Randomized comparison between antibiotics alone and antibiotics plus granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived in cancer patients with fever and neutropenia.
A prospective, randomized study was conducted to determine if recombinant human granulocyte-macrophage colony-stimulating factor (rh-GMCSF) (Escherichia coli-derived) could improve response rates to antibiotic therapy and shorten the duration of neutropenia in cancer patients. A total of 107 febrile neutropenic cancer patients were randomly assigned to empiric therapy with ticarcillin-clavulanate (4 g ticarcillin + 0.1 g clavulanate i.v. every 4 hours) plus netilmicin (2 mg/kg i.v. every 8 hours) with or without rh-GMCSF (3 micrograms/kg per day i.v.). Clinical improvement, duration of neutropenia, and toxicity were monitored. Addition of rh-GMCSF to the antibiotics significantly improved the response rate (96% versus 82%, P = 0.03), but not the survival rate (93% versus 93%), in the evaluable patients. This difference in response rate was not significant when considering all patients in an intent-to-treat analysis. The number of patients who recovered from severe neutropenia ( < 100 cells/microliter) during the period of observation in the study was significantly greater among patients receiving the colony-stimulating factor, although the median duration of neutropenia was not affected. Superinfections and subsequent infections were not significantly different among the two treatment regimens. Side effects were more common among patients treated with the colony-stimulating factor. Our data do not support the routine administration of rh-GMCSF with antibiotics for patients with fever and neutropenia. Further studies should be conducted to identify those patients most likely to benefit from rh-GMCSF therapy, such as patients with persistent profound neutropenia and refractory infections.


An integrated two-step filtering strategy of collision cross-section interval predicting and mass defect filtering for targeted identification of analogues in herbal medicines using liquid chromatography-ion mobility-mass spectrometry.
Rapid identification of chemical analogues in herbal medicines using liquid chromatography-mass spectrometry was an efficient tool for discoveries of potentially active ingredients. Multi-dimensional combination of various separation technologies could significantly enhance the capacities for detection of trace components and discrimination of multiple isomers. In this study, an integrated two-step filtering strategy on liquid chromatography-ion mobility tandem with quadrupole-time-of-flight mass spectrometry (LC-IM-QTOF MS) was developed for identification of analogues in complex matrixes. The extracted raw data were preliminarily filtered by a collision-cross section (CCS) interval generated from power regression with confidence level at 99% for prediction of analogues. Then, the remained ions were further screened using a mass defect filtering (MDF) window based on m/z and decimal m/z of potential skeletons and substituents. By applying this strategy, 86, 102, 73, and 57 isoquinoline alkaloids were identified in herbal materials of Coptis chinensis Franch (CC), C. deltoidea C.Y.Cheng et Hsiao (CD), C. teeta Wall (CT), and Corydalis yanhusuo W.T.Wang (CY). The integrated two-step filtering presented higher efficiencies on exclusion of the background interference and reducing the false-positive rates than previously reported approaches. This study facilitated the application of LC-IM-MS on small molecular analysis and promoted the discoveries of bioactive components of herbal medicines for further pharmacological researches and quality control.


Pyrazoloquinazolines: Synthetic strategies and bioactivities.
Numerous N-heterocycles are indisputably evidenced to exhibit myriad biological activities. In the recent past, attempts made to condense the various heterocycles have resulted in derivatives possessing better bioactivities. Among many such condensed heterocycles, pyrazoloquinazolines have managed to hold the attention of many researchers, owing to the broad spectrum of activities they portray. This review is the first of its kind to congregate the various pyrazoloquinazolines reported until now and categorizes these structurally isomeric classes into eleven different groups based on the fusion pattern of the ring such as [1,5-c], [5,1-b], [4,3-h], etc. Furthermore, this review is a concerted effort to highlight design, synthetic strategies as well as biological activities of each class of this condensed heterocycle. Structure-activity relationship studies and in silico approaches wherever reported have also been discussed. In addition, manuscript also offers scope for design, synthesis and generation of libraries of unreported classes of pyrazoloquinazolines for the biological evaluation.


A mathematical model of neutrophil production and control in normal man.
A comprehensive mathematical model of neutrophil production in normal man is presented. The model incorporates three control elements which regulate homeostatically the rates of release of marrow cells to proliferation, maturation, and to the blood. The steady state properties of the model are demonstrated analytically. The basic equations of the model, which are nonlinear, have been integrated numerically. The solutions so obtained display graphically the dynamical response of the system to various perturbations, which simulate experimental investigations that have been made in the past of granulocytopoiesis. By an appropriate choice of values of the parameters characterizing the system, it is shown how most of the principal kinetic properties of the neutrophil production and control system are represented in a quantitative manner.


Analysing and modelling train driver performance.
Arguments for the importance of contextual factors in understanding human performance have been made extremely persuasively in the context of the process control industries. This paper puts these arguments into the context of the train driving task, drawing on an extensive analysis of driver performance with the Automatic Warning System (AWS). The paper summarises a number of constructs from applied psychological research thought to be important in understanding train driver performance. A 'situational model' is offered as a framework for investigating driver performance. The model emphasises the importance of understanding the state of driver cognition at a specific time ('Now') in a specific situation and a specific context.


Regional myocardial function after repetitive brief episodes of ischemia: effect of altering the duration of the reperfusion period.
How recovery of regional contractile function in myocardium is influenced by alterations in the duration of reperfusion after repetitive brief coronary artery occlusions was investigated in chronically instrumented, conscious dogs. All animals underwent five 5 minute left anterior descending coronary artery occlusions with a final 5-hour reperfusion period. Dogs were randomly assigned to one of three groups determined by the duration of reperfusion (5, 10, or 15 minutes) between successive 5-minute occlusion periods. A shortening of the duration of the reperfusion period between occlusions led to reduced recovery and progressive deterioration in systolic shortening after multiple occlusion-reperfusion sequences. With 15-minute reperfusion periods, the percentage of segment shortening (%SS) during the first through fourth reperfusion periods ranged from 17.1 +/- 2.6% to 18.2 +/- 1.8% and did not differ from the preocclusion control value (18.8 +/- 1.7%) by the end of the final reperfusion period. In contrast, in those dogs with 5-minute reperfusion periods, %SS was significantly reduced from the preocclusion control value (20.2 +/- 2.2%) at the completion of the final 5-hour reperfusion period (11.4 +/- 1.5%). Results of the present study indicate that after only a few brief periods of coronary artery occlusion, rapid and cumulative deterioration in regional contractile function can occur when the duration of intermittent reperfusion is sufficiently brief.


Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial.
Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer. We did a phase 1-2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20-25 mg/m2 and intravenous carboplatin area under the curve (AUC) 3-4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m2 with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868. Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m2 and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5-37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5-5·7) to 7·3 months (95% CI 5·5-8·2; hazard ratio 0·69, 95% CI 0·50-0·95, p=0·018). In the phase 2 study, the most common grade 3-5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths. Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane-platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned. Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.


Reflex sympathetic dystrophy following neck dissections.
Reflex sympathetic dystrophy (RSD), which is a disorder that occurs after injury or surgery on the extremities, has not been reported as a complication of neck dissections until now. A group patients with head and neck cancer have been examined to determine the incidence of RSD in neck dissections. Forty-six patients with head and neck cancer, who had undergone neck dissections together with the removal of the primary tumor, were evaluated for RSD on their routine controls. The presentation of RSD in two patients who were treated with radical neck dissection is probably a result of sympathetic hyperactivity that is secondary to surgical trauma.


Factors influencing students' decision in choosing obstetrics and gynecology as a career in a university hospital in Central Saudi Arabia.
To determine factors influencing final year medical undergraduate trainees at King Saud University in choosing a career in Obstetrics and Gynecology. In this cross sectional study, the undergraduate final year medical students and interns at King Saud University, Riyadh, Saudi Arabia were asked to complete a survey instrument designed to assess possible attracting and detracting factors. The survey was conducted from January 2010 to February 2010. Factors were analyzed in a univariable and multivariable analysis. The survey was distributed to 507 students. Completed questionnaires were returned by 330 participants (response rate 65%). Overall, 32 (9.7 %) of students listed Obstetrics and Gynecology in their top 3 choices. The rotation of students through Obstetrics and Gynecology was the most influential factor attracting 81.3% of the students who chose to take this course. Faculty interaction was a major reason for attracting students accounting for 71.9%, but resident interaction was less attractive where only 37.5% of students mentioned that they were affected positively by residents. Hands-on experience such as performing deliveries and other procedures were significant attracting factors. (p=0.006 and p=0.004). The findings in this study will hopefully aid in recruiting trainees to the specialty of Obstetrics and Gynecology in Saudi Arabia. Identifying the 5 major attracting factors from our study will allow our institute to integrate these factors in Obstetrics and Gynecology curriculum design, eventually increasing interest in postgraduate training in this specialty.


Understanding Vaccine Hesitancy Among Parents of Children With Autism Spectrum Disorder and Parents of Children With Non-Autism Developmental Delays.
Parents of children with autism spectrum disorder (ASD) may be at greater risk for developing antivaccine beliefs that lead to vaccine delays and/or refusals for their children. We investigated current parental vaccine hesitancy, parents' beliefs about causes of children's developmental delays, and children's vaccination histories among parents of children with ASD or non-ASD developmental delays. Data were analyzed from 89/511 parents (17.4%) who completed the Parent Attitudes About Childhood Vaccines questionnaire and the Revised Illness Perception Questionnaire; 46.1% had childhood vaccination records available. Overall, 21/89 (23.6%, 95% confidence interval [CI]: 15.0-34.0) of parents were vaccine hesitant (ASD n = 19/21 [90.5%], non-ASD n = 2/21 [9.5%]). Parents of children with ASD were significantly more likely to agree with "toxins in vaccines" as a cause of their child's developmental delays (28.4% vs 5.0%, P = .034). The odds of being vaccine hesitant were 11.9 times (95% CI 2.9-48.0) greater among parents who agreed versus disagreed that toxins in vaccines caused their children's developmental delays. Rates of prior vaccine receipt did not differ between hesitant and nonhesitant groups.


The effect of meniscal status on knee stability and function after anterior cruciate ligament reconstruction.
The purpose of this study was to examine the relationship of meniscal status at the time of anterior cruciate ligament (ACL) reconstruction with the ultimate function and stability of the knee joint. Seventy-one patients were studied prospectively following bone-patellar tendon-bone ACL reconstruction. Subjects were divided into six subgroups relative to the integrity (intact, partial meniscectomy, complete meniscectomy) of the two menisci. After a minimum of 2 years of follow-up (range 2-4.1 years), 56 subjects were available for subjective, objective, and radiographic assessment. Meniscal status at the time of ACL reconstruction proved to have no significant bearing on the ultimate stability of the knee. However, individuals who had undergone meniscal excision reported subjective complaints and activity limitations more commonly than those with intact menisci (p < 0.05). Radiographic changes also were more common in the meniscectomized subset.


A detailed phenotypic assessment of individuals affected by MFRP-related oculopathy.
To determine the spectrum of mutations and phenotypic variability within patients with mutations in membrane-type frizzled related protein gene (MFRP). Individuals were initially ascertained based on a phenotype similar to that previously published in association with MFRP mutations. Affected patients underwent a full ophthalmic examination (best-corrected visual acuity, slit-lamp examination, applanation tonometry, and fundoscopy), color fundus photography, optical coherence tomography, autofluorescence imaging, and electrophysiology. MFRP was identified by a genome-wide scan in the fourth-largest autozygous region in one consanguineous family. Sanger sequencing of all the exons and intron-exon boundaries of MFRP was undertaken in the affected individuals. Seven affected individuals from four families were identified as having mutations in MFRP. Patients from two families were homozygous for mutations already previously described (c.1143_1144 insC and c.492 delC), while those from the other two were compound heterozygous for mutations (c.201G>A and c.491_492 insT, and c.492 delC, and c.1622_1625 delTCTG), three of which were novel. There was considerable phenotypic variability within and among families. Autofluorescence imaging revealed the central macula to be relatively well preserved. Foveal cysts and optic nerve head drusen were present in two of the four families. Electrophysiology results showed rod-cone dystrophy with mild to moderate reduction in macular function in all affected members. We report three novel MFRP mutations and expand the phenotypic data available on patients with MFRP mutations.


Autologous platelet concentrates in extraction sockets for the prevention of osteoradionecrosis: a systematic review of controlled clinical trials.
This systematic review aimed to assess whether the use of autologous platelet concentrates immediately after tooth extraction would prevent ORN in patients treated with radiotherapy (RT) for head and neck cancer (HNC). MEDLINE, Embase, Ovid, Scopus, Web of Science, CENTRAL Cochrane, and OpenGrey databases were searched (up to, and including, June 2021) by two independent reviewers to identify studies, followed by further manual search. As inclusion and exclusion criteria for the studies, only controlled clinical trials (randomized or not) were considered. The risk of bias of each included study was assessed using the Cochrane Risk of Bias Tool. Of the 129 potentially eligible studies, only 2 were included, both randomized controlled clinical trials; however, one used platelet-rich plasma and another leukocyte- and platelet-rich fibrin. Overall, both autologous platelet concentrates had no effect on the outcome assessed. The use of autologous platelet concentrates seems not to be beneficial for ORN prevention following tooth extractions in HNC patients treated with RT; however, according to the available evidence, a reliable statement cannot be made.


Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson's disease model.
We have previously reported that cambinol (DDL-112), a known inhibitor of neutral sphingomyelinase-2 (nSMase2), suppressed extracellular vesicle (EV)/exosome production in vitro in a cell model and reduced tau seed propagation. The enzyme nSMase2 is involved in the production of exosomes carrying proteopathic seeds and could contribute to cell-to-cell transmission of pathological protein aggregates implicated in neurodegenerative diseases such as Parkinson's disease (PD). Here, we performed in vivo studies to determine if DDL-112 can reduce brain EV/exosome production and proteopathic alpha synuclein (αSyn) spread in a PD mouse model. The acute effects of single-dose treatment with DDL-112 on interleukin-1β-induced extracellular vesicle (EV) release in brain tissue of Thy1-αSyn PD model mice and chronic effects of 5 week DDL-112 treatment on behavioral/motor function and proteinase K-resistant αSyn aggregates in the PD model were determined. In the acute study, pre-treatment with DDL-112 reduced EV/exosome biogenesis and in the chronic study, treatment with DDL-112 was associated with a reduction in αSyn aggregates in the substantia nigra and improvement in motor function. Inhibition of nSMase2 thus offers a new approach to therapeutic development for neurodegenerative diseases with the potential to reduce the spread of disease-specific proteopathic proteins.


Use of a highly sensitive assay for cardiac troponin T and N-terminal pro-brain natriuretic peptide to diagnose acute rejection in pediatric cardiac transplant recipients.
Biomarkers have been proposed to augment or replace endomyocardial biopsy (EMB) to diagnose acute transplant rejection (AR). A new, highly sensitive assay for troponin T detects levels of cardiac troponin T (cTnT) 10- to 100-fold lower than standard assays but has not been investigated in transplant patients. N-terminal pro-brain natriuretic peptide (NT-proBNP) has not been evaluated in pediatric transplant patients. The purpose of this pilot study was to evaluate the association of cTnT and NT-proBNP with AR in pediatric cardiac transplant patients. Plasma was obtained at the time of EMB from pediatric patients ≥ 1 year old. N-terminal pro-brain natriuretic peptide was measured in fresh plasma at the time of biopsy, and cTnT was measured from frozen, stored samples using the highly sensitive assay for troponin T. Biomarker data were correlated with EMB results. Cellular AR was defined as an International Society for Heart and Lung Transplantation biopsy score of grade ≥ 2R. Fifty-three blood samples were obtained from 42 patients (mean age 11 years). Seven episodes of AR occurred in 5 patients. Biopsies with vs without AR were associated with higher cTnT (median [interquartile range {IQR}] 66 [45-139] vs 7 [2-13] pg/mL, P = .001) and NT-proBNP (median [IQR] 11,169 [280-23,317] vs 334 [160-650] pg/mL, P < .01). After successful treatment of AR in 5 patients, cTnT fell markedly (median [IQR] 53.5 [44.8-66.5] to 10.7 [1.5-16.4], P = .05). In this pilot study, we found marked elevation of cTnT and NT-proBNP among children with AR. Moreover, reduction in cTnT levels after treatment paralleled improvement in EMB results. If these findings are confirmed in larger prospective studies, monitoring with these biomarkers may obviate surveillance EMB.


Therapeutic role of eicosapentaenoic and arachidonic acid in benzo(a) pyrene-induced toxicity in HUVEC endothelial cells.
Endothelial cells are characterized by intense metabolic activity and control of homeostasis. Exposure to benzo(a)pyrene (BaP) plays an important role in the etiology of atherosclerosis. The study aimed to determine the effect of arachidonic (ARA), and eicosapentaenoic acid (EPA) on pro-inflammatory gene and protein levels in human umbilical vein endothelial cells (HUVEC) exposed to BaP. Cyclooxygenase-2 (COX-2), aryl hydrocarbon receptor (AHR), and glutathione S transferase Mu1 (GSTM1) proteins expression were analyzed by Western blot. Prostaglandin synthase 2 (PTGS2), AHR, GSTM1, phospholipase A2 (PLA2G4A), cytochrome P450 CYP1A1, intercellular adhesion molecule-1 (ICAM-1), endothelial nitric-oxide synthase (NOS3), and vascular adhesion molecule-1 gene expression (VCAM-1) was analyzed in Real time-qPCR. Phospholipase A2 activity was measured using the ELISA technique, and CYP1A1 activity was analyzed in luminescence assay. The highest amount of COX-2, the most increased activity of CYP1A1 and cPLA2, and overexpression of GSTM1, CYP1A1, ICAM-1, and VCAM-1 gene was observed in HUVEC cells treated with BaP. After co-treatment with BaP and ARA or EPA, an increase of GSTM1 level was observed. Incubation of endothelial cells with ARA or EPA and BaP resulted in lower CYP1A1 and cPLA2 activities and lower expression of VCAM-1 and ICAM-1 genes. Significant overexpression of AHR, GSTM1, CYP1A1, PTGS2, PLA2G4A, and NOS3 genes was noted in cells treated with EPA and BaP. Our data suggest a beneficial effect of EPA and ARA on endothelial function. Thus, it justifies further research on the participation of fatty acids in the regulation of physiological and pathological processes in endothelial cells.


In vivo distribution of 14C radiolabeled soman [3,3-dimethyl-2-butoxy)-methylphosphorylfluoride) in the central nervous system of the rat.
Radiolabeled 14C soman, a potent anticholinesterase, was administered to rats at a dose of 0.75 LD50 (17.3 micrograms/kg, i.m.). Prior to being quick frozen, the animals were held for 2 min, 32 min or 48 h after dosing. Analysis of autoradiographs taken from cryostat sections through the central nervous system (CNS) showed that at 2 and 32 min radiolabel was primarily distributed in the blood, the choroid plexus and the cerebrospinal fluid (CSF), with several brain nuclei showing small increases in labeling density. At 48 h there was marked accumulation of radiolabel in the caudate and accumbens nuclei compared to all other brain areas. The above results showed little similarity between cholinesterase localization and distribution of radiolabel.


Elucidation of the structure and characterization of the gene cluster of the O-antigen of Cronobacter sakazakii G2592, the reference strain of C. sakazakii O7 serotype.
The O-specific polysaccharide from the lipopolysaccharide of Cronobacter sakazakii G2592 was studied by sugar analysis along with 1D and 2D (1)H and (13)C NMR spectroscopy, and the following structure of the pentasaccharide repeating unit was established: [See figure in text]. This structure is unique among the known bacterial polysaccharide structures, which is in accord with classification of strain G2592 into a new C. sakazakii serotype, O7. It is in agreement with the O-antigen gene cluster of this strain, which was found between the housekeeping genes JUMPStart and gnd and characterized by sequencing and tentative assignment of the gene functions.


Late-onset myocardial infarction and autoimmune haemolytic anaemia in a COVID-19 patient without respiratory symptoms, concomitant with a paradoxical increase in inflammatory markers: a case report.
In December 2019, a new coronavirus (named severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) spread from China, causing a pandemic in a very short time. The main clinical presentation of SARS-CoV-2 infection (COVID-19, coronavirus disease-2019) is pneumonia, but several cardiovascular complications may also occur (e.g., acute coronary syndromes, pulmonary embolism, stroke, arrhythmias, heart failure and cardiogenic shock). Direct or indirect mechanisms induced by SARS-CoV-2 could be implicated in the pathogenesis of these events. We report herein the third case of COVID-19 autoimmune haemolytic anaemia (AIHA) reported so far, which occurredwithout any other possible explanations in a Caucasian patient. The patient also suffered from ST-elevation myocardial injury. Both complications occurred quite late after COVID-19 diagnosis and were probably precipitated by systemic inflammation, as indicated by a significant delayed increase in inflammatory markers, including interleukin-6 (IL-6).


Compliance with a new quality standard regarding administration of prophylactic antibiotics before cesarean section.
Administering prophylactic antibiotics before cesarean section (CS) decreases postpartum infections significantly. They should be administered within 60 min prior to CS. In 2014 the Israeli Ministry of Health introduced the administration of pre-operative antibiotic prophylaxis for CS as a quality criterion. This was immediately adopted by the Galilee Medical Center (GMC). This study aimed to examine the compliance to this quality standard in the GMC under 3 criteria: the type of antibiotics, timing of administration, and use of one dose only. Data of women who underwent CS from the day of introducing the new quality standard on January 1, 2014, to July 31, 2015, were retrospectively analyzed. The study included 1790 women who delivered by elective (24.4%) or emergency CS. In general, the medical staff's compliance to this quality standard was 90.9; 95.6% of the patients received the correct antibiotic, 94.6% had it within 65 min before surgery to 5 min after it, and 100% received it in less than 24 h. There was an increase in the overall compliance rate with time (logistic regression, p = .001). During the day shift, 60.4% of CS were emergency surgeries while during the on-call shift (evening and night) almost all (99%) of the CS were emergencies (p < .001, 2-sided). In morning shift's emergency CS, only 4.1% of the cases were not given prophylactic antibiotics as against 7.8% in the on-call shift (p = .005). Over a period of 18 months, the compliance to the new quality standard of administering prophylactic antibiotics before CS was 90.9%. It was particularly high in the subgroup of elective CS during the morning shift. This high compliance rate may be attributed to the introduction of clear guidelines and assignment of a specific team member, the anesthesiologist, to administer the medication.Key pointsCompliance rate to the guideline was 90.9%.Compliance was better in the morning shift.Compliance was better for elective cesarean section.Compliance was not affected by time.


Identified Transmission Dynamics of Middle East Respiratory Syndrome Coronavirus Infection During an Outbreak: Implications of an Overcrowded Emergency Department.
A total 130 cases of Middle East respiratory syndrome coronavirus were identified during a large hospital outbreak in Saudi Arabia; 87 patients and 43 healthcare workers. The majority (80%) of transmission was healthcare-acquired (HAI) infection, with 4 generations of HAI transmission. The emergency department was the main location of exposure.


Comprehensive sexuality education linked to sexual and reproductive health services reduces early and unintended pregnancies among in-school adolescent girls in Zambia.
Advancing the health of adolescents, particularly their sexual and reproductive health, including HIV prevention and care, is a development imperative. A critical part for improving their wellbeing and economic development is the social status accorded to adolescent girls and young women (AGYW). However, AGYW in many countries including Zambia, encounter health challenges that stem from gender inequalities, lack of empowerment, inaccurate knowledge on sexuality, and poor access to sexual and reproductive health (SRH) services and information. Addressing the knowledge gaps through comprehensive sexuality education (CSE) and improving access to SRH services and appropriate information, should reduce school attrition from early and unintended pregnancies (EUP) and enhance realization of their full potential. The aim was to reduce EUP and improve SRH outcomes among AGYW in Zambia through provision of CSE linked to receptive SRH services. A 3-Arm randomized control study collected cross-sectional data at baseline, midline and Endline. Schools where CSE was being routinely provided were randomized into a non-intervention arm (arm1), an intervention arm in which information on available SRH services was provided in schools by health workers to complement CSE, (arm 2), and arm 3 in which pupils receiving CSE were also encouraged or supported to access pre-sensitized, receptive SRH services. Following 3 years of intervention exposure (CSE-Health Facility linkages), findings showed a significant decline of in-school pregnancies amongst AGYW in both intervention arms, with arm two exhibiting a more significant decline, having recorded only 0.74% pregnancies at endline (p < 0.001), as well as arm 3, which recorded 1.34% pregnancies (p < 0.001). No significant decline was recorded in the CSE only control arm. Trends in decline of pregnancies started to show by midline, and persisted at endline (2020), and when difference in differences test was applied, the incident rate ratios (IRR) between the none and exposed arms were equally significant (p < 0.001). Linking provision of CSE with accessible SRH services that are receptive to needs of adolescents and young people reduces EUP, which provides the opportunity for higher retention in school for adolescent girls.


Protective and detrimental effects of kaempferol in rat H4IIE cells: implication of oxidative stress and apoptosis.
Flavonoids are ubiquitous substances in fruits and vegetables. Among them, the flavonol kaempferol contributes up to 30% of total dietary flavonoid intake. Flavonoids are assumed to exert beneficial effects on human health, e.g., anticancer properties. For this reason, they are used in food supplements at high doses. The aim of this project was to determine the effects of kaempferol on oxidative stress and apoptosis in H4IIE rat hepatoma cells over a broad concentration range. Kaempferol is rapidly taken up and glucuronidated by H4IIE cells. The results demonstrate that kaempferol protects against H2O2-induced cellular damage at concentrations which lead to cell death and DNA strand breaks in the absence of H2O2-mediated oxidative stress. Preincubation with 50 microM kaempferol exerts protection against the loss of cell viability induced by 500 microM H2O2 (2 h) while the same concentration of kaempferol reduces cell viability by 50% in the absence of H2O2 (24 h). Preincubation with 50 microM kaempferol ameliorates the strong DNA damage induced by 500 microM H2O2 while 50 microM kaempferol leads to a significant increase of DNA breakage in the absence of H2O2. Preincubation with 50 microM kaempferol reduces H2O2-mediated caspase-3 activity by 40% (4 h) while the same concentration of kaempferol leads to the formation of a DNA ladder in the absence of H2O2 (24 h). It is concluded that the intake of high dose kaempferol in food supplements may not be advisable because in our cellular model protective kaempferol concentrations can also induce DNA damage and apoptosis by themselves.


Polymorphisms in genes involved in folate metabolism as risk factors for oedematous severe childhood malnutrition: a hypothesis-generating study.
Severe childhood malnutrition (SCM) occurs as both oedematous and non-oedematous syndromes. The reasons why some children develop oedematous SCM (OSCM) have remained elusive but differences in clinical presentation among malnourished children from similar backgrounds suggests that there might be inter-individual variation in susceptibility to OSCM. To estimate the strength of the association between variants of three genes involved in folate/methyl group metabolism [methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and cystathionine beta-synthase (CBS)] and risk of OSCM. Patients previously admitted to the Tropical Metabolism Research Unit (TMRU) for treatment of either OSCM (cases, n = 74) or non-oedematous SCM (NOSCM, controls, n = 50) were recruited. Genotypes at four sites within the three genes (MTHFR C677T, MTHFR A1298C, MTR A2756G and CBS 844ins68) were determined using PCR-based assays. The MTHFR 677T [odds ratio (OR) 0.63, 95% CI 0.2-1.7] and MTR 2756G (OR 0.74, 95% CI 0.4-1.4) alleles were associated with moderate reduction in risk of OSCM whereas the CBS 844ins68 allele (OR 1.4, 0.7-2.4) was associated with an increased risk. None of these risks was significant at the 5% level. Genetic variation within folate/methyl group metabolic pathways might have a small but potentially important influence on risk of OSCM. Additional, larger data-sets will be required to test the specific hypotheses (about the putative effect size and direction of association) generated in this preliminary study. Such observations have the potential to improve our understanding of the pathogenesis of clinical heterogeneity in severe malnutrition.


Characterization of the interaction of the cervane alkaloid, imperialine, at muscarinic receptors in vitro.
The action of the cervane alkaloid, imperialine, has been assessed at M1, M2 and M3 receptors in functional assays and at M1, M2, M3 and putative M4 sites in binding studies. In functional studies, imperialine acted as a selective surmountable antagonist at M2 receptors in guinea-pig isolated atria and uterus (-log KB = 7.7 and 7.4, respectively), in comparison to M1 receptors in canine isolated saphenous vein (-log KB = 6.9) or M3 receptors in a range of guinea-pig isolated smooth muscles including ileum, trachea, fundus, seminal vesicle or oesophagus (-log KB = 6.6-6.8). In rat aorta, the -log KB value at the M3 receptor (5.9) was slightly, but significantly, lower. In competition radioligand binding studies, imperialine was also selective toward to M2 sites in rat myocardium (-log Ki = 7.2) with respect to M1 and M3 sites (rat cerebral cortex, rat submaxillary gland; -log Ki = 6.1 and 5.7, respectively). However, it did not significantly discriminate between rat cardiac M2 sites and putative M4 sites in rabbit lung (-log Ki = 6.9). Imperialine resembles the alkaloid himbacine in terms of its pharmacological profile at muscarinic receptor subtypes in that it acts as an M2 selective antagonist with respect to M1 or M3 sites. It may also provide a second, commercially available, antagonist with which to discriminate between M1 and M4 receptors.


CHOROIDAL BLOOD FLOW: Review and Potential Explanation for the Choroidal Venous Anatomy Including the Vortex Vein System.
To review control mechanisms for blood flow in the choroid, propose a system by which venous outflow is controlled by a Starling resistor, and propose an explanation for the choroidal venous architectural anatomy. The main blood flow control mechanisms were reviewed including autoregulation, neurovascular coupling, and myogenic regulation. Applicable blood flow control mechanisms in the brain, a high flow organ in a low compliance outer shell, were used to examine analogous processes that may be occurring in the choroid. There does not seem to be effective autoregulation in the choroid, although myogenic mechanisms may be present. There is a sophisticated neural innervation that provides partial control. Like the brain, the eye has a high pulsatile blood flow rate and is encased in a noncompliant casing. As part of modulating pulsatile pressure in the cranium, the brain uses venous storage and a Starling resistor effect to modulate venous outflow. An analogous function in the eye could be provided by the choroid, which contains fascicles of large veins that converge in vortices to drain out of the eye. This vortex area seems to be where the Starling resistor effect is possible. This mechanism would have important impact on theories of many ocular diseases including central serous chorioretinopathy and spaceflight-associated neuroocular syndrome. Control of blood flow is critical in the choroid, and this control seems to extend to the venous outflow system. Abnormalities in venous outflow may critically affect function in predictable pathogenic mechanisms.


Chronic cocaine administration to rats alters the distribution of cell types recorded in vitro within the dorsolateral septal nucleus.
We investigated persistent changes in single-neuron activity in the dorsolateral septal nucleus (DLSN) induced by chronic administration of cocaine. Intracellular recording techniques were utilized with an in vitro brain slice preparation to examine the effects of in vivo chronic cocaine administration, for 7 days or 14 days, on the distribution of electrophysiologically characterized DLSN cells. We have previously distinguished DLSN neurons into three major types (I, II, and III), based upon their action potential configuration and firing pattern. This study demonstrated that type III neurons were over-represented in brain slices obtained from rats treated chronically with cocaine in vivo for 14 days when compared with brain slices obtained from rats treated either with cocaine for only 7 days or with saline and never exposed to cocaine. These data provide further evidence that neurons undergo plastic changes following chronic cocaine administration.


A genetic variant of hypoxia-inducible factor-1alpha is associated with adverse outcomes in acute kidney injury.
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that mediates many cellular responses to tissue hypoxia, a common feature of acute kidney injury (AKI). Here we studied 241 patients with AKI and determined the relationship to adverse outcome of a non-synonymous polymorphism in the coding region of the HIF-1alpha gene where a C to T substitution occurs at position +85 in exon 12, a change known to enhance transactivation. The baseline characteristics of the patients were not different among genotype groups except for a significantly higher prevalence of shock and number of failed organs in T-allele carriers. A significant genotype-phenotype association was found for plasma levels of vascular endothelial growth factor-A but not angiopoietin-2, two downstream targets of HIF-1alpha. Compared to the CC genotype, T-allele carriers had significantly higher adjusted odds for dialysis requirement or in-hospital death; assisted mechanical ventilation or dialysis requirement; and the composite of assisted mechanical ventilation, dialysis requirement or in-hospital death. The trend for higher plasma angiopoietin-2 levels was associated with significantly higher adjusted odds for in-hospital death; dialysis requirement or in-hospital death; and the composite outcome of assisted mechanical ventilation, dialysis, or in-hospital death. Despite the limited cohort size, our study found this particular HIF-1alpha genetic variant to be associated with disease severity and adverse outcomes in AKI. Larger studies are needed to confirm these relationships.


Diethylstilbestrol and clear cell vaginal carcinoma. Reappraisal of the epidemiologic evidence.
The association between DES and the development of clear cell vaginal carcinoma may have several alternative explanations rather than a cause- and-effect relation. One important possibility is that susceptibility bias, arising from reasons for use of the drug in a problem pregnancy, is a prime source of the observed effect in the case-control studies. Rather than being a cause of clear cell vaginal carcinoma, exposure to DES would serve as a prognostic "marker" to identify women born of problem pregnancies that increased their risk for development of the disease. Since medical advances in prenatal and perinatal care allowed these problem pregnancies to be carried to the term delivery of a viable child, DES may have been associated with an increased occurrence of clear cell vaginal carcinoma--without causing the disease. Another alternative hypothesis is needed to account for the high rates of reported previous exposure to DES in the case subjects of the two case-control studies. These rates may have been elevated by some form of interviewer bias or recall bias. The relatively high incidence of clear cell vaginal carcinoma that would be expected from the results of these case-control studies has not been observed in cohort studies. No instances of clear cell vaginal carcinoma have thus far been found in suitably assembled cohorts of women exposed to DES in utero. The history of science contains abundant examples of fervently held beliefs about cause- and-effect relations that were later found to be erroneous. The existing evidence of a DES/vaginal cancer relation is currently too weak for the causal role of DES to be regarded as established. To get better evidence, the problems of biased comparison and biased data can be addressed in at least three ways. The first is to carry out an appropriately objective new case-control study, with suitably chosen control subjects; the second is to study the issue of susceptibility bias by getting additional information about the occurrence of problem pregnancies in the mothers of patients with clear cell vaginal carcinoma who were not exposed to DES; the third is to review past tissue specimens from previously diagnosed genital adenocarcinomas, searching for clear cell cancers that may have been unrecognized. Until the suspected biases are addressed and either confirmed or refuted, the relation between DES and clear cell vaginal carcinoma remains a statistical association that is unaccompanied by the quality of evidence required for scientific conclusions.


MAC-ELISA and ELISA inhibition methods for detection of antibodies after yellow fever vaccination.
The IgM antibody capture ELISA (MAC-ELISA) and ELISA inhibition methods for the detection of antibodies against dengue virus were modified to detect antibodies against yellow fever virus. Tests were carried out in 21 persons vaccinated with 17D and compared with the Plaque reduction neutralizing test. Of 17 naive subjects vaccinated, 16 (94%) seroconverted using the MAC-ELISA test and 14 (82%) seroconverted (or >/=fourfold titer increase) in the ELISA inhibition method. Cross-reactivity was evaluated by both tests and resulted in a high specificity to IgM antibodies against yellow fever, when all the samples from vaccinated individuals were negative by MAC-ELISA using dengue antigen. However, 10.7% of the positive dengue sera from the Santiago de Cuba epidemic cross-reacted by MAC-ELISA using yellow fever antigen. ELISA inhibition method showed high cross-reactivity when the 21 sera pairs were worked with yellow fever and dengue antigens. The MAC-ELISA and ELISA inhibition methods have become indispensable tools in our laboratory in order to maintain a surveillance system for dengue and dengue hemorrhagic fever. They are relatively rapid, simple, and they do not require sophisticated equipment. Both MAC-ELISA and ELISA inhibition methods for yellow fever could be useful for diagnosis, surveillance and yellow fever vaccine evaluation.


Microwave synthesis and evaluation of phenacylhomoserine lactones as anticancer compounds that minimally activate quorum sensing pathways in Pseudomonas aeruginosa.
The bacterial quorum sensing (QS) signal molecule 3-oxo-dodecanoyl-L-homoserine lactone (OdDHL) is produced by the opportunistic pathogen Pseudomonas aeruginosa and controls expression of virulence factors associated with life threatening infections in immune compromised individuals. OdDHL has also demonstrated anticancer activity, yet its ability to enhance pathogenicity of P. aeruginosa compromises further consideration as a potential anticancer agent. In search of acylhomoserine lactones that selectively inhibit cancer cell growth, a library of phenacylhomoserine lactone analogues has been prepared by microwave synthesis and evaluated for cancer growth inhibition and quorum sensing activation. Comparative SAR analysis demonstrates that both anticancer and QS signaling systems require long acyl side chains with a 3-oxo substitution for maximum activity. Compound 12b, 3-oxo-12-phenyldodecanoyl-L-homoserine lactone, was identified as a lead compound with strong cancer growth inhibitory activity that minimizes activation of QS signaling pathways in a P. aeruginosa reporter assay.


Deep genomic characterization highlights complexities and prognostic markers of pediatric acute myeloid leukemia.
Pediatric acute myeloid leukemia (AML) is an uncommon but aggressive hematological malignancy. The poor outcome is attributed to inadequate prognostic classification and limited treatment options. A thorough understanding on the genetic basis of pediatric AML is important for the development of effective approaches to improve outcomes. Here, by comprehensively profiling fusion genes as well as mutations and copy number changes of 141 myeloid-related genes in 147 pediatric AML patients with subsequent variant functional characterization, we unveil complex mutational patterns of biological relevance and disease mechanisms including MYC deregulation. Also, our findings highlight TP53 alterations as strong adverse prognostic markers in pediatric AML and suggest the core spindle checkpoint kinase BUB1B as a selective dependency in this aggressive subgroup. Collectively, our present study provides detailed genomic characterization revealing not only complexities and mechanistic insights into pediatric AML but also significant risk stratification and therapeutic strategies to tackle the disease.


Carbohydrate complexity and proportion of serum FSH isoforms reflect pituitary-ovarian activity in perimenopausal women and depot medroxyprogesterone acetate users.
FSH is synthesized and secreted in multiple glycosylation variants with different oligosaccharide structures; the endocrine milieu regulates the composition of FSH carbohydrate moiety. To characterize serum FSH isoforms according to their sialic acid content and oligosaccharide complexity in regularly menstruating women and in depot medroxyprogesterone acetate (DMPA) users during the menopausal transition. Subjects and methods Ten regularly menstruating perimenopausal women aged 45-52, with mid-follicular phase FSH levels < or =10 IU/l and 10 regularly menstruating women, aged 20-39, were included. Blood samples were collected on the ninth day of the menstrual cycle. Twenty DMPA users were divided into two groups (n = 10) according to age: DMPA(1), age range 20-39 and DMPA(2), age range 45-52. Blood samples were collected 90 +/- 5 days after the last injection of DMPA. Oestradiol (E(2)), inhibin B (Inh B), Pro-alphaC levels and the relative abundance of FSH isoforms on the basis of charge (preparative isoelectric focusing) and carbohydrate complexity (Concanavalin A chromatography) were determined. Decreased Inh B and moderately elevated E(2) levels were observed in perimenopausal women associated with an increase in FSH sialylation and a decrease in its oligosaccharide complexity. DMPA induced changes in the hormonal profile and FSH molecular microheterogeneity; the secreted hormone was more heterogeneous and its oligosaccharides were less complex under this condition. Serum FSH glycoforms with increased sialylation and decreased oligosaccharide complexity reflect the decline of the gonadal activity induced either by age or by the use of a DMPA as a contraceptive.


Artificial intelligence applications for pediatric oncology imaging.
Machine learning algorithms can help to improve the accuracy and efficiency of cancer diagnosis, selection of personalized therapies and prediction of long-term outcomes. Artificial intelligence (AI) describes a subset of machine learning that can identify patterns in data and take actions to reach pre-set goals without specific programming. Machine learning tools can help to identify high-risk populations, prescribe personalized screening tests and enrich patient populations that are most likely to benefit from advanced imaging tests. AI algorithms can also help to plan personalized therapies and predict the impact of genomic variations on the sensitivity of normal and tumor tissue to chemotherapy or radiation therapy. The two main bottlenecks for successful AI applications in pediatric oncology imaging to date are the needs for large data sets and appropriate computer and memory power. With appropriate data entry and processing power, deep convolutional neural networks (CNNs) can process large amounts of imaging data, clinical data and medical literature in very short periods of time and thereby accelerate literature reviews, correct diagnoses and personalized treatments. This article provides a focused review of emerging AI applications that are relevant for the pediatric oncology imaging community.


[An effect of cabergoline on alcohol consumption and DRD2 expression in the brain of rats with chronic alcohol intoxication].
Cabergoline is a high selective agonist of dopamine D2 receptors (D2R). The activation of D2R plays an important role in the regulation of dopamine transmission, the imbalance of which is thought to underlie the development of alcohol motivation. To examine this possibility, cabergoline effects on alcohol consumption and brain DRD2 expression in rats with chronic alcohol intoxication were studied. Male Wister rats were studied using the following methods: modelling of chronic alcohol intoxication, testing in «10% alcohol vs water» choice regimen, quantitative RT-PCR. Systemic administration of 0.5 mg/kg of cabergoline significantly decreases alcohol intake in alcohol-preferring rats. At the same time, cabergoline elevates the DRD2 expression in the midbrain and striatum of high-alcohol-preferring rats but not in intact (alcohol-naïve) animals. The involvement of cabergoline in the DRD2 expression may lead to the decrease in alcohol motivation. These findings indicate that cabergoline needs further investigations as a new potential medication for alcohol use disorder.


[Protective Effects of Akkermansia muciniphila and Amuc_1100 Protein on Rats on High-Fat Diet Combined with Streptozotocin Injection].
To explore the protective effects of live or pasteurized Akkermansia muciniphila and Amuc_1100 protein on a rat model of diabetes mellitus induced by high-fat diet (HFD) combined with streptozotocin (STZ). A total of 96 Sprague-Dawley (SD) rats were randomly assigned to 8 groups, including 6 experimental groups and 2 control groups, with 12 rats in each group. HFD combined with STZ injection was given to the rats to create a simulated model of the progression of diabetes mellitus type 2. In addition, the rats were treated with different doses of live or pasteurized Akkermansia muciniphila or Amuc_1100 protein by way of gavage for 8 weeks simultaneously. Plasma samples were collected to determine the level of parameters related to lipid and glucose metabolism, and inflammation mediators. Colon tissue specimens were collected for HE staining. Stool samples of the rats were collected for 16S rRNA gene sequencing. Compared with the HFD control group, rats in the group treated with Akkermansia muciniphila exhibited significantly lower body mass gain ( P<0.01) and lower plasma TNF-α level ( P<0.05). Administration of Akkermansia muciniphila or Amuc_1100 protein increased the number of goblet cells and mucin secretion. The β diversity analysis of the samples showed no overall difference in the intervention groups. Oral administration of Akkermansia muciniphila can effectively ameliorate HFD-induced metabolic disorders, including body mass gain and systemic inflammation. Akkermansia muciniphila and Amuc_1100, to a certain degree, improved the gut barrier function. After eight weeks of intervention, there was no significant impact on the structure of the gut microbiota.


Reliability of the McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey among black and white women.
Coronary heart disease (CHD) mortality rates are higher among women, particularly black, than men. Women's mortality rates may reflect difficulty in recognizing CHD prodromal symptoms (PS) but reliable screening instruments for women are scarce. The McSweeney Acute and Prodromal Myocardial Infarction Symptom Survey (MAPMISS) captures women's PS presentation, but has limited testing among black women. To assess the test-retest reliability of the MAPMISS PS section for black and white women. The sample was recruited from women enrolled in a longitudinal study examining the predictive validity of the MAPMISS. The MAPMISS was re-administered to 42 women (22 white, 20 black) 3-5 days after baseline assessment. Women endorsed an average of 7.5 PS (SD 4.8; range 0-20) initially and 7.6 (SD 4.7; range 0-20) at retest. Over half of the women (54.8%) of both races endorsed the same number of PS at test and retest; for 69%, the number endorsed at both testings differed by no more than one. Percentage agreement and kappa statistics on the number ofPS endorsed were excellent overall and by race. PS test and retest scores, reflecting PS intensity and frequency, were highly correlated overall (r = 0.92, p < 0.001) and separately for white (r = 0.93, p < 0.001) and black women (r = 0.91,p < 0.001). Racial differences were insignificant. Findings indicate (i) the MAPMISS PS score has excellent test-retest reliability (r = 0.92) when administered to women without a history of CHD, and (ii) test-retest reliability is as strong for black (r = 0.91) as for white women (r = 0.93).


Impact of genetic testing on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia (GenTLe-FH): a randomised waiting list controlled open-label study protocol.
Familial hypercholesterolemia (FH) is an autosomal-dominant inherited genetic disease. High-throughput sequencing quickly and comprehensively detects causative variants of FH-related genes (LDLR, PCSK9, APOB and LDLRAP1). Although the presence of causative variants in FH-related genes correlates with future cardiovascular events, it remains unclear whether detection of causative gene mutation and disclosure of its associated cardiovascular risk affects outcomes in patients with FH. Therefore, this study intends to evaluate the efficacy of counselling future cardiovascular risk based on genetic testing in addition to standard patients' education programme in patients with FH. A randomised, waiting-list controlled, open-label, single-centre trial will be conducted. We will recruit patients with clinically diagnosed FH without previous history of coronary heart disease from March 2018 to December 2019, and we plan to follow up participants until March 2021. For the intervention group, we will perform genetic counselling and will inform an estimated future cardiovascular risk based on individuals' genetic testing results. The primary endpoint of this study is the plasma low-density lipoprotein cholesterol level at 24 weeks after randomisation. The secondary endpoints assessed at 24 and 48 weeks are as follows: blood test results; smoking status; changes of lipid-lowering agents' regimen and Patients Satisfaction Questionnaire Short Form scores among the four groups divided by the presence of genetic counselling and genetic status of FH. This study will be conducted in compliance with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects and all other applicable laws and guidelines in Japan. This study protocol was approved by the IRB at Kanazawa University. We will disseminate the final results at international conferences and in a peer-reviewed journal. UMIN000029375.


A randomized, double-blind, placebo-controlled phase 2 study of α4β2 agonist ABT-894 in adults with ADHD.
Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel α4β2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners' Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of α4β2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted.


Delivery of Anti-IFNAR1 shRNA to Hepatic Cells Decreases IFNAR1 Gene Expression and Improves Adenoviral Transduction and Transgene Expression.
Chronic liver injury leads to advanced fibrosis, cirrhosis, and hepatocellular carcinoma. Genetical cell treatment related to the use of adenovirus (Ads) has proven to be beneficial and efficient in the recovery of hepatic diseases. Nevertheless, they are highly immunogenic and trigger an immune response where interferons type 1 (IFN-I) play a very important role. Three shRNAs against the Interferon-1 receptor (IFNAR1) were designed and cloned in pENTR/U6 plasmid and amplified in DH5α cells. Huh7 cells were transfected with these plasmids in the presence or absence of 1 × 109 viral particles/ml of adenovirus containing the green fluorescent protein gene used as a reporter. Transfection with the shRNA plasmids partially inhibited the IFNAR1 expression. This inhibition substantially decreased antiviral response, demonstrated by the decrease of IFNAR1, IFN-α, and TNF-α gene expression, and the decrease at protein levels of IFNAR1, Protein kinase RNA-activated (PKR), and phosphorylated STAT1, allowing higher adenoviral transduction and transgene expression. Interestingly it was seen shRNA inhibited macrophage activation. These results suggest that the inhibition of the IFN-I pathway could be a strategy to minimize the immune response against Adenoviral vectors allowing higher Adenovirus transduction extending the transgene expression.


Isoenzyme variation in schizonts of Plasmodium vivax from Burma.
Fifteen isolates of blood containing Plasmodium vivax were collected from hospital in-patients in Rangoon and the schizonts were harvested for starch gel electrophoresis of the following parasite isoenzymes--glucose phosphate isomerase (GPI) (EC.126.96.36.199), NADP-dependent glutamate dehydrogenase (GDH) (EC.220.127.116.11), lactate dehydrogenase (LDH) (EC.18.104.22.168) and 6-phosphogluconate dehydrogenase (6PGD) (EC.220.127.116.11). Variation was found only in GPI. The other three isoenzymes appeared to be invariant in all the isolates. Forms of GPI were recorded in two isolates of P. vivax which differed from those reported for P. falciparum; these new forms were designated GPI-4 and GPI-5.


Laparoscopic microwave ablation and enucleation of small renal masses: preliminary experience.
Advancements in imaging and laparoscopy have led to the expansion of minimally invasive techniques in the ablation of small renal masses (SRMs). We report the results of a study aimed at assessing the efficacy of thermoablative microwave (MW) effects on SRMs and the haemostatic as well as necrotic MW effects on the parenchyma surrounding the neoplasm. From November 2008 to October 2010, 10 patients with SRMs underwent laparoscopy-guided Tru-Cut biopsy, MW tumour ablation, and enucleation. Mean age was 66 yr (range: 46-84 yr). Mean renal tumour diameter was 2.75 cm (range: 1.3-4.2 cm). MW antennas were applied one to three times depending on tumour volume, location, and shape. After MW thermoablation, laparoscopic enucleation was performed to evaluate the histopathologic and haemostatic effects of MW. The mean MW antenna application time was 14.1 min (range: 4-30 min). Enucleation did not require renal pedicle clamping in any of the cases because no significant bleeding took place. Preablation pathology revealed clear cell renal carcinoma of Fuhrman grade I-II in all cases. Postablation pathology showed extensive coagulative necrosis without skipped tumour areas. No intra- or postoperative complications were reported. Histopathologic effects on SRMs provide consistent proof of principle for future studies.


Ricinus communis agglutinin I reacting and non-reacting butyrylcholinesterase in human cerebrospinal fluid.
Differences in glycosylation of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in human brain, plasma and cerebrospinal fluid (CSF) have been investigated by means of their interaction with agarose-immobilized lectins. Most of the AChE in brain and CSF was associated to concanavalin A (Con A), Lens culinaris (LCA) and Triticum vulgaris (WGA) agglutinins, but little activity was adsorbed to Ricinus communis agglutinin I (RCAI). Brain, plasma and CSF BuChE was almost fully bound to Con A, LCA and WGA-agarose. Brain BuChE was unable to react with RCA (RCA-BuChE), the plasma enzyme was completely bound to the lectin (RCA+BuChE) and BuChE from CSF of normal children was partially fixed to RCA (RCA +/- BuChE). BuChE in CSF of children with meningitis fully reacts with the lectin. The data suggest that the proportion of RCA+BuChE in CSF of children with meningitis is increased, this enzyme probably coming from plasma.


Preparation of Tyr-C-peptide from genetically altered human insulin precursor.
C-peptide radioimmunoassay (C-peptide RIA) is widely used in determination of pancreatic B-cell secretion activity. 125I labeled Tyr-C-peptide is indispensable in C-peptide RIA kit. Herein we discuss a way of obtaining recombinant Tyr-C-peptide. Arg32Tyr human pro-insulin mutant (R32Y-proinsulin) gene was constructed by site-directed mutagenesis and overexpressed in Escherichia coli. Purified R32Y-proinsulin was converted to insulin and Tyr-C-peptide by trypsin and carboxypeptidase B codigestion. Tyr-C-peptide was isolated through reverse-phase HPLC (RP-HPLC) and identified by C-peptide RIA and amino acid analysis.


Molecular tagging of biocontrol fungus Trichoderma asperellum and its colonization in soil.
To conduct molecular tagging of the biocontrol fungus Trichoderma asperellum strain T4 and elucidate its colonization patterns in soil. We constructed an expression vector harbouring a hygromycin B-resistant gene (hph) and an efficient green fluorescent protein (egfp) gene. By applying Agrobacterium AGL-1-mediated genetic transformation technology, we conducted molecular tagging of T. asperellum and monitored the colonization dynamics of T. asperellum in soil. The results of tracking five independent transformants of T. asperellum indicated that its expansion rates ranged from 4·7 to 6·8 cm week-1 . After inoculation in soil, the quantities of T. asperellum could be maintained at over 10 × 104 CFU per gram soil in the first year. In the third year after inoculation, the quantities of T. asperellum in soil were still higher than 1 × 103 CFU per gram soil. In addition, molecularly tagged T. asperellum in soil in the second year (i.e. 12 months) after inoculation could still reach the biocontrol effect on cucumber Rhizoctonia rot by more than 74%. Trichoderma asperellum strain T4 is capable of effectively colonizing in soil and surviving for more than 1 year. This study has provided the scientific basis for applying T. asperellum as the biocontrol fungus for prevention and control of plant diseases.


A comparison between cyclosporin A and methylprednisolone plus azathioprine on bronchial healing following canine lung autotransplantation.
The effects of two low-dose immunosuppressive therapies upon the healing of the bronchial anastomosis and skin wounds following lung autotransplantation were evaluated. Autotransplantation was performed in three groups of dogs: Group 1 (nine dogs) received no immunosuppression, Group 2 (seven dogs) received postoperative immunosuppression with methylprednisolone (2 mg/kg) and azathioprine (1.5 mg/kg), and Group 3 (four dogs) received postoperative immunosuppression with cyclosporin A (20 mg/kg/day). Skin incisions 7 cm in length were made in the dorsal region of each dog. Dogs were put to death 23 days postoperatively, and the breaking strength of the bronchial anastomoses and skin wounds was evaluated with the Instron Universal Testing Machine, with a cross-head speed of 0.5 cm/min. Bronchial breaking strengths were similar in Groups 1 and 3 and significantly higher than in Group 2 (p less than 0.001). Skin breaking strengths were similar in Groups 1 and 3 and significantly higher than in Group 2 (p less than 0.001). Scanning electron microscopic (SEM) studies of both skin and bronchial wounds showed normal formation of collagen bundles in Groups 1 and 3 but a disorganized pattern in Group 2. Our results suggest that low-dose immunosuppression with methylprednisolone and azathioprine significantly affects wound healing and breaking strength of both bronchial anastomoses and healed skin incisions following canine lung autotransplantation. Immunosuppression with cyclosporin A had no adverse effect on either bronchial or skin healing.


Interactions between H2O2 and dissolved organic matter during granular activated carbon-based residual H2O2 quenching from the upstream UV/H2O2 process.
Granular activated carbon (GAC) filtration can be employed to synchronously quench residual H2O2 from the upstream UV/H2O2 process and further degrade dissolved organic matter (DOM). In this study, rapid small-scale column tests (RSSCTs) were performed to clarify the mechanisms underlying the interactions between H2O2 and DOM during the GAC-based H2O2 quenching process. It was observed that GAC can catalytically decompose H2O2, with a long-lasting high efficiency (>80% for approximately 50,000 empty-bed volumes). DOM inhibited GAC-based H2O2 quenching via a pore-blocking effect, especially at high concentrations (10 mg/L), with the adsorbed DOM molecules being oxidized by the continuously generated ·OH; this further deteriorated the H2O2 quenching efficiency. In batch experiments, H2O2 could enhance DOM adsorption by GAC; however, in RSSCTs, it deteriorated DOM removal. This observation could be attributed to the different ·OH exposure in these two systems. It was also observed that aging with H2O2 and DOM altered the morphology, specific surface area, pore volume, and the surface functional groups of GAC, owing to the oxidation effect of H2O2 and ·OH on the GAC surface as well as the effect of DOM. Additionally, the changes in the content of persistent free radicals in the GAC samples were insignificant following different aging processes. This work contributes to enhancing understanding regarding the UV/H2O2-GAC filtration scheme, and promoting the application in drinking water treatment.


Assessing safety concerns of interstitial lung disease associated with antibody-drug conjugates: a real-world pharmacovigilance evaluation of the FDA adverse event reporting system.
Antibody-drug conjugates have revolutionized cancer therapy due to their selectivity and efficacy. However, concerns have been raised regarding the potential effects of trastuzumab deruxtecan in interstitial lung diseases. This study aimed to investigate the safety signals and time to onset of antibody-drug conjugates induced interstitial lung disease. We utilized the FDA Adverse Event Reporting System database (2004-2022) to identify interstitial lung disease safety signals in 13 FDA-approved antibody-drug conjugates. Disproportionality analysis was conducted to estimate the reporting odds ratios for interstitial lung disease. Seven antibody-drug conjugates exhibited safety signals of interstitial lung disease: trastuzumab deruxtecan [reporting odds ratio, ROR (95% confidence intervals, CI) = 64.15 (57.07-72.10)], enfortumab vedotin [ROR (95% CI) = 5.24 (3.25-8.43)], trastuzumab emtansine [ROR (95% CI) = 3.62 (2.90-4.53)], brentuximab vedotin [ROR (95% CI) = 3.22 (2.49-4.17)], polatuzumab vedotin [ROR (95% CI) = 2.56 (1.59-4.12)], gemtuzumab ozogamicin [ROR (95% CI) = 2.53 (1.70-3.78)], and inotuzumab ozogamicin [ROR (95% CI) = 2.33 (1.21-4.49)]. Five antibody-drug conjugates with limited reports were excluded from further analysis: belantamab mafodotin, loncastuximab tesirine, mirvetuximab sorafenib, tisotumab vedotin, and moxetumomab pasudotox. Japan and the United States were the primary reporting countries. This real-world study highlights high safety signals of interstitial lung disease associated with antibody-drug conjugates. Clinicians should be aware of these safety concerns and risk factors and implement early identification measures for their patients. Future research should prioritize comprehensively exploring the relationship between antibody-drug conjugates and lung diseases.


Comparison between Sequential Organ Failure Assessment score (SOFA) and Cardiac Surgery Score (CASUS) for mortality prediction after cardiac surgery.
Our purpose was to evaluate and compare the accuracy of the "Sequential Organ Failure Assessment" score (SOFA) and the "Cardiac Surgery Score" (CASUS) for the prediction of mortality after cardiac surgery. Between January 1, 2007 and December 31, 2008 we prospectively included all consecutive adult patients admitted to our intensive care unit (ICU) after cardiac surgery. Both scoring systems were calculated daily from the 1st day in the ICU (day of operation) until the 7th ICU day. We evaluated the ICU mortality prediction of both models using calibration and discrimination statistics. 2801 patients (29.6% females) were included. Mean age was 66.9 ± 10.7 years. Intensive care unit mortality was 5.2%. The calibration of the "Sequential Organ Failure Assessment Score" and "Cardiac Surgery Score" was reliable for all days (p ≥ 0.05). CASUS was more accurate in predicting survival and mortality compared to SOFA for all days, as evidenced by the larger areas under the Receiver Operating Characteristic curves. Both CASUS and SOFA are reliable mortality prediction tools after cardiac surgery. However, CASUS was more accurate in predicting the individual patient's risk of mortality. Thus, use of the CASUS in cardiac surgery intensive care units is recommended.


Prophylactic effects of sporoderm-removed Ganoderma lucidum spores in a rat model of streptozotocin-induced sporadic Alzheimer's disease.
Ganoderma lucidum (G. lucidum, Lingzhi), also known as "immortality mushroom" has been broadly used to improve health and longevity for thousands of years in Asia. G. lucidum and its spores have been used to promote health, based on its broad pharmacological and therapeutic activity. This species is recorded in Chinese traditional formula as a nootropic and has been suggested to improve cognitive dysfunction in Alzheimer's disease. However, little is known about the nootropic effects and molecular mechanism of action of G. lucidum spores. The present study investigated the protective effects of sporoderm-deficient Ganoderma lucidum spores (RGLS) against learning and memory impairments and its mechanism of action. In the Morris water maze, the effects of RGLS on learning and memory impairments were evaluated in a rat model of sporadic Alzheimer's disease that was induced by an intracerebroventricular injection of streptozotocin (STZ). Changes in amyloid β (Aβ) expression, Tau expression and phosphorylation, brain-derived neurotrophic factor (BDNF), and the BDNF receptor tropomyosin-related kinase B (TrkB) in the hippocampus were evaluated by Western blot. Treatment with RGLS (360 and 720 mg/kg) significantly enhanced memory in the rat model of STZ-induced sporadic Alzheimer's disease and reversed the STZ-induced increases in Aβ expression and Tau protein expression and phosphorylation at Ser199, Ser202, and Ser396. The STZ-induced decreases in neurotrophic factors, including BDNF, TrkB and TrkB phosphorylation at Tyr816, were reversed by treatment with RGLS. These findings indicate that RGLS prevented learning and memory impairments in the present rat model of STZ-induced sporadic Alzheimer's disease, and these effects depended on a decrease in Aβ expression and Tau hyperphosphorylation and the modulation of BDNF-TrkB signaling in the hippocampus.


The procoagulant factor of leukaemic promyelocytes: demonstration of immunologic cross reactivity with human brain tissue factor.
A procoagulant activity was found in the immature cells from patients with acute promyelocytic leukaemia. It was demonstrated that this activity was related to tissue factor. The protein component of tissue factor from brain extract was purified by Nemerson's technique and injected into rabbits to obtain anti-TF antibodies. Similar antibodies were produced against the promyelocyte extract. The anti-brain tissue factor antibodies neutralized the tissue factor activity of promyelocyte extract, and antibodies against immature cells were able to neutralize the tissue factor activity of human brain extract. In immunoprecipitation studies a reaction of partial identity appeared between one component of promyelocyte extract and one component of brain tissue factor. The data demonstrated that the promyelocyte procoagulant is antigenically related to brain tissue factor.


Hooking Together Sigmoidal Monomers into Supramolecular Polymers.
Supramolecular polymers show great potential in the development of new materials because of their inherent recyclability and their self-healing and stimuli-responsive properties. Supramolecular conductive polymers are generally obtained by the assembly of individual aromatic molecules into columnar arrays that provide an optimal channel for electronic transport. A new approach is reported to prepare supramolecular polymers by hooking together sigmoidal monomers into 1D arrays of π-stacked anthracene and acridine units, which gives rise to micrometer-sized fibrils that show pseudoconductivities in line with other conducting materials. This approach paves the way for the design of new supramolecular polymers constituted by acene derivatives with enhanced excitonic and electronic transporting properties.


MHC class I chain-related gene a alleles distinguish malnutrition-modulated diabetes, insulin-dependent diabetes, and non-insulin- dependent diabetes mellitus patients from eastern India.
Insulin-dependent diabetes mellitus (IDDM) is a polygenic disorder with an autoimmune basis for disease development. In addition to HLA, a second susceptibility locus for IDDM has been identified to lie in the major histocompatibility class III region. MIC-A is located in the MHC class III region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MIC-A gene identifies trinucleotide repeat (GCT) microsatellite polymorphism in exon 5. Five alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional nucleotide insertion (GGCT) are identified. The alleles are A4, A5, A5.1, A6, and A9. The aim of our study was to find the association of MIC-A alleles with IDDM, malnutrition-modulated diabetes mellitus (MMDM), and non-insulin-dependent diabetes mellitus (NIDDM) patients. IDDM (n = 52), MMDM (n = 41), NIDDM (n = 212), and healthy controls (n = 73) from Cuttack, in eastern India, were studied. Of the 212 NIDDM patients analyzed, 96 of them were found to be positive for either GAD65 or IA-2 antibodies. Autoantibodies to GAD65 and IA-2 were measured by radioligand binding assay using (35)S-labeled recombinant human GAD65 and IA-2 in an in vitro transcription/translation system. Autoantibody-positive NIDDM patients (n = 96) and adult healthy controls for NIDDM (n = 113) were also compared. These autoantibody-positive NIDDM patients are considered as slow-onset IDDM or latent autoimmune diabetes in adults (LADA) patients. The samples were analyzed for MIC-A by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. The results of the MIC-A typing are: allele 9 of MIC-A is positively associated (OR 3.62; P < 0.001), and allele 4 is negatively associated (OR 0.31; P < 0.05) with MMDM patients compared to controls. Allele 5 is positively associated with IDDM (OR 2.64; P < 0.05) when compared to controls. Allele 5.1 is positively associated in the autoantibody-positive NIDDM patients compared to adult controls. Our findings of a significant increase of allele A9 in MMDM patients compared to healthy controls suggest that MMDM is immunogenetically different from IDDM in eastern India. MIC-A is important in the pathogenesis of MMDM patients from Cuttack. MIC-A alleles distinguish acute-onset IDDM from slow-onset IDDM, indicating that this molecule may be important for delaying the onset of IDDM with the result that these patients are diagnosed clinically as NIDDM.


Humoral response to SARS-CoV-2 vaccination promises to improve the catastrophic prognosis of hemodialysis patients as a result of COVID-19: the COViNEPH Project.
Introduction: There is an urgent need to check the efficacy of SARS-CoV-2 vaccination among hemodialysis patients who are known to have large abnormalities of acquired immunity and a catastrophic risk of death from COVID-19. Objectives: In this cross-sectional study, we aimed to assess the humoral response following vaccination with the BNT162b2 (BioNTech / Pfizer Comirnaty) vaccine. Patients and methods: We analyzed the titer magnitude of the IgG antibodies directed against SARS-CoV-2 spike antigen 14 to 21 days after the second dose of the BNT162b2 vaccine in a group of hemodialysis patients who have not been confirmed with SARS-CoV-2 infection yet, compared with HD patients with a history of COVID-19. A total of 126 hemodialysis patients were stratified based on evidence of a previous infection with SARS-CoV-2 confirmed by the detection of viral RNA or nucleocapsid-specific IgG antibodies. Results: S-antigen immune response with a median (interquartile range) antibody titer of 366 (193–691) AU/ml was seen in 87 of 91 infection-naïve hemodialysis patients (95.6%), and in 68 (74.7%), a strong humoral response was observed with an anti-S antibodies titer greater than 200 AU/ml. Older patients were less likely to develop a response to S-antibodies (P <0.001). The median (interquartile range) S-antigen antibody titer in 35 previously infected hemodialysis patients was over 12-fold higher than in infection-naïve hemodialysis patients: 4620 (1240–7820) AU/ml (P <0.001). There were no significant differences in S-antibody titer between symptomatic and asymptomatic previously infected hemodialysis patients. Conclusions: Our study demonstrated that the majority of hemodialysis patients achieved a high immunization rate after vaccination with BNT162b2. Whether this translates into protecting this population from COVID-19 requires further research.


The clinical implications of brushite calculi.
The clinical history of 30 patients with a total of 46 proved brushite urinary calculi was reviewed. The patients were active metabolically with 87% having a history of multiple calculi. Of the brushite stones 61% appeared hyperdense on x-ray but they had no consistent shape. Of the patients who were metabolically evaluated 82% had treatable abnormalities. Treatment with percutaneous nephrostolithotomy or ureteroscopy and ureteral lithotripsy was 92% successful in rendering the patient stone-free, whereas, extracorporeal shock wave lithotripsy monotherapy resulted in a stone-free rate of only 11%. Brushite stone patients require aggressive treatment, full metabolic evaluation and close clinical followup.


Lipase immobilization on a novel class of Zr-MOF/electrospun nanofibrous polymers: Biochemical characterization and efficient biodiesel production.
In this study, due to the favorable properties of MOF compounds and fibrous materials, new nanostructures of Zr-MOF/PVP nanofibrous composites were synthesized by electrospinning procedure. The related features of these samples were characterized by relevant analyzes, including SEM, BET surface area analysis, XRD, and FTIR spectroscopy. The final product showed significant properties such as small particle size distribution, large surface area, and high crystallinity. This strategy for producing these nanostructures could lead to new compounds as novel alternative materials for biological applications. Lipase MG10 was successfully immobilized on the mentioned nanofibrous composites and biochemically characterized. The lipase activity of free and immobilized lipases was considered by measuring the absorbance of pNPP (500 μM in 40 mM Tris/HCl buffer, pH 7.8, and 0.01% Triton X100) at 37 °C for 30 min. Different concentrations of glutaraldehyde, different crosslinking times, different times of immobilization, different enzyme loading, and different pH values have been optimized. Results showed that the optimized immobilization condition was achieved in 2.5% glutaraldehyde, after 2 h of crosslinking time, after 6 h immobilization time, using 180 mg protein/g support at pH 9.0. The immobilized enzyme was also totally stable after 180 min incubation at 60 °C. The free enzyme showed the maximum activity at pH 9.0, but the optimal pH of the immobilized lipase was shifted about 1.5 pH units to the alkaline area. The immobilized lipase showed about 2.7 folds (78%) higher stability than the free enzyme at 50 °C. Some divalent metal ions, including Cu2+ (22%), Co2+ (37%), Mg2+ (12%), Hg2+ (11%), and Mn2+ (17%) enhanced the enzyme activity of immobilized enzyme. The maximum biodiesel production (27%) from R. communis oil was obtained after 18 h of incubation by lipase MG10. The immobilized lipase displayed high potency in biodiesel production, about 83% after 12 h of incubation. These results indicated the high potency of Zr-MOF/PVP nanofibrous composites for efficient lipase immobilization.


Effective uptake of decontaminating agent (citric acid) from aqueous solution by mesoporous and microporous materials: an adsorption process.
The presence of citric acid in decontamination waste can cause complexation of the radioactive cations resulting in interferences in their removal by various treatment processes such as chemical precipitation, ion-exchange, etc., which are employed for the removal of radioactivity and may cause potential danger to the environment. Mesoporous Al-MCM-41 (Si/Al=30, 51, 72 and 97) and Si-MCM-41 molecular sieves were synthesized hydrothermally and characterized by XRD, BET (surface area) and FT-IR to evaluate the removal of citric acid through an adsorption process. Adsorption of citric acid over Al-MCM-41 shows the applicability of Freundlich and Langmuir isotherm and follows first order kinetics. The effects of contact time, concentration of citric acid, adsorbents (various Si/Al ratios of Al-MCM-41, Si-MCM-41, Hbeta zeolite and commercial carbon) and pH have been investigated. It has been found that the amount of citric acid adsorbed per unit gram of catalyst followed the order Al-MCM-41 (Si/Al=30)>Al-MCM-41 (Si/Al=51)>activated charcoal>Al-MCM-41 (Si/Al=72)>Al-MCM-41 (Si/Al=97)>Si-MCM-41>Hbeta zeolite.


Uncertain futures and unsolicited findings in pediatric genomic sequencing: guidelines for return of results in cases of developmental delay.
Massively parallel sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), may reveal unsolicited findings (UFs) unrelated to the diagnostic aim. Such techniques are frequently used for diagnostic purposes in pediatric cases of developmental delay (DD). Yet policy guidelines for informed consent and return of UFs are not well equipped to address specific moral challenges that may arise in these children's situations. In previous empirical studies conducted by our research group, we found that it is sometimes uncertain how children with a DD will develop and whether they could come to possess capacities for autonomous decision-making in the future. Parents sometimes felt this brought them into a Catch-22 like situation when confronted with choices about UFs before undergoing WES in trio-analysis (both the parents' and child's DNA are sequenced). An important reason for choosing to consent to WES was to gain more insight into how their child might develop. However, to make responsible choices about receiving or declining knowledge of UFs, some idea of their child's future development of autonomous capacities is needed. This undesirable Catch-22 situation was created by the specific policy configuration in which parents were required to make choices about UFs before being sequencing (trio-analysis). We argue that this finding is relevant for reconfiguring current policies for return of UFs for WES/WGS and propose guidelines that encompass two features. First, the informed consent process ought to be staged. Second, differing guidelines are required for withholding/disclosing a UF in cases of DD appropriate to the level of confidence there is about the child's future developmental of autonomous capacities. When combined with a dynamic consent procedure, these two features of our guidelines could help overcome significant moral challenges that present themselves in the situations of children undergoing genomic sequencing for clarifying a DD.


Remodeling of immunological biomarkers in patients with chronic hepatitis C treated with direct-acting antiviral therapy.
The HCV treatment with DAAs has offered a unique opportunity to analyze the changes in the immune system caused by the rapid inhibition of viral replication. We sought to analyze the kinetics profiles of serum biomarkers (LuminexTM) in fifty patients with chronic hepatitis C enrolled in a longitudinal investigation carried out before (baseline), during (W2-4 and W8-12 weeks) and post-treatment (W12-24 weeks) with sofosbuvir plus daclatasvir or simeprevir. The results demonstrated a clear biomarker overproduction in HCV patients at baseline. The kinetics timeline of baseline fold changes upon DAAs treatment revealed an early decline of CXCL8, CCL4, IL-6, IL-15, IL-17, IL-9, GM-CSF and IL-7 at W8-12 and a late shift towards lower levels of CCL3, CCL2, CCL5, IL1β, TNF-α, IL-12, IFN-γ, IL1-Ra, IL-4, IL-10, IL-13, PDGF, VEGF, G-CSF at W12-24. Our data demonstrated that HCV treatment with DAAs resulted in a clear change of the serum biomarker overproduction, hallmark of untreated HCV patients. High ALT (>69U/L), low platelet (≤150,000/mm3) and cirrhosis status at baseline were factors related to delayed immune response shift, as well as, in the kinetics of baseline fold changes in serum biomarkers. These findings added novel evidences for the immunological restoration process triggered by DAAs.


Ureter Injury as a Complication of Oblique Lumbar Interbody Fusion.
Oblique lumbar interbody fusion is a commonly used surgical method of achieving lumbar interbody fusion. There have been some reports about complications of oblique lumbar interbody fusion at the L2-L3 level. However, to our knowledge, there have been no reports about ureter injury during oblique lumbar interbody fusion. We report a case of ureter injury during oblique lumbar interbody fusion to share our experience. A 78-year-old male patient presented with a history of lower back pain and neurogenic intermittent claudication. He was diagnosed with spinal stenosis at L2-L3, L4-L5 level and spondylolisthesis at L4-L5 level. Symptoms were not improved after several months of medical treatments. Then, oblique lumbar interbody fusion was performed at L2-L3, L4-L5 level. During the surgery, anesthesiologist noticed hematuria. A retrourethrogram was performed immediately by urologist, and ureter injury was found. Ureteroureterostomy and double-J catheter insertion were performed. The patient was discharged 2 weeks after surgery without urologic or neurologic complications. At 2 months after surgery, an intravenous pyelogram was performed, which showed an intact ureter. Our study shows that a low threshold of suspicion of ureter injury and careful manipulation of retroperitoneal fat can be helpful to prevent ureter injury during oblique lumbar interbody fusion at the upper level.


Improvement of thermal comfort indices in agroforestry systems in the southern Brazilian Amazon.
Agroforestry systems can minimize heat stress and improve cattle welfare, but the influence of the forest component in microclimatic changes in the southern Amazon remains unclear. This study aimed to compare the thermal comfort indices in grass monoculture and integrated systems. The three systems were pasture under full sunlight (PFS), integrated (triple-row) livestock-forestry (ILFT), and integrated (single-row) livestock-forestry (ILFs), across four seasons, for two years, from June 2017 to June 2019. We assessed photosynthetically active radiation (PAR), air temperature, relative humidity, black globe temperature, and wind speed. Thermal comfort indices such as temperature-humidity index (THI), black globe temperature-humidity index (BGHI), and radiant thermal load (RTL) were calculated based on microclimate data daily-collected from 8:00 to 16:00. The ILFT mean THI (76.8) was slightly lower than ILFS and PFS. The BGHI and RTL values decreased as shading increased (PFS > ILFs > ILFT). The most challenging heat stress conditions for grazing animals occurred predominately during winter and autumn. In conclusion, the presence of trees in pastures of the southern Amazon improved the microclimate and, consequently, the thermal comfort indices. Agroforestry systems can foster an environment with a more suitable thermal comfort or less restrictive to animal performance, which contribute to mitigating global climate change for forage-livestock systems in Brazilian Amazon.


Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin.
Seven patients with advanced locoregional or metastatic squamous cell carcinoma of the skin were treated with cis-daimminedichloroplatin (cisplatin) and 5-fluorouracil (5-FU). Responses were seen in six of seven patients (three partial responses [PR] and three complete responses [CR]). One patient is alive and disease-free at 2 years. These results indicate that cisplatin and 5-FU is an effective combination regimen that should be used in future clinical trials in squamous cell carcinoma of the skin.


Diagnosis of Generalized Pustular Psoriasis.
Generalized pustular psoriasis (GPP) is a severe rare skin disease characterized by widespread eruption of sterile superficial macroscopic pustules with or without systemic inflammation. Generalized pustular psoriasis flares may lead to life-threatening multiorgan complications, which highlights the need for rapid and accurate diagnosis. However, the rarity of the disease and its heterogeneous cutaneous and extracutaneous symptoms, and the resemblance of symptoms to other skin conditions, pose considerable challenges to the timely diagnosis and treatment of patients with GPP. Current laboratory tests used for GPP diagnosis are generally not GPP specific, and are mainly focused on the assessment of inflammatory markers and clinical and histopathologic features of GPP, and emerging genetic screening approaches. A differential diagnosis to distinguish GPP from other similar conditions requires careful assessment of the patient's skin symptoms, potential disease triggers, medical history, histopathologic features, laboratory tests, and clinical disease course. The comprehensive interpretation of these assessments can be challenging owing to the lack of standardized global guidelines. While there is currently a lack of standardized international guidelines for the diagnosis of GPP, recent advances in our understanding of the genetics and pathogenesis of the disease have provided new opportunities to enhance diagnosis. In the future, defining specific GPP subtypes using genetic and histopathologic strategies will guide therapeutic decisions, allowing patients to achieve their treatment goals without delay. In this article, we provide an overview of the current diagnostic methods, differential diagnostic strategies, and future advances in the diagnosis of GPP, as well as features of GPP variants.


Nonpharmacologic and Rehabilitative Strategies to Address Chronic Pain.
With benefits on pain and pain-related outcomes and low-risk profile, there has been an emphasis on nonpharmacologic management of chronic pain. Physical therapy uses exercises, manual therapies, and electrotherapy. Exercises include aerobic, strengthening, and flexibility exercises. Aquatic exercises have similar efficacy to land-based exercises. Multidisciplinary care uses a biopsychosocial approach. All are effective for pain-related outcomes. Occupational therapy focuses on ergonomics, joint protection, orthoses, and assistive devices. Limited evidence exists for taping, orthoses, assistive devices, thermotherapy, and education on pain-related outcomes. Weight loss in patients who are overweight or obese is effective for pain reduction in knee arthritis.


The genetics of dopa decarboxylase in Drosophila melanogaster. I. Isolation and characterization of deficiencies that delete the dopa-decarboxylase-dosage-sensitive region and the alpha-methyl-dopa-hypersensitive locus.
A detailed cytogenetic investigation of 16 overlapping deficiencies in the 36C-40A region on the left arm of the second chromosome (2L) in Drosophila melanogaster is reported. These deficiencies permit a localization of both the dopa-decarboxylase-dosage-sensitive region and the alpha-methyl-dopa-hypersensitive locus, l(2) amd, to the same region, 37B10-37C7.


The effects of the wood preservative copper dimethyldithiocarbamate in the hippocampus of maternal and newborn Long-Evans rats.
The potential toxic effects on human health and deleterious effects to the environment by copper dimethyldithiocarbamate (CDDC), an alternative wood preservative to chromated copper arsenate (CCA) have not been investigated. This study describes the neurotoxicity and accumulation of copper in the hippocampus of maternal and newborn Long-Evans rats following a subacute exposure to CDDC. Pregnant rats (220-270g) were treated daily with 0mg/kg, 25mg/kg, 50mg/kg, or 75mg/kg CDDC by oral gavage starting from day 6 of gestation and continuing to parturition. Following parturition, maternal and newborn rats were euthanized and brain tissues were removed, processed, and stored for analysis. Electron microscopy revealed demyelination and by-products of peroxidative damage in treated maternal hippocampi. Treated newborn hippocampi exhibited numerous degenerating mitochondria, membrane bound inclusion bodies, and vacuoles containing degraded structures. Graphite furnace atomic absorption spectrophotometry (GFAAS) demonstrated a significant increase in copper concentration in the tissues of treated animals as compared to controls. Western blot analysis revealed an induction of stress proteins HO-1 and Hsp70 and the formation of 4-hydroxy-2-nonenal (4HNE) adducts. CDDC was shown to be toxic to the brains, at all doses used and this toxicity is attributable to copper-induced lipid peroxidation.