Dissection of two drug-targeted regions of Hepatitis C virus subtype 4a infecting Egyptian patients.
Recently, treatment of HCV infection has been improved after the development of direct acting antivirals (DAAs) which target different viral proteins (NS3-4A, NS5A and NS5B). The activity and effectiveness of these DAAs are affected by the presence of resistance associated substitutions (RASs). This study aimed to characterize HCV genotypes circulating among Egyptian HCV patients, to dissect the full sequences of HCV NS3-4A and NS5B regions, and to characterize RASs associated with NS3-4A and NS5B inhibitors in HCV treatment-naïve patients. Genotyping of 80 HCV samples from treatment-naïve patients was done using restriction fragment length polymorphism and phylogenetic analysis based on some full NS5B sequences. Results showed the prevalence of HCV subtype 4a. Twenty four new full sequences of NS3-4A and NS5B regions of subtype 4a were deposited in the GenBank database. In general, the substitutions associated with NS3-4A-targeting drugs were absent predicting possible responsiveness of Egyptian HCV patients to these drugs. In addition, the absence of amino acid substitutions associated with resistance to Sofosbuvir may predict good response to treatment with Sofosbuvir. Some amino acid substitutions associated with resistance to different classes of non-nucleoside inhibitors were detected. Further investigations on treated Egyptian HCV patients may evaluate the effectiveness of the massively used drugs. Many predicted T-cell-binding epitopes in NS3-4A and NS5B regions were found to be highly conserved in the currently studied isolates; a finding that might be important for HCV vaccine development. We demonstrated potential NS3 epitopes that could be used in engineering T cells against HCV epitopes.


Motor performance and back pain in children and adolescents: a systematic review and meta-analysis protocol.
The relationship between motor performance and back pain in children and adolescents remains unclear. This article describes the protocol for a systematic review to summarize the knowledge about the association between motor performance, such as agility, flexibility, balance, strength, muscle endurance, and cardiorespiratory fitness, and back pain. Thus, our aim is to identify the influence of motor performance on back pain among children and adolescents. Two independent researchers will search MEDLINE, Scopus, Embase, SPORTDiscus, and CINAHL databases, with no period or language restrictions. We will include cross-sectional, cohort, case-control, and controlled clinical trial studies based on the following criteria: (a) participants from 6 to 19 years of age, (b) assessment of motor performance, (c) assessment of back pain, and (d) report measures of associations between motor performance and back pain. Study quality and risk of bias will be assessed using an adapted version of the Downs and Black instrument. Grading of Recommendations, Assessment, Development, and Evaluations will be used to assess the strength of the body of evidence. Meta-analyses of association measures will be performed for each type of motor performance, separately for different study types. The results will be reported using forest to show the pooled effect of findings and funnel plots to assess precision of the data. If studies are not homogeneous, results from the meta-analyses will not be reported. Associations will then be synthesized descriptively using a pragmatic approach. This systematic review will provide critical insights into the association between motor performance and back pain among children and adolescents; this information may help support clinical practice guidelines as well as public health programs. Protocol was written according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). PROSPERO CRD42020178496.


Morphine reduces the interest for natural rewards.
Alongside a pathological, excessive, motivation for substances of abuse, substance use disorder (SUD) patients often show a dramatic loss of interest for naturally rewarding activities, such as positive peer social interaction and food intake. Yet, pre-clinical evidence of the latter SUD features remains scarce and inconsistent. In the current study, we investigated the effect of non-rewarding and rewarding doses of morphine upon social behaviour, motivation for and intake of palatable food, in male and female C57BL/6J mice. First, the rewarding effects of two relatively low morphine doses (1.25 and 2.5 mg/kg) were assessed using a newly established single substance administration/conditioning trial conditioned place preference (CPP) paradigm. Then, morphine (1.25 and 2.5 mg/kg) effects upon social behaviour, motivation for and intake of palatable food were examined by the three-chamber (3-CH), an operant behaviour and a palatable food preference test, respectively. Morphine (2.5 mg/kg) induced CPP in both male and female mice, whereas morphine (1.25 mg/kg) induced CPP only in female mice. Both morphine doses (1.25 and 2.5 mg/kg) reduced sociability, motivation for and intake of palatable food in male and female mice, independently of cognitive function or locomotor activity. Female mice were more sensitive than male mice to the rewarding effects of morphine. Moreover, both a non-rewarding and a rewarding dose of morphine impaired the interest for naturally rewarding activities, indicating that brain reward systems might be more sensitive to the deleterious than to the rewarding effects of substances of abuse.


Changes in sleep pattern after sleep deprivation.
Total sleep deprivation (TSD) was performed for one night with 11 healthy male students and three-consecutive-recovery night-sleep was recorded. Special attention was paid to the analysis of the individual difference in SWS(min, %) on the baseline and recovery nights. The total sleep time increased on the first recovery night compared to the baseline, but it decreased significantly on the second and third recovery nights. Stage 1(%) decreased significantly on the first and second recovery nights. Stage SWS(min) showed a significant increase on the first recovery night, while SWS(%) increased significantly on the first and second recovery nights. As for Stage REM(%), there was no significant difference between the baseline and the recovery nights. There was a positive correlation between SWS(min) on the baseline and that on the recovery nights. SWS(%) also showed the same results as those obtained with SWS(min). Between SWS(min) in the baseline and the increase rate of SWS(min) on the first recovery night, there was a significant inverse correlation, while there was a tendency to inverse correlation on the second and third recovery nights. As to SWS(%), there was a significant inverse correlation between SWS(%) in the baseline and the increase rate of SWS(%) on the first and third recovery nights.


Novel IKKβ inhibitors discovery based on the co-crystal structure by using binding-conformation-based and ligand-based method.
IκB kinase β (IKKβ), an attractive anti-inflammation and anti-cancer target, plays a crucial role in the activation of NF-κB signalling pathway. To identify novel IKKβ inhibitors, we combined structure-based and ligand-based methods based on the co-crystal structure of IKKβ. According to the chemical similarity, 162 reported IKKβ inhibitors were divided into five classes. For each class, a 3D pharmacophore model was established based on the binding conformations of the compounds. The validated models were further used in virtual screening. Twelve drugable compounds were retained for biological test, resulting in two novel inhibitors with IC50 values lower than 10 μM. Compared to other models, our method considers the crystal structure of IKKβ for the first time.


A New Flavonoid from Camellia sinensis Fermented Tea.
A new flavonoid, quercetin 3-0-α-L-rhamnopyranosyl-(l-6)-(2-E-p-coumaroyl)-D-D-glucopyranoside-4'-O-α-L-rhamnopyranoside, was isolated from the fermented tea of Camellia sinensis L. (Pu-erh tea) from China. The chemical structure was elucidated based on analyses of the spectroscopic data.


The survival impact of delayed surgery and adjuvant chemotherapy on stage II/III rectal cancer with pathological complete response after neoadjuvant chemoradiation.
Neoadjuvant concurrent chemoradiation (CCRT) is standard treatment for clinical stage II/III rectal cancers. However, whether patients with pathological complete response (pT0N0, pCR) should receive adjuvant chemotherapy and whether delayed surgery will influence the pCR rate remains controversial. A nationwide population study was conducted using the Taiwan Cancer Registry Database from January 2007 to December 2013. Kaplan-Meier survival analysis was performed. Cox proportional hazards models were used to estimate multivariate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). Of the 1,914 patients who received neoadjuvant CCRT, 259 (13.6%) achieved pCR and had better survival (adjusted HR: 0.37, 95% CI: 0.24-0.58; p < 0.001). The cumulative rate of pCR rose up to 83.4% in the 9th week and slowly reached a plateau after the 11th week. Among the patients with pCR, those who received adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy (adjusted HR: 0.72, 95 CI: 0.27-1.93; p = 0.52). By subgroup analysis, those younger than 70-year old and received adjuvant chemotherapy had better survival benefit than those without adjuvant chemotherapy (adjusted HR: 0.19, 95% CI: 0.04-0.97; p = 0.046). Delayed surgery by 9-12 weeks after the end of neoadjuvant CCRT can maximize the pCR rate, which is correlated with better survival. Adjuvant chemotherapy may be considered in patients with pCR and aged <70-year old, but further prospectively randomized controlled trials are warranted to validate these findings.


Implementation of the Uniform Donor History Questionnaire across the American Red Cross Blood Services: increased deferral among repeat presenters but no measurable impact on blood safety.
The Uniform Donor History Questionnaire (UDHQ) was implemented across the American Red Cross Blood Services in 2005. This study assessed the potential impact of changes inherent in UDHQ implementation on deferral and on prevalence of infectious disease markers among donated units. Deferral and donation records were extracted and analyzed for the period of April 1, 2005, to September 30, 2005, after the implementation of the UDHQ and for the same period in the previous year. For comparison, most of the questions in the UDHQ were aligned with corresponding questions in the previous questionnaire, although such alignment could not be exact because of changes in the wording and organization of the questions. From 2004 (1 year previously) to 2005 (UDHQ), significant changes in deferral rate were observed for different groups of deferral questions, with the largest being +99.2 percent for "man who had sex with another man" and +92.0 percent for "receipt of blood, tissue, organ, or clotting factor concentrates or a bleeding condition or a blood disease" among repeat presenters. Changes to the educational material and the wording of questions, elimination of compound questions, and other concurrent changes could have contributed to the changed deferral rates. There was no significant change in prevalence rates of major infectious disease markers. Implementation of the UDHQ impacted on donor deferral, including increased deferral among repeat presenters. No significant impact was observed for infectious disease marker rates. Further monitoring for longer-term trends is recommended.


Characterization of ureaplasmas isolated from preterm infants with and without bronchopulmonary dysplasia.
A PCR assay was used to analyze endotracheal aspirates from preterm infants for Ureaplasma parvum versus U. urealyticum. U. parvum was detected more often than U. urealyticum. There was no significant difference or trend in the prevalence of either species between infants with or without bronchopulmonary dysplasia when isolated alone.


Robust QFT control design for a multivariable torsion/bending of rotational nanoscanner.
This paper proposes a reasonable, practical, and novel method for designing a robust controller for two degrees of freedom nano-electromechanical scanners based on the combination of quantitative feedback theory (QFT) and the Taguchi method. Although the main primary of this paper devotes to rotational control, an investigation of two-degree freedom (rotational/bending) is studied by employing the Taguchi method. A moveable main plate suspended by two nano-beams over a fixed substrate electrode is used to represent the scanner. The nanoscanner is thoroughly analyzed using the most comprehensive modeling design, considering the elastic, electrical, Casimir force and moment, and squeezes film damping. The nanoscanner's governing equations are initially derived by considering both rotation and deformation. In addition, because the size dependency of materials is significant in ultra-small structures, we developed the constitutive equations within the context of the modified couple stress theory to integrate the effect of scale dependency. Next, system uncertainties have been wholly addressed to achieve an accurate model. As a result, using robust control methods such as quantitative feedback theory to precisely control nano-scanners in the presence of uncertainties is inevitable. The quantitative feedback approach transforms the nonlinear plant into a family of linear uncertain plants in the first part. This is accomplished using a fixed-point theorem, after which appropriate disturbance rejection boundaries are discovered. In this problem, quantitative feedback controllers and checking the system's stability at any frequency and time are intended to solve the tracking problem and the disturbance rejection issue. Due to the uncertainty associated with the system model's complexity and accuracy, we employ a QFT controller to control the system. Moreover, because this system has only one input and two outputs, and changing the controller's gain is complicated, the Taguchi method has been employed to enhance better performance. Nonlinear simulations of the tracking issue are carried out, and the results demonstrate the effectiveness of the developed controllers and prefilters. The findings show that using the suggested approach effectively overcomes the challenges to robust control of a nonlinear rotational nanoscanner, and also the system achieves the best angle and deflection adjustment accuracy.


Seasonal distribution and prevalence of diarrheagenic Escherichia coli in different aquatic environments in Taiwan.
Diarrheagenic Escherichia coli (DEC) are the most common agents of diarrhea. Waterborne DEC could pose a potential health risk to human through agricultural, household, recreational, and industrial use. There are few published reports on the detection of DEC and its seasonal distribution in aquatic environments. The presence of DEC in different types of aquatic environments was investigated in this study. Water samples were collected from major rivers, water reservoirs, and recreational hot springs throughout Taiwan. Moreover, an intensive water sampling plan was carried out along Puzih River. The detection of DEC target genes was used to determine the presence of enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), and Shiga toxin-producing E. coli (STEC). Among the 383 water samples analyzed, DEC was found in 122 (31.8%) samples. The detection rate varied by genotype, raging from 3.6% for STEC to 17.2% for EPEC. The DEC detection rate was higher from river waters than reservoirs and hot springs. In addition, DEC was detected at a higher rate in spring and summer. The presence of EPEC was significantly associated with total coliform levels among hot spring samples. Moreover, the presence of ETEC in river water samples was associated with heterotrophic plate counts. Water with EPEC differed significantly in pH from Puzih River samples. These results suggest that seasonal characteristics may affect the presence of DEC in different aquatic environments, and water quality indicators may be indicative of the presence of DEC.


Analysis of gut microbiota in patients with Williams-Beuren Syndrome reveals dysbiosis linked to clinical manifestations.
Williams-Beuren syndrome (WBS) is a multisystem genetic disease caused by the deletion of a region of 1.5-1.8 Mb on chromosome 7q11.23. The elastin gene seems to account for several comorbidities and distinct clinical features such including cardiovascular disease, connective tissue abnormalities, growth retardation, and gastrointestinal (GI) symptoms. Increasing evidence points to alterations in gut microbiota composition as a primary or secondary cause of some GI or extra-intestinal characteristics. In this study, we performed the first exploratory analysis of gut microbiota in WBS patients compared to healthy subjects (CTRLs) using 16S rRNA amplicon sequencing, by investigating the gut dysbiosis in relation to diseases and comorbidities. We found that patients with WBS have significant dysbiosis compared to age-matched CTRLs, characterized by an increase in proinflammatory bacteria such as Pseudomonas, Gluconacetobacter and Eggerthella, and a reduction of anti-inflammatory bacteria including Akkermansia and Bifidobacterium. Microbial biomarkers associated with weight gain, GI symptoms and hypertension were identified. Gut microbiota profiling could represent a new tool that characterise intestinal dysbiosis to complement the clinical management of these patients. In particular, the administration of microbial-based treatments, alongside traditional therapies, could help in reducing or preventing the burden of these symptoms and improve the quality of life of these patients.


Use of a Targeted Exome Next-Generation Sequencing Panel Offers Therapeutic Opportunity and Clinical Benefit in a Subset of Patients With Advanced Cancers.
Smaller hotspot-based next-generation sequencing (NGS) panels have emerged to support standard of care therapy for patients with cancer. When standard treatments fail, it is unknown whether additional testing using an expanded panel of genes provides any benefit. The purpose of this study was to determine if larger sequencing panels that capture additional actionable genes, coupled with decision support, translates into treatment with matched therapy after frontline therapy has failed. A prospective protocol accrued 521 patients with a wide variety of refractory cancers. NGS testing using a 46- or 50-gene hotspot assay, then a 409-gene whole-exome assay, was sequentially performed in a Clinical Laboratory Improvement Amendments-certified clinical laboratory. A decision-support team annotated somatic alterations in clinically actionable genes for function and facilitated therapeutic matching. Survival and the impact of matched therapy use were determined by Kaplan-Meier estimate, log-rank test, and Cox proportional hazards regression. The larger NGS panel identified at least one alteration in an actionable gene not previously identified in the smaller sequencing panel in 214 (41%) of 521 of enrolled patients. After the application of decision support, 41% of the alterations in actionable genes were considered to affect the function of the gene and were deemed actionable. Forty patients (40 of 214 [19%]) were subsequently treated with matched therapy. Treatment with matched therapy was associated with significantly improved overall survival compared with treatment with nonmatched therapy (P = .017). Combining decision support with larger NGS panels that incorporate genes beyond those recommended in current treatment guidelines helped to identify patients who were eligible for matched therapy while improving overall treatment selection and survival. This survival benefit was restricted to a small subset of patients.


Cloning of a human seven-transmembrane domain receptor, LESTR, that is highly expressed in leukocytes.
Several chemotactic agonists including interleukin-8 (IL-8) and related cytokines have been shown to activate and attract leukocytes via seven-transmembrane domain, GTP-binding protein-coupled receptors. A cDNA clone, LESTR, encoding a protein of 352 amino acids, corresponding to a novel receptor of this type, was isolated from a human blood monocyte cDNA library. The sequence of the deduced protein, LESTR (leukocyte-derived seven-transmembrane domain receptor), has 92.6% identity with that of a recently reported bovine neuropeptide Y (NPY) receptor, boLCR1 (Rimland, J., Xin, W., Sweetnam, P., Saijoh, K., Nestler, E. J., and Duman, R. S. (1991) Mol. Pharmacol. 40, 869-875). LESTR, however, is more similar (> 34%) to the IL-8 receptors, IL-8R1 and IL-8R2, than to several NPY receptors of different origin (< 20%). In the monocyte library, LESTR cDNA fragments were about 20 times as frequent as cDNA coding for IL-8R1 and IL-8R2, and much higher levels of LESTR- than IL-8R-specific mRNA were found in human blood neutrophils and lymphocytes. LESTR transcripts, by contrast, were low or undetectable in several neuroblastoma cell lines that are widely used to study NPY functions. Transfected cells expressing high levels of LESTR mRNA did not bind radiolabeled NPY, IL-8, NAP-2, GRO alpha, PF4, IP10, MCP-1, MCP-3, MIP-1 alpha, HC14, I309, RANTES, C3a, or LTB4. NPY also failed to bind to neutrophils, monocytes, and lymphocytes, to elicit responses in vitro such as Ca2+ changes, shape change, chemotaxis, enzyme release, and the respiratory burst, and to induce leukocyte accumulation upon injection in rats and rabbits. Although the ligand for LESTR could not be identified among a large number of chemotactic cytokines, the high expression in white blood cells and the marked sequence relation to IL-8R1 and IL-8R2 suggest that LESTR may function in the activation of inflammatory cells.


Management of anticoagulation in pregnant women with venous thromboembolism: An international survey of clinical practice.
Venous thromboembolism (VTE) is an important cause of maternal morbidity and mortality. During pregnancy, VTE is treated with low-molecular-weight-heparin (LMWH). Studies assessing the optimal duration and peripartum management of therapeutic anticoagulation are lacking. This survey aimed to assess clinician practices for the management of anticoagulation in pregnant women with acute VTE. An electronic survey consisting of clinical scenarios addressing anticoagulation management for VTE in pregnancy was created. The target sample was clinicians likely to be involved in the management of pregnant women with acute VTE. The survey completion rate and proportion of individuals selecting a response were determined. 96 respondents completed the survey including general internists (56.3%), hematologists (21.9%), and obstetricians (6.3%). In the management of a VTE in first or second trimester, most respondents preferred therapeutic LMWH until 6 weeks postpartum. In the first and second trimester, 48.0% and 37.5% of respondents, respectively, opted to reduce the dose of anticoagulation after 3 or 6 months. 29.2% of physicians opted for bridging with intravenous heparin around delivery when treating a VTE in the third trimester. 73.0% perceived an increased risk of clinically relevant non-major bleeding associated with the use of therapeutic anticoagulation in the peripartum and postpartum periods. The survey highlights a wide variability of practice in the management of therapeutic anticoagulation in pregnancy. Larger scale studies with relevant clinical outcomes including thrombosis and bleeding risks are needed to inform clinical practice.


Impact of prostate imaging quality (PI-QUAL) score on the detection of clinically significant prostate cancer at biopsy.
To investigate the impact of Prostate Imaging Quality (PI-QUAL) scores on the diagnostic performance of multiparametric MRI (mpMRI) in a targeted biopsy cohort. 300 patients who underwent both mpMRI and biopsy were included. PI-QUAL scores were retrospectively assigned by two radiologists in consensus and were correlated to pre-biopsy PI-RADS scores and biopsy outcomes. Clinically significant prostate cancer (csPCa) was defined as ISUP grade ≥ 2. Image quality was optimal (PI-QUAL ≥ 4) in 249/300 (83%) and suboptimal (PI-QUAL < 4) in 51/300 (17%). The proportion of PI-RADS 3 scores referred for biopsy was higher in scans of suboptimal vs optimal quality (51% vs 33%). For PI-QUAL < 4 scans, the positive predictive value (PPV) was lower compared to PI-QUAL ≥ 4 (35% [95%CI: 22, 48] vs 48% [95%CI: 41, 55]; difference -13% [95%CI: -27, 2]; p 0.090), as was the detection rate of csPCa in both PI-RADS 3 and PI-RADS 4-5 (15% vs 23% and 56 vs 63%, respectively). The overall MRI quality increased over time. Scan quality may affect the diagnostic performance of prostate mpMRI in patients undergoing MRI-guided biopsy. Scans of suboptimal quality (PI-QUAL < 4) were associated with lower PPV for csPCa.


Riboflavin treatment in a case with l-2-hydroxyglutaric aciduria.
L-2-hydroxyglutaric aciduria (LHGuria) is a rare neurometabolic disorder, which has characteristic clinical and laboratory features. The recent findings imply that LHG dehydrogenase is responsible for the disease and is FAD-dependent. Therefore, it might be expected that riboflavin could enhance any residual activity. We present our observations from nearly 2-year-long riboflavin treatment in a 16-year-old boy with LHGuria. During riboflavin treatment of 100 mg/d, partial improvement in his cognitive and motor performances was observed. Urinary LHG excretion decreased from 5990 mmol/mol creatinine to 1490 mmol/mol creatinine. Moreover, when riboflavin treatment was interrupted, significant disturbances in both symptoms and urinary LHG excretion (6360 mmol/mol creatinine) occurred in the patient. After the resettlement of riboflavine treatment, the patient resumed to his previous clinical status in a week. The improvement went further minimally under the dose of 200mg/d, but no further improvement happened with 300 mg/d. The present case suggests that riboflavin could be considered as a potential therapeutic approach in LHGuria until the optimal treatment of LHGuria is established.


Inhibition of prostaglandin and leukotriene generation by the plant alkaloids tetrandrine and berbamine.
We compared the effects of two bisbenzylisoquinoline compounds on leukotriene and prostaglandin generation by human monocytes and neutrophils. The results show that tetrandrine had a much greater effect than berbamine on leukotriene generation. However, both compounds were equally potent in suppression of prostaglandin generation. This inhibitory effect on prostaglandin generation can be overcome by exogenous arachidonic acid (AA), suggesting that the site of inhibition is not on the cyclooxygenase enzyme complex, but more proximally on the phospholipase-mediated release of AA from the cell membrane, similar to the action of corticosteroids. These results, together with previous findings of inhibitory effects on other inflammatory mediators such as histamine, platelet-activating-factor (PAF) and interleukin 1 (IL-1) indicate that these plant alkaloids may be useful lead compounds for the development of a new class of anti-inflammatory drugs.


[Brain and medullar neurosarcoidosis, complicated by stroke with local vasculitis].
Central nervous system localizations of sarcoidosis remain rare. The brain, mainly the posterior fossa, or the spinal cord, mainly cervical, may be involved. We report the case of a white female presenting a stroke of the head of the caudate nuclei with spontaneous hemorrhage transformation related to and associated with rare encephalic and spinal cord sarcoidosis. The magnetic resonance angiography (MRA) of the intracranial vessels showed images of vasculitis. Treatment of the neurologic localizations was difficult.


Transport stress in Southern chamois (Rupicapra pyrenaica) and its modulation by acepromazine.
Chamois have been translocated for more than 100 years but their stress response to transport remains to be elucidated. In this study, 21 free-ranging Southern chamois were captured, physically restrained and then transported. The animals were randomly injected intramuscularly with acepromazine (nine adult males, one adult female and one yearling male) or saline (five adult males, two adult females and three yearling males). Heart rate and body temperature were monitored with telemetric devices, and blood samples were obtained at capture, immediately before and immediately after transport to determine haematological and serum biochemical parameters. Heart rate and blood parameters (erythrocytes, haemoglobin, packed cell volume, leukocytes, monocytes, band neutrophils, lactate, muscular enzymes and creatinine) indicated that transport was more stressful than previous physical restraint. Acepromazine reduced the adverse consequences of transport stress, as demonstrated by heart rate, body temperature, cortisol, creatinine, muscular enzymes, urea, sodium and potassium.


A compact planar low-energy-gap molecule with a donor-acceptor-donor nature based on a bimetal dithiolene complex.
We present the first report of a compact, planar and low-energy-gap molecule based on a π-conjugated bimetal system comprising a tetrathiooxalate (tto) skeleton. The observed low HOMO-LUMO energy gap (1.19 eV) is attributed to its donor-acceptor-donor (D-A-D) nature because the skeleton acts as an electron acceptor as well as a tiny and noninnocent bridging moiety.


Analysis of a multi-type resurgence of Mycobacterium bovis in cattle and badgers in Southwest France, 2007-2019.
Although control measures to tackle bovine tuberculosis (bTB) in cattle have been successful in many parts of Europe, this disease has not been eradicated in areas where Mycobacterium bovis circulates in multi-host systems. Here we analyzed the resurgence of 11 M. bovis genotypes (defined based on spoligotyping and MIRU-VNTR) detected in 141 farms between 2007 and 2019, in an area of Southwestern France where wildlife infection was also detected from 2012 in 65 badgers. We used a spatially-explicit model to reconstruct the simultaneous diffusion of the 11 genotypes in cattle farms and badger populations. Effective reproduction number R was estimated to be 1.34 in 2007-2011 indicating a self-sustained M. bovis transmission by a maintenance community although within-species Rs were both < 1, indicating that neither cattle nor badger populations acted as separate reservoir hosts. From 2012, control measures were implemented, and we observed a decrease of R below 1. Spatial contrasts of the basic reproduction ratio suggested that local field conditions may favor (or penalize) local spread of bTB upon introduction into a new farm. Calculation of generation time distributions showed that the spread of M. bovis has been more rapid from cattle farms (0.5-0.7 year) than from badger groups (1.3-2.4 years). Although eradication of bTB appears possible in the study area (since R < 1), the model suggests it is a long-term prospect, because of the prolonged persistence of infection in badger groups (2.9-5.7 years). Supplementary tools and efforts to better control bTB infection in badgers (including vaccination for instance) appear necessary.


Delivery of adjuvant sequential dose-dense FEC-Doc to patients with breast cancer is feasible, but dose reductions and toxicity are dependent on treatment sequence.
This study prospectively investigates the impact of dose densification and altering sequence of fluorouracil, epirubicin and cyclophosphamide [FEC(100)] and docetaxel [Doc] on dose delivery and tolerability of adjuvant chemotherapy in breast cancer patients. 117 patients with high-risk primary operable breast cancer were randomized (1:1:2:2) to conventional (three cycles of 3-weekly FEC(100) then three cycles of 3-weekly Doc 100 mg/m(2) or reverse sequence) or dose-dense (dd) treatment (four 10- to 11-day cycles of FEC(75) then four 2-weekly cycles of Doc 75 mg/m(2), or the reverse). In the dd arms, pegfilgrastim was given on day 2 of each cycle, but only as secondary prophylaxis in conventional arms. The primary endpoint was the proportion of patients completing intended cycles at relative dose intensity >or=85% and this was achieved by 95% of patients in each group except for the ddDoc-->FEC group (90%). Dose intensity in the dd arms increased by 48% for FEC and 11% for docetaxel, compared with the conventional arms (both P < 0.001). Doc dose reductions were more frequent with dd treatment and when Doc was given after FEC. Grade 3-4 neutropenia was significantly more frequent with conventional treatment, while fatigue and hand-foot syndrome were numerically more common with dd treatment, particularly when Doc was given after FEC. Discussion Delivery of adjuvant sequential ddFEC and Doc is feasible with growth factor support, and chemotherapy sequence appeared to affect delivery of target doses and toxicity.


Reelin through the years: From brain development to inflammation.
Reelin was originally identified as a regulator of neuronal migration and synaptic function, but its non-neuronal functions have received far less attention. Reelin participates in organ development and physiological functions in various tissues, but it is also dysregulated in some diseases. In the cardiovascular system, Reelin is abundant in the blood, where it contributes to platelet adhesion and coagulation, as well as vascular adhesion and permeability of leukocytes. It is a pro-inflammatory and pro-thrombotic factor with important implications for autoinflammatory and autoimmune diseases such as multiple sclerosis, Alzheimer's disease, arthritis, atherosclerosis, or cancer. Mechanistically, Reelin is a large secreted glycoprotein that binds to several membrane receptors, including ApoER2, VLDLR, integrins, and ephrins. Reelin signaling depends on the cell type but mostly involves phosphorylation of NF-κB, PI3K, AKT, or JAK/STAT. This review focuses on non-neuronal functions and the therapeutic potential of Reelin, while highlighting secretion, signaling, and functional similarities between cell types.


The Israeli residential center for alcoholics 1982-1987.
This paper touches upon three primary topics: description of the treatment methods and approaches that have proven to be most useful and successful in Israel's only residential center for alcoholics; summary of recent findings about the characteristics of alcoholics that have been treated at the residential center during the years 1982-1987 (the findings revealed a high percentage of married alcoholics and of unemployment) and some details about the follow-up investigation and the evaluation of the effectiveness of the center's treatment modality. The relatively high abstention rate - 40.9% of all patients (51.2% of those who completed treatment) - is the most important result of the study. Thus, this article integrates research data and relevant features of the Israeli residential treatment experience, in which the emphasis on involving the family is greater than elsewhere.


Lithium Treatment Aggregates the Adverse Effects on Erythrocytes Subjected to Arsenic Exposure.
The present study was designed to investigate the effects of lithium treatment on red blood cells which were given arsenic exposure. Long-term lithium therapy is being extensively used for the treatment of bipolar disorders. Arsenic is a group I carcinogen and a major toxic pollutant in drinking water that affects millions of people worldwide. Male SD rats were segregated into four groups, viz. normal control, lithium treated, arsenic treated, and lithium + arsenic treated. Lithium was supplemented as lithium carbonate at a dose level of 1.1 g/kg diet for a period of 8 weeks. Arsenic was given in the form of sodium arsenite at a dose level of 100 ppm in drinking water, ad libitum, for the same period. Lysates of red blood cells were used to investigate the effects of lithium and arsenic treatments on anti-oxidant enzymes, reduced glutathione (GSH), and lipid peroxidation (LPO) levels. Various hematological parameters, activities of Na+ K+ ATPase and delta-aminolevulinic acid dehydratase (δ-ALAD) were also assessed. A significant reduction was observed in the activities of antioxidant enzymes, GSH levels, total erythrocyte counts, Na+ K+ ATPase, and ALAD enzyme activities in lysates of red blood cells when exposed either to lithium or arsenic. In addition, a significant increase in the levels of malondialdehyde (MDA), lymphocytes, neutrophils, and total leukocytes was also observed following lithium as well as arsenic treatments. However, when arsenic-treated rats were subjected to lithium treatment, a pronounced alteration was noticed in all the above parameters. Therefore, we conclude that lithium supplementation to the arsenic-treated rats enhances the adverse effects on red blood cells and therefore use of lithium may not be medicated to patients who are vulnerable to arsenic exposure through drinking water. It can also be inferred that adverse effects of lithium therapy may get aggravated in patients thriving in the arsenic-contaminated area.


Isolation of cDNA clones for human adenosine deaminase.
Clones encoding human adenosine deaminase (ADA) were isolated from a cDNA library made from the lymphoblastoid cell line MOLT-4. The isolation procedure was based on the selection of clones hybridizing with a radioactive probe complementary to an RNA preparation, which had been highly enriched in ADA-specific mRNA. The latter RNA preparation was obtained by size-fractionating MOLT-4 RNA and selecting fractions that were translatable into ADA. The assay for the presence of ADA in the in vitro translation products, was based on immunoprecipitation with a specific anti-ADA serum. The antiserum used was shown to precipitate a 42-kDal protein with the properties of ADA. Positive clones were further screened by means of hybrid-released in vitro translation assays. Two clones were obtained which were able to select mRNA that could be translated into a 42-kDal protein immunoprecipitable with the ADA-antiserum. By use of Southern blots containing DNA from somatic cell hybrids, one of these ADA cDNA clones was assigned to the human chromosome 20 known to contain the ADA gene.


Morphology and release kinetics of protein-loaded porous poly(l-lactic Acid) spheres prepared by freeze-drying technique.
Freeze-drying a biodegradable polymer, poly(L-lactic acid) (PLLA), from 1,4-dioxane solutions provided very porous spherical particles of ca. 3 mm in radius with specific surface area of 8-13 m(2) g(-1). The surface of the particle was found to be less porous compared with its interior. To apply the freeze-dried PLLA (FDPLLA) to drug delivery system, its morphology and drug releasing kinetics were investigated, bovine serum albumin (BSA) being used as a model drug compound. Immersion of FDPLLA into a BSA aqueous solution gave BSA-loaded FDPLLA, where mass fraction of the adsorbed BSA reached up to 79%. Time-dependent release profile of BSA in water suggested a two-step mechanism: (1) very rapid release of BSA deposited on and near the particle surface, which results in an initial burst, and (2) leaching of BSA from the interior of the particle by the diffusion process. It was suggested that the latter process is largely governed by the surface porosity. The porosity of both the interior and surface was found to decrease remarkably as the concentration of the original PLLA/1,4-dioxane solution increases, C(0). Thus, C(0) is a key parameter that controls the loading and releasing of BSA.


Water effects on the deformation and fracture behaviors of the multi-scaled cellular fibrous bamboo.
Natural bamboo with different water weight contents (0%, 6% and 22%) had distinguishingly different mechanical properties, where samples with water contents of 22% had tensile strength and elongations increased by ∼30% and ∼200% than the dry (0%), respectively. The deformation and fracture process was synchronously recorded and analyzed with the aid of the acoustic emission (AE), during which there were three kinds of real time fracture behaviors recognized: matrix (multi-walled parenchyma cells) failure, interfacial (fiber/fiber or fiber/parenchyma cell walls) dissociations and fiber breakage. More interfacial dissociations and higher fracture energy were detected as more water was added, since water molecules can make great differences on the bamboo's inner micro-structures and the mechanical properties. During the fracture process of the wet bamboo detected by AE, matrix failure and interfacial dissociations contributed most of the elongation, and the strength were mainly depended on the fiber breakage and interfacial dissociations. The discovered structural toughening mechanisms within the multi-scaled structures were microfiber bridging, multi-walled fiber pull-out, micro warts buckling and crack deflection. The micro-structural toughening effects were strengthened by the cellulose-hemicellulose-lignin complexes and a certain content of water molecules within the multi-scaled fibrous cellular structures, which are collaboratively working and ensuring the high mechanical performance of the natural bamboo. The mechanical behaviors during the whole fracture process of bamboo were investigated by acoustic emission (AE). During the fracture process there were three kinds of fracture behaviors recognized by AE: matrix (parenchyma cells) failure, interfacial (fiber/fiber or fiber/parenchyma cell walls) dissociations and fiber breakage. The mechanical performance was greatly influenced by water contents (0%, 6% and 22%). Wet bamboos had higher fracture energy than the dry ones. There was more interfacial dissociation behaviors detected as more water was absorbed within the multi-scaled structures. The micro structural toughening mechanisms were strengthened by the macromolecular complexes and water molecules, which are working together and ensuring the excellent mechanical properties of the natural bamboo.


Effect of Rural Clinical Placements on Intention to Practice and Employment in Rural Australia: A Systematic Review.
Supporting the provision of clinical placement (CP) experiences in rural areas is a strategy used worldwide to promote the rural health workforce. While there is international evidence for this intervention in medicine, there is limited understanding of the influence of rural CP for nursing, midwifery, allied health, and dentistry health professions in Australia, which have received substantial federal investment. This review examined the relationship between rural CP and non-medicine health students' future rural practice intentions and workforce outcomes. Four databases were systematically searched; papers were screened using defined criteria and appraised using the mixed-methods appraisal tool (MMAT). Findings were synthesized using a critical narrative approach. The methodological quality of the 29 eligible studies (13 quantitative non-randomized, 10 mixed method, 4 qualitative, 2 quantitative description) was appraised. Ten high-quality studies were identified. The review found that positive CP experiences may influence intention to practice rurally amongst undecided students and serve as a reinforcing experience for those students already interested in rural practice. There were mixed findings regarding the influence of CP length. The review also found that there is currently only evidence for the short-term effects of CP on students' future practice outcomes in rural areas with focus thus far on early practice outcomes. Those looking to use rural CP to promote the rural health workforce should focus on supporting the quality of a large number of CP experiences that are undertaken in rural areas, as there are currently differing findings on the role of rural CP length. Future studies of rural CP should consider greater use of social and educational theories to guide them.


An indication for conjoint treatment: an application based on an assessment of individual psychopathology.
Conjoint treatment is advocated as the treatment of choice for a particular class of patients who do not seem able, at least initially, to benefit from individual exploratory psychotherapy. These people identify a person or persons, usually a spouse, as the primary cause of their difficulty. They show no initial capacity for self-observation. Their needs are childlike, and they show limitations in skills and a striking inability to sustain mutually gratifying relationships. The conjoint situation seems capable of initiating self-observation by confronting them with the reality of the person about which they are making claims. As a therapy, it also initiates an improvement in their marital relationship, thereby helping them potentially to gain that which they crave so desperately, but had been unable to realize except in compromise form, that is, in fantasy or in a relationship with a therapist.


Nutrition care processes from intensive care unit admission to inpatient rehabilitation: A retrospective observational study.
Extended duration of nutrition interventions in critical illness is a plausible mechanism of benefit and of interest to inform future research. The aim of this study was to describe nutrition processes of care from intensive care unit (ICU) admission to discharge from inpatient rehabilitation. This was a single-center retrospective study conducted at a health care network in Melbourne, Australia. Adult patients in the ICU >48 h and discharged to inpatient rehabilitation within 28 d were included. Dietitian assessment data and nutrition impacting symptoms were collected until day 28. Data are presented as n (%), mean ± SD or median (interquartile range). Fifty patients were included. Of the 50 patients, 28 were men (56%). Patients were 65 ± 19 y of age with an Acute Physiology And Chronic Health Evaluation II score 15.5 ± 5.2. ICU length of stay (LOS) was 3 d (3-6), acute ward LOS was 10 d (7-14), and rehabilitation LOS was 17 d (8-37). Patients assessed by a dietitian and days to assessment in ICU, acute ward, and rehabilitation were 43 (86%) and 1 (0-1); 42 (84%) and 1 (1-3), and 32 (64%) and 2 (1-4) d, respectively. Oral nutrition was the most common mode: 40 (80%) in the ICU and 48 (96%) on the acute ward and rehabilitation. There was at least one nutrition impacting symptom reported in 44 patients (88%). Rehabilitation LOS was longer than in the ICU or acute wards, yet patients in rehabilitation were assessed the least by a dietitian and time to assessment was longest. Symptoms that impact nutrition intake were common; nutrition interventions beyond the acute care setting in critical illness need investigation.


Joint action of polycyclic aromatic hydrocarbons: predictive modeling of sublethal toxicity.
Polycyclic aromatic hydrocarbons (PAHs) typically contaminate the environment as complex assemblages of different chemical compounds. Modeling approaches provide a means of estimating the toxicity of these PAH mixtures. In the present study, we tested the hypothesis that the joint effects of four PAHs: pyrene, phenanthrene, fluoranthene and naphthalene, on the growth rate of the crustacean Daphnia magna during sub-chronic exposure could be accurately predicted using a mathematical algorithm for concentration addition based upon the assumption that these PAHs impact growth by a common mode of action. Assessment of the individual toxicity of the four PAHs confirmed that these compounds elicited the common effect of retarding growth of daphnids at concentrations below those that were lethal to the organisms. Using the experimentally derived toxicity parameters for the individual chemicals, the toxicity of multiple mixtures of these four PAHs was modeled. These mixtures were based on concentrations reported in the environment and on equi-toxic concentrations. The effects of over 140 combinations of four mixture formulations on the growth rate of daphnids were experimentally determined and compared to model predictions. The concentration addition models tended to over predict the joint toxicity of these PAH mixtures and experimental data was better represented by an alternative model based upon the concept of independent joint action. Mixtures at environmentally relevant concentrations were predicted and experimentally demonstrated to have no effect on daphnid growth rates. Results indicate that PAHs elicit toxicity to daphnids by multiple mechanisms and demonstrate an appropriate modeling approach to assess the toxicity of these mixtures.


Stability and degradation in triple cation and methyl ammonium lead iodide perovskite solar cells mediated via Au and Ag electrodes.
Perovskite solar cells (PSCs), particularly based on the methyl ammonium lead iodide (MAPbI3) formulation, have been of intense interest for the past decade within the photovoltaics (PV) community, given the stupendous rise in power conversion efficiencies (PCEs) attributed to these perovskite formulations, where PCEs have exceeded 25%. However, their long-term stability under operational conditions and environmental storage are still prime challenges to be overcome towards their commercialization. Although studies on the intrinsic perovskite absorber stability have been conducted previously, there are no clear mechanisms for the interaction of electrode-induced absorber degradation pathways, which is the focus of this study. In this report, we have conducted a comprehensive analysis on the impact of the electrode collector layer, specifically Ag and Au, on the degradation mechanism associated with the MAPbI3 and a triple cation absorber, Cs0.05FA0.79MA0.16PbI2.45Br0.55. Notably, Au-based PSCs for both absorbers in an n-i-p architecture showed superior PCE over Ag-based PSCs, where the optimized PCE of MAPbI3 and triple cation-based PSCs was 15.39% and 18.21%, respectively. On the other hand, optimized PCE of MAPbI3 and triple cation-based PSCs with Ag electrodes was 3.02% and 16.44%, respectively. In addition, the Ag-based PSCs showed a rapid decrease in PCE over Au-based PSCs through operational stability measurements. We hypothesize the mechanism of degradation, arising from the Ag interaction with the absorber through the formation of AgI in the PSCs, leads to corrosion of the perovskite absorber, as opposed to the benign AuI when Au electrodes are used in the solar cell stack. Additionally, novel use of photoluminescence spectroscopy (PL) here, allowed us to access key features of the perovskite absorber in situ, while it was in contact with the various layers within the n-i-p solar cell stack. A quenching in the PL peak in the case of Ag-contacted MAPbI3 provided direct evidence of the Ag corrupting the optical properties of the absorber through the formation of AgI which our X-ray diffraction (XRD) results confirmed. This was supported by the fact that an emission peak was still present in the triple cation Ag-device. For the Au-contacted MAPbI3 the presence of a well-defined PL peak, though attenuated from the triple cation Au-device, suggested the AuI does not quell the emission spectrum for either the triple cation or the MAPbI3 absorber. The findings should aid in the understanding and design of new electrode materials with PSCs, which will help accelerate their introduction into the commercial sector in the future.


Flavored e-liquids increase cytoplasmic Ca2+ levels in airway epithelia.
E-cigarettes are noncombustible, electronic nicotine-delivery devices that aerosolize an e-liquid, i.e., nicotine, in a propylene glycol-vegetable glycerin vehicle that also contains flavors. While the effects of nicotine are relatively well understood, more information regarding the potential biological effects of the other e-liquid constituents is needed. This is a serious concern, because e-liquids are available in >7,000 distinct flavors. We previously demonstrated that many e-liquids affect cell growth/viability through an unknown mechanism. Since Ca2+ is a ubiquitous second messenger that regulates cell growth, we characterized the effects of e-liquids on cellular Ca2+ homeostasis. To better understand the extent of this effect, we screened e-liquids for their ability to alter cytosolic Ca2+ levels and found that 42 of 100 flavored e-liquids elicited a cellular Ca2+ response. Banana Pudding (BP) e-liquid, a representative e-liquid from this group, caused phospholipase C activation, endoplasmic reticulum (ER) Ca2+ release, store-operated Ca2+ entry (SOCE), and protein kinase C (PKCα) phosphorylation. However, longer exposures to BP e-liquid depleted ER Ca2+ stores and inhibited SOCE, suggesting that this e-liquid may alter Ca2+ homeostasis by short- and long-term mechanisms. Since dysregulation of Ca2+ signaling can cause chronic inflammation, ER stress, and abnormal cell growth, flavored e-cigarette products that can elicit cell Ca2+ responses should be further screened for potential toxicity.


Benign cutaneous histiocytic tumors in childhood and adolescence, excluding Langerhans' cell proliferations. A clinicopathologic and immunohistochemical analysis.
Clinical and light-microscopic findings were reviewed in 60 benign histiocytic tumors of the skin arising in patients who were 19 years of age or younger. These lesions were placed in five categories, based on the presence or absence of Touton giant cells, the relative content of vacuolated polygonal cells and spindle cells, and the extent of stromal collagen in the proliferations. The resulting distribution included 16 cases of classic juvenile xanthogranuloma (JXG), four examples of xanthomatous JXG, 11 "transitional" JXG, 11 histiocytomas, and 18 dermatofibromas. The histological appearances of the lesions were related to the elapsed time between their clinical presentation and biopsy sampling. Intervals of 3.5, 3.5, 3.6, 7, and 13.4 months were noted for each histologic group, respectively. Hence, "early" lesions (JXG variants) showed no differences in clinical duration, but significantly longer evolutions were observed for histiocytomas and dermatofibromas. Immunohistochemical studies were conducted utilizing antibodies to several "histiocytic" markers (CD68, cathepsin B, MAC387), CD45 antigen, and S-100 protein. Cathepsin B was universally expressed by all tumors, but its intensity and scope were variable. In addition, only dermatofibromas failed to show CD68 positivity. Scattered mononuclear inflammatory cells in the lesions were CD45 reactive, whereas other cell types were not so labeled. MAC387 was absent in all cases. These findings suggest that these lesions do indeed show histiocytic differentiation, and that they are probably related to peripheral blood monocytes antigenically. Differences in the histologic appearances of these cutaneous histiocytic proliferations of childhood may simply reflect dissimilar periods of clinical growth before biopsies are performed.


The role of NLRP3 in regulating gingival epithelial cell responses evoked by Aggregatibacter actinomycetemcomitans.
Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) has myriads of virulence factors among which leukotoxin provides A. actinomycetemcomitans with the advantage to thrive in the surrounding hostile environment and evade host immune defences. The NLRP3 inflammasome has been associated with periodontal disease development. However, our understanding of the involvement of caspase-1, caspase-4, and NLRP3 in the release of IL-1β and other inflammatory mediators from gingival epithelial cells during a A. actinomycetemcomitans infection is limited. The aim of this study was to investigate how the inflammasome-associated proteins caspase-1, caspase-4 and NLRP3 regulate the immune response of gingival epithelial cells during a A. actinomycetemcomitans infection. Human gingival epithelial cells (Ca9-22) deficient in NLRP3, caspase-1 or caspase-4 were created using CRISPR/Cas9. Gingival epithelial cells were stimulated with the A. actinomycetemcomitans low-leukotoxic strain NCTC9710 or the highly leukotoxic JP2 strain HK 165 for 6, 12 and 24 h. The results showed that the JP2 strain HK1651 induced higher IL-1β and IL-1RA release and mediated more epithelial cell death compared to the NCTC9710 strain. These findings were found to be capsase-1, caspase-4 and NLRP3-dependant. A targeted protein analysis of inflammation-related proteins showed that the expression of 37 proteins were identified as being significantly altered after HK1651 infection compared to unstimulated Cas9 and NLRP3-deficient cells. Of the 37 proteins, 23 of these inflammation-related proteins released by NLRP3-deficient cells differed significantly compared to Cas9 cells after infection. This suggests that NLRP3 has a broad effect on the inflammatory response in gingival epithelial cells.


Dietary nitrate supplementation does not influence thermoregulatory or cardiovascular strain in older individuals during severe ambient heat stress.
What is the central question of this study? Does dietary nitrate supplementation with beetroot juice attenuate thermoregulatory and cardiovascular strain in older adults during severe heat stress? What is the main finding and its importance? A 7-day nitrate supplementation regimen lowered resting mean arterial pressure in thermoneutral conditions. During heat stress, core and mean skin temperatures, vasodilatory responses, sweat loss, heart rate and left ventricular function were unchanged, and mean arterial pressure was only transiently reduced, post-supplementation. These data suggest nitrate supplementation with beetroot juice does not mitigate thermoregulatory or cardiovascular strain in heat-stressed older individuals. This study tested the hypothesis that dietary nitrate supplementation with concentrated beetroot juice attenuates thermoregulatory and cardiovascular strain in older individuals during environmental heat stress. Nine healthy older individuals (six females, three males; aged 67 ± 5 years) were exposed to 42.5 ± 0.1°C and 34.0 ± 0.5% relative humidity conditions for 120 min before (CON) and after 7 days of dietary nitrate supplementation with concentrated beetroot juice (BRJ; 280 ml, ∼16.8 mmol of nitrate daily). Core and skin temperatures, body mass changes (indicative of whole-body sweat loss), skin blood flow and cutaneous vascular conductance, forearm blood flow and vascular conductance, heart rate, arterial blood pressures and indices of cardiac function were measured. The 7-day beetroot juice regimen increased plasma nitrate/nitrite levels from 27.4 ± 15.2 to 477.0 ± 102.5 μmol l-1 (P < 0.01) and lowered resting mean arterial pressure from 90 ± 7 to 83 ± 10 mmHg at baseline under thermoneutral conditions (P = 0.02). However, during subsequent heat stress, no differences in core and skin temperatures, skin blood flow and vascular conductance, forearm blood flow and vascular conductance, whole-body sweat loss, heart rate, and echocardiographic indices of systolic function and diastolic filling were evident following nitrate supplementation (all P > 0.05). Mean arterial pressure was lower in BRJ vs. CON during heat stress (treatment-by-time interaction: P = 0.02). Overall, these findings suggest that dietary nitrate supplementation with concentrated beetroot juice does not attenuate thermoregulatory or cardiovascular strain in older individuals exposed to severe ambient heat stress.


An emerging role of astrocytes in aging/neuroinflammation and gut-brain axis with consequences on sleep and sleep disorders.
Understanding the role of astrocytes in the central nervous system has changed dramatically over the last decade. The accumulating findings indicate that glial cells are involved not only in the maintenance of metabolic and ionic homeostasis and in the implementation of trophic functions but also in cognitive functions and information processing in the brain. Currently, there are some controversies regarding the role of astrocytes in complex processes such as aging of the nervous system and the pathogenesis of age-related neurodegenerative diseases. Many findings confirm the important functional role of astrocytes in age-related brain changes, including sleep disturbance and the development of neurodegenerative diseases and particularly Alzheimer's disease. Until recent years, neurobiological research has focused mainly on neuron-glial interactions, in which individual astrocytes locally modulate neuronal activity and communication between neurons. The review considers the role of astrocytes in the physiology of sleep and as an important "player" in the development of neurodegenerative diseases. In addition, the features of the astrocytic network reorganization during aging are discussed.


Health Risk Assessment, Composition, and Distribution of Polycyclic Aromatic Hydrocarbons (PAHs) in Drinking Water of Southern Jharkhand, East India.
The studies on polycyclic aromatic hydrocarbons (PAHs) occurrence, distribution, health risk, and composition in drinking water are limited in India and worldwide. The main objective of this study was to find the contaminant sources, composition, health risk, and distribution of USEPA's 16 priority pollutant PAHs in the drinking water samples collected between July 2019 to September 2019 from six districts of Southern Jharkhand. The Σ16PAHs mean ± standard deviation [SD] concentration values were ordered as East Singhbhum (ES) (21.5 ± 14.8 ng L-1) > West Singhbhum (WS) (16.57 ± 13.21 ng L-1) > Saraikela Kharsawan (SK) (11.48 ± 9.92 ng L-1) > Khunti (KH) (10.32 ± 9.09 ng L-1) > Simdega (SM) (9.96 ± 7.85 ng L-1) > Gumla (GU) (9.41 ± 8.63 ng L-1). The results show that ES and WS districts' groundwater samples were more contaminated by the PAHs, which may be attributed to the presence of many small-, medium-, and large-scale industries and high vehicular density in these districts. The concentrations of lower molecular weight ring (3-rings) and middle molecular weight ring (4-rings) PAHs were dominant throughout all drinking samples. The concentration of the 3-ring PAH Anthracene and 4-ring PAH Fluoranthene were dominant in all districts. The molecular ratios suggested that the potential sources of PAHs are fuel combustion and coal, grass, and wood burning. Risk assessment shows that the incremental lifetime cancer risk and risk index (RI) were ranged from 0.02 × 10-10 to 4.93 × 10-10 for children and 0.01 × 10-10 to 2.98 × 10-10 for adults. The RI values for seven carcinogenic PAHs were 8.83 × 10-10 for children and 7.38 × 10-10 for adults. Although the carcinogenic risks were within the permissible values, chronic exposure to PAHs through the ingestion of drinking water could still be a human health concern.


Preparation and properties of side-chain cleavage cytochrome P-450 from bovine adrenal cortex by affinity chromatography with pregnenolone as ligand.
A method is described for preparing cytochrome P-450 (side-chain cleavage) from bovine adrenocortical mitochondria, by affinity chromatography on pregnenolong-Sepharose beads. The cytochrome P-450 appears in two fractions, a large form of heterogeneous molecular weight (large P-450) and a form of molecular weight 850 000 composed of 16 apparently identical subunits (molecular weight 52 000-53 000); this form is referred to as protein 16. Electrophoresis on polyacrylamide gel yields one main band and two minor bands; the appearance of the gels is identical whether the starting material is large P-450 or protein 16 or protein 16 prepared by an entirely different method. Yields of protein 16 can be increased by rechromatography on pregnenolone-Sepharose of large P-450 made 0.1 mM in NADPH. Large P-450 shows greater than 10 heme groups per 16 subunits and is less active enzymatically than protein 16. Chromatography on Sepharose and analytical ultracentrifugation show that large P-450 is heterogeneous with respect to molecular weight. Protein 16 shows a heme content of 8 nmol/mg protein and for both large P-450 and protein 16 heme content by CO-difference spectroscopy is in agreement with values by pyridine hemochromogen. This method of preparing P-450 is convenient and both large P-450 and protein 16 are highly purified.


Effects of Ethanol on the Cerebellum: Advances and Prospects.
Alcohol abuse causes cerebellar dysfunction and cerebellar ataxia is a common feature in alcoholics. Alcohol exposure during development also impacts the cerebellum. Children with fetal alcohol spectrum disorder (FASD) show many symptoms associated specifically with cerebellar deficits. However, the cellular and molecular mechanisms are unclear. This special issue discusses the most recent advances in the study of mechanisms underlying alcoholinduced cerebellar deficits. The alteration in GABAA receptor-dependent neurotransmission is a potential mechanism for ethanol-induced cerebellar dysfunction. Recent advances indicate ethanol-induced increases in GABA release are not only in Purkinje cells (PCs), but also in molecular layer interneurons and granule cells. Ethanol is shown to disrupt the molecular events at the mossy fiber - granule cell - Golgi cell (MGG) synaptic site and granule cell parallel fibers - PCs (GPP) synaptic site, which may be responsible for ethanol-induced cerebellar ataxia. Aging and ethanol may affect the smooth endoplasmic reticulum (SER) of PC dendrites and cause dendritic regression. Ethanol withdrawal causes mitochondrial damage and aberrant gene modifications in the cerebellum. The interaction between these events may result in neuronal degeneration, thereby contributing to motoric deficit. Ethanol activates doublestranded RNA (dsRNA)-activated protein kinase (PKR) and PKR activation is involved ethanolinduced neuroinflammation and neurotoxicity in the developing cerebellum. Ethanol alters the development of cerebellar circuitry following the loss of PCs, which could result in modifications of the structure and function of other brain regions that receive cerebellar inputs. Lastly, choline, an essential nutrient is evaluated for its potential protection against ethanol-induced cerebellar damages. Choline is shown to ameliorate ethanol-induced cerebellar dysfunction when given before ethanol exposure.


[Living will, durable power of attorney and legal guardianship in the trauma surgery routine : Data from a geriatric trauma center].
Due to the increasing number of elderly patients, trauma surgeons are often confronted with end-of-life treatment decisions. Advance directives can help reduce the lack of clarity in those situations. The aim of this study was to identify the presence of living wills, durable power of attorney, legal guardianship and appointment of guardianship in the geriatric trauma center of a university hospital. The data of all patients treated in our geriatric trauma center from 01/01/2013 to 03/31/2014 were analyzed regarding the presence of a living will, durable power of attorney, legal guardianship and appointment of guardianship as well as the procedure of documenting those items. Out of 181 patients, 63 % (n = 114) had one or more of these documents. Most frequently used was the durable power of attorney in 33 % (n = 59), followed by a living will in 27 % (n = 48), legal guardianship in 20 % (n = 37) and appointment of guardianship in 7 % (n = 12). The existence of those documents was recorded in 88 % (n = 100) of patients within 24 h after admission; documentation in the medical records was found in 58 % (n = 66). A large proportion of patients had one or more of the documents named above. In this respect, standardized documentation of advance directives in the medical record is an important issue for all persons involved.


Clinical Pharmacokinetics of Daprodustat: Results of an Absorption, Distribution, and Excretion Study With Intravenous Microtracer and Concomitant Oral Doses for Bioavailability Determination.
Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated for treatment of anemia in chronic kidney disease. This phase 1, nonrandomized, 2-period, crossover study in 6 healthy men characterized the absorption, distribution, and excretion of daprodustat when administered as oral and intravenous (IV) doses of unlabeled and radiolabeled daprodustat ([14 C]-GSK1278863). Tolerability and pharmacokinetic properties of daprodustat, and its 6 metabolites in the systemic circulation, were also evaluated. The mean recovery of radiolabeled daprodustat was ≈95% by day 5, with the majority in feces and minor renal elimination, indicating that daprodustat and metabolites are primarily eliminated via hepatobiliary and fecal routes. Approximately 40% of total circulating radioactivity in plasma following both IV and oral administration was daprodustat; thus, 60% was attributed to metabolites. It was estimated that ≈80% of daprodustat was absorbed across the gastrointestinal tract, and ≈18% cleared by hepatic extraction. Pharmacokinetics were essentially dose proportional, with moderate (≈66%) oral tablet bioavailability. Following IV administration, daprodustat plasma clearance (19.3 L/h) and volume of distribution (14.6 L) were low, suggesting low tissue distribution outside systemic circulation with likely low penetration into tissues. Daprodustat was generally well tolerated, with no deaths or serious or significant adverse events reported.


A validated capillary electrophoresis method for simultaneous determination of ezetimibe and atorvastatin in pharmaceutical formulations.
A simple, precise, and sensitive capillary electrophoresis technique coupled with a diode array detector has been developed for the separation and simultaneous determination of ezetimibe and atorvastatin in pharmaceutical formulations. Separation of both ezetimibe and atorvastatin was achieved utilizing fused silica capillary (58 cm × 75 μm ID) and background electrolyte solution that consisted of phosphate buffer (2.5 mM, pH 6.7): methanol (70:30 v/v). The proposed method was validated by testing its specificity, linearity, precision, accuracy, recovery, and detection limit/quantitation limit values. The method was linear over the range 2.5-50 μg/ml for ezetimibe (r = 0.9992) and 1-100 μg/ml for atorvastatin (r = 0.9999). Within-day and between-day RSD for ezetimibe and atorvastatin were ⩽5.6% and ⩽2.9%, respectively. The detection limit was 0.07 μg/ml for ezetimibe and 0.06 μg/ml for atorvastatin. The validated method was successfully employed for the determination of ezetimibe and atorvastatin in tablets with no interfering peaks from common pharmaceutical excipients. The percentage recoveries of the two drugs from their tablets were 99.80 ± 1.76 and 100.19 ± 1.83, respectively.


Ultra-long silver nanowires prepared via hydrothermal synthesis enable efficient transparent heaters.
Ultra-long silver nanowires (AgNWs) with an aspect ratio of >2000 were prepared by the hydrothermal synthesis method. The influence of reaction time (4-32 h), reaction temperature (150-180 °C), polyvinylpyrrolidone (PVP) molecular weight (10 000-1 300 000 g mol-1), PVP concentration (50-125 mM), glucose concentration (5.6-22.4 mM) and CuCl2 concentration (2-20 μM) on the AgNW length was investigated systematically. The optimum conditions provided nanowires with an average diameter of 207 nm, an average length of 234 μm and a maximum length of 397 μm. Finally, a AgNW electrode was prepared on a glass substrate and used in transparent heater application. The transparent heater enabled outstanding heat-generating properties, reaching >200 °C within 70 s with an applied voltage of 5 V. Our results demonstrate how increasing the aspect ratio of ultra-long AgNWs is beneficial for both optical and electronic applications in terms of increased transmission and a more efficient Joule effect in the heater application. In addition, our results show that AgNWs with different lengths can be simply obtained by tuning synthesis parameters.


Management of obstructive colorectal cancer: evaluation of preoperative bowel decompression using ileus tube drainage.
This study evaluated a better treatment for patients with obstructive colorectal cancer (CRC) that have a poor prognosis. This study compared the outcomes of 138 patients with obstructive CRC, including 70 primary resections, 50 resections after bowel decompression using an ileus tube, and 18 delayed resections after colostomy. The ileus tube and delayed resection groups included more left-sided primary lesions. The physiologic POSSUM, types 3-4, tumor size, CEA, and hospital stay of the delayed resection group were different, in comparison to both the primary resection and ileus tube groups. The histopathological type and depth of invasion of the delayed resection group included less well types and more T4 than those of the ileus tube group. The operative blood loss of the delayed resection group was more than that of the ileus tube group. There were no differences in the overall and disease-free survival among the three groups. Separately analyzing the data of the right-sided cancer group and the left-sided cancer group demonstrated that primary resection might be acceptable for right-sided obstructive CRC and delayed resection might be done for patients with poorer general conditions (high PPS) and poorer oncological prognostic factors such as more type 3/type 4 cases, a larger tumor size, a less well-differentiated histopathological type, more T4 cases, and a higher CEA level.


Specific indications and clinical outcome in patients with subcutaneous implantable cardioverter-defibrillator (ICD) - A nationwide multicentre registry.
Subcutaneous implantable cardioverter-defibrillators (S-ICD) are an innovative and less invasive alternative to transvenous ICD (TV-ICD) in selected patients. We aimed to investigate the underlying diseases and the specific indications for implanting S-ICD in clinical practice, as well as the prevalence of shock delivery and complications. From December 2012, data of 236 patients (30,5% female; age 48,6±16,8years) were gathered from 12 centres in Austria. Follow-up data over a period of 1,7±1,1years were available for 231 patients (in total 359,2 patient-years). Predominant underlying diseases were ischemic cardiomyopathy (iCMP; 32,0%), idiopathic ventricular fibrillation (22,6%) and dilated cardiomyopathy (dCMP; 17,3%). The most frequent indications for implantation were sudden cardiac death survival (27,4%), primary prevention for iCMP (23,9%) and for dCMP (12,8%), and previous explantation of TV-ICD (12,4%). Appropriate shocks were documented in 16 patients (6,9%), iCMP being the predominant underlying disease. Arrhythmia conversion was successful in all patients, efficacy of the first shock was 96%. Inappropriate shock rate was 5,2%, predominantly caused by oversensing of T wave or artefacts. A device upgrade to an ICD system with pacing function was necessary in <1%. Clinical complications needing surgical revision occurred in 8 patients (3,5%). S-ICD were mostly implanted for primary prevention, one fourth of our cases were sudden death survivors. Clinical and functional complication rate was relatively low. In conclusion, S-ICD is a safe and efficient alternative in a larger population of ICD candidates, when no cardiac pacing is needed. EC-number: C-136-17.


Lymphomas with plasmablastic features: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.
Lymphomas with plasmablastic features are a heterogeneous group of aggressive and mostly uncommon neoplasms of varied aetiologies, presenting in immunocompetent individuals as well as in immunodeficiency, associated with EBV and Kaposi sarcoma virus infections, and some as progression from indolent B-cell lymphomas. They show overlapping diagnostic features and pose a differential diagnosis with other aggressive B-cell lymphomas that can downregulate the B-cell expression programme. The spectrum of rare reactive proliferations and all lymphomas defined by plasmablastic features, together with an expanding range of poorly characterised, uncommon conditions at the interface between reactive lymphoid proliferations and neoplasia submitted to the session V of the 20th European Association for Haematopathology/Society for Hematopathology lymphoma workshop are summarised and discussed in this paper.


Metastatic paraspinal abscess and paraplegia secondary to dental extraction.
An unusual case of metastatic paraspinal abscess and paraplegia is presented. This was a consequence of simple dental extractions and subsequent bacteraemia from a neglected mouth. Neurosurgical intervention and tissue culture yielded organisms almost certainly of dental origin. No alternative primary nidus of infection could be found. The importance of oral health to general health is emphasised.


Assessment of a novel method to detect clarithromycin-resistant Helicobacter pylori using a stool antigen test reagent.
The resistance rate of Helicobacter pylori to clarithromycin (CAM) is high among infected children in Japan. Therefore, a new method for detecting CAM-resistant H. pylori using a minimally invasive technique is strongly desired. We aimed to investigate the clinical usefulness of our newly developed nested polymerase chain reaction-quenching probe (Nested PCR-QP) method using stool specimens. We first evaluated our method using a residual solution of the H. pylori stool antigen test for adolescents. Then, we evaluated our method using culture testing for adults. Among 57 middle school students with H. pylori, the Nested PCR-QP test results of 53 (90.3%) were able to be analyzed. A total of 28 students had CAM resistance mutations. We found a genetic mutation in 28 students and no mutation in 23 students, and these results were consistent with those of PCR-direct sequencing. In the 23 adults who were diagnosed with H. pylori infection using the rapid urease test and culture testing, we were able to use Nested PCR-QP for analyzing 21 adults who tested positive in the stool H. pylori antigen test. The results obtained for all 21 adults were consistent with those obtained via the drug susceptibility test. Our novel method could be useful for non-invasively detecting CAM resistance mutations in H. pylori. This may help select a drug to reduce eradication failure rates against H. pylori. Trial registration This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (no. UMIN000030632, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034977 ) on 29 December 2017.


Endogenous potentials after anterior temporal lobectomy.
The scalp topography of endogenous potentials was studied in patients who had previously undergone unilateral anterior temporal lobectomy (ATL). These excisions include medial temporal lobe (MTL) structures that have been shown to generate large potentials during tasks that evoke P3 at the scalp. Following right or left ATL, patients showed no differences from unoperated control subjects in overall amplitude of P3 or any other potential measured. The topography of P3 was very similar in both ATL groups and the control subjects, with no differences in laterality. These results suggest that the MTL is not the major generator of the P3 recorded at the scalp in the tasks studied here.


Clinical features of Poncet's disease. From the description of 198 cases found in the literature.
Poncet's disease (PD) is an entity described as a reactive arthritis due to tuberculous infection elsewhere from the joints. PD existence has been questioned; however, more cases have been reported over the years. Due to its rare nature, little is known about the clinical picture of this disease and no prospective studies had been made to address this issue. We performed a systematic review of the written literature on PD in different databases using the key words "Poncet's disease," "tuberculous rheumatism," and "tuberculous reactive arthritis." Out of 78 articles, 198 patients were included in the analysis, plus our patient. Several characteristic patterns were found. Also, a review of the pathogenesis and some hypotheses are made. PD is a well-defined entity, which should be taken as a reactive arthritis for future studies given the increase in TB incidence and prevalence around the world, especially in high-burden countries.


Antitumor and antimetastatic activity of the differentiating agent N-methylformamide in murine tumor systems.
N-Methylformamide (NMF), a cell-differentiating agent, was assessed for its antitumor activity against a fibrosarcoma (FSA), a hepatocarcinoma (HCA-I) and a mammary carcinoma (MCA-K), syngeneic to C3Hf/Kam mice. Tumors were grown as solitary tumors in the leg or as artificial or spontaneous micrometastases in the lung. NMF, at a dose of 300 mg/kg, was administered i.p. daily for 6 to 18 days. NMF slowed the growth of FSA and HCA-I tumors and totally inhibited the growth of the MCA-K tumor. However, the effect was transient; tumors resumed their pretreatment growth rate upon cessation of the treatment. Histologically, MCA-K tumors treated with NMF (300 mg/kg daily for six days) underwent considerable cell depopulation and reduction in mitotic activity. The number of artificial metastases, as well as the incidence and the number of spontaneous metastases, were markedly reduced by NMF. This resulted in a prolongation of the survival of mice that had artificial metastases of MCA-K tumor. The in vitro clonogenicity of MCA-K, but not of FSA or HCA-I cells, was reduced. However, in vivo reduction of MCA-K cell clonogenicity was minimal, if any. Thus, NMF is effective in restricting the growth of both solitary tumors and metastases, but the degree of response is highly dependent on tumor type.


Fate of metals contained in waste electrical and electronic equipment in a municipal waste treatment process.
In Japan, waste electrical and electronic equipment (WEEE) that is not covered by the recycling laws are treated as municipal solid waste. A part of common metals are recovered during the treatment; however, other metals are rarely recovered and their destinations are not clear. This study investigated the distribution ratios and substance flows of 55 metals contained in WEEE during municipal waste treatment using shredding and separation techniques at a Japanese municipal waste treatment plant. The results revealed that more than half of Cu and most of Al contained in WEEE end up in landfills or dissipate under the current municipal waste treatment system. Among the other metals contained in WEEE, at least 70% of the mass was distributed to the small-grain fraction through the shredding and separation and is to be landfilled. Most kinds of metals were concentrated several fold in the small-grain fraction through the process and therefore the small-grain fraction may be a next target for recovery of metals in terms of both metal content and amount. Separate collection and pre-sorting of small digital products can work as effective way for reducing precious metals and less common metals to be landfilled to some extent; however, much of the total masses of those metals would still end up in landfills and it is also important to consider how to recover and utilize metals contained in other WEEE such as audio/video equipment.


Conditions necessary for quantifying ethyl methanesulfonate-induced mutations to purine-analogue resistance in Chinese hamster V79 cells.
We have investigated conditions necessary to quantify the relationship between exposure to a mutagen, ethyl methanesulfonate (EMS), and the frequency of mutation induction at the hypoxanthine-guanine phosphoribosyl transferase locus in V79 cells. Maximal expression of potential mutants has been achieved by either subculturing at fewer than 5 X 10(5) cells/100-mm dish at 2-day intervals or by daily feeding of cultures. An expression period of 5 days (measure from 1 day after the initiation of treatment with the chemical mutagen) should be allowed, since at least 4 days of expression is required to reach to steady maximum of mutation frequency. It appears that there is no concentration dependence of expression time necessary to reach a plateau of mutation frequency with increasing concentrations of EMS up to 1.6 mg/ml. About 1.25 X 10(5) cells/100-mm dish or fewer should be plated for selection to avoid the loss of mutants which occurs at 1.5 X 10(5) cells/dish, presumably through cross-feeding (metabolic cooperation). The use of 6-thioguanine in hypoxanthine-free medium (supplemented with dialyzed fetal calf serum) appears to be a very stringent condition for selection. Mutation induction by EMS as a function of EMS exposure (EMS concentration X treatment time) increases linearly with concentration up to 12 h. For these treatment periods, the observed mutation frequencies for EMS are directly proportional to mutagen exposure regardless of the duration of the treatment.


Characterization of the probiotic strain Vagococcus fluvialis in the protection of European sea bass (Dicentrarchus labrax) against vibriosis by Vibrio anguillarum.
Aquaculture is one of the main sources of income in many countries worldwide. Intensive farms are often affected by different infectious diseases that can decrease their final production. To control this situation, several antibiotics are frequently used with known environmental consequences. The aim of this study was to analyze different bacterial strains isolated from of gilthead sea bream, sea bass, sole and meagre guts, for use as probiotics in aquaculture. The strains were evaluated in vitro through various mechanisms of selection, such as the production of antagonistic effects against pathogens, production of antibacterial substance, adhesion to the intestinal mucus, competition for nutrients or binding site, and growth in intestinal mucus. A total of 50 bacterial strains were analyzed and only one showed excellent in vitro results for consideration as a candidate to be analyzed in vivo. The strain, identified as Vagococcus fluvialis, showed good protection against Vibrio anguillarum 975-1 in vivo in the experimental challenge, showing a relative percent survival of 42.3% higher than positive control group. Therefore, in conclusion we consider this strain to be a good candidate for use as a future probiotic in aquaculture.


Functional reconstitution of bacterially expressed human potassium channels in proteoliposomes: membrane potential measurements with JC-1 to assay ion channel activity.
Structure-function studies on ion channels have been greatly facilitated by the cloning of cDNAs from a variety of sources. However, obtaining detailed structural information on these proteins requires overexpression, purification and reconstitution in a functionally competent form. In this communication, we report on the functional reconstitution of a human potassium channel, Kv1.4, overexpressed in bacteria. We have assessed the activity of these channels using a spectroscopic assay with a potential-sensitive dye, JC-1. The presence of ion channels renders proteoliposomes selectively permeable to potassium ions as monitored by measurements of transmembrane electrical potential. We have optimised conditions wherein a 12% change in the fluorescence signal of the carbocyanine dye JC-1 per 10 mV change in membrane potential is obtained. Using this assay, we find that the reconstituted protein is potassium selective and its activity is blocked by 4-aminopyridine, a known potassium channel blocker.


Characterization of stirred yoghurt enriched with probiotics and beetroot and its therapeutic potential in experimental type 2 diabetes.
Type-2 diabetes is the most prevalent metabolic disease, which calls for researchers to find many natural products that are effective in fighting diabetes and its complications. Stirred yoghurt samples were prepared, enriched with probiotics, and fortified with either 1% or 2% of the fine powder of beetroots. The chemical, physical, sensorial, and microbial properties of the yoghurt samples were studied over a 15-day storage period. The total phenolic compounds, flavonoids, antioxidant activity as well as the reducing power of the dried beetroot and the yoghurt samples were assessed.The prepared yoghurt samples were evaluated in type 2 diabetic rats. Fortification with beetroot led to an increase of the total phenolic compounds, antioxidant activity, and the probiotic counts in the prepared yoghurt. The intervention with the prepared yoghurt samples resulted in an increase in the number of beneficial bacteria in diabetic rats' feces, hypoglycemic effect, and suppression in the elevation of C-reactive protein (CRP) and thyroid stimulating hormone (TSH). This study suggests that stirred yoghurt enriched with probiotics and fortified with beetroot have therapeutic potential for type 2 diabetes.


Setting health standards for the 21st century.
To describe the nature, substance, and impact of health standards and to speculate on how they may change during the early years of the 21st century. The health care system has experienced dramatic changes over the past three decades. Health standards now cover the spectrum from statutes to regulations to guidelines, as well as less compulsory forms, and address every aspect of health, including the availability, quality, and cost of services; the safety, efficacy, and quality of products; the adequacy of processes and analytic methods; and the value and cost-effectiveness of health technologies and services. Standards cover promotion, protection, and gatekeeping functions. They are established in response to specific needs and are driven by social and political agendas; social policy will drive standards development to a greater extent in the 21st than in the 20th century. Technology advances are stimulating new forms of standards, primarily gatekeeping standards. Standards raise the question of compliance. The trend is increasingly toward less compulsory, more discretionary standards, with a greater percentage being established by quasi-official and voluntary bodies. 21st century health standards must balance the rights of access with protection from unsafe, ineffective, and poor quality products and services during a period when decisions must be made faster. They must be more flexible, enabling consumers to choose their level of protection. Such standards will pose the same concerns about adequacy, equity, and freedom of choice as health standards pose now. Whether we will use 21st century standards to improve and advance our health as well as systems, products, and services that contribute to health more effectively than we have in the 20th century is a question to ponder.


Male attitudes towards family planning in the Limpopo province of South Africa.
Women often do not receive support from their partners with regards to family planning (FP), which can lead to hesitancy and inconsistent use. This study sought to understand the male attitudes that contribute to this. A qualitative descriptive study was conducted in 2019 using focus group discussions (FGDs) with purposively selected men aged ≥ 25 years and in a relationship with a woman of childbearing age. An open-ended question guide was used to explore men's perceptions regarding FP. The discussions were recorded, translated and transcribed verbatim, whereafter transcripts were coded and analysed thematically. Three major themes were identified, namely: (1) the advantages of FP, including financial benefits and the prevention of sexually transmitted infections and unwanted pregnancy; (2) the disadvantages of FP, including perceived adverse effects on men and women, as well as marital difficulties; and (3) the exclusion of men from FP by health workers and their partners. Men felt ambivalent towards FP. They were aware of the benefits thereof, but were hesitant to allow their female partners to use contraceptives, because of several misconceptions about the adverse effects. This underscores the need to involve men in FP programmes.


Analysis of adherence to an early mobilization protocol in an intensive care unit: Data collected prospectively over a period of three years by the clinical information system.
To determinate the adherence and barriers of our early mobilization protocol in patients who had received mechanical ventilation >48h in routine daily practice through clinical information system during all Intensive Care Unit (ICU) stay. Observational and prospective cohort study. Polyvalent ICU over a three-year period (2017-2019). Adult patients on mechanical ventilation >48h who met the inclusion criteria for the early mobilization protocol. None. Demographics, adherence to the protocol and putative hidden adherence, total number of mobilizations, barriers, artificial airway/ventilatory support at each mobilization level and adverse events. We analyzed 3269 stay-days from 388 patients with median age of 63 (51-72) years, median APACHE II 23 (18-29) and median ICU stay of 10.1 (6.2-16.5) days. Adherence to the protocol was 56.6% (1850 stay-days), but patients were mobilized in only 32.2% (1472) of all stay-days. The putative hidden adherence was 15.6% (509 stay-days) which would increase adherence to 72.2%. The most common reasons for not mobilizing patients were failure to meeting the criteria for clinical stability in 241 (42%) stay-days and unavailability of physiotherapists in 190 (33%) stay-days. Adverse events occurred in only 6 (0.4%) stay-days. Data form Clinical Information System showed although adherence was high, patients were mobilized in only one-third of all stay-days. Knowing the specific reason why patient were not mobilized in each stay-day allow to develop concrete decisions to increase the number of mobilizations.


Troublesome colostomies and urinary stomas treated with suction-assisted lipectomy.
To investigate the effectiveness of liposuction as treatment in troublesome colostomies and urinary stomas in selected patients. Open clinical study. University hospital, Norway. 8 consecutive patients with colostomies (n = 2) or urinary stomas (n = 6) who required treatment with liposuction above or around the stoma, mainly for leakage. Syringe-assisted liposuction under local anaesthesia. Change in stoma function, particularly reduction in the incidence of leakage, and by the patients' satisfaction graded according to a four point scale. All patients noted considerable improvements in stoma function, or abdominal contour, or both. Troublesome colostomies and urinary stomas can in selected patients be successfully treated with liposuction above or around the stoma.


Targeted Energy Metabolomics Combined with Spatial Metabolomics Study on the Efficacy of Guhong Injection Against Cerebral Ischemia Reperfusion.
Optimizing the metabolic phenotype to improve cerebral function is critical for treatment of cerebral ischemia-reperfusion (I/R) injury. Guhong injection (GHI), which comprised safflower extract and aceglutamide, is widely prescribed in Chinese medicine for the treatment of cerebrovascular diseases. In this study, a combination of LC-QQQ-MS and MALDI-MSI were utilized to explore tissue-specific metabolic alterations in the brain of I/R, as well as to evaluate the therapeutic effect of GHI. Pharmacological evaluation demonstrated that GHI can significantly improve infarction rate, neurological deficit, cerebral blood flow, and neuronal damage in I/R rats. Based on LC-QQQ-MS, 23 energy metabolites were found to be significantly altered in the I/R group compared to the sham group (P < 0.05). After GHI treatment, 12 metabolites, including G6P, TPP, NAD, citrate, succinate, malate, ATP, GTP, GDP, ADP, NADP, and FMN showed a significant tendency of returning to baseline values (P < 0.05). Based on MALDI-MSI, 4 metabolites in glycolysis and TCA, 4 metabolites in nucleic acid metabolism, 4 amino acid metabolites, and 6 metabolites were discovered and compared between the different groups in the four special regions of cortex, hippocampus, hypothalamus, and striatum. Parts of these were found to have significant changes after I/R in the special brain region, and were regulated by GHI. The study provides comprehensive and detailed information for specific metabolic reprogramming of brain tissue in rats with I/R, and the therapeutic effect of GHI. Schema describing the discovery strategies of integrated LC-MS and MALDI-MSI to identify cerebral ischemia reperfusion metabolic reprogramming and GHI therapeutic effects.


Effects of age and gender on in vitro properties of human liver microsomal monooxygenases.
Aging in humans is associated with marked declines in the disposition of numerous drugs and other xenobiotics that require hepatic biotransformation before elimination. Considerable pharmacokinetic evidence in humans, coupled with data on in vitro liver microsomal monooxygenase functions generated in inbred male rodent models, has implicated impaired liver phase I drug metabolism (i.e., diminished efficacy of microsomal monooxygenases) in reduced drug clearance in the elderly. This study (1) assessed the in vitro activities and amounts of liver microsomal monooxygenases as a function of donor age and gender in healthy humans and (2) provides the most extensive and comprehensive data to date demonstrating the absence of significant age- and gender-dependent differences in the activities and contents of human liver monooxygenases.


Detection of small RNAs containing the 5'- and the 3'-end sequences of viral genome during West Nile virus replication.
In the first step of flavivirus replication, the 5'-end of viral genomic RNA is thought to interact with the 3'-end of the genomic RNA at the complimentary sequences (CSs) located at both ends of the genomic RNA. However, there is little evidence of direct interaction between the two ends of the viral genomic RNA in virus-replicating cells. Herein, we show that viral small negative-strand RNA species, composed of two ends corresponding to the upstream of the 5'-end CS and the downstream of the 3'-end CS of viral genomic RNA, were synthesized during viral replication. We hypothesized that the viral small negative-sense RNAs were synthesized during viral negative-sense RNA synthesis through the template-jumping of viral RNA-dependent RNA polymerase from the 3'-end to the 5'-end of viral genomic RNA used as a template. Our present results strongly indicate that the two ends of viral genomic RNA associate with each other during viral replication.