Process for developing rehabilitation practice recommendations for individuals with traumatic brain injury.
Attempts at measuring quality of rehabilitation care are hampered by a gap in knowledge translation of evidence-based approaches and lack of consensus on best practices. However, adoption of evidence-based best practices is needed to minimize variations and improve quality of care. Therefore, the objective of this project was to describe a process for assessing the quality of evidence of clinical practices in traumatic brain injury (TBI) rehabilitative care. A multidisciplinary team of clinicians developed discipline-specific clinical questions using the Population, Intervention, Control, Outcome process. A systematic review of the literature was conducted for each question using Pubmed, CINAHL, PsychInfo, and Allied Health Evidence databases. Team members assessed the quality, level, and applicability of evidence utilizing a modified Oxford scale, the Agency for Healthcare Research and Quality Methods Guide, and a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation scale. Draft recommendations for best-practice were formulated and shared with a Delphi panel of clinical representatives and stakeholders to obtain consensus. Evidence-based practice guidelines are essential to improve the quality of TBI rehabilitation care. By using a modified quality of evidence assessment tool, we established a process to gain consensus on practice recommendations for individuals with TBI undergoing rehabilitation.


HLA-DRB1*07:01 allele is primarily associated with the Diego a alloimmunization in a Brazilian population.
The Diego blood group presents a major polymorphic site at Residue 854, causing a proline (Di(b) antigen) to leucine (Di(a) antigen) substitution. Di(a) alloimmunization has been observed among Asian and Native South American populations. Considering that Brazilians represent a genetically diverse population, and considering that we have observed a high incidence of Di(a) alloimmunization, we typed HLA-DRB1 alleles in these patients and performed in silico studies to investigate the possible associated mechanisms. We studied 212 alloimmunized patients, of whom 24 presented immunoglobulin G anti-Di(a) , 15 received Di(a+) red blood cells and were not immunized, and 1008 were healthy donors. HLA typing was performed using commercial kits. In silico analyses were performed using the TEPITOPEpan software to identify Diego-derived anchor peptide binding to HLA-DRB1 molecules. Residue alignment was performed using the IMGT/HLA for amino acid identity and homology analyses. HLA-DRB1*07:01 allele was overrepresented in Di(a) -alloimmunized patients compared to nonimmunized patients and to healthy donors. Two motifs were predicted to be potential epitopes for Di(a) alloimmunization, the WVVKSTLAS motif was predicted to bind several HLA-DR molecules, and the FVLILTVPL motif exhibited highest affinity for the HLA-DRB1*07:01 molecule. Pocket 4 of the DRB1*07:01 molecule contained specific residues not found in other HLA-DRB1 molecules, particularly those at Positions 13(Y), 74(Q), and 78(V). Individuals carrying the HLA-DRB1*07:01 allele present an increased risk for Di(a) alloimmunization. The identification of susceptible individuals and the knowledge of potential sensitization peptides are relevant approaches for transfusion care, diagnostic purposes, and desensitization therapies.


Does High Protein Intake During First Week of Life Improve Growth and Neurodevelopmental Outcome at 18 months Corrected Age in Extremely Preterm Infants?
To examine whether high protein intake during the first week of life alters the growth and neurodevelopmental outcomes at 18 mo corrected age (CA) in preterm infants born < 29 wk. This was a retrospective cohort study of preterm infants (<29 wk) before and after introduction of nutritional policy targeting higher protein intake during the first week of life. The authors compared the growth and neurodevelopmental outcomes at 18 mo CA between infants born before (epoch 1) and after (epoch 2) the introduction of nutrition policy. Of 171 eligible infants who completed follow-up at 18 mo CA, 87 (51 %) were in post intervention group (epoch 2). The mean (± SD) gestational age (26.3 ± 1.49 wk vs. 26.2 ± 1.48 wk) and birth weight (947 ± 220 g vs. 924 ± 225 g) were similar between the two groups. At 18 mo CA, there were no significant differences in the growth and neurodevelopmental impairment rates between the two groups. Logistic regression analysis revealed that high protein intake (>3.5 g/kg/d) was not associated with improved neurodevelopmental outcome (OR 1.49, 95 % CI 0.52-4.26). High protein intake during the first week of age was not associated with better growth or neurodevelopmental outcome at 18 mo CA in preterm infants.


The efficacy of diphencyprone immunotherapy for the treatment of cutaneous warts: a systematic review and meta-analysis.
Cutaneous warts, a common skin condition, may resolve spontaneously or become recalcitrant. Diphencyprone has been shown by many studies to have efficacy in treating warts, with varied results. We aimed to perform a meta-analysis of the cure rate following the use of diphencyprone immunotherapy as a cutaneous wart treatment. The databases of Medline, PubMed, Embase, ClinicalTrials.gov, and Cochrane Controlled Trials Register were searched for prospective and retrospective cohort studies and randomized controlled trials reporting a cure rate for diphencyprone immunotherapy between 1984 and 2018. The Comprehensive Meta-Analysis software (Biostat Inc) was used to perform a meta-analysis of the diphencyprone pool efficacy. A total of 153 studies were obtained by searching the databases. After screening for eligibility, 14 studies were included (6 prospective studies, 4 retrospective studies, 3 randomized controlled trials, and 1 case report), representing a total of 851 patients. The random-effects pooled efficacy for diphencyprone was 75.5% (95% CI, 64.6%-83.9%; I2 = 87%). Diphencyprone immunotherapy has a high efficacy to cure warts. This method may be used as an adjunctive modality for the treatment of warts in cases of conventional treatment failure.


Effects of Deep Brain Stimulation of the Subthalamic Nucleus on the Postoperative Levodopa Response: One Year Follow Up.
To investigate the effect of preoperative levodopa responsiveness to clinical outcomes in the first postoperative year, and to evaluate the changes in the postoperative levodopa responsiveness in patients undergoing subthalamic nucleus (STN) deep brain stimulation (DBS). Forty-nine Parkinson?s Disease (PD) patients undergoing bilateral DBS of the STN were included in this study. Their clinical motor symptoms were assessed preoperatively by UPDRS Part III score in both OFF and ON medication states. Postoperatively, the assessments were obtained in three consecutive conditions. Preoperatively and postoperatively, the percentage difference between these two scores was evaluated as levodopa response. Mean age was 54.6 ± 9 years (27?70). Levodopa response significantly decreased postoperatively by 56% a year. Compared with preoperative med on and postoperative stim on / med on scores, the clinical results of the first year were obtained and an improvement of 25% on the UPDRS 3 score was observed. Compared with preoperative levodopa response and clinical outcomes, better clinical results were obtained in patients with higher preoperative levodopa response (p < 0.05). In this study, we confirm that the response of L-dopa decreases after DBS of the STN. The reasons for this finding are not clear. However, DBS of the STN allows for the reduction of PD medications and improvement of daily life activities, motor function, motor fluctuations, and dyskinesia.


Membrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor.
The Angiotensin II Type 1 (AT1) receptor is one of the most widely studied GPCRs within the context of biased signaling. While the AT1 receptor is activated by agonists such as the peptide AngII, it can also be activated by mechanical stimuli such as membrane stretch or shear in the absence of a ligand. Despite the importance of mechanical activation of the AT1 receptor in biological processes such as vasoconstriction, little is known about the structural changes induced by external physical stimuli mediated by the surrounding lipid membrane. Here, we present a systematic simulation study that characterizes the activation of the AT1 receptor under various membrane environments and mechanical stimuli. We show that stability of the active state is highly sensitive to membrane thickness and tension. Structural comparison of membrane-mediated vs. agonist-induced activation shows that the AT1 receptor has distinct active conformations. This is supported by multi-microsecond free energy calculations that show unique landscapes for the inactive and various active states. Our modeling results provide structural insights into the mechanical activation of the AT1 receptor and how it may produce different functional outcomes within the framework of biased agonism.


Temporal and spatial changes and influencing factors of low-carbon economy efficiency in China.
Low-carbon development has always been an important focus of China's economic transformation. In order to promote the development of low-carbon economy, this study used SBM-DEA model to evaluate China's provincial LCEE from 2005 to 2019, studied its temporal and spatial evolution law, used spatial autocorrelation to explore the correlation of China's provincial LCEE, and explored the key influencing factors of LCEE with Tobit model. The empirical results show that the LCEE of most provinces in China is declining, and there are significant differences among different regions in China. Because the eastern region of China can rely on its own human resources, capital environment, and economic foundation, the overall LCEE level is relatively high, while the central and western regions still have obvious deficiencies due to industrial conditions, geographical location, and other factors. LCEE has significant spatial correlation, and neighboring provinces have spillover effects on local LCEE. On this basis, the key factors that affect LCEE are determined. Urbanization level, traffic level, economic development level, financial development, investment in fixed assets, and energy consumption are the important factors that affect LCEE in China, but these influences vary from province to region. It is more reasonable for local governments to develop low-carbon economy according to their own conditions.


Serotonergic conversion of MPTP and dopaminergic accumulation of MPP+.
[3H]MPP+ had lower Km and higher Vmax values for its accumulation in rat brain synaptosomes than did [3H]MPTP. The kinetic parameters favored the uptake of [3H]MPP+ in the striatum to that in hypothalamus, whereas they were equally favorable for the uptake of [3H]MPTP in both regions. Hypothalamic uptake of [3H]MPTP and [3H]MPP+ was inhibited by desipramine, imipramine, norepinephrine, and serotonin. Striatal uptake of [3H]MPP+ and [3H]MPTP was blocked by nomifensine and dopamine. These results support the concept that MPTP accumulates in serotonergic neurons where it is oxidized by monoamine oxidase B to MPP+, which is released and then is selectively accumulated in dopaminergic neurons via the dopamine uptake system.


[Multidrug-resistant tuberculosis in children: about two cases].
Multidrug-resistant tuberculosis in children is a severe form of tuberculosis, which remains a major health problem especially in developing countries. We report the case of two children treated, during our training, for multidrug-resistant tuberculosis and put on second-line regimen.


Comparative transcriptomics of Pleurotus eryngii reveals blue-light regulation of carbohydrate-active enzymes (CAZymes) expression at primordium differentiated into fruiting body stage.
Blue light is an important environmental factor which could induce mushroom primordium differentiation and fruiting body development. However, the mechanisms of Pleurotus eryngii primordium differentiation and development induced by blue light are still unclear. The CAZymes (carbohydrate-active enzymes) play important roles in degradation of renewable lignocelluloses to provide carbohydrates for fungal growth, development and reproduction. In the present research, the expression profiles of genes were measured by comparison between the Pleurotus eryngii at primordium differentiated into fruiting body stage after blue light stimulation and dark using high-throughput sequencing approach. After assembly and compared to the Pleurotus eryngii reference genome, 11,343 unigenes were identified. 539 differentially expressed genes including white collar 2 type of transcription factor gene, A mating type protein gene, MAP kinase gene, oxidative phosphorylation associated genes, CAZymes genes and other metabolism related genes were identified during primordium differentiated into fruiting body stage after blue light stimulation. KEGG results showed that carbon metabolism, glycolysis/gluconeogenesis and biosynthesis of amino acids pathways were affected during blue light inducing primordia formation. Most importantly, 319 differentially expressed CAZymes participated in carbon metabolism were identified. The expression patterns of six representative CAZymes and laccase genes were further confirmed by qRT-PCR. Enzyme activity results indicated that the activities of CAZymes and laccase were affected in primordium differentiated into fruiting body under blue light stimulation. In conclusion, the comprehensive transcriptome and CAZymes of Pleurotus eryngii at primordium differentiated into fruiting body stage after blue light stimulation were obtained. The biological insights gained from this integrative system represent a valuable resource for future genomic studies on this commercially important mushroom.


A novel method for the administration of metacercariae of Fasciola hepatica to adult cattle.
A gelatin bolus containing the infective stage of Fasciola hepatica was prepared and administered to adult cattle. The bolus was formed to fit into the nozzle of a standard size bolus-type dosing gun. Administration proved easy and effective causing minimal stress to the animal, yet ensuring that experimental infection took place.


Neurodegenerative disease-associated mutants of a human mitochondrial aminoacyl-tRNA synthetase present individual molecular signatures.
Mutations in human mitochondrial aminoacyl-tRNA synthetases are associated with a variety of neurodegenerative disorders. The effects of these mutations on the structure and function of the enzymes remain to be established. Here, we investigate six mutants of the aspartyl-tRNA synthetase correlated with leukoencephalopathies. Our integrated strategy, combining an ensemble of biochemical and biophysical approaches, reveals that mutants are diversely affected with respect to their solubility in cellular extracts and stability in solution, but not in architecture. Mutations with mild effects on solubility occur in patients as allelic combinations whereas those with strong effects on solubility or on aminoacylation are necessarily associated with a partially functional allele. The fact that all mutations show individual molecular and cellular signatures and affect amino acids only conserved in mammals, points towards an alternative function besides aminoacylation.


Phase II study of aclarubicin in patients with lymphoma.
Aclarubicin, a new anthracycline antibiotic with less cardiotoxicity relative to doxorubicin, was utilized in 33 patients with advanced lymphoma at a dose of 100 mg/m2 iv every 3 weeks. Five patients developed partial response (2, 2, 2, 4, and 8+ months). None of the patients who had received prior anthracycline responded to aclarubicin. The dose-limiting toxic effect was hematologic. One of ten patients having serial measurements of cardiac function had a significant reduction in left ventricular function, but cardiac symptoms did not occur.


SOCS3 ablation in SF1 cells causes modest metabolic effects during pregnancy and lactation.
Previous studies have shown that leptin resistance is a key feature that leads to gestational metabolic adaptions. We hypothesized that leptin sensitivity in the ventromedial nucleus of the hypothalamus (VMH) plays a critical role regulating gestational metabolic changes. In the present study, we generated a mouse model carrying ablation of the suppressor of cytokine signaling 3 (SOCS3) in steroidogenic factor-1 (SF1) cells, which include the VMH, in order to investigate whether increased leptin sensitivity in this neuronal population prevents at least part of the metabolic changes typically observed during gestation and lactation. As predicted by the inhibitory effects of SOCS3 in leptin signaling, pregnant SF1 SOCS3 KO mice exhibited increased leptin sensitivity in the VMH, since an acute leptin injection induced a 95% increase in the STAT3 phosphorylation in this nucleus, compared to control animals (p = 0.02). Despite that, SF1 SOCS3 KO mice showed similar weight gain, food intake, hypothalamic neuropeptide expression and serum leptin levels during pregnancy compared to control littermates. Unexpectedly, SF1 SOCS3 KO mice exhibited glucose intolerance during pregnancy. SF1 SOCS3 KO mice also presented a lower body weight (-3%; p < 0.05) during mid and late lactation, although food intake, litter size and offspring growth were not affected. Our findings suggest that increased leptin sensitivity in the VMH causes modest metabolic effects and is not sufficient to prevent major metabolic adaptations of pregnancy and lactation.


Cellular impact and selectivity of half-sandwich organorhodium(III) anticancer complexes and their organoiridium(III) and trichloridorhodium(III) counterparts.
Half-sandwich organorhodium(III) complexes and their trichloridorhodium(III) counterparts are potent anticancer agents that enhance the formation of reactive oxygen species and invoke a strong induction of apoptosis in leukemia cells. The antiproliferative activity towards human MCF-7 and HT-29 adenocarcinoma cells of novel nonintercalating complexes containing the 5-substituted phenanthroline ligands 5,6-dimethylphenanthroline, 5-chlorophenanthroline, and 5-nitrophenanthroline (phen*) increases dramatically in the order [(η(5)-C(5)Me(5))IrCl(phen*)](CF(3)SO(3)) < [(η(5)-C(5)Me(5))RhCl(phen*)](CF(3)SO(3)) < mer-[RhCl(3)(DMSO)(phen*)] (DMSO is dimethyl sulfoxide). Improved activity was also achieved by attaching a cell-penetrating peptide to the dipyrido[3,2-a:2',3'-c]phenazine (dppz) ligand of an organorhodium(III) complex. Whereas 5-substitution led to significant improvements in the activity of the organoiridium(III) and trichloridorhodium(III) compounds in comparison with the parent phenanthroline complex, the IC(50) values of their organorhodium(III) counterparts remained effectively invariable. The high activities of the trichloridorhodium(III) complexes (IC(50) = 0.06-0.13 μM) were accompanied by pronounced selectivity towards human cancer cells in comparison with immortalized HEK-293 cells. In contrast, [(η(5)-C(5)Me(5))RhCl(5,6-Me(2)phen)](CF(3)SO(3)) (phen is phenanthroline) was markedly more active towards BJAB lymphoma cells than ex vivo healthy leukocytes and caused an immediate decrease in cellular adhesion possibly associated with interactions with membrane proteins. Its dppz analogue invoked an initial increase in glycolysis to compensate for reduced respiration before inducing a delayed onset of cell death. Strong antimitochondrial activity with respiration impairment and release of cytochrome c was established for both complexes.


Sudden unexpected death in epilepsy (SUDEP): development of a safety checklist.
The incidence of sudden death appears to be 20 times higher in patients with epilepsy compared with the general population. Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is still underestimated by healthcare professionals and this may reflect the mistaken belief that epilepsy is a benign condition. The risk of death associated with epilepsy appeared rarely to have been discussed with patients or their families. It appears the decision to discuss SUDEP and also to peg SUDEP risk is arbitrary and clinical. Unfortunately there is no structured evidenced mechanism at present to represent person centered risk of SUDEP and there is currently no easy manner or template to have this discussion with the family and the patient. We conducted a detailed literature review in Medline, Embase and Psychinfo databases to extract the common risk factors as evidenced from literature till date. Research into risk factors has identified a number of risk factors for SUDEP, some of which are potentially modifiable. Based on the literature review, we believe that the ascertained risk factors could be employed in clinical practice as a checklist to reduce an individual patient's risk of SUDEP. The SUDEP safety checklist may be of practical use in reducing risks in some individuals and is definitely of use in helping communication. An evidence based checklist identifying the major risk factors can help both clinicians and patients to focus on minimizing certain risk factors and promote safety by focusing on the modifiable factors and guide treatment. It can be a tool to open a person centered discussion with patients and to outline how individual behaviors could impact on risk.


Cerebrofacial venous metameric syndrome type 2+3: face is the index of brain.
We describe a rare case of a 20-year-old man who presented with an extensive facial and orbital venous malformation associated with multiple intracranial venous malformations. The co-existence of cerebrofacial venous malformations points towards a common final pathway in development of these malformations. Our findings are consistent with few previous similar case descriptions. In addition, we describe some novel observations which, to the best of our knowledge, have not been described in the literature. This case reinforces the concept of metameric and segmental distribution of cerebrofacial vasculature, and the aberrations thereof leading to the metameric venous malformations, as proposed by Lasjaunias et al.


Construction of ultrasonic nanobubbles carrying CAIX polypeptides to target carcinoma cells derived from various organs.
Ultrasound molecular imaging is a novel diagnostic approach for tumors, whose key link is the construction of targeted ultrasound contrast agents. However, available targeted ultrasound contrast agents for molecular imaging of tumors are only achieving imaging in blood pool or one type tumor. No targeted ultrasound contrast agents have realized targeted ultrasound molecular imaging of tumor parenchymal cells in a variety of solid tumors so far. Carbonic anhydrase IX (CAIX) is highly expressed on cell membranes of various malignant solid tumors, so it's a good target for ultrasound molecular imaging. Here, targeted nanobubbles carrying CAIX polypeptides for targeted binding to a variety of malignant tumors were constructed, and targeted binding ability and ultrasound imaging effect in different types of tumors were evaluated. The mean diameter of lipid targeted nanobubbles was (503.7 ± 78.47) nm, and the polypeptides evenly distributed on the surfaces of targeted nanobubbles, which possessed the advantages of homogenous particle size, high stability, and good safety. Targeted nanobubbles could gather around CAIX-positive cells (786-O and Hela cells), while they cannot gather around CAIX-negative cells (BxPC-3 cells) in vitro, and the affinity of targeted nanobubbles to CAIX-positive cells were significantly higher than that to CAIX-negative cells (P < 0.05). Peak intensity and duration time of targeted nanobubbles and blank nanobubbles were different in CAIX-positive transplanted tumor tissues in vivo (P < 0.05). Moreover, targeted nanobubbles in CAIX-positive transplanted tumor tissues produced higher peak intensity and longer duration time than those in CAIX-negative transplanted tumor tissues (P < 0.05). Finally, immunofluorescence not only confirmed targeted nanobubbles could pass through blood vessels to enter in tumor tissue spaces, but also clarified imaging differences of targeted nanobubbles in different types of transplanted tumor tissues. Targeted nanobubbles carrying CAIX polypeptides can specifically enhance ultrasound imaging in CAIX-positive transplanted tumor tissues and could potentially be used in early diagnosis of a variety of solid tumors derived from various organs.


Magnesium pyrophosphates in enzyme mimics of nucleotide synthases and kinases and in their prebiotic chemistry.
Derivatives of ribosyl pyrophosphate have been synthesized, and examined with magnesium salts in the coupling of the ribose unit to various nucleophiles, including pyrazole and 2-chloroimidazole. Only with the magnesium salt present did they generate the ribosyl cation by binding to the leaving group and then couple the ribose derivative with nucleophiles. The role of magnesium salts in phosphorylation of methanol by ATP was also examined. Here a remarkable effect was seen: phosphorylation by ATP was slowed with low concentrations of Mg(2+) but accelerated by higher concentrations. Related effects were also seen in the effect of Mg(2+) on phosphorylation by ADP. The likely mechanisms explain these effects.


[Nalbuphine--properties and clinical use].
Nalbuphine--a new opioid drug with agonistic-antagonistic action is presented. The action of the drug is discussed in the light of present theory of opioid receptors. On the basis of literature reports the experiences are analyzed of the clinical use of nalbuphine.


[Medical biostatistics with GMRC Shiny Stats - learning by doing].
Biostatistics are omnipresent in the scientific and medical literature and are an essential skill for any health student. We have developed a practical training tool - GMRC Shiny stats - an interactive application specifically dedicated to medical data statistical analysis. The application has been designed to provide an analysis workflow corresponding to the usual progression of an experienced statistician during data analysis. The most common statistical analyses can be performed (descriptive statistics, inferences according to frequentist methods, survival analyses, correlation, agreement measurements, etc.). GMRC Shiny stats is intuitive and user-friendly and assists students in choosing the most appropriate statistical tests. With all these functionalities, students can learn statistical analysis by doing. Getting involved in the statistical analysis and processing of their own data is likely to improve their biostatistics skills.


Impact of the single site order in LTC: exacerbation of an overburdened system.
The long-term care (LTC) sector has been at the epicentre of COVID-19 in Canada. This study aimed to understand the impact that the Single Site Order (SSO) had on staff and leadership in four LTC homes in the Lower Mainland of British Columbia, Canada. A mixed method study was conducted by analyzing administrative staffing data. Overtime, turnover, and job vacancy data were extracted and analyzed from four quarters before (April 2019 - March 2020) and four quarters during the pandemic (April 2020 - March 2021) using scatterplots and two-part linear trendlines across total direct care nursing staff and by designation (i.e., registered nurses (RNs), licenced practical nurses (LPNs) and care aids (CAs)). Virtual interviews were conducted with a purposive sample of leadership (10) and staff (18) from each of the four partner care homes (n = 28). Transcripts were analyzed in NVivo 12 using thematic analysis. Quantitative data indicated that the total overtime rate increased from before to during the pandemic, with RNs demonstrating the steepest rate increase. Additionally, while rates of voluntary turnover showed an upward trend before the pandemic for all direct care nursing staff, the rate for LPNs and, most drastically, for RNs was higher during the pandemic, while this rate decreased for CAs. Qualitative analysis identified two main themes and sub-themes: (1) overtime (loss of staff, mental health, and sick leave) and (2) staff turnover (the need to train new staff, and gender/race) as the most notable impacts associated with the SSO. The results of this study indicate that the outcomes due to COVID-19 and the SSO are not equal across nursing designations, with the RN shortage in the LTC sector highly evident. Quantitative and qualitative data underscore the substantial impact the pandemic and associated policies have on the LTC sector, namely, that staff are over-worked and care homes are understaffed.


Management of side-effects.
The current treatment of chronic hepatitis C is the triple combination of pegylated interferon, ribavirin and a new direct-acting antiviral [either telaprevir (TVR) or boceprevir (BOC)]. This new association produces better viral response rates, but may induce or enhance adverse events, which can lead to discontinuation of treatment. TVR regimens are associated with an increased risk of dermatological side-effects such as rash, albeit generally mild. In these cases, optimal skincare treatments, including emollient creams and topical corticosteroids, allow the continuation of antiviral treatment. In a minority of cases, the rash may be severe and life-threatening, leading to immediate discontinuation of all treatments. The goal for the physician is to differentiate severe cutaneous adverse reactions (SCARs), including DRESS (drug reactions with eosinophilia and systemic symptoms). Anaemia is also more frequent with triple combinations using TVR or BOC. The management of anaemia requires the use of erythropoietin alpha (EPO) and the need to decrease ribavirin doses. Thus, monitoring haemoglobin has to be more frequent in difficult-to-treat patients such as cirrhosis cases; nevertheless, despite the use of EPO and ribavirin-dose adaptation, blood transfusion is sometimes still required. Thus, triple combination therapy with a DAA is effective, but it increases the rate of adverse events, and adds to the well-known adverse effects of pegylated interferon and ribavirin. This suggests the need for a different clinical and biological management of patients treated with the triple combination.


Factors associated with willingness to take extended release naltrexone among injection drug users.
Although opioid-agonist therapy with methadone or buprenorphine/naloxone is currently the mainstay of medical treatment for opioid use disorder, these medications often are not well accepted or tolerated by patients. Recently, extended release naltrexone (XR-NTX), an opioid antagonist, has been advanced as an alternative treatment. The willingness of opioid-addicted patients to take XR-NTX has not been well described. Opioid-using persons enrolled in a community-recruited cohort in Vancouver, Canada, were asked whether or not they would be willing to take XR-NTX. Logistic regression was used to independently identify factors associated with willingness to take the medication. Among the 657 participants surveyed between June 1, 2013, and November 30, 2013, 342 (52.1%) were willing to take XR-NTX. One factor positively associated with willingness was daily heroin injection (adjusted odds ratio [AOR] = 1.53; 95% confidence interval [CI] = 1.02-2.31), whereas Caucasian ethnicity was negatively associated (AOR = 0.59; 95% CI = 0.43-0.82). Satisfaction with agonist therapy (13.4%) and unwillingness to stop opioids being used for pain (26.9%) were the most common reasons for being unwilling to take XR-NTX. A high level of willingness to take XR-NTX was observed in this setting. Interestingly, daily injection heroin use was positively associated with willingness, whereas Caucasian participants were less willing to take XR-NTX. Although explanations for unwillingness were described in this study, further research is needed to investigate real-world acceptability of XR-NTX as an additional option for the treatment of opioid use disorder.


Modeling the crosstalk between the circadian clock and ROS in Neurospora crassa.
The circadian clock regulates the expression of clock-controlled genes and adapts to environmental changes. Reactive oxygen species (ROS) also undergo circadian rhythms and have a role in circadian timekeeping. To elucidate crosstalk between ROS and the circadian clock in Neurospora crassa, we build an integrative network model, characterizing the circadian oscillator, ROS system and their interactions. Notably, the (de)phosphorylation and nuclear-cytoplasmic shuttling of clock proteins are modeled in detail. Simulation results quantitatively reproduce the essential features of circadian rhythm (both in constant darkness and under light/dark cycles) and the changes in period length and phase when ROS levels are altered under diverse conditions. This work clarifies the effects of three interactions between ROS and the clock on the circadian rhythm, suggesting that the regulation of WCC activity by protein phosphatase 2A in an O2--dependent manner plays a predominant role. The functional significance of such modulations is also discussed.


Serotonergic ergoline derivatives.
Novel classes of 13- and 14-tertbutyl-ergoline derivatives were prepared, and characterised in vitro for their affinity for adrenergic, dopaminergic and serotonergic binding sites. This study particularly examines the importance of the presence and the position of the tert-butyl group in conferring either significant 5-HT1A or 5-HT2 affinity and selectivity respectively.


Elevation of serum CA125 in carcinomas of the fallopian tube, endometrium, and endocervix.
An immunoradiometric assay with the use of a monoclonal antibody can detect an antigenic determinant (CA125) in peripheral blood from more than 80% of patients with epithelial ovarian cancer. In this report elevated levels of CA125 were detected in serum from patients with adenocarcinomas of the fallopian tube, endometrium, and endocervix. Among patients with endometrial cancer, CA125 levels were elevated in recurrent or disseminated disease but not with tumors confined to the uterus.


Thiazoles with cyclopropyl fragment as antifungal, anticonvulsant, and anti-Toxoplasma gondii agents: synthesis, toxicity evaluation, and molecular docking study.
Synthesis and investigation of antifungal, anticonvulsant and anti-Toxoplasma gondii activities of ten novel (2-(cyclopropylmethylidene)hydrazinyl)thiazole 3a-3j are presented. Among the derivatives, compounds 3a-3d and 3f-3j possess very high activity against Candida spp. ATCC with MIC = 0.015-7.81 µg/ml. Compounds 3a-3d and 3f-3j possess also very high activity towards most of strains of Candida spp. isolated from clinical materials with MIC = 0.015-7.81 µg/ml. The activity of these compounds is similar and even higher than the activity of nystatin used as positive control. Additionally, compounds 3c and 3e showed interesting anticonvulsant activities in the MES test, whereas compounds 3f and 3i demonstrated the anticonvulsant activity in PTZ-induced seizures. Noteworthy, none of these compounds impaired animals' motor skills in the rotarod test. Moreover, thiazoles 3a, 3h, and 3j showed significant anti-Toxoplasma gondii activity, with IC50 values 31-52 times lower than those observed for sulfadiazine. The results of the cytotoxicity evaluation, anti-Candida spp. and anti-Toxoplasma gondii activity studies showed that Candida spp. and Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mouse L929 fibroblast and the African green monkey kidney (VERO) cells. Molecular docking studies indicated secreted aspartic proteinase (SAP) as possible antifungal target.


A new building block for anion supramolecular chemistry. Study of carbazolocarbazole as anion receptor.
A novel carbazolocarbazole system has been evaluated as an anion receptor in DMF solution. A good affinity has been detected for oxoanions. The anion binding studies have been contrasted by different experimental techniques.


Treatment response trajectories in residential PTSD programs for veterans: A national cohort investigation.
Although improving residential PTSD care is a priority for the Department of Veterans Affairs, previous evaluations have been limited by a lack of systematic data collection across more than two timepoints. This study used recently available data to assess symptom trajectories in a large, national sample of veterans who engaged in residential PTSD treatment. Group-based trajectory analysis PROC TRAJ was used to identify PTSD residential treatment response in a national cohort of veterans (n = 10,832) and the subset of veterans (n = 6515) receiving evidence-based psychotherapy (EBP). PTSD symptoms were assessed at intake, discharge, and 4-month follow-up. Predictors of trajectory membership were estimated using multinomial models. For the full cohort, a three-group trajectory model provided the best fit with the following identified groups: "Severe/Stable" (51.8%), "Moderate/Rebound" (40.1%), and "Mild/Rebound" (8.1%). For the EBP sub-cohort, a three-group trajectory model was selected with the following groups: "Severe/Stable" (58.5%), "Moderate/Rebound" (34.1%), and "Mild/Rebound" (7.4%). Across all trajectories, psychological distress, pain severity, substance use, Iraq/Afghanistan combat era, non-White race, and treatment dropout were associated with poorer treatment response. In the EBP sub-cohort, homelessness and unemployment at the time of admission were also associated with poorer treatment outcomes to varying degrees. This study demonstrates that residential treatment for PTSD is associated with heterogeneous treatment trajectories which highlight the need to continue to explore and improve residential PTSD treatment outcomes. Our results underscore the importance of obtaining follow-up data and identifying ways to maintain therapeutic gains following discharge.


Use of arterial devascularization and cytotoxic drugs in 30 patients with the carcinoid syndrome.
Thirty patients with symptoms of the carcinoid syndrome and other symptoms not controlled by pharmacological agents were analysed with respect to the value of various treatment measures used. Tumour devascularization was carried out in 11 patients, either by surgical ligation of the main hepatic artery (6) or by percutaneous arterial embolization (5). The latter was shown to be the safer technique, both with respect to initial morbidity/mortality and other side effects. Control of flushing and diarrhoea was achieved in 80% and the technique was also repeated on one occasion with success when symptoms recurred. The use of cytotoxic drugs alone, including 5-fluorouracil, cyclophosphamide and Adriamycin produced symptomatic relief in only 4 of the 22 patients treated. They should only be considered if devascularization by arterial embolization proves impossible or cannot be repeated when symptoms recur.


Neurochemical evidence for agmatine modulation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity.
Agmatine treatment is known to exert neuroprotective effects in several models of neurotoxic and ischemic brain and spinal cord injuries. Here we sought to find out whether agmatine treatment would also prove to be neuroprotective in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Concomitant daily treatment (intraperitoneal injections) with agmatine (100 mg/kg for 5 days) and MPTP (40 mg/kg for 2 days) exacerbated MPTP-related toxicity as evidenced by a larger reduction in dopamine uptake into striatal synaptosomes (42.4% as compared to 58.3% of control, respectively). In contrast, agmatine treatment commencing after MPTP, produced partial protection (31%) against MPTP dopaminergic toxicity. The findings implicate agmatine in mechanisms regulating MPTP neurotoxicity, but underscore the characteristic neuroprotective efficacy of agmatine when applied after the insult.


Pathophysiology of chronic urticaria.
To review the literature on the pathogenesis of chronic urticaria (excluding physical urticaria). PubMed was searched using the keywords urticaria and either chronic or autoimmune or pathogenesis for articles published from January 1972 to June 2007. All searches were limited to the English language. References from review articles on chronic urticaria were also considered for inclusion in this review. The authors selected relevant and current sources for inclusion in this review. No concise pathogenic mechanism has been identified for all cases of chronic urticaria, although evidence for a serologic mediator that may be autoimmune in nature has been identified in many cases. The activation of basophils and/or mast cells is a central feature in any theory proposed to explain this troubling disease. Further research is needed to better define the mechanism or mechanism(s) responsible for the development of chronic urticaria. Such research will lead to more effective and possibly even curative treatments.


Association of Generalized and Abdominal Obesity with Diabetic Retinopathy in Chinese Type 2 Diabetic Patients.
Obesity has been proposed to promote the progression of diabetic retinopathy (DR), but previous studies have not shown consistent results. We aimed to explore the association between generalized and abdominal obesity and DR risk, and to assess the joint effect of these two different types of obesity on DR development. A nested case-control study within a large prospective study on type 2 diabetes was conducted in communities in Huai'an City, Jiangsu Province, China. Cases were individuals who had diagnoses of DR during the 6-year follow-up. A total number of 1544 DR cases and 1:1 matched controls were included. Binomial and multinomial logistic regression models were used to investigate the effects of obesity on DR occurrence and DR severity. Compared with individuals in the first tertile of the baseline waist-to-hip ratio (WHR), subjects in the third tertile at baseline had significantly higher risk of DR (OR 1.44, 95% CI 1.17-1.78) during the follow-up period. Conversely, body mass index (BMI) (continuous) had an adjusted OR of 0.97 (95% CI 0.95-0.99) of developing DR. Individuals with low BMI and high WHR levels were identified as a high-risk population with a higher likelihood of developing DR (OR 1.65, 95% CI 1.17-2.33) than those in the lowest BMI category and simultaneously in the first WHR tertile. Type 2 diabetic individuals with low BMI levels and high WHR levels had a significantly increased risk of developing DR which indicated that isolated abdominal obesity might be involved in the pathogenesis of DR.


Progressive symmetrical erythrokeratoderma: report of a Turkish family and evaluation for loricrin and connexin gene mutations.
We report here the first Turkish patient with progressive symmetric erythrokeratoderma. The patient's skin lesions appeared in the axillae at 3 months of age, and gradually spread to other flexural areas and to the trunk. Dermatological examination of the boy at 3.5 years of age revealed symmetric, hyperkeratotic plaques with erythematous outlines on the neck, wrists, armpits, trunk and posterior knees. The histopathological changes were nonspecific, including marked hyperkeratosis, irregular acanthosis, focal papillomatosis and perivascular lymphocytic infiltrates. Molecular studies of the loricrin (LOR), connexin 31 (GJB3) and connexin 30.3 (GJB4) genes did not identify a disease-causing mutation. These results further underline the genetic heterogeneity of the erythrokeratodermas.


Thyrotoxic cardiomyopathy and encephalopathy in a paraplegic man.
Case report. Thyrotoxicosis complicating spinal cord injury is more common than generally appreciated. To raise the level of awareness, the following case of fatal thyrotoxicosis is presented. A 77-year-old man, paralyzed at the T12 level for 46 years, developed a sudden 42 lb weight loss, dyspnea, interscapular pain, 120/40 mm Hg blood pressure, a nodular thyroid gland, atrial fibrillation, progressive cardiac enlargement, left ventricular ejection fraction diminishing from 30 to 10% and a persistently low level of thyrotropic hormone, 0.05-0.2 microU ml(-1) (normal 0.35-5.5 microU ml(-1)). As coronary artery bypass grafting had been carried out 6 years earlier and other signs of thyrotoxicosis-exophthalmos, lid lag, sweating, tremor and diarrhea-were absent, recurrent arteriosclerotic heart disease was assumed and a trial of thyroid suppression not attempted. He eventually developed depression and memory loss and died in heart failure after a 4-year course of this illness. This case probably represented a toxic multinodular goiter in an elderly paraplegic man with potentially treatable cardiovascular and nervous system complications.


Excess weight at time of presentation of myocardial infarction is associated with lower initial mortality risks but higher long-term risks including recurrent re-infarction and cardiac death.
To evaluate the influence of elevated body mass index (BMI) on short- and long-term survival following acute myocardial infarction (AMI). Recent studies suggest an obesity survival paradox in individuals undergoing percutaneous coronary intervention with better 30-day and 1-year outcomes in obese relative to normal weight patients. We tested a similar obesity paradox hypothesis following acute myocardial infarction. Short- and long-term all-cause mortality, and risk of recurrent AMI were evaluated according to BMI status in 894 consecutive survivors of AMI <80 years of age admitted to the Mayo Clinic Coronary Care Unit between January 1, 1988 and April 16, 2001. Normal weight, overweight and obesity were defined as BMI <25, 25-29.9, and >30 kg/m(2), respectively. Overall mortality following hospital discharge was significantly lower in overweight and obese patients and was mostly attributable to lower 6-month mortality (adjusted HR = 0.47, P = 0.01 for BMI >25 kg/m(2)) relative to normal weight patients, while long-term mortality among 6-month survivors was similar in all 3 groups. The risk of recurrent AMI was higher in patients with BMI >25 kg/m(2) (adjusted HR = 2.30, P = 0.01). Overweight and obese patients were significantly more likely to die from cardiac rather than non-cardiac causes (P < 0.01). Following AMI, overweight and obese individuals although paradoxically protected from short-term death have a long-term mortality risk that is similar to normal weight individuals. Younger age at the time of initial infarction and fewer non-cardiovascular comorbidities presumably explain the short-lived obesity survival paradox following myocardial infarction.


Influence of organic acids on heat resistance characteristics of Talaromyces flavus ascospores.
Three strains of Talaromyces flavus were investigated for their tolerance to organic acids during and after exposure to elevated temperatures. Fumaric, sorbic and benzoic acids were clearly more lethal than acetic, malic, citric and tartaric acids, and lethality was enhanced as the pH of the heating medium was reduced from 5.0 to 2.5. The effects of sorbic and benzoic acids on viability of ascospores varied depending upon the strain and were influenced by other constituents in the heating medium. Ascospores of a T. flavus strain with greater heat tolerance were larger and less ellipsoid in shape than ascospores of a less heat-tolerant strain, as observed by scanning electron microscopy. While both strains are known to develop heat resistance with age, no external differences in shape, degree of ornamentation and size could be discerned between ascospores as influenced by age (11 and 51 day old) of cultures.


Purification and characterization of Leydig cell luteinizing hormone receptor.
We have purified the testicular luteinizing hormone (LH/human choriogonadotropin (hCG)) receptor by sequential affinity chromatography on hCG-Sepharose. The purified LH/hCG receptor was identified as a single protein of Mr = 90,000 +/- 2,000 on sodium dodecyl sulfate-gel electrophoresis (SDS-PAGE), showed high affinity binding for hCG, and a binding capacity of 3.8 nmol/mg of protein. Electrophoretically blotted receptor retained the ability to bind 125I-hCG on nitrocellulose membrane, and the Mr of radioactive band was consistent with that revealed by silver staining. Autoradiography after SDS-PAGE analysis of cross-linked purified receptor-hCG complex showed Mr = 145,000 and Mr = 105,000 bands. These results are consistent with a Mr value for the receptor of 90,000 after accounting for contribution by the intact hormone or its alpha-subunit. Analysis of the free receptor by fast protein liquid chromatography on Superose 12 revealed a single peak of binding activity for 125I-hCG which eluted in the position of Mr = 200,000-240,000 in the presence of Triton X-100. Since a single protein species is observed under reducing or nonreducing conditions in SDS-PAGE, the receptor could exist in the membrane as a dimeric form composed of subunits Mr = 90,000 associated through noncovalent interactions. The pure receptor can be phosphorylated in vitro by the catalytic subunit of cAMP-dependent protein kinase (approximately 0.3 mol of phosphate/mol of receptor). This phosphorylation does not affect the binding characteristics of the receptor. The method described is simple and allows rapid purification of microgram amounts of biological active Leydig cell LH/hCG receptor for structural, functional, and immunological studies.


Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis.
Familial adenomatous polyposis (FAP) is a dominantly inherited condition predisposing to colorectal cancer. The recent isolation of the responsible gene (adenomatous polyposis coli or APC) has facilitated the search for germ line mutations in affected individuals. Previous authors have used the RNase protection assay and the single-strand conformation polymorphisms procedure to screen for mutations. In this study we used denaturing gradient gel electrophoresis (DGGE). DGGE analysis of 10 APC exons (4, 5, 7, 8, 9, 10, 12, 13, 14, and part of 15) in 33 unrelated Dutch FAP patients has led to the identification of eight novel germ line mutations resulting in stop codons or frameshifts. The results reported here indicate that (1) familial adenomatous polyposis is caused by an extremely heterogeneous spectrum of point mutations; (2) all the mutations found in this study are chain terminating; and (3) DGGE represents a rapid and sensitive technique for the detection of mutations in the unusually large APC gene. An extension of the DGGE analysis to the entire coding region in a sufficient number of clinically well-characterized, unrelated patients will facilitate the establishment of genotype-phenotype correlations. On the other hand, the occurrence of an extremely heterogeneous spectrum of mutations spread throughout the entire length of the large APC gene among the FAP patients indicates that this approach may not be useful as a rapid presymptomatic diagnostic procedure in a routine laboratory. Nevertheless, the above DGGE approach has incidentally led to the identification of a common polymorphism in exon 13. Such intragenic polymorphisms offer a practical approach to a more rapid procedure for presymptomatic diagnosis of FAP by linkage analysis in informative families.


Per- and polyfluoroalkyl substances target and alter human prostate stem-progenitor cells.
Per- and polyfluorinated alkyl substances (PFAS) are a large family of widely used synthetic chemicals that are environmentally and biologically persistent and present in most individuals. Chronic PFAS exposure have been linked to increased prostate cancer risk in occupational settings, however, underlying mechanisms have not been interrogated. Herein we examined exposure of normal human prostate stem-progenitor cells (SPCs) to 10 nM PFOA or PFOS using serial passage of prostasphere cultures. Exposure to either PFAS for 3-4 weeks increased spheroid numbers and size indicative of elevated stem cell self-renewal and progenitor cell proliferation. Transcriptome analysis using single-cell RNA sequencing (scRNA-seq) showed 1) SPC expression of PPARs and RXRs able to mediate PFAS effects, 2) the emergence of a new cell cluster of aberrantly differentiated luminal progenitor cells upon PFOS/PFOA exposure, and 3) enrichment of cancer-associated signaling pathways. Metabolomic analysis of PFAS-exposed prostaspheres revealed increased glycolytic pathways including the Warburg effect as well as strong enrichment of serine and glycine metabolism which may promote a pre-malignant SPC fate. Finally, growth of in vivo xenografts of tumorigenic RWPE-2 human prostate cells, shown to contain cancer stem-like cells, was markedly enhanced by daily PFOS feeding to nude mice hosts. Together, these findings are the first to identify human prostate SPCs as direct PFAS targets with resultant reprogrammed transcriptomes and metabolomes that augment a preneoplastic state and may contribute to an elevated prostate cancer risk with chronic exposures.


Lessons learned from a decade of clinical trials of high-dose chemotherapy in ovarian cancer.
Ovarian cancer is one of the most chemosensitive solid tumors and therefore a good example to explore high-dose chemotherapy (HDC). Interest in pursuing this treatment arose in the late 1980s following the success of HDC in treating hematological cancers and improvements in supportive care with peripheral blood stem cells. Experience from phase II trials and analysis of Bone Marrow Transplant Registry data led to the launch of several randomized phase III trials in the late 1990 s. Initial enthusiasm for this treatment was in part due to the preliminary positive data emerging from HDC in breast cancer. Five randomized trials of HDC in ovarian cancer have been conducted and all experienced difficulty in recruitment. Their different designs and results are reviewed, as well as some of the lessons that have been learned about HDC in solid tumors in the last decade.


Erratum to: Humanization of the mouse mammary gland by replacement of the luminal layer with genetically engineered preneoplastic human cells.
Due to a typesetting error, the labelling was changed and the figures in this article [1] were presented in the order 2, 4, 10, 6, 1, 3, 5, 7, 8, 9, 11, 12, 13, 14 and the supplementary figure links were inverted. The revised version has the figures in the correct order.


Doppler sonography and color duplex imaging for planning a perforator flap.
The most critical factor to predict viability for any muscle perforator flap is an adequate circulation. Therefore, it is advantageous during preoperative planning to have the capability to localize the requisite cutaneous perforator. Color duplex imaging fulfills this requirement and permits the identification of additional characteristics, including caliber, course, and flow velocity of essential perforators and any source vessel. Nevertheless, with the current state of technology, Doppler sonography remains a more rapid, convenient, and simpler method for perforator localization.


Effects of various dietary selenium intakes on the levels of blood glutathione-peroxidase and selenium in long-term fed rats.
Female Sprague-Dawley rats were fed a torula diet or wheat diets containing 4 levels of Se partially supplemented (24-402 ppb) for 120 days. Selenium content and glutathione-peroxidase (GSH-Px) activity in plasma and erythrocytes were measured every 20 days. In rats fed torula diet or basal wheat diet, plasma Se (P-Se) increased for up to 60 days, then remained constant, while erythrocytes Se (E-Se) and E-GSH-Px decreased in basal-diet rats during the first 40-60 days, then increased. In rats fed supplemented diets, P-Se and P-GSH-Px increased more rapidly than E-Se and E-GSH-Px, plateauing at 60-80 days. The best correlation was found between P-GSH-Px and dietary Se indicating that this index is the most sensitive for evaluating changes resulting from different Se intakes. In addition, correlations became more significant with time. The results from rats fed a low Se diet suggest the existence of regulatory mechanisms working in different ways and at different times in plasma and erythrocytes.


Coronavirus - A Crippling Affliction to Humans.
Coronaviruses hold idiosyncratic morphological features and functionality. The members of this group have a remarkable capability of infecting both animals and humans. Inimitably, the replication of the RNA genome continues through the set of viral mRNA molecules. Coronaviruses received least attention until 2003 since they caused only minor respiratory tract illnesses. However, this changed exclusively with the introduction of zoonotic SARS-CoV in 2003. In 2012, MERS-CoV emerged and confirmed this group of viruses as the major causative agents of severe respiratory tract illness. Today, Coronavirus Disease 2019 (i.e., COVID-19) has turned out to be a chief health problem that causes a severe acute respiratory disorder in humans. Since the first identification of COVID-19 in December 2019 in Wuhan, China, this infection has devastatingly spread all around the globe leading to a crippling affliction for humans. The strain is known as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and WHO (the World Health Organization) has termed this new pandemic disease as Coronavirus Disease (COVID-19). COVID-19 is still spreading, with an estimated 136 million confirmed cases and more than 2.94 million deaths worldwide so far. In the current scenario, there is no particular treatment for COVID-19; however, remarkable efforts for immunization and vaccine development can be observed. Therefore, the execution of precautions and proper preventive measures are indispensable to minimize and control the community transmission of the virus. This review summarizes information related to the pathophysiology, transmission, symptoms, the host defense mechanism plus immunization and vaccine development against COVID-19 including the patents filed.


Measuring Pedestrian Collision Detection With Peripheral Field Loss and the Impact of Peripheral Prisms.
Peripheral field loss (PFL) due to retinitis pigmentosa, choroideremia, or glaucoma often results in a highly constricted residual central field, which makes it difficult for patients to avoid collision with approaching pedestrians. We developed a virtual environment to evaluate the ability of patients to detect pedestrians and judge potential collisions. We validated the system with both PFL patients and normally sighted subjects with simulated PFL. We also tested whether properly placed high-power prisms may improve pedestrian detection. A virtual park-like open space was rendered using a driving simulator (configured for walking speeds), and pedestrians in testing scenarios appeared within and outside the residual central field. Nine normally sighted subjects and eight PFL patients performed the pedestrian detection and collision judgment tasks. The performance of the subjects with simulated PFL was further evaluated with field of view expanding prisms. The virtual system for testing pedestrian detection and collision judgment was validated. The performance of PFL patients and normally sighted subjects with simulated PFL were similar. The prisms for simulated PFL improved detection rates, reduced detection response times, and supported reasonable collision judgments in the prism-expanded field; detections and collision judgments in the residual central field were not influenced negatively by the prisms. The scenarios in a virtual environment are suitable for evaluating PFL and the impact of field of view expanding devices. This study validated an objective means to evaluate field expansion devices in reproducible near-real-life settings.


Polypyrimidine tract binding protein 1 (PTBP1) contains a novel regulatory sequence, the rBH3, that binds the prosurvival protein MCL1.
The maturation of RNA from its nascent transcription to ultimate utilization (e.g., translation, miR-mediated RNA silencing, etc.) involves an intricately coordinated series of biochemical reactions regulated by RNA-binding proteins (RBPs). Over the past several decades, there has been extensive effort to elucidate the biological factors that control specificity and selectivity of RNA target binding and downstream function. Polypyrimidine tract binding protein 1 (PTBP1) is an RBP that is involved in all steps of RNA maturation and serves as a key regulator of alternative splicing, and therefore, understanding its regulation is of critical biologic importance. While several mechanisms of RBP specificity have been proposed (e.g., cell-specific expression of RBPs and secondary structure of target RNA), recently, protein-protein interactions with individual domains of RBPs have been suggested to be important determinants of downstream function. Here, we demonstrate a novel binding interaction between the first RNA recognition motif 1 (RRM1) of PTBP1 and the prosurvival protein myeloid cell leukemia-1 (MCL1). Using both in silico and in vitro analyses, we demonstrate that MCL1 binds a novel regulatory sequence on RRM1. NMR spectroscopy reveals that this interaction allosterically perturbs key residues in the RNA-binding interface of RRM1 and negatively impacts RRM1 association with target RNA. Furthermore, pulldown of MCL1 by endogenous PTBP1 verifies that these proteins interact in an endogenous cellular environment, establishing the biological relevance of this binding event. Overall, our findings suggest a novel mechanism of regulation of PTBP1 in which a protein-protein interaction with a single RRM can impact RNA association.


Complement C3a receptor antagonist alleviates tau pathology and ameliorates cognitive deficits in P301S mice.
Human tauopathies, including Alzheimer's disease (AD), are a major class of neurodegenerative diseases characterized by intracellular deposition of pathological hyperphosphorylated forms of Tau protein. Complement system is composed of many proteins, which form a complex regulatory network to modulate the immune activity in the brain. Emerging studies have demonstrated a critical role of complement C3a receptor (C3aR) in the development of tauopathy and AD. The underlying mechanisms by which C3aR activation mediates tau hyperphosphorylation in tauopathies, however, remains largely unknown. Here, we observed that the expression of C3aR is upregulated in the brains of P301S mice - a mouse model of tauopathy and AD. Pharmacologic blockade of C3aR ameliorates synaptic integrity and reduced tau hyperphosphorylation in P301S mice. Besides, the administration of C3aR antagonist (C3aRA: SB 290157) improved spatial memory as tested in the Morris water maze. Moreover, C3a receptor antagonist inhibited tau hyperphosphorylation by regulating p35/CDK5 signaling. In summary, results suggest that the C3aR plays an essential role in the accumulation of hyperphosphorylated Tau and behavioral deficits in P301S mice. C3aR could be a feasible therapeutic target for the treatment of tauopathy disorders, including AD.


Enhanced charge carrier transfer process in nickel titanate nanostructures for environmental remediation of industrial dye.
The effective charge carrier transfer process in one-dimensional (1D) NiTiO3 nanofibers and NiTiO3 nanoparticles was demonstrated experimentally, showcasing an effective photocatalytic enhancement under visible light ambience. The rhombohedral crystal structure of NiTiO3 nanostructures was confirmed using X-ray diffractometer (XRD). The morphology and optical characteristics of the synthesized nanostructures were characterized using scanning electron microscopy (SEM) and UV-visible spectroscopy (UV-Vis). Nitrogen adsorption-desorption analysis corresponding to NiTiO3 nanofibers showcased porous structures with an average pore size of ~3.9 nm. The photoelectrochemical (PEC) measurement studies revealed an enhanced photocurrent for the NiTiO3 nanostructures, confirming enhanced charge carriers transportation in fibers than in particles due to the delocalized electrons in the conduction band, thereby hindering the photoexcited charge carrier's recombination. The photodegradation efficiency of methylene blue (MB) dye under the visible light irradiation revealed an enhancement in the rate of degradation for NiTiO3 nanofibers when compared to NiTiO3 nanoparticles.


GH-independent cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to dilated and ischemic cardiomyopathy.
To investigate acute cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to ischemic (iCMP) and dilated cardiomyopathy (dCMP). We studied the effect of intravenous hexarelin administration on growth hormone (GH) levels and left ventricular ejection fraction (LVEF) evaluated by radionuclide angiography in eight patients with dCMP (age 53.0+/-2.8, LVEF 16.7+/-2.1%) and five patients with iCMP (age 52.0+/-2.8 years, LVEF 22.6+/-2.1). Results were compared with a group of seven normal subjects (age 37.4+/-3.4 years, LVEF 64.0+/-1.5%) and seven patients with severe growth-hormone deficiency (GHD; age 42.0+/-4.4 years, LVEF 50.0+/-1.9%) previously studied with the same methodology. In dCMP and iCMP patients hexarelin induced a similar significant (P<0.05) increase in GH levels. In iCMP patients hexarelin induced a LVEF increase (peak LVEF 26.2+/-2.5%, P<0.05) as observed in normals and GHD, while in dCMP LVEF was unchanged (peak LVEF 17.7+/-1.7, P=NS). In all groups other hemodynamic parameters were unchanged. Acute hexarelin administration increases LVEF in iCMP patients (as in normals and GHD) but not in dCMP patients in spite of a similar GH releasing effect and basal LVEF. A possible explanation of the positive inotropic effect of hexarelin in iCMP could be a direct stimulation on viable myocardium or myocardial contractile reserve.


Simplifying mental math: Changing how added sugars are displayed on the nutrition facts label can improve consumer understanding.
Proposed variations to Nutrition Facts Labels (NFL) have included the display of added sugars (AS) content, but its impact on consumer understanding is poorly understood. To examine the degree to which different formats for displaying AS influence consumer understanding, perceptions, and purchase intentions. Randomized-controlled online experiment. A sample of 2509 U.S adults. Participants were randomized to 1 of 8 conditions and viewed 10 food or beverage images with either: (1) no label (control); (2) the current NFL (without AS); (3) the proposed NFL without AS; or the proposed NFL with AS in (4) grams, (5) grams and teaspoons, (6) grams and percent Daily Value (%DV), (7) grams with high/medium/low text, or (8) grams with high/medium/low text and %DV. ANCOVAs compared scores on quizzes that assessed the accuracy of judgments about AS, overall nutrition understanding and purchase intentions. Presenting AS in grams plus high/medium/low text with and without %DV led to the highest AS understanding scores (85% and 83% correct, respectively) compared to 70% correct when AS was not on the label or was displayed in grams only (74% correct). Displaying AS in teaspoons did not significantly improve understanding beyond grams alone. Consumers were best able to determine which of two products was healthier when AS was presented as %DV (68% correct) versus displayed in grams alone (60% correct), but %DV did not differ from high/medium/low text or teaspoons. None of the labels influenced purchase intentions relative to no label. Displaying AS on the NFL in grams with high/medium/low text, %DV, or the combination of the two, improved consumer understanding more than presenting it in grams or teaspoons.


Characterization of hepatitis B virus X gene: in vitro translation of mRNA from COS-1 cells transfected with the X gene.
To elucidate the biological role of the X region of HBV DNA, we constructed an expression plasmid pSV2HBx by inserting the StuI/BglII fragment of HBV DNA into the pSV2 vector. Although X region products were not identified in vivo in transfected COS-1 cells, transcripts were translated in vitro and a 17-k Da protein was immunoprecipitated with an antibody raised against a synthetic peptide corresponding to the carboxy terminus of the X region open reading frame. Among 68 HBV carrier sera tested, two were found to contain antibodies reactive to the in vitro translation product. These results suggest that the X region is a gene which can be actually expressed at some stage of HBV infection.


Gastrointestinal malignancies in a young tropical African population.
The records of 695 patients with confirmed gastroenterological malignancies over a 10 year period (January 1976-December 1985) were analysed. Of these, 264 patients (37.98%) were below the age of 40 years. Primary liver cell carcinoma was the commonest malignancy while gallbladder and oropharyngeal cancers were the least common. Most of the patients (66.3%) were in their fourth decade. The prognosis was poor as most of the patients presented late.


View from beneath: pathology in focus. Synovial sarcoma of hypopharynx.
Synovial sarcoma of the hypopharynx is a rare neoplasm. To date only 23 cases of synovial sarcoma of the hypopharynx have been reported in the literature. An additional case in an 18-year-old male is presented. This is the first case of synovial sarcoma in the hypopharynx to be reported in Singapore. The presentation was that of a mass in the hypopharynx; progressive dysphagia, intermittent hoarseness and gradual airway compromise. A CT scan was valuable in determining the site of origin and extent of the lesion. Histopathology was diagnostic. Treatment comprised of wide surgical excision of the tumour and post-operative radiotherapy.


Anthracycline incorporation in human lymphocytes. Kinetics of uptake and nuclear concentration.
Fluorescence emission spectra from anthracycline-treated cells suspended in buffer have been studied. The kinetics of uptake and the nuclear concentration of anthracyclines in human lymphocytes have thus been determined using the fluorescence properties of these drugs. Four anthracyclines have been used: adriamycin (ADR), 4'-O-tetrahydropyranyl-adriamycin (THP-ADR), carminomycin (CAR) and aclacinomycin A (ACM). We have shown that no quenching of the drug fluorescence is obtained through interaction of the drugs with the various components of the cell except the nucleus. No quenching is observed with cells lacking nucleus such as platelets and erythrocytes. Quenching of drug fluorescence occurs when drugs intercalate between base pairs of DNA only. This allows rapid determination of the amount of drug intercalated between nuclear base pairs in the steady state. We have thus estimated that one molecule of drug can bind for every 10, 8.3, 10 and 6.7 DNA base pairs in the case of ADR, THP-ADR, ACM and CAR, respectively. The kinetics of drug incorporation into the nucleus, once the cells have been solubilized with triton X-100, is very fast for the four drugs. However, the kinetics of drug uptake by the intacts cells strongly depends on the nature of the drug. When 10(9) cells/l are incubated with 1 microM drug, 50% of the final nuclear concentration is reached within 97 min, 3.2 min, 3.0 min and 1.2 min in the case of ADR, THP-ADR, CAR and ACM, respectively. The kinetics directly correlates with the polarity of the molecule.


Presence of metallo-beta-lactamases (MBL), extended-spectrum beta-lactamase (ESBL) & AmpC positive non-fermenting Gram-negative bacilli among Intensive Care Unit patients with special reference to molecular detection of blaCTX-M & blaAmpC genes.
Non-fermenting Gram-negative bacilli (NFGNB) including Pseudomonas aeruginosa and Acinetobacter baumannii have been implicated in a variety of infections, particularly in the Intensive Care Units (ICUs). This study was aimed to overview the burden of multidrug-resistant NFGNB causing infections in ICU and also to assess the occurrence of extended-spectrum beta-lactamases (ESBLs), AmpC and metallo-beta-lactamases (MBLs) among these isolates. Bacterial culture, identification and antibiotic susceptibility were carried out. ESBLs and AmpC were detected both phenotypically and genotypically. MBL was detected by modified Hodge and imipenem-ethylenediaminetetraacetic acid double-disc synergy test. NFGNB represented 45 (37%) of total 121 Gram negative isolates. Multidrug resistance was observed in 66.9 per cent and 72.5 per cent isolates of P. aeruginosa and A. baumannii, respectively. Detection by phenotypic methods showed presence of ESBL, AmpC and MBL in 21.4, 51.1 and 21.4 per cent isolates, respectively. When detected genotypically by polymerase chain reaction, ESBL and AmpC were detected in 21.4 and 41.4 per cent of NFGNB isolates, respectively. BlaCTX-M (21.4%) was the most prevalent gene responsible for ESBL production. Most of the NFGNB isolated from ICU patients were multidrug-resistant and producers of ESBL, AmpC and MBL. A regular surveillance is required to detect ESBL, AmpC and MBL producers, especially in ICU patients.


The effect of subarachnoid erythrocyte lysate on brain injury: a preliminary study.
Abundant erythrocytes remain and lyse partially in the subarachnoid space after severe subarachnoid haemorrhage (SAH). But the effect of subarachnoid erythrocyte lysate on brain injury is still not completely clear. In this study, autologous erythrocytes (the non-lysate group) and their lysate (the lysate group) were injected separately into the cistern magna of rabbits to induce a model of experimental SAH, although the control group received isotonic sodium chloride solution instead of erythrocyte solution. Results showed that vasospasm of the basilar artery was observed at 72 h after experimental SAH, but there was no significant difference between the non-lysate group and the lysate group. Brain injury was more severe in the lysate group than in the non-lysate group. Meanwhile, the levels of peroxiredoxin 2 (Prx2), IL-6 and TNF-α in brain cortex and in CSF were significantly higher in the lysate group than those in the non-lysate group. These results demonstrated that brain injury was more likely to be caused by erythrocyte lysate than by intact erythrocytes in subarachnoid space, and inflammation response positively correlated with Prx2 expression might be involved in mechanism of brain injury after SAH.


Diagnosis of pancreatic cancer by endoscopic retrograde cholangiopancreatography and pancreozymin secretin test.
Eighy cases with carcinoma of the pancreas were divided into 10 groups according to the location and size of the tumor. Drip infusion cholangiography, percutaneous transphepatic cholangiography, hypotonic duodenography and endoscopic retrograde cholangiopancreatography were employed for this classification. Comparison of cholangiopancreatograms (ERCP) with results of the biliary and pancreatic secretory function assessed by pancreozymin secretin test (PS test clarifies secretory capacity of the exocrine pancreas. But combination of ERCP and PS test with cytology is necessary for the correct diagnosis of the pancreatic cancer and it is hoped that the combination may excavate the disease in the early stage.


The 2007 national practice benchmark: results of a national survey of oncology practices.
Long-term trends in the cost of pharmaceutical goods purchased by community oncology practices seem to have dramatically changed in 2007, potentially ending an era of practice growth built on the economic engine of in-office chemotherapy provision.


Genetic manipulation of photosynthesis to enhance crop productivity under changing environmental conditions.
Current global agricultural production needs to be increased to feed the unconstrained growing population. The changing climatic condition due to anthropogenic activities also makes the conditions more challenging to meet the required crop productivity in the future. The increase in crop productivity in the post green revolution era most likely became stagnant, or no major enhancement in crop productivity observed. In this review article, we discuss the emerging approaches for the enhancement of crop production along with dealing to the future climate changes like rise in temperature, increase in precipitation and decrease in snow and ice level, etc. At first, we discuss the efforts made for the genetic manipulation of chlorophyll metabolism, antenna engineering, electron transport chain, carbon fixation, and photorespiratory processes to enhance the photosynthesis of plants and to develop tolerance in plants to cope with changing environmental conditions. The application of CRISPR to enhance the crop productivity and develop abiotic stress-tolerant plants to face the current changing climatic conditions is also discussed.


Transferrin receptors on human B and T lymphoblastoid cell lines.
Experiments demonstrating the existence of receptors for iron-saturated transferrin on both B and T lymphoblastoid cell lines of human origin are described. Binding of 125I-labeled transferrin is rapid, saturable and reversible. It can be specifically inhibited by unlabeled transferrin but not by other proteins. The number of receptors on T cell lines determined by Scatchard analysis is almost double the number on B cell lines but the binding affinities are equal. The putative transferrin receptor can be removed from the cell by the proteolytic enzymes papain and trypsin, and is re-expressed during overnight incubation at 37 degrees C. Resynthesis is inhibited by puromycin. The receptor can be solubilized by deoxycholate, and retains transferrin binding capacity when non-covalently attached to an amphipathic matrix consisting of deoxycholate-coupled poly(L-lysyl) Agarose.


[Localization of the gene for phosphoglycolate phosphatase (PGP) on the chromosome 16 by interspecific hybridization (author's transl)].
Eight primary man-mouse (C11D/TK-) hybrids, twenty three primary and seven secondary man-hamster (CH/HGPRT-) were analyzed for human phosphoglycolate phosphatase (PGP) and for human chromosomes. The following results were obtained: 1. A positive correlation is observed between the chromosome 16 and PGP. 15 hybrids are chr.16+PGP+, 14 hybrids are chr.16-PGP- and 4 hybrids are chr.16-PGP+. 2. The percentage of dissociation between PGP and the chr.16 is low (12%) in comparison with the high percentage of dissociation between PGP and the other autosomes (between 37% and 65%). 3. Excepted the chromosome 16, the other autosomes are observed in hybrids PGP-. These different results indicate the localization of the gene for human PGP on the chromosome 16. The dissociation results chr.16-PGP+ are explained by the breakage of the chr.16 in the hybrids.


Correction: Improved bladder contractility after transplantation of human mesenchymal stem cells overexpressing hepatocyte growth factor into underactive bladder from bladder outlet obstruction models of rats.
[This corrects the article DOI: 10.1371/journal.pone.0261402.].


Multi-scale alignment of respiratory cilia and its relation to mucociliary function.
The tracheobronchial tree is lined by a mucociliary epithelium containing millions of multiciliated cells. Their integrated oscillatory activity continuously propels an overlying pollution-protecting mucus layer in cranial direction, leading to mucociliary clearance - the primary defence mechanism of the airways. Mucociliary transport is commonly thought to co-emerge with the collective ciliary motion pattern under appropriate geometrical and rheological conditions. Proper ciliary alignment is therefore considered essential to establish mucociliary clearance in the respiratory system. Here, we used volume electron microscopy in combination with high-speed reflection contrast microscopy in order to examine ciliary orientation and its spatial organization, as well as to measure the propagation direction of metachronal waves and the direction of mucociliary transport on bovine tracheal epithelia with reference to the tracheal long axis (TLA). Ciliary orientation is measured in terms of the basal body orientation (BBO) and the axonemal orientation (AO), which are commonly considered to coincide, both equivalently indicating the effective stroke as well as the mucociliary transport direction. Our results, however, reveal that only the AO is in line with the mucociliary transport, which was found to run along a left-handed helical trajectory, whereas the BBO was found to be aligned with the TLA. Furthermore, we show that even if ciliary orientation remains consistent between adjacent cells, ciliary orientation exhibits a gradual shift within individual cells. Together with the symplectic beating geometry, this intracellular orientational pattern could provide for the propulsion of highly viscous mucus and likely constitutes a compromise between efficiency and robustness.


Exclusion of fluid lipid during compression of monolayers of mixtures of dipalmitoylphosphatidylcholine with some other phosphatidylcholines.
Monolayers composed of dipalmitoylphosphatidylcholine and one of four fluid phosphatidylcholines have been studied for their ability to attain low minimum surface tension during compression at two different speeds. The minimum surface tension depended on the compression rate and the proportions of the fluid and rigid lipid in the monolayer. The type of fluid lipid used in the monolayer also affected the minimum surface tension.


Impact of Bladder Neck Involvement on Recurrence in Patients With Non-muscle-invasive Bladder Cancer: An Analysis Based on a Time-dependent Model.
Tumor location in bladder neck has reported to be a prognostic factor for non-muscle-invasive bladder cancer (NMIBC). We investigated the impact of bladder neck involvement (BNI) on recurrence in NMIBC using time-dependent covariate analysis. We enrolled 585 Japanese patients who underwent transurethral resection for bladder tumors at a single center from 2000 to 2016 and were pathologically diagnosed with Ta and T1 NMIBC. Each patient at each recurrence was assigned to a separate time-dependent stratum with its own baseline hazard function according to the Prentice-Williams-Peterson gap time model for analyzing recurrent events. Over a median follow-up period of 41.3 months (interquartile range, 18.0-82.3 months), 253 (43.2%) patients experienced a total of 475 recurrences. Among the 1001 total transurethral resection procedures, BNI was observed in 122 (12.2%) cases. The 3-year cumulative recurrence rates of patients with and without BNI were 62.5% and 46.3%, respectively. Multivariable analysis revealed that number of tumors ≥ 4 (sub-hazard ratio [SHR], 1.48; P = .004), intravesical bacillus Calmette-Guérin therapy (SHR, 0.44; P < .001), and BNI (SHR, 1.59; P = .004) were all independent predictors of recurrence. Assigning 1 point for each of these 3 predictive factors, the resulting scores enabled us to classify patients into 3 prognostic groups that were clearly stratified according to recurrence. Our time-dependent covariate analysis shows that BNI is a significant risk factor for recurrence in NMIBC. Our prognostic model incorporating BNI is an easy means of estimating recurrence risk and determining optimal management for individual patients.


N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics.
Cysteine has been exploited as the binding site of covalent drugs. Its high sensitivity to oxidation is also important for regulating cellular processes. To identify new ligandable cysteines which can be hotspots for therapy and to better study cysteine oxidations, we develop cysteine-reactive probes, N-acryloylindole-alkynes (NAIAs), which have superior cysteine reactivity owing to delocalization of π electrons of the acrylamide warhead over the whole indole scaffold. This allows NAIAs to probe functional cysteines more effectively than conventional iodoacetamide-alkyne, and to image oxidized thiols by confocal fluorescence microscopy. In mass spectrometry experiments, NAIAs successfully capture new oxidized cysteines, as well as a new pool of ligandable cysteines and proteins. Competitive activity-based protein profiling experiments further demonstrate the ability of NAIA to discover lead compounds targeting these cysteines and proteins. We show the development of NAIAs with activated acrylamide for advancing proteome-wide profiling and imaging ligandable cysteines and oxidized thiols.


CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures.
Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q(10) deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ(10) deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.[1812_1813insG] were identified. The missense mutations were introduced into the yeast ABC1/COQ8 gene and expressed in a Saccharomyces cerevisiae strain in which the ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.


Minimally invasive management of bile leak after laparoscopic cholecystectomy.
Bile leakage is an uncommon complication of cholecystectomy.The bile may originate from the gallbladder bed, the cystic duct or rarely from injury to a major bile duct.This study aims to evaluate the efficacy of minimal access endoscopic and percutaneous techniques in treating symptomatic bile leak. Twenty-one patients with symptomatic bile leak following laparoscopic cholecystectomy underwent assessment of the extent of the bile leak via ultrasound/CT and ERCP. Following diagnosis, the patients were treated by sphincterotomy and biliary drainage and, if necessary, percutaneous drainage of the bile collection. Only one patient required primary surgical treatment following diagnosis of a major duct injury.The other 20 were treated by a combination of sphincterotomy (including a stent in most) plus percutaneous drainage in six. In 19 of 20, this minimal access approach stopped the leak. Most patients who present with bile leakage after cholecystectomy can be managed successfully by means of ERCP with percutaneous drainage of any large bile collection.


Pharmacokinetics of rimantadine hydrochloride in patients with chronic liver disease.
Six patients with chronic liver disease and six sex-, age (+/- 5 years)-, and weight (+/- 5 kg)-matched healthy control subjects received a single dose of two 100 mg tablets rimantadine HCl. Eight additional patients with chronic liver disease who were not matched to healthy subjects received a single dose of two 100 mg tablets of rimantadine HCl. Blood and urine samples were collected and rimantadine concentrations were determined by a GCMS method. The values for maximum plasma concentration, AUC, elimination half-life, and renal clearance were not significantly different between patients and control subjects, independent of the statistical analyses (parametric and nonparametric) used. The mean apparent elimination half-life, volume of distribution, and total clearance in the matched patients with liver disease were 32 hours, 24 L/kg, and 676 ml/min, respectively. Renal clearance and the amount excreted in the urine unchanged were 63 ml/min and 10%, respectively. In conclusion, rimantadine pharmacokinetics were not appreciably altered in patients with less severe chronic liver disease.


Enhanced recovery after surgery for the treatment of congenital duodenal obstruction.
Enhanced recovery after surgery (ERAS) has been widely used in adult surgery. However, ERAS has not been reported in neonatal surgery. The present prospective study explored the application value of ERAS in treating congenital duodenal obstruction (CDO). A total of 68 cases of CDO were collected from October 1, 2017 to July 31, 2019. We divided patients with a prenatal diagnosis of congenital duodenal obstruction into the ERAS group and those who were diagnosed the disease after birth into the control group. The ERAS group adopted ERAS-related measures, and the control group followed the usual measures. The study compared the differences in the gestational age, birth weight, length of hospital stay (LOS), complications, feeding intolerance, and weight one month after surgery between the two groups. A total of 49 patients were included in the analysis, including 23 who were allocated to the ERAS group and 26 to the control group. The LOS was 9.696±1.222 days in the ERAS group and 12.654±1.686 days in the control group, resulting in a significantly shorter LOS in the ERAS group than in the control group (p<0.001). One month after surgery, the neonates in the ERAS group weighted significantly more than those in the control group. No differences were observed in birth weight, gestational age, and the incidence of complications or feeding intolerance between the two groups. In this single-center study, the implementation of neonate-specific ERAS for CDO surgery was feasible and safe and led to a shorter LOS without increasing the incidence of complications or feeding intolerance. Treatment Study LEVEL OF EVIDENCE: Level III.


Outcomes and predictors of response to fractionated radiotherapy as primary treatment for intracranial meningiomas.
Surgery is the primary treatment for most meningiomas. However, primary fractionated radiotherapy (fRT) remains an option for patients with larger meningiomas in challenging anatomic locations or patients at prohibitively high surgical risk. Outcome prediction for these patients is uncertain and cannot be guided by histopathology without available tumor tissue from surgery. Therefore, we aimed to assess the clinical factors that contribute to treatment failure in a large cohort of meningiomas consecutively treated with fRT as primary therapy, with the goal of identifying predictors of response. Patients treated with primary fRT for intracranial meningiomas from 1998 to 2017 were reviewed. Those who received primary surgical resection, radiosurgery, previous fRT, or had <6 months of clinical follow-up were excluded. We applied logistic regression and Cox regression modeling to ascertain key predictors of treatment failure, progression-free survival (PFS), and adverse events (AE) following fRT. Our cohort included 137 meningiomas, 21 of which progressed after fRT (median PFS 3.45 years). Progressive meningiomas had a larger median gross tumor volume (GTV) compared to those that remained stable (19.1 cm3 vs 9.6 cm3, p = 2.86 × 10-2). GTV > 11.27 cm3 was independently predictive of progression and larger GTV was associated with higher risk of significant (grades 3/4) AE following fRT. Cavernous sinus and optic nerve sheath meningiomas had overall excellent outcomes post-fRT. We present a large cohort of meningiomas treated with primary fRT and find GTV and anatomic location to be key predictors of outcome, adding to the complex treatment considerations for this heterogeneous disease.


Sorption study of long-lived 94Nb on laterite: Effects of physicochemical parameters on sorption.
Zr-Nb alloy is used as the pressure tube in pressurized heavy water reactors (PHWR). Prolonged neutron irradiation of the pressure tubes leads to the formation of a long-lived radioisotope 94Nb. Thus, the discharged pressure tubes possess huge 94Nb activity which persists for a prolonged period.If these discharged pressure tubes come in contact with ground water, 94Nb isotope may leach and migrate and this can lead to a long-term radiological impact in the environment.In the present study, we have explored the capability of laterite as a filler material for the containment and retarding the migration of 94Nb. In this regard, detailed characterization of the laterite soil was carried out using energy dispersive X-ray fluorescence (EDXRF), X-ray diffraction (XRD), fourier transform infra-red spectrometry (FTIR), total cation exchange capacity determination, zeta potential measurement and thermogravimetric analysis (TGA). The sorption study of 94Nb on laterite was carried and the effects of different physico-chemical parameters like pH, ionic strength, temperature and equilibration time were evaluated. Ionic strength, temperature and time dependent sorption studies assist to explore the probable sorption mechanism of 94Nb on laterite, which helps in understanding the migration behaviour of 94Nb in natural aquatic environment. This study suggests that laterite is a promising material in containment of 94Nb isotope owing to its good cation exchange behaviour in the acidic medium and ability to form surface complex in the neutral medium.


Inconsistency of allometric scaling for dissociative anesthesia of wild felids.
To evaluate allometric scaling for ketamine-xylazine (KX) anesthesia in wild felids using domestic cats for reference. Prospective single-phase non-blinded study. Six domestic cats and 13 wild felids (five Leopardus pardalis, five Puma concolor, one Panthera onca and two Panthera leo). Six domestic cats (4.1 ± 0.8 kg, REF1) were anesthetized by intramuscular administration of ketamine (15 mg kg(-1) ) and xylazine (1 mg kg(-1) ). Wild cats were divided into three groups based on body weight: 12.9 ± 2.4 kg (G1; n = 7), 43.0 ± 15.7 kg (G2; n = 4) and 126.0 ± 7.8 kg (G3; n = 2). Ketamine and xylazine doses were calculated based on allometric scaling of the basal metabolic rate (BMR = 70 × body mass(0.75) ). Afterwards, the six domestic cats were administered mean KX doses calculated for G1 and G2 (REF2). The heart rate, systolic arterial pressure, respiratory frequency, pH, the venous partial pressure of carbon dioxide, bicarbonate and lactate concentrations were recorded for up to 60 minutes. Additional doses were required in 12 out of the 13 wild cats. Anesthesia was not achieved in G3. Latency periods in wild felids were longer than REF1 and REF2. Anesthesia duration in REF1 was longer than that in the other groups. Recovery from anesthesia in REF1 and REF2 was longer than G1 and G2. Physiological variables remained within the range limits for the species. G1 baseline lactate concentration was higher than in the other groups. KX anesthesia established by allometric scaling of BMR from doses administered to domestic cats did not predict reliable anesthetic doses for wild cats. Dose rates calculated with this method must not be applied to these species.


[The MDR3 gene mutation: a rare cause of progressive familial intrahepatic cholestasis (PFIC)].
A 47-year old man complained about persistant pain and cholestasis 12-years after a cholescystectomy. In his family, all his brothers and sisters had cholecystectomy. Genetic explorations revealed a MDR3 gene mutation. All symptoms disappeared with a treatment by ursodesoxycholic acid. MDR3 gene mutation is to be researched in all cases of familial cholestasis.


Development of in vitro embryo production systems for red deer (Cervus elaphus). Part 2. The timing of in vitro nuclear oocyte maturation.
The time course of in vitro red deer nuclear oocyte maturation was determined. Ovaries were obtained at slaughter and oocytes were aspirated from follicles greater than 2mm in diameter. Oocytes with compact cumulus cells were matured in 50 microl microdrops (10 per drop) under mineral oil containing TCM 199 supplemented with 0.33 mM pyruvate, 10 microg LH and FSH, 1 microg oestradiol and 10% foetal bovine serum. Oocytes were matured at 39 degrees C and 5% CO(2) in air. At 3h intervals (0-27 h) oocytes were removed from incubation, cumulus expansion scored and removed, and fixed oocytes in ethanol:acetic acid (3:1) for 48 h. Oocytes were stained with lacmoid (1%) and nuclear maturation assessed. Oocytes were arrested in the germinal vesicle (GV) stage at aspiration and up to 6h of incubation. The nuclear membrane began to disperse after 6h and by 10.6+/-0.6h of incubation 75% of the oocytes exhibited germinal vesicle breakdown (GVBD). The mean time for 50% of the oocytes to reach metaphase one (MI) and metaphase two (MII) was 11.7+/-0.4 and 24.8+/-0.9h, respectively. Cumulus oophorus were tightly compacted at aspiration and did not begin expansion until 12h of culture. Full expansion was complete by 18 h of culture. Corona radiata cells did not begin expansion until 15 h and were fully expanded by 24h. Results indicate that in vitro red deer oocyte maturation follows a similar time course of nuclear maturation as reported for bovine and ovine oocytes.


Diversity of the enzymatic activity in the lipoxygenase gene family of Arabidopsis thaliana.
Lipoxygenases (LOX) catalyze the oxygenation of polyunsaturated fatty acids, the first step in the biosynthesis of a large group of biologically active fatty acid metabolites collectively named oxylipins. In the present study we report the characterization of the enzymatic activity of the six lipoxygenases found in the genome of the model plant Arabidopsis thaliana. Recombinant expressed AtLOX-1 and AtLOX-5 had comparable oxygenase activity with either linoleic acid or linolenic acid. AtLOX-2, AtLOX-3, AtLOX-4 and AtLOX-6 displayed a selective oxygenation of linolenic acid. Analyses by high-performance liquid chromatography and gas chromatography-mass spectrometry demonstrated that AtLOX-1 and AtLOX-5 are 9S-lipoxygenases, and AtLOX-2, AtLOX-3, AtLOX-4 and AtLOX-6 are 13S-lipoxygenases. None of the enzymes had dual positional specificity. The determined activities correlated with that predicted by their phylogenetic relationship to other biochemically-characterized plant lipoxygenases.