Agaricus brasiliensis polysaccharides stimulate human monocytes to capture Candida albicans, express toll-like receptors 2 and 4, and produce pro-inflammatory cytokines.
Agaricus brasiliensis is a medicinal mushroom with immunomodulatory and antitumor activities attributed to the β-glucans presented in the polysaccharide fraction of its fruiting body. Since β-glucans enhance cellular immunoresponsiveness, in this study we aimed to evaluate the effect of an acid-treated polysaccharide-rich fraction (ATF) of A. brasiliensis on the ability of human monocytes to adhere/phagocyte C. albicans yeast cells, their expression of pattern recognition receptors and their ability to produce cytokines. Adhesion/phagocytosis of FITC-labeled C. albicans was evaluated by flow cytometry. Cells were incubated with specific fluorochrome-labeled antibodies for TLR2 and 4, βGR and MR and also evaluated by flow cytometry. Monocytes were cultured with ATF, and culture supernatants were collected for analysis of in vitro cytokine production by ELISA (TNF-α, IL-1β, IL-12 and IL-10). ATF significantly increased the adherence/phagocytosis of C. albicans by monocytes and this was associated with enhanced expression of TLR2 and TLR4, while no effect was observed on βGR or MR. Moreover, expression of TLR4 and TLR2 was associated with higher levels of in vitro production of TNF-α and IL-1, respectively. Production of IL-10 was also increased by ATF treatment, but we found no association between its production and the expression of Toll-like receptors. Our results provided us with evidence that A. brasiliensis polysaccharides affect human monocytes probably through the modulation of Toll-like receptors.


The role of digitalis in acute myocardial infarction.
Digitalis is useful in the control of atrial tachyarrhythmias complicating acute myocardial infarction, whether or not congestive heart failure is present. The drug can also be helpful in patients in the subacute and chronic phases of myocardial infarction if congestive heart failure is present. Digitalis is not, however, the drug of choice in the treatment of patients with left ventricular dysfunction complicating acute myocardial infarction.


Priming and cryopreservation of microencapsulated marrow stromal cells as a strategy for intervertebral disc regeneration.
A challenge in using stromal cells for intervertebral disc (IVD) regeneration is their limited differentiation capacity in vivo without exogenous growth factor (GF) supplementation. Priming of stromal cells prior to transplantation may offer a feasible strategy to overcome this limitation. Furthermore, the ability to cryopreserve cells could help alleviate logistical issues associated with storage and transport. With these critical translational challenges in mind, we aimed to develop a strategy involving priming and subsequent cryopreservation of microencapsulated bone marrow stromal cells (BMSCs). In phase one, we utilised the electrohydrodynamic atomisation process to fabricate BMSC-encapsulated microcapsules that were primed with TGF-β3 for 14 d after which they were cultured for a further 21 d under basal or GF supplemented media conditions. Results showed that priming induced differentiation of BMSC microcapsules such that they synthesised significant amounts of sGAG (61.9 ± 2.0 μg and 55.3 ± 6.1 μg for low and high cell densities) and collagen (24.4 ± 1.9 μg and 55.3 ± 4.6 μg for low and high cell densities) in continued culture without GF supplementation compared to Unprimed microcapsules. Phase two of this work assessed the extracellular matrix forming capacity of Primed BMSC microcapsules over 21 d after cryopreservation. Notably, primed and cryopreserved BMSCs successfully retained the ability to synthesise both sGAG (24.8 ± 2.7 μg and 75.1 ± 11.6 μg for low and high cell densities) and collagen (26.4 ± 7.8 μg and 93.1 ± 10.2 μg for low and high cell densities) post-cryopreservation. These findings demonstrate the significant potential of priming and cryopreservation approaches for IVD repair and could possibly open new horizons for pre-designed, 'off-the-shelf' injectable therapeutics.


A ticking time bomb hidden in plain sight.
The deer tick transmits nearly half of the known tick-borne pathogens in the United States, and its expanding geographic range increases the risk of human infection. To decrease the abundance of and infection risk from deer ticks, approaches that include vaccines for human use and for animal hosts are desired.


Cranial nerve injury is associated with dual antiplatelet therapy use and cervical hematoma after carotid endarterectomy.
To determine predictors of cranial nerve injury (CNI) after carotid endarterectomy (CEA). Consecutive CEAs performed over a 5-year period were enrolled in this study. Outcomes analyzed included 30-day major adverse event rate (composite of stroke, death, and myocardial infarction), death, stroke, disabling stroke, myocardial infarction, cervical hematoma and CNI rate, reoperation, and hospital readmission at 30 days. There were 1258 CEAs were included in the study, 1168 (93%) were performed using an eversion technique. Patients with symptoms comprised 27% of the cohort (n = 340). At 30 days, there were no deaths, 23 major adverse events (1.8%), 11 strokes (0.9%: nine minor, two major), 12 myocardial infarctions (0.9%), 41 cervical hematomas (3.3%), 9 reoperations (0.7%) and 10 hospital readmissions (0.8%). Median duration of stay was 1 day (interquartile range, 1-2 days). CNI rate at discharge was 2.3% (n = 29). Two patients (9%) had more than one cranial nerve affected. The marginal mandibular branch of the facial nerve was most frequently involved (n = 16; 52%), followed by the hypoglossal (n = 9; 29%), the vagus (n = 4; 13%), and the spinal accessory nerve (n = 2; 6%). Horner's syndrome, consistent with an injury to the cervical sympathetic chain, occurred in 13 patients (1%) who had a true cranial nerve affected as well. The vast majority (94%) of these CNIs and all Horner's syndrome neurapraxias were transient; only the two accessory lesions persisted at their follow-up visit (median, 32 months; range, 8-72 months). Significant predictors for CNI included diabetes (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.0-6.2; P = .048), cervical hematoma (OR, 41.7; 95% CI, 13.8-125.4; P < .001), and dual antiplatelet therapy (OR, 4.4; 95% CI, 1.7-11.4; P = .002). CNI is predominantly a transient complication, but is associated significantly with dual antiplatelet therapy use and the occurrence of a postoperative cervical hematoma. Scrupulous attention to hemostasis might reduce the incidence of CNI.


Schilling test: physiologic basis for and use as a diagnostic test.
With the advent of binding assays for vitamin B12 in blood, the Schilling test, which involves administration of radioactive B12 to a patient and subsequent urine collection for 24 to 48 h, fell into disuse in many laboratories. However, the test is still the only way to actually measure whether vitamin B12 is being absorbed through the terminal ilium. By administering radioactive vitamin B12, along with a preparation of intrinsic factor (IF), lack of functional IF may also be demonstrated. The Schilling test requires that attention be paid to a number of parameters, including the amount of radioactive vitamin B12 administered and the completeness of the urine collection. These factors, and others required for correct performance of the test, are discussed in this article.


[Systems analysis of colour music corrective effect].
In the context of P. K. Anokhin's theory of functional systems, the corrective effects of various combinations of medical therapeutical resonance music (MTRM) and dynamic colour exposure were analyzed. As compared to rehabilitative music programmes, MRTM was shown to have a more pronounced relaxing effect as manifested both in the optimization of emotion and in the activity of autonomic regulation of cardiovascular functions. On combined MRTM and dynamic colour flow exposures, the relaxing effect is most marked. In the examinees, the personality and situation anxieties diminish, mood improves, cardiovascular parameters become normal, the rate of metabolic processes and muscular rigidity reduce, the spectral power of alpha-rhythm increases, these occurring predominantly in the anterior region of the brain. The findings suggest the high efficiency of the chosen way of normalizing the functional status of man.


Selecting the appropriate psychotherapies for individuals with traumatic brain injury: what works and what does not?
When traditional psychotherapy is provided to patients with traumatic brain injuries (TBIs), the primary focus is on treating mood changes such as depression, anxiety or anger. However, traditional psychotherapeutic methods developed specifically for mood changes fall short when treating most TBI patients. In large part, this is because the psychological adjustment difficulties that most TBI patients face are linked to life-altering changes that are interwoven with permanent physical, cognitive, and social sequelae. In addition, mood changes in TBI patients are also caused by vocational and financial losses. The sudden onset of these unfamiliar and interdependent problems necessitates a psychotherapeutic approach that acknowledges the inherent challenges of coping with multiple life-altering changes. For patients who experience a shattered sense of self, interventions need to be explored to make life meaningful following a TBI. An existentially-oriented approach is introduced in the following steps: (1) identifying pre-injury future expectations, (2) examining how the TBI has altered these expectations, (3) grieving the loss of the expected future, and (4) developing a realistic future that is existentially meaningful. Pivotal gains are achieved when patients rebuild their lives according to their own core values. TBI patients can benefit from existential psychotherapy.


Genetic polymorphisms associated with increased risk of developing chronic myelogenous leukemia.
Little is known about inherited factors associated with the risk of developing chronic myelogenous leukemia (CML). We used a dedicated DNA chip containing 16 561 single nucleotide polymorphisms (SNPs) covering 1 916 candidate genes to analyze 437 CML patients and 1 144 healthy control individuals. Single SNP association analysis identified 139 SNPs that passed multiple comparisons (1% false discovery rate). The HDAC9, AVEN, SEMA3C, IKBKB, GSTA3, RIPK1 and FGF2 genes were each represented by three SNPs, the PSM family by four SNPs and the SLC15A1 gene by six. Haplotype analysis showed that certain combinations of rare alleles of these genes increased the risk of developing CML by more than two or three-fold. A classification tree model identified five SNPs belonging to the genes PSMB10, TNFRSF10D, PSMB2, PPARD and CYP26B1, which were associated with CML predisposition. A CML-risk-allele score was created using these five SNPs. This score was accurate for discriminating CML status (AUC: 0.61, 95%CI: 0.58-0.64). Interestingly, the score was associated with age at diagnosis and the average number of risk alleles was significantly higher in younger patients. The risk-allele score showed the same distribution in the general population (HapMap CEU samples) as in our control individuals and was associated with differential gene expression patterns of two genes (VAPA and TDRKH). In conclusion, we describe haplotypes and a genetic score that are significantly associated with a predisposition to develop CML. The SNPs identified will also serve to drive fundamental research on the putative role of these genes in CML development.


Selected factors affecting Staphylococcus aureus within silastic catheters.
Catheter-related infections are frequent complications in hospitalized patients, and Staphylococcus aureus is a frequent etiologic agent. Little is known about factors that contribute to the growth and viability of S. aureus within contaminated catheters. In vitro experiments assessed the ability of S. aureus to adhere to silastic catheter tubing. The effects of heparin, serum, and calcium on initial bacterial adherence were also assessed. Additional experiments quantified the effect of ethanol locking on S. aureus viability within catheter-associated biofilms produced after 48 to 72 h incubation of S. aureus with catheters under conditions of nutrient flow. Scanning electron microscopy visualized the effect of ethanol locking on the morphology of bacterial vegetations adherent to the catheter wall. S. aureus readily adhered (in a dose dependent manner) to silastic catheters incubated with bacteria for 15 min, and adherence was not affected by calcium or heparin (even though heparin adhered to the silastic tubing and S. aureus is known to express heparin-binding proteins). S. aureus adherence was inhibited by serum but not albumin. Ethanol locking (5 min to 24 h) of catheters containing mature 48 to 72 h S. aureus biofilms resulted in no detectable bacterial viability, although scanning electron microscopy revealed similar bacterial vegetations adherent to control and ethanol-treated catheters. S. aureus adherence to silastic catheters was inhibited by serum, but the active inhibitory component was not albumin. Ethanol locking efficiently sterilized S. aureus contaminated catheters, although nonviable bacterial vegetations remained on the ethanol-treated catheters.


Pediatric blast lung injury from a fireworks-related explosion.
Blast injuries related to explosions have been described in the literature but are uncommon in children. We describe a multisystem blast injury in a child resulting from a commercial firework-related explosion in her home. She presented with respiratory failure, shock, altered level of consciousness, and multiple orthopedic injuries. The patient required immediate stabilization and resuscitation in the emergency department and a prolonged hospitalization. This report reviews the spectrum of injuries that are seen in blast-related trauma and the emergency measures needed for rapid stabilization of these critical patients.


An Integrated Sleep and Reward Processing Model of Major Depressive Disorder.
Major depressive disorder with comorbid sleep disturbance has been associated with negative outcomes, including lower rates of treatment response and a greater likelihood of depressive relapse compared to those without sleep disturbance. However, little, if any, research has been conducted to understand why such negative treatment outcomes occur when sleep disturbance is present. In this conceptual review, we argue that the relationship of sleep disturbance and negative treatment outcomes may be mediated by alterations in neural reward processing in individuals with blunted trait-level reward responsivity. We first briefly characterize sleep disturbance in depression, discuss the nature of reward processing impairments in depression, and summarize the sleep/reward relationship in healthy human subjects. We then introduce a novel Integrated Sleep and Reward model of the course and maintenance of major depressive disorder and present preliminary evidence of sleep and reward interaction in unipolar depression. Finally, we discuss limitations of the model and offer testable hypotheses and directions for future research.


Factors affecting nurses' attitudes in Israel toward patients who present them with Internet medical information.
Nurses regularly encounter patients bringing with them medical data from the Internet. The purpose of the present study was to examine the prevalence of these encounters, nurses' attitudes to these patients, and the factors that might influence their attitudes. A cross-sectional study of a convenience sample of 110 nurses (32 practical nurses, 35 registered nurses and 43 academically trained nurses). The main variables measured were: attitudes toward patients presenting Internet information, professional self-esteem, and three indices of Internet use. The results show that most nurses had encountered patients presenting Internet medical information and held positive attitudes to them. Nurses with such experience had more positive attitudes than nurses with no such experience. Professional self-esteem and indices of Internet use were also positively correlated to favorable attitudes to these patients. Regression analysis showed that professional self-esteem and Internet self-efficacy predicted attitudes to these patients. Since the number of patients presenting Internet information can only multiply, there is a need to prepare and train nurses for encounters with such patients.


Alteration of the cytosolic-mitochondrial distribution of high-energy phosphates during global myocardial ischemia may contribute to early contractile failure.
Depending on its duration, temporary myocardial ischemia leads to a disturbance of myocardial function before irreversible cellular necrosis is developed. Mechanical, electrical, and metabolic disturbances were suggested to be possible mechanisms accounting for the altered mechanical performance in ischemic hearts. To further investigate the alteration of myocardial energy metabolism on the subcellular level, we determined, by means of nonaqueous fractionation, the cytosolic-mitochondrial distribution of high-energy phosphates and other metabolites (ATP, ADP, phosphocreatine, creatine, and inorganic phosphate) in ischemic (zero-flow) guinea pig hearts after isolated perfused working heart preparation. Additional experiments using 31P nuclear magnetic resonance spectroscopy were performed to determine pHi and [Mg2+]i changes during global ischemia. The total ATP content of myocardial tissue dropped only slowly to 76% of control ATP at 10 minutes and to 51% at 30 minutes and reached almost zero at 60 minutes of ischemia. However, striking differences were observed on the subcellular level: While cytosolic phosphocreatine was almost completely consumed after 3 minutes of ischemia (from 19.1 +/- 1.6 to 3.3 +/- 0.5 mmol/L), ATP concentration in the cytosol decreased within 30 minutes from 8.4 +/- 0.6 to only 5.4 +/- 0.9 mmol/L. Mitochondrial ATP was rapidly and linearly reduced to 60% after 5 minutes of ischemia and was nearly unmeasurable after a further 20 minutes. Thus, in contrast to the breakdown of phosphocreatine in cytosol, the only slight alteration of cytosolic ATP reveals a reduction in cytosolic ATP utilization. Moreover, the unaffected cytosolic-mitochondrial difference in the phosphorylation potential of ATP demonstrates the intact function of the ADP/ATP carrier during early ischemia. These results might indicate a disturbance of the functional coupling between carrier and phosphocreatine kinase (phosphocreatine shuttle), which could be of importance for the early contractile failure in myocardial ischemia.


Liver X receptors (LXR) as therapeutic targets in dyslipidemia.
Liver X receptors (LXR) alpha and beta belong to a family of nuclear receptors which form heterodimers with the retinoid X receptor (RXR) and, upon ligand binding, stimulate the expression of target genes. LXR were initially described as orphan receptors and later oxidized cholesterol derivatives (oxysterols) were identified as their natural ligands. In addition, several synthetic LXR agonists such as T0901317 and GW3965 were synthesized. Oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore LXR operate as cholesterol sensors which protect from cholesterol overload by inhibiting intestinal cholesterol absorption, stimulating cholesterol efflux from cells to high-density lipoproteins (HDL), its transport to the liver, conversion to bile acids, and biliary excretion. In addition, LXR agonists activate fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and liver steatosis. Lipogenic effect seems is the most important negative feature of LXR agonists considered as potential hypolipidemic drugs. Some of currently used drugs also affect LXR signaling. For example, statins may impair LXR signaling by inhibiting oxysterol synthesis, whereas fibrates and thiazolidinediones increase LXR expression and activity.


How is alcohol consumption affected if we account for under-reporting? A hypothetical scenario.
This study predicts the implications of under-reporting of alcohol consumption in England for alcohol consumption above Government drinking thresholds. Two nationally representative samples of private households in England were used: General LiFestyle survey (GLF) and Health Survey for England (HSE) 2008. Participants were 9608 adults with self-reported alcohol consumption on heaviest drinking day in the last week (HSE) and 12 490 adults with self-reported average weekly alcohol consumption (GLF). Alcohol consumption in both surveys was revised to account for under-reporting in three hypothetical scenarios. The prevalence of drinking more than UK Government guidelines of 21/14 (men/women) alcohol units a week, and 4/3 units per day, and the prevalence of binge drinking (>8/6 units) were investigated using logistic regression. Among drinkers, mean weekly alcohol intake increases to 20.8 units and mean alcohol intake on heaviest drinking day in the last week increases to 10.6 units. Over one-third of adults are drinking above weekly guidelines and over three-quarters drank above daily limits on their heaviest drinking day in the last week. The revision changes some of the significant predictors of drinking above thresholds. In the revised scenario, women have similar odds to men of binge drinking and higher odds of drinking more than daily limits, compared with lower odds in the original survey. Revising alcohol consumption assuming equal under-reporting across the population does not have an equal effect on the proportion of adults drinking above weekly or daily thresholds. It is crucial that further research explores the population distribution of under-reporting.


Childhood cancer and hypercalcemia: report of a case treated with pamidronate.
Hypercalcemia in a 4-year-old boy with non-Hodgkin lymphoma treated with pamidronate is presented. The child had relapsed disease with bone metastasis. Hypercalcemia is rare in children, and bisphosphonates are relatively new agents for the treatment of hypercalcemia. Information concerning their use in the treatment of hypercalcemia in childhood is limited. We found that pamidronate is effective and has no significant side effects in a child.


Advances in artificial intelligence-based microbiome for PMI estimation.
Postmortem interval (PMI) estimation has always been a major challenge in forensic science. Conventional methods for predicting PMI are based on postmortem phenomena, metabolite or biochemical changes, and insect succession. Because postmortem microbial succession follows a certain temporal regularity, the microbiome has been shown to be a potentially effective tool for PMI estimation in the last decade. Recently, artificial intelligence (AI) technologies shed new lights on forensic medicine through analyzing big data, establishing prediction models, assisting in decision-making, etc. With the application of next-generation sequencing (NGS) and AI techniques, it is possible for forensic practitioners to improve the dataset of microbial communities and obtain detailed information on the inventory of specific ecosystems, quantifications of community diversity, descriptions of their ecological function, and even their application in legal medicine. This review describes the postmortem succession of the microbiome in cadavers and their surroundings, and summarizes the application, advantages, problems, and future strategies of AI-based microbiome analysis for PMI estimation.


Trends in Surgical Aortic Valve Replacement in More Than 3,000 Consecutive Cases in the Era of Transcatheter Aortic Valve Implantations.
Objectives Biological prostheses for surgical aortic valve replacement (sAVR) are increasingly being considered in patients < 60 years of age. Likely, preserving the option of performing a transcatheter valve-in-valve (ViV) procedure in cases of structural valve deterioration has contributed to this development. We assessed the use pattern in sAVR over an 11-year period. Methods From 2002 through 2012, a total of 3,172 patients underwent sAVR at our center. Results Mean age was 70.4 ± 10.6 years and mortality was 1.9%. From 2002 to 2012, mean manufacturer given valve size increased from 22.8 ± 1.7 to 23.9 ± 2.0 mm (p < 0.001). Mean true internal diameter and effective orifice area increased from 19.6 to 20.3 mm (p = 0.027) and 1.41 to 1.56 cm(2) (p < 0.001), respectively. Use of mechanical valves decreased from 10.9 to 1.8% (p < 0.001), and patients were younger in 2012 than in 2002 (52.8 ± 16.5 vs. 41.0 ± 14.3 years; p = 0.028). Conclusion Profound change of use pattern in sAVR was observed as indication for biological prostheses became more liberal. Larger prostheses were implanted during the observational period. Especially in younger patients, optimal sizing is essential to preserve the option for subsequent ViV procedures.


Senior nurses' perspectives on the transfer of opioid substitution treatment clients from clinics to community pharmacy.
There is unmet demand for opioid substitution treatment (OST) in New South Wales, Australia, with many public clinics reporting long waitlists. Recently, some community pharmacies have reported a lack of referrals from public clinics. To obtain insight into this apparent contradiction, this study explored the perspectives of senior nurses in public OST clinics regarding client transfers to community pharmacies. Semi-structured interviews were conducted with nine senior nurses from eight (20%) public OST clinics in New South Wales regarding: the nurses' experience in OST provision, factors affecting client transfer, opinions on pharmacy OST services and relationships with community pharmacies. Interviews were audio-recorded and transcribed verbatim. NVivo was used for initial analysis and coding of the transcripts. Emerging themes were repeatedly analysed and refined by consensus discussion. Most clinics reported being at or over capacity. Nurse identified barriers to transfer included: difficulty motivating reluctant clients, clients' unwillingness to pay for pharmacy supervised dispensing, lack of convenient pharmacy providers and unstable clients. Despite overall good collaborations with community pharmacies, some aspects could be improved, especially face-to-face visits and education around clinic procedures. This study highlights the complex barriers encountered by senior nurses in the transfer of OST clients from clinics to community pharmacies. Improved collaboration with pharmacies and subsidised or standardised dispensing fees may enhance the transfer of clients to pharmacies and improve clinics throughput. [Bui J, Day C, Hanrahan J, Winstock A, Chaar B. Senior nurses' perspectives on the transfer of OST clients from clinics to community pharmacy. Drug Alcohol Rev 2015;34:495-98].


Analysis of the post-translational processing of alpha-MSH in the pituitaries of the chondrostean fishes, Acipenser transmontanus and Polyodon spathula.
Multiple forms of alpha-MSH were isolated from the pituitaries of the white sturgeon, Acipenser transmontanus, and the paddlefish, Polyodon spathula, following fractionation of the pituitary extracts by reversed-phase HPLC. In both species, immunoreactive forms which eluted with the same retention times as synthetic mammalian ACTH(1-13)NH2, monoacetylated alpha-MSH, and diacetylated alpha-MSH were detected. In the pituitary of the sturgeon, N-acetylated forms of alpha-MSH represented 91% of the total alpha-MSH isolated. However, in the pituitary of the paddlefish, N-acetylated forms of alpha-MSH accounted for only 45% of the total alpha-MSH isolated. The presence of N-acetylated forms of alpha-MSH in the pituitaries of representatives of the two extant genera of chondrostean fish coupled with the observation that N-acetylated forms of alpha-MSH are present in the pituitaries of cladistian and neopterygian fishes indicates that the alpha-MSH specific N-acetylation mechanism evolved prior to the radiation of the Actinopterygii. A conspicuous feature of the chondrostean alpha-MSH N-acetylation reaction was the low levels of diacetylated alpha-MSH produced relative to the levels of monoacetylated alpha-MSH. Similar observations have been made for the cladistian fish, Calamoichthys calabaricus, and the cartilaginous fish, Hydrolagus colliei. However, in holostean fishes, lungfishes, and tetrapods, the diacetylated form of alpha-MSH is the major end product produced in the intermediate pituitary. The phylogenetic implications of these observations will be discussed.


Heart rate variability in rats acclimatized to high altitude.
The aims of this study were to relate heart morphology and functions changes to heart rate variability (HRV) components after acclimatization to high altitude and to define whether preadaptation to hypoxia could modulate HRV responses to acute hypoxic stress. Doppler-echocardiographic studies of the left ventricle were performed in female Wistar rats before, during, and after a 10-week exposure to moderate hypobaric hypoxia (CH rats, approximately 4000 m simulated) or normoxia (N rats, approximately 55 m). Right ventricular morphology and function and pulmonary artery pressure were evaluated using heart catheterization. Spectral analysis of HRV was studied after exposure in conscious unrestrained rats in normoxia and during acute hypoxic stress. Necropsy right ventricular hypertrophy and intraventricular and pulmonary artery hypertension were found in CH rats compared with N rats. Echocardiographic left ventricular morphology and functions were similar between the groups after exposures. Compared to the control group, CH rats had similar heart rates and HRV components when measured in normoxia. During acute hypoxic stress, HRV decreased in all rats, but less in CH rats. These results support the hypothesis that long-term mild hypoxia may moderate sympathetic activation induced by acute hypoxia and that right ventricular hypertrophy cannot be the direct cause of such a shift in sympathovagal nerve interaction during acute hypoxic stress.


Profiles of piRNA abundances at emerging or established piRNA loci are determined by local DNA sequences.
Piwi-interacting RNAs (piRNAs) ensure transposable element silencing in Drosophila, thereby preserving genome integrity across generations. Primary piRNAs arise from the processing of long RNA transcripts produced in the germ line by a limited number of telomeric and pericentromeric loci. Primary piRNAs bound to the Argonaute protein Aubergine then drive the production of secondary piRNAs through the "ping-pong" amplification mechanism that involves an interplay with piRNAs bound to the Argonaute protein Argonaute-3. We recently discovered that clusters of P-element-derived transgenes produce piRNAs and mediate silencing of homologous target transgenes in the female germ line. We also demonstrated that some clusters are able to convert other homologous inactive transgene clusters into piRNA-producing loci, which then transmit their acquired silencing capacity over generations. This paramutation phenomenon is mediated by maternal inheritance of piRNAs homologous to the transgenes. Here we further mined our piRNA sequencing data sets generated from various strains carrying transgenes with partial sequence homology at distinct genomic sites. This analysis revealed that same sequences in different genomic contexts generate highly similar profiles of piRNA abundances. The strong tendency of piRNAs for bearing a U at their 5' end has long been recognized. Our observations support the notion that, in addition, the relative frequencies of Drosophila piRNAs are locally determined by the DNA sequence of piRNA loci.


The enclosed ward management strategies in psychiatric hospitals during COVID-19 outbreak.
During the COVID-19 pandemic, as a large city located in Southwest China, Chengdu was mainly affected by imported cases. For a psychiatric hospital, the enclosed management model, the crowded wards and the uncooperative patients are the risk factors of nosocomial infection. Admitting new patients while preventing the COVID-19 outbreak within the institutions was a crucial challenge. The Mental Health Centre of Chengdu proposed a series of effective management strategies to deal with the rapidly evolving situation during the COVID-19 pandemic which included regulation for the inpatients, their families and staff, and achieved Zero infection in our hospital.


Production of secondary metabolites using tissue culture-based biotechnological applications.
Plants are the sources of many bioactive secondary metabolites which are present in plant organs including leaves, stems, roots, and flowers. Although they provide advantages to the plants in many cases, they are not necessary for metabolisms related to growth, development, and reproduction. They are specific to plant species and are precursor substances, which can be modified for generations of various compounds in different plant species. Secondary metabolites are used in many industries, including dye, food processing and cosmetic industries, and in agricultural control as well as being used as pharmaceutical raw materials by humans. For this reason, the demand is high; therefore, they are needed to be obtained in large volumes and the large productions can be achieved using biotechnological methods in addition to production, being done with classical methods. For this, plant biotechnology can be put in action through using different methods. The most important of these methods include tissue culture and gene transfer. The genetically modified plants are agriculturally more productive and are commercially more effective and are valuable tools for industrial and medical purposes as well as being the sources of many secondary metabolites of therapeutic importance. With plant tissue culture applications, which are also the first step in obtaining transgenic plants with having desirable characteristics, it is possible to produce specific secondary metabolites in large-scale through using whole plants or using specific tissues of these plants in laboratory conditions. Currently, many studies are going on this subject, and some of them receiving attention are found to be taken place in plant biotechnology and having promising applications. In this work, particularly benefits of secondary metabolites, and their productions through tissue culture-based biotechnological applications are discussed using literature with presence of current studies.


Fortnightly variations in the flow velocity of Rutford Ice Stream, West Antarctica.
Most of the ice lost from the Antarctic ice sheet passes through a few fast-flowing and highly dynamic ice streams. Quantifying temporal variations in flow in these ice streams, and understanding their causes, is a prerequisite for estimating the potential contribution of the Antarctic ice sheet to global sea-level change. Here I show that surface velocities on a major West Antarctic Ice Stream, Rutford Ice Stream, vary periodically by about 20 per cent every two weeks as a result of tidal forcing. Tidally induced motion on ice streams has previously been thought to be limited to diurnal or even shorter-term variations. The existence of strong fortnightly variations in flow demonstrates the potential pitfalls of using repeated velocity measurements over intervals of days to infer long-term change.


Evaluation of the parotid gland. Comparison of sialography, non-contrast computed tomography, and CT sialography.
Sialography, non-contrast computed tomography (NCCT), and CT sialography (CTS) were compared in 40 patients with parotid disease. While NCCT and CTS proved to be superior to sialography in most cases, with NCCT being as good as CTS for demonstration of parotid masses, sialography was preferred over both NCCT and CTS for evaluation of inflammatory disease. The role of percutaneous needle aspiration is discussed, and protocols for evaluation of both parotid masses and inflammatory disease are presented.


Quantification of 2-Hydroxyglutarate Enantiomers by Liquid Chromatography-mass Spectrometry.
Two enantiomers of 2-hydroxyglutarate (2HG), L (L2HG) and D (D2HG), are metabolites of unknown function in mammalian cells that were initially associated with separate and rare inborn errors of metabolism resulting in increased urinary excretion of 2HG linked to neurological deficits in children (Chalmers et al., 1980; Duran et al., 1980; Kranendijk et al., 2012). More recently, investigators have shown that D2HG is produced by mutant isocitrate dehydrogenase enzymes associated with a variety of human malignancies, such as acute myeloid leukemia, glioblastoma multiforme, and cholangiocarcinoma (Cairns and Mak, 2013; Dang et al., 2009; Ward et al., 2010). By contrast, we and others have shown that L2HG accumulates in response to cellular reductive stressors like hypoxia, activation of hypoxia inducible factors, and mitochondrial electron transport chain defects (Oldham et al., 2015; Reinecke et al., 2011; Intlekofer et al., 2015; Mullen et al., 2015). Each enantiomer is produced and metabolized in independent biochemical pathways in reactions catalyzed by separate enzymes and utilizing different cofactors with presumably different consequences for cellular metabolism (Kranendijk et al., 2012). Therefore, as research into the roles of D2HG and L2HG in human metabolism continues, it becomes increasingly important for investigators to consider each enantiomer independently (Struys, 2013). Several methods for quantification of biochemically relevant enantiomers in general have been developed and typically include enzymatic assays using enzymes specific for one enantiomeric species or the other, the use of chiral chromatography medium to facilitate chromatographic separation of enantiomers prior to spectroscopy, or the use of chiral derivatization reagents to convert a mixture of enantiomers to diastereomers with differing physical and chemical properties facilitating their chromatographic separation. In this protocol, we report the adaptation of a previously published derivatization method using diacetyl-l-tartaric anhydride (DATAN) for the quantification of 2HG enantiomers (Figure 1) (Oldham et al., 2015; Struys et al., 2004).


Solitary Metastasis of Clear Renal Cell Carcinoma to Thyroid Gland: Three reported cases with review of the literature.
Metastasis to the head and neck and more specifically to the thyroid gland from distant primary tumors is less common in comparison to the local regional metastasis of squamous cell carcinomas of the upper aero-digestive tract. Preoperative diagnosis of these cases can be difficult. The authors present three cases with distant solitary metastases of clear renal cell carcinoma to the thyroid gland with ambiguous mechanism of tumor spread to the thyroid. Solitary metastases of clear renal cell carcinomas are an uncommon variant of metastasis of this tumor and may imitate thyroid well differentiated carcinoma which most commonly affects the thyroid gland. Therefore, thorough endocrinological investigation of the thyroid gland is necessary. The recommended therapy of renal cell carcinoma metastasis includes surgical removal of all cancerous tissues - i.e. of the gland with the possibly infiltrated adjacent tissues, as well as removal of the affected lymph nodes - selective radical neck dissection. In our study, we discuss the clinical picture, pathology, diagnosis, differential diagnosis and prognosis together with literature review.


Cinnamylindoline derivatives: synthesis and factor Xa (FXa) inhibitory activities.
A series of cinnamylindoline derivatives were synthesized, and their factor Xa (FXa) inhibitory activities and selectivity over trypsin were evaluated. Among them, some novel derivatives showed potent FXa inhibitory activities and good selectivity over trypsin. Especially, (E)-2-{5-[1-(acetimidoyl)piperidin-4-yloxy]-2-[2-(5-amidino-2-hydroxyphenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic acid (22f) having 2-hydroxycinnamyl moiety exhibited the most potent FXa inhibitory activity in vitro. Furthermore, 22f also exhibited potent anticoagulant activities in vitro.


Development of an improved rhodium catalyst for z-selective anti-markovnikov addition of carboxylic acids to terminal alkynes.
To develop more active catalysts for the rhodium-catalyzed addition of carboxylic acids to terminal alkynes furnishing anti-Markovnikov Z enol esters, a thorough study of the rhodium complexes involved was performed. A number of rhodium complexes were characterized by NMR, ESI-MS, and X-ray analysis and applied as catalysts for the title reaction. The systematic investigations revealed that the presence of chloride ions decreased the catalyst activity. Conversely, generating and applying a mixture of two rhodium species, namely, [Rh(DPPMP)2][H(benzoate)2] (DPPMP=diphenylphosphinomethylpyridine) and [{Rh(COD)(μ2-benzoate)}2], provided a significantly more active catalyst. Furthermore, the addition of a catalytic amount of base (Cs2CO3) had an additional accelerating effect. This higher catalyst activity allowed the reaction time to be reduced from 16 to 1-4 h while maintaining high selectivity. Studies on the substrate scope revealed that the new catalysts have greater functional-group compatibility.


An integrated transcriptome and metabolome analysis reveals the gene network regulating flower development in Pogostemon cablin.
Pogostemon cablin is a well-known protected species widely used in medicine and spices, however the underlying molecular mechanisms and metabolite dynamics of P. cablin flower development remain unclear due to the difficulty in achieving flowering in this species. A comparison of the transcriptome and widely targeted metabolome during P. cablin flower development was first performed in this study. Results showed that a total of 13,469 differentially expressed unigenes (DEGs) and 371 differentially accumulated metabolites (DAMs) were identified. Transcriptomic analysis revealed that the DEGs were associated with starch and sucrose metabolism, terpenoid biosynthesis and phenylpropanoid biosynthesis. Among these DEGs, 75 MIKC-MADS unigenes were associated with the development of floral organs. Gibberellins (GAs), auxin, and aging signaling might form a cross-regulatory network to regulate flower development in P. cablin. According to the metabolic profile, the predominant DAMs were amino acids, flavonoids, terpenes, phenols, and their derivatives. The accumulation patterns of these predominant DAMs were closely associated with the flower developmental stage. The integration analysis of DEGs and DAMs indicated that phenylpropanoids, flavonoids, and amino acids might be accumulated due to the activation of starch and sucrose metabolism. Our results provide some important insights for elucidating the reproductive process, floral organ, and color formation of P. cablin flowers at the molecular level. These results will improve our understanding of the molecular and genetic mechanisms involved in the floral development of P. cablin.


[Comparison of thawing of plasma by microwave or water bath: preliminary longitudinal biological study of hemostatic parameters].
Exploration of haemostasis was performed on plasmas thawed in an experimental microwave oven comparatively to a 37 degrees C water bath. Factor VIII:R:Ag, procoagulant and antigenic fibrinogen, and Fg:C/Fg:Ag ratio were found to be significantly, slightly decreased with microwave thawing. Factor VIII:C and VIII:C/VIII:R:Ag ratio were found to be increased with microwaves. Antigenic fractions were decreased because of partial precipitation. In addition, Fibrinogen slightly lost its activity; on the contrary, factor VIIIC was activated by micro-waves. All this allows to select parameters for new experimental microwave ovens development.


[Pollution Characteristics and Source Analysis of Atmospheric VOCs in the Coastal Background of the Pearl River Delta].
As an important precursor of ozone, volatile organic compounds (VOCs) have attracted much attention. This study analyzed the temporal variation and composition of atmospheric VOCs in the coastal background of the Pearl River Delta, using real-time online monitoring data of VOCs obtained at the Yangmeikeng Ecological Environment Monitoring Station from August 2019 to July 2020. The major sources of VOCs were identified using a receptor model based on the PMF (positive matrix factorization) and HYSPLIT (hybrid single particle Lagrangian integrated trajectory) models. The results showed that the annual mean concentration of anthropogenic VOCs in the coastal background area of the Pearl River Delta was 9.30×10-9(volume fraction). There was obvious seasonal variation of VOCs in this area, with higher values in autumn and winter and lower values in summer. The coastal background area of the Pearl River Delta exhibited a different diurnal variation pattern to that of cities and other backgrounds. While the peak of VOCs concentration mainly occurred in the morning, from 10:00 to 11:00, concentration remained at a low level during the early morning and after 15:00. Ethylene, propylene, toluene, isopentane, isoprene, m/p-xylene, n-butane, and acetylene were the key species that affected the chemical composition of VOCs. The air masses affecting the coastal background area of the Pearl River Delta were mainly short-distance air masses from elsewhere in the province (25%), ocean air masses (27%), coastal air masses (31%), and inland air masses outside the province (17%). Among them, the average concentration of VOCs was lowest under the influence of ocean air masses, which is mainly affected by the mixed source of ship emissions and aging VOCs, gasoline volatilization, and vehicle emissions. In comparison, the concentration level of VOCs increased by 70.1% to 148.8% under the influence of other air masses. The transmission effects of industrial sources, LNG and LPG volatiles, and petrochemical sources were more prominent. Generally, the atmosphere of coastal background areas was severely affected by anthropogenic pollution, especially by air pollution masses transported from the land, while the impact of pollution by ships near shore and tourist traffic cannot be ignored.


Honokiol Inhibits Constitutive and Inducible STAT3 Signaling via PU.1-Induced SHP1 Expression in Acute Myeloid Leukemia Cells.
Constitutive and inducible activation of signal transducer and activator of transcription 3 (STAT3) signaling facilitates the carcinogenesis in most human cancers including acute myeloid leukemia (AML). Negative regulators, such as protein tyrosine phosphatases SHP1, inhibit the activated STAT3 signaling. In this study, we investigated the effect of honokiol (HNK), a constituent of Magnolia officinalis, on the STAT3 signaling. STAT3 signaling and SHP1 expression were measured by quantitative real-time PCR and western blotting in leukemic cell lines and primary AML blasts treated with HNK. HNK decreased the phosphorylated STAT3 but not the total STAT3 through increasing the expression of SHP1. In addition, HNK inhibited transcription activity of STAT3, reduced nuclear translocation of STAT3, and decreased the expression of STAT3 target genes. Knockdown of SHP1 by small hairpin RNA (shRNA) or treatment with vanadate, a protein tyrosine phosphatases inhibitor, abolished HNK-induced STAT3 inhibition, suggesting that SHP1 plays an important role in the inhibition of STAT3 signaling by HNK. Further, HNK increased the expression of transcript factor PU.1, which had been reported to activate the expression of SHP1 via binding SHP1 promoter region. Knockdown of PU.1 reversed HNK-induced upregulation of SHP1 and inactivation of STAT3 signaling. Finally, HNK increased the expression of PU.1 and SHP1 in hematopoietic progenitors isolated from patients with AML. In conclusion, our data have shown a regulatory mechanism underlying the inhibition of STAT3 signaling by HNK. Therefore, as a relative non-toxic compound, HNK may offer a therapeutic advantage in the clinical treatment for AML.


A Novel Dye-Modified Metal-Organic Framework as a Bifunctional Fluorescent Probe for Visual Sensing for Styrene and Temperature.
A novel fluorescent probe (C460@Tb-MOFs) was designed and synthesized by encapsulating the fluorescent dye 7-diethylamino-4-methyl coumarin (C460) into a terbium-based metal-organic framework using a simple ultrasonic impregnation method. It is impressive that this dye-modified metal-organic framework can specifically detect styrene and temperature upon luminescence quenching. The sensing platform of this material exhibits great selectivity, fast response, and good cyclability toward styrene detection. It is worth mentioning that the sensing process undergoes a distinct color change from blue to colorless, providing conditions for the accurate visual detection of styrene liquid and gas. The significant fluorescence quenching mechanism of styrene toward C460@Tb-MOFs is explored in detail. Moreover, the dye-modified metal-organic framework can also achieve temperature sensing from 298 to 498 K with high relative sensitivity at 498 K. The preparation of functionalized MOF composites with fluorescent dyes provides an effective strategy for the construction of sensors for multifunctional applications.


Cytochrome P450 enzyme activities in the Australian brushtail possum trichosurus vulpesula: a comparison with the rat, rabbit, sheep and chicken.
A comparative study of cytochrome P450 phase 1 biotransformation enzyme activities of the Australian brushtail possum was conducted. Since its introduction to New Zealand this animal pest has caused considerable agricultural and ecological problems. The objective of this work was to probe for potential biochemical weaknesses that may be exploited for designing a more species-specific method of toxicological control of the possum population in New Zealand. Liver microsomal enzyme content and the kinetics of in vitro biotransformation reactions in the possum were quantified and compared with those of the rabbit, rat, chicken and sheep. Significant (p > 0.05) species variations in the liver cytochrome P450 enzyme content were observed. All mammals, including the possum, had considerably higher cytochrome P450, cytochrome b5 and cytochrome reductase levels than the chicken. The chicken had the highest specific phase 1 biotransformation activity (Vmax) for all except 1 of the 8 xenobiotics tested. Among the mammals studied, P450 (Vmax) values in the possum were similar or higher than in the rabbit, rat or sheep. The Km values varied significantly (p > 0.05) between species. The Km for 7-hydroxylation of coumarin was highest in the rat. In comparison with other species, the possum had a lower Km for aromatic hydroxylation of aniline, N-demethylation of N,N-dimethyl aniline, and N-dimethyl aniline, but a higher Km for 0-demethylation of 7-methoxycoumarin, 7-hydroxylation of coumarin, and 0-deethylation of acetophenetidin. It was concluded that phase 1 biotransformation of xenobiotics in the possum is similar to or more efficient than in the other animals tested.


Managing the 'seamless service': Primary Care Groups in the new NHS.
This paper reports on empirical work examining the consequences for the development of the role of Primary Care Groups of the shift from competition (in the internal market) to relationships based on collaboration and partnership. Previous work (Conway and Willcocks, 1998; Willcocks and Conway, 1999) firstly developed a conceptual framework emphasizing the development of relationships between Primary Care Groups and their key stakeholders (for example, Health Authorities, Local Authorities and Trusts) and, secondly, sought to test this framework empirically through case study analysis of two Primary Care Groups in the north of England. This paper takes the research further and focuses on one of these Primary Care Groups, providing an in-depth analysis of particular issues such as the rationale for the particular configuration of this organization and the chosen working arrangements, the role and function of the Board and individual members, and the problems encountered in the first year of operation.


A case of serotonin syndrome and mutism associated with methadone.
A patient was seen on the palliative care service at our institution who developed serotonin syndrome and mutism associated with methadone use. Serotonin syndrome is often described as a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities, but not all of these findings are consistently present in all patients with the disorder. The incidence of the serotonin syndrome is thought to mirror the increasing number of proserotonergic agents being used in clinical practice. In 2002, the Toxic Exposure Surveillance System, which receives case descriptions from office-based practices, inpatient settings, and emergency departments, reported 26,733 incidences of exposure to selective serotonin-reuptake inhibitors (SSRIs) that caused significant toxic effects in 7349 persons and resulted in 93 deaths. Serotonin syndrome is not an idiopathic drug reaction; it is a predictable consequence of excess serotonergic agonism of central nervous system (CNS) receptors and peripheral serotonergic receptors. The myriad of symptoms with which serotonin syndrome may present is compounded by the fact that more than 85% of physicians are unaware of serotonin syndrome as a clinical diagnosis. Other SSRIs such as fluoxetine and fluvoxamine have been shown to increase methadone plasma concentrations in dependent patients. Although the exact mechanism is unknown, there are several pathways via which a significant interaction could occur. This would include the effects methadone has on N-methyl-D-aspartate (NMDA) in addition to the impact of methadone on the cytochrome P450 enzyme system. The mainstay of treatment of serotonin syndrome is withdrawal of the offending agent and supportive care. These actions resulted in resolution of our patient's symptoms. Serotonin syndrome is becoming more common, and with the utilization of polypharmacy on many palliative care services should be considered as unifying differential diagnosis in the appropriate setting.


Hepatitis E in developed countries: current status and future perspectives.
Hepatitis E virus (HEV) was for many years thought to be found almost exclusively in developing countries, where it is a major health issue. Recent studies have shown that HEV causes acute and chronic infection in developed countries. In these geographical settings, HEV is primarily a porcine zoonosis caused by genotypes 3 (HEV3) and 4 (HEV4). The clinical phenotype of hepatitis E continues to emerge, and recent data show that HEV is associated with a range of neurological syndromes including Guillain-Barré syndrome and neuralgic amytrophy.


Fetal prostate growth and development.
Normal fetal and newborn prostates were studied to evaluate growth patterns, histogenesis, and secretory activity. Whole cross-sectioned prostates harvested from 107 necropsies of fetuses and newborns ages 20 weeks gestation to 1 month of age were used. Development of the prostate occurred in three stages: bud stage (20-30 weeks gestation), bud-tubule stage (31-36 weeks gestation), and acinotubular stage (37-42 weeks gestation). Squamous metaplasia often appeared in the urethra, utricle, and primary lobular ducts, and occasional microcysts were noted. PAS and alcian blue-PAS positive secretion were present in 65% of the specimens by 20-30 weeks gestation and in over 87% of the specimens by 37 or more weeks gestation. Secretory activity was most prominent in the lateral regions of the peripheral zone. Prostate-specific antigen was only weakly detected throughout the prenatal period and was not related to secretory activity as evidenced by the PAS technique.


From medical manners to moral reasoning: an historical overview of bioethics in the University of Cape Town's Faculty of Health Sciences.
The history of bioethics in the Faculty of Health Sciences of the University of Cape Town (UCT) follows a similar pattern to elsewhere. At first, bioethics received little formal attention, but there has been a flowering of interest over the last few decades. There has also been a shift from a professionally insular view of bioethics to one informed by non-medical disciplines. While this pattern is to be found in many parts of the world, there are some distinctive, but not unique, features of bioethics at South Africa's oldest medical school.


Improved Quantification of Cerebral Vein Oxygenation Using Partial Volume Correction.
Purpose: Quantitative susceptibility mapping (QSM) enables cerebral venous characterization and physiological measurements, such as oxygen extraction fraction (OEF). The exquisite sensitivity of QSM to deoxygenated blood makes it possible to image small veins; however partial volume effects must be addressed for accurate quantification. We present a new method, Iterative Cylindrical Fitting (ICF), to estimate voxel-based partial volume effects for susceptibility maps and use it to improve OEF quantification of small veins with diameters between 1.5 and 4 voxels. Materials and Methods: Simulated QSM maps were generated to assess the performance of the ICF method over a range of vein geometries with varying echo times and noise levels. The ICF method was also applied to in vivo human brain data to assess the feasibility and behavior of OEF measurements compared to the maximum intensity voxel (MIV) method. Results: Improved quantification of OEF measurements was achieved for vessels with contrast to noise greater than 3.0 and vein radii greater than 0.75 voxels. The ICF method produced improved quantitative accuracy of OEF measurement compared to the MIV approach (mean OEF error 7.7 vs. 12.4%). The ICF method provided estimates of vein radius (mean error <27%) and partial volume maps (root mean-squared error <13%). In vivo results demonstrated consistent estimates of OEF along vein segments. Conclusion: OEF quantification in small veins (1.5-4 voxels in diameter) had lower error when using partial volume estimates from the ICF method.


Can Gaming Increase Antibiotic Awareness in Children? A Mixed-Methods Approach.
e-Bug is a pan-European educational resource for junior and senior school children, which contains activities covering prudent antibiotic use and the spread, treatment, and prevention of infection. Teaching resources for children aged 7-15 years are complemented by a student website that hosts games and interactive activities for the children to continue their learning at home. The aim of this study was to appraise young people's opinions of 3 antibiotic games on the e-Bug student website, exploring children's views and suggestions for improvements, and analyzing change in their knowledge around the learning outcomes covered. The 3 games selected for evaluation all contained elements and learning outcomes relating to antibiotics, the correct use of antibiotics, and bacteria and viruses. A mixed methodological approach was undertaken, wherein 153 pupils aged 9-11 years in primary schools and summer schools in the Bristol and Gloucestershire area completed a questionnaire with antibiotic and microbe questions, before and after playing 3 e-Bug games for a total of 15 minutes. The after questionnaire also contained open-ended and Likert scale questions. In addition, 6 focus groups with 48 students and think-aloud sessions with 4 students who had all played the games were performed. The questionnaire data showed a significant increase in knowledge for 2 out of 7 questions (P=.01 and P<.001), whereas all questions showed a small level of increase. The two areas of significant knowledge improvement focused around the use of antibiotics for bacterial versus viral infections and ensuring the course of antibiotics is completed. Qualitative data showed that the e-Bug game "Body Busters" was the most popular, closely followed by "Doctor Doctor," and "Microbe Mania" the least popular. This study shows that 2 of the e-Bug antibiotic educational games are valuable. "Body Busters" effectively increased antibiotic knowledge in children and had the greatest flow and enjoyment. "Doctor Doctor" also resulted in increased knowledge, but was less enjoyable. "Microbe Mania" had neither flow nor knowledge gain and therefore needs much modification and review. The results from the qualitative part of this study will be very important to inform future modifications and improvements to the e-Bug games.


Memory test performance under three different waveforms of ECT for depression.
Thirty-eight patients suffering from severe depression were given a course of ECT (Electroconvulsive therapy) in one of three waveforms. These were high-energy sine wave (HS), high-energy pulse (HP), and low-energy pulse (LP). Patients were assigned to one of these treatments on a double-blind basis. The patients were given a battery of memory tests before ECT commenced, after three treatments, at the termination of treatment, and two weeks after the last treatment. The marked improvement in both verbal and nonverbal memory scores was attributed to the lifting of depression. No significant differences were found between the memory scores of the three treatment groups at any point during the treatment period.


The role of part-time arrangements in the sustainability of midwifery continuity of care models in Australia: An integrative review.
International maternity care experts have called for expanding midwiferyled continuity of care (MCoC) models. However, the number of models need augmentation as the number of women receiving this care is small. The majority of the midwifery workforce in Australian public health systems comprises women who work part-time. This aspect of the midwifery workforce demands careful consideration when attempting to change a maternity care system and sustain new models of care. Sparse research has been undertaken to explore whether part-time factors could play a role in the growth and sustainability of MCoC in Australia. This integrative review aims to analyze the role of parttime practice arrangements in the sustainability of MCoC models in Australia. Following a systematic search of research databases (CINAHL, ScienceDirect, Cochrane Database of Systematic Reviews, and Proquest) and screening the literature with eligibility criteria including keywords related to midwifery continuity of care, workforce arrangements and full-time equivalent (FTE), eight Australian research articles were identified for evaluation. The articles were appraised for bias using the Mixed Methods Appraisal Tool (MMAT) and data were analyzed using an integrated convergent narrative synthesis method. The resulting themes from the synthesis suggest that part-time MCoC roles may support the sustainability of the MCoC workforce without reducing quality of care to women. In various studies, midwives reported that FTE (full-time equivalent) of 0.5 may not meet the job's demands. However, this is likely influenced by local context and caseload size rather than the quantum of each midwife's FTE. The quality of the studies is limited due to the small scale of the studies; however, the qualitative results give a depth of understanding to the strengths and challenges that part-time arrangements in MCoC add to the midwifery workforce. This review recommends that part-time arrangements in MCoC models in Australia be evaluated in conjunction with other routinely analyzed workforce data. Further considerations should be made by midwifery managers, leaders, stakeholders, and decision makers responsible for developing and supporting part-time job arrangements in caseload models of care in Australia.


Genetic analyses for deciphering the status and role of photoperiodic and maturity genes in major Indian soybean cultivars.
Allelic combinations of major photoperiodic (E1, E3, E4) and maturity (E2) genes have extended the adaptation of quantitative photoperiod sensitive soybean crop from its origin (China ∼35◦N latitude) to both north (up to ∼50◦N) and south (up to 40◦S) latitudes, but their allelic status and role in India (6-35◦N) are unknown. Loss of function and hypoactive alleles of these genes are known to confer photoinsensitivity to long days and early maturity. Early maturity has helped to adapt soybean to short growing season of India. We had earlier found that all the Indian cultivars are sensitive to incandescent long day (ILD) and could identify six insensitive accessions through screening 2071 accessions under ILD. Available models for ILD insensitivity suggested that identified insensitive genotypes should be either e3/e4 or e1 (e1-nl or e1-fs) with either e3 or e4. We found that one of the insensitive accessions (EC 390977) was of e3/e4 genotype and hybridized it with four ILD sensitive cultivars JS 335, JS 95-60, JS 93-05, NRC 37 and an accession EC 538828. Inheritance studies and marker-based cosegregation analyses confirmed the segregation of E3 and E4 genes and identified JS 93-05 and NRC 37 as E3E3E4E4 and EC 538828 as e3e3E4E4. Further, genotyping through sequencing, derived cleaved amplified polymorphic sequences (dCAPS) and cleaved amplified polymorphic sequences (CAPS) markers identified JS 95-60 with hypoactive e1-as and JS 335 with loss of function e3-fs alleles. Presence of photoperiodic recessive alleles in these two most popular Indian cultivars suggested for their role in conferring early flowering and maturity. This observation could be confirmed in F2 population derived from the cross JS 95-60 × EC 390977, where individuals with e1-as e1-as and e4e4 genotypes could flower 7 and 2.4 days earlier, respectively. Possibility of identification of new alleles ormechanism for ILD insensitivity and use of photoinsensitivity in Indian conditions have been discussed.


Targeted therapies for renal cell carcinoma.
The management of patients with metastatic renal cell carcinoma (RCC) has changed dramatically over the past few years. Nephrectomy remains an important intervention for localized RCC but systemic therapy is the mainstay of treatment for patients who relapse after surgery or who have metastatic RCC. Before 2005, medical therapies for RCC were limited to cytokine therapies, which are very toxic and benefit only a small percentage of patients. In 2017, therapeutic agents now include kinase and immune checkpoint inhibitors. Contemporary research with these agents is now focusing on combinatorial and perioperative therapy. The field is now faced with the evolving challenge of how to select the best therapy for each patient during their natural history of disease, which has created a strong interest in modern sequencing and molecular approaches to identify biomarkers to personalize treatments. New therapeutic agents and approaches are associated with different toxicities and financial burdens, which require consideration of value by measuring clinical benefit, toxicity, and the cost of each drug with an organized framework. In this Review, we discuss the mechanisms underlying RCC and how improved molecular understanding helped the development of therapies, as well as biomarkers of response to treatment. We also discuss the value of these agents and their impact on personalization of therapy and drug development for RCC.


Rat bite fever in a total knee arthroplasty: an unusual case of periprosthetic joint infection.
Periprosthetic joint infection (PJI) is a serious complication of orthopedic arthroplasty surgery. Rat bite fever is a rare infection with Streptobacillus moniliformis (S. moniliformis). Rat bite fever can lead to serious complications such as pyogenic infection of joints, bacteremia, endocarditis and even death. We hereby present the first case of a patient with a total knee arthroplasty, infected with S. moniliformis, successfully treated by surgical debridement, antibiotics and implant retention (DAIR). The patient was a 64-year-old female. S. moniliformis was isolated from blood cultures and an aspirate of the left knee by 16S rRNA gene polymerase chain reaction technique. It was assumed that the S. moniliformis had a systemic origin and secondarily infected the knee due to fever nine days before the onset of symptoms of the knee. The patient was successfully managed with DAIR and intravenous administration of ceftriaxone for six weeks and oral doxycycline for another six weeks. S. moniliformis is a rare pathogen and is difficult to culture. The 16S rRNA sequencing is helpful in the determination of a causative microorganism in the case of a culture-negative PJI. A DAIR procedure in combination with 12 weeks of antibiotics could successfully treat S. moniliformis prosthetic joint infection.


The charge for going by foot: modifying the surface of podocytes.
The podocyte is a highly differentiated cell which forms a crucial component of the glomerular filtration barrier. It maintains a large filtration surface through the slit membranes and counteracts the distension of the glomerular basement membrane. The podocyte is covered with an anionic glycocalyx believed to be important in the maintenance of foot process structures, but the mechanisms of the cellular interaction between podocyte charge and its function are not clearly understood. It has been speculated that the charge selectivity of the glomerular barrier is influenced by angiotensin II. In experimental models of glomerular nephropathy neutralization of the polyanionic surface with polycations causes a retraction of podocyte foot processes. The effect of polycations is energy and Ca2+ dependent and results in tyrosine kinase induced phosphorylation of proteins of the foot processes. Charge alterations of the podocyte seem also associated with proteinuria in several human glomerular diseases such as membranous or diabetic nephropathy. The knowledge of the interaction between charge and podocyte function might offer new strategies in the treatment of glomerular diseases.


A Rare Case of Phlegmonous Gastritis in a Previously Healthy Male: A Case Report.
Though rare, phlegmonous gastritis (PG) is a serious and life-threatening infection of the gastric submucosa and mucosa. Many factors have been associated with PG, including malignancy, chronic alcohol use, and immunocompromised states. Clinical presentation of PG is often non-specific, and diagnosis is often delayed. Early recognition and starting antibiotics significantly reduce overall mortality. We describe a case of a previously healthy male who presented with moderate abdominal pain and was found to have PG that was treated with an extensive course of antibiotics and total parental nutrition. Contrary to previously described cases in the literature, our patient had no predisposing factors, highlighting the importance of suspecting PG even in the absence of such factors and demonstrating the effectiveness of antibiotics in this disease.


13C-carrier DNA shortens the incubation time needed to detect benzoate-utilizing denitrifying bacteria by stable-isotope probing.
The active bacterial community able to utilize benzoate under denitrifying conditions was elucidated in two coastal sediments using stable-isotope probing (SIP) and nosZ gene amplification. The SIP method employed samples from Norfolk Harbor, Virginia, and a Long-Term Ecosystem Observatory (no. 15) off the coast of Tuckerton, New Jersey. The SIP method was modified by use of archaeal carrier DNA in the density gradient separation. The carrier DNA significantly reduced the incubation time necessary to detect the (13)C-labeled bacterial DNA from weeks to hours in the coastal enrichments. No denitrifier DNA was found to contaminate the archaeal (13)C-carrier when [(12)C]benzoate was used as a substrate in the sediment enrichments. Shifts in the activity of the benzoate-utilizing denitrifying population could be detected throughout a 21-day incubation. These results suggest that temporal analysis using SIP can be used to illustrate the initial biodegrader(s) in a bacterial population and to document the cross-feeding microbial community.


EUS-Guided Diagnosis of Gastric Subepithelial Lesions, What Is New?
Gastric subepithelial lesions (SELs) are intramural lesions that arise underneath the gastric mucosa. SELs can be benign, but can also be malignant or have malignant potential. Therefore, correct diagnosis is crucial. Endosonography has been established as the diagnostic gold standard. Although the identification of some of these lesions can be carried out immediately, solely based on their echo characteristics, for certain lesions histological examination is necessary. Sometimes histology can be inconclusive, especially for smaller lesions. Therefore, new methods have been developed in recent years to assist decision making, such as contrast enhanced endosonography, EUS elastography, and artificial intelligence systems. In this narrative review we provide a complete overview of the gastric SELs and summarize the new data of the last ten years concerning the diagnostic advances of endosonography on this topic.


Results of intermediate measures from a population-based, randomized trial of mammographic screening prevalence and detection of breast carcinoma among Asian women: the Singapore Breast Screening Project.
Although increasing rates of breast carcinoma incidence have been observed in Asian countries, appropriate strategies for detecting early stage breast carcinoma in such communities have been difficult to formulate, particularly because no large population screening trial specifically involving Asian women has been reported. The objective of this study was to evaluate the effectiveness and quality of mammography as a screening technique for Singaporean women, who are predominantly Chinese. In this prospective study, 166,600 women in Singapore ages 50-64 years were randomized to either 2-view mammography without physical examination (67,656) or observation (97,294, controls) over 2 years. Of these women, 28,231 (41.7%) responded and were screened; they were more likely to be married, have more formal education, be working, be Chinese, and be in a higher socioeconomic group (P < 0.001 for all variables). To assess for response bias that could affect outcome, results were also evaluated for nonrespondents (n = 39,425). The incidence rate of cancers among nonrespondents (1 per 1000 woman-years) was less than the 1.3 in women not invited to have screening (P = 0.03, relative risk [RR], 1.3; 95% confidence interval [CI], 1.0-1.7). However, cancers arising from nonrespondents did not differ significantly in stage distribution when compared with cancers within the control group. For every 1000 women screened, 4.8 cancers were detected. The prevalence ratio (the number of cancers detected per 1000 women at first screening divided by the corresponding incidence rate in controls per year) was 3.6 for screened women and 2.4 for women invited to have screening. The majority of cancers detected through screening were early stage, with 64% as either ductal carcinoma in situ (26%) or Stage I disease (38%) and was significantly more than the corresponding 26% in women not invited to have screening (P < 0.001). When only invasive cancers were considered, screened women still had more early cancers, with 65% having no lymph node involvement, compared with 47% in the group not invited to have screening (P = 0.001; RR, 1.4; 95% CI, 1.2-1.7). Women who were screened had half the risk of having Stage II or later cancers (P < 0.0001; RR, 0.5; 95% CI, 0.4-0.7) when compared with women not invited to have screening. This higher detection rate of early cancers through screening was accomplished with acceptable recall rates of 8% for further mammographic films or physical examination and a biopsy rate of 1.0% (10 per 1000 women screened). The interval cancer rate was 2.1 per 10,000 women screened in the first year of follow-up. These positive results of intermediate measures suggest that, in Asian communities, screening mammography could be an important modality for detecting early stage breast carcinoma. However, the low compliance rates suggest that health education efforts must focus on issues related to acceptability if such programs are to succeed.


Densely Packed CO2 Aids Charge, Spin, and Lattice Ordering Partially Fluctuated in a Porous Metal-Organic Framework Magnet.
Partial charge fluctuations in the charge-ordered state of a material, often triggered by structural disorders and/or defects, can significantly alter its physical characteristics, such as magnetic long-range ordering. However, it is difficult to post-chemically fix such accidental partial fluctuations to reconstruct a uniform charge-ordered state. Herein, we report CO2 -aided charge ordering demonstrated in a CO2 -post-captured layered magnet, [{Ru2 (o-ClPhCO2 )4 }2 {TCNQ(OMe)2 }] ⋅ CO2 (1⊃CO2 ; o-ClPhCO2 - =ortho-chlorobenzoate; TNCQ(OMe)2 =2,5-dimethoxy-7,7,8,8-tetracyanoquinodimethane). Pristine porous layered magnet 1 had a partially charge-fluctuated ordered state, which provided ferrimagnetic ordering at TC =65 K. Upon loading CO2 , 1 adsorbed one mole of CO2 , forming 1⊃CO2 , and raising TC to 100 K. This was because of the vanishing charge fluctuations without significantly changing the framework structure. This research illustrates the post-accessible host-guest chemistry delicately combined with charge, spin, and lattice ordering in a spongy magnet. Furthermore, it highlights how this innovative approach opens up new possibilities for technology and nanoscale magnetism manipulation.


Sickness absence and shift work among Japanese factory workers.
To investigate the effect of shift work on long-term sickness absence (more than 7 calendar days), an 8-year follow-up study was carried out in a factory in Japan. The participants were male employees aged 18-54 years who were engaged in manufacturing sites. Shift patterns were classified by the number of non-daytime working days during the previous one-year. The causes of sickness absence were classified into three groups, 1) causes except injury, diseases of the musculoskeletal system and connective tissue, 2) injury, 3) diseases of the musculoskeletal system and connective tissue. The analysis of long-term sickness absences was based on the first occurrence. The age-adjusted incidence of sickness absence among shift workers who were on non-daytime shifts more than two-thirds of working days during the previous one year was significantly higher than that among other workers. After adjusting for confounding factors, a significant high risk still existed for this group of workers taking sickness absence for all causes and causes except for injury and the musculoskletal disorders. These findings suggest that shift workers who are engaged on a particular shift schedule are more likely to take leave due to sickness.


Peptide nucleic acids and the origin of life.
The possibilities of pseudo-peptide-DNA mimics like PNA (peptide nucleic acid) having a role for the prebiotic origin of life prior to an RNA world is discussed on the basis of literature data showing that this type of molecules might have formed on the primitive earth (or other places in the universe), as well as data indicating the possibilities of template-directed PNA chemical replication and ligation. In particular, the merits of an achiral prebiotic genetic material is discussed.


Photosensitization of thymine nucleobase by benzophenone derivatives as models for photoinduced DNA damage: Paterno-Büchi vs energy and electron transfer processes.
Time-resolved and product studies have shown that there is a strong interaction between drugs containing the benzophenone chromophore and the free thymidine nucleoside. In quantitative terms, such an interaction is stronger for the lowest lying npi* triplet states (S-ketoprofen) than for mixed npi*-pipi* triplets (fenofibrate and fenofibric acid), as indicated by the quenching rate constants. This is consistent with a Paterno-Büchi photoreaction, where the initial step is the formation of a new bond between the excited carbonyl oxygen and one of the thymine olefinic carbons. Actually, oxetanes are obtained as photoproducts when benzophenone is irradiated in the presence of thymidine. Hence, triplet-triplet energy transfer resulting in formation of cyclobutane pyrimidine dimers, which would be thermodynamically disfavored, does not seem to play a major role. However, in DNA, the contribution of energy transfer could be higher, due to the lower energy of the thymine triplet in the biomacromolecule. These results are discussed in connection with the observed DNA damage upon photosensitization with ketoprofen, fenofibrate, and fenofibric acid.


Perovskites with the Framework-Forming Xenon.
The Group 18 elements (noble gases) were the last ones in the periodic system to have not been encountered in perovskite structures. We herein report the synthesis of a new group of double perovskites KM(XeNaO6) (M = Ca, Sr, Ba) containing framework-forming xenon. The structures of the new compounds, like other double perovskites, are built up of the alternating sequence of corner-sharing (XeO6) and (NaO6) octahedra arranged in a three-dimensional rocksalt order. The fact that xenon can be incorporated into the perovskite structure provides new insights into the problem of Xe depletion in the atmosphere. Since octahedrally coordinated Xe(VIII) and Si(IV) exhibit close values of ionic radii (0.48 and 0.40 Å, respectively), one could assume that Xe(VIII) can be incorporated into hyperbaric frameworks such as MgSiO3 perovskite. The ability of Xe to form stable inorganic frameworks can further extend the rich and still enigmatic chemistry of this noble gas.


Induction of mania in depression by paroxetine.
An investigation of the proportion of patients who have experienced mania with antidepressant treatment and their characteristics would seem to be of clinical use. The purpose of this clinical study was to examine the predictors of induction of mania in depression patients as a result of paroxetine treatment. A retrospective cohort analysis was carried out among depression patients treated in the Department of Psychiatry, Kawasaki Medical School Hospital, Kurashiki, Japan, in 2000 and 2001. Some 79 patients were identified who were receiving paroxetine to treat depression. A variety of clinical factors including gender, the type of depression, frequency of episodes, family history, age and daily dose were examined as possible predictors of induction of mania by paroxetine. Seven (8.86%) of the 79 paroxetine-treated patients developed mania. A Cox proportional hazards analysis showed the type of depression and the history of family psychiatric illness to be independent predictive factors of the induction of mania by paroxetine treatment. The rate of mania induction of paroxetine is not substantially different from that found for conventional antidepressants. The type of depression and the history of family psychiatric illness may be considered as predictors of mania induction in depression patients taking paroxetine treatment.


Exploring nurses' experience about facilitating factors in medication administration based on clinical judgment of nurses: A content analysis.
Clinical judgment of nurses to conduct medication orders is based on patient assessment, medication knowledge, observation, and interpretation of the data collected. This process is influenced by many factors. This study aims to explore nurses' experience about facilitating factors in medication administration based on clinical judgment of nurses. This qualitative study was part of an approved project research of the Iranian National Institute of Health Research, which was conducted in Kurdistan University of Medical Sciences in 2015. Based on purposive sampling of 18 participants, 26 open and semistructured interviews were conducted. Based on conventional content analysis method and using MAXQDA2010, coding and categorizing the data were applied. During the analysis, data collection continued until saturation. Analysis of the data led to the emergence of five themes, including the implementation of evidence-based medication orders, situational-based medication orders, medication orders in critical condition, educational interventions in medication orders, and supporting the nurses as facilitator of the implementation of medicinal orders based on clinical judgment of nurses. In response to constraints such as the routines, clinical crisis and lack of evidence in medicinal orders, nurses used following ways to fix these barriers and facilitators. Combining evidence such as clinical guidelines, physician's views based on patients, and clinical conditions proved the best facilitator. It is recommended that, using these results, a perfect background for the proper administration of medication orders by nurses should be provided.


The structural and functional domains of plant thylakoid membranes.
In plants, the stacking of part of the photosynthetic thylakoid membrane generates two main subcompartments: the stacked grana core and unstacked stroma lamellae. However, a third distinct domain, the grana margin, has been postulated but its structural and functional identity remains elusive. Here, an optimized thylakoid fragmentation procedure combined with detailed ultrastructural, biochemical, and functional analyses reveals the distinct composition of grana margins. It is enriched with lipids, cytochrome b6 f complex, and ATPase while depleted in photosystems and light-harvesting complexes. A quantitative method is introduced that is based on Blue Native Polyacrylamide Gel Electrophoresis (BN-PAGE) and dot immunoblotting for quantifying various photosystem II (PSII) assembly forms in different thylakoid subcompartments. The results indicate that the grana margin functions as a degradation and disassembly zone for photodamaged PSII. In contrast, the stacked grana core region contains fully assembled and functional PSII holocomplexes. The stroma lamellae, finally, contain monomeric PSII as well as a significant fraction of dimeric holocomplexes that identify this membrane area as the PSII repair zone. This structural organization and the heterogeneous PSII distribution support the idea that the stacking of thylakoid membranes leads to a division of labor that establishes distinct membrane areas with specific functions.


The War on COVID-19 Pandemic: Role of Rehabilitation Professionals and Hospitals.
The global outbreak of coronavirus disease 2019 has created an unprecedented challenge to the society. Currently, the United States stands as the most affected country, and the entire healthcare system is affected, from emergency department, intensive care unit, postacute care, outpatient, to home care. Considering the debility, neurological, pulmonary, neuromuscular, and cognitive complications, rehabilitation professionals can play an important role in the recovery process for individuals with coronavirus disease 2019. Clinicians across the nation's rehabilitation system have already begun working to initiate intensive care unit-based rehabilitation care and develop programs, settings, and specialized care to meet the short- and long-term needs of these individuals. We describe the anticipated rehabilitation demands and the strategies to meet the needs of this population. The complications from coronavirus disease 2019 can be reduced by (1) delivering interdisciplinary rehabilitation that is initiated early and continued throughout the acute hospital stay, (2) providing patient/family education for self-care after discharge from inpatient rehabilitation at either acute or subacute settings, and (3) continuing rehabilitation care in the outpatient setting and at home through ongoing therapy either in-person or via telehealth.


Significance of thrombin in bleomycin-induced pulmonary fibrosis.
To clarify the role of thrombin in fibroblast growth and the development of pulmonary fibrosis in bleomycin-induced interstitial lung disease, we examined the relationship of thrombin activity to fibroblast growth-stimulating activity (FGA) in bronchoalveolar lavage fluid (BALF) from bleomycin-treated rats. Male Wistar rats were given a single intratracheal injection of bleomycin, bronchoalveolar lavage was performed 2, 6 and 15 days later, and the BALF was assayed for thrombin activity and FGA. Higher FGA than the control value was detected in the BALF from rats on Day 6 after bleomycin administration. In bleomycin-treated rats, thrombin activity in the BALF was significantly elevated on Day 2, and maximal on Day 6. The FGA of the BALF from bleomycin-treated rats on Day 6 was significantly decreased by its treatment with various thrombin inhibitors, such as alpha 1-antitrypsin, antithrombin III, hirudin and MD-805. On ammonium sulfate fractionation most of the thrombin activity was recovered in the fraction of 35-50% saturation in which most of the FGA was detected. These results suggest that the FGA of the BALF from bleomycin-treated rats was at least partly due to thrombin, and that thrombin is responsible, at least in part, for fibroblast growth and pulmonary fibrosis in bleomycin-induced interstitial lung disease.


Excess mortality among patients with multiple sclerosis in Denmark has dropped significantly over the past six decades: a population based study.
Lifetime expectancy in multiple sclerosis (MS) is reduced. Few studies have had sufficient follow-up or sufficient number of patients to assess if survival has improved with time. However, a recent meta-analysis found no time-dependent change in MS excess mortality across studies over recent decades. To investigate whether short-term all-cause excess mortality in patients with MS in the total Danish population has changed over the last six decades. We included all patients with MS recorded in the nationwide Danish MS Registry with definite or probable MS and onset from 1950 through 1999. The Danish Civil Registration System provided date of death for all deceased patients with follow-up in 2015, and Statistics Denmark supplied specific population mortality. We calculated excess number of death per 1000 person-years (EDR) and standardised mortality ratio (SMR). We included 18 847 patients among whom 6102 had died as opposed to 2492 expected deaths. EDR was 10.63 (95% CI 10.19 to 11.09) and a SMR was 2.45 (95% CI 2.39 to 2.51). The 15-year EDR dropped gradually from 11.29 (95% CI 9.95 to 12.73) in the 1950-1959 onset cohort to 2.56 (95% CI 1.98 to 3.18) in the 1990-1999 onset cohort, and SMR dropped from 4.48 (95% CI 4.06 to 4.92) to 1.80 (95% CI 1.62 to 1.99). The decline in short-term excess mortality in MS started decades before disease-modifying treatment of MS became available, before use of MRI became widespread, and before the McDonald diagnostic criteria were introduced. A change in the MS cohorts with fewer malignant cases may be a significant contributor.


Creatinine clearance and risk of early mortality in patients undergoing coronary artery bypass grafting.
We sought to evaluate renal function assessed on the basis of calculated creatinine clearance as a predictor of early mortality and postoperative complications in patients undergoing coronary artery bypass grafting and to assess whether calculated creatinine clearance is superior to serum creatinine concentration in predicting early death postoperatively. Six thousand seven hundred eleven consecutive patients without dialysis-dependent renal insufficiency undergoing a first isolated coronary artery bypass grafting were included. Preoperative serum creatinine concentrations and creatinine clearance calculated by using the Cockroft-Gault formula were related to mortality within 30 days postoperatively. There were 136 early deaths. After adjustment for age and other confounders in multivariate analyses, moderate (calculated creatinine clearance 30-60 mL/min) and severe (calculated creatinine clearance < 30 mL/min) renal insufficiency predicted early mortality (odds ratio of 2.4 [95% confidence interval, 1.2-4.8] and odds ratio of 4.8 [95% confidence interval], 1.6-13.9, respectively) compared with normal (calculated creatinine clearance > or = 90 mL/min) renal function. The area under the receiver operating characteristic curve for calculated creatinine clearance and serum creatinine concentration was 0.71 and 0.62, respectively, yielding a difference of 0.08 (P = .0004). No increased risk of mediastinitis or bleeding was observed in patients with renal insufficiency. Moderate and severe renal insufficiency independently increase the risk of early death after coronary artery bypass grafting. Our results indicate that calculated creatinine clearance is a better predictor of early mortality postoperatively than serum creatinine concentration.


Endocytosis of pulchellin and its recombinant B-chain into K-562 cells: binding and uptake studies.
Most of the type 2 ribosome-inactivating proteins (RIPs) are toxins formed by an RNA-N-glycosidase A-chain polypeptide linked to a lectin B-chain by a single disulfide bond. Members of this protein class vary greatly in cytotoxity, correlating more with B-chain diversity rather than to A-chain differences. Pulchellin is a type 2 ribosome-inactivating protein toxin found in the seeds of Abrus pulchellus tenuiflorus. Recombinant pulchellin B-Chain (rPBC) has been previously produced as inclusion bodies in Escherichia coli and successfully refolded recovering biological activity. New approaches for using this kind of protein as a biotechnological tool require a better understanding of cell targeting, binding, uptake, intracellular routing and delivery. In this work, cell adhesion experiments were used to determine the interaction of rPBC with mammalian cells. Fluorescence and confocal microscopy revealed the intracellular localization and trafficking. Subcellular sorting of the native pulchellin could also be determined. The results support that the endosomal internalization pathway and the retrograde transport through the Golgi apparatus might be used by both native protein and rPBC.


Novel Dioxolane Ring Compounds for the Management of Phytopathogen Diseases as Ergosterol Biosynthesis Inhibitors: Synthesis, Biological Activities, and Molecular Docking.
Thirty novel dioxolane ring compounds were designed and synthesized. Their chemical structures were confirmed by 1H NMR, HRMS, and single crystal X-ray diffraction analysis. Bioassays indicated that these dioxolane ring derivatives exhibited excellent fungicidal activity against Rhizoctonia solani, Pyricularia oryae, Botrytis cinerea, Colletotrichum gloeosporioides, Fusarium oxysporum, Physalospora piricola, Cercospora arachidicola and herbicidal activity against lettuce (Lactuca sativa), bentgrass (Agrostis stolonifera), and duckweed (Lemna pausicostata). Among these compounds, 1-((2-(4-chlorophenyl)-5-methyl-1,3-dioxan-2-yl)methyl)-1H-1,2,4-triazole (D17), 1-(((4R)-2-(4-chlorophenyl)-4-methyl-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole (D20), 1-((5-methyl-2-(4-(trifluoromethyl)phenyl)-1,3-dioxan-2-yl)methyl)-1H-1,2,4-triazole (D22), and 1-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-triazole (D26) had broad spectrum fungicidal and herbicidal activity. The IC50 values against duckweed were 20.5 ± 9.0, 14.2 ± 6.7, 24.0 ± 11.0, 8.7 ± 3.5, and 8.0 ± 3.1 μM for D17, D20, D22, and D26 and the positive control difenoconazole, respectively. The EC50 values were 7.31 ± 0.67, 9.74 ± 0.83, 17.32 ± 1.23, 11.96 ± 0.98, and 8.93 ± 0.91 mg/L for D17, D20, D22, and D26 and the positive control difenoconazole against the plant pathogen R. solani, respectively. Germination experiments with Arabidopsis seeds indicated that the target of these dioxolane ring compounds in plants is brassinosteroid biosynthesis. Molecular simulation docking results of compound D26 and difenoconazole with fungal CYP51 P450 confirmed that they both inhibit this enzyme involved in ergosterol biosynthesis. The structure-activity relationships (SAR) are discussed by substituent effect, molecular docking, and density functional theory analysis, which provided useful information for designing more active compounds.


Sodium chloride intake: is lower always better?
Current treatment of kidney disease is not completely satisfactory, particularly when initiated in the late stages of renal progression. There is an urgent need for additional interventions, especially reduction of salt intake, which is rather high in the Western world. In this commentary we provide a critical assessment of post hoc analyses of recent interventional and observational studies on the effect of salt intake on renal and cardiovascular outcomes. To evaluate the mechanisms and safety of reduced salt intake, studies specifically designed to assess salt intake as an endpoint are needed. This approach will have implications for health care policies and labeling of the salt content of purchased foods.


Providing medication therapy management for smoking cessation patients.
Nearly 50 years ago, the Surgeon General of the US Public Health Service released the first report of the Surgeon General's Advisory Committee on Smoking and Health. The report concluded that cigarette smoking caused lung and laryngeal cancer as well as bronchitis. Today, smoking is one of the leading preventable causes of deaths in the United States. Research has shown that it potentially causes more deaths than human immunodeficiency virus, illegal drug use, alcohol use, motor vehicle injuries, and firearm-related incidents. Health care providers play a critical role in guiding and directing patients to quit smoking by introducing them to smoking-cessation options. This is due to the fact that if these patients quit, they can reduce their cardiovascular risk. Pharmacists, being one of the easily accessible health care providers, have an advantage over other clinicians when it comes to influencing patients to quit smoking and to modify their lifestyles. Pharmacists through medication therapy management directly interact with these patients to manage medications as well as behavioral factors.