Aptamer-Functionalized Upconverting Nanoformulations for Light-Switching Cancer-Specific Recognition and In Situ Photodynamic-Chemo Sequential Theranostics.
Biomarker-activatable theranostic formulations offer the potential for removing specific tumors with a high diagnostic accuracy and a significant pharmacological effect. Herein, we developed a novel activatable theranostic nanoformulation UAS-PD [upconversion nanophosphor (UCNP)-aptamer/ssDNA-pyropheophorbide-a (PPA)-doxyrubicin (DOX)], which can recognize specific cancer cells with sensitivity and trigger the localized photodynamic destruction and enhanced chemotherapy. UAS-PD was constructed by the conjugation of UCNPs and aptamer probes containing the photosensitizer PPA and the chemotherapeutic drug DOX. When cancer cells are present, the UAS-PD specifically binds to PTK7, an overexpressed protein present on the surface of cancer cells, through conformational recombination of the aptamer structure and switches its upconversion luminescence from 655 to 540 nm. This long-lived ratiometric optical signal provides an ultrasensitive detection limit as low as 3.9 nM for PTK7. Changes in the conformation of UAS-PD can also induce PPA to approach UCNPs, which can produce cytotoxic singlet oxygens under near-infrared excitation to destroy the cell membrane and enhance its permeability for the simultaneously released DOX that targets cellular DNA degradation, which results in a highly effective tumor-killing effect by synergistic extra-intracellular sequential damage.


A Multiplex Allele Specific Polymerase Chain Reaction (MAS-PCR) for the Detection of Factor V Leiden and Prothrombin G20210A.
In order to determine the frequencies of factor V Leiden and prothrombin G20210A point mutations in the Iranian population with Azeri Turkish origin. 120 unrelated individuals from general population randomly selected and were examined for factor V Leiden and prothrombin G20210A mutations using a multiplex allele specific polymerase chain reaction (MAS-PCR) assayOutcomes: The frequency of prothrombin G20210A mutation was 2.08%, which means 5 chromosomes out of 240 chromosomes had prothrombin G20210A mutation. The distribution of prothrombin 20210 GG, GA, AA genotypes and prothrombin 20210A allele were 37(92.5%), 3(7.5%), 0(0%) and 3(3.75%) in males and 78(97.5%), 2(2.5%), 0(0%) and 2(1.25%) in females, respectively. Factor V Leiden was not found in our tested group (zero chromosomes out of 240 chromosomes). Analysis of the observed frequencies in the studied groups indicates that there is no statistically significant difference between females and males, regarding prothrombin G20210A mutation (p value>0.05). This is the first study in its own kind in this population and implies that the frequency of Factor V Leiden G1691A (R506Q, FV-Leiden) allele is extremely low but the prothrombin G20210A mutation is more frequent in the tested group.


Increased Risk of Sexually Transmitted Infections in Men Who Have Sex With Men Taking Preexposure Prophylaxis: A Meta-analysis.
Men who have sex with men (MSM) are a priority population for preexposure prophylaxis (PrEP) for HIV prevention. We summarized the surveillance data from the studies of MSM taking PrEP versus before taking PrEP to investigate the possible increased risk of sexually transmitted infections (STIs). Two researchers independently searched 5 databases from January 2012 to April 2022 to identify relevant studies reporting the incidence density of syphilis, gonorrhea, and chlamydia infection. Subgroup analyses based on the type and location of research were conducted. The publication bias was detected by Egger's publication bias plot. Twenty studies met the inclusion criteria for the meta-analysis. The pooled estimate of incidence density of syphilis was 9.53 per 100 person-years (PY), whereas 36.48 per 100 PY for chlamydial infection and 34.79 per 100 PY for gonorrhea, higher than the MSM before taking PrEP. The results of the subgroup analysis showed that the incidence density tended to be lower in prospective studies than in retrospective studies and lower in North American studies than in other regions' studies. The high incidence of STIs in the MSM taking PrEP needs to be increasingly appreciated, and more effective prevention method for STIs is valuable among MSM alongside HIV prevention uptake.


Comparative analysis of neural transcriptomes and functional implication of unannotated intronic expression.
The transcriptome and its regulation bridge the genome and the phenome. Recent RNA-seq studies unveiled complex transcriptomes with previously unknown transcripts and functions. To investigate the characteristics of neural transcriptomes and possible functions of previously unknown transcripts, we analyzed and compared nine recent RNA-seq datasets corresponding to tissues/organs ranging from stem cell, embryonic brain cortex to adult whole brain. We found that the neural and stem cell transcriptomes share global similarity in both gene and chromosomal expression, but are quite different from those of liver or muscle. We also found an unusually high level of unannotated expression in mouse embryonic brains. The intronic unannotated expression was found to be strongly associated with genes annotated for neurogenesis, axon guidance, negative regulation of transcription, and neural transmission. These functions are the hallmarks of the late embryonic stage cortex, and crucial for synaptogenesis and neural circuit formation. Our results revealed unique global and local landscapes of neural transcriptomes. It also suggested potential functional roles for previously unknown transcripts actively expressed in the developing brain cortex. Our findings provide new insights into potentially novel genes, gene functions and regulatory mechanisms in early brain development.


Comparison of the endothelialization of small intestinal submucosa, dacron, and expanded polytetrafluoroethylene suspended in the thoracoabdominal aorta in sheep.
This study was undertaken to evaluate and compare endothelialization of small intestinal submucosa (SIS), Dacron, and expanded polytetrafluoroethylene (ePTFE) in high-pressure flow without aortic wall contact and to evaluate the suitability of SIS as a vascular graft material. In 12 adult sheep, three types of membrane leaflets of similar thickness (approximately 200 mum) were suspended within large square stents without contact with the thoracoabdominal aortic wall: SIS (n = 12), Dacron (n = 12), and ePTFE (n = 12). Each animal received one leaflet of each material. Aortograms were obtained before and after percutaneous implantation and when the animal was killed at 8 weeks (n = 6) or 18 weeks (n = 6). Cell coverage and remodeling of SIS, Dacron, and ePTFE membranes were assessed by gross and histologic microscopic examinations. Thirty-five successfully implanted leaflets were evaluated. SIS showed progressive remodeling. Thirty-three leaflets exhibited thickening as a result of neointimal formation and endothelialization, most likely from circulating endothelial cells. Dacron exhibited the greatest and most progressing degree of neointimal formation and endothelialization, followed by SIS and then ePTFE. With SIS and ePTFE, neointimal formation decreased with time, but endothelialization was stable. Uneven neointimal formation and endothelialization on the outer surfaces and distal leaflet positions were seen. SIS showed progressive remodeling with moderate and regressive neointimal formation and moderate stable endothelialization. Further study of its durability and incorporation into the aortic wall needs to be performed to evaluate its suitability as a cover for aortic endografts.


Persistent exercise intolerance following cardiac transplantation despite normal oxygen transport.
To define the respective roles of the periphery and central oxygen transport in the exercise limitation of heart transplanted patients (HTR), we compared 11 HTR (15.1 +/- 10.8 months after transplantation) to six age and weight matched normal controls (C), during an incremental exercise test (30 W/3 min steps; supine position), up to peak exercise level. The C stopped between 120 and 240 W (mean = 180 +/- 39 W), whereas the HTR all reached 90 W, with a significantly lower oxygen uptake (VO2), cardiac index (CI) and arterio-venous oxygen difference (AVO2D) values (respectively VO2: 16.6 +/- 2.6 vs 30.0 +/- 9.3 ml.min-1.kig-1 STPD; CI: 6.84 +/- 1.10 vs 10.55 +/- 2.86l.min-1.m-2; AVO2D: 94 +/- 13 vs 109 +/- 9 ml.l-1; all p < 0.05) but with similar lactate (LA) values (respectively 7.25 +/- 1.98 vs 7.71 +/- 1.55 mmol.l-1; p = NS). At the 90 W step which corresponds to the peak level that all the HTR reached, the C were close to their anaerobic threshold and showed similar parameters of oxygen transport (VO2: 17.4 +/- 2.0; CI: 7.50 +/- 0.41; AVO2D:90 +/- 10) but a lower lactate level (LA: 2.93 +/- 4.76; p < 0.002). At the same intermediate exercise levels VO2, CI and AVO2D were similar in both groups, while the closely matched LA and ventilation increased faster in HTR, reaching significantly higher levels as soon at the 30 W step. This evidence for an increased anaerobic exercise energy generation in HTR suggests that the periphery participates significantly in their exercise limitation, a phenomenon that might be improvable by retraining. means+/-standard deviation.


A model for the size distribution of marine microplastics: A statistical mechanics approach.
The size distribution of marine microplastics provides a fundamental data source for understanding the dispersal, break down, and biotic impacts of the microplastics in the ocean. The observed size distribution at the sea surface generally shows, from large to small sizes, a gradual increase followed by a rapid decrease. This decrease has led to the hypothesis that the smallest fragments are selectively removed by sinking or biological uptake. Here we propose a new model of size distribution, focusing on the fragmentation of marine plastics. The model is inspired by ideas from statistical mechanics. In this model, the original large plastic piece is broken into smaller pieces once by the application of "energy" or work by waves or other processes, under two assumptions, one that fragmentation into smaller pieces requires larger energy and the other that the occurrence probability of the "energy" exponentially decreases toward larger energy values. Our formula well reproduces observed size distributions over wide size ranges from micro- to mesoplastics. According to this model, the smallest fragments are fewer because large "energy" required to produce such small fragments occurs more rarely.


Presence of vertebral fractures is highly associated with hiatal hernia and reflux esophagitis in Japanese elderly people.
Recent studies have shown the correlation between vertebral fractures (VFs) and gastrointestinal disorders in postmenopausal women. The aim of this study was to assess the association between VFs and hiatal hernia (HH) and/or reflux esophagitis (RE) in our patient population of both men and women. We analyzed retrospective data of 280 patients aged 60 years or older (140 men and 140 women, mean +/- SD 73.5 years +/-7.05) who had undergone upper gastrointestinal endoscopy and chest X-rays in our hospital from August 2005 to February 2006. We analyzed the correlation between the presence of VFs and the presence of HH and/or RE. The incidence of RE in this study was 13.9% (39/280) and that of HH was 30.0% (84/280). Among these patients, 12.1% (41/280) had VFs. The incidence of RE in patients with VFs was 24.4% (10/41) and without VFs was 12.1% (29/239), with the difference being significant between those with and without VFs (p<0.05). The incidence of HH in patients with VFs was 43.9% (18/41) and in those without VFs was 27.6% (66/239), p<0.05. We subdivided subjects into four groups: HH only group, RE only group, HH/RE group and neither condition present group. We compared the incidence of VFs among these groups. VFs were observed in 16.4% (11/67) of the HH only group, 13.6% (3/22) of the RE only group, 41.2% (7/17) of the HH/RE group and 11.5% (20/174) in the neither condition present group. There was a significant difference in the incidence of VFs between the HH/RE group and neither condition present group (p<0.05). The presence of VFs was significantly associated with the presence of either RE or HH. This association became more significant when HH and RE were present together in elderly Japanese people.


The Retina and Other Light-sensitive Ocular Clocks.
Ocular clocks, first identified in the retina, are also found in the retinal pigment epithelium (RPE), cornea, and ciliary body. The retina is a complex tissue of many cell types and considerable effort has gone into determining which cell types exhibit clock properties. Current data suggest that photoreceptors as well as inner retinal neurons exhibit clock properties with photoreceptors dominating in nonmammalian vertebrates and inner retinal neurons dominating in mice. However, these differences may in part reflect the choice of circadian output, and it is likely that clock properties are widely dispersed among many retinal cell types. The phase of the retinal clock can be set directly by light. In nonmammalian vertebrates, direct light sensitivity is commonplace among body clocks, but in mice only the retina and cornea retain direct light-dependent phase regulation. This distinguishes the retina and possibly other ocular clocks from peripheral oscillators whose phase depends on the pace-making properties of the hypothalamic central brain clock, the suprachiasmatic nuclei (SCN). However, in mice, retinal circadian oscillations dampen quickly in isolation due to weak coupling of its individual cell-autonomous oscillators, and there is no evidence that retinal clocks are directly controlled through input from other oscillators. Retinal circadian regulation in both mammals and nonmammalian vertebrates uses melatonin and dopamine as dark- and light-adaptive neuromodulators, respectively, and light can regulate circadian phase indirectly through dopamine signaling. The melatonin/dopamine system appears to have evolved among nonmammalian vertebrates and retained with modification in mammals. Circadian clocks in the eye are critical for optimum visual function where they play a role fine tuning visual sensitivity, and their disruption can affect diseases such as glaucoma or retinal degeneration syndromes.


Discovery of Potent Deuterated Compounds as Potential KRASG12D Inhibitors in Cancer Therapy.
The disclosure in this Patent Highlight describes a new class of deuterated compounds that bind directly to KRASG12D and block its activity. These exemplary deuterated compounds are potentially useful as pharmaceuticals that may possess desirable properties, including bioavailability, stability, and therapeutic index. This may have significant influence in drugs absorption, distribution, metabolism, excretion, and half-life when administered to a human or animal. The replacement of C-H with C-D increases the kinetic isotope effect, which makes the C-D bond up to ∼10 times stronger than the C-H bond.


High-throughput identification of novel conotoxins from the Chinese tubular cone snail (Conus betulinus) by multi-transcriptome sequencing.
The venom of predatory marine cone snails mainly contains a diverse array of unique bioactive peptides commonly referred to as conopeptides or conotoxins. These peptides have proven to be valuable pharmacological probes and potential drugs because of their high specificity and affinity to important ion channels, receptors and transporters of the nervous system. Most previous studies have focused specifically on the conopeptides from piscivorous and molluscivorous cone snails, but little attention has been devoted to the dominant vermivorous species. The vermivorous Chinese tubular cone snail, Conus betulinus, is the dominant Conus species inhabiting the South China Sea. The transcriptomes of venom ducts and venom bulbs from a variety of specimens of this species were sequenced using both next-generation sequencing and traditional Sanger sequencing technologies, resulting in the identification of a total of 215 distinct conopeptides. Among these, 183 were novel conopeptides, including nine new superfamilies. It appeared that most of the identified conopeptides were synthesized in the venom duct, while a handful of conopeptides were identified only in the venom bulb and at very low levels. We identified 215 unique putative conopeptide transcripts from the combination of five transcriptomes and one EST sequencing dataset. Variation in conopeptides from different specimens of C. betulinus was observed, which suggested the presence of intraspecific variability in toxin production at the genetic level. These novel conopeptides provide a potentially fertile resource for the development of new pharmaceuticals, and a pathway for the discovery of new conotoxins.


Metabolism of Indole-3-Acetic Acid: II. Oxindole Pathway in Parthenocissus tricuspidata Crown-Gall Tissue Cultures.
An indoleacetic acid oxidase preparation from an acetone powder of Parthenocissus tricuspidata crown-gall tissue has been examined. An intermediate in the reaction is 3-hydroxymethyloxindole and nonenzymic conversion of it to 3-methyleneoxindole was observed. Neither reaction mixtures nor 3-methyleneoxindole have any auxin-like activity in Avena or wheat coleoptile bioassays. In vivo studies show that although 53% decarboxylation of indoleacetic acid was observed in 48 hours, only a small amount of 3-methyloxindole could be recovered from the medium. The other decarboxylated products remain to be identified but are not 3-hydroxymethyloxindole or 3-methyleneoxindole.


Factors permitting prolonged translation by isolated pea chloroplasts.
The following parameters were found to prolong the time-course of translation by isolated pea (Pisum sativum, cv Progress No. 9) chloroplasts: addition of other amino acids (an effect synergistic with sufficient free Mg(2+)), use of lower light intensities, and additions of inorganic phosphate and ATP. In a chloroplast system which includes these parameters, active translation usually extends to almost an hour. The total amount of leucine incorporated is routinely 60 to 100 nanomoles/milligram chlorophyll and often 200 nanomoles/milligram chlorophyll. Accurate estimation of the amount of amino acid incorporated depends on supplying the labeled amino acid at a concentration sufficient to overcome isotope dilution effects from endogenous pools. Approximately 39 thylakoid and 60 stroma polypeptides were visible on autoradiographs after labeling with [(35)S]methionine. Label in a few of the polypeptide bands was increased or decreased by specific changes in the reaction conditions. Due to the long period of activity and the large number of labeled products, this chloroplast system should be useful for future studies of chloroplast translation.


A Numerical Study on 3D Printed Cementitious Composites Mixes Subjected to Axial Compression.
Aptly enabled by recent developments in additive manufacturing technology, the concept of functionally grading some cementitious composites to improve structural compression forms is warranted. In this work, existing concrete models available in Abaqus Finite Element (FE) packages are utilized to simulate the performance of some cementitious composites numerically and apply them to functional grading using the multi-layer approach. If yielding good agreement with the experimental results, two-layer and three-layer models case combinations are developed to study the role of layer position and volume. The optimal and sub-optimal performance of the multi-layer concrete configurations based on compressive strength and sustained strains are assessed. The results of the models suggest that layer volume and position influence the performance of multi-layer concrete. It is observed that when there exists a substantial difference in material strengths between the concrete mixes that make up the various layers of a functionally graded structure, the influence of position and of material volume are significant in a two-layer configuration. In contrast, in a three-layer configuration, layer position is of minimal effect, and volume has a significant effect only if two of the three layers are made from the same material. Thus, a multilayered design approach to compression structures can significantly improve strength and strain performance. Finally, application scenarios on some structural compression forms are shown, and their future trajectory is discussed.


The importance of keeping regular: accurate guidance to the public on low-risk drinking levels.
The aim of this study was to argue that recommendations to the general public on daily amounts for low-risk alcohol consumption must retain the word 'regular' in order to avoid being rejected. Narrative review of the evidence-base for daily limits to alcohol consumption, the guidance the public actually receives in the UK and media reactions to this guidance. Evidence for daily limits (not more than 3-4 units for men and 2-3 units for women) rests on epidemiological surveys that enquire about 'average' or 'usual' amounts of consumption and this is reflected by the use of 'regular' or 'consistent' in the UK Government's Sensible Drinking report in 1995 and in guidance currently issued by the English Department of Health. In contrast, guidance the public actually receives often omits the word 'regular' and implies that the limits in question are maximum daily amounts. Media reactions to this inaccurate information suggest that the general public is likely to find these recommendations incredible and to reject them. If guidance to the public on daily drinking amounts is to stand any chance of being credible and effective, it must be accurate and must therefore retain the word 'regular'.


Why is now the best time for approaching the significant relation between "life and medicine".
The present paper is aimed to analyze the need for an adequate engagement in a better understanding of the relation between "Life and Medicine", within the increasing importance of the patient's point of view, while quality of life is managed within medicine and even going beyond. It is necessary to reconsider the essential role of communication in an adequate offering of the right answers in accordance with the changes in medical care, quality of life being one benefit. Science should inform the news agenda on the way of building a collaborative environment, turning up the conversation focused on patients' lives, while practicing medicine with an open heart for the physician-patient-family relationship and based on models of quality of life outcomes. That is why it is important to create new knowledge and competencies starting from intangible resources such as an engagement as a consequence of a communication programme which produces an increased level of perception of the outcomes of the necessary mature actions as meeting and surpassing patient expectations, not forgetting the vulnerability to the way in which choices are described. From here is resulting the imperative of the development of better abilities in innovation, differentiation, branding and patient-driven health care service, largely opening the window of opportunity for the educational mission to educate marketers who make a difference by taking the lead from a strategic planning position.


Characterization of Uterine Motion in Early Gestation Using MRI-Based Motion Tracking.
Magnetic resonance imaging (MRI) is a promising non-invasive imaging technique that can be safely used to study placental development and function. However, studies of the human placenta performed by MRI are limited by uterine motion and motion in the uterus during MRI remains one of the major limiting factors. Here, we aimed to investigate the characterization of uterine activity during MRI in the second trimester of pregnancy using MRI-based motion tracking. In total, 46 pregnant women were scanned twice (first scan between 14 and 18 weeks and second scan between 19 and 24 weeks), and 20 pregnant subjects underwent a single MRI between 14 and 18 weeks GA, resulting in 112 MRI scans. An MRI-based algorithm was used to track uterine motion in the superior-inferior and left-right directions. Uterine contraction and maternal motion cases were separated by the experts, and unpaired Wilcoxon tests were performed within the groups of gestational age (GA), fetal sex, and placental location in terms of the overall intensity measures of the uterine activity. In total, 22.3% of cases had uterine contraction during MRI, which increased from 18.6% at 14-18 weeks to 26.4% at 19-24 weeks GA. The dominant direction of the uterine contraction and maternal motion was the superior to the inferior direction during early gestation.


Psychopathology in children of alcoholics.
To assess psychopathology in 125 and 158 children who are offspring of alcoholic and control parents. Parents and children were interviewed by means of structured interviews. Parents were interviewed about themselves and about their children. Teacher reports were obtained. A total of 158 young people ages 6 to 18 years were in the study, although some of the analyses use only 125. Children of alcoholic parents showed higher rates of oppositional and conduct disorders but not attention deficit disorder. Children of alcoholic parents did not have significantly higher rates of depression, but they may be at risk for anxiety. These children also showed increased incidence of alcohol and other substance use but not abuse or dependence as defined by DSM-III. Few differences were detected with respect to self-esteem and achievement tests among the groups. There were no differences in the rates of psychopathology between offspring of alcoholic versus antisocial parents. These data indicate that children of alcoholics exhibit high rates of psychopathology and may be at risk specifically for oppositional and conduct disorders but not for depression. There are few differences between alcoholics and controls with respect to self-esteem and achievement tests.


Case Report: Two New Cases of Autosomal-Recessive Hypertrophic Cardiomyopathy Associated With TRIM63-Compound Heterozygous Variant.
Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary diseases, and it is associated with fatal complications. The clinical heterogeneity of HCM requires risk prediction models to identify patients at a high risk of adverse events. Most HCM cases are caused by mutations in genes encoding sarcomere proteins. However, HCM is associated with rare genetic variants with limited data about its clinical course and prognosis, and existing risk prediction models are not validated for such patients' cohorts. TRIM63 is one of the rare genes recently described as a cause of HCM with autosomal-recessive inheritance. Herein, we present two cases of HCM associated with TRIM63-compound heterozygous variants in young male sportsmen. They demonstrated progressively marked hypertrophy, advanced diastolic dysfunction, a significant degree of fibrosis detected by magnetic resonance imaging, and clear indications for implantable cardioverter-defibrillator. One of the cases includes the first description of TRIM63-HCM with extreme hypertrophy. The presented cases are discussed in light of molecular consequences that might underlie cardiac and muscle phenotype in patients with mutations of TRIM63, the master regulator of striated muscle mass.


Melotenine A, a cytotoxic monoterpenoid indole alkaloid from Melodinus tenuicaudatus.
Melotenine A (1), an unprecedented skeleton with a 6/5/5/6/7 pentacyclic rearranged ring system, was isolated from Melodinus tenuicaudatus. The structure was elucidated by means of spectroscopic methods and further confirmed by the single-crystal X-ray diffraction analysis. A possible biogenesis was also proposed. Melotenine A exhibited potential inhibition against five human cancer cell lines.


Availability and affordability of priority life-saving medicines for under-five children in health facilities of Tigray region, northern Ethiopia.
In developing countries, child health outcomes are influenced by the non-availability of priority life-saving medicines at public sector health facilities and non-affordability of medicines at private medicine outlets. This study aimed to assess availability, price components and affordability of priority life-saving medicines for under-five children in Tigray region, Northern Ethiopia. A cross-sectional study was conducted in Tigray region from December 2015 to July 2016 using a standard method developed by the World Health Organization and Health Action International (WHO/HAI). Data on the availability and price of 27 priority life-saving medicines were collected from 31 public and 10 private sectors. Availability and prices were expressed in percent and median price ratios (MPRs), respectively. Affordability was reported in terms of the daily wage of the lowest-paid unskilled government worker. The overall availability of priority life-saving drugs in this study was low (34.1%). The average availabilities of all surveyed medicines in public and private sectors were 41.9 and 31.5%, respectively. The overall availability of medicines for malaria was found to be poor with average values of 29.3% for artemisinin combination therapy tablet, 19.5% for artesunate injection and 0% for rectal artesunate. Whereas, the availability of oral rehydration salt (ORS) and zinc sulphate dispersible tablets for the treatment of diarrhea was moderately high (90% for ORS and 82% for zinc sulphate). Medicines for pneumonia showed an overall percent availability in the range of 0% (ampicillin 250 mg and 1 g powder for injection and oxygen medicinal gas) to 100% (amoxicillin 500 mg capsule). The MPRs of 12 lowest price generic medicines were 1.5 and 2.7 times higher than the international reference prices (IRPs) for the private and public sectors, respectively. About 30% of priority life-saving medicines in the public sector and 50% of them in the private sector demanded above a single daily wages to purchase the standard treatment of the prevalent diseases of children. The lower availability, high price and low affordability of lowest price generic priority life-saving medicines in public and private sectors reflect a failure to implement the health policy on priority life-saving medicines in the region.


Potential therapeutic effects of avenanthramide-C against lung toxicity caused by silver nanoparticles injection in rats.
Most clinical investigations about the impact of nanoparticles on cells and tissues show that nanoparticles may enter the human body by means of respiratory tracts. Humans, animals, plants and environments are continually presented to a wide scope of business items containing silver nanoparticles (Ag NPs) in their piece. Ag NPs, utilized in various consumer products as room showers, surface cleaners, wound dressings, food storage containers and many textiles. The current examination planned to explore the defensive role of Avenanthramide-C (Avns) contrary to the lung toxicity initiated by Ag NPs injection in rats. 40 male Wistar rats were separated into 4 groups (Gp1, control; Gp2, Avns; Gp3, Ag NPs; Gp4, Ag NPs+Avns). Current results revealed that; Ag NPs induced a significant depletion in RBCs count, hemoglobin, platelets counts and a significant increase in total WBCs, lung injury, cyclooxygenase-2 (COX2) and TNFα expressions as compared to control. Treatments of Ag NPs with Avenanthramide-C extract (Ag NPs+Avns) improved the lung structure and blood complete pictures as compared to Ag NPs group.


Perceived Barriers to Including Students with Visual Impairments in General Physical Education.
The purpose of this study was to examine barriers perceived by teachers when including students with visual impairments in general physical education. Teachers (52 males, 96 females) who had children with visual impairments in their physical education classes were surveyed prior to in-service workshop participation. The most prevalent barriers were professional preparation, equipment, programming, and time. A logistic regression analysis, regressing gender, in-service training, number of students with visual impairments taught, masters degree attained, masters hours spent on visual impairments (yes or no), undergraduate hours spent on visual impairments (yes or no), and years of experience failed to indicate significant predictors of professional preparation as a barrier, Model χ2 (6, n = 148) = 4.48, p > .05.


[Efficacy of Tranexamic Acid to decrease perioperative bleeding in primary total reverse arthroplasty].
Reverse shoulder arthroplasty improves function and pain in patients with glenohumeral osteoarthritis and rotator cuff deficiency. However, it is associated with significant blood loss and postoperative hematoma (PO) formation. To determine the efficacy of tranexamic acid (ATXM) to decrease perioperative bleeding in patients undergoing primary reverse shoulder arthroplasty. Cohort of 31 patients undergoing reverse primary arthroplasty, in two groups: group A (17 patients) were given 1 g IV of preoperative tranexamic acid and group B (14 patients) to whom it was not administered. Preoperative hemoglobin and hematocrit were recorded and then after 24 hours of surgery, and quantified bleeding in drainage at 24 hours, as well as blood transfusion needs. The changes presented were statistically compared. Demographic data did not show significant differences between the two groups. There is a tendency to reduce bleeding in surgical drainage in patients with ATXM (115.6 ml vs. 162.65 ml p = 0.0768), in the decrease of hemoglobin (2.16 g/dl vs. 2.79 g/dl p = 0.1257) and hematocrit (6.67% vs. 7.95% p = 0.3431). There was a significant reduction in the use of blood products in patients with ATXM (p = 0.0441). There is a tendency to have less PO bleeding in patients undergoing primary reverse arthroplasty with the use of ATXM and a lower PO blood transfusion requirement.


Intestinal epithelial cell-derived semaphorin 7A negatively regulates development of colitis via αvβ1 integrin.
The intestinal immune system is constantly challenged by commensal bacteria; therefore, it must maintain quiescence via several regulatory mechanisms. Although intestinal macrophages (Ms) have been implicated in repression of excessive inflammation, it remains unclear how their functions are regulated during inflammation. In this study, we report that semaphorin 7A (Sema7A), a GPI-anchored semaphorin expressed in intestinal epithelial cells (IECs), induces IL-10 production by intestinal Mϕs to regulate intestinal inflammation. Sema7A-deficient mice showed severe signs of dextran sodium sulfate-induced colitis due to reduced intestinal IL-10 levels. We further identified CX3CR1(+)MHC class II(int)F4/80(hi)CD11b(hi) Mϕs as the main producers of IL-10 via αvβ1 integrin in response to Sema7A. Notably, Sema7A was predominantly expressed on the basolateral side of IECs, and its expression pattern was responsible for protective effects against dextran sodium sulfate-induced colitis and IL-10 production by Mϕs during interactions between IECs and Mϕs. Furthermore, we determined that the administration of recombinant Sema7A proteins ameliorated the severity of colitis, and these effects were diminished by IL-10-blocking Abs. Therefore, our findings not only indicate that Sema7A plays crucial roles in suppressing intestinal inflammation through αvβ1 integrin, but also provide a novel mode of IL-10 induction via interactions between IECs and Mϕs.


Cardinality Balanced Multi-Target Multi-Bernoulli Filter with Error Compensation.
The cardinality balanced multi-target multi-Bernoulli (CBMeMBer) filter developed recently has been proved an effective multi-target tracking (MTT) algorithm based on the random finite set (RFS) theory, and it can jointly estimate the number of targets and their states from a sequence of sensor measurement sets. However, because of the existence of systematic errors in sensor measurements, the CBMeMBer filter can easily produce different levels of performance degradation. In this paper, an extended CBMeMBer filter, in which the joint probability density function of target state and systematic error is recursively estimated, is proposed to address the MTT problem based on the sensor measurements with systematic errors. In addition, an analytic implementation of the extended CBMeMBer filter is also presented for linear Gaussian models. Simulation results confirm that the proposed algorithm can track multiple targets with better performance.


Color Doppler ultrasonography for prediction of malignant ovarian tumors.
The purpose of this cross-sectional study was to evaluate whether the pulsatility index determined by the color Doppler sonography could be used to distinguish between benign and malignant ovarian tumors. A total of 120 patients who had their ovarian tumors removed surgically at the Department of Obstetrics and Gynecology, Faculty of Medicine Siriraj Hospital, Mahidol University were included in the study. Each patient had color Doppler sonography performed prior to laparotomy. The Doppler results were compared to the histological diagnosis of the ovarian tumors. Of the 113 patients whose intratumoral blood flow could be evaluated, the pulsatility index was significantly lower in malignant lesions than in benign lesions (0.85 +/- 0.46 vs 1.63 +/- 0.64, p<0.001). The sensitivity, specificity, and accuracy of the pre-operative pulsatility index (< or = 1.0) in detecting malignant ovarian tumors were 82.9 per cent, 80.8 per cent, and 81.4 per cent, respectively; with 65.9 per cent positive predictive value, 91.3 per cent negative predictive value, 19.2 per cent false positive rate, and 17.1 per cent false negative rate. The present results suggest that color Doppler sonography may be a useful clinical tool in the pre-operative evaluation of ovarian masses. However, the pulsatility indexes showed considerable overlap between benign and malignant lesions, indicating that color Doppler sonography has limitations in the differentiation of benign from malignant ovarian masses. The cost of the equipment and experience requirement also limits its use in general gynecologic practice.


Leishmanicidal activity of aurones.
This is the first report on aurones as a new class of natural products with leishmanicidal activity. A series of aurones with drug-potential for Leishmania infections was identified in vitro using both a direct cytotoxicity test against extracellular promastigotes of Leishmania donovani, L. infantum, L. enriettii, and L. major, and a test against intracellular amastigote L. donovani residing within murine macrophages. The compounds proved to be active at concentrations in the microgram range between 0.4 and 5.0 microg/ml. When tested against murine bone marrow-derived macrophages as a mammalian host cell control, all compounds showed only moderate cytotoxicity (EC50 2.32-25.0 microg/ml).


Fast-track cardiac care for adult cardiac surgical patients.
Fast-track cardiac care is a complex intervention involving several components of care during cardiac anaesthesia and in the postoperative period, with the ultimate aim of early extubation after surgery, to reduce length of stay in the intensive care unit and in the hospital. Safe and effective fast-track cardiac care may reduce hospital costs. This is an update of a Cochrane review first published in 2003, updated in 2012 and updated now in 2016. To determine the safety and effectiveness of fast-track cardiac care compared with conventional (not fast-track) care in adult patients undergoing cardiac surgery. Fast-track cardiac care intervention includes administration of low-dose opioid-based general anaesthesia or use of a time-directed extubation protocol, or both. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 5), MEDLINE (January 2012 to May 2015), Embase (January 2012 to May 2015), the Cumulative Index to Nursing and Allied Health Literature (CINAHL; January 2012 to May 2015) and the Institute for Scientific Information (ISI) Web of Science (January 2012 to May 2015), along with reference lists of articles, to identify additional trials. We applied no language restrictions. We included all randomized controlled trials of adult cardiac surgical patients (coronary artery bypass grafts, aortic valve replacement, mitral valve replacement) that compared fast-track cardiac care and conventional (not fast-track) care groups. We focused on the following fast-track interventions, which were designed for early extubation after surgery: administration of low-dose opioid-based general anaesthesia during cardiac surgery and use of a time-directed extubation protocol after surgery. The primary outcome was risk of mortality. Secondary outcomes included postoperative complications, reintubation within 24 hours of surgery, time to extubation, length of stay in the intensive care unit and in the hospital, quality of life after surgery and hospital costs. Two review authors independently assessed trial quality and extracted study data. We contacted study authors for additional information. We calculated a Peto odds ratio (OR) for risk of mortality and used a random-effects model to report risk ratio (RR), mean difference (MD) and 95% confidence intervals (95% CIs) for all secondary outcomes. We included 28 trials (4438 participants) in the updated review. We considered most participants to be at low to moderate risk of death after surgery. We assessed two studies as having low risk of bias and 11 studies high risk of bias. Investigators reported no differences in risk of mortality within the first year after surgery between low-dose versus high-dose opioid-based general anaesthesia groups (OR 0.53, 95% CI 0.25 to 1.12; eight trials, 1994 participants, low level of evidence) and between a time-directed extubation protocol versus usual care (OR 0.80, 95% CI 0.45 to 1.45; 10 trials, 1802 participants, low level of evidence).Researchers noted no significant differences between low-dose and high-dose opioid-based anaesthesia groups in the following postoperative complications: myocardial infarction (RR 0.98, 95% CI 0.48 to 1.99; eight trials, 1683 participants, low level of evidence), stroke (RR 1.17, 95% CI 0.36 to 3.78; five trials, 562 participants, low level of evidence) and tracheal reintubation (RR 1.77, 95% CI 0.38 to 8.27; five trials, 594 participants, low level of evidence).Comparisons with usual care revealed no significant differences in the risk of postoperative complications associated with a time-directed extubation protocol: myocardial infarction (RR 0.59, 95% CI 0.27 to 1.31; eight trials, 1378 participants, low level of evidence), stroke (RR 0.85, 95% CI 0.33 to 2.16; 11 trials, 1646 participants, low level of evidence) and tracheal reintubation (RR 1.34, 95% CI 0.74 to 2.41; 12 trials, 1261 participants, low level of evidence).Although levels of heterogeneity were high, low-dose opioid anaesthesia was associated with reduced time to extubation (reduction of 4.3 to 10.5 hours, 14 trials, 2486 participants, low level of evidence) and length of stay in the intensive care unit (reduction of 0.4 to 7.0 hours, 12 trials, 1394 participants, low level of evidence). Use of a time-directed extubation protocol was associated with reduced time to extubation (reduction of 3.7 to 8.8 hours, 16 trials, 2024 participants, low level of evidence) and length of stay in the intensive care unit (reduction of 3.9 to 10.5 hours, 13 trials, 1888 participants, low level of evidence). However, these two fast-track care interventions were not associated with reduced total length of stay in the hospital (low level of evidence). Low-dose opioid-based general anaesthesia and time-directed extubation protocols for fast-track interventions have risks of mortality and major postoperative complications similar to those of conventional (not fast-track) care, and therefore appear to be safe for use in patients considered to be at low to moderate risk. These fast-track interventions reduced time to extubation and shortened length of stay in the intensive care unit but did not reduce length of stay in the hospital.


Computerised patient record with distributed objects.
The vast spectrum of information and functionality requirements imposed on a Computerised Patient Record (CPR), fueled by an ever changing and expanding business model demands information system interoperability. The management of information, created across the continuum of care, and associated information system functionality, can not be provided by data interchange to and from monolithic applications. WebDoctor is a Computerised Patient Record (CPR) which is fully used at the Institute of Oncology in Ljubljana, Slovenia--a hospital with 500 beds and more than 200 users, all of them medical professionals. The data are stored in an underlying Oracle hospital data base. For logging the username and password security is used. WebDoctor uses Internationalization APIs. Currently GUI is currently written in Slovenian language, but can be easily adapted to any other language. It is available in either Metal or Windows look. Search for patients is based on CPR No. or partial data from demographics. All the available patients data can be found on a single screen divided into several tab sections. The tab sections cover general and speciality data. The general data include demographics, admissions and diagnoses, meanwhile the speciality data are divided into Labs where data are represented numerically by date or by type and graphically with the ability of detailed view in separate window, Radiology where results are represented in textual form as well as pictures together with a special viewer to provide detailed analyses and Radioisotopes where results are also being represented in textual form together with a graphical representation. WebDoctor is running on virtually any platform. It achieved the 100% Java Certification which places the application among the firsts if not the first of this kind in the healthcare industry. It excels with a small and light client which doesn't exceed the 150K.


Functional analysis of mouse hepatocytes differing in DNA content: volume, receptor expression, and effect of IFNgamma.
Polyploidy and binuclearity are characteristics of the mammalian liver. Increasing polyploidisation occurs with age and after administration of various drugs and chemicals. This study was designed to examine the function of ploidy by addressing several questions: (1) Does the increase in size of polyploid hepatocytes have any physiological function by altering surface receptor expression such as intercellular adhesion molecule-1 (ICAM-1, CD54) or IFNgammaR? and (2) Do polyploid cells respond differently to inflammatory cytokines such as interferon gamma (IFNgamma)? We have developed a method to accurately measure the volume of live isolated hepatocytes using confocal microscopy and image analysis. Using flow cytometry, we have shown that the expression of ICAM-1 increases with increasing DNA content and IFNgammaR is not detectable on isolated mouse hepatocytes. Diploid (2n), tetraploid (4n) and octoploid (8n) hepatocytes were found to be equally susceptible to IFNgamma-induced apoptosis in vitro. Although the function of polyploidy remains unanswered, we have described some of the characteristics of polyploidy in isolated hepatocytes and in vitro.


Manipulation of depth cues in photographs.
In a previous paper, the depth cues contained in a photograph were described. This paper looks at the photographic controls available to the photographer or illustrator when manipulating depth cues. The manipulations described here are mostly those achieved in the camera, although considerable control is available through computer manipulation or printing techniques after the photograph is taken.


Genotoxicity of 2-bromo-3'-chloropropiophenone.
Impurities are present in any drug substance or drug product. They can be process-related impurities that are not completely removed during purification or are formed due to the degradation of the drug substance over the product shelf-life. Unlike the drug substance, impurities generally do not have beneficial effects and may present a risk without associated benefit. Therefore, their amount should be minimized. 2-Bromo-3'-chloropropiophenone (BCP) is an impurity of bupropion, a second-generation antidepressant and a smoking cessation aid. The United States Pharmacopeia recommends an acceptable level for BCP that is not more than 0.1% of the bupropion. Because exposure to genotoxic impurities even at low levels is of significant concern, it is important to determine whether or not BCP is genotoxic. Therefore, in this study the Ames test and the in vitro micronucleus assay were conducted to evaluate the genotoxicity of BCP. BCP was mutagenic with S9 metabolic activation, increasing the mutant frequencies in a concentration-dependent manner, up to 22- and 145-fold induction over the controls in Salmonella strains TA100 and TA1535, respectively. BCP was also positive in the in vitro micronucleus assay, resulting in up to 3.3- and 5.1-fold increase of micronucleus frequency for treatments in the absence and presence of S9, respectively; and 9.9- and 7.4-fold increase of aneuploidies without and with S9, respectively. The addition of N-acetyl-l-cysteine, an antioxidant, reduced the genotoxicity of BCP in both assays. Further studies showed that BCP treatment resulted in induction of reactive oxygen species (ROS) in the TK6 cells. The results suggest that BCP is mutagenic, clastogenic, and aneugenic, and that these activities are mediated via generation of reactive metabolites.


Sclerostin and Its Involvement in the Pathogenesis of Idiopathic Scoliosis.
Idiopathic scoliosis is a disorder of unknown etiology. Bone biopsies from idiopathic scoliosis patients revealed changes at cellular and molecular level. Osteocytic sclerostin is downregulated, and serum level of sclerostin is decreased. Osteocytes in idiopathic scoliosis appear to be less active with abnormal canaliculi network. Differentiation of osteoblasts to osteocytes is decelerated, while Wnt/β-catenin signaling pathway is overactivated and affects normal bone mineralization that leads to inferior mechanical properties of the bone, which becomes susceptible to asymmetrical forces and causes deformity of the spinal column. Targeting bone metabolism during growth by stimulating sclerostin secretion from osteocytes and restoring normal function of Wnt/β-catenin signaling pathway could, in theory, increase bone strength and prevent deterioration of the scoliotic deformity.


Regulation of skin and islet allograft survival in mice treated with costimulation blockade is mediated by different CD4+ cell subsets and different mechanisms.
Donor-specific transfusion (DST) and a brief course of anti-CD154 monoclonal antibody (mAb) induces permanent islet and prolonged skin allograft survival in mice. Induction of skin allograft survival requires the presence of CD4 cells and deletion of alloreactive CD8 cells. The specific roles of CD4 and CD4CD25 cells and the mechanism(s) by which they act are not fully understood. We used skin and islet allografts, a CD8 T cell receptor (TCR) transgenic model system, and in vivo depleting antibodies to analyze the role of CD4 cell subsets in regulating allograft survival in mice treated with DST and anti-CD154 mAb. Deletion of CD4 or CD25 cells during costimulation blockade induced rapid rejection of skin but only minimally shortened islet allograft survival. Deletion of CD4 or CD25 cells had no effect upon survival of healed-in islet allografts, and CD25 cell deletion had no effect upon healed-in skin allograft survival. In the TCR transgenic model, DST plus anti-CD154 mAb treatment deleted alloreactive CD8 T cells, and anti-CD4 mAb treatment prevented that deletion. In contrast, injection of anti-CD25 mAb did not prevent alloreactive CD8 T cell deletion. These data document that (1) both CD4CD25 and CD4CD25 cells are required for induction of skin allograft survival, (2) CD4CD25 T cells are not required for alloreactive CD8 T cell deletion, and (3) CD4CD25 regulatory cells are not critical for islet allograft tolerance. It appears that skin and islet transplantation tolerance are mediated by different CD4 cell subsets and different mechanisms.


Inhibition of E2-induced expression of BRCA1 by persistent organochlorines.
Environmental persistent organochlorines (POCs) biomagnify in the food chain, and the chemicals are suspected of being involved in a broad range of human malignancies. It is speculated that some POCs that can interfere with estrogen receptor-mediated responses are involved in the initiation and progression of human breast cancer. The tumor suppressor gene BRCA1 plays a role in cell-cycle control, in DNA repair, and in genomic stability, and it is often downregulated in sporadic mammary cancers. The aim of the present study was to elucidate whether POCs have the potential to alter the expression of BRCA1. Using human breast cancer cell lines MCF-7 and MDA-MB-231, the effect on BRCA1 expression of chemicals belonging to different classes of organochlorine chemicals (the pesticide toxaphene, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and three polychlorinated biphenyls [PCB#138, PCB#153 and PCB#180]) was measured by a reporter gene construct carrying 267 bp of the BRCA1 promoter. A twofold concentration range was analyzed in MCF-7, and the results were supported by northern blot analysis of BRCA1 mRNA using the highest concentrations of the chemicals. All three polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin reduced 17beta-estradiol (E2)-induced expression as well as basal reporter gene expression in both cell lines, whereas northern blot analysis only revealed a downregulation of E2-induced BRCA1 mRNA expression in MCF-7 cells. Toxaphene, like E2, induced BRCA1 expression in MCF-7. The present study shows that some POCs have the capability to alter the expression of the tumor suppressor gene BRCA1 without affecting the cell-cycle control protein p21Waf/Cip1. Some POCs therefore have the potential to affect breast cancer risk.


[Risk factors of diabetic nephropathy progression in patients with a long history of diabetic mellitus as shown by a retrospective analysis].
To ascertain prognostic factors defining the risk of progression of diabetic nephropathy (DN) in patients with diabetes mellitus (DM) type 1 and 2 suffering from DM over 20 years. A one-stage comparative trial studied 141 patients with DM type 1 and 149 patients with DM type 2 with DN of different severity and 20 year history of the disease. The follow-up study covered 34 CD-1 patients and 45 CD-2 patients with normo-, micro- and macroalbuminuria. The groups were made by the principle case-control. The control group consisted of 24 patients with DM-1 and 19 patients with DM-2 having stable renal function, the case group consisted of 10 and 26 patients, respectively, with DN progression. A total duration of the follow-up was 6 years. The end point of the analysis was chronic renal failure (CRF). Multivariate regression analysis has shown that the following risk factors of microalbuminuria in DM-1 and DM-2 are independent: the level of HbA1c (RR 3,1 and 2.7, respectively) and duration of arterial hypertension (RR 2.1 and 2.0, respectively); proteinuria - HbA1c (RR 4.4 and 3.4, respectively), systolic blood pressure (RR 3.4 and 3.1, respectively), CRF - systolic blood pressure (RR 5.0 and 4.5, respectively), triglycerides (RR 2.8 and 4.9, respectively) and hemoglobin (RR 3.3 and 5.3, respectively). IN DM-2 other risk factors of CRF were male sex (RR 2.0), family history of hypertension (RR 3.8) and 24-h proteinuria > 2 g (RR 6.7). Inadequate compensation of carbohydrate metabolism (HbA1c), arterial hypertension and dyslipidemia are main risk factors of MAU and its progression to proteinuria in DM patients. In progression of DN to CRF main risk factors are hypertension, dyslipidemia and severity of anemia.


First trimester diagnosis of Pallister-Killian syndrome in a fetus with suggestive abnormalities.
Pallister-Killian Syndrome is a rare, sporadic chromosomal disorder characterized by a tetrasomy 12p often in mosaic. It is only in 2000 that the first case of PKS was diagnosed in the first trimester further to an increased nuchal translucency. Report a new case. To our knowledge, we present the first case of early prenatal diagnosis of Pallister Killian Syndrome due to the presence of an increased nuchal translucency, a diaphragmatic hernia, a typical facial dysmorphism and a micromelia of a predominantly rhizomelic type . A chorionic cells biopsy showed a normal karyotype. The diagnosis was revealed on cytogenetic analysis of amniotic fluid sampling. The main ultrasound indicators of PKS seem to be: Hydramnios, congenital diaphragmatic hernia (CDH) and a micromelia of a rhizomelic type. The Hydrops fetalis, hygroma coli or increased nuchal translucency (INT), fetal overgrowth, ventriculomegaly and presence of a sacral appendix are less common. The amniocentesis with the study of the karyotype on amniotic cells is considered to be the gold standard for the diagnosis of PKS. A good morphological study during the first trimester in search of ultrasound abnormalities highly suggestive of PKS is able to direct the cytogenetic study.


Anti Thymocyte Globulin-Based Treatment for Acquired Bone Marrow Failure in Adults.
Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG as well. For this review, we extensively searched the present literature for evidence that ATG can lead to enduring remissions in different forms of acquired multi- or single-lineage bone marrow failure. We conclude that ATG-based therapy can lead to an enduring hematopoietic response and increased overall survival (OS) in patients with acquired aplastic aplasia. In patients with hypocellular myelodysplastic syndrome, ATG can lead to a hematological improvement without changing the OS. ATG seems less effective in acquired single-lineage failure diseases like Pure Red Cell Aplasia, Amegakaryocytic Thrombocytopenia and Pure White Cell Aplasia, suggesting a different pathogenesis in these bone marrow failure states compared to aplastic anemia. T cell depletion is hypothesized to play an important role in the beneficial effect of ATG but, as ATG is a mixture of polyclonal antibodies binding to different antigens, other anti-inflammatory or immunomodulatory effects could play a role as well.


GaAs junction field effect transistors for low-temperature environments.
Thermal, electrical, and noise characteristics of a GaAs junction FET are described. Low voltage noise [1.5+/-0.2 nV/(Hz)(1/2) at T =4.2 K] and insensitivity to temperature change in the range 1.3< or =T < or =300 K make it suitable for low-temperature applications.


The role of proteomics in depression research.
Depression is a severe neuropsychiatric disorder affecting approximately 10% of the world population. Despite this, the molecular mechanisms underlying the disorder are still not understood. Novel technologies such as proteomic-based platforms are beginning to offer new insights into this devastating illness, beyond those provided by the standard targeted methodologies. Here, we will show the potential of proteome analyses as a tool to elucidate the pathophysiological mechanisms of depression as well as the discovery of potential diagnostic, therapeutic and disease course biomarkers.


[Adjuvant chemotherapy using S-1 for curatively resected gastric cancer-the nationwide clinical trial].
Actually there has been no established adjuvant therapy for curable gastric cancer. Thus it is strongly recommended in the guidelines to actively carry out clinical trials. A large scale clinical trial on adjuvant chemotherapy for gastric cancer using S-1 (ACTS-GC) started in 2001. This was the first large trial having the surgery alone as control after 1980. The target population was Stage II, IIIA, IIIB, and the expected hazard ratio was less than 0.70. Between October 2001 and December 2004, for 3 years and 2 months, 1,056 patients were enrolled. Thus it was proven that we should carry out a pivotal study instead of making meta-analysis in the field of gastric cancer. Certainly, the results of this trial will strongly affect the clinical practice in Japan. If the results are negative, the use of adjuvant chemotherapy in practice and in social insurance might be restricted.


Effect of microwaves on the current-phase relation of superconductor-normal-metal-superconductor josephson junctions.
We investigate the current-phase relation (CPR) of long diffusive superconductor-normal-metal-superconductor (Nb/Ag/Nb) Josephson junctions in thermodynamic equilibrium and under microwave irradiation. While in equilibrium good agreement with the predictions of quasiclassical theory is found, we observe that the shape of the CPR can be strongly affected by microwave irradiation. Close to a Josephson-phase difference phi approximately pi, the supercurrent can be strongly suppressed when increasing the rf power. Our results can be understood in terms of microwave excitation of low-lying Andreev bound states across the minigap in the junction. In the frequency interval studied, this mechanism becomes important, when the minigap closes at phi approximately pi.


Namibia: HIV and pre-employment testing.
In May 2000, the Namibian Labour Court ruled that the Namibian Defense Force (NDF) is not entitled to exclude people from recruitment on the grounds of their HIV status. Acting Judge Harold Levy had ruled that excluding a person from employment purely on the basis of being HIV positive was unfair labor practice and constituted discrimination. However, this will not be the end of the matter. Defense Minister Erkki Nghimtina said that an appeal would be lodged against the judgement in the interest of ensuring that Namibia had a healthy and strong military. AIDS Law Unit Lawyer, Michaela Figueira, lauded the judgement as a brilliant breakthrough, which put Namibia law on HIV/AIDS in the forefront of legal developments in the field internationally. "We will appeal", Nghimtina commented, when approached at the National Assembly. The judgement, he added, was tantamount to allowing for the recruitment into the NDF of blind and crippled people. Nghimtina said he still stood by statements he had made in the National Assembly 2 weeks before, when the Minister told fellow Parliamentarians that the NDF could not recruit HIV positive people because they were ill, and the country could not be defended by ill persons. "We need a strong (defense) force--a healthy force", he said. "We have to have physically strong, healthy people, who can carry out hard tasks. This, we cannot compromise". Commenting on the unanimous testimony from both sides in the Labor Court case, that an HIV positive status, did not necessarily mean that a person was in any way physically unfit for military duty. Nghimtina answered that the NDF needed to recruit members for the long term. People with HIV, he added, could be employed elsewhere, but not in the NDF.


Improved Glass Surface Passivation for Single-Molecule Nanoarrays.
Single-molecule fluorescence techniques provide a critical tool for probing biomolecular and cellular interactions with unprecedented resolution and precision. Unfortunately, many of these techniques are hindered by a common problem, namely, the nonspecific adsorption of target biomolecules. This issue is mostly addressed by passivating the glass surfaces with a poly(ethylene glycol) (PEG) brush. This is effective only at low concentrations of the probe molecule because there are defects inherent to polymer brushes formed on glass coverslips due to the presence of surface impurities. Tween-20, a detergent, is a promising alternative that can improve surface passivation, but it is incompatible with living cells, and it also possesses limited selectivity for glass background over metallic nanoparticles, which are frequently used as anchors for the probe molecules. To address these issues, we have developed a more versatile method to improve the PEG passivation. A thin film of hydrogen silsesquioxane (HSQ) is spin-coated and thermally cured on glass coverslips in order to cover the surface impurities. This minimizes the formation of PEG defects and reduces nonspecific adsorption, resulting in an improvement comparable to Tween-20 treatment. This approach was applied to single-molecule nanoarrays of streptavidin bound to AuPd nanodots patterned by e-beam lithography (EBL). The fluorescence signal to background ratio (SBR) on HSQ-coated glass was improved by ∼4-fold as compared to PEG directly on glass. This improvement enables direct imaging of ordered arrays of single molecules anchored to lithographically patterned arrays of metallic nanodots.


Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction.
TNF is a key inflammatory cytokine. Using a modified tandem affinity purification approach, we identified HOIL-1 and HOIP as functional components of the native TNF-R1 signaling complex (TNF-RSC). Together, they were shown to form a linear ubiquitin chain assembly complex (LUBAC) and to ubiquitylate NEMO. We show that LUBAC binds to ubiquitin chains of different linkage types and that its recruitment to the TNF-RSC is impaired in TRADD-, TRAF2-, and cIAP1/2- but not in RIP1- or NEMO-deficient MEFs. Furthermore, the E3 ligase activity of cIAPs, but not TRAF2, is required for HOIL-1 recruitment to the TNF-RSC. LUBAC enhances NEMO interaction with the TNF-RSC, stabilizes this protein complex, and is required for efficient TNF-induced activation of NF-kappaB and JNK, resulting in apoptosis inhibition. Finally, we demonstrate that sustained stability of the TNF-RSC requires LUBAC's enzymatic activity, thereby adding a third form of ubiquitin linkage to the triggering of TNF signaling by the TNF-RSC.


Small extracellular vesicles containing miR-30a-3p attenuate the migration and invasion of hepatocellular carcinoma by targeting SNAP23 gene.
Cancer cells under hypoxic, endoplasmic reticulum, and reactive oxygen species stress secrete copious amounts of small extracellular vesicles (sEVs) to promote tumor metastasis. The effects of blocking stress-induced sEV release on tumor metastasis remain unknown. We found that miR-30a-3p was selectively sorted into sEVs by hepatocellular carcinoma (HCC) cells under the influence of multiple stressors. miR-30a-3p removal from cancer cells through sEVs promoted HCC cell migration and invasion, whereas exogenous overexpression of miR-30a-3p could inhibit migration, invasion, and sEV release by directly targeting SNAP23. HCC cells efficiently absorbed hepatic stellate cell (HSC) sEVs, providing an advantage in the treatment of HCC using HSC sEVs. Treatment with HSC sEVs rich in miR-30a-3p cargo effectively attenuated HCC migration, invasion, and metastasis. Overall, sEVs containing miR-30a-3p decreased sEV secretion as well as the migration, invasion, and metastasis of HCC by directly targeting SNAP23, thereby providing an effective strategy to attenuate metastasis of HCC.


Circuits for local and global signal integration in primary visual cortex.
Contrast-dependent changes in spatial summation and contextual modulation of primary visual cortex (V1) neuron responses to stimulation of their receptive field reveal long-distance integration of visual signals within V1, well beyond the classical receptive field (cRF) of single neurons. To identify the cortical circuits mediating these long-distance computations, we have used a combination of anatomical and physiological recording methods to determine the spatial scale and retinotopic logic of intra-areal V1 horizontal connections and inter-areal feedback connections to V1. We have then compared the spatial scales of these connectional systems to the spatial dimensions of the cRF, spatial summation field (SF), and modulatory surround field of macaque V1 neurons. We find that monosynaptic horizontal connections within area V1 are of an appropriate spatial scale to mediate interactions within the SF of V1 neurons and to underlie contrast-dependent changes in SF size. Contrary to common beliefs, these connections cannot fully account for the dimensions of the surround field. The spatial scale of feedback circuits from extrastriate cortex to V1 is, instead, commensurate with the full spatial range of center-surround interactions. Thus these connections could represent an anatomical substrate for contextual modulation and global-to-local integration of visual signals. Feedback projections connect corresponding and equal-sized regions of the visual field in striate and extrastriate cortices and cover anisotropic parts of visual space, unlike V1 horizontal connections that are isotropic in the macaque. V1 isotropic connectivity demonstrates that anisotropic horizontal connections are not necessary to generate orientation selectivity. Anisotropic feedback connections may play a role in contour completion.


An Open-Label Uncontrolled Trial of the Efficacy and Safety of a Hug with Singing and Rocking for Promotion of Relaxation in Pediatric Patients with Severe Motor and Intellectual Disabilities: Study Protocol.
Children with severe motor and intellectual disabilities (SMID) are continually exposed to stress due to their need to receive daily care. In particular, chronic physical and acute mental stress derived from daily medical care due to unstable health status are issues specific to SMID children. Therefore, it is important to approach these issues for the maintenance of their lives and quality of life. Seventeen children with a SMIDmedical care dependent group (SMID-MCDG) score of 25 or more will be enrolled in this study. Intervention by a hug while singing and rocking will be performed once a week for 24 weeks. The practitioner will sing, and slowly rock the child back and forth. Primary endpoint is high-frequency component of heart rate variability by frequency analysis. Secondary endpoints are low-frequency/high-frequency components of heart rate variability by frequency analysis, activity of salivary amylase, the incidence of adverse events, and changes in appearance. Frequency analysis of heart beat changes and salivary amylase activity are used as physiological indexes for assessing response to being held while singing and rocking. In this study, we will examine the efficacy and safety of hugging while singing and rocking as a practice of Ryouiku to promote relaxation in SMID-MCDG children.


Mechanism of intestinal transport of an organic cation, tributylmethylammonium in Caco-2 cell monolayers.
Many quaternary ammonium salts are incompletely absorbed after their oral administration and may also be actively secreted into the intestine. However, the underlying mechanism(s) that control the transport of these cations across the intestinal epithelium is not well understood. In this study, the mechanism of absorption of quaternary ammonium salts was investigated using Caco-2 cell monolayers, a human colon carcinoma cell line. Tributylmethyl-ammonium (TBuMA) was used as a model quaternary ammonium salts. When TBuMA was administrated at a dose of 13.3 imole/kg via iv and oral routes, the AUC values were 783.7 +/- 43.6 and 249.1 +/- 28.0 micormole x min/L for iv and oral administration, indicating a lower oral bioavailability of TBuMA (35.6%). The apparent permeability across Caco-2 monolayers from the basal to the apical side was 1.3 times (p < 0.05) greater than that from the apical to the basal side, indicating a net secretion of TBuMA in the intestine. This secretion appeared to be responsible for the low oral bioavailability of the compound, probably mediated by p-gp (p-glycoprotein) located in the apical membrane. In addition, the uptake of TBuMA by the apical membrane showed a Na+ dependency. Thus, TBuMA appears to absorbed via a Na+ dependent carrier and is then secreted via p-gp related carriers.


Assessment of the Consultation Rate with General Practitioners in the Initial Phase of the COVID-19 Pandemic.
Background: The COVID-19 pandemic affected the functioning of healthcare systems (HSs) in a way that was difficult to foresee earlier. It quickened the introduction of e-medicine, and changed the manner and number of services provided in the open medical setting. Aim: To assess variations in the consultation rate of patients in primary healthcare centers (PHCs) in consecutive months of the pandemic. Method: Data collected from two PHCs located in Olsztyn (Poland) were analyzed retrospectively. Collectively, these two centers provide care for approximately 20,000 inhabitants and perform approximately 100,000 medical services annually. The analysis was based on data covering the period April-July of the years 2010-2020, consisting in total of 337,510 medical services records. Results: A large, statistically significant decrease in the consultation rate (consultation rate understood as the number of individuals seeking consultation in relation to the number of people under care in a given time period) was revealed in each age group in the initial phase of the pandemic. In consecutive months, the approximated consultation rate achieved mean long-term values. Conclusions. The largest reduction in the consultation rate was revealed in the youngest age group, with the smallest occurring in the oldest. In the group of patients older than 65 years of age, the consultation rate after 3 months of the pandemic was the same as before the outbreak. Variations in the consultation rate were independent of the epidemiological situation. During the study, we observed an increased level of the administrative and paperwork activities carried out by PHC physicians.


Promoting sunscreen use and sun-protective practices in NCAA athletes: Impact of SUNSPORT educational intervention for student-athletes, athletic trainers, and coaches.
Student-athletes (SAs) have an increased skin cancer risk on account of significant ultraviolet exposure; however, their sun-protective practices are suboptimal. A novel program, Stanford University Network for Sun Protection, Outreach, Research, and Teamwork (SUNSPORT), was designed to target SAs, coaches, and athletic trainers (ATs). To measure the impact of educational intervention on sun protection beliefs and practices of SAs. A survey of sun protection beliefs and practices was administered to National Collegiate Athletic Association athletes before and after intervention. SUNSPORT dermatologists educated SAs, coaches, and ATs regarding skin cancer risk and prevention methods. The main outcome was frequency of sunscreen use by SAs before versus after intervention. A total of 846 National Collegiate Athletic Association athletes were surveyed between September 23, 2012, and September 20, 2015. After intervention, significant increases were observed in sunscreen use 4 or more days per week by SAs (from 26% to 39% [P = .02]), SAs spoken to by their coach about sun safety (from 26% to 57% [P = .0001]), and SA recognition of higher skin cancer risk (from 54% to 67% [P = .04]). Intervention in only 1 West Coast university and no paired data. Following the SUNSPORT intervention, SAs were significantly more likely to use sunscreen, especially if encouraged by their coach. This study emphasizes that education directed to SAs, ATs, and coaches can improve sun-protective practices in SAs.


Proposed classification of pseudomyxoma peritonei: influence of signet ring cells on survival.
The nomenclature and classification of pseudomyxoma peritonei (PMP) is confusing and controversial. Numerous classification systems have been proposed, none of which are easily reproducible or a useful guide for treatment. Patients with PMP of appendiceal origin were identified from our institution's database. Kaplan-Meier analyses were performed based on a proposed new PMP classification, a three-tiered grading system designated PMP1, PMP2, and PMP3. These results were compared with the established schemes by Ronnett and Bradley et al. There were 211 patients included in the analysis with a mean age of 51 ± 12 years at diagnosis. For PMP1, 86 patients (40.8%) included cases with abundant extracellular mucin and columnar nonstratified epithelium without dysplasia or atypia. For PMP3, 50 patients (23.7%) consisted of PMP with any percentage of signet ring cells (SRCs), For PMP2, 75 patients (35.5%) included all other patients. The mean age (± standard deviation) for PMP 1, 2, and 3 were 51 ± 12, 51 ± 12, and 51 ± 10 years, respectively (P = 0.90). The three groups had similar sex distribution (P = 0.24) and resection status (P = 0.47). Kaplan-Meier analyses showed median survivals of 120, 88, and 40 months and 5-year survival rates of 85.7, 63.05, and 32.2 per cent (P < 0.0001) for PMP 1, 2, and 3, respectively. Three distinct categories, PMP1, 2, and 3, were identified, which provide better stratification in terms of overall survival and represent differences in tumor biology that may impact treatment recommendations.


[The application of a Salmonella typhimurium biotyping method to the epidemiological surveys and surveillance].
In order to explore a new and effective means to the investigation and surveillance on Salmonella typhimurium infection, the authors applied a biotyping method of S. typhimurium invented by Duguid to the surveillance of nosocomial infection and tracing of infected case as well as cause of food-poisoning. Results showed that the major biotypes of strains isolated from children of acquired nosocomial infection with biotypes of strains from hospital environment and medical staff were quite similar. The biotype of cultures from the urine in a paralytic patient was the same as from the environment of the household and the wife's hands. The biotypes of strains identified from food-poison cases and leftovers was the same as isolated from ducks. It is believed that nosocomicial infection among children was caused by contamination of bacteria in hospital environment and carriers of medical staff. The urinary infection of a paralytic patient was due to environment pollution of the household, but not to nosocomial infection. The food-poisoning case was caused by the consumption of ducks infected with the bacteria.


Molecular mechanisms underlying SHP-1 gene expression.
SHP-1, a protein-tyrosine phosphatase with two src-homology 2 domains, is expressed predominantly in hematopoietic and epithelial cells and has been implicated in numerous signaling pathways as a negative regulator. Two promoters direct the expression of human and murine SHP-1, and two types of transcripts (I) and (II) SHP-1, are initiated from each of these promoters. The cDNA sequences of (I)SHP-1 and (II)SHP-1 are identical except in the 5' untranslated region and in the first few coding nucleotides. In this report, we show that promoter usage is similar in mouse and human hematopoietic cells, but different in epithelial cells. In human epithelial cells, only (I)SHP-1 transcripts were expressed. In addition, 4beta-phorbol 12-myristate 13-acetate up-regulates human (I)SHP-1 transcript expression in SKOV3 cells (an ovarian cancer cell line). Indirect evidence suggests that nuclear factor-kappaB might play a role in this induction. We also show that a 12-bp repeat in the distal SHP-1 promoter, which directs (I)SHP-1 expression, is of functional relevance as deletion of one copy of this E-box-containing 12-bp repeat resulted in a significant decrease in promoter activity. Electrophoretic mobility shift assays and supershift experiments showed that the upstream stimulatory factors USF1 and USF2 hetero-dimerize and interact with this 12 bp repeat. Our results suggest that USFs which have antiproliferative functions might regulate the expression of SHP-1, which itself is predominantly a negative growth regulator.


Novel approach to assess the emissivity of the human skin.
To study the radiation emitted by the human skin, the emissivity of its surface must be known. We present a new approach to measure the emissivity of the human skin in vivo. Our method is based on the calculation of the difference of two infrared images: one acquired before projecting a CO(2) laser beam on the surface of the skin and the other after such projection. The difference image contains the radiation reflected by the skin, which is used to calculate the emissivity, making use of Kirchhoff's law and the Helmholtz reciprocity relation. With our method, noncontact measurements are achieved, and the determination of the skin temperature is not needed, which has been an inconvenience for other methods. We show that it is possible to make determinations of the emissivity at specific wavelengths. Last, our results confirm that the human skin obeys Lambert's law of diffuse reflection and that it behaves almost like a blackbody at a wavelength of 10.6 microm.


Sacubitril-valsartan for the treatment of hypertension in China: A cost-utility analysis based on meta-analysis of randomized controlled trials.
Sacubitril-valsartan was recommended for heart failure (HF) and proven cost-effective in HF. Recently, sacubitril-valsartan has been recommended to treat hypertension by the Chinese expert consensus. The cost utility of sacubitril-valsartan for hypertension remains uninvestigated. A meta-analysis of randomized controlled trials (RCTs) was performed to investigate the real efficacy of sacubitril-valsartan on blood pressure, compared with angiotensin receptor blockers or placebo. A lifetime Markov model was developed to compare the cost utility of sacubitril-valsartan vs. valsartan. The primary outcome was the incremental cost-utility ratio (ICUR), representing the ratio of incremental costs to the incremental utility. The willingness-to-pay (WTP) threshold was three times of per capita gross domestic product (GDP) in China in 2021. Sacubitril-valsartan was considered cost-effective if the ICUR obtained was lower than the WTP threshold, otherwise, sacubitril-valsartanis was not cost-effective. A total of 10 RCTs of 5,781 patients were included in the meta-analysis. For comparison of sacubitril-valsartan 400 mg/day vs. valsartan 320 mg/day, a reduction in blood pressure (BP) of -5.97 (-6.38, -5.56) (p < 0.01) was observed. Cost-utility analysis showed that for a 60-year-old patient with hypertension, if sacubitril-valsartan was prescribed as the antihypertensive agent, he had a life expectancy of 11.91 quality-adjusted life-years (QALYs) with costs of 65,066 CNY, and if valsartan was prescribed as the antihypertensive agent, the life expectancy would be 11.82 QALY with costs of 54,769 CNY; thus, an ICUR of 108,622 CNY/QALY was obtained, lower than the WTP threshold. Compared with valsartan, sacubitril-valsartan is more effective in reducing blood pressure and may result in more quality-adjusted life-year, although with higher costs. Sacubitril-valsartan is cost-effective for hypertension in the current China setting under the willingness-to-pay threshold of 3 times of per capita GDP.


The Clinical Performance of Narrow Diameter Implants Versus Regular Diameter Implants: A Meta-Analysis.
The purpose of this study is to analyze 1- and 3-year clinical performances of narrow diameter implants (NDIs) versus regular diameter implants (RDIs). A search of electronic databases and a manual search was performed for the time period January 2000 to April 2018. A meta-regression was used to evaluate the effects of the "fixed effects" model on the implant survival rates, prosthesis success rates and marginal bone loss (MBL) with follow-up time of 1 year and 3 years. Of the 11 studies included, the overall combined 1-year implant survival rates were 98.14% for NDIs and 98.20% for RDIs. The overall combined 3-year implant survival rates were 98.71% for NDIs and 98.84% for RDIs. The corresponding values for 1-year prosthesis success rates were 96.94% for NDIs and 99.25% for RDIs. The corresponding values for 3-year prosthesis success rates were 89.25% for NDIs and 96.55% for RDIs. The meta-regression showed no significant differences between NDIs and RDIs regarding implant survival rates, prosthesis success rates, and MBL in 1-year and 3-year follow-up (P > .05). The results of this meta-analysis concluded that the implant diameter did not affect its survival rates, prosthesis success rates, and MBL in 1 and 3 years. The use of NDIs instead of bone augmentation procedures with RDIs did not affect its survival rates, prosthesis success rates, and MBL in the short-term and middle-term. However, more high-quality randomized controlled trials and long follow-up studies are needed on this topic.


Mixed quantum-classical equilibrium: Surface hopping.
We re-examine the analysis of the equilibrium limits of the fewest switches surface hopping algorithm for mixed quantum-classical dynamics. In contrast with previously reported results, we show that surface hopping does not, in general, exactly yield Boltzmann equilibrium, but that in practice the observed deviations are quite small. We also demonstrate that surface hopping does approach the exact equilibrium distribution in both the limits of small adiabatic splitting and/or strong nonadiabatic coupling. We verify these analytical results with numerical simulations for a simple two-level quantum system connected to a bath of classical particles.


C-peptide and its correlation to parameters of insulin resistance in the metabolic syndrome.
The progress of metabolic syndrome (MetS) continues with the onset of type-2 diabetes mellitus (Type-2 DM) along with linkage to other disorders such as neurodegenerative, especially Alzheimer's disease (AD), via oxidative stress and low grade systemic inflammatory process. Type-2 DM and AD are health disorders of priority research. The treatment for an individual suffering with Type- 2 DM and/or AD requires monitoring by clinicians. The aim of this study was to investigate the role of C-peptide and its correlation to insulin resistance, body mass index (BMI), β cell function, insulin sensitivity, lipid profile and hemoglobin A1c (HbA1c). The study was designed to include 96 Type-2 DM individuals from India. 58.3% males and 41.7% females were selected and fasting blood samples were collected for estimation of fasting C-peptide, fasting blood sugar (FBS), postprandial blood sugar (PPBS), HbA1c and lipid profile. Analysis was done on Hitachi912 and Elecsys 2010 using Roche reagents and standard controls. Anthropometries to calculate BMI and β cell function, insulin sensitivity, and insulin resistance were obtained. The statistical tool ANOVA, followed by calculation of p-value and r � value were applied for investigating correlation of C-peptide levels to those of high density lipoprotein-C (HDL-C), low density lipoprotein-C (LDL-C), triglycerides (TGL), HbA1c, β cell function, insulin sensitivity and insulin resistance. Highly significant positive correlations were observed in different quantiles of C-peptide levels to the studied parameters of MetS, BMI and % β cell function. Lower HDL-C level was found to be significantly related to higher C-peptide levels. Similarly, TGL and C-peptide levels displayed a significant positive correlation. A significant negative correlation was observed between C-peptide quantiles and % sensitivity. Thus, insulin resistance showed a positive correlation until the fourth quantile. No significant correlation was observed between C-peptide and HbA1c levels. This study demonstrates that assessment of C-peptide levels is a useful tool to monitor the progress of MetS among patients suffering from Type-2 DM and AD, as these disorders are intertwined to each other by common metabolic pathways. Assessment of C-peptide levels, along with HDL-C levels, in patients can be used to monitor insulin resistance.


[Lactose intolerance].
The most common problem limiting milk consumption worldwide is lactose intolerance (LI), which is defined as the experience of gastrointestinal symptoms due to the intake of lactose-containing food. When symptoms ensue the intake of milk, the condition is referred as milk intolerance, and it may or may not be due to LI. The most common cause of LI is primary lactase deficiency which occurs in 30% of Mexican adults when one glass of milk is consumed (12-18 g of lactose). LI occurs in less than 15% of adults after the intake of this dose of lactose. Another cause of lactose intolerance is due to secondary lactase deficiency, which occurs because lactase is reduced due to diseases that affect the intestinal mucosa. Lactose intolerance can be eliminated or significantly reduced by elimination or reduction of the intake of milk and milk containing products. Recent studies demonstrate that when β-casein-A1 contained in milk is hydrolyzed it produces β-casomorphine-7 which is an opioid associated with milk intolerance.


Distortion-dependent unhooking of interstrand cross-links in mammalian cell extracts.
Interstrand cross-links (ICLs) are formed by many chemotherapeutic agents and may also arise endogenously. The mechanisms used to repair these lesions remain unclear in mammalian cells. Repair in Escherichia coli and Saccharomyces cerevisiae requires an initial unhooking step to release the tethered DNA strands. We used a panel of linear substrates containing different site-specific ICLs to characterize how structure affects ICL processing in mammalian cell extracts. We demonstrate that ICL-induced distortions affect NER-dependent and -independent processing events. The NER-dependent pathway produces dual incisions 5' to the site of the ICL as described previously [Bessho, T., et al. (1997) Mol. Cell. Biol. 17 (12), 6822-6830] but does not release the cross-link. Surprisingly, we also found that the interstrand cross-linked duplexes were unhooked in mammalian cell extracts in a manner independent of the NER pathway. Unhooking occurred identically in extracts prepared from human and rodent cells and is dependent on ATP hydrolysis and metal ions. The structure of the unhooked product was characterized and was found to contain the remnant of the cross-link. Both the NER-mediated dual 5' incisions and unhooking reactions were greatly stimulated by ICL-induced distortions, including increased local flexibility and disruption of base pairs surrounding the site of the ICL. These results suggest that in DNA not undergoing transcription or replication, distortions induced by the presence of an ICL could contribute significantly to initial cross-link recognition and processing.


Serious infections among unselected patients with ST-elevation myocardial infarction treated with contemporary primary percutaneous coronary intervention.
Contemporary studies assessing the frequency, characteristics, and outcomes of serious infections (SIs) in patients presenting a ST-elevation myocardial infarction are scarce. Prospective cohort of consecutive patients undergoing primary percutaneous coronary intervention (pPCI). Serious infection was defined as the presence of infection that prolonged hospitalization. Community-acquired infection (CAI) was defined by SI diagnosed in the first 72 hours of hospitalization, whereas hospital-acquired infections (HAI) were those diagnosed after 72 hours of hospital admission. From December 2009 to November 2012, 1,486 patients were included in the analysis. Serious infection was present in 58 (3.9%) individuals; 30 (2%) patients had CAI and 28 (1.9%) patients had HAI. Respiratory tract infection was responsible for 82% of the SI. Patients with SI were older, had more comorbidities, and had worse angiographic results of the pPCI procedure when compared with those without SIs. After multivariable adjustment, SI was associated with an approximately 10-fold risk of 30-day death. Patients with CAI had more often a history of smoking, Killip III/IV on hospital admission, worse pPCI, and angiographic results than did patients with HAI. However, no differences were seen in 30-day major cardiovascular outcomes between patients with CAI and HAI. In a contemporary cohort of unselected ST-elevation myocardial infarction patients representative of the daily practice, SI was uncommon but associated with worse pPCI results and high risk of mortality. The occurrences of CAI or HAI were similar, but CAI patients presented distinctly worse angiographic outcomes than did patients with HAI.


Is There A Correlation Between COVID-19 and Hepatitis A and Hepatitis E Serum Antibody Level?
The prevalence of COVID-19 and its severity have been observed to be on a lower level in underdeveloped countries with poorer standards of hygiene. This disparity may be attributed to the higher seroprevalence of other viral diseases, which can result in the presence of antibodies protective against COVID-19. Two of the widespread diseases in such countries are infection to hepatitis A and E viruses (HAV and HEV). In the present study, we explored the relationship between the level of antibodies against these viruses and the susceptibility to COVID-19. Ninety patients were studied in two groups of controls and cases, each consisting 45 individuals. The cases were patients with the clinical symptoms of COVID-19 and positive RT-PCR test results. The controls were individuals referred to the respiratory triage of Imam Khomeini Hospital Complex and were not demonstrating relevant clinical symptoms of COVID-19 and their RT-PCR test results were negative. Levels of HAV and HEV antibodies were measured and compared in these two groups. The median of HAV antibody level was 13.6 (IQR=11.5-16.9) and 13.2 (IQR =10.7-14.7) in cases and controls, respectively, showing no statistically significant difference (P=0.1). Likewise, the median of HEV antibody level was 6.7 (IQR=5.3-7.1) and 7.1 (IQR=6.3-7.5) in cases and controls, respectively, which again showed no statistically significant difference (P=0.41). The present study was carried out in a region with a relatively high prevalence of HAV and HEV infections. Contrary to our expectations, no statistically significant relationship was observed between the levels of antibodies against these viruses and the susceptibility to COVID-19. Further studies with larger sample sizes and in other countries are needed to come to a definite conclusion.


Histone Deacetylase 6-Controlled Hsp90 Acetylation Significantly Alters Mineralocorticoid Receptor Subcellular Dynamics But Not its Transcriptional Activity.
The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily that transduces the biological effects of corticosteroids. Its best-characterized role is to enhance transepithelial sodium reabsorption in response to increased aldosterone levels. In addition, MR participates in other aldosterone- or glucocorticoid-controlled processes such as cardiovascular homeostasis, adipocyte differentiation or neurogenesis, and regulation of neuronal activity in the hippocampus. Like other steroid receptors, MR forms cytosolic heterocomplexes with heat shock protein (Hsp) 90), Hsp70, and other proteins such as immunophilins. Interaction with Hsp90 is thought to maintain MR in a ligand-binding competent conformation and to regulate ligand-dependent and -independent nucleocytoplasmatic shuttling. It has previously been shown that acetylation of residue K295 in Hsp90 regulates its interaction with the androgen receptor and glucocorticoid receptor (GR). In this work we hypothesized that Hsp90 acetylation provides a regulatory step to modulate MR cellular dynamics and activity. We used Hsp90 acetylation mimic mutant K295Q or nonacetylatable mutant K295R to examine whether MR nucleocytoplasmatic shuttling and gene transactivation are affected. Furthermore, we manipulated endogenous Hsp90 acetylation levels by controlling expression or activity of histone deacetylase 6 (HDAC6), the enzyme responsible for deacetylation of Hsp90-K295. Our data demonstrates that HDAC6-mediated Hsp90 acetylation regulates MR cellular dynamics but it does not alter its function. This stands in contrast with the down-regulation of GR by HDAC6, suggesting that Hsp90 acetylation may play a role in balancing relative MR and GR activity when both factors are co-expressed in the same cell.


Complex visual discrimination of tridimensional patterns in rats: progressive learning improves discriminative and recognition capacities.
The purpose of these experiments was to evaluate the rat's discriminative capacities when facing tridimensional patterns. The behavioral approach involved 3 steps: (1) After establishing a brightness discrimination in a Y-maze (S+ = dark, S- = bright), tridimensional objects were introduced into the goal boxes. (2) Brightness differences were gradually attenuated during the course of the fading procedure and correct responding to the tridimensional patterns was obtained. (3) This procedure had a second fading phase where configurational differences between these patterns were progressively reduced. All animals trained with this method of successive approximations learned the discrimination to a 90% criterion; whereas control animals, given the same complex discrimination without any shaping procedure, failed to learn. These experiments show that success or failure in the acquisition of a visual task is specific to the training method used. Our fading procedure produced complex discrimination behavior.