Targeting of tissue plasminogen activator into the regulated secretory pathway of neuroendocrine cells.
Plasma levels of tissue plasminogen activator (tPA) increase rapidly in response to specific vasoactive agents, trauma, and neural stimulation. This response has been attributed to acute release of tPA from stored pools within the vascular endothelium and from catecholamine storage vesicles of chromaffin cells. We have tested directly whether tPA can be sorted into the regulated secretory pathway using the murine pituitary-derived neuroendocrine cell line AtT-20 transfected with tPA cDNA. Clones of AtT-20 cells expressing tPA were isolated, and targeting of tPA into the regulated secretory pathway was demonstrated by (1) stimulation of tPA secretion with 8-bromo-cAMP, the secretagogue which promotes the release of dense granule contents; (2) colocalization with ACTH, an endogenous protein that is stored in dense core granules; and (3) retention of newly synthesized tPA in the cell for prolonged periods of time. Laser scanning confocal microscopy analysis of cells immunostained with antibodies to tPA and ACTH showed colocalization at the tips of the neuritic processes under the cytoplasmic membrane, a region where dense granules are known to migrate after maturation. Treatment of the cells with 5 mM 8-bromo-cAMP for 30 min resulted in a 2.41+/-0.36-fold increase in tPA secretion. Both the magnitude of the stimulatory effect and the fraction of the intracellular tPA released were the same regardless of the tPA expression level in the various clones. Pulse-chase experiments showed that a portion of newly synthesized tPA is retained in the cell for at least 4 h and is released into the culture medium in response to 8-bromo-cAMP. These studies indicate that tPA, under the appropriate conditions, can be targeted into the regulated secretory pathway and can be stored for later release by cellular stimuli.


The clinical features and image characteristics of Meniere's disease patients with endolymphatic hydrops confirmed by enhanced magnetic resonance imaging.
To analyze and summarize the clinical features and image characteristics of Meniere's Disease (MD) patients with Endolymphatic Hydrops (EH) confirmed by enhanced Magnetic Resonance Imaging (MRI). 252 MD patients with EH confirmed by MRI were enrolled. All patients met the diagnostic criteria for MD and underwent intravenous gadolinium injection. After 4 h, MR examinations were performed. The Nakashima grading standard was used to classify EH and evaluate its correlation with clinical features. Different degrees of EH were shown in all MD patients, and 157 of the 252 (62.3%) patients showed significant EH, 95 of the 252 (37.7%) patients showed mild EH. Only 89 (35.3%) met the diagnostic criteria for definite MD, and the remaining 163 (64.7%) patients met the diagnostic criteria for probable MD. Compared with patients with unilateral EH, the symptoms of the first affected ear of patients with bilateral EH were more serious. The degree of EH was related to the degree of hearing loss (p < 0.05). MRI with intravenous gadolinium injection can provide a better assessment of EH in MD patients. The clinical features of MD patients with EH confirmed by enhanced MRI did not fully meet the existing diagnostic criteria for definite MD. Including the diagnosis of EH in the diagnostic criteria of MD can increase the diagnosis rate of MD. The degree and distribution of EH may be related to the degree of hearing loss.


Aerosol technique-based carbon-encapsulated hollow mesoporous silica nanoparticles for synergistic chemo-photothermal therapy.
Near-infrared (NIR)-responsive drug delivery systems have enhanced tumor ablative efficiency through permeation and retention effects. Graphene oxide (GO) has shown great potential both in photothermal therapy and in drug delivery. Thus, in this study, we designed an ambient spark-generated GO, wrapped on topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSN-NH2-TPT-CGO), to function as an efficient platform for pH-dependent sustained release of TPT. HMSN-NH2-TPT-CGO also exhibited a combined chemo-photothermal effect within a single carrier system. This developed system was stable with a uniform particle size (∼190 nm) and was demonstrated to possess a sufficient heat-absorbing capacity to induce tumor cell ablation. We performed the ablation of tumor cells both in vitro and in vivo in combination with photothermal therapy and chemotherapy using the spark-generated functional GO and HMSN. The prepared nanocarriers demonstrated high cellular uptake, apoptosis, and G0/G1 cell cycle arrest. In vivo study using the MDA-MB-231 xenograft model revealed the ultraefficient tumor ablative performance of HMSN-NH2-TPT-CGO compared with that of free TPT, with no toxic effect on vital organs. Altogether, the optimized nanocarriers presented a significant potential to act as a vehicle for cancer treatment. STATEMENT OF SIGNIFICANCE: This is the first study that uses spark-generated graphene oxide nanoflakes to cover the topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSNs) to treat breast cancer. Dense silica was used as a hard template to prepare the HMSNs attributing to a high drug payload. The concentration of Na2CO3 was precisely controlled to minimize the silica etching time within 70 min. The use of the nanographene flakes served a dual purpose, first, by acting as a capping agent to prevent the premature release of drug and, second, by serving as a nano heater that significantly ablates the tumor cells. The prepared nanocarriers (NCs) exhibited effective and enhanced in vitro and in vivo apoptosis, as well as significant tumor growth inhibition even after 15 days of treatment time, with no toxic effect to the vital organs. The NCs enhanced in vitro tumor cell killing effects and served as an effective carrier for in vivo tumor regression, thereby highlighting the enormous potential of this system for breast cancer therapy.


Effect of exposure to balanced salt solution upon the hardness of the crystalline lens.
The nucleus confers most of the hardness upon the lens, water content decreases towards the centre of the nucleus and a relative dehydration accompanies increased hardness in some cataractous lenses. It is a possibility that exposure and incubation of the inner layers of the nucleus to balanced salt solution (BSS) can result in the softening of the nucleus. This study aimed to investigate the effect of BSS upon the lens hardness. Nuclear colour element of cataract was graded biomicroscopically. Following extracapsular cataract surgery the lens nucleocortex was divided into two equal parts and each half was allocated randomly to incubation in BSS or air for 5 min before the hardness of each section was assessed by an automated guillotine. Following incubation with BSS the mean force necessary to bisect the lens was 0.50 N and in the control air group the mean force was 0.64 N. The lenses in the BSS-treated group were consistently softer than those in the control group, with a mean softening of 18.3% (P=0.001). The amount of softening was not related to the nuclear colour (P=0.6) or age (P=0.1). Softening of the lens through physical disruption has previously been reported. This study describes the phenomenon of nuclear softening following exposure to BSS, indicating that lens softening can occur through biochemical means.


Strategies for Sustainable Production of Hydrogen Peroxide via Oxygen Reduction Reaction: From Catalyst Design to Device Setup.
An environmentally benign, sustainable, and cost-effective supply of H2O2 as a rapidly expanding consumption raw material is highly desired for chemical industries, medical treatment, and household disinfection. The electrocatalytic production route via electrochemical oxygen reduction reaction (ORR) offers a sustainable avenue for the on-site production of H2O2 from O2 and H2O. The most crucial and innovative part of such technology lies in the availability of suitable electrocatalysts that promote two-electron (2e-) ORR. In recent years, tremendous progress has been achieved in designing efficient, robust, and cost-effective catalyst materials, including noble metals and their alloys, metal-free carbon-based materials, single-atom catalysts, and molecular catalysts. Meanwhile, innovative cell designs have significantly advanced electrochemical applications at the industrial level. This review summarizes fundamental basics and recent advances in H2O2 production via 2e--ORR, including catalyst design, mechanistic explorations, theoretical computations, experimental evaluations, and electrochemical cell designs. Perspectives on addressing remaining challenges are also presented with an emphasis on the large-scale synthesis of H2O2 via the electrochemical route.


Sustained therapeutic efficacy and safety of oral propafenone for treatment of chronic ventricular arrhythmias: a 2-year experience.
Thirty-two men with chronic ventricular arrhythmias responded to propafenone, a new potent antiarrhythmic agent, in short-term trials with 85% or greater reduction of total ventricular premature complexes (VPCs) per hour, 95% or greater reduction of ventricular couplets (VCs) per hour, and 100% abolition of ventricular tachycardia (VT) beats per 24 hours. These patients were continued on long-term propafenone therapy to assess sustained therapeutic efficacy and safety. Thirty patients completed 1 year and 26 patients completed 2 years of testing with this agent; one patient died of sudden death and another died of a noncardiac cause. Although there were significantly fewer patient responders at 1 and 2 years, the majority of patients (greater than 79%) continued to respond optimally to propafenone. Side effects were minor and included bitter taste, dizziness, congestive heart failure, fatigue, and significant prolongation of the PR and QRS intervals. Propafenone has sustained antiarrhythmic efficacy after 2 years without serious toxicity.


Patterns of cell thickness oscillations during directional migration of Physarum polycephalum.
The functional relationship between the velocity of cell locomotion and intracellular spatial patterns of thickness oscillations in the acellular slime mould Physarum polycephalum was studied. The freely migrating plasmodial cells of 300-800 µm length were tadpole-shaped and displayed thickness oscillations along their longitudinal (body) axis. Two distinct patterns of intracellular thickness oscillations were observed in dependence on the locomotive velocity. The first mode consisted of a single travelling wave that propagated from the rear to the front of the cell. This pattern occurred when the plasmodium migrated slowly. The second mode was a multinodal standing wave that was found during events of fast propagation. Transitions between these two types of cell thickness oscillation patterns took place in narrow propagation velocity intervals. We discuss the possible mechanism leading to these patterns, which are conjectured to modulate both the intracellular pressure and the velocity of free locomotion of the cell.


Differential associations between glomerular filtration rate and duration of obesity depending on the presence or absence of left ventricular diastolic dysfunction.
A robust and consistent association between increasing body mass index (BMI) and chronic kidney disease (CKD) has been reported in several observational studies. Obesity remains the main preventable risk factor for CKD because it largely mediates diabetes and hypertension, the 2 most common etiologies for end-stage kidney disease (ESKD). Obesity is associated weakly with early stages of kidney disease but strongly with kidney progression to ESKD, even after adjustment for hypertension and diabetes. To assess the relationship between estimated glomerular filtration rate (eGFR) and trans-thoracic echocardiography left ventricular function parameters in a cohort of patients with obesity. Cross-sectional study involving 324 obese (BMI=44.0±2.2Kg/m(2)) apparently healthy asymptomatic patients with an eGFR >60ml/min/1.73m(2). Each patient underwent transthoracic echocardiography and a blood testing. The eGFR was addressed by the CKD-EPI formula. All patients had a normal systolic function whereas 24.5% disclosed diastolic dysfunction (DD). Hypertension and type 2 diabetes mellitus prevalence were 34.5% and 4.5% (respectively). All patients disclosed an eGFR >60ml/min while none of them disclosed hyperfiltration (eGFR >120ml/min). eGFR correlated inversely with BMI and the duration of obesity and positively with diastolic function parameters (P<0.001 for all, respectively). Patients with diastolic dysfunction displayed lower eGFR (P<0.0005) and longer duration of obesity (P<0.0005). Obesity and its duration are likely to impose hemodynamic changes affecting simultaneously both heart (diastolic dysfunction) and kidney (decreased glomerular filtration rate). Larger prospective studies are warranted.


Discovery of novel Glutaminase allosteric inhibitors through drug repurposing and comparative MMGB/PBSA and molecular dynamics simulation.
GLS1 enzymes (Glutaminase C (GAC) and kidney-type Glutaminase (KGA)) are gaining prominence as a target for tumor treatment including lung, breast, kidney, prostate, and colorectal. To date, several medicinal chemistry studies are being conducted to develop new and effective inhibitors against GLS1 enzymes. Telaglenastat, a drug that targets the allosteric site of GLS1, has undergone clinical trials for the first time for the therapy of solid tumors and hematological malignancies. A comprehensive computational investigation is performed to get insights into the inhibition mechanism of the Telaglenastat. Some novel inhibitors are also proposed against GLS1 enzymes using the drug repurposing approach using 2D-fingerprinting virtual screening method against 2.4 million compounds, application of pharmacokinetics, Molecular Docking, and Molecular Dynamic (MD) Simulations. A TIP3P water box of 10 Å was defined to solvate both enzymes to improve MD simulation reliability. The dynamics results were validated further by the MMGB/PBSA binding free energy method, RDF, and AFD analysis. Results of these computational analysis revealed a stable binding affinity of Telaglenastat, as well as an FDA approved drug Astemizole (IC50 ∼ 0.9 nM) and a novel para position oriented methoxy group containing Chembridge compound (Chem-64284604) that provides an effective inhibitory action against GAC and KGA.


[Histological study of the bone marrow in 96 cases of Waldenstrom's macroglobulinemia. An evaluation with clinical, haematological and biological data (author's transl)].
Bone marrow biopsy in Waldenstrom's macroglobulinemia shows three types of lesions: lympho-plasmocytic and reticular infiltration, which is the most common, reticular infiltration, and aplastic marrow, more seldom. In all cases the reticulinic network is increased and thickened. These lesions are diffuse or nodular. Diffuse infiltration is more severe and has a median duration of 62 months instead of 82 months in nodular infiltration.


Spread of a new Chlamydia trachomatis variant from men who have sex with men to the heterosexual population after replacement and recombination in ompA and pmpH genes.
Sexually transmitted infections are frequently related to outbreaks in high-risk populations due to the dense sexual networks. We wanted to determine the dissemination of a Chlamydia trachomatis variant characterized by the pmpH-recombinant gene between L and G genotypes, which was previously described in a high-risk population. A total of 449 samples were analysed in two periods ranging from 2009 to 2015 for detection of the pmpH-recombinant gene. For those samples yielding positive amplification, a sampling was selected for phylogenetic reconstructions based on sequencing of five chromosomal genes. Globally this variant was found in 113 of the 449 samples (25%). During the first years (2009-13), this variant was found almost exclusively in rectal samples (30/112 samples) of men who have sex with men and in only one non-rectal sample (1/63). In 2014, this variant was also found in urethral and pharyngeal samples (1/24 and 1/7, respectively). However, in 2015, an epidemiological change was observed as the proportion of this variant had increased in rectal samples (20/51; 39%) and non-rectal samples, including cervical samples (51/142; 36.4%). The molecular characterization revealed the replacement of the ompA gene belonging to subtype G in samples recovered from 2009 to 2013 by the ompA gene belonging to subtype J after 2013. Our data would support the evidence that subtype J could be a 'subtype bridge' between different sexual networks, as subtype J has been found in men who have sex with men and heterosexual populations in similar proportions. This work reveals the necessity of implementing molecular surveillance in extra-rectal samples to help us understand the gaps in transmission.


Glucuronidation of 3'-azido-3'-deoxythymidine: human and rat enzyme specificity.
Since preclinical studies indicated that 3'-azido-3'-deoxythymidine (AZT, zidovudine, Retrovir, BW A509U), a potent anti-HIV agent, is not metabolized extensively in rats, rabbits, mice, guinea pigs, cats, or dogs, the extensive biotransformation of AZT observed in humans was not expected. On average, approximately 75% of an oral AZT dose is recovered in human urine as a single metabolite while only 14-18% of the dose is recovered unchanged. Ultraviolet, infrared, nuclear magnetic resonance, and mass spectra and enzymatic degradation characterized the isolated major metabolite as a 5'-O-glucuronide (3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine, GAZT), a very unique nucleoside metabolite. These observations suggest that UDP-glucuronosyltransferase (UDPGT), EC220.127.116.11, mediates the in vivo biotransformation of AZT to GAZT. Since glucuronidation is one of the major conjugation reactions involved in the metabolic conversion of xenobiotics to more polar, water-soluble metabolites, it is an important detoxification pathway in humans. Therefore, it is important to understand the enzymatic basis for the discrepancy between metabolism of AZT in laboratory mammals and humans. This is especially relevant in light of the use of laboratory mammals to predict the metabolism of novel pharmaceutical agents in humans. The study presented herein confirms that liver UDPGT does catalyze the glucuronidation of AZT and that the higher substrate efficiency of AZT with human enzyme compared to rodent enzyme may account for metabolic differences observed in vivo.


Clinical and Molecular Spectrum of Muscular Dystrophies (MDs) with Intellectual Disability (ID): a Comprehensive Overview.
Muscular dystrophies encompass a wide and heterogeneous subset of hereditary myopathies that manifest by the structural or functional abnormalities in the skeletal muscle. Some pathogenic mutations induce a dysfunction or loss of proteins that are critical for the stability of muscle cells, leading to progressive muscle degradation and weakening. Several studies have well-established cognitive deficits in muscular dystrophies which are mainly due to the disruption of brain-specific expression of affected muscle proteins. We provide a comprehensive overview of the types of muscular dystrophies that are accompanied by intellectual disability by detailed consulting of the main libraries. The current paper focuses on the clinical and molecular evidence about Duchenne, congenital, limb-girdle, and facioscapulohumeral muscular dystrophies as well as myotonic dystrophies. Because these syndromes impose a heavy burden of psychological and financial problems on patients, their families, and the health care community, a thorough examination is necessary to perform timely psychological and medical interventions and thus improve the quality of life.


Serum, plasma, and dried blood spot high-sensitivity C-reactive protein enzyme immunoassay for population research.
C-reactive protein (CRP) is used as a biomarker of morbidity and mortality risk in studies of population health, and is essential to interpretation of several micronutrient biomarkers. There is thus a need for a robust high-sensitivity CRP (hsCRP) measurement method for large-scale, non-clinical studies. We developed an efficient, inexpensive assay suitable for quantifying CRP across the physiological range using any blood specimen type. The ELISA uses readily available monoclonal antibodies to measure CRP in serum, plasma, or dried blood spots (DBS) made from venous or capillary blood. Assay performance was evaluated by standard methods, including comparison with a previously described assay. Effects of specimen type were tested by measuring CRP in 52 matched serum, plasma, and venous and capillary dried blood spot specimens. Long- and short-term CRP stability were evaluated. Assessments of assay limits of detection, linearity, recovery, imprecision, and concordance with an established method (Pearson correlation=0.988, n=20) demonstrated the validity of the new assay. CRP measurements in serum, plasma, and DBS had Pearson correlations from 0.974 to 0.995, n=52, but CRP in serum was on average 1.6 times (SD 0.37) higher than in DBS. CRP was stable in frozen serum for up to 34 months, but DBS CRP declined quickly with exposure to ambient temperatures, and across long-term storage at -20°C. This hsCRP assay is a robust and inexpensive tool designed for use in large-scale population health research. Our results indicate that DBS CRP is less stable than previously reported.


Spectroscopic and theoretical approach of DNA interaction and anticancer studies of bio-pharmaceutically active pyrimidine derived Cu(II) and Zn(II) complexes.
New metal(II) complexes (CuL2 and ZnL2) with pyrimidine appended Schiff base ligand (HL) were synthesized and characterized by diverse spectroscopic methods, reveals the proposed structure of metal(II) complexes possess square planar geometry. DNA interaction ability of isolated compounds was studied by UV-Visible, fluorescence, viscometric and electrochemical methods and the results showed that isolated compounds intercalated with calf thymus DNA (CT-DNA). In addition, anticancer activities of HL, CuL2, and ZnL2 have been evaluated by MTT assay, signifying moderate cytotoxic activity on selected cancer cell lines and less toxicity on NHDF normal cell line due to the specific targeting of pyrimidine analogues. Moreover, antioxidant activities of isolated compounds towards diverse free radicals have been studied by spectrophotometric methods. These results showed that CuL2 has better antioxidant ability than HL and ZnL2. Finally, antimicrobial activities of isolated compounds against selected antimicrobial pathogens exposed that CuL2 has better antimicrobial activity on E. coli and C. albicans than other antimicrobial pathogens. The DFT calculations have been done to get the optimized geometry of the ligand and the metal complexes. In order to get a broad understanding of the interactions of these synthesized metal complexes, a detailed molecular docking analysis is taken up.


Expression and localization of cysteine dioxygenase mRNA in the liver, lung, and kidney of the rat.
The expressions of cysteine dioxygenase (CDO) gene in the liver, lung, skeletal muscle, and kidney were studied by in situ hybridization with a cDNA probe from rat liver CDO under normal conditions. Significant expression of the CDO gene was detected in the liver, lung, and kidney, but not skeletal muscle. In the liver, the signal was confined to the cytoplasm of the hepatocytes. Furthermore, the signal was stronger in the periportal than that in the perivenous areas. In the lung, an intensive signal was found in the bronchiolar epithelium. As to the kidney, an intensive signal was observed in the distal convoluted tubules, while no signal was found in the proximal convultions.


[2,6-Bis(1H-benzimidazol-2-yl-kappaN3)pyridine-kappaN](dimethylformamide-kappaO)(thiosulfato-kappa2O,S)nickel(II) monohydrate.
The structure of the title compound, [Ni(ths)(bbip)(dmf)].H(2)O [ths is thiosulfate, S(2)O(3); bbip is 2,6-bis(1H-benzimidazol-2-yl)pyridine, C(21)H(13)N(5); and dmf is dimethylformamide, C(3)H(7)NO], is monomeric, with the nickel ion octahedrally surrounded by an N,N',N"-tridentate bbip molecule, an S,O-bidentate ths molecule and an O-monodentate dmf molecule. The H atoms of the hydration water molecule and the amino groups of bbip are involved in hydrogen bonding and determine a spatial organization of broad layers parallel to (001), which are connected by weak interactions.


Estimated economic impact of pre-filled ephedrine syringes in the operating room.
Syringes of ephedrine are usually prepared ahead of time in order to reduce the time to injection. Commercial pre-filled syringes of ephedrine have been introduced to minimize the amount of waste. Our primary objective was to determine the economic impact of commercial syringes. We hypothesized that costs could be reduced compared to standard syringes. Using data extracted from our medical records system, we retrospectively measured the total dose of ephedrine received per patient in 2013 to estimate the number of administered standard syringes. The proportion of administered standard syringes was calculated as the total number of administered standard syringes divided by the number of delivered ampoules in 2013. Thereafter, we calculated the annual cost difference as the difference between the cost for commercial syringes and the cost for standard syringes. Endpoints were calculated overall and for each operating room. At least one dose of ephedrine was given in 19,422 patients (44,943 administrations). The overall proportion of administered standard syringes was estimated to 52.8%. The threshold proportion of administered standard syringes for which commercial syringes would add no extra cost was 20.4%. In 30/32 operating rooms, the proportion of administered standard syringes was higher than 20.4%. The overall cost increase with commercial syringes was estimated to 51,567 €. Among operating rooms, incremental costs varied between -703 and 5086 €. Based on our findings, pre-filled ephedrine commercial syringes do not appear to reduce costs.


The effect of tricyclic antidepressants (TA) on the circulatory system in primary arterial hypertension.
The cardio-vascular reactions after i.m. application of 0.4 mg/kg of TA (imipramine, amitryptyline and nortryptyline) were compared in normotonics and patients suffering from essential hypertonia. It was found, that systolic blood pressure decreased significantly after the drugs only in hypertonic patients, whereas diastolic blood pressure fall was marked more in the normotonic group. In both groups, no apparent changes in heart action were noticed after the drugs. The TA caused a stronger increase of urine excretion of NE, E, VMA and NMN and MN in hypertonics than in normotonics.


Automatic quantitation of cell colonies on petri dishes by computerized image analysis.
Clonogenic assay is one of the most sensitive assays, widely used to evaluate the effects of antineoplastic agentsin vitro. A computer program was developed on an IBAS 2.0 Image Analysis System for automated quantiation of cell colonies and clone area on Petri dishes. The sensitivity of the clonogenic assay can be greatly increased by evaluating the mean area of the clones. The program gives an objective, accurate and fast evaluation of large samples. It is simple to use and offers a high degree of flexibility. Special algorithms and techniques have been implemented for good quantitation of both connected and well-separated colonies and to reduce the background noise and the general error rate. The principles and solutions presented are applicable to any other image analysis system.


The molecular weight of bovine lactoferrin.
The molecular weight of bovine lactoferrin in a neutral solvent (e.g. 0.2 M NaC1, pH 7.8 20 degrees C) has been determined using high-speed sedimentation equilibrium at various concentrations and speeds. Under these conditions the protein behaved as a single thermodynamic component with a weight-average molecular weight [MW]C=0 = 93000 plus or minus 2000 and a second virial coefficient B = 4.3-10(-5) mol-ml(-1)-g(-2). This value of the molecular weight is in good agreement with values previously reported by Groves (J. Am. Chem. Soc. 82, 3345-3350, 1960) and Szuchet and Johnson (Eur. Polym. J. 2, 115-128, 1966); it is, however, in disagreement with the more recent value given by Castellino et al. (J. Biol. Chem. 245, 4269-4275, 1970). The possible reasons for this discrepancy are discussed.


Electronic Structures of AlGaN2 Nanotubes and AlN-GaN Nanotube Superlattice.
The electronic properties of single-wall AlGaN2 nanotubes were investigated using first-principles calculations and generalized gradient approximation. All AlGaN2 nanotubes considered are semiconductors, but their band structures depend on their chirality and size due to curvature effect and symmetry. The zigzag AlGaN2 nanotubes are direct band gap semiconductors, while armchair AlGaN2 nanotubes are indirect band gap semiconductors. The calculations on the electronic properties of AlN-GaN nanotubes superlattice show that the band gap engineering can be realized by changing the composition of the AlN-GaN nanotubes superlattice.


Baseline scintigraphic abnormalities by myocardial perfusion imaging predict echocardiographic response to cardiac resynchronization therapy in nonischemic cardiomyopathy.
Significant myocardial scar in the posterolateral left ventricle (LV) has been associated with a diminished response to cardiac resynchronization therapy (CRT) in patients with coronary artery disease, but the effects of resting perfusion abnormalities in nonischemic cardiomyopathy (NICM) are yet to be described. We sought to characterize the effect of myocardial perfusion abnormalities upon echocardiographic outcomes of CRT in patients with NICM. Twenty-one patients (mean age 64.4 +/- 13.3; 71.4% male; mean left ventricular ejection fraction [LVEF] 20.2 +/- 6.9%) with NICM who underwent CRT implantation and Thallium-201 single positron emission computed tomography (SPECT) myocardial perfusion imaging (MPI) were included. MPI studies were read quantitatively, assigning each of 17 myocardial segments a perfusion score (0-4) and cumulatively generating a summed perfusion score (SPS). The LV lead position was determined by chest radiography. Echocardiograms were performed both before and after (median 12 mo) CRT in 15 patients. Echocardiographic response, defined as > or = 15% relative increase in LVEF, was documented in 8 (53.3%) of 15 patients. All patients (5/5) with an SP < or =6 responded to CRT, whereas only 30.0% (3/10) with an SPS > or = 6 responded (odds ratio 3.33 [95% confidence interval {CI} 1.29-8.59]; p = 0.01). All nonresponders had inferior perfusion defects. Defect density adjacent to the LV lead tip had little demonstrable effect upon CRT efficacy. The presence of significant myocardial perfusion defects negatively influences echocardiographic response to CRT in NICM. These findings warrant prospective confirmation and histopathological correlation with explanted hearts.


Stereoselective Total Synthesis of KAE609 via Direct Catalytic Asymmetric Alkynylation to Ketimine.
A direct catalytic asymmetric alkynylation protocol is applied to provide the requisite enantioenriched propargylic α-tertiary amine, allowing for the stereoselective total synthesis of KAE609 (formerly NITD609 or cipargamin).


Renal transplantation using non-heart-beating donors: a potential solution to the organ donor shortage in Canada.
There is a chronic shortage of cadaveric organ donors for renal transplantation, which might be solved by the use of non-heart-beating donors (patients who suffer cardiac arrest and whose kidneys are harvested subsequently when irreversible heart and respiratory function occur). We carried out a chart review to determine whether the renal transplantation rate would improve if a non-heart-beating donor program was introduced at a Canadian centre. We reviewed the charts of all 1547 patients who died in the emergency department or intensive care unit of the Ottawa Hospital, a tertiary care centre serving 1.2 million people in eastern Ontario, between January 1999 and May 2001. The number of potential non-heart-beating donors was determined by the use of predefined criteria. The number of additional kidneys that could be obtained with a non-heart-beating donor program was estimated and compared to the actual number of kidneys procured from conventional brain-dead donors during the same period. The potential increase in the renal transplantation rate was calculated. There were 83 potential non-heart-beating donors during the 29-month study period. The mean (and standard deviation) age of the donors was 40.6 (13.1) years, and 20% were female. The mean serum creatinine value was 75 (29) micromol/L; 44.6% of donors died secondary to trauma. We estimated that the use of non-heart-beating donors would have provided 14 to 41 additional donors during the study period (12-34 kidneys/yr). The cadaveric renal transplantation rate would have increased between 30% and 87%. The cadaveric renal transplantation rate could improve significantly if non-heart-beating donors were used in Canadian hospitals.


Gut with the Program: Direct Reprogramming toward Intestinal Epithelium Realized.
Intestinal organoids offer great promise for modeling intestinal diseases; however, harvesting intestinal tissue is invasive and directed hPSC differentiation protocols are laborious and costly. In this issue of Cell Stem Cell, Miura and Suzuki (2017) describe the direct conversion of somatic cells from both mice and humans into robust intestinal epithelial tissue.


Long-term treated intensive care patients outcomes: the one-year mortality rate, quality of life, health care use and long-term complications as reported by general practitioners.
The purpose of this study was to determine the one-year mortality rate and its predictors regarding long-term intensive care-treated patients together with their health-related quality of life (HRQL), place of living, healthcare use and long-term complication characteristics after intensive care unit (ICU) discharge. A retrospective cohort study was performed in a 20-bed mixed ICU. The patients that were treated for more than 72 h between 2007 and 2012 were included in this study. The one-year mortality rate was calculated, and the characteristics of the ICU survivors that died within one year after ICU discharge were further analysed. For all patients, the Dutch version of the SF-36 questionnaire was used to assess their current HRQL. The results were compared with a normal population. Additionally, patients were questioned about their place of living, and their general practitioners (GPs) were questioned about the patients' possible long-term complications. Seven hundred and forty patients were included in this study, and their one-year mortality rate was 28 %, of which half died within the first week after ICU discharge. The one-year mortality rate predictors included age at the time of ICU admission, APACHE IV-predicted mortality score, number of comorbidities and ICU re-admissions. The ICU survivor HRQL was significantly lower compared with the normal population. Half of the patients did not return to their pre-hospital place of living, and numerous possible long-term complications were reported, particularly decreased tolerance, chronic fatigue and processing problems of relatives. One-year mortality rate of long-term ICU-treated patient was 28 %, and this was predicted by age, disease severity, comorbidities and ICU re-admissions. The ICU survivors reported a lower HRQL, and a minority of these patients returned home directly after hospital discharge; however, GPs reported numerous possible long-term complications.


miR171 modulates induction of somatic embryogenesis in citrus callus.
Overexpression of miR171 restored SE competence in the recalcitrant citrus callus, and inhibition of miR171 function weakened SE competence in the strongly embryogenic citrus callus. Somatic embryogenesis (SE) is an important way of in vitro regeneration for plants. For perennial woody crops such as citrus, embryogenic callus is usually induced from unfertilized aborted ovules and widely used in biotechnology aided breeding. However, SE capacity always declines in callus during subculture, which makes regeneration difficult and hinders the application of biotechnology. We previously found that miR171 may be a regulator of SE in citrus, based on the abundant expression of csi-miR171c in the embryogenic callus and during SE of citrus. Here, we report that miR171 promotes SE and is required for SE in citrus. Overexpression of miR171 restored SE competence in the recalcitrant callus of 'Guoqing No.1' Satsuma mandarin (G1), whereas inhibition of miR171 function by Short Tandem Target Mimic (STTM) weakened SE competence in the strongly embryogenic callus of 'Valencia' sweet orange (V). The comparative transcriptomic analysis in miR171 overexpressed callus line (OE) and the wild type callus (WT) indicated that overexpression of miR171 decreased the expression level of its SCARECROW-LIKE (CsSCL) targets, and activated stress response related biological processes and metabolic processes that are required for cell differentiation. However, CsSCLs were up-regulated in the OE callus during SE induction process, which activated the cell division and developmental processes that are required for embryogenesis progress. Our results validate the function of miR171 in regulation of SE and reveal the biological responses provoked by miR171 in citrus that may promote SE.


Phthalate derivative DEHP disturbs the antiproliferative effect of camptothecin in human lung cancer cells by attenuating DNA damage and activating Akt/NF-κB signaling pathway.
Plasticizers/phthalates play a facilitating role in the development of cancer and help the tumor to grow and metastasize. Camptothecin (CPT) and its derivatives are known to have anticancer properties of inhibiting cell growth, promoting cell apoptosis, and increasing autophagy. Therefore, in this study, we investigated whether the presence of di(2-ethylhexyl) phthalate (DEHP) could hinder apoptosis and autophagy caused by CPT in non-small cell lung cancer (NSCLC) cells. We found that DEHP interferes with CPT-induced apoptosis and autophagy and increases the prosurvival pathway by reducing the DNA damage marker γ-H2AX and activating the Akt and NF-κB pathways. Furthermore, we also confirmed that combining DEHP with 3-MA has additive effects in inhibiting autophagy and apoptosis in NSCLC cells. Taken together, our findings show that DEHP could affect CPT-induced anticancer treatment and provide evidence to show that DEHP induces chemoresistance in CPT-based chemotherapy.


(Cobaltoceniumyl-amido)-pyridinium hexa-fluorido-phosphate.
The title compound, [Co(C5H5)(C10H9N2)]PF6, was synthesized from deproton-ated 1-amino-pyridinium iodide, followed by microwave-assisted nucleophilic aromatic substitution of iodo-cobaltocenium iodide. After anion exchange with potassium hexa-fluorido-phosphate, the title compound crystallizes as orange prisms in the space group Pc. This very stable pyridine nitrene adduct is the first example of a cobaltocenium derivative, formally containing a nitrene nitro-gen species.


CD163 and CD206 expression does not correlate with tolerance and cytokine production in LPS-tolerant human monocytes.
Lipopolysaccharide (LPS)-tolerant monocytes produce small amounts of inflammatory cytokines, which is one of the characteristics of the alternative activated macrophages (AAM). These cells exhibited an increased expression of CD206 and CD163. Given the functional similarities of AAMs with the modulation of monocytes' functions observed during sepsis and LPS-tolerance, we evaluated whether the inhibition of inflammatory cytokine production by LPS-tolerant monocytes is associated with the phenotype of cells expressing CD206 and CD163. We investigated whether tolerant human monocytes would modulate their expression of CD206 and CD163, markers of alternative activation, and whether the level of their expression would be related to cytokines detection. Tolerance to LPS was induced in peripheral blood mononuclear cell by pre-incubating the cells with increasing concentrations of LPS. The expression of CD206 and CD163 and intracellular TNF-α and IL-6 was determined 24 h after LPS challenge by flow cytometry. No differences in CD163 expression were observed between tolerant and non-tolerant cells, while the expression of CD206, which was decreased following LPS stimulation in non-tolerized cells, was further reduced in tolerant cells. Decreased production of inflammatory cytokines was observed in the tolerized cells, regardless of the expression of CD163 and CD206, with the exception of IL-6 in CD206+ monocytes, which was similarly expressed in both tolerized and non-tolerized cells. The effect of LPS in the expression of CD163 and CD206 on monocytes is not reverted in LPS tolerant cells, and the inhibition of inflammatory cytokines in tolerant cells is not related with modulation of these receptors. © 2016 International Clinical Cytometry Society.


Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression.
Thioredoxin-2 (TXN2) is a mitochondrial protein and represents one of the intrinsic antioxidant enzymes. It has long been recognized that mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of Alzheimer's disease (AD). We hypothesized that mitochondrial TXN2 might play a role in AD-like pathology. In this study, we found that in SH-SY5Y and HEK cells stably express full-length human amyloid-β precursor protein (HEK-APP), TXN2 silencing or over-expression selectively increased or decreased the transcription of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), respectively, without altering the protein levels of others enzymes involved in the catalytic processing of APP. As a result, β-amyloid protein (Aβ) levels were significantly decreased by TXN2. In addition, in cells treated with 3-nitropropionic acid (3-NP) that is known to increase reactive oxygen species (ROS) and promote mitochondrial dysfunction, TXN2 silencing resulted in further enhancement of BACE1 protein levels, suggesting a role of TXN2 in ROS removal. The downstream signaling might involve NFκB, as TXN2 reduced the phosphorylation of p65 and IκBα; and p65 knockdown significantly attenuated TXN2-mediated regulation of BACE1. Concomitantly, the levels of cellular ROS, apoptosis-related proteins and cell viability were altered by TXN2 silencing or over-expression. In APPswe/PS1E9 mice, an animal model of AD, the cortical and hippocampal TXN2 protein levels were decreased at 12 months but not at 6 months, suggesting an age-dependent decline. Collectively, TXN2 regulated BACE1 expression and amyloidogenesis via cellular ROS and NFκB signaling. TXN2 might serve as a potential target especially for early intervention of AD.


Vaccines to protect Hereford cattle against the cattle tick, Boophilus microplus.
Vaccines made from gut and gut and synganglion tissue dissected from Boophilus microplus gave 87% and 80% protection, respectively, compared with adjuvant-injected controls in cattle against three infestations with 20,000 larval ticks administered over 14 days. A vaccine prepared from synganglion alone did not protect cattle. Ticks collected from vaccinated cattle produced 95% and 91% fewer eggs, respectively, than ticks from control animals. Vaccinated cattle were protected (36%) 7 months after they had been immunized with tick antigens. Antibody responses to the vaccines were detected by enzyme-linked immunosorbent assay (ELISA).


Amniocentesis before 15 weeks' gestation: outcome, risks, and technical problems.
Between January 1, 1979, and May 30, 1986, 4750 amniocenteses were performed by a single physician at the University of California, Davis, Medical Center. Of these procedures 541 (11.4%) were considered early amniocenteses (performed before the fifteenth week since last menstrual period). The medical records were reviewed for maternal age, amniocentesis indication, ultrasound findings, location of the placenta, location of the needle insertion (transplacental versus nontransplacental), color of the amniotic fluid, results of prenatal testing, complications of procedure, and pregnancy outcome. Complete follow-up data were possible for 308 subjects and obtained for 298 (96.8%). There were 11 miscarriages (3.6%), two stillbirths (0.7%), and one neonatal death (0.3%), resulting in a total postprocedural loss rate of 4.7% (14/298). If those patients with a preamniocentesis history of bleeding are eliminated, the total postprocedural rate of loss is 3.3% (7/211). Miscarriage within 2 weeks of amniocentesis occurred in 1.7% of procedures (5/298). No significant difference in pregnancy outcome was noted between transplacental and nontransplacental amniocentesis.


The inferior impact of antibody-mediated rejection on the clinical outcome of kidney allografts that develop de novo thrombotic microangiopathy.
Antibody-mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co-presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing. Thirty-two TMA cases overlapping with AMR (AMR+ TMA) were studied, which involved 14 cases of sAMR+ TMA and 18 cases of dAMR+ TMA. Thirty TMA cases free of AMR features (AMR- TMA) were enrolled as control group. The ratio of complete response to treatment was similar between AMR- TMA and AMR+ TMA group (23.3% vs. 12.5%, p = 0.33), or between sAMR+ TMA and dAMR+ TMA group (14.3% vs. 11.1%, p = 0.79). At eight yr post-transplantation, the death-censored graft survival (DCGS) rate of AMR- TMA group was 62.8%, which was significantly higher than 28.0% of AMR+ TMA group (p = 0.01), but similar between sAMR+ TMA and dAMR+ TMA group (30.0% vs. 26.7%, p = 0.92). Overall, the intimal arteritis and the broad HLA (Human leukocyte antigens) mismatches were closely associated with over time renal allograft failure. The AMR+ TMA has inferior long-term graft survival, but grafts with sAMR+ TMA or dAMR+ TMA have similar characteristics and clinical courses.


Single-cell c-myc gene expression in relationship to nuclear domains.
Nuclear locations of the c-myc gene and its transcripts (c-myc (T)) have been investigated in relation to nuclear domains involved in RNA synthesis and processing. Transcription of the c-myc gene appears to be linked to the late G(1)- and preferentially to S-phases of the cell cycle. The c-myc gene and its transcripts were positioned non-randomly within the interphase nucleus; additionally, c-myc RNA signals accumulated at nucleoli. Using oligo-probes, designed to exon II and exon III of the c-myc gene, single c-myc (T) was preferentially observed in human carcinoma HT29 and A549 cells. Conversely, human embryonal teratocarcinoma NTERA cells were characterized by the presence of multiple c-myc RNA signals located in both the nucleoli and nucleoplasm. When accumulated at nucleoli, c-myc (T) occupied the periphery of this organelle, though not those associated with the cultivation surface. In HT29 cells, approximately 80% of c-myc (T) co-localized with the RNAP II positive regions, so-called transcription factories. However, in approximately 20% of the cells with c-myc transcripts, the c-myc (T) was released from the site of synthesis, and was not associated with either transcription factories or SC35 domains. In approximately 60% of nuclei with c-myc (T), these signals were located in close proximity to the SC35 regions, but promyelocytic leukaemia bodies were associated with c-myc (T) only in approximately 20% of the nuclei. Taken together, c-myc RNA signals were positioned in the most internal parts of the cell nuclei preferentially associated with the nucleoli. Specific nuclear and nucleolar positioning probably reflects the kinetics of c-myc RNA metabolism.


Bioactive materials for in vivo sweat gland regeneration.
Loss of sweat glands (SwGs) commonly associated with extensive skin defects is a leading cause of hyperthermia and heat stroke. In vivo tissue engineering possesses the potential to take use of the body natural ability to regenerate SwGs, making it more conducive to clinical translation. Despite recent advances in regenerative medicine, reconstructing SwG tissue with the same structure and function as native tissue remains challenging. Elucidating the SwG generation mechanism and developing biomaterials for in vivo tissue engineering is essential for understanding and developing in vivo SwG regenerative strategies. Here, we outline the cell biology associated with functional wound healing and the characteristics of bioactive materials. We critically summarize the recent progress in bioactive material-based cell modulation approaches for in vivo SwG regeneration, including the recruitment of endogenous cells to the skin lesion for SwG regeneration and in vivo cellular reprogramming for SwG regeneration. We discussed the re-establishment of microenvironment via bioactive material-mediated regulators. Besides, we offer promising perspectives for directing in situ SwG regeneration via bioactive material-based cell-free strategy, which is a simple and effective approach to regenerate SwG tissue with both fidelity of structure and function. Finally, we discuss the opportunities and challenges of in vivo SwG regeneration in detail. The molecular mechanisms and cell fate modulation of in vivo SwG regeneration will provide further insights into the regeneration of patient-specific SwGs and the development of potential intervention strategies for gland-derived diseases.


Antianginal efficacy and safety of controlled-delivery diltiazem QD versus an equivalent dose of immediate-release diltiazem TID.
Controlled-delivery once-daily diltiazem (qd), 180 mg and 360 mg, was assessed in two multicenter, randomized, double-blind, placebo-controlled trials using a 3 x 3 Latin square design. Both studies compared the controlled-delivery dosage form to the same total daily dose of immediate-release diltiazem administered three times daily (tid) and to placebo. The primary measure of efficacy was the time to termination of the exercise tolerance test (ETT) at 2, 8, and 24 hours after the morning dose. There were no significant differences in time to ETT termination between the qd and tid formulations at any time, except at 24 hours with 180 mg qd versus 60 mg tid. The comparison to placebo showed that diltiazem 180 mg qd, 360 mg qd, and 120 mg tid significantly lengthened the time to ETT termination (p < 0.05) at all time points, while diltiazem 60 mg tid did not differ from placebo at any time point. The qd formulation also increased the time to 1-mm ST-segment depression and reduced the number of angina attacks and the amount of nitroglycerin used when compared to placebo. No new or unusual adverse events were noted. Diltiazem controlled-release capsules administered once daily are safe and effective for the treatment of patients with chronic stable angina.


Involvement of CRH-R2 receptor in eating behavior and in the response of the HPT axis in rats subjected to dehydration-induced anorexia.
Wistar rats subjected to dehydration-induced anorexia (DIA), with 2.5% NaCl solution as drinking water for 7 days, decrease by 80% their food intake and present some changes common to pair-fed food restricted rats (FFR) such as: weight loss, decreased serum leptin and expression of orexigenic arcuate peptides, increasing the anorexigenic ones and serum corticosterone levels. In contrast, the response of the HPT axis differs: DIA animals have increased TRH expression in PVN and present primary as opposed to the tertiary hypothyroidism of the FFR. Exclusive to DIA is the activation of CRHergic neurons in the lateral hypothalamus (LH) that project to PVN. Since TRH neurons of the PVN contain CRH receptors, we hypothesized that the differences in the response of the HPT axis to DIA could be due to CRH regulating TRHergic neurons. CRH effect was first evaluated on TRH expression of cultured hypothalamic cells where TRH mRNA levels increased after 1h with 0.1nM of CRH. We then measured the mRNA levels of CRH receptors in the PVN of male and female rats subjected to DIA; only those of CRH-R2 were modulated (down-regulated). The CRH-R2 antagonist antisauvagine-30 was therefore injected into the PVN of male rats, during the 7 days of DIA. Antisauvagine-30 induced a higher food intake than controls, and impeded the changes produced by DIA on the HPT axis: PVN TRH mRNA, and serum TH and TSH levels were decreased to similar values of FFR animals. Results corroborate the anorexigenic effect of CRH and show its role, acting through CRH-R2 receptors, in the activation of TRHergic PVN neurons caused by DIA. These new data further supports clinical trials with CRH-R2 antagonists in anorexia nervosa patients.


New aureolic acid antibiotics. I. Screening, isolation, characterization and biological properties.
A new antibiotic complex was isolated from the fermentation broth of Streptomyces aburaviensis PA-39856. The individual factors, demethylolivomycins A, B and demethylchromomycins A2, A3 were separated and purified by preparative HLC. These antibiotics possess high activities against Gram-positive bacteria and P388 leukemia in mice.


COVID-19 Case Report: An 84-Year-Old Man with Exacerbation of Multiple Comorbidities Due to COVID-19 Managed by a Multidisciplinary Team Using Patient-Reported Outcomes.
BACKGROUND When treating patients with comorbidities who are infected with severe acute respiratory syndrome as a result of SARS-CoV-2, it is crucial to offer multidisciplinary treatment that takes into consideration all of the health conditions with which they have been diagnosed. In particular, clinicians should not lose sight of the patient experience, which we can be assessed with the help of patient-reported outcomes (PROs). CASE REPORT An 84-year-old man infected with SARS-CoV-2 was already suffering from multiple health conditions, including Type 2 diabetes mellitus. He most likely was receiving cortisone therapy and had chronic pain with spondylosis with radiculopathy, bilateral gonarthrosis following total knee replacement, malaise, and fatigue. The patient received acute inpatient care in a hospital that provides complementary medical therapies. We collected clinical and patient-reported data on quality of life, physical functions, the sensation of pain, psychological well-being, and symptoms while taking into account the degree of chronicity of the conditions, the level of the patient's pain, and his hospitalization in an isolation ward. We stabilized clinical parameters related to the patient's main underlying health conditions (blood glucose and pain levels and oxygen saturation). The PROs we collected demonstrated a significant improvement on discharge. CONCLUSIONS Applying PROs can be helpful in obtaining a more comprehensive picture of a patient with COVID-19, in which "the patient is given a voice," in addition to being assessed by others. The knowledge gained can then be made available to the interdisciplinary treatment team to be incorporated into the treatment plan.


Classification of neuropathic pain in cancer patients.
Neuropathic pain can affect up to 40% in patients with cancer, which could be related to the tumour, treatment or comorbid diseases. Effective assessment to diagnose neuropathic pain is crucial in order to choose the right treatment. There is to date no systematic classification system; the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain developed a neuropathic pain grading system intended to be used for both clinical and research purposes, and a recent review describes a step-by-step process for applying the grading system in a clinical setting for cancer pain. We have combined these recommendations to outline a clinically relevant process to classify neuropathic pain in patients with cancer.


A new shallow underground gas-proportional counting lab--first results and Ar-37 sensitivity.
A new ultra-low-background proportional counter was recently developed with an internal volume of 100 cm(3) and has been characterized at pressures from 1-10 atm with P-10 (90% Ar, 10% methane) gas. This design, along with a counting system providing event digitization and passive and active shielding, has been developed to complement a new shallow underground laboratory (30 m water-equivalent). Backgrounds and low-level reference materials have been measured, and system sensitivity for (37)Ar has been calculated.


Portuguese adaptation of the Chronic Heart Failure Knowledge Questionnaire (KQCHF).
A patient's knowledge of heart failure (HF) is associated with better outcomes. The more information patients have about their illness, the less likely they are to be readmitted to the hospital. Such knowledge includes the cause, symptoms, probable duration, and expected evolution of the clinical picture. In Portugal, a tool for testing patient knowledge is an unmet need. Therefore, this study aimed to adapt and test the Chronic Heart Failure Knowledge Questionnaire (KQCHF) for the Portuguese context. This work includes three cross-sectional studies. In Study 1, subjects were divided between before and after receiving information about HF. In Study 2, participants answered the questionnaire before and after reading the brochure. In Study 3, KQCHF was applied to patients with HF. Studies 1 and 2 were carried out in the general population. Study 3 was carried out with HF outpatients. Convenience sampling was applied to participants in the three studies. In Study 1 (n = 45), those who received information had better scores (9.2 ± 1.9) than those who did not (6.0 ± 2.3). In Study 2 (n = 21), the scores were higher after reading the brochure (10.4 ± 1.7 vs. 6.5 ± 2.9). In Study 3 (n = 169), women had better scores than men (9.1 ± 2.1 vs. 8.3 ± 2.2, overall: 8.5 ± 2.2), and knowledge was correlated with education (r = .340, p < .001) and age (r = -.170, p = .030). The Portuguese adaptation of KQCHF captured relevant knowledge about HF and has shown promising results for clinical and research purposes. The questionnaire can be useful in assessing HF patients' knowledge of their disease and as a basis for the implementation of general and personalised educational strategies to improve HF knowledge and, therefore, promote health literacy and self-care.


Tissue metallothionein concentrations in mice and humans with hyperglycemia.
Besides participating in tissue zinc homeostasis and protecting against heavy metal toxicities, metallothionein (MT) is known as an antioxidant. Increased MT activity can ameliorate diabetic hyperglycemia, and subjects with less MT synthesis are more prone to diabetic complications. However, whether tissue MT status is varied in the subjects with diabetes mellitus remains unclear. This study was undertaken to measure tissue MT levels in laboratory mice (serum, liver, and epididymal adipose tissue) and humans (serum) with hyperglycemia. Tissue MT levels were measured by enzyme-linked immunosorbent assay. The results showed that MT status in serum and adipose tissue did not markedly differ between the subjects with and without hyperglycemia. In addition, streptozotocin- and high-fat-diet-induced hyperglycemic mice had higher while ob/ob mice had lower liver MT levels than that of normal control mice. Furthermore, serum MT levels tended to correlate with glycemia values in mice. The results of this study indicate that serum MT value does not differ in subjects with hyperglycemia and cannot be used as an index to evaluate the susceptibility or progress of diabetes mellitus.


Detecting Multiethnic Rare Variants.
Genome-wide association studies have identified many common genetic variants which are associated with certain diseases. The identified common variants, however, explain only a small portion of the heritability of a complex disease phenotype. The missing heritability motivated researchers to test the hypothesis that rare variants influence common diseases. Next-generation sequencing technologies have made the studies of rare variants practicable. Quite a few statistical tests have been developed for exploiting the cumulative effect of a set of rare variants on a phenotype. The best-known sequence kernel association tests (SKATs) were developed for rare variants analysis of homogeneous genomes. In this chapter, we illustrate applications of the SKATs and offer several caveats regarding them. In particular, we address how to modify the SKATs to integrate local allele ancestries and calibrate the cryptic relatedness and population structure of admixed genomes.


GABA-ergic pathways in the goldfish retina.
A high-affinity uptake mechanism for [3H]-gamma-aminobutyric acid (GABA) has been localized to type H1 cone horizontal cells and type Ab pyriform amacrine cells in the retina of the goldfish by light and electron microscopy autoradiography. By stimulating isolated retinas with colored lights during incubation we have been able to use [3H]-GABA uptake as a probe of light-evoked changes in membrane potential. All colors of lights increase and darkness decreases [3H]-GABA uptake by H1 cone horizontal cells. Our model of voltage dependence of GABA uptake predicts that all colors of light should hyperpolarize H1 cone horizontal cells and other investigators have shown by intracellular recording and dye-marking that type H1 cone horizontal cells hyperpolarize to all wavelengths of light. We have also obtained evidence that dark-induced depolarization of cone horizontal cells leads to release of GABA. Type Ab pyriform amacrine cells show maximal [3H]-GABA uptake in darkness and when exposed to green or blue lights, but red lights dramatically suppress uptake. We predict these neurons to be red-depolarizing, and recent intracellular recordings and dye-marking by Famiglietti et al. ('77) support our conclusions. Synaptic relations of apparently GABA-ergic neurons were investigated in the electron microscope. We propose type H1 cone horizontal cells to be both pre- and post-synaptic to red-sensitive cones and type Ab pyriform amacrine cells to be both pre- and post-synaptic to red-sensitive center-depolarizing bipolar cells.


An overview of common psychiatric problems among adolescent and young adult females: Focus on mood and anxiety.
Adolescence is a dynamic period of learning and adaptation. It provides unique opportunities in which adolescents strive to become independent, generative young adults. However, with these strides come increased prevalence in psychiatric symptomatology. Among adolescent girls, anxiety disorders are the most common condition followed by mood disorders. Mood disorders, specifically depression, result in the greatest impairment. Factors such as body mass index and early pubertal onset are associated with poorer mental health such as depression. In addition, depression is a top risk factor for suicide particularly among youth aged 13-17 years. We provide a brief description of the most common mood disorders, along with assessment tools, among teen and young adult females. Then, special considerations for psychiatric presentation among this young population will be presented.


Isolation of the membranes of an enterotoxigenic strain of Escherichia coli and distribution of enterotoxin activity in different subcellular fractions.
The intracellular localization of enterotoxin in Escherichia coli AP1, a strain of porcine origin which produces high levels of heat-labile, but no heat-stable enterotoxin, has been examined. The cytoplasmic and outer membranes of this strain both contained enterotoxin activity, while the membranes isolated from a serologically related non-enterotoxigenic strain (E. coli AP2) also of porcine origin, did not show enterotoxin activity. The periplasmic fraction isolated from the enterotoxigenic strain contained considerable enterotoxin activity, but this activity was associated with outer membrane fragments present in the periplasmic fraction. Thus, of the total cellular enterotoxin activity, about 55%, 15% and 30% were present in the outer membrane, cytoplasmic membrane and the cell cytoplasm, respectively. The specific activity of enterotoxin was 20 units per mg protein in the cytoplasm and 90 and 150 units per mg protein in the cytoplasmic and outer membranes, respectively.


Nonfamilial, vibration-induced angioedema.
Vibratory angioedema is a rare form of physical angioedema. A Mexican-American boy presented with vibration-related prolonged angioedema of the hands at age 16. After the use of a controlled vibratory stimulus, 10 volunteers and seven members of the family (three generations) developed expected transient erythema and whealing reaction of the skin at the site of contact. However, with the same vibrating stimulus the patient developed large erythematous swelling that lasted for 12 hr. Vibratory challenge study revealed a rapid rise and fall in plasma histamine. No increase in levels of plasma histamine were detected from the nonstimulated arm. Prausnitz-Küstner testing was negative. Light and electron microscopic study of the mast cell revealed degranulation and extensive fragmentation of the granules from the stimulated site. No degranulation was seen in the contralateral unstimulated site. A state of tolerance to vibration was induced by graded increased exposure to vibratory stimulus and the patient's clinical problem was eliminated.


Adsorption/desorption of naphthalene and phenanthrene in a binary competitive system in the riparian zone.
Polycyclic aromatic hydrocarbons (PAHs) such as naphthalene (Nap) and phenanthrene (Phe) are organic pollutants that are of concern because of their environmental toxicity. Adsorption is a promising process for the removal of Nap and Phe from water and soil. The riparian zone between a river and a riparian aquifer, which is rich in adsorption medium, may be important for PAH remediation. Nap and Phe may be removed from the surface water through adsorption by the media in the riparian zone. However, there is still a lack of the removal patterns and mechanisms of media in the riparian zone to remediate water contaminated by Nap and Phe simultaneously. In this study, focusing on the typical PAHs (Nap and Phe) as target pollutants, batch static adsorption and desorption experiments of Nap and Phe were carried out to explore the competitive adsorption mechanisms of Nap and Phe in the binary system. Batch dynamic adsorption experiments were conducted to ascertain the adsorption regulation of Nap and Phe in sediments during the recharge of groundwater by river water in a riparian zone. The static adsorption experiment results showed that competitive adsorption of Nap and Phe occurred, and a mutual inhibitory effect of Nap and Phe adsorption was observed in the binary system. Phe had a stronger inhibitory effect on Nap, Phe was preferentially adsorbed on the medium in binary adsorption. The results of batch dynamic experiments showed that, in terms of adsorption, the riparian zone in the study area showed stronger performance for removal of Phe than Nap. The results of this paper could be useful for alleviating Nap and Phe pollution of groundwater and developing treatment protocols for groundwater exposed to Nap and Phe.


The benefits of chemotherapy in patient subgroups with unresectable non-small-cell lung cancer.
Cisplatin-based chemotherapy improves survival in advanced non-small-cell lung cancer. Using data from phase III trials of mitomycin, ifosfamide and cisplatin, this paper investigates whether the beneficial effect of chemotherapy on survival and quality of life seen overall is limited to certain patient subgroups. The survival benefit of chemotherapy was compared with standard treatment using hazard ratios for subgroups specified by stage, sex, age, histology and performance status (PS). The effect on quality of life was investigated for three subgroups defined by performance status. The overall unstratified hazard ratio for all 797 eligible patients shows a 16% reduction in the risk of death with chemotherapy (P = 0.02). This benefit was seen for both locally advanced and extensive stage disease (significantly in extensive disease). Subgroups defined by sex, age and histology consistently benefitted from chemotherapy. The hazard ratios for the three levels of performance status suggest that PS2 patients gain no survival benefit from chemotherapy. In contrast, these patients experienced the greatest improvement in quality of life during the first six weeks of chemotherapy. Subgroup analysis suggests that the prolongation of life from cisplatin-based chemotherapy is confined to PS0/1 patients. Palliation is greater in PS2 patients.


Partial purification and some properties of a phospholipase C from Pseudomonas sp. strain KS3.2.
An extracellular phospholipase C was partially purified from Pseudomonas sp. strain KS3.2. The enzyme was composed of an approximately 18-kDa peptide. Maximal enzyme activity was found at pH 7.2 and 50 degrees C. The enzyme retained activity between pH 8 and 9, and 50% activity at about 52 degrees C for 30 min. The enzyme sample showed the highest activity on phosphatidylcholine and low activity toward other phospholipids.


[Negative change in the potential of the cat cerebral cortex after transcallosal stimulation].
The slow negativity (SN) evoked with rhythmic transcallosal stimulation in anesthetized cats is generated in the upper layers of the cortex. The amplitude and duration of SN increased after the application of tetraethylammonium solution to the surface of the cortex. The SN seems to reflect mainly the glial depolarization.


Synthesis and characterization of thermally responsive N-isopropylacrylamide hydrogels copolymerized with novel hydrophobic polyphenolic crosslinkers.
Two series of thermosensitive hydrogels were synthesized by copolymerizing N-isopropylacrylamide (NIPAAm) with various contents of novel hydrophobic crosslinkers, curcumin multiacrylate (CMA) and quercetin multiacrylate (QMA). The compositions of the resulting hydrogels were characterized using solid state-NMR (ss-NMR), and the temperature dependent swelling behavior and lower critical solution temperature (LCST) were characterized using swelling studies and differential scanning calorimetry (DSC). Increasing the crosslinker content resulted in a significant decrease in the LCST and swelling ratio of hydrogels, which could be attributed to the increased hydrophobicity introduced by CMA or QMA. All of the hydrogels demonstrated temperature responsive swelling with the extent of swelling decreasing with increasing crosslinker content. The lower crosslinker content gels displayed sharper phase transitions, while the high crosslinker content gels had broader phase transitions.


Age and morphological changes in the Epiponini wasp Polybia paulista Von Ihering (Hymenoptera: Vespidae).
The division of labor is a central theme in the study of social insects. In bees and wasps, this activity is regulated by age polyethism. Important physiological and morphological changes have been widely studied in the polyethism of honeybee workers. In contrast, this is a relatively unexplored subject in social vespids. Our goal was to determine if there are detectable morphological changes in the body of the Epiponini wasp Polybia paulista Von Ihering or in certain glands in relation to age polyethism. We observed changes in the body weight, the salivary gland, and the mandibular gland that were associated with age, and our results suggest that social relationships and task performance are important to these changes. This contrasts with observations in Polistes and is different from the Apis mellifera Linnaeus age polyethism model.


Ibuprofen-induced papillary necrosis causing bilateral ureteric obstruction.
Ibuprofen, a non-steroidal anti-inflammatory drug, is the mainstay in the management of pain and fever in children. In most children, ibuprofen is well tolerated and does not produce significant adverse effects. We report a case of acute papillary necrosis causing bilateral ureteric obstruction induced by ibuprofen.


Bipolar cells in monkey retina selective for the cones likely to be blue-sensitive.
Bipolar cells are a class of retinal interneurone with dendrites in the outer plexiform layer that contact photoreceptors, and axons terminating in the inner plexiform layer where they convey the centre responses of ganglion cells. In the monkey, many of whose ganglion cells respond to stimuli selective for each of the three different cones. There are five types of cone bipolar cells: flat and invaginating midget; diffuse, flat and invaginating cone; and giant, bistratified. Although many of the monkey's ganglion cells are specific for one of the three different cone mechanisms, none of the bipolar cells are known to connect to the morphologically identified counterparts of the different spectral types of cones as in teleost retina. Here, however, I describe a bipolar cell found in Golgi preparations of the rhesus monkey retina which displays an apparently selective and patterned distribution of its dendritic contacts with cone pedicles in the outer plexiform layer. The intercone spacing of dendritic contacts and their distribution match the intercone spacing and proportion of cones thought to be blue-sensitive.


Religiosity and Spirituality of Resident Physicians and Implications for Clinical Practice-the SBRAMER Multicenter Study.
To assess the attitudes, knowledge, and experiences of Brazilian resident physicians regarding religiosity/spirituality (R/S), factors associated with addressing this issue, and its influence on clinical practice. We report results of the multicenter "Spirituality in Brazilian Medical Residents" (SBRAMER) study involving 7 Brazilian university centers. The Network for Research Spirituality and Health (NERSH) scale (collecting sociodemographic data, opinions about the R/S-health interface, and respondents' R/S characteristics) and the Duke Religion Index were self-administered. Logistic regression models were constructed to determine those factors associated with residents' opinions on spirituality in clinical practice. The sample comprised 879 resident physicians (53.5% of total) from all years of residency with 71.6% from clinical specialties. In general, the residents considered themselves spiritual and religious, despite not regularly attending religious services. Most participants believed R/S had an important influence on patient health (75.2%) and that it was appropriate to discuss these beliefs in clinical encounters with patients (77.1%), although this was not done in routine clinical practice (14.4%). The main barriers to discussing R/S were maintaining professional neutrality (31.4%), concern about offending patients (29.1%), and insufficient time (26.2%). Factors including female gender, clinical specialty (e.g., internal medicine, family medicine, psychiatry) as opposed to surgical specialty (e.g., surgery, obstetrics/gynecology, orthopedics), having had formal training on R/S, and higher levels of R/S were associated with greater discussion of and more positive opinions about R/S. Brazilian resident physicians held that religious and spiritual beliefs can influence health, and deemed it appropriate for physicians to discuss this issue. However, lack of training was one of the main obstacles to addressing R/S issues in clinical practice. Educators should draw on these data to conduct interventions and produce content on the subject in residency programs.


Cytosol androgen receptors in guinea pig brain and pituitary.
Cytosol androgen receptors were assayed in guinea pig brain and pituitary tissues, using [3H]R1881 as ligand. These receptors had an apparent Kd of 0.04 nM and were androgen-specific (R1881 greater than dihydrotestosterone greater than testosterone = estradiol greater than progesterone). Concentrations of cytosol androgen receptors in castrated adult male guinea pigs were 12.2, 11.6, 6.9, 2.6 and 1.3 fmol per mg protein in anterior pituitary, hypothalamus, medial preoptic area, amygdala and cortex, respectively. No significant differences in receptor levels were observed between castrated adult males and females. The concentration of androgen receptors was significantly lower in the hypothalamus, medial preoptic area and anterior pituitary of castrated neonatal males than in castrated adult male guinea pigs. The systemic injection of the alpha 1-adrenergic antagonist, prazosin, had no significant influence on androgen receptor levels in castrated males in any brain area.


[Propagation of hepatitis E virus in several cell lines including human embryo lung diploid cell KMB17].
To investigate the hepatitis E virus (HEV) sensitive cells and its tissue culture conditions. The HEV from dejecta supernatant of patients with acute hepatitis E was amplified and activated by passaged in Rhesus. Then, the positive dejecta samples of infected monkeys were dealt with super-centrifugation and virus for culture was obtained. Various human-derived (including KMB17, A549, BEL7402, and Hela) and non-human primates derived cells (Vero) were inoculated with HEV. Sensitivity of cells to HEV was measured by CPE (cytopathic effect), RT-PCR and immunofluorescence. CPE in KMB17, A549 and BEL7402 cells appeared during 7-9 days, meanwhile, cells shelled during 11-13 days on the first filial generation. The existence of HEV genome +RNA and replicated -RNA was still detectable by RT-PCR after the tenth filial generation. Neither CPE nor amplification of HEV genome RNA could be detected in Hela and Vero cells after the second to fourth filial generation. HEV could also be detected from inoculated KMB17 cells by immunofluorescence and RT-PCR. It indicates that KMB17, A549 and BEL7402 cells are sensitive to HEV under the experimental culture conditions, while Hela and Vero cells are insensitive. Tissue culture system of HEV in certain filial generation is established.


Specific loss of the extrinsic 18 KDa protein from photosystem II upon heating to 47 degrees C causes inactivation of oxygen evolution likely due to Ca release from the Mn-complex.
Exposure of Photosystem II (PS II) membrane particles from spinach to a temperature of 47 degrees C caused the rapid release of the 18 kDa protein in parallel to inactivation of oxygen evolution. Previously, it has been suggested that the first heat-jump response involves rapid Ca release from the Mn complex of O2-evolution, followed by the slower release of (2 + 2) MnII ions [Pospisil P et al. (2003) Biophys J 84: 1370-1386]. Here, the predicted biphasic MnII release to the bulk was verified by atomic absorption spectroscopy (AAS). Analysis of laser flash-induced delayed fluorescence transients suggests that the loss of the essential Ca ion from the Mn4Ca complex in the dark is due to the loss of the 18 kDa protein. The S2-state multiline EPR signal of the Mn complex was still generated in heat-treated PS II presumably lacking Ca, but retaining four Mn ions.


Who should measure quality of life, the doctor or the patient?
The extent to which a doctor or health professional can make a valid assessment of a patient's quality of life, anxiety and depression was investigated in a series of cancer patients. Doctors and patients filled out the same forms, viz. the Karnofsky, Spitzer, Linear Analogue Self Assessment Scales and a series of simple scales designed for this study, at the same time. Correlations between the two sets of scores were poor, suggesting that the doctors could not accurately determine what the patients felt. A further study examining the reproducibility of these scales demonstrated considerable variability in results between different doctors. It is concluded that if a reliable and consistent method of measuring quality of life in cancer patients is required, it must come from the patients themselves and not from their doctors and nurses.


Antenatal diagnosis of partial agenesis of the corpus callosum: a benign cause of ventriculomegaly.
Dilation of the posterior horns of the cerebral ventricles may be an early finding of fetal hydrocephalus, but it is also the hallmark of partial agenesis of the corpus callosum. Reported is the first precise prenatal diagnosis of posterior agenesis of the corpus callosum. Accurate diagnosis allows for appropriate obstetric management.


Subepicardial aneurysm of left ventricle adjacent to the aortic root: demonstration on multidetector CT.
We report a case of subepicardial aneurysm, which developed in the anterobasal portion of the left ventricle wall and extended into the space between the aortic root and the right ventricular outflow tract (RVOT). Multidetector computed tomography (MDCT) demonstrates this rare aneurysm well.


Prevention of free radical-induced myocardial injury by allopurinol. Experimental study in cardiac preservation and transplantation.
To determine the role of free radical-induced injury during heart preservation and transplantation, we harvested hearts from 28 mongrel dogs (12.5 to 16.5 kg), divided them into four groups, and orthotopically transplanted them. A group of seven hearts were orthotopically transplanted immediately after excision (group A). A second group of seven animals received allopurinol pretreatment (50 mg/kg/day) for 72 hours, and the hearts were orthotopically transplanted immediately after excision (group B). A third group of seven hearts were transplanted after continuous perfusion with oxygenated modified Collins solutions at 4 degrees C, pH 7.4, and a pressure of 20 mm Hg for 18 hours (group C). A fourth group of seven animals received allopurinol pretreatment (50 mg/kg/day) for 72 hours, and the hearts were orthotopically transplanted after perfusion with modified Collins solutions in the same manner as group C hearts (group D). The generation of free radicals, estimated by measurement of thiobarbituric acid reactive substances (malondialdehyde) in the coronary effluent, stayed at low levels during perfusion in groups C and D and also remained at low levels during operational ischemia in group A and B. During reperfusion, their levels abruptly and significantly increased and were associated with a corresponding increase in creatinine kinase MB isoenzyme (malondialdehyde levels at 30 minutes' reperfusion: A, 2.25 +/- 0.43; B, 1.55 +/- 0.25 nmol/ml/100 gm wet weight [p less than 0.05 versus group A]; C, 2.67 +/- 0.28; D, 1.77 +/- 0.27 nmol/ml/100 gm wet weight [p less than 0.05 versus group C]). In the allopurinol pretreatment groups, allopurinol significantly slowed the appearance of malondialdehyde and the release of creatinine kinase MB isoenzyme during reperfusion. Furthermore, cardiac functions during reperfusion, expressed as percent of control (mean +/- standard deviation), were significantly better in the allopurinol pretreatment groups than in the untreated groups: maximum first derivative of left ventricular pressure: A, 76.4 +/- 9.5; B, 99.7 +/- 14.3 [p less than 0.05 versus group A]; C, 25.2 +/- 2.6; D, 42.7 +/- 7.9 [p less than 0.05 versus group C]). These results indicate that (1) the generation of oxygen free radical is not significant during perfusion with modified Collins solutions nor during operational ischemia, but only during reperfusion, and (2) allopurinol reduces free radical-induced injury during reperfusion. Allopurinol has potential application in the prevention of reperfusion injury during heart transplantation.


Phototherapy for Prurigo Nodularis: Our Experience and a Review of the Literature.
Prurigo nodularis is a chronic inflammatory skin disease characterized by highly pruritic nodular lesions that cause constant itching and scratching and significant quality-of-life impairment. It has been described in a range of conditions, including skin diseases (mainly atopic dermatitis) and metabolic, neurological, and psychiatric disorders. The pathophysiological mechanisms are largely unknown. Various modalities of phototherapy have been described as appropriate and safe treatments for achieving clinical control and alleviating symptoms. In this article, we describe our experience with phototherapy in patients with prurigo nodularis. Retrospective observational study of patients who received their first cycle of phototherapy to treat prurigo nodularis between March 2011 and October 2019. Information was collected on epidemiological and clinical characteristics, concomitant treatments, type and duration of phototherapy, maximum dose reached, and response to treatment. We studied 44 patients (30 women and 14 men) with a median age of 65.5years. The most common form of phototherapy used was narrowband UV-B phototherapy (34 cycles, 77.27%) followed by a combination of UV-B and UV-A phototherapy (8 cycles). Response to treatment was considered satisfactory (clearance rate of ≥75%) in 24 patients (55.4%). Phototherapy is a suitable treatment for prurigo nodularis in a considerable proportion of patients. It can be used as monotherapy or combined with other treatments.


Non-targeting control for MISSION shRNA library silences SNRPD3 leading to cell death or permanent growth arrest.
In parallel with the expansion of RNA interference (RNAi) techniques, accumulating evidence indicates that RNAi analyses might be seriously biased due to the off-target effects of gene-specific short hairpin RNAs (shRNAs). Our findings indicated that off-target effects of non-targeting shRNA comprise another source of misinterpreted shRNA-based data. We found that SHC016, which is one of two non-targeting shRNA controls for the MISSION (commercialized TRC) library, exerts deleterious effects that lead to elimination of the shRNA-coding cassette from the genomes of cultured murine and human cells. Here, we used a lentiviral vector with inducible SHC016 expression to confirm that this shRNA induces apoptosis in murine cells and senescence or mitotic catastrophe depending on the p53 status in human tumor cells. We identified the core spliceosomal protein, small nuclear ribonucleoprotein Sm D3 (SNRPD3), as a major SHC016 target in several cell lines and confirmed that CRISPRi knockdown of SNRPD3 mimics the effects of SHC016 expression in A549 and U251 cells. The overexpression of SNRPD3 rescued U251 cells from SHC016-induced mitotic catastrophe. Our findings disqualified non-targeting SHC016 shRNA and added a new premise to the discussion about the sources of uncertainty in RNAi results.


Perceptions of pre-clerkship medical students and academic advisors about sleep deprivation and its relationship to academic performance: a cross-sectional perspective from Saudi Arabia.
The medical student population is believed to be at an increased risk for sleep deprivation. Little is known about students' perceptions towards sleep deprivation and its relationship to academic performance. The aim of study is to explore the perceptions of medical students and their academic advisors about sleep deprivation and its relationship to academic performance. The study took place at Alfaisal University, College of Medicine, Riyadh, Saudi Arabia. An online, anonymous, cross-sectional, self-rating survey was administered to first-, third-year students and their academic advisors. Two-tailed Mann-Whitney U test was used to compare the mean 5-point Likert scale responses between students according to gender, academic year and cumulative grade point average (cGPA). A total of 259 students and 21 academic advisors participated in the survey (response rates: 70.6 and 84%, respectively). The vast majority of students agreed that sleep deprivation negatively affects academic performance (78.8%) and mood (78.4%). Around 62.2 and 73.7% of students agreed that the demanding medical curriculum and stress of final exams lead to sleep deprivation, respectively. While 36.7% of students voiced the need for incorporation of curricular separate courses about healthy sleep patterns into medical curriculum, a much greater proportion of students (45.9%) expressed interest in extracurricular activities about healthy sleep patterns. Interestingly, only 13.5% of students affirmed that they were counselled about sleep patterns and academic performance by their academic advisors. There were several statistically significant differences of means of students' perceptions according to gender, academic year and cGPA. Despite almost all academic advisors (95.5%) asserted the importance of sleep patterns to academic performance, none (0%) inquired about sleep patterns when counselling students. Nineteen academic advisors (90.5%) recommended incorporation of sleep patterns related learning into medical curricula; among those, only 1 (n = 1/19; 5.3%) recommended learning as a separate course whereas the majority (n = 18/19; 94.7%) recommended learning in forms of extracurricular activities and integration into relevant ongoing courses. Our results showed that students had correct conceptions about the negative impact of sleep deprivation on academic performance and mood. Also, our results highlighted the need for curricular/extracurricular education and counseling about healthy sleep patterns.


The effects of horseradish peroxidase on the concentration of 5-hydroxytryptamine and platelet counts in blood of rabbits and guinea pigs.
When HRP was injected i.v. in rabbits and guinea pigs, a rapid fall in the number of circulating platelets and the concentration of 5 HT occurred. Platelet aggregates were trapped in lung capillaries. The aggregation was reversible and the return of platelets to the circulation concomitant with a rise in blood 5 HT concentration.


[Circulating recipient cells contribute to graft coronary arteriosclerosis].
Despite recent advances in immunosuppressive therapy, accelerated coronary atherosclerosis remains a major problem in the long-term survival of cardiac transplant recipients. However, the pathogenesis of the transplant-associated atherosclerosis remains largely unknown. The origin of the neointimal cells was investigated by heterotopic heart transplantation between the wild-type mouse and the ROSA26 mouse that expresses LacZ ubiquitously (LacZ-mouse). Coronary arteries of the cardiac allograft developed neointimal hyperplasia consisting of alpha-smooth muscle actin-positive cells. When a heart from a wild-type mouse was transplanted into a LacZ-mouse, most of the neointimal cells expressed LacZ whereas the medial cells were negative. In contrast, when a heart from a LacZ-mouse was transplanted into a wild-type mouse, most of the neointimal cells were negative for LacZ whereas the medial cells expressed LacZ. In situ hybridization of the allografts from female to male mice revealed that most of the neointimal cells corresponded to cells from the recipients. Blood cells include progenitors of smooth muscle cells, which attach to the graft endothelia, differentiate into smooth muscle cells and proliferate, thus contributing to neointima formation. Our findings suggest a new therapeutic strategy that involves targeting of homing, differentiation and proliferation of putative smooth muscle progenitor cells to prevent proliferative vascular diseases.


A positive feedback cycle between the alarmin S100A8/A9 and NLRP3 inflammasome-GSDMD signalling reinforces the innate immune response in Candida albicans keratitis.
Fungal keratitis is a severe sight-threatening ocular infection, without effective treatment strategies available now. Calprotectin S100A8/A9 has recently attracted great attention as a critical alarmin modulating the innate immune response against microbial challenges. However, the unique role of S100A8/A9 in fungal keratitis is poorly understood. Experimental fungal keratitis was established in wild-type and gene knockout (TLR4-/- and GSDMD-/-) mice by infecting mouse corneas with Candida albicans. The degree of mouse cornea injuries was evaluated by clinical scoring. To interrogate the molecular mechanism in vitro, macrophage RAW264.7 cell line was challenged with Candida albicans or recombinant S100A8/A9 protein. Label-free quantitative proteomics, quantitative real-time PCR, Western blotting, and immunohistochemistry were conducted in this research. Herein, we characterized the proteome of mouse corneas infected with Candida albicans and found that S100A8/A9 was robustly expressed at the early stage of the disease. S100A8/A9 significantly enhanced disease progression by promoting NLRP3 inflammasome activation and Caspase-1 maturation, accompanied by increased accumulation of macrophages in infected corneas. In response to Candida albicans infection, toll-like receptor 4 (TLR4) sensed extracellular S100A8/A9 and acted as a bridge between S100A8/A9 and NLRP3 inflammasome activation in mouse corneas. Furthermore, the deletion of TLR4 resulted in noticeable improvement in fungal keratitis. Remarkably, NLRP3/GSDMD-mediated macrophage pyroptosis in turn facilitates S100A8/A9 secretion during Candida albicans keratitis, thus forming a positive feedback cycle that amplifies the proinflammatory response in corneas. The present study is the first to reveal the critical roles of the alarmin S100A8/A9 in the immunopathology of Candida albicans keratitis, highlighting a promising approach for therapeutic intervention in the future.


Experiences with intrathecally enhanced computed tomography.
Computed tomographic cisternography (CTC) shows small normal and pathological structures in the extracerebral CSF spaces in an excellent way and is able to differentiate communicating from non-communicating CSF-containing cysts in congenital malformations and acquired lesions. The main value of the CTC is in the examination of CSF dynamics. A report is given about our experiences with 121 patients. The dynamic flow patterns are divided into eight groups. The results are discussed in detail with suggestions as to the treatment.


Plasma lipids in beta-thalassemia minor.
Because total cholesterol levels have been found to be lower in patients affected by thalassemia major and intermedia, we examined the plasma lipid pattern of 628 beta-thalassemia trait carriers and 4552 controls in order to evaluate whether the plasma lipid impairment is also present in the heterozygous state. Total cholesterol and low density lipoprotein (LDL)-cholesterol levels were significantly lower in beta-thalassemia trait carriers when compared to controls, whereas plasma triglycerides and high density lipoprotein (HDL)-cholesterol levels did not differ between the two groups. We suggest that accelerated erythropoiesis and increased uptake of LDL by macrophages and histiocytes of the reticuloendothelial system are the main determinants of low plasma cholesterol levels in heterozygous thalassemia.


Characterization of protective immune responses in local lymphoid tissues after drug-attenuated infections with Ostertagia ostertagi in calves.
In the present study, cell-surface markers and cytokine gene expression of lymphocytes from the local lymph nodes were studied 9 days after primary infection with Ostertagia ostertagi in previously naive calves or in calves previously immunized with multiple, chemically attenuated infections. Changes in lymphocyte populations were assessed by flow cytometry utilizing monoclonal antibodies specific for bovine cell-surface markers. Changes observed in the percentages of lymphoid populations after challenge were similar in animals immunized by either three or five drug-attenuated infections. In both immunized groups, the CD4+/CD8+ ratio was significantly higher than in naive animals after challenge infections. In addition, both immunized groups showed significantly lower levels of Ig-bearing cells upon experimental challenge when compared to animals with a primary experimental infection. No differences were observed in the number of gammadelta or interleukin 2 receptor (IL-2R) positive cells. The levels of mRNA for IL-4, IL-10, IL-15, IFN-gamma and TGF-beta1 were examined by competitive RT-PCR. After challenge, the levels of these cytokines were lower in animals immunized by five drug-attenuated infections, and in the case of IL-4 and TGF-beta1, these differences were statistically significant. These results indicate that animals exhibiting protection from reinfection with O. ostertagi do not show a shift to higher percentages of Ig+ cells characteristic of a primary infection. In addition, protected animals appear to show a decreased IL4 and TGF-beta1 response upon challenge when compared to non-immune animals.


Relationship of phenotypic and genetic variation in Plantago lanceolata to disease caused by Fusarium moniliforme var. subglutinans.
Naturally established individuals of Plantago lanceolata with the inflorescence disease caused by Fusarium moniliforme var. subglutinans had more inflorescences and were more likely to be male-sterile than healthy plants. Half-sib families planted in the field varied in the percentage of diseased plants, the number of inflorescences per plant, the incidence of male-sterility, and the pattern of inflorescence phenology. The rankings of families with respect to disease incidence was, however, not simply related to their reproductive phenotypes. Plants derived from field genotypes with a history of disease were slightly more likely to become diseased than plants derived from healthy genotypes. Inflorescence infection was more severe on plants derived from genotypes with a known history of disease. Since the fungus reduces seed production in the plants it infects, differential incidence of disease based on plant phenotype and genotype may have ecological and evolutionary consequences for the host population.