A qualitative investigation of the decision to return to sport after anterior cruciate ligament reconstruction: to play or not to play.
Primary anterior cruciate ligament (ACL) reconstruction is known to have excellent outcomes, but many patients do not return to their preinjury level of sport participation. Previous studies have used subjective outcome scores to evaluate this discrepancy, but none to date has used qualitative, in-depth patient interviews. To understand the factors influencing a patient's decision to return to his or her preinjury level of sport after ACL reconstruction. Extrinsic and intrinsic factors may affect one's decision to return to sport after primary ACL reconstruction despite good functional knee scores. Case series; Level of evidence, 4. An experienced interviewer conducted qualitative, semistructured interviews of 31 patients, aged 18 to 40 years, who had undergone primary ACL reconstruction surgery. All participated in sport before injury and had a minimum 2-year follow-up with no further surgeries or knee injuries. Qualitative analysis was then performed to derive codes, categories, and themes. An assessment of preinjury and current sport participation by type, level of competition, and Marx activity score, along with patient-reported knee function, was also conducted. Patient interviews revealed 3 overarching themes: fear, lifestyle changes, and innate personality traits. Elements of these factors were shown to largely influence the decision to return to the preinjury sport both in those patients who had returned and those who had not returned to sport. Less common factors included the surgeon's advice not to return, depressed mood, and persistent knee pain. Patients who did not return to their preinjury level of sport after primary ACL reconstruction despite having good knee function were largely influenced by fear, shifts in priority, and individual personalities. This study highlights the importance for treating physicians to recognize and address psychological factors and lifestyle changes that largely contribute to a patient's postoperative decision to return to sport. Results from this study will allow surgeons and health care professionals to educate patients contemplating surgery and to better understand the recovery process not only from sport-related surgeries but other surgical interventions with the goal of returning to activity.


Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells.
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a dual-function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two nonmalignant human mammary epithelial cell lines that form polarized, growth-arrested structures (acini) when cultured in three-dimensional laminin-rich extracellular matrix gels (lrECM). As acini begin to form, PTEN accumulates both in the cytoplasm and at cell-cell contacts where it colocalizes with the E-cadherin/beta-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function-blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in Skbr-3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in three-dimensional lrECM, indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus seems to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells.


Engineering Tissue-Informed Biomaterials to Advance Pulmonary Regenerative Medicine.
Biomaterials intentionally designed to support the expansion, differentiation, and three-dimensional (3D) culture of induced-pluripotent stem cells (iPSCs) may pave the way to cell-based therapies for chronic respiratory diseases. These conditions are endured by millions of people worldwide and represent a significant cause of morbidity and mortality. Currently, there are no effective treatments for the majority of advanced lung diseases and lung transplantation remains the only hope for many chronically ill patients. Key opinion leaders speculate that the novel coronavirus, COVID-19, may lead to long-term lung damage, further exacerbating the need for regenerative therapies. New strategies for regenerative cell-based therapies harness the differentiation capability of human iPSCs for studying pulmonary disease pathogenesis and treatment. Excitingly, biomaterials are a cell culture platform that can be precisely designed to direct stem cell differentiation. Here, we present a closer look at the state-of-the-art of iPSC differentiation for pulmonary engineering, offer evidence supporting the power of biomaterials to improve stem cell differentiation, and discuss our perspective on the potential for tissue-informed biomaterials to transform pulmonary regenerative medicine.


The Adenosinergic System as a Therapeutic Target in the Vasculature: New Ligands and Challenges.
Adenosine is an adenine base purine with actions as a modulator of neurotransmission, smooth muscle contraction, and immune response in several systems of the human body, including the cardiovascular system. In the vasculature, four P1-receptors or adenosine receptors-A₁, A2A, A2B and A₃-have been identified. Adenosine receptors are membrane G-protein receptors that trigger their actions through several signaling pathways and present differential affinity requirements. Adenosine is an endogenous ligand whose extracellular levels can reach concentrations high enough to activate the adenosine receptors. This nucleoside is a product of enzymatic breakdown of extra and intracellular adenine nucleotides and also of S-adenosylhomocysteine. Adenosine availability is also dependent on the activity of nucleoside transporters (NTs). The interplay between NTs and adenosine receptors' activities are debated and a particular attention is given to the paramount importance of the disruption of this interplay in vascular pathophysiology, namely in hypertension., The integration of important functional aspects of individual adenosine receptor pharmacology (such as in vasoconstriction/vasodilation) and morphological features (within the three vascular layers) in vessels will be discussed, hopefully clarifying the importance of adenosine receptors/NTs for modulating peripheral mesenteric vascular resistance. In recent years, an increase interest in purine physiology/pharmacology has led to the development of new ligands for adenosine receptors. Some of them have been patented as having promising therapeutic activities and some have been chosen to undergo on clinical trials. Increased levels of endogenous adenosine near a specific subtype can lead to its activation, constituting an indirect receptor targeting approach either by inhibition of NT or, alternatively, by increasing the activity of enzymes responsible for ATP breakdown. These findings highlight the putative role of adenosinergic players as attractive therapeutic targets for cardiovascular pathologies, namely hypertension, heart failure or stroke. Nevertheless, several aspects are still to be explored, creating new challenges to be addressed in future studies, particularly the development of strategies able to circumvent the predicted side effects of these therapies.


An assessment of chemotherapy-induced nausea and vomiting direct costs in three EU countries.
chemotherapy-induced nausea and vomiting (CINV) has been commonly reported as one of the most distressing adverse effects among treated patients with cancer. Inadequately treated, CINV can lead to increased resource utilization and severely impair patients' daily functioning and quality of life. Direct costs include acquisition cost of antiemetic drugs and rescue medication, administration devices, add-on treatments, such as hydration, and additional patient care, that is, nursing and physician time, unscheduled office visits, emergency room admissions, and, in some cases, extended hospitalization or readmission. There are many reports on the cost-effectiveness of antiemetic drugs, but information on the total cost per patient associated with CINV is limited. The costs associated with severe CINV episodes are considered responsible for the most significant part of the expenditures. The aim of this study was to investigate the management of CINV episodes in three European health-care environments and to estimate direct costs associated with severe CINV episodes. An online survey addressed to Italian, German, and French oncologists and oncology nurses was performed. The survey included 41 questions about the management and the resource utilization for patients experiencing any CINV episode during the 6-month period preceding the survey. Furthermore, the cost associated with severe CINV episode management was estimated by adopting the National Health Service's perspective. A large proportion of patients receiving chemotherapy experienced a CINV episode (34.4% in Italy, 50.2% in France, and 40.4% in Germany); among those, 8.8% in Italy, 11.6% in France, and 19.2% in Germany experienced a severe CINV episode. Compared with Italy, Germany and France presented a greater hospitalization rate following an unplanned visit to the oncology ward or an emergency room access due to CINV. In Italy, the mean cost per patient with a severe CINV episode resulted in approximately €389, about half of the mean cost in France (€750) and a third of the mean cost in Germany (€1,017). Severe CINV episodes requiring hospitalization, day hospital, or hospitalization extension involve a significant cost for the National Health Services; additional studies should be conducted in order to evaluate potential ways to offset these expenses.


UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD.
Ubiquilin (UBQLN) proteins are a dynamic and versatile family of proteins found in all eukaryotes that function in the regulation of proteostasis. Besides their canonical function as shuttle factors in delivering misfolded proteins to the proteasome and autophagy systems for degradation, there is emerging evidence that UBQLN proteins play broader roles in proteostasis. New information suggests the proteins function as chaperones in protein folding, protecting proteins prior to membrane insertion, and as guardians for mitochondrial protein import. In this review, we describe the evidence for these different roles, highlighting how different domains of the proteins impart these functions. We also describe how changes in the structure and phase separation properties of UBQLNs may regulate their activity and function. Finally, we discuss the pathogenic mechanisms by which mutations in UBQLN2 cause amyotrophic lateral sclerosis and frontotemporal dementia. We describe the animal model systems made for different UBQLN2 mutations and how lessons learnt from these systems provide fundamental insight into the molecular mechanisms by which UBQLN2 mutations drive disease pathogenesis through disturbances in proteostasis.


Molecular Mechanism of Tau Misfolding and Aggregation: Insights from Molecular Dynamics Simulation.
Tau dysfunction has a close association with many neurodegenerative diseases, which are collectively referred to as tauopathies. Neurofibrillary tangles (NFTs) formed by misfolding and aggregation of tau are the main pathological process of tauopathy. Therefore, uncovering the misfolding and aggregation mechanism of tau protein will help to reveal the pathogenic mechanism of tauopathies. Molecular dynamics (MD) simulation is well suited for studying the dynamic process of protein structure changes. It provides detailed information on protein structure changes over time at the atomic resolution. At the same time, MD simulation can also simulate various conditions conveniently. Based on these advantages, MD simulations are widely used to study conformational transition problems such as protein misfolding and aggregation. Here, we summarized the structural features of tau, the factors affecting its misfolding and aggregation, and the applications of MD simulations in the study of tau misfolding and aggregation.


Complement activation and C3 binding by serum-sensitive and serum-resistant strains of Pseudomonas aeruginosa.
The relationship among complement consumption, C3 deposition, and C3 fragmentation pattern was compared for serum-sensitive (Sers) and serum-resistant (Serr) strains of Pseudomonas aeruginosa. The Sers strains, which were mucoid strains derived from patients with cystic fibrosis, had lipopolysaccharide deficient in O-antigen side chains. These organisms generally activated much less complement per organism than their Serr counterparts, characterized by the presence of lipopolysaccharide with long lipopolysaccharide O side chains. Surprisingly, however, although the Serr strains consumed more total hemolytic complement, less C3 was deposited onto the surface of these strains than onto that of the Sers strains. Maximal C3 binding required the participation of both the classical and alternative complement pathways, although classical complement pathway involvement was more important for Serr strains. Finally, while more than half of the C3 deposited on most Sers strains was in the form of C3b, most of the C3 on the Serr strains was in the form of iC3b, indicating a more rapid and extensive conversion of C3b to iC3b on the surface of these strains. Limited complement activation by Sers mucoid strains of P. aeruginosa may confer a selective survival advantage to these organisms in colonizing the airways of patients with cystic fibrosis.


Partnership history and mental health over time.
To describe the mental health of men and women with differing histories of partnership transitions. Data from nine waves of the British Household Panel Survey, a stratified general population sample, were used to calculate age standardised ratios and 95% confidence intervals for mean General Health Questionnaire scores for groups with different partnership transition histories. 2127 men and 2303 women aged under 65 who provided full interviews at every survey wave. Enduring first partnerships were associated with good mental health. Partnership splits were associated with poorer mental health, although the reformation of partnerships partially reversed this. Cohabiting was more beneficial to men's mental health, whereas marriage was more beneficial to women's mental health. The more recently a partnership split had occurred the greater the negative outcome for mental health. Women seemed more adversely affected by multiple partnership transitions and to take longer to recover from partnership splits than men. Single women had good mental health relative to other women but the same was not true for single men relative to other male partnership groups. Partnership was protective of mental health. Mental health was worse immediately after partnership splits, and the negative outcomes for health were longer lasting in women. Future work should consider other factors that may mediate, confound, or jointly determine the relation between partnership change and health.


Gonadotrope-specific deletion of Dicer results in severely suppressed gonadotropins and fertility defects.
Pituitary gonadotropins follicle-stimulating hormone and luteinizing hormone are heterodimeric glycoproteins expressed in gonadotropes. They act on gonads and promote their development and functions including steroidogenesis and gametogenesis. Although transcriptional regulation of gonadotropin subunits has been well studied, the post-transcriptional regulation of gonadotropin subunits is not well understood. To test if microRNAs regulate the hormone-specific gonadotropin β subunits in vivo, we deleted Dicer in gonadotropes by a Cre-lox genetic approach. We found that many of the DICER-dependent microRNAs, predicted in silico to bind gonadotropin β subunit mRNAs, were suppressed in purified gonadotropes of mutant mice. Loss of DICER-dependent microRNAs in gonadotropes resulted in profound suppression of gonadotropin-β subunit proteins and, consequently, the heterodimeric hormone secretion. In addition to suppression of basal levels, interestingly, the post-gonadectomy-induced rise in pituitary gonadotropin synthesis and secretion were both abolished in mutants, indicating a defective gonadal negative feedback control. Furthermore, mutants lacking Dicer in gonadotropes displayed severely reduced fertility and were rescued with exogenous hormones confirming that the fertility defects were secondary to suppressed gonadotropins. Our studies reveal that DICER-dependent microRNAs are essential for gonadotropin homeostasis and fertility in mice. Our studies also implicate microRNAs in gonadal feedback control of gonadotropin synthesis and secretion. Thus, DICER-dependent microRNAs confer a new layer of transcriptional and post-transcriptional regulation in gonadotropes to orchestrate the hypothalamus-pituitary-gonadal axis physiology.


Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets.
In preclinical studies, pomalidomide mediated both direct antitumor effects and immune activation by binding cereblon. However, the impact of drug-induced immune activation and cereblon/ikaros in antitumor effects of pomalidomide in vivo is unknown. Here we evaluated the clinical and pharmacodynamic effects of continuous or intermittent dosing strategies of pomalidomide/dexamethasone in lenalidomide-refractory myeloma in a randomized trial. Intermittent dosing led to greater tumor reduction at the cost of more frequent adverse events. Both cohorts experienced similar event-free and overall survival. Both regimens led to a distinct pattern but similar degree of mid-cycle immune activation, manifested as increased expression of cytokines and lytic genes in T and natural killer (NK) cells. Pomalidomide induced poly-functional T-cell activation, with increased proportion of coinhibitory receptor BTLA(+) T cells and Tim-3(+) NK cells. Baseline levels of ikaros and aiolos protein in tumor cells did not correlate with response or survival. Pomalidomide led to rapid decline in Ikaros in T and NK cells in vivo, and therapy-induced activation of CD8(+) T cells correlated with clinical response. These data demonstrate that pomalidomide leads to strong and rapid immunomodulatory effects involving both innate and adaptive immunity, even in heavily pretreated multiple myeloma, which correlates with clinical antitumor effects. This trial was registered at www.clinicaltrials.gov as #NCT01319422.


Embracing ambiguities and valuing ourselves: issues of validity in action research.
Further elucidation is required on the validity of action research. The tendency of nurse action researchers to rely on perspectives of validity from qualitative or ethnographic research only gives a partial picture. Three categories of validity regarding action research are proposed in order to develop understandings and to stimulate debate: dialectical, critical and reflexive. Tensions and processes, moral responsibilities, reflexivity and accounts of action research are discussed to illuminate the validity of action research. The complexity and contradictions inherent even when attempting to demonstrate its validity are highlighted and illustrated with reference to examples of action research.


Compassion practice by Ugandan nurses who provide HIV care.
Compassion is fundamental to ethical nursing practice; it represents a commitment to acknowledge and respond to the suffering of the patient. Many structural, economic, and sociopolitical challenges confront Ugandan nurses in their efforts to incorporate compassion into their care of persons with HIV illness. After reviewing the literature related to compassion fatigue, the author describes nursing in sub-Saharan Africa and presents a qualitative study exploring the impact of education on 24 nurses' lives, including their capacity to avoid or mitigate the development of compassion fatigue. Data were collected through interviews, observation, and focus group discussions. Findings illustrate the barriers participants faced in providing competent care and the liberating effects of new knowledge and skills. Engaging in meaningful relationships, maintaining hopeful attitudes, and advocating for the profession were found to transform and affirm the nurses' approach toward their work and enhance their experiences of compassion satisfaction. The author discusses the unique aspects of the experience of compassion among Ugandan nurses caring for persons with HIV illness.


Lhx3 and Lhx4 suppress Kolmer-Agduhr interneuron characteristics within zebrafish axial motoneurons.
A central problem in development is how fates of closely related cells are segregated. Lineally related motoneurons (MNs) and interneurons (INs) express many genes in common yet acquire distinct fates. For example, in mouse and chick Lhx3 plays a pivotal role in the development of both cell classes. Here, we utilize the ability to recognize individual zebrafish neurons to examine the roles of Lhx3 and its paralog Lhx4 in the development of MNs and ventral INs. We show that Lhx3 and Lhx4 are expressed by post-mitotic axial MNs derived from the MN progenitor (pMN) domain, p2 domain progenitors and by several types of INs derived from pMN and p2 domains. In the absence of Lhx3 and Lhx4, early-developing primary MNs (PMNs) adopt a hybrid fate, with morphological and molecular features of both PMNs and pMN-derived Kolmer-Agduhr' (KA') INs. In addition, we show that Lhx3 and Lhx4 distinguish the fates of two pMN-derived INs. Finally, we demonstrate that Lhx3 and Lhx4 are necessary for the formation of late-developing V2a and V2b INs. In conjunction with our previous work, these data reveal that distinct transcription factor families are deployed in post-mitotic MNs to unequivocally assign MN fate and suppress the development of alternative pMN-derived IN fates.


Breaking of Gauge Symmetry in Lattice Gauge Theories.
We study perturbations that break gauge symmetries in lattice gauge theories. As a paradigmatic model, we consider the three-dimensional Abelian-Higgs (AH) model with an N-component scalar field and a noncompact gauge field, which is invariant under U(1) gauge and SU(N) transformations. We consider gauge-symmetry breaking perturbations that are quadratic in the gauge field, such as a photon mass term and determine their effect on the critical behavior of the gauge-invariant model, focusing mainly on the continuous transitions associated with the charged fixed point of the AH field theory. We discuss their relevance and compute the (gauge-dependent) exponents that parametrize the departure from the critical behavior (continuum limit) of the gauge-invariant model. We also address the critical behavior of lattice AH models with broken gauge symmetry, showing an effective enlargement of the global symmetry, from U(N) to O(2N), which reflects a peculiar cyclic renormalization-group flow in the space of the lattice AH parameters and of the photon mass.


Spanish version of the Phubbing Scale: Internet addiction, Facebook intrusion, and fear of missing out as correlates.
Phubbing is an increasingly common behavior that involves using a smartphone in a social setting of two or more people and interacting with the phone rather than with the other people. Research to date on phubbing has measured it using different scales or single questions, and therefore standard measures with appropriate psychometric properties are needed to improve its assessment. The aim of our study was to develop a Spanish version of the Phubbing Scale and to examine its psychometric properties: factor structure, reliability, and concurrent validity. Participants were 759 Spanish adults between 18 and 68 years of age. They completed an online survey. The results support a structure that is consistent with the original validation study, with two factors: Communication Disturbance and Phone Obsession. Internal consistency was found to be adequate. Evidence of concurrent validity was provided via a hierarchical regression model that showed positive associations with measures of internet addiction, Facebook intrusion, and fear of missing out. These results indicate that the Spanish version of the Phubbing Scale exhibits appropriate psychometric properties.


[Effect of positive transverse acceleration on the transmitting properties of human operators].
The results of experimental studies of the effect of +Gz acceleration on the transmissive properties of the man-operator involved in the tracking system are discussed. With an increase of the acceleration value and the exposure time the law of distribution of tracking errors made by the operator varies from the normal to the uniform pattern. The estimates of the quality of tracking of a complex signal upon an exposure of the operator to accelerations of different values are given.


Adiabatic N-soliton interactions of Bose-Einstein condensates in external potentials.
A perturbed version of the complex Toda chain (CTC) has been employed to describe adiabatic interactions within an N-soliton train of the nonlinear Schrödinger equation. Perturbations induced by weak quadratic and periodic external potentials are studied by both analytical and numerical means. It is found that the perturbed CTC adequately models the N-soliton train dynamics for both types of potentials. As an application of the developed theory, we consider the dynamics of a train of matter-wave solitons confined to a parabolic trap and optical lattice, as well as tilted periodic potentials. In the last case, we demonstrate that there exist critical values of the strength of the linear potential for which one or more localized states can be extracted from a soliton train. An analytical expression for these critical strengths for expulsion is also derived.


Oxygen limitation induces acid tolerance and impacts simulated gastro-intestinal transit in Listeria monocytogenes J0161.
: Listeria monocytogenes is a food-borne pathogen and the causative agent of listeriosis, a severe infection to those with a pre-disposition. Infections often arise through consumption of contaminated foods, where high intrinsic resistance to food processing practises permit survival and growth. Several practises, including refrigeration, acidification and oxygen limitation are ineffective in controlling L. monocytogenes, therefore foods which do not undergo thermal processing, e.g. ready-to-eat products, are considered high risk. While the responses to several food processing practises have been investigated, there are few reports on the responses of L. monocytogenes to oxygen limitation. Therefore the aim of this study was to investigate the effects of oxygen limitation on stress response andsurvival capacity during simulated gastro-intestinal transit. Anaerobiosis induced an acid tolerance response, causing cells to be more resistant to organic and inorganic acids than aerobically grown counterparts (p < 0.05). Using a gastro-intestinal transit model it was found that anaerobic growth induced an acid tolerance response which enhanced resistance to pH 2.5 simulated gastric juice (SGJ) compared to aerobically grown cells (p < 0.05). This response was most pronounced in exponential phase cells. However, exposure of stationary phase cells to pH 3.5 SGJ enhanced bile tolerance, suggesting a link between acid and bile tolerance. The responses of L. monocytogenes to oxygen limitation are not extensively studied. These findings provide an initial insight into the effects of anaerobiosis on stress response and survival potential in L. monocytogenes. While it appears anaerobiosis may impact these, further work is required to confirm these findings are not strain specific.


Functional-characterization of developing tumor vascular system and drug delivery (review).
This review summarizes our recent experiments on the process of tumor vascularization and character of tumor vessels. By vitalscopic observation with transparent chambers in rats, we found that the sites where tumor vessels originated were usually terminal portions of terminal arterioles and that an intricate tumor vascular network was constructed from incorporated preexisting vessels and newly formed vessels by three different modes, i.e., sprouting, cross-connecting and splitting. Observation and hydrogen clearance studies showed that tumor blood flow changed remarkably during the development of the tumor vascular network. At an early stage of tumor growth, there were some regions of high flow in the tumor. At an advanced stage, however, there was a rapid increase in low-flow or no-flow areas which were resistant to access of anticancer drugs and oxygen. Angiotensin II-induced hypertension produced a several-fold increase in tumor blood flow without increasing tissue blood flow of normal tissues. These good conditions for drug delivery to tumor tissue are able to enhance therapeutic effects of chemotherapy, irradiation, antibody and photodynamic therapy.


Influence of polymorphism in DNA repair and defence genes on p53 mutations in bladder tumours.
We studied the effects of polymorphisms in nine genes involved in DNA repair and detoxification on occurrence and type of p53 mutation in 327 bladder cancer patients. The included polymorphisms are XPC(Lys939Gln), XPD(Lys751Gln), XPG(Asp1104His), XRCC1(Arg3999Gln), XRCC3(Thr241Met), NBS1(Glu185Gln), cyclin D1(Pro241Pro), MTHFR(Ala222Val and Glu429Ala) and NQO1(Arg139Trp and Pro187Ser). We found increased risk for p53 mutation among cyclin D1 variant allele homozygotes (OR 2.4 CI 0.8-6.7). Among non-smokers, 75% (3/4) with p53 mutation but only 12.5% (3/24) without p53 mutations were XRCC3 241Met homozygotes (P=0.03). Among smokers, all p53 transversions (3/3), but only 41.7% (5/12) of p53 transitions were found among carriers of the XPC 939Gln allele. Individuals carrying the NQO1 187Ser allele showed increased risk for p53 transversions (OR 4.7, CI 0.9-26.1). All (2/2) NQO1 139Trp allele carriers but only 17.5% (7/40) of the Arg139 homozygotes had p53 transversions. Our findings suggest that altered repair and detoxification due to genetic polymorphism may influence the occurrence of p53 mutations in bladder cancer.


Filopodium retraction is controlled by adhesion to its tip.
Filopodia are thin cell extensions sensing the environment. They play an essential role during cell migration, cell-cell or cell-matrix adhesion, by initiating contacts and conveying signals to the cell cortex. Pathogenic microorganisms can hijack filopodia to invade cells by inducing their retraction towards the cell body. Because their dynamics depend on a discrete number of actin filaments, filopodia provide a model of choice to study elementary events linked to adhesion and downstream signalling. However, the determinants controlling filopodial sensing are not well characterized. In this study, we used beads functionalized with different ligands that triggered filopodial retraction when in contact with filopodia of epithelial cells. With optical tweezers, we were able to measure forces stalling the retraction of a single filopodium. We found that the filopodial stall force depends on the coating of the bead. Stall forces reached 8 pN for beads coated with the β1 integrin ligand Yersinia Invasin, whereas retraction was stopped with a higher force of 15 pN when beads were functionalized with carboxyl groups. In all cases, stall forces increased in relation to the density of ligands contacting filopodial tips and were independent of the optical trap stiffness. Unexpectedly, a discrete and small number of Shigella type three secretion systems induced stall forces of 10 pN. These results suggest that the number of receptor-ligand interactions at the filopodial tip determines the maximal retraction force exerted by filopodia but a discrete number of clustered receptors is sufficient to induce high retraction stall forces.


[Kinetic properties of partially purified glucosephosphate dehydrogenase of human erythrocytes].
Partially purified glucose-6-phosphate dehydrogenase was isolated from small amounts of human erythrocytes (15-20 ml). The Km value for glucose-6-phosphate was 35.0 +/- 3.0 micronM, the Km for NADP was 4.27 +/- 0.3 micronM. The optimal activity of the enzyme was at pH 9.0. Glucose-6-phosphate dehydrogenase, dialyzed in presence of 1-10(-5) M NADP, had critical temperature about 52 degrees within 10 min of incubation; without NADP it was at 45 degrees. The method for isolation and purification of the enzyme was modified.


Renal manifestation of pustulosis palmaris et plantaris.
Diffuse proliferative glomerulonephritis without IgA deposits (DPGN) in patients with pustulosis palmaris et plantaris (PPP) is described. This association has not been previously reported. Although PPP was resolved transiently after tonsillectomy, it was worsened coincidently at the time of exacerbation of DPGN. Improvement of proteinuria and PPP was observed after antiplatelet therapy. It was suggested that the renal manifestation and the development of PPP were associated.


Identifying Stops and Moves in WiFi Tracking Data.
There are multiple methods for tracking individuals, but the classical ones such as using GPS or video surveillance systems do not scale or have large costs. The need for large-scale tracking, for thousands or even millions of individuals, over large areas such as cities, requires the use of alternative techniques. WiFi tracking is a scalable solution that has gained attention recently. This method permits unobtrusive tracking of large crowds, at a reduced cost. However, extracting knowledge from the data gathered through WiFi tracking is not simple, due to the low positional accuracy and the dependence on signals generated by the tracked device, which are irregular and sparse. To facilitate further data analysis, we can partition individual trajectories into periods of stops and moves. This abstraction level is fundamental, and it opens the way for answering complex questions about visited locations or even social behavior. Determining stops and movements has been previously addressed for tracking data gathered using GPS. GPS trajectories have higher positional accuracy at a fixed, higher frequency as compared to trajectories obtained through WiFi. However, even with the increase in accuracy, the problem, of separating traces in periods of stops and movements, remains similar to the one we encountered for WiFi tracking. In this paper, we study three algorithms for determining stops and movements for GPS-based datasets and explore their applicability to WiFi-based data. We propose possible improvements to the best-performing algorithm considering the specifics of WiFi tracking data.


Interpleural bupivacaine for pain relief after transthoracic endoscopic sympathectomy for primary hyperhidrosis.
Interpleural local anesthetic has been reported to provide good postoperative pain relief in patients receiving thoracotomy or upper abdominal surgery. However, there were few reports regarding interpleural local anesthetic for postoperative pain relief in patients receiving transthoracic endoscopic sympathectomy for palmar hyperhidrosis. The aim of the present study was to evaluate the effect of interpleural bupivacaine for postoperative pain relief in patients receiving transthoracic endoscopic sympathectomy for palmar hyperhidrosis. Sixty adult patients undergoing bilateral transthoracic endoscopic sympathectomy were randomly divided into two groups (n = 30, each group) for study. At the end of surgery, patients in group 1 were given bilaterally an injection of 0.5% interpleural bupivacaine (10 ml) through the surgical endoscope, whereas those in the group 2 who were not given any treatment at the juncture served as control. Postoperatively, intravenous morphine 2.5 mg was given luxuriously to the patients at their request at intervals of 30 min. The intensity of postoperative pain was assessed at rest and during cough with visual analogue scale (VAS, 0-10 points). It was showed that at rest the pain scores were less in group 1 than in group 2 within 4 h postoperatively. During cough, group 1 also had less VAS scores than group 2 within 5 h postoperatively. Furthermore, patients in group 1 consumed less intravenous morphine than those in group 2 within 6 h postoperatively. Interpleural bupivacaine significantly decreased the intensity of postoperative pain and morphine consumption in patients undergoing transthoracic endoscopic sympathectomy for palmar hyperhidrosis. We are looking forward to seeing that with the addition of epinephrine to the anesthetic solution and a considerable increase of dosage and/or volume of bupivacaine may provide a better and longer pain relief, about which further studies are needed.


Attachment of bacteria to soft contact lenses.
A total of 25 soft contact lenses from 17 asymptomatic contact lens wearers and eight patients with contact lens-associated giant papillary conjunctivitis were examined by scanning electron microscopy. Structures that resembled bacteria were present on the anterior surface of seven lenses. All lenses showed a coating of granular mucus-like deposits. Some bacteria were seen scattered randomly over the surface, with no apparent attachment to the lens, whereas others were attached to the coated surface by thin, flagella-like foot processes, the distal ends of which were unattached. These attached bacteria were cylindrical in shape. Several bacteria showed a constriction centrally. Some bacteria were covered by the surface coating, while others, which were round to ovoid in shape, appeared partially embedded in the coating itself. Aggregations of bacteria were seen around clumps of mucus-like debris.


[The clinical characteristics of the early manifestations of disseminated sclerosis].
An analysis was performed of features of incipient manifestations of multiple sclerosis in 648 patients with a primary diagnosis having been made at the Ukrainian Centre for Study of Demyelinating Diseases over 1992-1996. Incipient manifestations of disseminated sclerosis revealed themselves predominantly as sensory, motor, visual, and coordination impairment against the background of pain sensations, paresthesias and pronounced asthenia of the nervous system. Knowledge of disseminated sclerosis debut is important for the diagnosis of the condition to be made and treatments to be administered in a timely fashion.


Supratentorial and spinal pediatric ependymomas display a hypermethylated phenotype which includes the loss of tumor suppressor genes involved in the control of cell growth and death.
Epigenetic alterations, including methylation, have been shown to be an important mechanism of gene silencing in cancer. Ependymoma has been well characterized at the DNA copy number and mRNA expression levels. However little is known about DNA methylation changes. To gain a more global view of the methylation profile of ependymoma we conducted an array-based analysis. Our data demonstrated tumors to segregate according to their location in the CNS, which was associated with a difference in the global level of methylation. Supratentorial and spinal tumors displayed significantly more hypermethylated genes than posterior fossa tumors, similar to the 'CpG island methylator phenotype' (CIMP) identified in glioma and colon carcinoma. This hypermethylated profile was associated with an increase in expression of genes encoding for proteins involved in methylating DNA, suggesting an underlying mechanism. An integrated analysis of methylation and mRNA expression array data allowed us to identify methylation-induced expression changes. Most notably genes involved in the control of cell growth and death and the immune system were identified, including members of the JNK pathway and PPARG. In conclusion, we have generated a global view of the methylation profile of ependymoma. The data suggests epigenetic silencing of tumor suppressor genes is an important mechanism in the pathogenesis of supratentorial and spinal, but not posterior fossa ependymomas. Hypermethylation correlated with a decrease in expression of a number of tumor suppressor genes and pathways that could be playing an important role in tumor pathogenesis.


Acute Metabolic Effects of Olanzapine Depend on Dose and Injection Site.
Atypical antipsychotics (AAPs), such as olanzapine (OLZ), are associated with metabolic side effects, including hyperglycemia. Although a central mechanism of action for the acute effects on glycemia has been suggested, evidence for peripheral versus central effects of AAPs has been mixed and has not been explored for an effect of OLZ on the respiratory exchange ratio (RER). Here, we tested the hypothesis that some inconsistencies in the glycemic responses are likely a result of different doses and central sites of injection. We also compared the effects of central versus peripherally administered OLZ on the RER of unsedated rats. Third ventricle infusion of OLZ at 0.3 mg/kg caused hyperglycemia within 30 minutes, with a higher dose (1.8 mg/kg) needed to elicit a similar response in the lateral ventricles. In contrast, 3 mg/kg of OLZ was needed to raise blood glucose within 30 minutes when given intragastrically, and 10 mg/kg resulted in a prolonged hyperglycemia lasting at least 60 minutes. Third ventricle injection of OLZ significantly decreased RER after 75 minutes, whereas intragastric OLZ resulted in a faster drop in RER after 30 minutes. Since changes in glycemia were most sensitive when OLZ was infused into the third ventricle, but effects on RER were more rapidly and efficaciously observed when the drug was given peripherally, these results raise the likelihood of a dual mechanism of action involving hypothalamic and peripheral mechanisms. Some discrepancies in the literature arising from central administration appear to result from the injection site and dose.


The jovian nebula: a post-voyager perspective.
Voyager 1 carried a diverse collection of magnetospheric probes through the inner Jovian magnetosphere in March 1979. The ensuing data analysis and theoretical investigation provided a comprehensive description of the Jovian nebula, a luminous torus populated with newly released heavy ions drawn from Io's surface. Recent refinements in Earth-based imaging instrumentation are used to extend the Voyager in situ picture in temporal and spatial coverage. An analysis of [SIII] and [SII] optical emissions observed during the Jovian apparitions of 1981 through 1983 reveals three distinct torus components. Regularities have been identified in the ion partitioning and ion densities in the hot outer and inner tori, sharply defined radial structure is found in the plasma near Io, and the relative permanence of the cool inner torus is inferred. An extended cloud of neutral material is required as a source of fresh ions in the nebula.


Does cryomaze injure the circumflex artery?: a preliminary search for occult postprocedure stenoses.
Ensuring the transmurality of the mitral isthmus lesion, a critical component of the cryomaze, entails mirror-image application of the cryoprobe both on endocardial and epicardial surfaces when carrying out ablation. Concerns of circumflex artery injury have been expressed during the epicardial application of the cryoprobe over the coronary sinus as the artery courses on the posterior surface of the sinus in the atrioventricular (AV) groove. The objective of this study was to analyze the incidence of significant injury to the circumflex artery and its impact on outcomes, if any, in those patients who have undergone cryomaze. Between August 2004 and December 2009, a total of 223 patients underwent argon-based cryoablation (120-second application at -140°C). After Western Institutional Review Board approval, 20 consecutive patients with normal results of preoperative coronary angiograms (right dominance, 75%; left dominance, 15%; codominant circulation, 10%) and who were at least 6 months postablation were enrolled in this study. The mean ± SD age was 60.74 ± 14.99 years, 35% were men, and 50% belonged to New York Heart Association class III/IV. The mean ± SD atrial fibrillation duration was 23.83 ± 36.28 months (65% were paroxysmal). Ten percent (n = 2) underwent primary cryomaze, 40% (n = 8) underwent cryomaze plus mitral valve repair, and 50% (n = 10) underwent two or more concomitant valvular procedures. Twelve patients underwent biatrial cryomaze, and eight underwent only left-sided cryomaze. All patients underwent a 24-hour Holter monitoring, electrocardiogram stress test, and a coronary computed tomographic angiogram, as per the protocol of this study. At discharge, 85% had normal sinus rhythm, whereas 15% of the patients were paced. On a mean ± SD follow-up at 32.57 ± 19.51 months, the Holter and/or pacemaker interrogation revealed AV synchrony in all patients-16 in sinus rhythm and 4 with heart block who converted to AV synchrony after subsequent pacemaker implantation. The stress test was available for 18 patients, and its results were negative in all of them. On the computed tomographic angiogram, 95% of the patients had a completely patent circumflex artery. Stenosis was noticed in only one patient (right dominant circulation), with a 30% to 40% tubular stenosis of the circumflex artery. However, this lesion corresponded to the P1 area of the mitral annulus and was significantly proximal on the circumflex to the P3 area, where the cryoprobe was applied during the cryomaze procedure. Barring one case of partial circumflex stenosis, likely due to the ongoing normal progression of coronary artery disease, these data derived from a limited prospective trial suggest that epicardial application during the cryomaze procedure does not cause anatomic or physiological compromise of the circumflex artery. Nevertheless, laboratory and anecdotal evidence exist that conflict with this conclusion, and caution should be exercised when applying cryothermy in the vicinity of coronary arteries.


Quality Improvement in Stroke Rehabilitation: A Scoping Review.
Quality improvement interventions are used extensively in health care, aiming to improve delivery and promote best practice. The impact of quality improvement interventions implemented in stroke rehabilitation remains unclear. The aim of this scoping review is to examine the different types of published quality improvement interventions in stroke rehabilitation and their impact on improving the quality of care. A scoping review was performed in the PubMed, Embase and CINAHL databases. QI studies evaluating interventions for stroke rehabilitation patients that were published up to August 2020 were included. The review looked at the types of quality improvement interventions that have been evaluated as well as the improvements/impacts reported for quality improvement interventions for stroke patients in rehabilitation. We reviewed 1580 studies, twelve quality improvement interventions met inclusion criteria and were included in the current study. Six studies involved organizational change, three studies involved provider education and audit-feedback and three studies involved provider education. Of the twelve quality improvement interventions that have been included, >90% reported improvements (91.6%). In the majority of cases, improvements were noted through implementation of a myriad of interventions. Several facilitators and barriers were noted during implementation and contributed to success or failure of the intervention. There is paucity of full-text peer-reviewed published research investigating quality improvement interventions for improving the quality of care in stroke rehabilitation. The current review offers value to healthcare providers in terms of key success factors, contextual factors, barriers and facilitators associated with improvements in stroke rehabilitation.


Detection of cross-reactive anti-DNA antibody idiotypes on renal tissue-bound immunoglobulins from lupus patients.
Cross-reactive anti-DNA antibody idiotypes have been identified on tissue-bound immunoglobulins in a study of renal biopsies from 26 systemic lupus erythematosus (SLE) patients. 12 (46%) biopsies were shown to have one or both the idiotypes tested for by anti-idiotypic reagents. The idiotypes were identified in the glomerular basement membrane, the mesangial cell cytoplasm, and in focal tuft proliferations. In contrast, in none of 24 immunoglobulin-positive disease control biopsies could either idiotype be demonstrated. Blocking studies in two patients indicated that the idiotypes were on anti-DNA antibodies. These findings indicate that some tissue-bound auto-antibodies are derived from related families of high-frequency germ line genes that are expressed in SLE patients. The potential role of anti-idiotypic therapy in SLE is discussed.


Receptive Field Formation in Natural Scene Environments. Comparison of Single-Cell Learning Rules.
We study several statistically and biologically motivated learning rules using the same visual environment: one made up of natural scenes and the same single-cell neuronal architecture. This allows us to concentrate on the feature extraction and neuronal coding properties of these rules. Included in these rules are kurtosis and skewness maximization, the quadratic form of the Bienenstock-Cooper-Munro (BCM) learning rule, and single-cell independent component analysis. Using a structure removal method, we demonstrate that receptive fields developed using these rules depend on a small portion of the distribution. We find that the quadratic form of the BCM rule behaves in a manner similar to a kurtosis maximization rule when the distribution contains kurtotic directions, although the BCM modification equations are computationally simpler.


LY 97241 accelerates the apparent rate of inactivation of transient outward K+ current: characterization of open channel block.
LY 97241 [(LY), p-nitro tertiary amine analog of clofilium] has been shown to prolong action potential duration in vitro but its effects on transient outward potassium current (Ito) are unknown. The authors investigated the effect of LY on Ito in rat ventricular myocytes using whole cell patch clamp techniques. LY resulted in a concentration-dependent inhibition of Ito amplitude (measured 30 msec after onset of depolarization) with an EC50 of 5.85 microM. The inhibitory effect of LY (10 microM) was seen at voltages from -30 to 70 mV (e.g., at 30 mV, LY reduced amplitude from a control of 7.29 +/- 0.30 to 3.05 +/- 0.22 pA/pF, P < .01, n = 10). The voltage-dependent block by LY was fitted by the Boltzmann equation, yielding a voltage for half-maximal block (V1/2) of -25.0 mV with a slope factor (k) of 13.8 mV. LY (10 microM) accelerated the rate of Ito inactivation from 41.9 +/- 3.5 to 16.0 +/- 1.6 msec without an effect on the peak of Ito (n = 10, P < .01). In contrast, 4-aminopyridine (4-AP, 1 mM) had no effect on the rate of inactivation but decreased the peak of Ito from 1.84 +/- 1.6 to 0.71 +/- 0.20 nA (n = 3). The time constant of onset of block (tau B) on Ito by 10 microM LY was fitted to a monoexponential function having a tau B of 14.5 +/- 1.5 msec. LY had no effect on the steady-state inactivation or recovery from inactivation of Ito.(ABSTRACT TRUNCATED AT 250 WORDS)


[A lack of systematic in stress-reducing measures but documented effect of mindfullness-based stress reduction].
Long-term stress is a major and still rising public health problem, which is associated with increased risk of disease and mortality. In this review, we find that a systematic literature search of stress-reducing interventions tested in a randomised controlled trial (RCT)-design in Denmark showed, that interventions are only tested one or two times and only by the same research group. Furthermore, the international literature is not reviewed sufficiently before developing new interventions. Mindfulness-based stress reduction is a well-tested stress-reducing intervention, which is tested in more than 100 RCTs. In Great Britain, Mindfulness All-Party Parliamentary Group has used this information to make recommendations to Parliament.


Fast temporal encoding and decoding with spiking neurons.
We propose a simple theoretical structure of interacting integrate-and-fire neurons that can handle fast information processing and may account for the fact that only a few neuronal spikes suffice to transmit information in the brain. Using integrate-and-fire neurons that are subjected to individual noise and to a common external input, we calculate their first passage time (FPT), or interspike interval. We suggest using a population average for evaluating the FPT that represents the desired information. Instantaneous lateral excitation among these neurons helps the analysis. By employing a second layer of neurons with variable connections to the first layer, we represent the strength of the input by the number of output neurons that fire, thus decoding the temporal information. Such a model can easily lead to a logarithmic relation as in Weber's law. The latter follows naturally from information maximization if the input strength is statistically distributed according to an approximate inverse law.


Sum frequency generation spectroscopy of imidazolium-based ionic liquids with cyano-functionalized anions at the solid salt-liquid interface.
A surface-sensitive nonlinear vibrational spectroscopic technique, sum frequency generation (SFG), has been used to study cyano-containing ionic liquids in contact with two different solid salt surfaces. Specifically, the interfacial chemistry of BaF2(111) single-crystal and solid NaCl{100} surfaces in contact with ionic liquids such as [BMIM][SCN], [BMIM][DCA], [BMIM][TCM], and [EMIM][TCB] has been investigated. Spectral features in both C-H and C-N stretching regions were assigned, with a detailed discussion of the nature of surface interactions and ordering of the ionic liquid ions at the interface of the different crystals. Results showed that [BMIM](+) cations adhered closely via Coulombic interactions to the negatively charged NaCl{100} surface, while [SCN](-), [TCM](-), and [DCA](-) anions revealed a strong electrostatic affinity to the positively charged BaF2(111) surface. Ions of the ionic liquid adsorbed to the solid salt surface to form a Helmholtz-like electric double layer. The linear [SCN](-) anion has a particularly strong affinity to the BaF2(111) surface, resulting in a first layer of anions directly in contact with BaF2(111) containing an effective negative surface excess charge. This promoted ordering of the cations in the second layer to counter the charge excess. At the BaF2(111)-[EMIM][TCB] interface, however, a strongly bound layer of anions populating the first layer resulted in a much larger counterion charge delivered near the crystal salt surface than required to effectively neutralize the initial surface charge from the crystal. As a result, strong resonances from the cation were observed at the BaF2(111) surface, suggesting a more complicated structure of the double layer at the interface than a simple Helmholtz-type model.


Differential impact of structurally different anti-diabetic drugs on proliferation and chemosensitivity of acute lymphoblastic leukemia cells.
Hyperglycemia during hyper-CVAD chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL) (Cancer 2004; 100: 1179-85). The optimal clinical strategy to manage hyperglycemia during hyper-CVAD is unclear. To examine whether anti-diabetic pharmacotherapy can influence chemosensitivity of ALL cells, we examined the impacts of different anti-diabetic agents on ALL cell lines and patient samples. Pharmacologically achievable concentrations of insulin, aspart and glargine significantly increased the number of ALL cells, and aspart and glargine did so at lower concentrations than human insulin. In contrast, metformin and rosiglitazone significantly decreased the cell number. Human insulin and analogs activated AKT/mTOR signaling and stimulated ALL cell proliferation (as measured by flow cytometric methods), but metformin and rosiglitazone blocked AKT/mTOR signaling and inhibited proliferation. Metformin 500 μM and rosiglitazone 10 μM were found to sensitize Reh cells to daunorubicin, while aspart, glargine and human insulin (all at 1.25 mIU/L) enhanced chemoresistance. Metformin and rosiglitazone enhanced daunorubicin-induced apoptosis, while insulin, aspart and glargine antagonized daunorubicin-induced apoptosis. In addition, metformin increased etoposide-induced and L-asparaginase-induced apoptosis; rosiglitazone increased etoposide-induced and vincristine-induced apoptosis. In conclusion, our results suggest that use of insulins to control hyperglycemia in ALL patients may contribute to anthracycline chemoresistance, while metformin and thiazolidinediones may improve chemosensitivity to anthracycline as well as other chemotherapy drugs through their different impacts on AKT/mTOR signaling in leukemic cells. Our data suggest that the choice of anti-diabetic pharmacotherapy during chemotherapy may influence clinical outcomes in ALL.


Genetic determinants of bone mass in adult women: a reevaluation of the twin model and the potential importance of gene interaction on heritability estimates.
We estimated genetic effects on bone density in pre- and postmenopausal twins and critically considered the assumptions of the twin model. Bone mass in the radius, lumbar spine, and hip, anthropometric measurements, usual calcium and caffeine intake, tobacco and alcohol use, number of pregnancies and live births, menstrual history, usual physical activity, and medical history were measured in a volunteer sample of 171 twin pairs [124 monozygotic (MZ) and 47 dizygotic (DZ)], aged 25-80, free of diseases known to affect bone mass or mineral metabolism. At all skeletal sites, MZ intraclass correlations exceeded DZ correlations for both pre- and postmenopausal women, yielding highly significant estimates of heritability for bone mass. Adjustments for height, age, and environmental characteristics did not reduce the heritability estimates. However, many of these estimates were unrealistically high, suggesting some violation(s) of the assumptions of the twin model. Thus, the familial resemblance in bone mass is due primarily to genetic effects at all skeletal sites and at all ages, although the importance of genetic effects is diminished with aging, as evidenced by increasing within-MZ pair variability in older women. Because of failures in the assumptions of the twin model, however, particularly the greater MZ environmental similarity and the probability of gene interaction, heritability estimates are probably too high and require cautious interpretation.


Diamondoid ether clusters in helium nanodroplets.
Diamondoid ethers were introduced into superfluid helium nanodroplets and the resulting clusters were analyzed by time-of-flight mass spectrometry. Clusters of higher abundances (magic number clusters) were identified and the corresponding potential cluster geometries were obtained from GFN2-xTB and DFT computations. We found that the studied diamondoid ethers readily self-assemble in helium nanodroplets and that London dispersion attraction between hydrocarbon subunits acts as a driving force for cluster formation. On the other hand, hydrogen bonding between ether oxygens and trace water molecules fosters the eventual breakdown of the initial supramolecular aggregate.


Studies of relationships between the GLUT10 Ala206Thr polymorphism and impaired insulin secretion.
This study aimed to investigate if the previously observed association between the GLUT10 Ala206Thr polymorphism and variation in fasting and oral glucose-induced serum insulin concentrations could be replicated in a large-scale population-based cohort of Danish whites. The GLUT10 Ala206Thr polymorphism was genotyped in a case-control study of 880 Type 2 diabetic patients and 4372 glucose-tolerant control subjects. The latter group was also enrolled in an assessment of fasting and post-OGTT circulating levels of plasma glucose and serum insulin in relation to genotype. The variant was genotyped by analysis of PCR-generated primer extension by matrix-assisted laser desorption/ionization time-of-flight analysis. The Ala206Thr variant was equally frequent among Type 2 diabetic patients and glucose-tolerant subjects (P = 0.9) and there was no difference in the distribution of genotype groups (P = 1.0). In the 4372 glucose-tolerant subjects there was no statistically significant association between the polymorphism and levels of fasting and post-oral glucose tolerance test plasma glucose and serum insulin along with the insulinogenic index and the homeostasis model of assessment for insulin resistance and insulin secretion. Likewise, in an age-stratified subgroup comprising 1264 subjects, we observed no relationships between the GLUT10 polymorphism and the selected metabolic features. The GLUT10 Ala206Thr polymorphism is not associated with Type 2 diabetes in the Danish population. Furthermore, in the present large-scale cohort, the polymorphism does not associate with phenotypes such as fasting and oral glucose-induced levels of plasma glucose and serum insulin.


[Various results and prospective trends in research on the immunology of spinal osteochondrosis with neurologic disorders].
The authors review the results of many-year studies concerning the immunological aspects of the pathogenesis of the peripheral nervous system involvement in osteochondrosis of the lumbar division of the vertebral column. On the basis of a great body of information a complex study of the role of humoral factors in the natural specific immunity, as well as the state of the T- and B-systems of immunity in patients with the non-radical and radical stages of the lumbar osteochondrosis was for the first time undertaken. The results obtained point to the participation of all the immunity links in the disease pathogenesis. This is an important prerequisite for the search for purposeful pathogenetic therapy of this widespread disease.


Degradation of the light-stress protein is mediated by an ATP-independent, serine-type protease under low-light conditions.
Green plants respond to light stress by induction of the light-stress proteins (ELIPs). These proteins are stable as long as the light stress persists but are very rapidly degraded during subsequent low light conditions. Here we report that the degradation of ELIPs is mediated by an extrinsic, thylakoid-associated protease which is already present in the membranes during light stress conditions. Partial purification of the protease by perfusion chromatography indicates that this proteolytic activity may be represented by a protein with an apparent molecular mass of 65 kDa. The ELIP-directed protease is localized in the stroma lamellae of the thylakoid membranes and does not require ATP or additional stromal factors for proteolysis. The protease has an optimum activity at pH 7.5-9.5 and requires Mg2+ for its activity. The ELIP-degrading protease show an unusual temperature sensitivity and becomes reversibly inactivated at temperatures below 20 degree C and above 30 degree C. Studies with protease inhibitors indicate that this enzyme belongs to the serine class of proteases. The enhanced degradation of ELIP in isolated thylakoid membranes after addition of the ionophore nigericin suggests that a trans-thylakoid delta pH or changes in ionic strength may be involved in the mechanism of protease activation.


Antrodia cinnamomea Confers Obesity Resistance and Restores Intestinal Barrier Integrity in Leptin-deficient Obese Mice.
Obesity is associated with metabolic disorders. Thus, obesity prevention and treatment are essential for health. Antrodia cinnamomea (AC) is a multifunctional medicinal fungus used for the treatment of various diseases and for preventing diet-induced obesity. Leptin deficiency causes over-eating and spontaneous obesity. The concomitant metabolic symptoms are more severe than diet-induced obesity. Here, we used leptin-deficient (ob/ob) mice as an animal model for over-feeding to study the effect of AC on obesity. We fed C57BL/6 mice (WT, ob+/+) and ob/ob mice with AC for four weeks before performing qRT-PCR and immunoblot analysis to elaborate AC-modulated mechanisms. Further, we used Caco-2 cells as a human intestinal epithelial barrier model to examine the effect of AC on intestinal permeability. Our results suggested that AC reduces lipid deposits of the liver and epididymal white adipose tissue (EWAT) by promoting lipid metabolism and inhibiting lipogenesis-associated genes and proteins in ob/ob mice. Moreover, AC effectively repaired intestinal-barrier injury caused by leptin deficiency and enhanced intestinal barrier integrity in Caco-2 cells. Interestingly, AC significantly reduced body weight and EWAT with no compromise on food intake in ob/ob mice. Thus, AC effectively reduced obesity caused by leptin-deficiency and can potentially be used as a nutraceutical for treating obesity.


[Oral complications of anorexia nervosa, bulimia nervosa and other metabolic disorders].
Eating disorders like anorexia nervosa and boulimia nervosa may have consequences for both the oral tissues and the salivary glands. In the oral cavity these eating disorders result frequently in dental erosion, but also in dental caries. The salivary glands are regularly swollen without pain; a hypofunction in the salivary secretory process may develop resulting in dry mouth feelings. In this paper these aspects will be reviewed and illustrated with patient cases.


Paleoenvironment of the earliest hominoids: new evidence from the oligocene avifauna of egypt.
Analysis of fossil birds from the Oligocene Jebel Qatrani Formation in the Fayum depression of Egypt, site of the oldest known hominoid primates, allows precise paleoenvironmental reconstruction of the climatic and biotic conditions that influenced some of the earliest stages of hominoid evolution. Unlike the fossil mammals of the Fayum, which belong largely to extinct groups, most of the birds are referable to living families, with some being close to modern genera. The avifauna consists mainly of aquatic species, with such forms as jacanas (Jacanidae) and shoebilled storks (Balaenicipitidae) indicating expanses of freshwater with dense floating vegetation. An avifauna closely analogous to that of the Fayum is found today only in a limited area of Uganda, north and west of Lake Victoria, a region of swampland bordered by forest and grasslands that presents marked faunal similarities to the environment inferred for the Egyptian Oligocene.


Insulin-like growth factor-1 (IGF-1) receptor-insulin receptor substrate complexes in the uterus. Altered signaling response to estradiol in the IGF-1(m/m) mouse.
Some of the actions of estradiol occur through stimulation of growth factor pathways in target organs. Tyrosine-phosphorylated (Tyr(P)) insulin-like growth factor-1 receptor (IGF-1R) and the insulin receptor substrate (IRS)-1 are found in the uterus of mice treated with estradiol. Immunoprecipitates of uterine Tyr(P) IRS-1 contained both p85, the regulatory subunit of phosphatidylinositol (PI) 3-kinase, and PI 3-kinase catalytic activity. Estradiol also stimulated binding of IRS-1 and PI 3-kinase to the IGF-1R. Depletion of IRS-1 from uterine extracts reduced PI 3-kinase associated with the receptor, which suggests that binding of the enzyme to IGF-1R occurs primarily in a complex that also contains IRS-1. Following treatment with estradiol, formation of Tyr(P) IGF-1R, Tyr(P) IRS-1, and the p85.IRS-1 complex was very weak in the uterus of IGF-1(m/m) mice, which are severely deficient in IGF-1. This indicated that most, if not all, of the estradiol-stimulated Tyr phosphorylation of uterine IRS-1 originates from ligand activation of IGF-1R kinase. IRS-2 was also Tyr-phosphorylated in the normal uterus and bound more IGF-1R and p85 in response to estradiol; however, a marked decrease in levels of uterine IRS-2 occurred 12-24 h after treatment with estradiol. Since IRS-2 was present in IGF-1R precipitates and a recombinant form of IGF-1 (long R3 IGF-1) stimulated formation of Tyr(P) IRS-2, hormonal activation of this docking protein probably occurs through the IGF-1R. In summary, our findings show that estrogen activation of uterine IGF-1R kinase results in enhanced binding of p85 (PI 3-kinase) to IRS-1 and IRS-2. The formation of one or both of these complexes may be important for the potent mitogenic action of this steroid. That estradiol stimulated a decrease of IRS-2, but not of IRS-1, suggests that these docking proteins have different roles in hormone-induced signaling in the uterus.


Development and Validation of a Scoring System for Assessment of Clinical Failure after Pediatric Robot-Assisted Laparoscopic Extravesical Ureteral Reimplantation: A Multi-Center Study.
We aimed to develop and validate a scoring system as an objective assessment tool for predicting clinical failure after pediatric robotic extravesical ureteral reimplantation. Data for this multi-institutional retrospective cohort was obtained from two tertiary referral hospitals. We defined clinical failure as incomplete radiographic resolution or post-operative febrile UTI. Patients were stratified into low, intermediate, and high-risk groups according to the score. External validation was performed using the model projected to the external validation cohort. An amount of 115 renal units in the development cohort and 46 renal units in the validation cohort were analyzed. The prediction score was calculated with weighted points to each variable according to their regression coefficient as age (year) + BMI + BBD times 10 + VUR grade times 7 + console time (h) + hospital stay times 6. The C-index of our scoring system was 0.850 and 0.770 in the development and validation cohorts, respectively. Clinical failure was significantly different among risk groups: 0% (low-risk), 3.3% (intermediate-risk), and 22.2% (high-risk) (p = 0.004) in the development cohort. A novel scoring system using multiple pre- and intra-operative variables provides a prediction of children at risk of failure after robotic extravesical ureteral reimplantation.


Zinc Inhibits TRPV1 to Alleviate Chemotherapy-Induced Neuropathic Pain.
Zinc is a transition metal that has a long history of use as an anti-inflammatory agent. It also soothes pain sensations in a number of animal models. However, the effects and mechanisms of zinc on chemotherapy-induced peripheral neuropathy remain unknown. Here we show that locally injected zinc markedly reduces neuropathic pain in male and female mice induced by paclitaxel, a chemotherapy drug, in a TRPV1-dependent manner. Extracellularly applied zinc also inhibits the function of TRPV1 expressed in HEK293 cells and mouse DRG neurons, which requires the presence of zinc-permeable TRPA1 to mediate entry of zinc into the cytoplasm. Moreover, TRPA1 is required for zinc-induced inhibition of TRPV1-mediated acute nociception. Unexpectedly, zinc transporters, but not TRPA1, are required for zinc-induced inhibition of TRPV1-dependent chronic neuropathic pain produced by paclitaxel. Together, our study demonstrates a novel mechanism underlying the analgesic effect of zinc on paclitaxel-induced neuropathic pain that relies on the function of TRPV1.SIGNIFICANCE STATEMENT The chemotherapy-induced peripheral neuropathy is a major limiting factor affecting the chemotherapy patients. There is no effective treatment available currently. We demonstrate that zinc prevents paclitaxel-induced mechanical hypersensitivity via inhibiting the TRPV1 channel, which is involved in the sensitization of peripheral nociceptors in chemotherapy. Zinc transporters in DRG neurons are required for the entry of zinc into the intracellular side, where it inhibits TRPV1. Our study provides insight into the mechanism underlying the pain-soothing effect of zinc and suggests that zinc could be developed to therapeutics for the treatment of chemotherapy-induced peripheral neuropathy.


[The effect of various cleansing methods for total fiber optic colonoscopy].
It is a fact that there are recent increasing trends of incidence of the colorectal carcinoma among other colorectal diseases. In such trend, the early detection remain to be most important by the air contrast barium enema and total fiber optic colonoscopy There are several ways to prepare the colon for barium enema and fiber optic colonoscopy which include several agents. The mechanical cleansing have been used most frequently since Brown's method was adapted to be most perfect for colon cleansing. The ideal laxatives and enema solutions were limited to adequate dose, it's effectiveness, patient's diet and bowel habit, minimal side effect, low cost and simple to perform. In order to compare the effectiveness of various cleansing solutions, six experimental methods were formed as shown; 1. normal saline enema, 2. castor oil with normal saline enema, 3. castor oil with soapsuds enema, 4. magnesium citrate with normal saline, 5. magnesium citrate with soapsuds enema and 6. ingestion of Golyetly solution. The authors have compared and determined the degree of cleanliness by an experienced endoscopist The total number of patients was 247, age distribution was 43 +/- 15 years old, and sex distribution was 133 males and 114 females. The grade I and II represented no difficulties at performing the fiber optic colonoscopy+, but grade III and IV had some difficulties, even unable to perform the fiber optic colonoscopy. The effectiveness the cleansing agents, represented with grade I and II was 95.9% (47/49) in method 6, 93.2% (54/58) in method 2, 83.3% (30/33) in method 3, 70.0% (28/40) in method 5, 66.7% (16/24) in method 1, and 45.7% (18/40) in method 4. Method 2 and 6 were the most effective in normal bowel habit patients. In constipated patients, method 6 was the most effective and all method except method 4 were effective in diarrhea patients. The degrees of less mucosal irritation by various bowel cleansing method were in the order of method 6(100%), 1(100%), 5(74%), 2(69%). In subjective symptoms and cleansing groups, abdominal distension, pain, nausea and vomiting were complained, and that's subject symptoms were in the order of method 3(88.9%), 6(79.6%), 1(75%), 5(72.5%), 2(72.4%), 4(67.5%). In conclusion, we believe that the Golytely of the mechanical cleansing solution for fiber optic colonoscopy was the most effective, but others depended on the patient's condition and bowel habit.


Observation of a secondary compressive lesion after treatment of caudal cervical spondylomyelopathy in a dog.
In a 7-year-old Doberman Pinscher with an atactic gait, neurologic examination revealed tetraparesis, conscious proprioceptive deficits, and rigid ventral flexion of the neck. Radiography and myelography revealed a ventral, extradural, dynamic compressive lesion between C6 and C7. Distraction decompression was performed, using cancellous bone screws and methylmethacrylate. After initial improvement, clinical signs recurred 2 weeks after surgery and progressed until the dog was euthanatized 6 weeks after surgery. Postmortem myelography revealed an extradural compressive lesion adjacent to the implant, between C5 and C6. Secondary compressive lesions induced by surgical or biomechanical alterations of the cervical portion of the spine may be complications of treatment of caudal cervical spondylomyelopathy.


SALARY SCALES OF TRAINED MEN AND WOMEN.
A comparison of salary scales of trained men shows rather clearly at the present time that (1) The pay scale of endowed and state universities and agricultural colleges is approximately like that of the commissioned officers of the army and the navy, but lacks the advantage of the retiring pension of three fourths pay. This pension often relieves the military and naval officer of the necessity of saving for old age. The saving required of the academic man to give him an equivalent retiring fund is not practicable at the present salary scale. (2) It shows that the academic salary scale is appreciably lower than that of the professional and scientific services of the national government at Washington. The retiring allowance of the government employee, though small, and in part contributed by the employee himself, gives him a distinct advantage. (3) The salaries of all groups above mentioned are very much lower than those paid in manufacturing enterprises to positions above the wage-earners. In order to make a concrete comparison, I will enumerate the positions that on the average command salaries of $3,000, $6,000 and $9,000 respectively in these different lines of work.


Characterization of protein production by caprine placental membranes: identification and immunolocalization of retinol-binding protein.
Caprine chorion, allantois and amnion from days 23, 28, 35, 39 and 45, and yolk sac from day 23 of pregnancy were isolated by dissection and cultured for 24 h in modified minimum essential medium in the presence of [35S] methionine. De novo-synthesized proteins released into the culture medium were analyzed by two-dimensional PAGE and fluorography. Patterns of protein production by these isolated extraembryonic membranes remained relatively unchanged from days 23 to 45 of pregnancy. Electrophoretic profiles of proteins synthesized by allantois and amnion were identical but distinct from that produced by chorion. Yolk sac was the major source of serum-like proteins. An acidic (pI 5.3-6.3) 22 kDa protein, which consisted of four isoelectric variants, was produced by all extraembryonic membranes and demonstrated to immunoreact with antiserum produced against bovine placental retinol-binding protein (RBP). Limited N-terminal sequence analysis of one major isoform indicated that the protein had complete homology with bovine RBP over the first 15 amino acids. Immunoreactive RBP was localized in epithelial cells lining the chorion, allantois and amnion. In this study, we have characterized and compared protein production by isolated extraembryonic membranes through days 23 to 45 of pregnancy and identified the 22 kDa protein as caprine RBP of placental origin.


Multi-profile Bayesian alignment model for LC-MS data analysis with integration of internal standards.
Liquid chromatography-mass spectrometry (LC-MS) has been widely used for profiling expression levels of biomolecules in various '-omic' studies including proteomics, metabolomics and glycomics. Appropriate LC-MS data preprocessing steps are needed to detect true differences between biological groups. Retention time (RT) alignment, which is required to ensure that ion intensity measurements among multiple LC-MS runs are comparable, is one of the most important yet challenging preprocessing steps. Current alignment approaches estimate RT variability using either single chromatograms or detected peaks, but do not simultaneously take into account the complementary information embedded in the entire LC-MS data. We propose a Bayesian alignment model for LC-MS data analysis. The alignment model provides estimates of the RT variability along with uncertainty measures. The model enables integration of multiple sources of information including internal standards and clustered chromatograms in a mathematically rigorous framework. We apply the model to LC-MS metabolomic, proteomic and glycomic data. The performance of the model is evaluated based on ground-truth data, by measuring correlation of variation, RT difference across runs and peak-matching performance. We demonstrate that Bayesian alignment model improves significantly the RT alignment performance through appropriate integration of relevant information. MATLAB code, raw and preprocessed LC-MS data are available at http://omics.georgetown.edu/alignLCMS.html. email@example.com. Supplementary data are available at Bioinformatics online.


The antioxidant paradox: less paradoxical now?
The term 'antioxidant paradox' is often used to refer to the observation that oxygen radicals and other reactive oxygen species are involved in several human diseases, but giving large doses of dietary antioxidant supplements to human subjects has, in most studies, demonstrated little or no preventative or therapeutic effect. Why should this be? First, the role of reactive oxygen species in the origin and/or progression of most human diseases is unclear, although they are probably important in cancer, neurodegenerative diseases and perhaps some others. Second, the endogenous antioxidant defences in the human body are complex, interlocking and carefully regulated. The body's 'total antioxidant capacity' seems unresponsive to high doses of dietary antioxidants, so that the amount of oxidative damage to key biomolecules is rarely changed. Indeed, manipulation of endogenous antioxidant levels (e.g. by supplying weak pro-oxidants) may be a more useful approach to treatment and prevention of diseases in which reactive oxygen species are important than is consumption of large doses of dietary antioxidants.


Simple skin closure.
Traditionally, general surgeons in the UK have shown little concern for the results of skin wound closure unless the wounds have undeniable cosmetic importance, as in surgery of the face, neck, or breasts. However, in recent years greater significance has been attached to the scarring and other complications that may result from skin sutures. Various techniques of wound closure, sutures, staples, clips, and other materials are now available to the surgeon. This article reviews these recent developments.


Serotonin increases cilia-driven particle transport via an acetylcholine-independent pathway in the mouse trachea.
Mucociliary clearance in the airways is driven by the coordinated beating of ciliated cells. Classical neuromediators such as noradrenalin and acetylcholine increase ciliary beat frequency and thus cilia-driven transport. Despite the fact that the neuromediator serotonin is ciliostimulatory in invertebrates and has been implied in releasing acetylcholine from the airway epithelium, its role in regulating cilia function in vertebrate airways is not established. We examined the effects of serotonin on ciliary beat frequency and cilia-driven particle transport in the acutely excised submerged mouse trachea and determined the sources of serotonin in this tissue by immunohistochemistry. Serotonin (100 microM) increased cilary beat frequency (8.9+/-1.2 Hz to 17.0+/-2.7 Hz) and particle transport speed (38.9+/-4.6 microm/s to 83.4+/-8.3 microm/s) to an extent that was comparable to a supramaximal dose of ATP. The increase in particle transport speed was totally prevented by methysergide (100 microM). Blockade of muscarinic receptors by atropine (1 microM) did not reduce the effect of serotonin, although it was effective in preventing the increase in particle transport speed mediated by muscarine (100 microM). Immunohistochemistry demonstrated serotonin in mast cells pointing towards mast cells and platelets as possible endogenous sources of serotonin. These results indicate that serotonin is a likely endogenous mediator that can increase cilia-driven transport independent from acetylcholine during activation of mast cells and platelets.


Could COVID expand the future of addiction research? Long-term implications in the pandemic era.
The COVID-19 pandemic has significantly impacted face-to-face research. This has propelled ideas and plans for more remote styles of research and provided new perspectives on conducting research. This paper aimed to identify challenges specific to conducting remote forms of experimental addiction research, although some of these challenges apply to all types of addiction research. The impact of the COVID-19 pandemic has led to important lessons for future addiction research. Although remote research has been conducted for decades, little experimental research has been performed remotely. To do so require a new perspective on what research questions we can ask and could also enable preferential capture of those who may be more reluctant to engage in research based in clinical settings. There may, however, be crucial factors that will compromise this process. We illustrate our argument with three real-world, ongoing case studies centred on gambling behaviour, opioid overdose, and cannabinoid psychopharmacology. We highlight the obstacles to overcome to enable more remote methods of study. The future of experimental research and, more generally, addiction research, will be shaped by the pandemic and may result in advantages, such as reaching different populations and conducting addiction research in more naturalistic settings.


Seasonal plasticity in photoprotection modulates UV-induced hsp gene expression in copepods from a clear lake.
Zooplankton from clear alpine lakes is exposed to stressful levels of solar UV radiation (UVR). As these pelagic organisms experience high UVR and large changes in solar radiation conditions between ice-free and ice-cover periods, they have evolved various strategies to minimize UVR exposure and damage. Here, we studied the relation between photoprotection levels (mycosporine-like amino acids, carotenoids), antioxidant capacities, and gene expression of heat shock proteins (hsps) as indicator of stress in the copepod Cyclops abyssorum tatricus during the course of a year. Expression of hsp60, hsp70, and hsp90 was measured in the field (baseline expression [BE]) and after UVR exposure in the laboratory. The BE differed among genes and seasons (hsp60: high during summer, hsp70 and hsp90: high during the ice-cover period). The gene expression of hsp70 was upregulated after exposure to UVR (up to 5.2-fold change), while hsp60 and hsp90 were only constitutively expressed. A strong seasonal pattern was found in the photoprotective compounds and antioxidant capacities, with highest levels during the ice-free period. The extent of upregulation of hsp70 gene expression increased with decreasing photoprotection levels and peaked 24 h post UVR exposure (9.6-fold change) at the time of lowest photoprotection (February). Our data suggest that hsp70 gene expression is modulated by seasonal plasticity in photoprotection. This ability of adequate stress response is essential for survival in highly variable ecosystems such as alpine lakes.


Structural Neural Substrates of Reading the Mind in the Eyes.
The ability to read the minds of others in their eyes plays an important role in human adaptation to social environments. Behavioral studies have resulted in the development of a test to measure this ability (Reading the Mind in the Eyes Test, revised version; Eyes Test), and have demonstrated that this ability is consistent over time. Although functional neuroimaging studies revealed brain activation while performing the Eyes Test, the structural neural substrates supporting consistent performance on the Eyes Test remain unclear. In this study, we assessed the Eyes Test and analyzed structural magnetic resonance images using voxel-based morphometry (VBM) in healthy participants. Test performance was positively associated with the gray matter volumes of the dorsomedial prefrontal cortex, inferior parietal lobule (temporoparietal junction), and precuneus in the left hemisphere. These results suggest that the fronto-temporoparietal network structures support the consistent ability to read the mind in the eyes.


[How much intervertebral disk tissue is in reality removed in percutaneous nucleotomy?].
In an experimental study with standardized conditions nuclear material of 40 human lumbar discs was excised. In 20 the non-automated discectomy method was used (NAPLD-method). In the other 20 the automated discectomy method (APLD-method). The excised material was weighted. After the removal, the material of the NAPLD-method was wet with isotonic saline over 45 minutes and again weighted. Afterwards the wet material of both methods was freeze dried and again weighted. The weight of the wet material of the NAPLD-method in relation to that of the freeze dried material was a factor 11 (average value: 7.7 g in relation to 0.7 g) and in the APLD-method a factor 15 (average value: 4.5 g in relation to 0.3 g). This means, that the uptake and distribution of the saline is different in both methods and for this reason it is not allowed to compare the wet weight of the two methods. This has to be considered in clinical comparative studies. Because the biomechanical changes after a discectomy are dependent of the amount of the excised nuclear material, the NAPLD- and APLD-method can only be compared when the amount of the excised material is changed in a freeze dried weight.


Pharmacokinetics of the triazole antifungal agent genaconazole in healthy men after oral and intravenous administration.
The pharmacokinetics of genaconazole, a potent new difluorophenyl-triazole antifungal agent, was studied in 12 healthy male volunteers following a single oral or intravenous administration of the drug. In a randomized two-way crossover design, each volunteer received either two 50-mg genaconazole tablets orally or a parenteral preparation containing 100 mg of genaconazole given as a 30-min intravenous infusion. Both dosage regimens were well tolerated. Blood and urine samples were collected up to 10 days after drug administration. Concentrations of genaconazole in plasma and urine were determined by a specific high-performance liquid chromatography assay with a limit of quantitation of 0.1 microgram/ml. Pharmacokinetic evaluation following oral and intravenous doses indicated that mean values for the area under the concentration-time curve from 0 h to infinity (137 and 136 micrograms.h/ml), half-life (50 and 49 h), volume of distribution (52 and 52 liters), and clearance (12 and 12 ml/min) were independent of the route of drug administration. The oral and intravenous administrations of genaconazole yielded virtually superimposable plasma concentration-time curves, resulting in an absolute bioavailability of 100%. Amounts of unchanged genaconazole found in urine samples from 0 to 240 h after oral and intravenous doses were comparable, and urinary excretion accounted for 76 and 78% of the administered dose, respectively. Renal clearances for the two routes of administration were also similar, and renal clearance accounted for over 80% of the total body clearance. The 100% absolute bioavailability of genaconazole regardless of the route of administration provides greater dosing flexibility in various clinical settings than currently exists.


Self-Supervised Learning for Label Sparsity in Computational Drug Repositioning.
The computational drug repositioning aims to discover new uses for marketed drugs, which can accelerate the drug development process and play an important role in the existing drug discovery system. However, the number of validated drug-disease associations is scarce compared to the number of drugs and diseases in the real world. Too few labeled samples will make the classification model unable to learn effective latent factors of drugs, resulting in poor generalization performance. In this work, we propose a multi-task self-supervised learning framework for computational drug repositioning. The framework tackles label sparsity by learning a better drug representation. Specifically, we take the drug-disease association prediction problem as the main task, and the auxiliary task is to use data augmentation strategies and contrast learning to mine the internal relationships of the original drug features, so as to automatically learn a better drug representation without supervised labels. And through joint training, it is ensured that the auxiliary task can improve the prediction accuracy of the main task. More precisely, the auxiliary task improves drug representation and serving as additional regularization to improve generalization. Furthermore, we design a multi-input decoding network to improve the reconstruction ability of the autoencoder model. We evaluate our model using three real-world datasets. The experimental results demonstrate the effectiveness of the multi-task self-supervised learning framework, and its predictive ability is superior to the state-of-the-art model.


Correlations of single nucleotide polymorphisms of CRYAA and CRYAB genes with the risk and clinicopathological features of children suffering from congenital cataract.
The study aims to explore the correlations of the single nucleotide polymorphisms (SNPs) of CRYAA and CRYAB with the risk and clinicopathological features of children with congenital cataract. The study enrolled 168 children diagnosed as congenital cataract (case group) and 172 normal children (control group) from May 2015 to May 2016. Genomic DNA extraction was performed using a QIAamp DNA blood mini kit. Polymerase chain reaction (PCR) products were genotyped using an ABI direct sequencer. Haplotype, allele, and genotype frequencies of CRYAA and CRYAB gene polymorphisms analyses were carried out using the SHEsis software. Logistic regression analysis was performed in order to analyze the risk factors for children suffering from congenital cataract. Presence of significant differences between the case and control groups' genotype and allele frequencies of CRYAA rs7278468 and CRYAB rs370803064/rs387907338. TA of CRYAB gene might increase congenital cataract risk in children, while GCG of CRYAA gene and GC of CRYAB gene might decrease congenital cataract risk in children. CRYAA rs7278468, CRYAB rs370803064/rs387907338 polymorphisms were significantly correlated to uncorrected visual acuity, best-corrected visual acuity, nystagmus, visual axis opacification, microcornea, lens opacity, posterior capsular thickening, and degrees of posterior capsule opacification after operation in children with congenital cataract. Logistic regression analysis revealed that the T allele of CRYAA rs7278468, A allele of CRYAB rs370803064, T allele of CRYAB rs387907338, family history, and TA haplotype of CRYAB gene were risk factors for children with congenital cataract. Our findings demonstrated that CRYAA rs7278468 and CRYAB rs370803064/rs387907338 are correlated with the risk and clinicopathological features of children suffering from congenital cataract.


Raised TSH is associated with endothelial dysfunction in Metabolic Syndrome: A case control study.
Endothelial dysfunction has been considered as one of the important factors in pathogenesis of Metabolic Syndrome (Met S). Subclinical hypothyroidism (SCH) has also been reported to be associated with Met S. The aim of our study is to evaluate the association of raised TSH with mediators of endothelial dysfunction in Met S with Subclinical hypothyroidism as compared to healthy controls. Study population consisted of 100 subjects, out of which 50 were cases of Met S and 50 were healthy controls. Met S group were further divided into two, based on the presence & absence of SCH. Serum insulin, T3, T4, TSH were measured by chemiluminescence based immunoassay (CLIA). Serum nitric oxide (NO) levels were measured by Modified Griess's method and serum endothelin-1 (ET-1) levels were measured by ELISA. Out of 50 cases of Met S, SCH was diagnosed in 22. The mean serum TSH levels were significantly higher in Met S cases as compared to healthy controls (5.7 ± 1.2 μIU/mL vs. 2.3 ± 1.6 μIU/mL, P <0.0001). Mean serum NO levels were significantly lower in Met S cases as compared to healthy control (15.4 ± 10 μM vs. 21 ± 10 μM, p = 0.009). Mean serum ET-1 levels were significantly higher in Met S cases as compared to healthy controls (2.68 ± 1.7 fmol/mL vs. 2.1 ± 0.84 fmol/mL, p = 0.011). On Pearson's correlation analysis, TSH showed positive correlation with ET-1 (r = 0.341, p = 0.001) and negative correlation with NO (r = -0.331, p = 0.001). Binary logistic regression analysis showed that TSH, NO and ET-1 has significant odd's ratio for predicting Met S. Met S cases were screened for thyroid abnormalities and found to have 44% of SCH along with co-existing endothelial dysfunction. Raised TSH in SCH could cause endothelial dysfunction which may lead to Met S and associated co-morbidities. Present study gives new insight in linking endothelial dysfunction and raised TSH in Met S. Therefore, Met S cases should be screened for SCH and treated appropriately to attenuate endothelial dysfunction and associated comorbidities in Met S.


Usefulness of fractional excretion of sodium in critically ill pre-term newborns.
The purpose of this prospective study was to measure the fractional excretion of sodium (FENa) in critically ill pre-term newborns (PTNB) in order to determine its cut point in the diagnosis of acute renal failure (ARF). This study included 52 newborns and was conducted from May, 1994 to May, 1995. Patients were divided in two groups: patients without ARF in group A (n = 47) and patients with ARF in group B (n = 5). No statistically significant differences were found in birth weight, extrauterine life span, serum sodium levels, urine creatinine and urinary volumes between the two groups, but there was a difference in gestational age, urinary sodium concentration and serum creatinine levels. Sensitivity and specificity were determined, and the critical level of FENa was 4% or greater for ARF diagnosis. The average FENa value for Group A was 1.4 +/- 1.4% with a median of 0.92%. In Group B, average FENa was 6.9 +/- 2.9% with a median of 8.5% (P < 0.001). We conclude that FENa is a valuable tool for the assessment of renal function in critically-ill PTNB, in spite of all other factors present in this population that could modify its values.