MM-HAR: Multi-Modal Human Activity Recognition Using Consumer Smartwatch and Earbuds.
Human Activity Recognition (HAR) is one of the important applications of digital health that helps to track fitness or to avoid sedentary behavior by monitoring daily activities. Due to the growing popularity of consumer wearable devices, smartwatches, and earbuds are being widely adopted for HAR applications. However, using just one of the devices may not be sufficient to track all activities properly. This paper proposes a multi-modal approach to HAR by using both buds and watch. Using a large dataset of 44 subjects collected from both in-lab and in-home environments, we demonstrate the limitations of using a single modality as well as the importance of a multi-modal approach. Moreover, we also train and evaluate the performance of five different machine learning classifiers for various combinations of devices such as buds only, watch only, and both. We believe the detailed analyses presented in this paper may serve as a benchmark for the research community to explore and build upon in the future.


Intravenous infusions of heparin and penicillins.
The chemical stability and anticoagulant activity of heparin (20 U/ml) were studied in five intravenous fluids at room temperature. Heparin remained stable and active for 24 hours in normal saline, but there was a rapid inactivation of 40 to 55% in solutions containing dextrose or lactate, as measured by chemical and biological methods.High concentrations of benzylpenicillin, ampicillin, or methicillin had no effect on heparin activity in normal saline or dextrose 5%: nor was the stability of the penicillins in these fluids affected to any marked extent by the presence of heparin. Ampicillin was, however, found to be unstable in dextrose 5%, and it would be preferable for it not to be added to dextrose infusions. It is concluded that heparin may be given intravenously in normal saline with benzylpenicillin, ampicillin, or methicillin but several other antibiotics were found to be unsuitable for concurrent infusion with heparin.


Structurally similar triphenylphosphine-stabilized undecagolds, Au11(PPh3)7Cl3 and [Au11(PPh3)8Cl2]Cl, exhibit distinct ligand exchange pathways with glutathione.
Ligand exchange is frequently used to introduce new functional groups on the surface of inorganic nanoparticles or clusters while preserving the core size. For one of the smallest clusters, triphenylphosphine (TPP)-stabilized undecagold, there are conflicting reports in the literature regarding whether core size is retained or significant growth occurs during exchange with thiol ligands. During an investigation of these differences in reactivity, two distinct forms of undecagold were isolated. The X-ray structures of the two forms, Au11(PPh3)7Cl3 and [Au11(PPh3)8Cl2]Cl, differ only in the number of TPP ligands bound to the core. Syntheses were developed to produce each of the two forms, and their spectroscopic features correlated with the structures. Ligand exchange on [Au11(PPh3)8Cl2]Cl yields only small clusters, whereas exchange on Au11(PPh3)7Cl3 (or mixtures of the two forms) yields the larger Au25 cluster. The distinctive features in the optical spectra of the two forms made it possible to evaluate which of the cluster forms were used in the previously published papers and clarify the origin of the differences in reactivity that had been reported. The results confirm that reactions of clusters and nanoparticles may be influenced by small variations in the arrangement of ligands and suggest that the role of the ligand shell in stabilizing intermediates during ligand exchange may be essential to preventing particle growth or coalescence.


[Positive screening and risk factors of postpartum depression in women who attended antenatal courses].
This study was designed to evaluate the prevalence of women screened positive for postpartum depression (PPD) and to investigate the main risk factors for PPD, in a large sample of Italian women. The sample (N=567) was recruited as part of 91 antenatal courses. Women were screened between the 6th and 12th week after birth, by filling the EPDS (Edinburg Postnatal Depression Scale). The validated cut-off score of ≥12 was used. Socio-demographic and clinical variables were investigated. Out of the 567 screened women, 42 (7.4%) were positive. A higher risk was found in women who, during pregnancy, had a depressed mood (OR=3.2) or suffered from anxiety (OR=6.3), had little (OR=4.8) or no (OR=6.5) psychological support from friends or family, or their partner (OR=4.4), had a baby given to crying (OR=7.8), had a low self-esteem (OR=4.8), or had had, as children, a mother that was often (OR=4.6) or always (OR=12.5) critical of them. The results of the study are in agreement with the literature considering social and family support and the presence of anxiety and/or depression during pregnancy as main risk factors for PPD. In disagreement with previous studies on risk factors for depressive disorders, we found that the economic status was not associated to PPD.


Analysis of Pseudomonas exotoxin activation and conformational changes by using monoclonal antibodies as probes.
Pseudomonas exotoxin (PE) is a protein toxin composed of three structural domains. In its native form, the toxin is a 66,000-Mr proenzyme that must be activated to express full ADP-ribosylating activity. To study the process of activation and accompanying conformational changes, we have isolated 10 monoclonal antibodies to a 40,000-Mr fragment of the toxin (PE40) that exhibits full enzyme activity but lacks the toxin's cell-binding domain and contains amino acids 253 to 613 (comprising domains II, Ib, and III). By using mutant PE molecules in which all of domain I and portions of domains II, Ib, and III were deleted, the locations of the epitopes for each of the antibodies were determined. Eight of these monoclonal antibodies were further characterized. Of these eight, all reacted with soluble PE40 and an interleukin-2-PE40 conjugate, but only two reacted strongly with native soluble PE. However, all eight reacted with PE after it had been immobilized on nitrocellulose or after it had been activated to express full ADP-ribosylating activity. Antibodies were also assessed for their ability to neutralize the cytotoxic activity of either PE or interleukin-2-PE40. These antibodies should be useful as probes for monitoring the activation and processing of PE that occur during endocytosis and in determining the location of epitopes that are important for toxin activity.


Interaction of phosphatidylcholine and α-tocopherol on the oxidation of sunflower oil and content changes of phosphatidylcholine and tocopherol in the emulsion under singlet oxygen.
Interaction of phosphatidylcholine (PC) and α-tocopherol (α-Toc) on the oxidation of oil in the emulsion consisting of sunflower oil and water under singlet oxygen at 25 °C was studied by determining peroxide value (PV) and conjugated dienoic acid (CDA) contents. Singlet oxygen was produced by chlorophyll b under 1700 lux. Single addition of PC or α-Toc decreased the values of peroxides and CDAs of oil in the emulsion via singlet oxygen quenching. PC and α-Toc showed simply additive interaction in decreasing the singlet oxygen oxidation of oil in the emulsion. α-Toc was a physical quencher of singlet oxygen in the emulsion, but PC involved chemical quenching in the antioxidant action. Chlorophyll and PC contents were decreased in the emulsion under singlet oxygen, while α-Toc was not. α-Toc protected chlorophyll and PC from degradation, and was a more important component than PC in the oil oxidation under singlet oxygen in the emulsion.


S-glutathiolation in life and death decisions of the cell.
Reversible S-glutathiolation of specific proteins at sensitive cysteines provides a powerful mechanism for the dynamic, post-translational regulation of many cellular processes, including apoptosis. Critical in ascribing any regulatory function to S-glutathiolation is its reversibility, mainly regulated by glutaredoxins. Apoptosis is a controlled form of cell death that plays fundamental roles during embryonic development, tissue homeostasis and some diseases. Much of what happens during the demolition phase of apoptosis is orchestrated primarily by caspases, the final executioners of cell death. Recent findings support an essential role for S-glutathiolation in apoptosis, often at the level of caspases or their inactive precursors, and several studies have demonstrated the importance of glutaredoxins in protecting against apoptosis. These observations have contributed to recent advances in apoptosis research. However, the effective relevance of protein S-glutathiolation and the precise molecular targets in apoptotic signalling remain unresolved and a key challenge for future research.


In a spin: the mysterious dancing epidemic of 1518.
In 1518, one of the strangest epidemics in recorded history struck the city of Strasbourg. Hundreds of people were seized by an irresistible urge to dance, hop and leap into the air. In houses, halls and public spaces, as fear paralyzed the city and the members of the elite despaired, the dancing continued with mindless intensity. Seldom pausing to eat, drink or rest, many of them danced for days or even weeks. And before long, the chronicles agree, dozens were dying from exhaustion. What was it that could have impelled as many as 400 people to dance, in some cases to death?


In vitro susceptibility of Cryptococcus neoformans isolates to five antifungal drugs using a colorimetric system and the reference microbroth method.
Minimum inhibitory concentrations (MICs) of amphotericin B, 5-flucytosine, fluconazole, itraconazole and ketoconazole were determined against 42 clinical isolates of Cryptococcus neoformans var. neoformans using the Alamar YeastOne colorimetric method and the NCCLS reference microdilution method. No strains with resistance to amphotericin B, itraconazole or ketoconazole were detected with either method. Using the reference method, the MICs of fluconazole were >/= 64 mg/L, whereas using the colorimetric method all MICs were >/=16 mg/L. The MIC values of 5-flucytosine were also higher using the reference method (8-16 mg/L for 32% of isolates) compared with the colorimetric method. The percentage of agreement between the methods, using a difference of two dilutions, was 70.7% for itraconazole, 73.2% for amphotericin B, 80% for fluconazole, 88% for 5-flucytosine and 95% for ketoconazole. Overall, we conclude that for fluconazole and 5-flucytosine, in a low but not insignificant number of isolates, results with the two methods are discordant, some isolates being found sensitive with the colorimetric test, but resistant with the reference method.


Factors associated with parental intention to vaccinate their child against influenza, Finland, February to March, 2022: a web-based survey.
BackgroundInfluenza vaccination for children aged 6 months to 6 years is included in the national vaccination programme in Finland. Although all vaccines in the programme are free of charge, national coverage of influenza vaccination among children under 3 years and 3-6 years during 2020/21 was 43% and 35% respectively, with regional differences.AimTo assess factors underlying parental vaccination intention in order to increase influenza vaccine uptake among children.MethodsWe conducted a web-based survey among parents (n = 17,844) of randomly selected eligible children (aged 6 months-6 years) in February-March 2022 in five Finnish municipalities from regions of high and low coverage. Logistic regressions were used to determine associations between vaccination intention and e.g. sociodemographic factors, attitudes and knowledge. Linkage to the national vaccination register was used to confirm realisation of vaccination intention after the study.ResultsParticipation rate was 13% (n = 2,322 parents). Influenza knowledge, trust in official information, responding parent's education level, adherence to the vaccination programme, number of children and changes in attitudes towards vaccination since COVID-19 were all associated with intention to vaccinate. Vaccination intention for children was 64%, and realised vaccination 51%.ConclusionDespite the low participation rate, both vaccinated and unvaccinated children were represented. Influenza vaccine uptake is not dependent on a single factor. Our results identified the need for open dialogue between parents and healthcare professionals, as the lack of vaccine being offered by healthcare professionals was the most reported reason for not vaccinating.


Describing the RN-BSN learner perspective: concerns, priorities, and practice influences.
This focus group study describes the concerns and priorities of women who are Registered Nurse Students (RNs) students (N = 35) enrolled in RN-Bachelor of Science in Nursing (BSN) programs located within a large metropolitan region. The study also explores the influences of BSN education on the nursing practice patterns of the RN students from the participants' viewpoints. Five focus groups were conducted. Findings revealed that accurate academic advisement, curriculum flexibility, and computer technology are important to RN-BSN students. RNs were concerned about the demands of the changing health care environment, meeting multiple and competing role demands, and meeting the financial demands of school. Although the participants did not believe that BSN education had affected their direct care of patients, they identified changes in indirect care practices. This study suggests that nursing school deans, administrators, and faculties should offer opportunities for RNs to develop skills in assertiveness, problem solving, and communication. Additionally, study findings suggest that RNs need the opportunity to reflect on various strategies for incorporating their new knowledge into their established practice.


Investigation of N-Terminal Phospho-Regulation of Uracil DNA Glycosylase Using Protein Semisynthesis.
Uracil DNA Glycosylase (UNG2) is the primary enzyme in humans that prevents the stable incorporation of deoxyuridine monophosphate into DNA in the form of U/A basepairs. During S-phase, UNG2 remains associated with the replication fork through its interactions with two proteins, Proliferating Cell Nuclear Antigen (PCNA) and Replication Protein A (RPA), which are critical for DNA replication and repair. In this work, we used protein semisynthesis and fluorescence anisotropy assays to explore the interactions of UNG2 with PCNA and RPA and to determine the effects of two UNG2 phosphorylation sites (Thr6 and Tyr8) located within its PCNA-interacting motif (PIP-box). In binding assays, we found that phosphorylation of Thr6 or Tyr8 on UNG2 can impede PCNA binding without affecting UNG2 catalytic activity or its RPA interaction. Our data also suggests that unmodified UNG2, PCNA, and RPA can form a ternary protein complex. We propose that the UNG2 N-terminus may serve as a flexible scaffold to tether PCNA and RPA at the replication fork, and that post-translational modifications on the UNG2 N-terminus disrupt formation of the PCNA-UNG2-RPA protein complex.


Use of Cardiac Resynchronization Therapy Among Eligible Patients Receiving an Implantable Cardioverter Defibrillator: Insights From the National Cardiovascular Data Registry Implantable Cardioverter Defibrillator Registry.
Cardiac resynchronization therapy (CRT) reduces the risk for mortality and heart failure-related events in select patients. Little is known about the use of CRT in combination with an implantable cardioverter defibrillator (ICD) in patients who are eligible for this therapy in clinical practice. To (1) identify patient, clinician, and hospital characteristics associated with CRT defibrillator (CRT-D) use and (2) determine the extent of hospital-level variation in the use of CRT-D among guideline-eligible patients undergoing ICD placement. Multicenter retrospective cohort from 1428 hospitals participating in the National Cardiovascular Data Registry ICD Registry between April 1, 2010, and June 30, 2014. Adult patients meeting class I or IIa guideline recommendations for CRT at the time of device implantation were included in this study. Implantation of an ICD with or without CRT. A total of 63 506 eligible patients (88.6%) received CRT-D at the time of device implantation. The mean (SD) ages of those in the ICD and CRT-D groups were 67.9 (12.2) years and 68.4 (11.5) years, respectively. In hierarchical multivariable models, black race was independently associated with lower use of CRT-D (odds ratio [OR], 0.77; 95% CI, 0.71-0.83) as was nonprivate insurance (OR, 0.90; 95% CI, 0.85-0.95 for Medicare and OR, 0.73; 95% CI, 0.65-0.82 for Medicaid). Clinician factors associated with greater CRT-D use included clinician implantation volume (OR, 1.01 per 10 additional devices implanted; 95% CI, 1.01-1.01) and electrophysiology training (OR, 3.13 as compared with surgery-boarded clinicians; 95% CI, 2.50-3.85). At the hospital level, the overall median risk-standardized rate of CRT-D use was 79.9% (range, 26.7%-100%; median OR, 2.08; 95% CI, 1.99-2.18). In a national cohort of patients eligible for CRT-D at the time of device implantation, nearly 90% received a CRT-D device. However, use of CRT-D differed by race and implanting operator characteristics. After accounting for these factors, the use of CRT-D continued to vary widely by hospital. Addressing disparities and variation in CRT-D use among guideline-eligible patients may improve patient outcomes.


A Comparative Study of Biomechanical and Geometrical Attributes of Abdominal Aortic Aneurysms in the Asian and Caucasian Populations.
In this work, we provide a quantitative assessment of the biomechanical and geometric features that characterize abdominal aortic aneurysm (AAA) models generated from 19 Asian and 19 Caucasian diameter-matched AAA patients. 3D patient-specific finite element models were generated and used to compute peak wall stress (PWS), 99th percentile wall stress (99th WS), and spatially averaged wall stress (AWS) for each AAA. In addition, 51 global geometric indices were calculated, which quantify the wall thickness, shape, and curvature of each AAA. The indices were correlated with 99th WS (the only biomechanical metric that exhibited significant association with geometric indices) using Spearman's correlation and subsequently with multivariate linear regression using backward elimination. For the Asian AAA group, 99th WS was highly correlated (R2 = 0.77) with three geometric indices, namely tortuosity, intraluminal thrombus volume, and area-averaged Gaussian curvature. Similarly, 99th WS in the Caucasian AAA group was highly correlated (R2 = 0.87) with six geometric indices, namely maximum AAA diameter, distal neck diameter, diameter-height ratio, minimum wall thickness variance, mode of the wall thickness variance, and area-averaged Gaussian curvature. Significant differences were found between the two groups for ten geometric indices; however, no differences were found for any of their respective biomechanical attributes. Assuming maximum AAA diameter as the most predictive metric for wall stress was found to be imprecise: 24% and 28% accuracy for the Asian and Caucasian groups, respectively. This investigation reveals that geometric indices other than maximum AAA diameter can serve as predictors of wall stress, and potentially for assessment of aneurysm rupture risk, in the Asian and Caucasian AAA populations.


An overview of patents on therapeutic monoclonal antibodies in Europe: are they a hurdle to biosimilar market entry?
As patents on many high-selling biological medicines are expiring, non-innovator versions, such as biosimilars, may enter this multi-billion dollar market. This study aims to map patents and patent applications for innovator as well as biosimilar monoclonal antibodies in Europe, and investigates legal challenges associated with patenting the innovator product and alleged infringing activities, focusing on consequences for biosimilar developers. Via an exploratory literature review in PubMed and a database analysis in Darts-ip, Derwent Innovation, and Espacenet, an overview of basic patents and exclusivity rights for some of the best-selling biologicals is given, supplemented with a detailed analysis of patents taken during the medicine's life cycle via three specific case studies (trastuzumab, bevacizumab, cetuximab). Case law was used to determine which patents were viewed by biosimilar developers as blocking market entry. For the selected monoclonal antibodies, the key protection instruments appeared to be the basic patent and the additional protection provided by a supplementary protection certificate. We observed that additional patents filed after the basic patent are hard to obtain and often insufficient in blocking market entry of biosimilars, but can in some cases be a substantial hurdle for biosimilar developers to overcome in patent litigation cases or to invent around, creating uncertainty on the launch date of a biosimilar on the market. These hurdles, however, seem to be surmountable, given that many cases were won by biosimilar developers. Also, biosimilars can be protected by filing new patents and these mainly pertain to new formulations.


Time to Return to School After 10 Common Orthopaedic Surgeries Among Children and Adolescents.
Return to school among adolescents is often overlooked in orthopaedic outcome studies. The purpose was to measure the time missed from school after 10 common orthopedic surgeries. Patients, 5 to 19 years old enrolled in elementary, middle, or high school, who underwent treatment for fixation of type III supracondylar humerus fracture, midshaft femur fracture fixation, isolated anterior cruciate ligament reconstruction, isolated partial menisectomy, adolescent idiopathic scoliosis fusion, closed reduction of both-bone forearm fracture, arthroscopic Bankart repair, hip arthroscopy with femoroacetabular impingement correction, limb length discrepancy correction, or surgical fixation of slipped capital femoral epiphysis during the 2014/2015 and 2015/2016 school years were identified for this Institutional Review Board-approved study. All patients were contacted after surgery to determine date of return to school, number of days in session, and number of school days missed. Two hundred six patients met the inclusion criteria for this study. Mean age at time of surgery was 13.0±3.8 years. There were 105 males (51%). Mean time to return to school overall was 13.0±15.2 days. Very few students (n=9; 4%) did not miss any school days during recovery from the procedure of interest. The average number of days missed from school for males was 6.6 days compared with 8.4 days in females (P=0.20). There was no difference between patients aged 5 to 12 years compared with those aged 13 to 19 years (7.1 vs. 7.7 d, respectively; P=0.69). On average, patients who underwent closed reduction of a both-bone forearm fracture returned to school the quickest following surgery (3.4±1.2 d) and missed the least amount of in-session school days (1.9±0.9 d), and those who underwent adolescent idiopathic scoliosis fusion were out of school the longest (42.3±21.4 d) and missed the greatest number of in-session school days (27.6±14.7 d). Information regarding average time missed from school for 10 common orthopaedic surgeries can be used by clinicians to counsel patients and their families regarding expected recovery time. Level IV.


Pathways from women's group-based programs to nutrition change in South Asia: A conceptual framework and literature review.
Improving the nutritional status of women and children in South Asia remains a high public health and development priority. Women's groups are emerging as platforms for delivering health- and nutrition-oriented programs and addressing gender and livelihoods challenges. We propose a framework outlining pathways through which women's group participation may facilitate improvements in nutrition. Evidence is summarized from 36 studies reporting on 24 nutritional indicators across infant and young child feeding (IYCF) practices, intake/diet, and anthropometry. Our findings suggest that women's group-based programs explicitly triggering behavior change pathways are most successful in improving nutrition outcomes, with strongest evidence for IYCF practices. Future investigators should link process and impact evaluations to better understand the pathways from women's group participation to nutritional impact.


Viral arthritis/tenosynovitis: a review.
A review if presented of viral arthritis/tenosynovitis, one of the clinical manifestations of avian reovirus infection in chickens. Since the detection of a viral etiology of arthritis/tenosynovitis in 1957, the disease has been reported in various parts of the world. Pathological features of the disease include inflammatory lesions in the extensor and flexor tendons and tendon sheaths of the posterior limbs and in the tibiotarsal joints. Hepatitis, myocarditis, hydropericardium, as well as intestinal and respiratory tract involvement are described in association with avian reovirus infection. The epizootiology, horizontal and vertical transmission of reovirus, as well as the role of maternal immunity and its application in breeder vaccination for the control of viral arthritis/tenosynovitis are described.


Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern.
We assessed the in vitro antiviral activity of remdesivir and its parent nucleoside GS-441524, molnupiravir and its parent nucleoside EIDD-1931 and the viral protease inhibitor nirmatrelvir against the ancestral SARS-CoV2 strain and the five variants of concern including Omicron. VeroE6-GFP cells were pre-treated overnight with serial dilutions of the compounds before infection. The GFP signal was determined by high-content imaging on day 4 post-infection. All molecules have equipotent antiviral activity against the ancestral virus and the VOCs Alpha, Beta, Gamma, Delta and Omicron. These findings are in line with the observation that the target proteins of these antivirals (respectively the viral RNA dependent RNA polymerase and the viral main protease Mpro) are highly conserved.


Feedbacks between conservation and social-ecological systems.
Robust ways to meet objectives of environmental conservation and social and economic development remain elusive. This struggle may in part be related to insufficient understanding of the feedbacks between conservation initiatives and social-ecological systems, specifically, the ways in which conservation initiatives result in social changes that have secondary effects on the environments targeted by conservation. To explore this idea, we sampled peer-reviewed articles addressing the social and environmental dimensions of conservation and coded each paper according to its research focus and characterization of these feedbacks. The majority of articles in our sample focused either on the effect of conservation initiatives on people (e.g., relocation, employment) or the effect of people on the environment (e.g., fragmentation, conservation efficacy of traditional management systems). Few studies in our sample empirically addressed both the social dynamics resulting from conservation initiatives and subsequent environmental effects. In many cases, one was measured and the other was discussed anecdotally. Among the studies that describe feedbacks between social and environmental variables, there was more evidence of positive (amplifying) feedbacks between social and environmental outcomes (i.e., undesirable social outcomes yielded undesirable environmental effects and desirable social outcomes yielded desirable environmental effects). The major themes within the sampled literature include conflict between humans and wild animals, social movements, adaptive comanagement, loss of traditional management systems, traditional ecological knowledge, human displacement and risks to livelihoods, and conservation and development. The narratives associated with each theme can serve as hypotheses for facilitating further discussion about conservation issues and for catalyzing future studies of the feedbacks between conservation and social-ecological systems.


No-touch pancreatectomy for invasive ductal carcinoma of the pancreas.
Pancreatectomy is the only effective treatment for cancers of the pancreas. Surgeons usually grasp tumors during pancreatectomy; however, this procedure may increase the risk of squeezing and shedding of the cancer cells into the portal vein, retroperitoneum, and/or peritoneal cavity. In an effort to overcome these problems, we have developed surgical techniques for no-touch pancreatectomy. From April 2008 through September 2013, 52 patients have been operated on no-touch pancreatectomy for invasive ductal carcinoma of the pancreas by a single operator (M.H.). Among them, 40 received pancreatoduodenectomy (PD), and 12 did distal pancreatectomy (DP). Twenty two cases (42%) required SMV-PV resection. This is a study to see if pancreatectomy can be technically done using a no-touch surgical technique without deteriorating the post-operative prognosis. During the procedure, the pancreatic tumor is neither grasped nor squeezed by the surgeon. Furthermore, for improved dissection of the retroperitoneal tissue (leftward and posterior margins for PD and rightward and posterior margins for DP), we use a hanging and clamping maneuver and dissection behind Gerota fascia. Overall 2- and 5-year survival rates were 64 and 42% with mean follow-up periods of 34.4 months (range: 6-68 months). Recurrence free 2- and 5-year survival rates were 49 and 31%, respectively. The 5-year survival rates of patients with JPS-stage III and those with JPS-stage IV were 57 and 20%, respectively. The 5-year survival rates of patients with UICC-stage IIA and those with UICC- stage IIB were 49 and 39%, respectively. Patients with UICC-stage III or IV did not survive for more than 2 years. No-touch pancreatectomy has many theoretic advantages that merit further investigation in future randomized controlled trials.


Melatonin modulates the fetal cardiovascular defense response to acute hypoxia.
Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability.


BEST: Bayesian estimation of species trees under the coalescent model.
BEST implements a Bayesian hierarchical model to jointly estimate gene trees and the species tree from multilocus sequences. It provides a new option for estimating species phylogenies within the popular Bayesian phylogenetic program MrBayes. The technique of simulated annealing is adopted along with Metropolis coupling as performed in MrBayes to improve the convergence rate of the Markov Chain Monte Carlo algorithm. http://www.stat.osu.edu/~dkp/BEST.


[Survey of the Efficacy of Long-term and Successive Pharmaceutical Care in Outpatient Chemotherapy by Oncology Pharmacy Specialists].
It is important that pharmacists ensure safe chemotherapy implementation. In addition to inspecting chemotherapeutic prescriptions according to patient condition and drug-drug interactions, the management of chemotherapy-induced adverse effects and associated pharmaceutical intervention is one of the most important responsibilities of pharmacists in medical care teams. In May 2016, an oncology pharmacist was set responsible for the specialized, long-term, and successive pharmaceutical care, including instructions about appropriate use of medication at an outpatient chemotherapy center. We evaluated the effectiveness of the continuous pharmaceutical care. The number of medication counseling and associated pharmaceutical interventions increased with time. Specifically, the number of pharmaceutical interventions (prescription questions and pharmaceutical proposals) was 745 (459 and 286, respectively) in the surveillance period, which significantly increased compared to that observed within the same duration before posting an oncology pharmacist. The adoption rate was approximately 70% for prescription questions and 98% for pharmaceutical proposals. We also found that approximately 70% of the proposals attenuated the painful symptoms. Furthermore, approximately 60% of all pharmaceutical interventions were established after the third visit; in particular, approximately 20% of the pharmaceutical proposals were suggested after the sixth visit, indicating that continuous medication counseling results in an increase in pharmaceutical proposals. In conclusion, long-term and successive pharmaceutical care by oncology pharmacy specialists in outpatient chemotherapy contributes to a safe and less onerous chemotherapy implementation, as it has been highly adopted, is effective in many cases, and has been proven to be important for risk management in chemotherapy.


Altercation of generations: genetic conflicts of pregnancy.
Pregnancy is traditionally viewed as a harmonious collaboration between mother and fetus. From this perspective, viviparity poses a series of problems that maternal and fetal genes work together to solve and the many complications of pregnancy are interpreted as evidence of the malfunctioning of an evolved system or of the failure of natural selection to achieve an adaptive goal. This view fails to recognize aspects of genetic conflict that lie at the heart of gestation. At least three interrelated sources of conflict can be identified: (i) conflict between genes expressed in the mother and genes expressed in the fetus/placenta (parent-offspring conflict); (ii) conflict between maternally-derived and paternally-derived genes within the fetal genome (genomic imprinting); and (iii) conflict between maternal genes that recognize themselves in offspring and the rest of the maternal genome (gestational drive).


Using Clinically Accessible Tools to Measure Sound Levels and Sleep Disruption in the ICU: A Prospective Multicenter Observational Study.
To use clinically accessible tools to determine unit-level and individual patient factors associated with sound levels and sleep disruption in a range of representative ICUs. A cross-sectional, observational study. Australian and New Zealand ICUs. All patients 16 years or over occupying an ICU bed on one of two Point Prevalence study days in 2015. Ambient sound was measured for 1 minute using an application downloaded to a personal mobile device. Bedside nurses also recorded the total time and number of awakening for each patient overnight. The study included 539 participants with sound level recorded using an application downloaded to a personal mobile device from 39 ICUs. Maximum and mean sound levels were 78 dB (SD, 9) and 62 dB (SD, 8), respectively. Maximum sound levels were higher in ICUs with a sleep policy or protocol compared with those without maximum sound levels 81 dB (95% CI, 79-83) versus 77 dB (95% CI, 77-78), mean difference 4 dB (95% CI, 0-2), p < 0.001. There was no significant difference in sound levels regardless of single room occupancy, mechanical ventilation status, or illness severity. Clinical nursing staff in all 39 ICUs were able to record sleep assessment in 15-minute intervals. The median time awake and number of prolonged disruptions were 3 hours (interquartile range, 1-4) and three (interquartile range, 2-5), respectively. Across a large number of ICUs, patients were exposed to high sound levels and substantial sleep disruption irrespective of factors including previous implementation of a sleep policy. Sound and sleep measurement using simple and accessible tools can facilitate future studies and could feasibly be implemented into clinical practice.


Ascorbic Acid Mitigates D-galactose-Induced Brain Aging by Increasing Hippocampal Neurogenesis and Improving Memory Function.
Ascorbic acid is essential for normal brain development and homeostasis. However, the effect of ascorbic acid on adult brain aging has not been determined. Long-term treatment with high levels of D-galactose (D-gal) induces brain aging by accumulated oxidative stress. In the present study, mice were subcutaneously administered with D-gal (150 mg/kg/day) for 10 weeks; from the seventh week, ascorbic acid (150 mg/kg/day) was orally co-administered for four weeks. Although D-gal administration alone reduced hippocampal neurogenesis and cognitive functions, co-treatment of ascorbic acid with D-gal effectively prevented D-gal-induced reduced hippocampal neurogenesis through improved cellular proliferation, neuronal differentiation, and neuronal maturation. Long-term D-gal treatment also reduced expression levels of synaptic plasticity-related markers, i.e., synaptophysin and phosphorylated Ca2+/calmodulin-dependent protein kinase II, while ascorbic acid prevented the reduction in the hippocampus. Furthermore, ascorbic acid ameliorated D-gal-induced downregulation of superoxide dismutase 1 and 2, sirtuin1, caveolin-1, and brain-derived neurotrophic factor and upregulation of interleukin 1 beta and tumor necrosis factor alpha in the hippocampus. Ascorbic acid-mediated hippocampal restoration from D-gal-induced impairment was associated with an enhanced hippocampus-dependent memory function. Therefore, ascorbic acid ameliorates D-gal-induced impairments through anti-oxidative and anti-inflammatory effects, and it could be an effective dietary supplement against adult brain aging.


Study of water-table behaviour for the Indian Punjab using GIS.
The state of Punjab (India) has witnessed a spectacular increase in agricultural production in the last few decades. This has been possible due to high use of fertilizers, good quality seeds and increased use of water resources. This increased demand of water resources has resulted in extensive use of groundwater in the central districts of the state and surface water (canals) in South-West Punjab, where groundwater is of poor quality in general. The state has been facing the twin problem of water table decline/rise in different parts. Efficient management relies on comprehensive database and regular monitoring of the resources. GIS is one of the important tools for integrating and analyzing spatial information from different sources or disciplines. It helps to integrate, analyze and represent spatial information and database of any resource, which could be easily used for planning of resource development, environmental protection and scientific researches and investigations. Geographical Information Systems (GIS) have been used for a variety of groundwater studies. Groundwater level change maps are useful in determining areas of greatest changes in storage in the regional systems. In this study, an attempt has been made to assess the long term groundwater behaviour of the state using GIS to visually and spatially analyze water level data obtained from the state and central agencies. The data was analysed for 0-3 m, 3-10 m, 10-20 m and beyond 20 m. The study revealed that per cent area with water table depth > 10 m was 20% in 1998 and has increased to 58% by 2006 which is critical limit for shifting from centrifugal pump to submersible pump.


Myotonic dystrophy: a cause of acute breathlessness not to be missed.
Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults, is an autosomal dominant disorder with a wide phenotypic spectrum ranging from oligosymptomatic forms to a life-threatening, multisystem disease. People with DM1 overall have a reduced life expectancy, mainly due to respiratory or cardiac causes. There is no cure but prompt, appropriate symptom management is essential to limit disease-related complications. We present a case of DM1, unrecognised when the patient presented with recurrent type 2 respiratory failure, and initially misdiagnosed as Guillain-Barré syndrome. This misdiagnosis subsequently led to unnecessary investigation and treatment before further detailed neurological examination and collateral family history gave the diagnosis. This case highlights the importance of considering a chronic neuromuscular disorder in patients presenting with acute respiratory failure and an unusual pattern of weakness.


A comparative transcriptome and proteomics analysis reveals the positive effect of supplementary Ca(2+) on soybean sprout yield and nutritional qualities.
Effects of Ca(2+) on yield and nutritional qualities of soybean sprout were investigated. Ca-treated sprouts had higher yield than water-treated ones. Metabolism of selected storage materials and bioactive substances in soybean sprouts was strengthened by Ca(2+). The phytic acid and saponin content of Ca-treated soybean sprouts were lower than those of control. Supplemental Ca(2+) increased content of gamma-aminobutyric acid, isoflavones, phenolics, and vitamins, respectively. These findings indicate that supplemental Ca(2+) can increase soybean sprout yield and improve its nutritional qualities. The comparative transcriptome and proteomics between water-treated and Ca-treated soybean sprouts were studied. As consequence 1912 genes and 460 proteins were up- or down-regulated after 4days of Ca(2+) treatment. The functional classification of these differentially expressed genes and proteins indicated their connection with primary/secondary metabolic pathways, ion transport, signal transduction, and transcriptional regulation. The results obtained here will enable to understand how changes in yield and nutritional quality are regulated by extra Ca(2+) in soybean sprouts. In this study, a total of 1912 genes and 460 proteins involved in the growth, storage material decomposition, and bioactive substance synthesis in soybean sprouts after treated with Ca(2+) were identified. This is the first report of a comprehensive transcriptomic and proteomic analysis of soybean sprout in response to supplemental Ca(2+).


Anatomy, histology, and vascularity of the glenoid labrum. An anatomical study.
We studied the gross, histological, and vascular anatomy of the glenoid labrum in twenty-three fresh-frozen shoulders from cadavera to demonstrate its cross-sectional anatomy, its microvascularity, and its attachments. The superior and anterosuperior portions of the labrum are loosely attached to the glenoid, and the macro-anatomy of those portions is similar to that of the meniscus of the knee. The superior portion of the labrum also consistently inserts directly into the biceps tendon, while its inferior portion is firmly attached to the glenoid rim and appears as a fibrous, immobile extension of the articular cartilage. The arteries supplying the periphery of the glenoid labrum come from the suprascapular, circumflex scapular, and posterior circumflex humeral arteries. In general, the superior and anterosuperior parts of the labrum have less vascularity than do the posterosuperior and inferior parts, and the vascularity is limited to the periphery of the labrum. Vessels supplying the labrum originate from either capsular or periosteal vessels and not from the underlying bone.


Characterization of the Salmonella typhimurium mgl operon and its gene products.
In Salmonella typhimurium and Escherichia coli the high-affinity galactose transport system, which contains a periplasmic galactose-binding protein as an essential component, is encoded by the mgl genes. The entire mgl region of S. typhimurium is contained on a 6.3-kilobase EcoRI restriction fragment, which has been cloned into plasmid vectors. We determined the extent of the mgl region on this fragment by Tn5 mutagenesis, examination of lacZ fusions to mgl genes, and subcloning smaller restriction fragments. Polyacrylamide gel electrophoresis of protein preparations derived from strains carrying different plasmids was used to identify the mgl gene products. We conclude that the mgl operon consists of four genes that form a single transcription unit: mglB, mglA, mglE, and mglC. The mglB gene codes for galactose-binding protein (33,000 daltons), mglA codes for a membrane-bound protein of 51,000 daltons, and mglC codes for a 29,000-dalton membrane protein. The mglE product was less well characterized. Its existence was inferred from a mglE-lacZ protein fusion located between mglA and mglC. In addition, the coupled transcription-translation in vitro system indicated that mglE codes for a 21,000-dalton protein.


Quantification of forces required for stabbing with screwdrivers and other blunter instruments.
In the UK, stabbing is the most common cause of homicide. The weapons used include knives, swords, screwdrivers and glass shards. Quantifying the exact force used in a stabbing incident is considered to be a difficult area due to the large number of variables present, such as sharpness of weapon, angle of attack and relative movements of the people involved. Having quantifiable data would allow a forensic pathologist to make a more informed decision when it comes to answering the commonly posed question in court "what was the degree of force involved in the stabbing incident?" The answer to this question is considered significant in determining an alleged assailant's intent to cause harm. This paper presents results of the first detailed study relating geometry of screwdrivers to the forces required for penetration. Additionally, a range of other blunt weapons such as pens and chisels have also been studied. A silicone rubber-foam analogue has been used as the main skin simulant owing to it having similar mechanical properties to that of human skin and giving highly repeatable results. Different screwdrivers of varying shape and size have been tested (i.e. slotted, Phillips, posidriv and Torx), along with other implements including chisels and pens. The weapon geometry was characterised and related to the peak force required for penetration. Our results show that there is a direct correlation between the cross-sectional area of a screwdriver head and the amount of force required for penetration. Screwdrivers with larger cross-sectional areas require a significantly greater force to penetrate (forces in the region of 100-120 N) but "sharper" slotted screwdrivers penetrate with much lower forces (~30 N). The forces required for penetrating the rubber-foam analogue with screwdrivers are higher than for "sharp" knives, but in some cases similar to the forces required for stabbing with "blunt" knives. For the other weapons such as chisels and biros, the force required for penetration was again high and there was found to be a good relationship between area of the implement making contact and penetration force.


[Diethylcarbamazine in the treatment of Bancroft's filariasis].
The authors presented a detailed review about the treatment of bancroftian filariasis with diethylcarbamazine. The interesting aspects about the drug discovery and the basic concepts about its pharmacology were reported in a summarised form. On the other hand, emphasis was made about the speculation done by several authors about the intriguing findings regarding its efficacy reported in the literature. Latter, it was brought the new advances about the disease, as for example, the visualization by ultrasound of living Wuchereria bancrofti adult worm on its natural host--the human being. This made possible the comprehension of several paradoxical issues reported, focusing the treatment of infection using diethylcarbamazine. So far, because of the lack of ideal drug with micro and macrofilaricidal properties, together with the new understand about the disease and the new parameters for monitoring the efficacy of the drug, diethylcarbamazine has back its importance conquered at the begin of its discovery, almost fifth years ago.


Longitudinal interactions between residual symptoms and physiological stress in the remitted symptom network structure of depression.
Residual symptoms and stress are amongst the most reliable predictors of relapse in remitted depression. Standard methodologies often preclude continuous stress sampling or the evaluation of complex symptom interactions. This limits knowledge acquisition relative to the day-to-day interactions between residual symptoms and stress. The study aims to explore the interactions between physiological stress and residual symptoms network structure in remitted depression. Twenty-two individuals remitted from depression completed baseline, daily diary (DD), and post-DD assessments. Self-reported stress and residual symptoms were measured at baseline and post-DD. Daily diaries required participants to use a wearable electrodermal activity (EDA) device during waking hours and complete residual symptom measures twice daily for 3-weeks. Two-step multilevel vector auto-regression models were used to estimate contemporaneous and dynamic networks. Depressed mood and concentration problems were central across networks. Skin conductance responses (SCRs), suicide, appetite, and sleep problems were central in the temporal and energy loss in the contemporaneous network. Increased SCRs predicted decreased energy loss. Residual symptoms and stress showed bi-directional interactions. Overall, depressed mood and concentration problems were consistently central, thus potentially important intervention targets. Non-obtrusive bio-signal measures should be used to provide the clinical evidence-base for modelling the interactions between depressive residual symptoms and stress. Practical implications are discussed throughout related to focusing on symptom-specific interactions in clinical practice, simultaneously reducing residual symptom and stress occurrences, EDA as pioneering signal for stress detection, and the central role of specific residual symptoms in remitted depression.


[Immunosuppressive therapy as a risk factor for new-onset diabetes after transplantation].
To analyze the modes of immunosuppressive therapy as a risk factor for new-onset diabetes after transplantation (NODAT) in kidney recipients. The retrospective analysis included data from 1367 recipients (755 men and 612 women) who lived more than one year after NODAT and were observed at the Moscow City Nephrology Center from January 1989 to December 2018. NODAT was established for 178 (13%) patients based on criteria from the World Health Organization and the American Diabetes Association. The modes of immunosuppressive therapy using cyclosporin A (CSA), tacrolimus (Tac), mTOR inhibitors, glucocorticoids in patients with NODAT and without NODAT were evaluated. To assess the impact of risk factors, descriptive statistics methods were used, the odds ratio (OR) and the 95% confidence interval (CI) were calculated. NODAT was diagnosed in 105 men and 73 women. The OR for men was 1.19 (95% CI 0.871.64), the OR for women was 0.84 (95% CI 0.611.15). At the time of transplantation, the average age of the kidney recipients in the NODAT group was higher than in the group without NODAT: 51 [43; 57] and 43 [32; 52] years, respectively (p=0.0001). Most patients with NODAT (82%) were older than 50 years, while in the group without NODAT, the proportion of patients of the same age was 48.5% (p=0.0001). Among patients without NODAT, transplantation of a kidney from a living donor was significantly more often compared with the group with NODAT+ (7.1% vs 1.1%;p=0.001). Among the recipients who received the regimen with CSA, diabetes developed in 75 (42.1%), those who received Tac in 102 (57.3%;p0.05). The chance (risk of development) of NODAT in patients receiving i-mTOR + Tac was 3.2 (95% CI 1.476.78;p=0.032), and for patients receiving i-mTOR + cyclosporin A, the chance of development NODAT was 1.95 (95% CI 0.884.35;p=0.044). 13% of recipients developed de novo kidney diabetes after allograft. Age at the time of allotransplantation, gender, as well as the use of tacrolimus in combination with i-mTOR are the most significant risk factors for the development of NODAT.


Novel scorpion venom peptide HsTx2 ameliorates cerebral ischemic brain injury in rats via the MAPK signaling pathway.
Ischemic stroke is a severe threat to human health due to its high recurrence, mortality, and disability rates. As such, how to prevent and treat ischemic stroke effectively has become a research hotspot in recent years. Here, we identified a novel peptide, named HsTx2 (AGKKERAGSRRTKIVMLKCIREHGH, 2 861.855 Da), derived from the scorpion Heterometrus spinifer, which showed obvious anti-apoplectic effects in rats with ischemic stroke. Results further demonstrated that HsTx2 significantly reduced formation of infarct area and improved behavioral abnormalities in ischemic stroke rats. These protective effects were likely exerted via activation of the mitogen-activated protein kinase (MAPK) signaling pathway, i.e., up-regulation of phosphorylated ERK1/2 in both rat cerebral cortex and activated microglia (AM); up-regulation of phosphorylated p38 (p-p38) in the cerebral cortex; and inhibition of phosphorylated JNK and p-p38 levels in the AM. In conclusion, this study highlights HsTx2 as a potential neuroprotective agent for stroke.


Abnormal expression of growth regulatory factors in Barrett's oesophagus.
1. In order to assess potential abnormalities in the control of mucosal proliferation, 30 patients with Barrett's oesophagus were studied in order to evaluate the presence and distribution of epidermal growth factor, transforming growth factor-alpha and epidermal growth factor receptor to determine the Ki-67 labelling index in the affected oesophageal mucosa. Serial sections were analysed immunohistochemically. Ten of the patients had adenocarcinoma in the Barrett's mucosa and the other 20 had differing histological types of Barrett's mucosa (10, intestinal-type; 10, fundic- or cardiac-type). 2. The expression of transforming growth factor-alpha, epidermal growth factor and epidermal growth factor receptor was increased and the Ki-67 labelling index was higher in Barrett's mucosa compared with normal gastric mucosa. The 'intestinal-type' of Barrett's mucosa had the greatest expression of transforming growth factor-alpha, epidermal growth factor receptor and the highest Ki-67 labelling index compared with the other types of Barrett's metaplasia. Five cases of 'intestinal-type' Barrett's metaplasia had especially high Ki-67 labelling indices and these patients over-expressed both transforming growth factor-alpha and epidermal growth factor receptor. The patients with adenocarcinomas in the Barrett's mucosa also over-expressed transforming growth factor-alpha and epidermal growth factor receptor, but not epidermal growth factor, compared with normal gastric mucosa. 3. In conclusion, both normal gastric mucosa and Barrett's mucosa have potential autocrine growth regulatory mechanisms, but Barrett's mucosa has increased expression of both of the measured ligands and of the epidermal growth factor receptor.


Ecological risk assessment of the antibiotic enrofloxacin applied to Pangasius catfish farms in the Mekong Delta, Vietnam.
Antibiotics applied in aquaculture production may be released into the environment and contribute to the deterioration of surrounding aquatic ecosystems. In the present study, we assessed the ecological risks posed by the use of the antibiotic enrofloxacin (ENR), and its main metabolite ciprofloxacin (CIP), in a Pangasius catfish farm in the Mekong Delta region, Vietnam. Water and sediment samples were collected in a stream receiving effluents from a Pangasius catfish farm that had applied ENR. The toxicity of ENR and CIP was assessed on three tropical aquatic species: the green-algae Chlorella sp. (72 h - growth inhibition test), the micro-invertebrate Moina macrocopa (48 h - immobilization test), and the Nile tilapia (Oreochromis niloticus). The toxic effects on O. niloticus were evaluated by measuring the cholinesterase (ChE) and catalase (CAT) activities in the fish brain and muscles, respectively, and by considering feed exposure and water exposure separately. Ecological risks were assessed by comparing maximum exposure concentrations with predicted no effect concentrations for cyanobacteria, green algae, invertebrates and fish derived with available toxicity data. The results of this study showed that maximum antibiotic concentrations in Pangasius catfish farm effluents were 0.68 μg L(-1) for ENR and 0.25 μg L(-1) for CIP (dissolved water concentrations). Antibiotics accumulated in sediments down-stream the effluent discharge point at concentrations up to 2590 μg kg(-1) d.w. and 592 μg kg(-1) d.w. for ENR and CIP, respectively. The calculated EC50 values for ENR and CIP were 111000 and 23000 μg L(-1) for Chlorella sp., and 69000 and 71000 μg L(-1) for M. macrocopa, respectively. Significant effects on the ChE and CAT enzymatic activities of O. niloticus were observed at 5 g kg(-1) feed and 400-50000 μg L(-1), for both antibiotics. The results of the ecological risk assessment performed in this study indicated only minor risks for cyanobacteria communities, suggesting that residual concentrations of ENR and CIP after medication are not likely to result in severe toxic effects on exposed aquatic ecosystems. However, more studies should be performed by considering other antibiotic treatments used in Pangasius catfish production and the potential ecotoxicological effects of relevant antibiotic mixtures on sediment communities.


6-Morpholino- and 6-amino-9-sulfonylpurine derivatives. Synthesis, computational analysis, and biological activity.
The synthesis of novel 6-chloro/morpholino/amino/-9-sulfonylpurine derivatives was accomplished in two ways, either (i) involving the condensation reaction of 6-chloropurine with commercially available arylsulfonyl chlorides in acetone and the presence of aqueous KOH at 0 °C, followed by the substitution of C6-chlorine with morpholine, or (ii) employing a reversed synthetic approach where 6-morpholinopurine and commercially available adenine bases were reacted with the corresponding alkyl, 2-arylethene and arylsulfonyl chlorides giving the N9 sulfonylated products, the latter particularly used where prior nonselective sulfonylation was observed. In both approaches, the sulfonylation reaction occurred regioselectively at the purine N9 position lacking any concurrent N7 derivatives, except in the case of a smaller methyl substituent on SO2 and the free amino group at C6 of the purine ring. The tautomeric features of initial N9 unsubstituted purines, as well as stability trends among the prepared N-9-sulfonylpurine derivates, were investigated using DFT calculations with an important conclusion that electron-donating C6 substituents are beneficial for the synthesis as they both promote the predominance of the desired N9 tautomers and help to assure the stability of the final products. The newly synthesized 6-morpholino and 6-amino-9-sulfonylpurine derivatives showed antiproliferative activity on human carcinoma, lymphoma, and leukemia cells. Among the tested compounds, 6-morpholino 17 and 6-amino 22 derivatives, with trans-β-styrenesulfonyl group attached at the N9 position of purine, proved to be the most effective antiproliferative agents, causing accumulation of leukemia cells in subG0 cell cycle phase.


[Rheological indicators of blood in patients with suppurative processes in the abdominal cavity].
Rheological properties of blood were studied in dynamics in 33 patients with different localization of purulent processes in the abdominal cavity. It was found that in patients with a limited purulent process the alterations of blood rheology corresponded to the clinical status of the patients and their parameters has a tendency to increase. In patients with generalized purulent processes the alterations of blood rheology did not correspond to the degree of the inflammatory process and pointed to manifestation of signs of coagulopathy of consumption requiring special many-component infusion-transfusion therapy.


Health services utilization among Latinos and white non-Latinos: results from a national survey.
Utilization patterns may be changing as managed care organizations actively market services to Latinos. This study compares use of any care, emergency services, inpatient hospitalization, nonemergency outpatient care only, and preventive care among 1,001 self-identified Latino and 1,107 white non-Latino adults. Data were from the 1994 Commonwealth Fund Survey of Minority Health. Latinos were less likely than white non-Latinos to have entered the health system for any type of care, to have been admitted to a hospital, or to have used preventive care. Access to a regular source of care along with financial factors reduced the ethnic/racial gap in the use of any care and preventive care, yet cultural and behavioral factors contributed little. Latinos in managed care plans, compared with fee-for-service systems, were twice as likely to receive preventive care. This suggests that managed care has the potential to reduce inequities in preventive care utilization.


Work-focused interventions that promote the labour market transition of young adults with chronic disabling health conditions: a systematic review.
Young adulthood is an important transitional life phase where careers are established. Young adults with chronic disabling health conditions are underrepresented in the labour market. Our study aims to examine the effectiveness of work-focused interventions that support the labour market transition of young adults with chronic disabling health conditions; and to examine whether the effectiveness of work-focused interventions differ across work transition phase (eg, preparation, entry and sustaining work, employment advancement) and disability type. A systematic review of articles published between January 1990 and July 2018 was conducted. Medline, EMBASE and PsycInfo were searched, and titles/abstracts and full texts of articles were reviewed for eligibility. Relevant articles were appraised for methodological quality. A best evidence synthesis was applied to medium-quality/high-quality studies to develop recommendations. 5816 articles were identified; 10 articles were relevant and of moderate-high methodological quality. Six intervention categories were identified which focused on young adults with mental health or intellectual/learning disabilities (n=3) and addressed employment preparation (n=10) and/or work entry (n=9). No interventions addressed at-work issues or career advancement. Strong evidence existed for tailored supported employment (SE) interventions having a positive impact on preparation and entry into competitive employment. Also, moderate evidence existed for the positive impact of SE on preparation and entry into competitive employment for young adults with mental health conditions. Tailored SE is recommended to foster preparation and entry into the labour market. Evidence-based interventions are needed to facilitate sustained work and career advancement of young adults living with different disabling health conditions.


A study examining the appropriateness of a self-rated alcohol-related clinical confidence tool as a method of measurement among registered hospital nurses using Rasch analysis.
This paper is a report of a study, which seeks to determine if self-reported estimates of RNs' self-rated confidence in responding to alcohol use in patients is a psychometrically sound measure. Alcohol-related harm is a global public health problem. Nurses are the largest group of health professionals worldwide, with evidence showing that despite being well placed to respond, they are not engaging in this important role. Instrument development. The study was a survey set in a large teaching hospital in England, UK. The Clinical Confidence Questionnaire was made available to a convenience sample of 200 RNs in 2007, with a response rate of 22%. Rasch analysis was used to develop a scale for future learning based on the conjoint estimates of registered hospital nurses abilities to meet needs of patients requiring nursing care of different complexities related to alcohol use in patients. Outcomes verify that registered hospital nurses' self-rated clinical confidence measures for their own nursing abilities in responding to alcohol use in patients can be reliably estimated and a hierarchical scale of learning can be generated to inform curricula content and learning processes. Current health policy in the UK identifies nurses as having a role in responding to alcohol-related harm. More focus should, therefore, be placed on ensuring that they are prepared to fully engage with patients in assessing and responding to alcohol use through specific education, training and skill development. The self-rated clinical confidence tool offers evidence as an acceptable method of measurement in this area.


Vaccinia virus protein N2 is a nuclear IRF3 inhibitor that promotes virulence.
Vaccinia virus (VACV) expresses many proteins that are non-essential for virus replication but promote virulence by inhibiting components of the host immune response to infection. These immunomodulators include a family of proteins that have, or are predicted to have, a structure related to the B-cell lymphoma (Bcl)-2 protein. Five members of the VACV Bcl-2 family (N1, B14, A52, F1 and K7) have had their crystal structure solved, others have been characterized and a function assigned (C6, A46), and others are predicted to be Bcl-2 proteins but are uncharacterized hitherto (N2, B22, C1). Data presented here show that N2 is a nuclear protein that is expressed early during infection and inhibits the activation of interferon regulatory factor (IRF)3. Consistent with its nuclear localization, N2 inhibits IRF3 downstream of the TANK-binding kinase (TBK)-1 and after IRF3 translocation into the nucleus. A mutant VACV strain Western Reserve lacking the N2L gene (vΔN2) showed normal replication and spread in cultured cells compared to wild-type parental (vN2) and revertant (vN2-rev) viruses, but was attenuated in two murine models of infection. After intranasal infection, the vΔN2 mutant induced lower weight loss and signs of illness, and virus was cleared more rapidly from the infected tissue. In the intradermal model of infection, vΔN2 induced smaller lesions that were resolved more rapidly. In summary, the N2 protein is an intracellular virulence factor that inhibits IRF3 activity in the nucleus.


Enzymes in colon cancer. General information.
Serum enzymes have not proved useful in evaluation of patients with early colon cancer, but certain enzymes such as transpeptidase, phosphohexone isosomerase, or 5'-nucleotidase have been of assistance in following the course of the disease, particularly in patients with metastatic spread to the liver. Attempts have been made to improve the utility of enzyme analysis in colon cancer by examination of enzyme patterns in colon biopsy specimens, feces, and colon washings. These studies, which will be summarized, are of importance in the possible development of diagnostic tools and as probes in the understanding of the etiology of colon cancer. The technical problems in carrying out these assays in humans, as well as the significance of the activity of aryl sulfatase, beta-glucuronidase, beta-glucosidase, lactic dehydrogenase, glucose-6-p-osphate dehydrogenase, and other enzymes will be considered.


[Effects of herb residue vermicompost on maize growth and soil fertility].
A pot experiment was conducted to evaluate the effects of herb residue vermicompost on maize growth and soil fertility. With the increasing application rate of vermicompost, the plant height, stem diameter, leaf area, and chlorophyll content of maize all increased significantly. After 60 days growth of maize, the soil bulk density in most vermicompost treatments decreased significantly. The soil pH in vermicompost treatments was significantly higher than that in CK and in chemical fertilization treatments. In addition, the soil total nitrogen and organic matter contents in vermicompost treatments were obviously higher than those in chemical fertilization treatments. It was suggested that herb residue vermicompost could be used as an efficient and high-quality organic fertilizer, and its appropriate application could improve soil physical structure, alleviate soil acidification, increase soil organic matter and nitrogen contents, and promote crop growth.


Sulfur Vacancy-Engineered Co3S4/MoS2-Interfaced Nanosheet Array for Enhanced Alkaline Overall Water Splitting.
Electrochemical water splitting, a crucial reaction for renewable energy storage, demands highly efficient and stable catalysts. Defect and interface engineering has been widely acknowledged to play a pivotal role in improving electrocatalytic performance. Herein, we demonstrate a facile strategy to construct sulfur vacancy (Sv)-engineered Co3S4/MoS2-interfaced nanosheet arrays to modulate the interface electronic structure in situ reduction with NaBH4. The abundant sulfur vacancies and well-arranged nanosheet arrays in Sv-Co3S4/MoS2 lead to pronounced electrocatalytic properties for hydrogen and oxygen evolution reactions (HER/OER) in an alkaline medium, with observed overpotentials of 156 and 209 mV at 10 mA cm-2, respectively. Additionally, as a bifunctional electrocatalyst, Sv-Co3S4/MoS2 requires a cell voltage of 1.67 V at 10 mA cm-2 for overall water splitting and exhibits long-term stability with activity sustained for more than 20 h. This study provides a novel approach to producing transition metal compound-interfaced electrocatalysts with rich vacancies under mild conditions, showcasing their potential for efficient water splitting applications.


Bronchodilator efficacy of extrafine glycopyrronium bromide: the Glyco 2 study.
An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate - a "fixed triple". This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 μg versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 μg twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 μg once daily. On the morning of Day 8 in all five periods, patients also received formoterol 12 μg. In study Part 1, 27 patients were recruited. All GB doses significantly increased from baseline forced expiratory volume in 1 second (FEV1) area under the curve (AUC0-12h) and peak FEV1, with a trend toward greater efficacy with higher GB dose. All adverse events were mild-moderate in severity, with a lower incidence with GB than placebo and no evidence of a dose-response relationship. In study Part 2, of 38 patients recruited, 34 completed the study. Adjusted mean differences from placebo in 12 h trough FEV1 on Day 7 (primary) were 115, 142 and 136 mL for GB 12.5, 25 and 50 μg BID, respectively (all P<0.001). GB 25 and 50 μg BID were superior (P<0.05) to GB 12.5 μg BID for pre-dose morning FEV1 on Day 8. For this endpoint, GB 25 and 50 μg BID were also superior to tiotropium. Compared with Day 7, addition of formoterol significantly increased Day 8 FEV1 peak and AUC0-12h with all GB doses and placebo (all P<0.001). All adverse events were mild-moderate in severity and there was no indication of a dose-related relationship. This study provides initial evidence on bronchodilation, safety and pharmacokinetics of extrafine GB BID. Overall, the results suggest that GB 25 μg BID is the optimal dose in patients with COPD.


Protein-protein interaction on lysozyme crystallization revealed by rotational diffusion analysis.
Intermolecular interactions between protein molecules diffusing in various environments underlie many biological processes as well as control protein crystallization, which is a crucial step in x-ray protein structure determinations. Protein interactions were investigated through protein rotational diffusion analysis. First, it was confirmed that tetragonal lysozyme crystals containing fluorescein-tagged lysozyme were successfully formed with the same morphology as that of native protein. Using this nondisruptive fluorescent tracer system, we characterized the effects of sodium chloride and ammonium sulfate concentrations on lysozyme-lysozyme interactions by steady-state and time-resolved fluorescence anisotropy measurements and the introduction of a novel interaction parameter, k(rot). The results suggested that the specific attractive interaction, which was reflected in the retardation of the protein rotational diffusion, was induced depending on the salt type and its concentration. The change in the attractive interactions also correlated with the crystallization/precipitation behavior of lysozyme. Moreover, we discuss the validity of our rotational diffusion analysis through comparison with the osmotic second virial coefficient, B(22), previously reported for lysozyme and those estimated from k(rot).


Defective gamma interferon production in leprosy. Reversal with antigen and interleukin 2.
Antigen and mitogen-induced gamma interferon (gamma-IFN) production was studied in peripheral blood mononuclear cells from 34 leprosy patients. 17 of 18 lepromatous leprosy and borderline lepromatous patients (LL and BL) failed to release gamma-IFN in response to specific antigen (Mycobacterium leprae) and displayed reduced responses to mitogen (concanavalin A) stimulation. In contrast, cells from six tuberculoid and borderline tuberculoid patients (TT and BT) produced considerable levels of gamma-IFN under the same experimental conditions. Normal controls failed to respond to M. leprae and most displayed good responses to concanavalin A. Mid-borderline patients (BB) showed intermediate levels of gamma-IFN release. gamma-IFN release by lepromatous patients could be partially restored with purified interleukin 2 and M. leprae antigen but not with interleukin 2 alone.


Strychnine-sensitive stabilization of postsynaptic glycine receptor clusters.
The cellular and molecular mechanisms underlying the postsynaptic aggregation of ionotropic receptors in the central nervous system are not understood. The glycine receptor (GlyR) and its cytoplasmic domain-associated protein, gephyrin, are clustered at the postsynaptic membrane and constitute a good model for addressing these questions. The glycine receptor is inhibited by strychnine. The effects of chronic strychnine treatment on the expression and cellular distribution of gephyrin and glycine receptor were therefore tested using primary cultures of spinal cord neurons. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that the glycine receptor alpha1, alpha2, beta subunits and gephyrin mRNAs were expressed at comparable levels in strychnine-treated and untreated cultures. The number of immunoreactive cells and the subcellular distribution of gephyrin and GlyR subunits was determined with standard and confocal immunofluorescence. The proportion of gephyrin and glycine receptor-immunoreactive (IR) cells was unaffected by strychnine treatment. Confocal microscopy revealed that the glycine receptor was mainly localized intracellularly near the nucleus. This cytoplasmic glycine receptor was not associated with the Golgi apparatus nor with the rough endoplasmic reticulum and therefore is not likely to correspond to neosynthesized proteins. The number of GlyR clusters on the somato-dendritic membrane was dramatically reduced on neurons displaying intracellular staining. In contrast, the subcellular distribution and the number of gephyrin clusters was not modified by the treatment. The fact that gephyrin postsynaptic localization was not modified by strychnine suggests that the aggregation of glycine receptor and gephyrin is governed by different mechanisms. The distribution of other cell surface molecules such as NCAM or GABAA receptor beta2/3 subunits was not modified by strychnine treatment. Chronic exposure of the cultures to tetrodotoxin did not affect gephyrin or glycine receptor cluster formation. Taken together, these results indicate that functional glycine receptor, but not electrical synaptic activity, is required for the formation of glycine receptor clusters.


Evaluation of screening programmes for gynaecological cancer.
A workshop of the Project on Evaluation of Screening Programmes of the International Union against Cancer (UICC) was held in Lyon, France. on November 20-22, 1984. The focus of the workshop was on screening for gynaecological cancer, especially for cancer of the cervix uteri. This report summarizes the presentations, conclusions and recommendations from the workshop.


Effect of biotic and abiotic elicitors on isoflavone biosynthesis during seed development and in suspension cultures of soybean (Glycine max L.).
The present investigation aimed to look at the effects of biotic and abiotic elicitors during Soybean seed development and cell suspension culture in isoflavones accumulation. The expression levels of four major genes viz., CHS7, CHS8, IFS2, and IFS1 involved on isoflavones biosynthesis during seed developmental stages from R5L-R7 was seen in both MAUS-2 and JS-335 Soybean varieties. The R7 stage showed 1.24-fold upregulation of IFS1transcript level and considered as the control for Soybean seed development. Both varieties during R6-R8 stages responded differently to the foliar application of 10 µM SA, 10 µM MJ and 0.1% Aspergillus niger. The IFS2 transcripts were upregulated by SA at the R7 stage with 5.21- and 4.68-fold in JS-335 and MAUS-2, respectively. IFS1 expression was significantly increased by A. niger treatment at R7 stage with 3.98- and 3.21-fold in MAUS-2 and JS-335, respectively. The expression of CHS7 and CHS8 by 10 μM SA at R7 level revealed maximum up-regulation of 0.51- and 1.01-fold in MAUS-2; 0.37- and 0.82-fold in JS-335, respectively. In the soybean callus suspension culture, biosynthetic genes were used to validate the effects of elicitor on isoflavones. Both biotic and abiotic treatments contribute to the upregulation of IFS1 and IFS2 expression, that in turn, leads to the accumulation of isoflavone in seed development as well as in suspension cultures. These data further suggested that the IFS2 is the key gene responsible for the isoflavone accumulation during elicitor treatment.


Inhibition of dendritic spine morphogenesis and synaptic transmission by activity-inducible protein Homer1a.
The postsynaptic density (PSD) proteins Shank and Homer cooperate to induce the maturation and enlargement of dendritic spines (Sala et al., 2001). Homer1a is an activity-inducible short-splice variant of Homer that lacks dimerization capacity. Here, we show that Homer1a reduces the density and size of dendritic spines in cultured hippocampal neurons in correlation with an inhibition of Shank targeting to synapses. Expression of Homer1a also decreases the size of PSD-95 clusters, the number of NMDA receptor clusters, and the level of surface AMPA receptors, implying a negative effect on the growth of synapses. In parallel with the morphological effects on synapses, Homer1a-expressing neurons show diminished AMPA and NMDA receptor postsynaptic currents. All of these outcomes required the integrity of the Ena/VASP Homology 1 domain of Homer1a that mediates binding to the PPXXF motif in Shank and other binding partners. Overexpression of the C-terminal region of Shank containing the Homer binding site causes effects similar to those of Homer1a. These data indicate that an association between Shank and the constitutively expressed long-splice variants of Homer (e.g., Homer1b/c) is important for maintaining dendritic-spine structure and synaptic function. Because Homer1a expression is induced by synaptic activity, our results suggest that this splice variant of Homer operates in a negative feedback loop to regulate the structure and function of synapses in an activity-dependent manner.


Schistosoma mansoni: challenge attrition during the lung phase of migration in vaccinated and serum-protected rats.
Serum harvested from Sprague-Dawley rats twice vaccinated with gamma-irradiated cercariae of Schistosoma mansoni is able to protect naive recipients against a challenge infection, but the challenge parasites are susceptible to immune elimination over a very short period of time. Thus, vaccinated rat serum protects recipients against a percutaneous cercarial challenge when transferred on Day +5 but not Day 0 and protects recipients against a tail vein challenge with 5-day-old lung worms when transferred on Days 0 or +1, but not Days +4 or +5. Rats challenged with lung worms via the tail vein and given serum on Day +3 exhibit approximately half the protection expressed by counterparts that received serum on Day 0. However, vaccinated rat serum does not protect naive recipients against a lung worm challenge introduced directly into the liver. These data indicate that immune elimination of challenge parasites in the vaccinated rat model is site-dependent rather than stage-dependent, and most probably occurs during the lung phase of parasite migration.


What are the Read Codes?
The Read Codes were initially developed by a general practitioner, Dr James Read from Loughborough, in the early 1980s and rapidly gained acceptance by general practitioners as a popular and useful mechanism for storing structured information about patients in individual, patient-based records, which were beginning to become popular in a few general practices at the time. This short article aims to explain the past and future development of the coding system in the National Health Service as a whole.


Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis.
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumour if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients' NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patient's CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients' or controls' CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation) were examined in the hippocampus on Day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patient's CSF antibodies, but not those infused with controls' CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of long-term potentiation. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301, despite this compound not antagonizing antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (i) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.


Protection against Legionnaire's Disease: Recombinant Flagellin A of Legionella pneumophila Can Induce Protective Immunity against Bacteremia in a BALB/c Murine Model.
To investigate the immunoprotective effects of the recombinant type A flagellin (FLA), the flaA gene of Legionella pneumophila serogroup 1 strain Paris was cloned into pET28a(+). Recombinant FLA (rFLA) was overexpressed in E. coli BL21 (DE3) and purified by Ni2+ exchange chromatography. Female BALB/c aged 6-8 weeks were immunized with 20 μg of rFLA. Nonimmunized mice along with mice inoculated with a sublethal dose of live L. pneumophila intravenously were considered as negative and positive controls, respectively. A significant serum antibody response was observed in female BALB/c mice immunized with rFLA. Production of IFN-γ and IL-12, and TNF-α in the serum and the splenocyte cultures, and antigen-specific splenocyte proliferation suggested a strong innate and adaptive cell-mediated immunity response in rFLA-immunized mice. Intravenous lethal challenge with L. pneumophila serogroup 1 (strain Paris) showed that 60% of mice immunized with rFLA survived in a 10-day follow-up survey. These results show that rFLA from L. pneumophila can elicit strong innate and adaptive immune responses and suggest the possibility of a long-term immunity against lethal challenge with L. pneumophila.


Mesenchymal stem cells shape microglia effector functions through the release of CX3CL1.
Mesenchymal stem cells (MSC) display a remarkable ability to modulate the immune response and protect the central nervous system mainly through the release of soluble factors in a paracrine fashion, affecting the functional behavior of cells in the tissues. Here we investigated the effect of the interaction between MSC and microglia in vitro, and we dissected the molecular and cellular mechanisms of this crosstalk. We demonstrated that MSC impair microglia activation by inflammatory cues through the inhibition of the expression and release of inflammatory molecules and stress-associated proteins. We showed that MSC significantly increase microglial expression and release of molecules associated with a neuroprotective phenotype such as CX3CR1, nuclear receptor 4 family, CD200 receptor, and insulin growth factor 1. Interestingly, MSC can enhance functional changes on microglia as depicted by the increase of intracellular calcium concentration and phagocytic activity. This last event is associated with an increased expression of triggering receptor expressed on myeloid cells-2, an innate immune receptor involved in phagocytosis in the absence of inflammation. The observed effects on CX3CR1-expressing microglia are due to the release of CX3CL1 by MSC, driven by inflammatory signals, as demonstrated by the reversal of the observed results when CX3CL1 expression was silenced in MSC or its release was blocked. Finally, we showed that exogenous CX3CL1 induce phenotypic and functional changes of microglia similar to those induced by MSC. These findings demonstrate that MSC instruct, through the release of CX3CL1, microglia responsiveness to proinflammatory signals by modulating constitutive "calming" receptors, typically expressed by "steady-state microglia" thus switching microglia from a detrimental phenotype to a neuroprotective one.


Indomethacin reduces the antihypertensive action of enalapril.
We evaluated the influence of indomethacin on the pharmacological actions of Enalapril in 9 uncomplicated essential hypertensives. While on chronic treatment with Enalapril, these patients randomly received indomethacin (50 mg bid) or a corresponding placebo for 1 week and the opposite treatment after a 2 week interval. Indomethacin, which decreased serum thromboxane B2 and urinary 6-keto prostaglandin-F1 alpha, reduced the plasma renin activity (PRA) increased by Enalapril. Indomethacin did not modify serum ACE, whose activity had been reduced by the ACE inhibitor. Mean blood pressure (MBP) values, which were significantly and to a similar extent reduced by Enalapril at the beginning of the cross-over, after placebo addition and at the end of the two week interval, were significantly increased by indomethacin, despite being still significantly lower than baseline values. These data show that systemic and renal prostaglandin (PG) synthesis inhibition induced by indomethacin can blunt the antihypertensive effect of chronic Enalapril treatment in patients with essential hypertension.


Regrow or Repair: An Update on Potential Regenerative Therapies for the Kidney.
Fifteen years ago, this journal published a review outlining future options for regenerating the kidney. At that time, stem cell populations were being identified in multiple tissues, the concept of stem cell recruitment to a site of injury was of great interest, and the possibility of postnatal renal stem cells was growing in momentum. Since that time, we have seen the advent of human induced pluripotent stem cells, substantial advances in our capacity to both sequence and edit the genome, global and spatial transcriptional analysis down to the single-cell level, and a pandemic that has challenged our delivery of health care to all. This article will look back over this period of time to see how our view of kidney development, disease, repair, and regeneration has changed and envision a future for kidney regeneration and repair over the next 15 years.


[Psychosis due to idiopathic basal ganglia calcification].
Idiopathic basal ganglia calcification is a rare neuropathological syndrome characterised by symmetrical and bilateral calcifications found primarily in the basal ganglia. Psychosis is describedas an acute presentation of idiopathic ganglia calcification. We describe the development of psychosis in a 48-year-old man, initially hospitalised on the neurology ward due to syncope. A ct scan of the brain showed bilateral, symmetrical calcification of the basal ganglia and nucleus dentatus. Laboratory research excluded other pathological disorders. The patient was referred to a psychiatric ward, where the administration of risperidone led to alleviation of his mental state. This case report underlines the importance of an accurate, comprehensive differential diagnosis and the associated significance of neuroimaging.


Quality by design approach for understanding the critical quality attributes of cyclosporine ophthalmic emulsion.
Restasis is an ophthalmic cyclosporine emulsion used for the treatment of dry eye syndrome. There are no generic products for this product, probably because of the limitations on establishing in vivo bioequivalence methods and lack of alternative in vitro bioequivalence testing methods. The present investigation was carried out to understand and identify the appropriate in vitro methods that can discriminate the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion formulations having the same qualitative (Q1) and quantitative (Q2) composition as that of Restasis. Quality by design (QbD) approach was used to understand the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion. The formulation variables chosen were mixing order method, phase volume ratio, and pH adjustment method, while the process variables were temperature of primary and raw emulsion formation, microfluidizer pressure, and number of pressure cycles. The responses selected were particle size, turbidity, zeta potential, viscosity, osmolality, surface tension, contact angle, pH, and drug diffusion. The selected independent variables showed statistically significant (p < 0.05) effect on droplet size, zeta potential, viscosity, turbidity, and osmolality. However, the surface tension, contact angle, pH, and drug diffusion were not significantly affected by independent variables. In summary, in vitro methods can detect formulation and manufacturing changes and would thus be important for quality control or sameness of cyclosporine ophthalmic products.


Tobacco free at the Indianapolis 500.
Most children are highly impressionable and easily influenced, particularly by people they admire. Role models in sports and entertainment who publicly use or commercially promote tobacco products potentially influence children to do the same. Motorsports events are saturated with tobacco sponsorship. We describe the counter-promotion of tobacco at the famed Indianapolis 500 and suggest other venues to continue this "Tobacco Free America" theme.


Enalapril dosage in progressive chronic nephropathy: a randomised, controlled trial.
In chronic renal failure, clearance of enalapril is reduced. Hence, a renoprotective effect may be achieved with lower doses than conventionally used. Since marked inter-patient variation in concentrations of enalaprilat has been shown in patients with renal failure despite equivalent dosage of enalapril, a direct comparison of the effect of high versus low plasma concentrations of enalaprilat on the progression of renal failure was undertaken. Forty patients with a median glomerular filtration rate (GFR) of 17 (6-35) ml/min/1.73 m2 were studied in an open-label, randomised trial comparing patients with a high (>50 ng/ml) with patients with a low (<10 ng/ml) target trough plasma concentration of enalaprilat. The dose of enalapril was titrated accordingly. The patients were followed for 12 months or until they needed renal replacement therapy. GFR was measured at 3-month intervals by the plasma clearance of 51Cr-EDTA, and the individual rates of progression of renal failure were calculated as the slope of GFR versus time plot. In the high-concentration group, the median enalaprilat trough concentration was 92.9 ng/ml (21.8-371.0 ng/ml) and in the low-concentration group it was 9.1 ng/ml (2.5-74.8 ng/ml) at 3 months follow-up (P<0.001). The median daily doses of enalapril were 10 mg (2.5-30 mg) and 1.88 mg (1.25-5 mg) in the high and low groups, respectively (P<0.001). In the high-concentration group, the mean+/-SE decline in renal function was 6.1+/-1.5 ml/min/1.73 m2 per year and in the low-concentration group it was 4.3+/-14.4 ml/min/1.73 m2 per year (P=0.48). Five patients in the high-concentration group reached end-stage renal failure whereas none in the low-concentration group did (P=0.04). There were no statistically significant differences in blood pressure level, concomitant antihypertensive therapy or urinary albumin excretion. However, the high-enalaprilat concentration group had an overall higher plasma potassium concentration of 0.42 mmol/l than the low group (P<0.001). In patients with moderate to severe renal insufficiency, a low concentration of enalaprilat afforded the same degree of renoprotection, blood pressure control and minimisation of proteinuria as a high concentration, during 12 months of follow-up. The high-dosage treatment was associated with a more pronounced tendency to hyperkalaemia. Thus, there seems to be no indication for increasing the daily dose of enalapril beyond what achieves adequate blood pressure control in this group of patients.


Merkel Cell Polyomavirus Small T Antigen Induces DNA Damage Response.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin with high rates of metastasis and mortality. Besides well-established factors including genetic mutations and UV-induced DNA damage in Merkel cell carcinogenesis, the recent discovery of the Merkel cell polyomavirus (MCPyV) has shed light on the viral etiology of MCC. In the current study, we provide novel evidence that MCPyV small T (sT) antigen induces the DNA damage response (DDR) pathway. Our data show that in human MCC cells, the presence of MCPyV is associated with hyperphosphorylation of histone H2AX, a marker for DNA damage. We observed that overexpression of MCPyV sT antigen induced the phosphorylation of histone H2AX as well as the activation of ataxia telangiectasia mutant (ATM), an upstream kinase important for H2AX phosphorylation. Moreover, we observed that MCPyV sT expression also induced the hyperphosphorylation of other ATM downstream molecules (including 53BP1 and CHK2) as well as the hypermethylation of histone 3 and histone 4. These findings disclose a novel link between MCPyV sT and the DDR pathway in MCC. Given that measurement of DDR is clinically useful for evaluating treatment response to radio- and chemotherapy, our findings warrant further investigation to evaluate the potential implications of this pathway for MCC management.