for a short time. Studies in macaques were well designed, but used SHIV, which has an attenuated course of infection. The available information suggests that the probability of emergence of drug resistance is small. Infections that occurred despite use of PrEP had reduced peak viremia, which could reduce HIV transmissibility. Mathematical modeling suggests that, although transmitted drug resistance may under some circumstances increase, the benefits of PrEP outweigh the risks associated with resistance. Tenofovir and emtricitabine are recommended in first-line treatment. The potentially limited impact of drug resistance should, therefore, be confirmed in daily practice. Surveillance of drug resistance is recommended in areas where PrEP is used. Patients that became infected despite use of PrEP should be closely monitored for virological failure.


[Influence of length of hospital stay on mortality after discharge in older patients with acute medical diseases].
To analyse whether hospital length of stay is associated with mortality at six months after discharge in the elderly. An observational longitudinal study of patients surviving at hospital discharge. A binary logistic regression analysis was performed to study factors related to extended stay (> 12 days). The relationship between mortality at 6 months and length-of-stay quartiles was studied using a Cox regression analysis. 1180 patients were studied with a mean age of 86.6 years (standard deviation: 6.9). The median length of stay was 8 days (interquartile range: 5-12). Six-month mortality was 26.1%. After adjusting for age, gender, main diagnosis, comorbidity, albumin at admission, functional deterioration at admission and functional and mental status at discharge, hospital stay above the median was associated with mortality at 6 months: 9-12 days, HR=1.79, 95% CI: 1.01-3.14; and > 12 days, HR=2.04, 95% CI: 1.19-3.53. Prolonged hospital stay is an independent risk factor for mortality at 6 months after discharge.


Forensic imaging: The sensitivities of various imaging modalities in detecting skeletal trauma in simulated cases of child abuse using a pig model.
Physical child abuse is a major problem in South Africa and throughout the world, and the detection of skeletal trauma in victims of abuse may be critical in the accurate investigation of these cases. Since many of these fractures are not detected during traditional autopsy, the use of various diagnostic imaging tools is implemented in order to aid in the detection of trauma. In South Africa, Lodox (low-dose full-body X-ray) is commonly used in forensic mortuaries and the aim of this study was to assess the sensitivities of CT, X-ray and Lodox, in comparison to dry bone as the gold standard, in detecting both the number of fractures and minimum number of impacts in piglets subjected to blunt force trauma. Ten piglets were beaten with a mallet post-mortem in every region of the body. CT, X-ray and Lodox scans were taken of each piglet, after which the piglets were macerated in order to conduct an osteological analysis of the remains. The number of fractures and impacts present in each scan and on the dry bone were recorded. CT scans were the most sensitive in identifying trauma in all regions of the body, detecting 73% of fractures and 79% of impacts. X-ray and Lodox scans were less sensitive in detecting both fractures (50% and 42% respectively) and impacts (59% and 54% respectively). An assessment of the directionality of trauma was possible using dry bone and CT scans, but not when using X-rays or Lodox scans. CT scans can be used to assess skeletal trauma in suspected victims of child abuse, but the use of X-ray and Lodox scans is not recommended other than for initial screening procedures. Osteological analysis, however, is still considered the gold standard and should be performed whenever possible.


Influence of marinades on survival during storage of acid-adapted and nonadapted Listeria monocytogenes inoculated post-drying on beef jerky.
The objective of the present study was to investigate the survival of acid-adapted and nonadapted Listeria monocytogenes inoculated post-drying on dried beef slices (beef jerky), which were treated (24 h, 4 degrees C) with the following marinades before drying at 60 degrees C for 10 h: (1) control (C), (2) traditional marinade (TM), (3) modified marinade; double the amount of TM with added 1.2% sodium lactate, 9% acetic acid, and 68% soy sauce with 5% ethanol (MM), (4) dipping into 5% acetic acid and then TM (AATM), and (5) dipping into 1% Tween 20 and then into 5% acetic acid followed by the TM (TWTM). Dried meat slices were inoculated with acid-adapted or nonadapted L. monocytogenes (ca. 5.7 log CFU/cm(2)) prior to aerobic storage at 25 degrees C for 60 days. Survivors were determined using tryptic soy agar with 0.1% pyruvate (TSAP) and PALCAM agar. Results showed that surviving bacterial populations on TWTM, AATM, and MM treatments were significantly (P<0.05) lower than those surviving on C and TM until 42 days of storage. By the end of 60 days of storage, bacterial populations in all treatments were not different regardless of acid adaptation or recovery media, except for treatment C inoculated with nonadapted cultures, which had significantly higher TSAP counts than other treatments. There was no significant (P> or =0.05) difference in survival of previously acid-adapted and nonadapted bacterial populations in samples of TWTM, AATM, and MM treatments. However, bacterial populations that were nonadapted were significantly higher than those that were acid-adapted on products of C and TM treatments on days 60 and 24, respectively. The earliest complete elimination (enrichment negative) of the pathogen occurred by day 28 (AATM) in products inoculated with acid-adapted cultures and by day 42 (TWTM and AATM) in products inoculated with nonadapted cultures. These results indicate that use of modified marinades in jerky processing and low water activity provided antimicrobial effects against possible post-processing contamination with L. monocytogenes.


Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in neurons in the central nervous system. It has been documented that HCN channels regulate the intrinsic excitability of pyramidal cells in the medial prefrontal cortex (mPFC) of rodents. Here, we report that HCN channels limited GABAergic transmission onto pyramidal cells in rat mPFC. The pharmacological blockade of HCN channels resulted in a significant increase in the frequency of both spontaneous and miniature inhibitory postsynaptic currents (IPSCs) in mPFC pyramidal cells, whereas potentiation of HCN channels reversely decreases the frequency of mIPSCs. Furthermore, such facilitation effect on mIPSC frequency required presynaptic Ca2+ influx. Immunofluorescence staining showed that HCN channels expressed in presynaptic GABAergic terminals, as well as in both soma and neurite of parvalbumin-expressing (PV-expressing) basket cells in mPFC. The present results indicate that HCN channels in GABAergic interneurons, most likely PV-expressing basket cells, constrain inhibitory control over layer 5-6 pyramidal cells by restricting presynaptic Ca2+ entry.


Estimation of human dose of staphylococcal enterotoxin A from a large outbreak of staphylococcal food poisoning involving chocolate milk.
An outbreak of gastroenteritis in a school district in the United States was determined to be staphylococcal food poisoning due to 2% chocolate milk containing staphylococcal enterotoxin A (SEA). Twelve one-half pint (approx 0.28 l) cartons of the 2% chocolate milk from this outbreak were analyzed for the quantity of SEA present in the milk. The amount of SEA in the cartons varied from 94 to 184 ng with the average being 144 ng (mean = 139 +/- 45). The attack rate for vomiting among those who consumed more than one carton was greater (38.3%) than among those who consumed only one carton (31.5%) with the highest attack rate among those who consumed three or more cartons (44.4%).


Heparin adsorption on activated charcoal.
By vitro studies have shown that sodium heparin adsorbs significantly at pH 7.4 conditions onto a typical activated charcoal. These results imply that enhanced heparin removal from blood should be anticipated in hemoperfusion systems that utilize uncoated charcoals.


Predicting allergic contact dermatitis: a hierarchical structure-activity relationship (SAR) approach to chemical classification using topological and quantum chemical descriptors.
A hierarchical classification study was carried out based on a set of 70 chemicals-35 which produce allergic contact dermatitis (ACD) and 35 which do not. This approach was implemented using a regular ridge regression computer code, followed by conversion of regression output to binary data values. The hierarchical descriptor classes used in the modeling include topostructural (TS), topochemical (TC), and quantum chemical (QC), all of which are based solely on chemical structure. The concordance, sensitivity, and specificity are reported. The model based on the TC descriptors was found to be the best, while the TS model was extremely poor.


Prognostic value of hypocholesterolemia in patients with gastric cancer.
According to previous studies, low serum total cholesterol (TC) is associated with higher cancer incidence and mortality. However, the prognostic implications of preoperative TC in patients with gastric cancer (GC) remain to be determined. A total of 1251 patients with GC, who underwent radical gastrectomy between 2005 and 2008, were recruited. Propensity score weighting (PSW) based on a generalized boosted method (GBM) was used to control for selection bias. After balancing the preoperative and operative covariates, low TC was associated with high incidence of complications (severe complication rate: 15.2% (Low TC) vs. 4.7% (Normal TC) vs 5.5% (High TC); p = 0.004). In multivariable analysis, lowering TC was associated with poor OS and RFS in weighted population. [OS: hazard ratio (HR) = 0.92; 95% CI = 0.867-0.980; P = 0.009 and RFS: HR = 0.93; 95% CI = 0.873-0.988; P = 0.02]. Preoperative TC is a useful predictor of postoperative survival and postoperative complications in patients with stage I-III GC and may help to identify high-risk patients for rational therapy, including nutritional support, and timely follow-up.


Tianhuang formula regulates adipocyte mitochondrial function by AMPK/MICU1 pathway in HFD/STZ-induced T2DM mice.
Tianhuang formula (THF) is a Chinese medicine prescription that is patented and clinically approved, and has been shown to improve energy metabolism, but the underlying mechanism remains poorly understood. The purpose of this study is to clarify the potential mechanisms of THF in the treatment of type 2 diabetes mellitus (T2DM). A murine model of T2DM was induced by high-fat diet (HFD) feeding combined with low-dose streptozocin (STZ) injections, and the diabetic mice were treated with THF by gavaging for consecutive 10 weeks. Fasting blood glucose (FBG), serum insulin, blood lipid, mitochondrial Ca2+ (mCa2+) levels and mitochondrial membrane potential (MMP), as well as ATP production were analyzed. The target genes and proteins expression of visceral adipose tissue (Vat) was tested by RT-PCR and western blot, respectively. The underlying mechanism of the regulating energy metabolism effect of THF was further explored in the insulin resistance model of 3T3-L1 adipocytes cultured with dexamethasone (DXM). THF restored impaired glucose tolerance and insulin resistance in diabetic mice. Serum levels of lipids were significantly decreased, as well as fasting blood glucose and insulin in THF-treated mice. THF regulated mCa2+ uptake, increased MMP and ATP content in VAT. THF increased the mRNA and protein expression of AMPK, phosphorylated AMPK (p-AMPK), MICU1, sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). THF could increase the mCa2+ level of 3T3-L1 adipocytes and regulate mitochondrial function. The protein expression of AMPK, p-AMPK, mCa2+ uniporter (MCU) and MICU1 decreased upon adding AMPK inhibitor compound C to 3T3-L1 adipocytes and the protein expression of MCU and MICU1 decreased upon adding the MCU inhibitor ruthenium red. These results demonstrated that THF ameliorated glucose and lipid metabolism disorders in T2DM mice through the improvement of AMPK/MICU1 pathway-dependent mitochondrial function in adipose tissue.


Evaluation of histological damage of solid organs after donor preconditioning with thymoglobulin in an experimental rat model.
Rabbit anti-rat thymoglobulin (rATG) administered to donors with brain death (BD) may improve organs quality. We explored the effects of rATG administered to BD donors in the histology of heart, lungs and small bowel in a rat experimental model. Animals were randomly assigned to 3 groups: V (n=5) no BD, 2h ventilation; BD (n=5) BD and 2h ventilation; BD and rATG: BD, 2h ventilation, rATG (10mg/kg) after BD diagnosis. Histopathological damage scores were based on neutrophil infiltration, airway epithelial cell damage, interstitial edema, hyaline membrane formation, and pulmonary hemorrhage (lungs); neutrophil infiltration and interstitial edema (heart); Park score (bowel). Lung damage was significantly lower in BD+rATG group: V 5 ± 1.6; BD 11.25 ± 0.5, BD+rATG 6.5 ± 1.9 (p<0.01). Heart: V 2.0 ± 0.81; BD 4.75 ± 1.25 and BD+rATG 3.5 ± 1.7 (p>0.05). Small bowel: BD 2.25 ± 0.96 vs. BD+rATG 1.00 ± 1.15 (n.s.). Histological damage amelioration in lung and attenuation tendency in heart and small bowel encourages research of cytoprotective strategies to improve organ viability.


Purification of capsid-like particles of infectious bursal disease virus (IBDV) VP2 expressed in E. coli with a metal-ion affinity membrane system.
Protein VP2, matured from the polyprotein encoded by the genome of infectious bursal disease virus (IBDV) and the primary host-protective immunogen of this virus, together with its two N-terminal truncated mutants were cloned and expressed in Escherichia coli. To obtain pure recombinant proteins for the development of an efficient subunit vaccine against IBDV infection, these three proteins were fused with six additional histidine residues at their C-termini as a His-purification-tag. Following purification employing immobilized metal-ion (Ni2+) affinity chromatography (IMAC), a purification fold of approximately 104 was achieved. Electron microscopic observation also demonstrated that all three E. coli-derived proteins form the morphology of icosahedral particles of approximately 25 nm in diameter. To reduce the cost of resin used for IMAC, self-prepared immobilized metal-ion affinity membranes (IMAM), i.e., commercial, regenerated cellulose membrane modified with iminodiacetic acid and immobilized with nickel ions, was applied to purify particles formed by these three proteins. A 104-fold of purification efficiency was also achieved by this membrane, showing that under the same conditions the recovery and purification efficiency of IMAM are comparable with those of IMAC. The pure VP2-formed particles thus obtained, coupled with their uniform dimensions, not only facilitate a better understanding of the structural biology of these immunogenic particles but also help the development of improved vaccines against this avian virus.


The cellular level of yeast ribosomal protein L25 is controlled principally by rapid degradation of excess protein.
When the gene dosage for the primary rRNA-binding ribosomal protein L25 in yeast cells was raised about 50-fold, the level of mature L25 transcripts was found to increase almost proportionally. The plasmid-derived L25 transcripts were structurally indistinguishable from their genomic counterparts, freely entered polysomes in vivo and were fully translatable in a heterologous in vitro system. Nevertheless, pulse-labelling for periods varying from 3-20 min did not reveal a significant elevation of the intracellular level of L25-protein. When pulse-times were decreased to 10-45 s, however, we did detect a substantial overproduction of L25. We conclude that, despite the strong RNA-binding capacity of the protein, accumulation of L25 is not controlled by an autogenous (pre-)mRNA-targeted mechanism similar to that operating in bacteria, but rather by extremely rapid degradation of excess protein produced.


Sialic acid is selectively involved in the interaction of agonists with M2 muscarinic acetylcholine receptors.
Neuraminidase and slight acid hydrolysis were used to investigate the role of sialic acid residues in the binding of muscarinic agonists and antagonists to membranes from tissues rich in M1 and M2 receptors. Membranes were pretreated with neuraminidase at pH 5 and the binding parameters were determined from competitive experiments with (3H)-quinuclidinylbenzylate. The removal of sialic acid residues reduced the affinity of muscarinic agonists for cerebellum, heart and lung membranes (M2), in contrast to striatum (M1). The affinity of antagonists was not affected. Thus, sialic acid is selectively involved in the interaction of agonists with M2 muscarinic receptors.


Fetal-maternal bleeding associated with genetic amniocentesis: real-time versus static ultrasound.
The incidence of fetal to maternal bleeding was studied in 773 consecutive patients having genetic amniocentesis by measuring maternal serum alpha-fetoprotein elevation following the procedure. The frequency of fetal to maternal bleeding was significantly lower in patients having amniocentesis immediately after real-time ultrasound (21 of 429 cases, 4.9%) when compared with patients having static B-mode ultrasound before the procedure (31 of 344 cases, 9.0%). A lower frequency of fetal to maternal bleeding was observed in the real-time group for anterior or partially anterior placentas (8.1%) and posterior or fundal posterior placentas (0%) when compared with the static B-mode group (12.9 and 5.2%, respectively). The rate of spontaneous abortion in patients with fetal to maternal bleeding (12.8%) was significantly higher than the rate in patients who did not demonstrate such bleeding (1.45%). The implications of these findings with regard to the safety of amniocentesis and the benefit of routine preliminary ultrasound evaluation are discussed.


Analysis of the Generation Z's Viewpoint from the Faith-Based Educational Institutions on the Toxic Positivity Phenomena: How and Why?
Toxic positivity is indicated by encouraging words spoken in difficult situations that force someone to feel good about themselves. It becomes a current issue around the Generation Z because of the realization that toxic positivity could have a negative impact on mental health and individual social relationships. This study aims to analyze the views of Generation Z on the phenomena of toxic positivity. The approach of this study was quantitative using descriptive methods.


Lymphatic treatments after orthopedic surgery or injury: A systematic review.
Orthopedic injuries in conjunction with extensive damage to tissues, bones and blood vessels, usually require a long recovery. Associated consequences are pain, movement limitations, decreased function and occasionally, prolonged edema, which can delay or interfere with the healing process. Lymphatic and compression therapy have become increasingly common, intending to reduce edema and pain, thus, promoting the recovery process. To examine the efficacy of methods commonly used to reduce edema after orthopedic injury or surgery, i.e. decongestive therapy, manual lymphatic drainage, and compression bandaging. English literature search was undertaken in January 2019, in the following databases: Cochrane Library, MEDLINE, PEDro. randomized controlled or quasi-controlled trials in adults who have edema or pain after recent limb trauma or surgery. Two independent assessors rated study quality and risk of bias using the PRISMA recommendations and PEDro score. We evaluated 71 papers. After excluding duplicated and irrelevant papers, 15 met the eligibility criteria (6 on lymphatic treatment and 9 on compression). Quality of papers ranged from 3 to 7 on PEDro score; of them, 13 were 1b Level of Evidence and two were 1c. After elective surgeries, when the significant edema appears or persists beyond recovery time, complex decongestive therapy and manual edema mobilization should be recommended in addition to conventional physical therapy. In acute injuries such as ankle or distal radius fractures, lymphatic treatments and compression bandaging should be considered as part of the therapeutic protocol. Nine studies evaluated different compression modalities found that only multilayer and long stretch compression significantly reduce edema.


Shear strength evaluation of composite-composite resin associations.
The aim of this study was to investigate the shear strength between distinct associations of different commercial composite resins and their fracture modes. Nine composite-composite associations (n=90) were prepared for shear strength evaluation and separated into the following groups: Z/Z (Filtek Z250 UD+Filtek Z250 A2); Z/D (Filtek Z250 UD+Durafill VS A2); Z/S (Filtek Z250 UD+Filtek Supreme YT); C/C (Charisma OA2+Charisma A2); C/D (Charisma OA2+Durafill VS A2); C/S (Charisma OA2+Filtek Supreme YT); H/H (Herculite XRV B2D+Herculite XRV B2E); H/D (Herculite XRV B2D+Durafill VS A2); H/S (Herculite XRV B2D+Filtek Supreme YT). Shear tests were carried out using universal mechanical test equipment with a load of 200kgf and speed of 0.5mm/min. Ultimate shear strength data (MPa) from all tested groups were submitted to analysis of variance (one-way ANOVA) and the Tukey test. The fractured surfaces of the test samples were visually evaluated by binocular stereomicroscope at 20 times magnification. Fractures were classified as either adhesive or cohesive or mixed. The highest ultimate shear strength observed for composite-composite associations was found for the groups: Z/Z, C/S, H/H, H/S, Z/S and C/C. Those associations containing the Durafill resin were weaker than the others. Microparticle RBC associations presented lower shear strength than hybrid and/or nanoparticle RBC associations, once the only significant difference was found when the Durafill resin was involved.


Automated On-Line Isolation and Fractionation Method for Subpopulations of Extracellular Vesicles.
Immunoaffinity chromatography (IAC) with selective antibodies immobilized on polymeric monolithic disk columns enables selective isolation of biomacromolecules from human plasma, while asymmetrical flow field-flow fractionation (AsFlFFF or AF4) can be used for further fractionation of relevant subpopulations of biomacromolecules (e.g., small dense low-density lipoproteins, exomeres, and exosomes) from the isolates. Here we describe how the isolation and fractionation of subpopulations of extracellular vesicles can be achieved without the presence of lipoproteins using on-line coupled IAC-AsFlFFF. With the developed methodology, it is possible to have fast, reliable, and reproducible automated isolation and fractionation of challenging biomacromolecules from human plasma with a high purity and high yields of subpopulations.


Quadrature-free immersed isogeometric analysis.
This paper presents a novel method for solving partial differential equations on three-dimensional CAD geometries by means of immersed isogeometric discretizations that do not require quadrature schemes. It relies on a newly developed technique for the evaluation of polynomial integrals over spline boundary representations that is exclusively based on analytical computations. First, through a consistent polynomial approximation step, the finite element operators of the Galerkin method are transformed into integrals involving only polynomial integrands. Then, by successive applications of the divergence theorem, those integrals over B-Reps are transformed into the first surface and then line integrals with polynomials integrands. Eventually, these line integrals are evaluated analytically with machine precision accuracy. The performance of the proposed method is demonstrated by means of numerical experiments in the context of 2D and 3D elliptic problems, retrieving optimal error convergence order in all cases. Finally, the methodology is illustrated for 3D CAD models with an industrial level of complexity.


Ureteral reimplantation: Lich method.
In utilizing the ureteral reimplantation procedure we have performed 76 reimplantations and have a 96 per cent success rate on our first operation. We review our clinical indications, material, and complications as well as our over-all results. We believe that this operation as outlined is as good or better than other previously reported types of ureteral reimplantation and has avoided some of the major hazards, including no postoperative obstruction.


Inhibitory effect of a lethal toxic fragment of staphylococcal alpha-toxin on cyclic AMP-dependent protein kinase activity.
The effect of a lethal toxic fragment of staphylococcal alpha-toxin on the activity of adenosine 3',5'-monophosphate(cyclic AMP)-dependent protein kinase was examined. 1. The lethal toxic fragment produced a dose-dependent decrease in both the binding of cyclic AMP to the regulatory subunit and phosphorylation activity of cyclic AMP-dependent protein kinase obtained from rabbit skeletal muscles up to a plateau at a 50% inhibitory effect. The decrease in the activity of protein kinase observed with low doses of the lethal toxic fragment (0.1 microM) resulted from a competitive inhibition, probably by its interaction with the cyclic AMP-binding site in the regulatory subunit molecule. 2. The effects of a lethal toxic fragment and epinephrine on the cyclic AMP level and protein kinase activity were investigated in the perfused rabbit heart slices. The lethal toxic fragment attenuated the stimulation of cyclic AMP-dependent protein kinase activity ratio by epinephrine. 3. It is suggested that the specific action of a lethal toxic fragment on the cellular membrane enzymes may be attributable to the inhibition of the cyclic AMP-dependent protein kinase activity.


Spatiotemporal convergence and divergence in the rat S1 "barrel" cortex.
The size and response magnitude of receptive fields were evaluated for cells in the rat cortical barrel-field by using standard vibrissal deflections of 1.14 degrees. Such stimuli fell within the plateau region of stimulus-response curves. The response of all neurones to all vibrissae within and surrounding centre-receptive fields were analysed for probability and latency of response. It was found that cells in supragranular layers had small centre-receptive fields (average 1.6 vibrissae) with small excitatory surrounds (1.5 vibrissae) while cells in the granular layers had small, powerful centre-receptive fields (1.4) with moderately large excitatory surrounds (2.6). Neurones in infragranular layers possessed large but weak centre-receptive fields (2.6) with large surrounds (3.5). Sixty-four neurones in layer IV were studied, the precise locations of which were identified by using dye lesioning and cytochrome oxidase staining. There were no differences in receptive field size for cells within septa and barrel hollows, but the latter were twice as likely to produce two or more spikes per stimulus from the principal vibrissa (65% against 33%). Histological analysis showed that the principal vibrissa was synonymous with the appropriate vibrissa for the barrel on 86% (55 of 64) of occasions. A quantitative analysis of convergent input to three neighbouring barrels (E1, E2, and D1) showed considerable graded overlap of receptive field surrounds, although facial hair adjacent to the mystacial pad only influenced cells on the edge of the barrel-field. Individual vibrissae exhibited significant divergent input to adjacent inappropriate barrels, being preferentially directed to distant septal rather than barrel hollow cells. An analysis of latencies showed that 40% of barrel hollow cells and 48% of barrel septal cells responded at short (less than 10 ms) latencies to their appropriate vibrissa. In contrast, responses to inappropriate vibrissae were overwhelmingly of long latency (10-greater than 30 ms), only 2% of inappropriate responses from barrel hollow cells and 13% from septal cells being of short latency. These results suggest that direct inputs largely project to appropriate barrels. The possibility that divergent inputs are generated by intracortical mechanisms is discussed.


Chlordecone alcohol formation in the Mongolian gerbil (Meriones unguiculatus): a model for human metabolism of chlordecone (kepone).
In seeking a practical animal model of chlordecone metabolism in humans, we found that among rats, hamsters, guinea pigs, or gerbils treated with a single injection of chlordecone, only in gerbils was this organo-chlorine pesticide converted to chlordecone alcohol, a reduced metabolite found in the stool of chlordecone poisoned humans. Analogous to these patients, chlordecone treated gerbils eliminated chlordecone alcohol exclusively in stool with none being detected in urine. Moreover, the gerbils excreted chlordecone alcohol in bile in an amount more than twice that of chlordecone and in the form of a glucuronide conjugate. The ratio of chlordecone to chlordecone alcohol in gerbil stool was 10 times higher than the ratio in human stool. This suggests that the newly recognized nonbiliary mechanism(s) for entry of chlordecone into the intestinal lumen (Boylan et al., Clin. Pharm. Ther. 25:579-585, 1979) may be extremely active in the gerbil. Biliary excretion of chlordecone alcohol in gerbils progressively increased following chlordecone treatment while biliary excretion of chlordecone remained unchanged. Incubation of the cytosolic fraction of gerbil liver homogenate in the presence of NADPH and chlordecone produced chlordecone alcohol, whereas rat liver cytosol was inactive. This observation indicates that bioreduction of chlordecone is catalyzed in gerbil liver by a species-specific reductase. Rats given [3H]-chlordecone alcohol excreted twice as much (80%) of the compound in stool after three days as compared to gerbils (40%), while the latter species accumulated three times more chlordecone alcohol in the liver than did the former. An unexpected finding was that the livers of these [3H]-chlordecone alcohol treated animals also contained chlordecone in amounts eight times (rat) and 14 times (gerbil) higher than the respective amounts of chlordecone alcohol. From this result, the existence of a separate enzyme(s) catalyzing dehydrogenation of chlordecone alcohol to chlordecone may be inferred.


p53 gene mutations in Bowen's disease in Koreans: clustering in exon 5 and multiple mutations.
We analyzed the p53 protein expression and gene mutations to evaluate the role of ultraviolet radiation or other carcinogens, and possible racial differences in 17 samples from 12 Korean patients with Bowen's disease. A simple microdissection technique was used to collect the tumor cells selectively. p53 protein expression was found in eight of 17 (47%) samples. Abnormalities in polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis were observed in 16 (94%) samples. A total of 14 missense mutations were detected in eight (47%) samples; 11 were clustered in exon 5 and the remaining three were located in exon 8. UV-like mutations were seen in five of 14 (36%) mutations, but no CC to TT transitions, UV-fingerprint mutations were observed. Multiple mutations were present in two cases and double mutation in a single case. Each lesion in multiple Bowen's disease showed different mutations and was suggested to be of different clonal origins. TP53-loss of heterozygosity (LOH) was detected in four out of 15 (27%) informative samples. Clustering of mutations in exon 5 suggests the role of another carcinogen in Koreans or Asians other than the UVR. Microdissection would increase the detection rate of the p53 gene mutations and LOH not only in skin cancer but also in precancerous lesions.


Absolute quantification of γH2AX using liquid chromatography-triple quadrupole tandem mass spectrometry.
Ser139-phosphorylated histone H2AX (γH2AX) is a useful biomarker of DNA double strand breaks. γH2AX has been conventionally detected by immunology-based methods using anti-γH2AX antibody, but quantitative analysis is difficult to perform with such methods. Here, we describe an absolute quantification method using liquid chromatography-triple quadrupole tandem mass spectrometry that is applicable to peptides derived from γH2AX (ATQA(pS)QEY) and unphosphorylated H2AX (ATQASQEY). Our method was successfully applied to histones extracted from human cervix adenocarcinoma HeLa S3 cells. The estimated number of molecules of γH2AX (ATQA(pS)QEY) per vehicle-treated HeLa S3 cell was 9.4 × 10(4) and increased to 6.2 × 10(5) molecules/cell after exposure to the DNA-damaging agent camptothecin (10 μM) for 1 h. The estimated total amount of H2AX (ATQA(pS)QEY + ATQASQEY) was 3.3-3.6 × 10(6) molecules/cell. Due to its broad adaptability and throughput performance, we believe that our method is a powerful tool for mechanistic studies of the DNA-damage response as well as for genotoxicity testing, cancer drug screening, clinical studies, and other fields.


Erythroid colony forming cells in aplastic anaemia.
The concentration and erythropoietin dependence of erythropoietic progenitor cells (CFU-E) were examined in 13 patients with aplastic anaemia at different stages of their disease. The CFU-E incidence was shown to be quantitatively diminished in aplastic anaemia but tended to recover to normal values if the disease recovered. In addition the CFU-E showed a qualitatively different response to stimulation by erythropoietin, being resistant to low concentrations but responsive to concentrations greater than 0.2 U/ml whereas there was a linear response in the controls up to 0.5 U/ml.


Corrigendum to "Bio-inspired intestinal scavenger from microfluidic electrospray for detoxifying lipopolysaccharide" [Bioact. Mater. 6 (2020) 1653-1662].
[This corrects the article DOI: 10.1016/j.bioactmat.2020.11.017.].


Impact of an immersive, interactive medical education initiative on guideline-based retinal disease management knowledge/competence and effectual practice change.
Retinal diseases, including wet or dry age-related macular degeneration, diabetic macular edema, and diabetic retinopathy (DR), are underdiagnosed and undertreated in the United States. Clinical trials support the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) therapies for several retinal conditions, but real-world data suggest underuse by clinicians, resulting in patients experiencing poorer visual outcomes over time. Continuing education (CE) has demonstrated effectiveness at changing practice behaviors, but more research is needed to understand whether CE can help address diagnostic and treatment gaps. This test and control matched pair analysis examined pre-/post-test knowledge of retinal diseases and guideline-based screening and intervention among 10,786 healthcare practitioners (i.e., retina specialists, ophthalmologists, optometrists, primary care providers, diabetes educators, pharmacists/managed care specialists, and other healthcare providers, such as registered nurses, nurse practitioners, and physician assistants) who participated in a modular, interactive CE initiative. An additional medical claims analysis provided data on practice change, evaluating use of VEGF-A inhibitors among retina specialist and ophthalmologist learners (n = 7,827) pre-/post-education, compared to a matched control group of non-learners. Outcomes were pre-/post-test change in knowledge/competence and clinical change in application of anti-VEGF therapy, as identified by the medical claims analysis. Learners significantly improved knowledge/competence scores on early identification and treatment, identifying patients who could benefit from anti-VEGF agents, using guideline-recommended care, recognizing the importance of screening and referral, and recognizing the importance of early detection and care for DR (all P-values = 0.003 to 0.004). Compared with matched controls, learners' incremental total injections for anti-VEGF agents for retinal conditions increased more after the CE intervention (P < 0.001); specifically, there were 18,513 more (new) anti-VEGF injections prescribed versus non-learners (P < 0.001). This modular, interactive, immersive CE initiative resulted in significant knowledge/competence gains among retinal disease care providers and changes in practice-related treatment behaviors (i.e., appropriate consideration and greater incorporation of guideline-recommended anti-VEGF therapies) among participating ophthalmologists and retina specialists compared to matched controls. Future studies will utilize medical claims data to show longitudinal impact of this CE initiative on treatment behavior among specialists and impact on diagnosis and referral rates among optometrists and primary care providers who participate in future programming.


Identification and heritability of fumonisin insensitivity in Zea mays.
Landraces of maize (Zea mays ssp. mays) and its wild teosinte relatives (Zea mays spp. parviglumis and mexicana) were surveyed for sensitivity to fumonisin B(1), a phytotoxin produced by the maize pathogen Gibberella moniliformis. Only two of 42 Z. mays samples were highly insensitive to FB(1) (ED(50) = ca. 200 microM). The teosintes and 76% of the maize landraces were moderately or highly sensitive to FB(1) (ED(50) < or = 30 microM), which indicates that FB(1) sensitivity is likely to be an ancestral trait in Z. mays. F(1) generations derived from crosses between FB(1)-sensitive maize inbred B73 and insensitive landraces were significantly less sensitive than B73. Thus, our data indicate that FB(1)-insensitivity is a relatively rare but heritable trait in maize. We also report the sensitivity of maize to other Gibberella toxins - beauvericin, diacetoxyscirpenol, and moniliformin.


Characterization of the cys gene locus from Allochromatium vinosum indicates an unusual sulfate assimilation pathway.
Homologues of the genes cysB, cysI, cysH, cysD, cysN, and selD were identified in the genome of the phototrophic purple sulfur bacterium Allochromatium vinosum (formerly Chromatium vinosum). On the basis of amino acid comparisons these genes encode a ferredoxin-dependent siroheme-sulfite reductase (CysI), a plant-type assimilatory APS reductase without thioredoxin domain (CysH), the two different subunits of heterodimeric ATP sulfurylase (CysDN), a transcriptional regulator (CysB) and a selenophosphate synthase (SelD). cysIHDN appear to form an operon and are preceded by cysB which is transcribed in the opposite direction. SelD is situated downstream of cysN and transcribed divergently to cysIHDN. The lack of a gene for APS kinase and presence of a gene for an assimilatory APS reductase implies that assimilatory sulfate reduction in A. vinosum proceeds along the pathway suggested for higher plants without intermediary formation of PAPS. Two completely separate pathways involving specialized enzymes are used for assimilatory sulfate reduction and dissimilatory sulfur oxidation in A. vinosum. The presence of cysB indicates that the genes for assimilatory sulfate reduction are expressed only in the absence of reduced sulfur compounds.


Dual-organ ablative surgery using a hand-assisted laparoscopic technique. A report of four cases.
In clinical situations where more than one procedure is required, a properly positioned hand-assist device can be used to obviate the need for two large incisions. We present four cases of hand-assisted laparoscopic nephrectomy combined with a simultaneous second organ extraction. Each of the four primary procedures, as well as one of the four secondary procedures, was performed using a hand-assisted laparoscopic technique. In two cases, the secondary procedure was performed with an open surgical technique through the hand-assist incision. For the remaining secondary procedure, we used a laparoscopically assisted technique.


Platelet-Rich Plasma Vs Autologous Blood Vs Corticosteroid Injections in the Treatment of Lateral Epicondylitis: A Systematic Review, Pairwise and Network Meta-Analysis of Randomized Controlled Trials.
To compare the effectiveness of platelet-rich plasma (PRP), autologous blood (AB), and corticosteroid injections in patients with lateral epicondylitis. Network meta-analysis. Randomized controlled trials (RCTs) that compared any two forms of injections among PRP, AB, and corticosteroid for the treatment of lateral epicondylitis were searched from inception to 30 November 2018, on PubMed, Embase, and Cochrane library. Two researchers independently selected and assessed the quality of RCTs with the Cochrane Risk of Bias Tool. All relevant data from the included studies were extracted and heterogeneity was checked by Cochran's Q test and inconsistency statistic (I2 ). Publication bias was evaluated by constructing contour-enhanced funnel plots. Stata 15 software was applied for pairwise meta-analysis and network meta-analysis. To explore the efficacy between different follow-up periods, we considered the duration within 2 months to be short term, whereas 2 months or more was considered long term. Twenty RCTs (n = 1271) were included in this network meta-analysis. According to ranking probabilities, corticosteroid ranked first for visual analog score (VAS) (surface under the cumulative ranking [SUCRA] = 90.7), modified Nirschl score (82.9), maximum grip strength (69.5), modified Mayo score (MMS) (77.9), and Patient-Related Tennis Elbow Evaluation (PRTEE) score (93.3) for the short-term period. For the long-term period, PRP ranked first for VAS (94.3), pressure pain threshold (99.8), Disabilities of Arm Shoulder and Hand (DASH) score (75.2), MMS (88.2), and the PRTEE score (81.8). PRP was associated with more improvement in pain intensity and function in the long term than were the comparators. However, in the short term, corticosteroids were associated with the most improvement.


Intracerebroventricular 5,7-DHT alters the in vitro function of rat cortical GABAA/benzodiazepine chloride ionophore receptor complexes.
We have earlier presented data indicating that the anxiolytic-like effect obtained in rats after depletion of brain 5-HT by means of PCPA or 5,7-DHT treatment is indirect and appears to involve the GABAA/benzodiazepine chloride ionophore receptor complex (GABAA/BDZ-RC), and that it is abolished by adrenalectomy. In the present series of experiments we have therefore investigated the 36Cl(-)-uptake in rat synaptoneurosomal preparations of central cortices from 5,7-DHT- and SHAM-lesioned animals. The GABA as well as the 3 alpha,5 alpha-tetrahydrodeoxycorticosterone (THDOC) induced picrotoxin-sensitive increase in 36Cl(-)-uptake was significantly lower than that observed in the SHAM-lesioned animals, indicating that the 5,7-DHT lesion has rendered the GABAA/BDZ-RC subsensitive to two of its tentative endogenous ligands. This effect of the 5,7-DHT lesion on the function on the GABAA/BDZ-RC was reversed by adrenalectomy, indicating that an intact adrenocortical function is required for the development of GABAA/BDZ-RC subsensitivity in 5,7-DHT-lesioned rats. A tentative conclusion of these findings is that the 5,7-DHT lesion induces an increase in release of GABA and/or barbiturate-like steroids and that this increase is reversed by adrenalectomy. The findings from these in vitro studies parallel those from our previous behavioral experiments and provide further support for the notion that a decreased serotonergic influence in the central nervous system may, possibly via the adrenocortical system, enhance the function of the GABAA/BDZ-RC.


Costing of a hospital-based outbreak of poultry-borne salmonellosis.
Poultry-borne salmonellosis is the most common form of foodborne infection in Scotland for which the vehicle can be identified, yet little is known about the costs imposed on society by this disease, or the costs of preventing it. The present study identifies and values the costs of a hospital based outbreak of poultry-borne salmonellosis. Account is taken of costs falling on individuals, the health services and society as a whole. Depending on assumptions made about the value of 'intangibles', the cost of the outbreak is estimated to be between pounds 200,000 and pounds 900,000.


Engaging people who use drugs in clinical research: integrating facilitated telemedicine for HCV into substance use treatment.
People who use drugs (PWUD) have difficulty participating in clinical research. We evaluated approaches to engage PWUD in clinical research, using facilitated telemedicine for hepatitis C virus (HCV) care as an example. We analyzed stakeholder interview transcripts and study-related data (i.e., progress reports, meeting minutes) from interrelated studies to understand engagement experiences at the patient, site, and organizational levels. Stakeholders include patient-participants, opioid treatment program (OTP) staff and administrators, and research team members involved in HCV management through facilitated telemedicine integrated into OTPs. Three themes emerged. Initially, the research team sought understanding of the unique culture and community of each OTP (Theme 1). The team built trusting relationships through education, communication, and feedback (Theme 2). Finally, the research team enhanced collaborative care and incorporated the patients' voice to improve health outcomes (Theme 3). Patient-participants and OTP staff endorsed the integrated HCV care approach. Engagement practices are summarized as the CREATE framework (C = culture, R = respect, E = educate, A = advantage, T = trust, E = endorse). PWUD engagement in clinical research is maximized by building trusting relationships with open communication channels. Understanding the community, demonstrating respect, and augmenting knowledge are foundational for engaging PWUD in clinical research. These practices are transferable to engagement of PWUD in clinical research broadly.


Selenium Mitigates Cadmium-Induced Adverse Effects on Trace Elements and Amino Acids Profiles in Chicken Pectoral Muscles.
Cadmium (Cd), as one of the most toxic heavy metals, has become a widespread environmental contaminant and threats the food quality and safety. The protective effect of selenium (Se) on Cd-induced tissue lesion and cytotoxicity in chicken has been extensively reported. The objective of this study was to investigate the antagonistic effect of Se on Cd-induced damage of chicken pectoral muscles via analyzing the trace elements and amino acids profiles. Firstly, 19 trace elements contents were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The results showed that under Cd exposure, the contents of Cd, lead (Pb), mercury (Hg), aluminum (Al), and lithium (Li) were significantly elevated, and the contents of Se, iron (Fe), and chromium (Cr) were significantly reduced. However, supplementing Se significantly reversed the effects induced by Cd. Secondly, the amino acids contents were detected by L-8900 automatic amino acid analyzer. The results showed that supplementing Se increased significantly Cd-induced decrease of valine (Val), leucine (Leu), arginine (Arg), and proline (Pro). Thirdly, the results of principal component analysis (PCA) showed that cobalt (Co), manganese (Mn), silicium (Si), and Pro may play special roles in response to the process of Se antagonizes Cd-induced damage of pectoral muscles in chickens. In summary, these results indicated that different trace elements and amino acids possessed and exhibited distinct responses to suffer from Se and/or Cd in chicken pectoral muscles. Notably, Se alleviated Cd-induced adverse effects by regulating trace elements and amino acids profiles in chicken pectoral muscles.


Teacher-student relationships and school adjustment: progress and remaining challenges.
This commentary highlights the ways in which the articles in this special issue contribute to the second generation of research on teacher-student relationships. Second generation research aims to increase our understanding of the development of these relationships, and the processes responsible for their effects, as well as to evaluate theoretically-informed interventions designed to enhance teacher-student interactions. Despite unanswered questions and challenges that confront this field of inquiry, the current state of knowledge is adequate to apply the knowledge gained to the task of increasing teachers' abilities to provide positive social and emotional learning environments, thereby improving students' learning and behavioral adjustment.


Potential antitumor agents IX: synthesis and antitumor activity of two analogues of ketocaine.
The reaction between o-hydroxybutyrophenone and tris(2-chloroethyl)amine gave two analogues (II, V) of the well-known local anesthetic ketocaine (I). Compounds II and V showed interesting antitumor activity in mice implanted with Ehrlich ascites tumor cells (% T/C = 149 at 5 mg/kg and 171 at 50 mg/kg, respectively). Further studies on the pharmacological behavior of these new compounds are in progress.


Genomic organization of prolactin and growth hormone coding sequences in dwarf and normal mice.
The genomic organization of DNA encoding growth hormone (GH) and prolactin (PRL) genes has been investigated in two types of homozygous dwarf mice and their normal counterparts. We have previously shown that dwarf mice of either strain fail to initiate pituitary synthesis of GH or PRL during perinatal development. Analysis by Southern transfer of restriction enzyme-digested DNA and hybridization to 32P-labeled cloned probes derived from bovine GH and rat PRL mRNAs revealed no evidence for deletions or rearrangements in or around the structural genes for GH or PRL in either dwarf genotype. In situ hybridization of the probes to pituitary and liver tissue slices failed to detect specifically hybridizing RNA species in dwarf pituitaries. These findings suggest that the pleiotropic effects of the dwarf mutations, which lead to abnormalities in transcription of the genes or in the processing of transcripts, may be due to blocks in the development of functional somatotrophs and mammotrophs.


Microsurgical anatomy of VII and VIII cranial nerves and related arteries in the cerebellopontine angle.
The relationships of VII and VIII cranial nerves and related arteries are reviewed in 26 preparations by microdissection techniques. These vessels may be grouped in large (AICA, PICA), medium (LA, SA, CSA, RPI) and small calibre (vasa nervorum, radicular and medullar branches). The importance of these structures in acoustic neuroma surgery, vestibular neurectomy and cross-compression syndromes is discussed. "Vascular loops" and "elongated arteries" are normal structures present at birth.


Genome-wide characterization and expression profiling of MAPK cascade genes in Salvia miltiorrhiza reveals the function of SmMAPK3 and SmMAPK1 in secondary metabolism.
The contribution of mitogen-activated protein kinase (MAPK) cascades to plant growth and development has been widely studied, but this knowledge has not yet been extended to the medicinal plant Salvia miltiorrhiza, which produces a number of pharmacologically active secondary metabolites. In this study, we performed a genome-wide survey and identified six MAPKKK kinases (MAPKKKKs), 83 MAPKK kinases (MAPKKKs), nine MAPK kinases (MAPKKs) and 18 MAPKs in the S. miltiorrhiza genome. Within each class of genes, a small number of subfamilies were recognized. A transcriptional analysis revealed differences in the genes' behaviour with respect to both their site of transcription and their inducibility by elicitors and phytohormones. Two genes were identified as strong candidates for playing roles in phytohormone signalling. A gene-to-metabolite network was constructed based on correlation analysis, highlighting the likely involvement of two of the cascades in the synthesis of two key groups of pharmacologically active secondary metabolites: phenolic acids and tanshinones. The data provide insight into the functional diversification and conservation of MAPK cascades in S. miltiorrhiza.


Routes of administration for adeno-associated viruses carrying gene therapies for brain diseases.
Gene therapy is a powerful tool to treat various central nervous system (CNS) diseases ranging from monogenetic diseases to neurodegenerative disorders. Adeno-associated viruses (AAVs) have been widely used as the delivery vehicles for CNS gene therapies due to their safety, CNS tropism, and long-term therapeutic effect. However, several factors, including their ability to cross the blood-brain barrier, the efficiency of transduction, their immunotoxicity, loading capacity, the choice of serotype, and peripheral off-target effects should be carefully considered when designing an optimal AAV delivery strategy for a specific disease. In addition, distinct routes of administration may affect the efficiency and safety of AAV-delivered gene therapies. In this review, we summarize different administration routes of gene therapies delivered by AAVs to the brain in mice and rats. Updated knowledge regarding AAV-delivered gene therapies may facilitate the selection from various administration routes for specific disease models in future research.


[Long term results of surgical treatment of ankle fractures with deltoid and tibio-fibular ligament tearing].
A series of 63 patients with fracture of lateral malleolus combined with deltoid and tibio-fibular syndesmosis tear is presented. The assessment carried out according to Weber's criteria at least 10 years after surgical reconstruction revealed over 90 per cent of good and excellent results. After failure analysis the authors conclude, that complex ligamentous injury needs to be surgically reconstructed.


CO2-induced growth enhancements of co-occurring tree species decline at different rates.
To elucidate how enriched CO2 atmospheres, soil fertility, and light availability interact to influence the long-term growth of tree seedlings, six co-occurring members of temperate forest communities including ash (Fraxinus americana L.), gray birch (Betula populifolia), red maple (Acer rubrum), yellow birch (Betula alleghaniensis), striped maple (Acer pensylvanicum), and red oak (Quercus rubra L.) were raised in a glasshouse for three years in a complete factorial design. After three years of growth, plants growing in elevated CO2 atmospheres were generally larger than those in ambient CO2 atmospheres, however, magnitudes of CO2-induced growth enhancements were contingent on the availability of nitrogen and light, as well as species identity. For all species, magnitudes of CO2-induced growth enhancements after one year of growth were greater than after three years of growth, though species' growth enhancements over the three years declined at different rates. These results suggest that CO2-induced enhancements in forest productivity may not be sustained for long periods of time. Additionally, species' differential growth responses to elevated CO2 may indirectly influence forest productivity via long-term species compositional changes in forests.


The PEST (Pathology, Epidemiology, Severity, Treatment) approach to optimizing antimicrobial therapy.
Selecting an empiric antimicrobial regimen can be difficult for early learners and misuse of antibiotics can lead to adverse events and antimicrobial resistance. There have been few interventions that have focused on improving antibiotic decision making, as a form of therapeutic reasoning, for post-graduate trainees. We describe here an approach to aid internal medicine interns in their therapeutic reasoning, particularly when it comes to diagnosing and empirically treating infections. The PEST (pathology, epidemiology, severity, treatment) model was created as a four-step approach to therapeutic reasoning and choosing an appropriate antimicrobial regimen for a given infectious disease syndrome. In February 2020, we conducted two independent teaching sessions for interns on the PEST approach. We assessed pre-and post-teaching responses to five clinical vignette-based questions. Results were presented as a percentage of interns who chose an appropriate antibiotic and provided sufficient therapeutic reasoning as defined by using at least three out of the four PEST criteria. Statistical analysis occurred via Fischer's exact test to determine the level of statistical significance between responses. Twenty-seven interns participated in the activity. At baseline, several interns had incorporated aspects of the PEST approach in their pre-teaching responses. Ten interns commented on the usefulness of such a systematic approach. While there was no statistically significant difference in antibiotic selection, the teaching session demonstrated a trend towards significance in improving therapeutic reasoning as defined by the PEST strategy. Our results suggested an improvement in using a structured cognitive tool such as the PEST approach to reinforce therapeutic reasoning, but the method did little to improve antibiotic selection. Some interns used select "PEST" concepts prior to the intervention suggesting that the PEST approach may enhance prior knowledge or clinical reasoning skills. Continued incorporation of the PEST approach using a case-based framework may solidify conceptual and practical knowledge of antimicrobial selection. Further studies are needed to assess the impact of such teaching interventions.


Different methods of detaching adherent cells and their effects on the cell surface expression of Fas receptor and Fas ligand.
In cell culture environment, some cells adhere firmly to the culture plates and may be vulnerable to cell detachment during passage. Therefore, it is important to harvest cells with a proper detaching method to maintain the viability of cells after detachment. Trypsinization is frequently used for cellular dissociation and detachment. However, most surface proteins and the extracellular matrix are degraded by enzymatic digestion. A mild cell detachment buffer, accutase, is recommended for the replacement of trypsin to dissociate adherent cells and thereby avoid cellular damage. In this study, we demonstrated that use of accutase for cellular detachment may compromise some surface proteins. Compared with ethylenediaminetetraacetic acid (EDTA)-based nonenzymatic cell dissociation buffers, accutase was associated with significant decreases in the surface Fas ligands and Fas receptors. Moreover, we found that accutase may be able to cleave surface Fas ligands into pieces. Our results also illustrated that surface proteins required 20 h to recover after accutase treatment. We demonstrated that using accutase to dissociate adherent cells compromised the expression of Fas ligands and Fas receptors on the cell surface. These findings indicate that it is important to choose suitable cell detachment buffers and allow cells to recover after detachment before experiments.


3,5-Di-bromo-4-carbamoyl-benzoic acid 2-propanol monosolvate.
In the title solvated crystal, C8H5Br2NO3·C3H8O, the acid mol-ecules form inversion dimers by pairwise N-H⋯O hydrogen bonds between carbamoyl groups and the carboxyl and carbamoyl groups link to form head-to-tail inversion dimers. The 2-propanol hydroxyl group inter-poses between adjacent head-tail pairs, resulting in C 3 3(10) chains of hydrogen bonds propagating along [100]. The mol-ecules of 2-propanol are disordered over two sets of sites in a 0.598 (8):0.402 (8) ratio. The best-fit planes of the carbamoyl group and benzene ring are inclined by 88.26 (11)°. This is a greater inclination than was previously reported with CH3, Cl, F or H in place of the Br atoms, although those analogues did not have a para carboxyl group.


Regdanvimab: First Approval.
Regdanvimab (Regkirona™) is a recombinant human monoclonal antibody targeted against the severe acute respiratory syndrome coronavirus 2. It is being developed by Celltrion Inc. for the treatment of coronavirus disease 2019 (COVID-19). In September 2021, regdanvimab received full approval in South Korea for the treatment of COVID-19 in elderly patients aged > 50 years with at least one underlying medical condition (obesity, cardiovascular disease, chronic lung disease, diabetes, chronic kidney disease, chronic liver disease, and patients on immunosuppressive agents) and mild symptoms of COVID-19 and in adult patients with moderate symptoms of COVID-19. This article summarizes the milestones in the development of regdanvimab leading to this first approval for COVID-19.


Laparoscopic fenestration of liver cysts in polycystic liver disease results in a median volume reduction of 12.5%.
Patients with polycystic liver disease (PCLD) may develop symptoms due to increased liver volume. Laparoscopic fenestration is one of the options to reduce liver volume and to relieve symptoms. This study was performed to evaluate the safety and efficacy of laparoscopic liver cyst fenestration. Twelve patients (all female, median age 45 years, range 35-58) with symptomatic PCLD were included between August 2005 and April 2007. Surgical data were recorded, liver volumes were measured on pre- and postoperative computed tomography (CT) scans, and patients completed a validated symptom-based questionnaire pre- and postoperatively. Median preoperative liver volume was 4,854 ml (range 1,606-8,201) and decreased to 4,153 ml postoperatively (range 1,556-8,232) resulting in median liver volume reduction of 12.5% (range +9.5 to -24.7%). Median procedural time was 123.5 min (range 50-318), and median hospitalization period was 3.5 days (range 1-8). Postoperative complications occurred in three patients including biliary leakage, obstruction of inferior vena cava and sepsis, all recovering with conservative management. Patients reported decreased symptoms of postprandial fullness and abdominal distension. Laparoscopic fenestration in PCLD patients results in volume reduction of 12.5% and decrease of symptoms.