Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment.
Alterations in vitamin D metabolism are generally thought to account for the hypocalcemia and osteopenia caused by long term treatment with anticonvulsant drugs. Regional variation in the incidence and severity of anticonvulsant drug-induced bone disease has been attributed to differences in sunlight exposure, with most reports coming from areas with limited sunshine or from institutionalized patients. Serum ionized calcium levels in 109 ambulatory adult epileptic outpatients receiving chronic anticonvulsant drug therapy in Georgia were decreased [4.73 +/- 0.02 (+/-SE) vs. 4.97 +/- 0.01 mg/dl; P less than 0.001). Immunoreactive PTH concentrations were increased (5.5 +/- 0.4 vs. 4.0 +/- 0.3 microliterEq /ml; P less than 0.005), while bone mineral content was reduced, averaging only 88.8% of the predicted normal values. Hypocalcemia and osteopenia occurred in spite of normal mean levels of serum 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D. The indirect relationship between serum concentrations of antiepileptic drugs and the serum ionized calcium level, and the lack of correlation with vitamin D metabolite levels suggested that hypocalcemia was independent of the effect of the drugs on vitamin D metabolism. Bone biopsies revealed increased osteoid but normal calcification front formation, accelerated mineralization rate, and decreased mineralization lag time indicative of increased skeletal turnover, rather than osteomalacia.


Contamination and restoration of groundwater aquifers.
Humans are exposed to chemicals in contaminated groundwaters that are used as sources of drinking water. Chemicals contaminate groundwater resources as a result of waste disposal methods for toxic chemicals, overuse of agricultural chemicals, and leakage of chemicals into the subsurface from buried tanks used to hold fluid chemicals and fuels. In the process, both the solid portions of the subsurface and the groundwaters that flow through these porous structures have become contaminated. Restoring these aquifers and minimizing human exposure to the parent chemicals and their degradation products will require the identification of suitable biomarkers of human exposure; better understandings of how exposure can be related to disease outcome; better understandings of mechanisms of transport of pollutants in the heterogeneous structures of the subsurface; and field testing and evaluation of methods proposed to restore and cleanup contaminated aquifers. In this review, progress in these many different but related activities is presented.


Establishment and Characterization of Free-Floating 3D Macrophage Programming Model in the Presence of Cancer Cell Spheroids.
Reprogramming of tumor-associated macrophages (TAMs) is a promising strategy for cancer immunotherapy. Several studies have shown that cancer cells induce/support the formation of immunosuppressive TAMs phenotypes. However, the specific factors that orchestrate this immunosuppressive process are unknown or poorly studied. In vivo studies are expensive, complex, and ethically constrained. Therefore, 3D cell interaction models could become a unique framework for the identification of important TAMs programming factors. In this study, we have established and characterized a new in vitro 3D model for macrophage programming in the presence of cancer cell spheroids. First, it was demonstrated that the profile of cytokines, chemokines, and surface markers of 3D-cultured macrophages did not differ conceptually from monolayer-cultured M1 and M2-programmed macrophages. Second, the possibility of reprogramming macrophages in 3D conditions was investigated. In total, the dynamic changes in 6 surface markers, 11 cytokines, and 22 chemokines were analyzed upon macrophage programming (M1 and M2) and reprogramming (M1→M2 and M2→M1). According to the findings, the reprogramming resulted in a mixed macrophage phenotype that expressed both immunosuppressive and anti-cancer immunostimulatory features. Third, cancer cell spheroids were shown to stimulate the production of immunosuppressive M2 markers as well as pro-tumor cytokines and chemokines. In summary, the newly developed 3D model of cancer cell spheroid/macrophage co-culture under free-floating conditions can be used for studies on macrophage plasticity and for the development of targeted cancer immunotherapy.


The prognostic value of preoperative prognostic nutritional index in patients with hypopharyngeal squamous cell carcinoma: a retrospective study.
To analyze the prognostic value of preoperative prognostic nutritional index (PNI) in predicting the survival outcome of hypopharyngeal squamous cell carcinoma (HPSCC) patients receiving radical surgery. From March 2006 to August 2016, 123 eligible HPSCC patients were reviewed. The preoperative PNI was calculated as serum albumin (g/dL) × 10 + total lymphocyte count (mm-3) × 0.005. These biomarkers were measured within 2 weeks prior to surgery. The impact of preoperative PNI on overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) were analyzed using Kaplan-Meier method and Cox proportional hazards model. Median value of 52.0 for the PNI was selected as the cutoff point. PNI value was then classified into two groups: high PNI (> 52.0) versus low PNI (≤ 52.0). Multivariate analysis showed that high preoperative PNI was an independent prognostic factor for better OS (P = 0.000), PFS (P = 0.001), LRFS (P = 0.005) and DMFS (P = 0.016). High PNI predicts superior survival in HPSCC patients treated with radical surgery. As easily accessible biomarkers, preoperative PNI together with the conventional TNM staging system can be utilized to enhance the accuracy in predicting survival and determining therapy strategies in these patients.


Mood state dissociates conflict adaptation within tasks and across tasks.
The present study investigated the influence of mood state (positive vs. negative) on the cognitive control process of conflict adaptation. A task-switching paradigm was applied, allowing to assess conflict adaptation both within tasks and across tasks. A success-failure manipulation was applied for mood induction. Within-task conflict adaptation tended to be larger in negative mood than in positive mood, in line with previous findings in the literature. Across-task conflict adaptation was also observed, but only in the positive mood group: Participants in positive mood showed larger conflict adaptation than participants in negative mood. We suggest that different cognitive mechanisms underlie this double dissociation: Within-task conflict adaptation is enhanced in negative mood because response conflict is aversive in nature, and is therefore congruent to negative mood states. Between-task conflict adaptation is only present in positive mood because of less distinct task representations under positive mood, leading conflict adaptation to transfer to the other task. The data show that influences of mood state on cognitive control are multifaceted, with some control processes being enhanced and others attenuated in negative relative to positive mood. (PsycINFO Database Record


Cutaneous manifestations of Wegener's granulomatosis: a clinicopathologic study of 17 patients and correlation to antineutrophil cytoplasmic antibody status.
Wegener's granulomatosis (WG), a systemic vasculitis, can be associated with cutaneous signs and symptoms before, during or after the diagnosis of systemic disease. We reviewed clinical and histologic features of cutaneous lesions from 17 patients with WG. The temporal relationship between development of cutaneous symptoms and onset of systemic disease was determined, and antineutrophil cytoplasmic antibody (ANCA) status of the patients was also established. In six patients, systemic and cutaneous disease developed concurrently. In eight patients, cutaneous disease developed after patients received the diagnosis of systemic disease. In three patients, cutaneous disease preceded systemic disease. Cytoplasmic ANCA or proteinase-3-ANCA [c-ANCA/proteinase 3 (PR3)-ANCA] serologic test results were negative for one patient when cutaneous disease developed, and one patient had c-ANCA/PR3-ANCA seroconversion a year before systemic disease developed. Histopathologic features of cutaneous WG were not limited to leukocytoclastic vasculitis; they also included acneiform perifollicular and dermal granulomatous inflammation and palisaded neutrophilic and granulomatous inflammation. Patients with WG can present initially with cutaneous symptoms. Histopathologic patterns vary, but leukocytoclastic vasculitis is most commonly noted. Patients with WG and skin lesions are likely to have positive c-ANCA/PR3-ANCA serologic test results.


Effects of inflammation on myopia: evidence and potential mechanisms.
As the most common type of refractive error, myopia has become one of the leading causes of visual impairment. With the increasing prevalence of myopia, there is a growing need to better understand the factors involved in its development. Inflammation, one of the most fundamental pathophysiological processes in humans, is a rapid response triggered by harmful stimuli and conditions. Although controlled inflammatory responses are necessary, over-activated inflammation is the common soil for many diseases. The impact of inflammation on myopia has received rising attention in recent years. Elevated inflammation may contribute to myopia progression either directly or indirectly by inducing scleral remodeling, and myopia development may also increase ocular inflammation. This article provides a comprehensive review of the interplay between inflammation and myopia and the potential biological mechanisms, which may present new targets for understanding the pathology of myopia and developing myopia therapies.


Increased Tryptophan Catabolism Is Associated With Increased Frequency of CD161+Tc17/MAIT Cells and Lower CD4+ T-Cell Count in HIV-1 Infected Patients on cART After 2 Years of Follow-Up.
HIV infection is associated with increased ratio between kynurenine and tryptophan (KTR) in plasma, increased microbial translocation, expansion of regulatory T cells (Tregs), and depletion of Tc17/mucosa-associated invariant T (MAIT) cells. The association between these parameters and the impact of KTR on CD4 T-cell recovery in HIV-infected patients on combination antiretroviral therapy (cART) after 2 years of follow-up was investigated. Forty-one HIV-infected individuals treated with cART for a minimum of 2 years were included. Tregs, CD161Tc17/MAIT cells, naive cells, immune activation, senescence, and apoptosis were measured using flow cytometry. Soluble CD14 (sCD14), lipopolysaccharide, and tryptophan metabolites in plasma were measured retrospectively before cART and at inclusion initiation using Limulus Amebocyte Lysate colometric assay, enzyme-linked immunosorbent assay, and tandem mass spectrometry, respectively. KTR was calculated, and patients were divided into 2 groups defined by high vs. low KTR. CD4 T-cell count was determined at inclusion and after 2 years of follow-up. KTR decreased after cART initiation. Patients on cART with high KTR displayed an immunological profile with high sCD14, high percentage Tregs, low percentage CD161Tc17/MAIT cells, low percentage naive cells, low CD4/CD8 ratio, and poor immune reconstitution after 2 years of follow-up compared with patients with low KTR. Our results support the hypothesis that tryptophan catabolism, indoleamine 2,3-dioxygenase 1 (IDO1) activation, microbial translocation, and perturbed distribution of Tregs and CD161Tc17/MAIT cells are part of a vicious circle that perpetuates exhaustion of the immune system and progression of untreated HIV infection and challenge immune reconstitution in patients on cART.


Massive Eccentric Wear of the Acetabular Cup after Polyethylene Liner Abrasion in Hip Arthroplasty may lead to a high Risk of Injury during Revision Surgery.
Polyethylene wear is known to be a major cause of long-term failure after primary hip arthroplasty which results in the activation of an innate immune response with subsequent osteolysis and component loosening. However, polyethylene wear in hip arthroplasty may be asymptomatic for a long time and following massive, eccentric abrasion of the cup with subluxation of the femoral head after fully polyethylene wear has not yet been described. Hereby, we present a case of rapid progressive eccentric wear of the acetabular cup after complete polyethylene liner abrasion in a ceramic-on-polyethylene bearing. A 80-year-old-lady presented on our emergency department with a subluxated hip arthroplasty on the right side implanted 30 years ago. The X-ray showed a Zweymüller stem combined with a Gartenmann cup and a ceramic head with excessive eccentric wear of the acetabular cup with razor blade sharp edges after fully polyethylene liner abrasion. Progressive eccentric wear of the acetabular cup after fully polyethylene liner abrasion in ceramic-on-polyethylene bearings in hip arthroplasty may be asymptomatic for a long time but may progress rapidly. To prevent patients from extensive revision surgery and the revision surgeon from serious injury due to intraoperatively findings such as razor blade sharp edges, routine long-term follow-up radiographic evaluation is crucial.


In vitro characterization of SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolone, monohydrochloride): a novel partial dopamine D2 and D3 receptor agonist and serotonin 5-HT1A receptor agonist.
Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.


Topsoil selenium (Se) under Se-rich farming in China: Current status, cropping impacts and ecological risk assessment.
Selenium (Se), as an essential microelement, can be supplied through Se-biofortified food from Se-rich soils and associated farming practices for human health, while it can also cause eco-risks if overapplied. In this study, a multi-scale spatiotemporal meta-analysis was conducted to guide sustainable Se-rich farming in China by combining a long-term survey with a reviewed database. The weighted mean concentration, spatial distribution of soil Se, nationwide topsoil Se variation from cropping impacts and its bioavailability-based ecological risks were assessed and quantified. The results showed that the weighted mean content (0.3 mg kg-1) of China was slightly higher than that of previous nationwide topsoil Se surveys, as more Se-rich areas were found in recent high-density sampling surveys. Cropping has overall reduced Se content by 9.5% from farmland across China and deprived more with the increase in farming rotation driven by geo-climatic conditions. Long-term cropping removed Se from Se-rich areas but accumulated it in Se-deficient areas. Additionally, the bioavailable Se content of topsoil in China ranged from 0 to 332 μg kg-1, and the bioavailability-based eco-risks indicated that high eco-risks only existed in overfertilized and extremely high-Se soils, such as in Enshi, Ziyang and some coalfield areas. This work provides evidence for the development of sustainable Se-rich farming with proper utilization of soil Se resources, simultaneously protecting the soil eco-environment.


Evaluation of health-related programmes in Africa: a vision for 2020.
Whereas systematic evaluation practice is over five decades old in economically developed continents (DCs), that culture has not yet taken root in Africa. To provide an overview of the current situation of health-related evaluation in the African Region; to envision an appropriate evaluation framework for the next two decades; and to provide overviews of what formative (FE) and summative (SE) evaluations are and how they could be conducted. Descriptive study. Health policies and plans evaluation in the WHO African Region. WHO Country Representatives for 25 African Countries. Non-intervention descriptive study. Availability and quality of long-term health plan (LTHP), health policy (HP), strategic plan (SP), operational plan (OP), and an evaluation culture. The study found that: 88%, 8%, 36%, 28% and 48% of the countries in the Region do not have LTHP, HP, SP, OP and evaluation culture. A conceptual evaluation framework, tools for formative and summative evaluations are proposed. It is envisioned that all partners for health development in Africa will cooperate with individual countries to develop (or strengthen) LTHPs, HPs, SPs, and Ministries of Health OPs (national, provincial and district level); and to make complementary investments in building technical and administrative capacity for evaluating implementation of District Operational Plans (DOPs).


Detailed analysis of skin conductance responses during a gambling task: Decision, anticipation, and outcomes.
Physiological arousal is considered a key factor of gambling behavior. Hence, to understand gambling behavior it is important to study the arousal responses during gambling. Moreover, crucial mechanisms of action could be uncovered by detailing the situations that produce an arousal response. A gamble, or bet, can be partitioned into three distinct phases: (a) decision phase, during which the information concerning the gamble is presented, outcomes are appraised, and a decision is made on how to gamble; (b) anticipation phase, during which the result of the gamble is awaited; (c) outcome phase, during which the outcome of the gamble is presented. Previous research on arousal responses to gambling have mostly measured tonic changes in arousal, and when phasic responses have been measured, analyses have generally concentrated on one of the gamble phases. The aim of the present study was to map the arousal responses during gambling in more detail by measuring skin conductance responses (SCRs) during all three gamble phases of a simple card game. The anticipation phase was found to produce the largest arousal response, suggesting anticipation to be a major contributor to arousal during gambling behavior. Risk behavior during the gambling task was mirrored in self-reported risk taking in everyday life, and risk-takers displayed smaller SCRs compared to nonrisk-takers during decision making, suggesting this as a possible biomarker for risk-taking individuals.


Flavor precursors and sensory-active sulfur compounds in alliaceae species native to South Africa and South America.
Profiles of S-substituted cysteine flavor precursors were determined in 42 Alliaceae species native to South Africa and South America. It was found that the pool of cysteine derivatives present in these plants is remarkably very simple, with S-((methylthio)methyl)cysteine 4-oxide (marasmin) being the principal flavor precursor, typically accounting for 93-100% of the pool. Out of the other cysteine derivatives, only minor quantities of methiin were present in some species. The marasmin-derived thiosulfinate marasmicin (2,4,5,7-tetrathiaoctane 4-oxide), a major sensory-active compound of the freshly disrupted plants, was isolated, and its organoleptic properties were evaluated. Furthermore, sulfur-containing volatiles formed upon boiling of these alliaceous species were studied by GC-MS. The profile of the volatiles formed was relatively simple, with 2,3,5-trithiahexane and 2,4,5,7-tetrathiaoctane being the major components. Despite the traditional belief, ingestion of the marasmin-rich plants was always accompanied by development of a strong "garlic breath". We believe that especially several Tulbaghia species deserve to attract much greater attention from the food industry thanks to their pungent garlicky taste and unusual yet pleasant alliaceous smell.


Multiple and configurable optical logic systems based on layered double hydroxides and chromophore assemblies.
Multiple and configurable fluorescence logic gates were fabricated via self-assembly of layered double hydroxides and various chromophores. These logic gates were operated by observation of different emissions with the same excitation wavelength, which achieve YES, NOT, AND, INH and INHIBIT logic operations, respectively.


* Design of an In Vitro Model of Cell Recruitment for Skeletal Muscle Regeneration Using Hepatocyte Growth Factor-Loaded Fibrin Microthreads.
Large skeletal muscle defects that result in volumetric muscle loss (VML) result in the destruction of the basal lamina, which removes key signaling molecules such as hepatocyte growth factor (HGF) from the wound site, eliminating the endogenous capacity of these injuries to regenerate. We recently showed that HGF-loaded fibrin microthreads increased the force production in muscle tissues after 60 days in a mouse VML model. In this study, we created an in vitro, three-dimensional (3D) microscale outgrowth assay system designed to mimic cell recruitment in vivo, and investigated the effect of HGF-loaded, cross-linked fibrin microthreads on myoblast recruitment to predict the results observed in vivo. This outgrowth assay discretely separated the cellular and molecular functions (migration, proliferation, and chemotaxis) that direct outgrowth from the wound margin, creating a powerful platform to model cell recruitment in axially aligned tissues, such as skeletal muscle. The degree of cross-linking was controlled by pH and microthreads cross-linked using physiologically neutral pH (EDCn) facilitated the release of active HGF; increasing the two-dimensional migration and 3D outgrowth of myoblasts twofold. While HGF adsorbed to uncross-linked microthreads, it did not enhance myoblast migration, possibly due to the low concentrations that were adsorbed. Regardless of the amount of HGF adsorbed on the microthreads, myoblast proliferation increased significantly on stiffer, cross-linked microthreads. Together, the results of these studies show that HGF loaded onto EDCn microthreads supported enhanced myoblast migration and recruitment and suggest that our novel outgrowth assay system is a robust in vitro screening tool that predicts the performance of fibrin microthreads in vivo.


Standard-Free Bioanalytical Approach for Absolute Quantitation of Drug Metabolites Utilizing Biosynthesis of Reciprocal Radio and Stable Isotopologues and Its Application.
The following work describes a combined enzymatic and bioanalytical method that permits absolute quantitation of metabolites in biological samples without the requirement for reference metabolite standards. This technique was exemplified using a radio (14C) isotopologue and a stable (13C6) isotopologue of acetaminophen as substrates for in vitro biosynthesis of the corresponding radio and stable isotope labeled metabolites, namely, 14C- and 13C6-glucuronides and sulfates. By supplanting the use of authentic metabolite standards, traditionally used to calibrate 13C6-metabolites via liquid chromatography-tandem mass spectrometry (LC-MS/MS), 13C6-metabolites were radiocalibrated by their 14C-isotopologues via liquid chromatography coupled with radioactivity detection and mass spectrometry (LC-RAD/MS). The radiocalibrated 13C6-isotopologues were in turn used to quantitate acetaminophen and its corresponding metabolites in rat plasma samples by LC-MS/MS. Variation between this and a conventional LC-MS/MS method using authentic standards for calibration was within ±17%, permitting its use in preclinical and clinical applications. Since authentic metabolite standards are not required under the concept of radio and stable isotopologues using adapted LC-RAD/MS protocols, significantly fewer resources are required to support accurate metabolite quantitation which in turn enables efficient analysis of simple and complex metabolite profiles.


Macroscopic characteristics of the umbilical cord in Standardbred, Thoroughbred and Warmblood horses.
The umbilical cord (UC), the connection between mother and fetus via the umbilical vessels, carries nutrients and oxygenated blood to the fetus through the umbilical vein and removes deoxygenated blood and waste products via the umbilical arteries. It is designed to protect blood flow to the fetus during pregnancy. In equine medicine, only a few studies have described the UC, and most of these involved Thoroughbreds. The present study describes and compares the macroscopic features of the equine umbilical cord in three different breeds and in relation to the foal's gender. In addition, a possible correlation between UC features and maternal and perinatal factors is investigated. One hundred and twenty four healthy mares with normal pregnancies were enrolled in the study and were divided into three groups according to their breed: 70 Standardbreds (STB), 38 Thoroughbreds (THB) and 16 Warmbloods (WAB). The following data were recorded: mare's age and parity, gestation length, placental weight, presence of fetal membrane alterations, UC length and number of coils in the amniotic and allantoic portions, and the Umbilical Coiling Index (UCI), which is the ratio between total coils and total UC length. The UCI has not been investigated previously in veterinary medicine. Furthermore, immediately after foaling, APGAR score, foal's weight and sex were recorded. All the STB and WAB were housed in Italy and the THB were housed in New Zealand. Mares' mean age was higher in WAB than in THB and STB; the latter had a significantly shorter gestation length. The foal's weight was positively correlated with placental weight in all breeds; and in STB, foal weight was positively related to parity and gestation length. Mean total UC length was comparable to previous reports in THB, STB and WAB. The lengths of the two UC portions were statistically different between STB and THB, where the amniotic portion was longer than the allantoic one. In each breed, total UC length was correlated with total number of coils (THB and STB = 5 ± 1; WAB = 6 ± 1), the UC amniotic length was positively correlated with the number of amniotic coils and the allantoic length was positively correlated with the number of allantoic coils. The UCI values were 0.09 in STB and THB and 0.1 in WAB. This study provides reference values for UCI that could be included in the gross placental evaluation if its clinical importance were demonstrated.


[Scrotal reconstruction by cutaneous expansion].
We report on a patient who underwent scrotal reconstruction by cutaneous expansion, a new technique utilized to repair the male genital area. The tissue obtained with this technique permits creating a scrotal pouch and completely free movement of the testes. Unlike the other methods, sufficient skin can be obtained with the exparsion technique. The morphological result achieved with this technique is clearly superior. The absence of scars is underscored.


Effects of metabolic control, patient education and initiation of insulin therapy on the quality of life of patients with type 2 diabetes mellitus.
The objective of this study was to evaluate the impact of initiation of insulin therapy, metabolic control and structured patient education on the diabetes-related quality of life (QoL) in insulin-treated patients with type 2 diabetes mellitus. This prospective study was conducted with 71 consecutively recruited patients with insulin-treated diabetes at the University hospital. All patients participated an inpatient diabetes treatment and teaching program (DTTP) for conventional insulin therapy (mean age 68.9 years, HbA1c 10.1+/-1.4%, diabetes duration 11.2 years (range: 0-25.5 years), body-mass-index 28.7+/-5.7 kg/m(2). Diabetes-related quality of life was assessed before and 6 months after participation in the DTTP using the standardized questionnaire of Lohr analysing the subscales: social relations, physical complaints, worries about the future, dietary restrictions, fear of hypoglycaemia, and daily struggles. Only patients switched on insulin therapy showed significant improvement in diabetes-related quality of life 6 months after participation in the DTTP (p=0.03), fewer physical complaints (p=0.03), fewer worries about the future (p=0.02), fewer daily struggles (p=0.01) and less fear of hypoglycaemia (p<0.001), while patients, who were already on insulin therapy showed no improvements in diabetes-related quality of life. Though, residual analysis reveals that effects on patients' QoL are mainly caused by improvements in metabolic control. Improvements in metabolic control have a significant effect on different diabetes-related quality of life domains in patients with diabetes mellitus. Appropriate interventions resulting in better metabolic control, such as starting on insulin therapy within a structured patient education program seem to be an effective approach to improve patients' diabetes-related quality of life.


Survivability and long-term stress reactivity levels following repeated exposure to nuclear magnetic resonance imaging procedures in rats.
The effect of exposure to the magnetic and radio-frequency fields associated with Nuclear Magnetic Resonance Imaging (MRI) on survivability and long-term stress reactivity levels was examined in male rats. Rats in the experimental condition were exposed to MRI for 22.5 minutes for five successive days (Expt. 1) or 23.3 minutes for twenty-one successive days (Expt. 2). Sham field exposed animals received the identical treatment as the exposed animals except that the magnetic and radio-frequency fields were absent. Control rats were also maintained. Thirteen to twenty-two months after the exposure procedure the remaining rats were sacrificed and their whole body, spleen, heart, thymus, and adrenal weights were recorded. Blood samples were taken for measurements of red and white blood cell counts, hemoglobin content, as well as adrenocorticotrophin and corticosterone levels. The results fail to provide any evidence for changes in survivability and long-term stress reactivity levels in rats exposed to MRI and thus give no grounds to challenge the view that MRI is a safe diagnostic procedure.


Redox remodeling allows and controls B-cell activation and differentiation.
During their differentiation to antibody-secreting plasma cells, B lymphocytes undergo dramatic changes in metabolism, structure, and function. Here we show that this transition entails extensive intra- and extracellular redox changes. Lipopolysaccharide (LPS)-driven activation and differentiation of naïve murine B splenocytes is paralleled by increased production of reactive oxygen species (ROS) from different sources, followed by a strong antioxidant response. This response includes upregulation of thioredoxin and of the cystine transporter xCT, and increased production and extracellular release of nonprotein thiols, mainly glutathione (GSH) and cysteine. Although ROS levels are higher in late-differentiating B cells, an early oxidative step is likely required to start the differentiation program, because inhibition of NADPH oxidase-dependent early ROS production impairs B-cell activation and differentiation. Addition of reducing agents such as 2-ME results in increased IgM secretion per cell, suggesting that the antioxidant response not only is aimed at restoring the redox homeostasis but also plays a functional role. A highly reduced environment coincident with the presence of large ROS-producing cells is observed in histologic sections of spleens from immunized mice, indicating that the redox modifications observed in LPS-induced B-cell differentiation in vitro occur also in vivo during physiologic immune responses.


Myofibroblastoma.
Myofibroblastoma of the breast is a rare benign mesenchymal tumor. We report a 61-year-old male case who presented to the orthopedic clinic with right shoulder pain. The physical and clinical examination was normal and he was referred to our clinic. Excision was performed and there were no postoperative complications.


A study of chromosomal changes associated with amplified dihydrofolate reductase genes in rat hepatoma cells and their dedifferentiated variants.
We have examined the karyological consequences of dihydrofolate reductase gene amplification in a series of six rat hepatoma cell lines, all derived from the same clone. Cells of three of these lines express a series of liver-specific functions whereas those of three others fail to express these functions. Cells of each line have been subjected to stepwise selection for methotrexate resistance and, in most cases, resistance is associated with a 40-50-fold amplification of sequences hybridizing to a dihydrofolate reductase cDNA probe. In one line no modified chromosome is observed, whereas in two others the amplified genes are associated with an expanded chromosomal region. R-banding analysis of these karyotypes showed that few changes have occurred. These observations apply to two of the well-differentiated lines, and to a variant able to revert to the differentiated state. In contrast, in the two stably dedifferentiated hepatoma cell lines, amplified dihydrofolate reductase genes are found on large chromosomes of variable size, on ring chromosomes, and on chromosomes containing terminal, median, or multiple centromeres. We conclude that the nature of the chromosomal changes associated with dihydrofolate reductase gene amplification are the result of differences in cell lines rather than in the protocols employed for selection.


Chemogenetic Inhibition of Dopamine D1-expressing Neurons in the Dorsal Striatum does not alter Methamphetamine Intake in either Male or Female Long Evans Rats.
The biochemical and molecular substrates of methamphetamine (METH) use disorder remain to be elucidated. In rodents, increased METH intake is associated with increased expression of dopamine D1 receptors (D1R) in the dorsal striatum. The present study assessed potential effects of inhibiting striatal D1R activity on METH self-administration (SA) by rats. We microinjected Cre-activated adeno-associated viruses to deliver the inhibitory DREADD construct, hM4D (Gi) - mCherry, into neurons that expressed Cre-recombinase (D1-expressing neurons) in the dorsal striatum of male and female transgenic Long Evans rats (Drd1a-iCre#3). Two weeks later, we trained rats to self-administer METH. Once this behavior was acquired, intraperitoneal injections of clozapine-N-Oxide (CNO) or its vehicle (sterile water) were given to rats before each METH SA session to determine the effect of DREADD-mediated inhibition on METH intake. After the end of the experiments, histology was performed to confirm DREADD delivery into the dorsal striatum. There were no significant effects of the inhibitory DREADD on METH SA by male or female rats. Post-mortem histological assessment revealed DREADD expression in the dorsal striatum. Our results suggest that inhibition of D1R in the dorsal striatum does not suppress METH SA. It remains to be determined if activating D1R-expressing neurons might have differential behavioral effects. Future studies will also assess if impacting D1R activity in other brain regions might influence METH SA.


Analysis of outcome of 6-month readmissions after percutaneous left atrial appendage occlusion.
Percutaneous left atrial appendage occlusion (LAAO) is an alternative strategy for prevention of thromboembolic events in patients with atrial fibrillation and unsuitable for long-term oral anticoagulation. The study aimed to evaluate the causes and timing of readmissions within 6 months following percutaneous LAAO in a real-world setting. We conducted a retrospective cohort study of percutaneous LAAO performed in the USA between January and June of 2016-2018 using the Nationwide Readmissions Database. Overall, 12 446 patients who underwent LAAO were included in the analyses and 3477 patients (28%) were readmitted within 6 months following the interventions. Readmitted patients were more often women (p=0.001). The index hospitalisation was characterised by longer duration of hospital stay (p<0.001) and complicated with acute kidney injury (p<0.001) among readmitted patients compared with those without readmissions. Readmissions within 6 months following the index intervention were mainly due to heart failure (13%) and gastrointestinal bleeding (12%). Characteristics associated with readmissions due to heart failure included previously known heart failure (HR 2.39; 95% CI 1.70 to 3.37), valvular heart disease (HR 1.39; 95% CI 1.05 to 1.84) and chronic kidney disease (HR 1.42; 95% CI 1.03 to 1.94). Readmissions due to gastrointestinal bleeding were associated with diabetes mellitus (HR 1.78; 95% CI 1.25 to 2.53), chronic kidney disease (HR 1.86; 95% CI 1.23 to 2.81) and previous anaemia (HR 2.41; 95% CI 1.54 to 3.77). After percutaneous LAAO, over a quarter of the patients in the USA required rehospitalisation within 6 months, mainly due to heart failure and gastrointestinal bleeding.


Relations between anxiety sensitivity's cognitive concerns and anxiety severity: brooding and reflection as serial multiple mediators.
The outbreak of COVID-19 has caused a major impact on productivity and life functioning, and also led to adverse emotional reactions. In the face of this public health event, increased anxiety is one of the most common emotional reactions. Previous studies have shown that anxiety sensitivity, rumination and anxiety are closely related. Various dimensions of anxiety sensitivity have different effects on anxiety. Also, rumination can be divided into brooding and reflection. To explore the relationships among anxiety sensitivity's cognitive concerns, anxiety and different types of rumination, we conducted an online survey during the outbreak of coronavirus (February 17-25, 2020), using the Anxiety Sensitivity Scale-3 (ASI-3), Ruminative Responses Scale (RSS), and Depression Anxiety Stress Scale-21 (DASS-21). The results showed significant positive correlations among anxiety sensitivity's cognitive concerns, anxiety, brooding and reflection. Furthermore, brooding and reflection had a chain mediation effect between cognitive concerns and anxiety, and the mediation effect of reflection was even stronger. Results suggest that anxiety sensitivity's cognitive concerns may not only affect anxiety directly, but also affect anxiety through rumination, especially reflection.


[Nasal Mucosa Absorption of Scutellariae Radix Extract in Rats and Its Two Preparations Phospholipid Complex and Submicron Emulsion].
To study the nasal mucosa absorption of Scutellariae Radix extract in rats and its two preparations phospholipid complex and submicron emulsion, and to evaluate the rationality of Scutellariae Radix extract modification technology and preparation form. According to the nasal absorption method, the absorption amount of Scutellariae Radix extract, phospholipid complex and submicron emulsion were determined. The absorption amount of Scutellariae Radix extract, phospholipid complex and submicron emulsion under the experimental conditions was improved in turn in 2 h and the absorption amount of submicron emulsion increased significantly. The absorption characteristics were passive diffusion. The modification methods and preparation form of Scutellariae Radix extract were scientific and reasonable.


[Medical treatment of acute pancreatitis (author's transl)].
For medical treatment of acute pancreatitis, only very few effective measures can be recommended. To put the gland to rest, the patient has to be maintained in a fasting state. Additionally, Cimetidine should be administered intravenously. A properly functioning nasogastric tube is an efficacious method of inducing the pancreas to rest. To maintain an adequate blood volume and in protecting the microcirculation of pancreas, the use of intravenous fluids that include colloids, is important. Sufficient replacement of electrolytes evidently seems to be indicated. Drug therapy consists of the administration of analgetics and of an adjuvant use of calcitonine or somatostatine, for reducing the pancreatic flow. Aprotinine given early and in sufficient amounts is to be recommended. Antibiotic prophylaxis should be utilized only when pancreatitis associated with biliary tract disease or postoperative pancreatitis seems to be apparent. Whenever systemic hypotension and shock occurs, plasma or dextran, together with sufficient but controlled amounts of intravenous fluids, must be administered. In acute renal failure dopamine has been used with success. Peritoneal dialysis or hemodialysis as an ultimate measure, has to be considered. In the case of respiratory distress syndrome, oxygen by nasal catheter must be applied.


[Surgical treatment of pulmonary echinococcosis].
The experience of surgical treatment of the pulmonary echinococcosis (PE) at 515 patients is generalized. Character of operative intervention at PE depends on cyst's localization and presence of complications. The method of echinococcectomy with the cappitonnage of fibrous capsule, which is the most effective method of PE surgical treatment, is expounded. The methods of fibrous capsule anti-parasitogenic treatment are described: chemical (10% solution of sodium chloride, chlorhexidinum, betalin), physical (laser radiation, stream of hot air), being most effective, simple and accessible. The methods of videothoracoscopic (VTO) and video-assisted echinococcectomy (VAE), at which application permits the rehabilitation period of patients diminishes considerably, are expounded. The amount of postoperative complications at VTO and VAE made 16.7%, at open echinococcectomy--2.7%. Lethality was 0.2% (one patient died).


The impact of the model for end-stage liver disease (MELD) on liver transplantation in one center in Brazil.
Presently the MELD score is used as the waiting list criterion for liver transplantation in Brazil. In this method more critical patients are considered priority to transplantation. To compare the results of liver transplantation when the chronologic waiting list was the criterion for organ allocation (pre-MELD era) with MELD score period (MELD era) in one liver transplantation unit in Brazil. The charts of the patients subjected to liver transplantation at the Hospital de Clínicas da Universidade Federal do Paraná, Curitiba, PR, Brazil, were reviewed from January of 2001 to August of 2008. Patients were divided into two groups: pre-MELD era and MELD era. They were compared in relation to demographics of donors and receptors, etiology of cirrhosis, cold and warm ischemia time, presence of hepatocellular carcinoma, MELD score and Child-Pugh score and classification at the time of transplantation, units of red blood cells transfused during the transplantation, intensive care unit stay, total hospital stay and 3 month and 1 year survival. Initially, 205 liver transplantations were analyzed. Ninety four were excluded and 111 were included: 71 on the pre-MELD era and 40 on the MELD era. The two groups were comparable in relation to donors and receptors age and sex, etiology of cirrhosis and cold and warm ischemia time. The receptors of the MELD era had more hepatocellular carcinoma than those of the pre-MELD era (37.5% vs 16.9%). Patients with hepatocellular carcinoma had less advanced cirrhosis on both eras. The MELD score was the same on both eras. Excluding the cases of hepatocellular carcinoma, MELD era score was higher than pre-MELD score (18.2 vs 15.8). There were an increased number of transplants on Child-Pugh A and C and a decreased number on Child-Pugh B receptors on MELD era. Both eras had the same need of red blood cells transfusion, intensive care unit stay and hospital stay. Also, 3 month and 1 year survival were the same: 76% and 74.6% on pre-MELD era and 75% and 70.9% on MELD era. In our center, after the introduction of MELD score as the priority criterion for liver transplantation there were an increased number of transplants with hepatocellular carcinoma. Excluding these patients, the receptors were operated upon with more advanced cirrhosis. Nevertheless the patients had the same need for red blood cells transfusion, intensive care unit and hospital stay and 3 months and 1 year survival.


Associations between family relationships and symptoms/strengths at kindergarten age: what is the role of children's parental representations?
The quality of the family relationships plays an important role in the development of children's psychopathology and in their socio-emotional development. This longitudinal study aims to investigate whether family relationships are related to children's symptoms/strengths at kindergarten, and whether family relationships are predictors of changes in children's symptoms/strengths between 5 and 6. Our main interest is to examine the role of children's parental representations. One hundred and fifty-three kindergarten children (67 girls, 86 boys) participated in this study. Children's parental representations were assessed using a story stem task (age 5). The family environment was assessed using parents' ratings (age 5). A multi-informant approach (parent, teacher, child) was employed to assess children's symptoms/strengths at 5 and 6. Children were interviewed using a standardised puppet interview. Parents and teachers completed questionnaires. Children's parental representations as well as the family environment were associated with children's symptoms/strengths at 5 and 6. When controlled for gender, children's representations were the only predictor of changes in symptoms/strengths between 5 and 6. A large number of negative parental representations at 5 predicted an increase in conduct problems. A large number of positive parental representations at 5 predicted an increase in pro-social behaviour. In terms of emotional symptoms and hyperactivity/inattention, symptoms at 5 were the only predictor for symptoms one year later. Our results suggest that kindergarten children's narrative representations may elaborate the processes underlying the expression of child disturbance and strengths, and underline the relevance of the play and narration of young children for diagnostics and therapy.


Nanostructured Antimicrobials for Quality and Safety Improvement in Dairy Products.
In the food sector, one of the most important economic activities is the dairy industry, which has been facing many challenges in order to meet the increasing demand by consumers for natural and minimally processed products with high quality. In this sense, the application of innovative and emerging technologies can be an interesting alternative, for example, the use of nanotechnology in packaging and as delivery systems. This technology has the potential to improve the quality and safety of dairy products, representing an interesting approach for delivering food preservatives and improving the mechanical, barrier and functional properties of packaging. Several applications and promising results of nanostructures for dairy product preservation can be found throughout this review, including the use of metallic and polymeric nanoparticles, lipid-based nanostructures, nanofibers, nanofilms and nanocoatings. In addition, some relevant examples of the direct application of nanostructured natural antimicrobials in milk and cheese are presented and discussed, as well as the use of milk agar as a model for a preliminary test. Despite their high cost and the difficulties for scale-up, interesting results of these technologies in dairy foods and packaging materials have promoted a growing interest of the dairy industry.


Inhibitors of HIV-1 proteinase containing 2-heterosubstituted 4-amino-3-hydroxy-5-phenylpentanoic acid: synthesis, enzyme inhibition, and antiviral activity.
A convenient procedure for the synthesis of 2-heterosubstituted statine derivatives as novel building blocks in HIV-protease inhibitors has been developed. The synthesis starts with protected L-phenylalaninols, which were converted to gamma-amino alpha, beta-unsaturated esters in a one-pot procedure. A highly diastereoselective epoxidation of the N-protected (E)-enoates, followed by regioselective ring opening of the corresponding 2,3-epoxy esters with a variety of heteronucleophiles, resulted in 2-heterosubstituted statine derivatives. The overall stereo-chemical outcome of the transformations meets the required configuration of HIV-protease inhibitors. The short, synthetically flexible, and highly diastereoselective synthesis of 2-heterosubstituted statines has enabled a broad derivation, covering the S3, S2, and S1'-S3' sites of the enzyme. In a series of 46 derivatives, several potent inhibitors were obtained with Ki values as low as 3.4 nM and antiviral activity in the lower nanomolar-range. The structural parameters of the compounds which determine the potency of inhibition and selectivity for the viral enzyme are discussed.


New approaches to invasive fungal infections.
Invasive fungal infections are typically difficult to prevent, diagnose, and treat; consequently, fungal infection-related mortality has become high, particularly among patients with prolonged neutropenia and severe graft-versus-host disease. However, much recent progress has been made in understanding the immune response to fungi and the epidemiology of infection, and new diagnostic tests and antifungal drugs have become available. This review will describe these most recent developments with the goal of evaluating new approaches to prevent, diagnose, and treat invasive fungal infections.


Heterogeneity of Drosophila nicotinic acetylcholine receptors: SAD, a novel developmentally regulated alpha-subunit.
Two genes, ard and als, are known to encode subunits of the nicotinic acetylcholine receptor (nAChR) in Drosophila. Here we describe the isolation of cDNA clones encoding a novel member (SAD, or alpha 2) of this receptor protein family. The deduced amino acid sequence displays high homology to the ALS protein and shares structural features with ligand binding nAChR alpha-subunits. Sad transcripts accumulate during major periods of neuronal differentiation and, in embryos, are localized in the central nervous system. Expression of SAD cRNA in Xenopus oocytes generates cation channels that are gated by nicotine. These data indicate heterogeneity of nAChRs in Drosophila.


High sensitivity determination of the remoxipride hydroquinone metabolite NCQ-344 in plasma by coupled column reversed-phase liquid chromatography and electrochemical detection.
An HPLC method for the determination of NCQ-344, a remoxipride metabolite with a hydroquinone structure, in human plasma is described. Special precautions for the sampling were necessary as the compound rapidly decomposes. An efficient clean-up of the plasma samples was necessary to make use of the inherent sensitivity of the electrochemical detector. This was accomplished by a fast and simple liquid-liquid extraction at pH 7.05 combined with further cleaning on-line by using a short cyanopropyl column as the first column in a column switching system. A heart-cut from the cyanopropyl column containing the NCQ-344 fraction was then injected onto the analytical octadecyl silica column and NCQ-344 was detected at an oxidation potential of 0.70 V. The absolute recovery was > 95% and concentrations down to 0.10 nM could be determined with acceptable precision. The NCQ-344 levels in a limited number of samples from patients given remoxipride were found to be between 0.10 and 1 nM. The remoxipride concentrations in the same samples were 5,000-20,000 nM.


Screening for prostate cancer: a study on the free and total prostate specific antigen.
A variety of biomarkers have been developed to monitor growth of cancerous diseases and to detect them at an early stage. Prostate-specific antigen (PSA) is a valuable prostate cancer biomarker that is now widely used for population screening, diagnosis, and monitoring of patients with prostate cancer. Other factors than prostate cancer can cause elevation of PSA levels therefore, free prostate specific antigen measurements in serum have been proposed in order to improve the specificity of laboratory identification of prostate cancer. The aim of our study was to evaluate the diagnostic significance of both total PSA and Free PSA in discriminating prostate cancer from other prostate diseases. Our study group consisted of 1201 males admitted at outpatient clinic aged between 35 and 84 years old (mean age 63 years). All laboratory measurements were performed on serum samples. The data were statistically analyzed by using descriptive statistics for Windows. The mean total PSA concentration evaluated among 1038 patients was 16.17 ng/mL whereas only Free PSA concentration was evaluated in 163 serum samples and resulted in a mean value of 2.67 ng/ml. In order to calculate the correlation between total and free PSA, data among 69 /1038 patients were further analyzed through statistical program software package for data analysis. Measuring serum free PSA concentrations along with PSA concentrations may provide higher accuracy for detecting prostate cancer and might eliminate unnecessary biopsies in the men with PSA of more than 4.0 ng/mL.


Dopaminergic treatment of acromegaly: different effects on hormone secretion and tumor size.
We studied the effects of long term treatment with bromocriptine (Br) or lisuride (L) on GH secretion and tumor size in 19 acromegalic patients with large pituitary adenomas. In 22 additional patients with smaller adenomas, only plasma GH levels were monitored during treatment. All patients underwent an acute test with 2.5 mg Br or 0.3 mg L and, on the basis of GH changes, were classified as responders, i.e. reduction in circulating GH concentrations by at least 50% below baseline, or as nonresponders. The chronic treatment was 5-20 mg/day Br in 26 patients or 0.3-2.0 mg/day L in 15 patients. Treatment was given for 4-26 months (mean +/- SE, 13.3 +/- 2.8 months). Plasma GH levels (baseline, 46.3 +/- 8.3 ng/ml) were significantly lower in the group as a whole (22.7 +/- 3.6 ng/ml; P less than 0.01) after the first month of treatment with dopamine agonist agents. GH levels decreased significantly in those acromegalic patients who responded to the acute test (P less than 0.001), but were unchanged in the nonresponders. In addition, there was a significant correlation between the maximal percent GH decrease in the acute test and the response during chronic treatment (r = 0.73; P less than 0.01). Computed tomography failed to show any tumor size changes in any of the GH nonresponders who had a macroadenoma . However, in two patients in the acute responder group with macroadenomas, chronic dopamine agonist therapy resulted in reduction of the extrasellar portion of the tumor (-30% and -40% of tumor area, respectively). These data show that although dopaminergic drugs lower GH levels and reverse signs and symptoms of active disease in those acromegalic patients who are responsive to an acute challenge, tumor size reduction occurred in a minority of such patients.


Phenotypic characterization of nonsocial behavioral impairment in neurexin 1α knockout rats.
Neurexins are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in autism spectrum disorder (ASD) patients. NRXN1-α knockout (KO) mice present behavioral impairments that resemble some of the core ASD symptoms of social impairment and inflexibility/stereotypy. At present, a thorough assessment of cognitive function has yet to be completed. Rats, containing a biallelic deletion of the NRNX1-α gene on a Sprague Dawley background were compared to littermate wild types across a range of tasks designed to test functional domains disrupted in ASD and other neurodevelopmental disorders, including sensory perception (prepulse inhibition), attention (latent inhibition), associative learning (instrumental and Pavlovian conditioning), and memory (rewarded alternation T maze and spatial discrimination). NRXN1α KO rats were found to present with large and persistent nonsocial deficits, including hyperactivity, deficits in simple instrumental learning, latent inhibition, and spatial-dependent learning. No deficit in sensorimotor gating was observed, despite the presence of an exaggerated startle response. Although KO animals were also able to learn a simple Pavlovian conditioning discrimination, they did display impaired latent inhibition. The presence of pronounced impairments in several domains in NRXN1α KO rats clearly suggests that nonsocial cognitive deficits can also be measured in an animal model of ASD. Further exploration of those deficits, both clinically and preclinically, as planned in the Innovative Medicines Initiative's European Autism Interventions: A Multicenter Study for Developing New Medications program, may help to better understand the brain circuitry involved in ASD and therefore open new avenues to advance novel therapies.


Probiotics are a good choice in remission of inflammatory bowel diseases: A meta analysis and systematic review.
Altered gut bacteria and bacterial metabolic pathways are two important factors in initiation and progression of inflammatory bowel disease (IBD). However, efficacy of probiotics in remission of patients with IBD has not been characterized. This study was performed on the studies that specifically assessed the efficacy of probiotics in attaining clinical response on patients with various types of IBD. The efficacy of variant species of probiotics in different conditions and the influence of study quality in outcomes of randomized controlled trials (RCTs) were also assessed. The RCTs were collected by searching in MEDLINE Web of Science and Google scholar. Then all studies were abstracted in abstraction form and the outcomes were analyzed with fixed-effect and mixed-effect models for assessment of efficacy of variant species of probiotics in subgroups of IBDs. Analysis of 9 trials showed that probiotics had not significant effect on Crohn's disease (CD) (p = 0.07) but analysis of 3 trials in children with IBD revealed a significant advantage (p < 0.01). Analysis of 18 trials revealed that probiotics in patients with Ulcerative colitis (UC) in different conditions have significant effects (p = 0.007). VSL#3 probiotics in patients with UC had significant effect (p < 0.01). Combination of Lactobacillus probiotic, prebiotics had significant effect (p = 0.03) only in patients with UC. Combination of Saccharomyces boulardii, Lactobacillus, and VSL#3 probiotics in CD had also a trend for efficiency (p = 0.057). In children with IBD, the combination of Lactobacillus with VSL#3 probiotics had significant effect (p < 0.01). Probiotics are beneficial in IBD, especially the combination ones in UC.


An Otx-related homeodomain protein binds an LHbeta promoter element important for activation during gonadotrope maturation.
The hormone-secreting cell types of the anterior pituitary differentiate in a specific spatial and temporal manner. The alpha-subunit of the glycoprotein hormones appears at embryonic d 11.5 in the mouse, followed by steroidogenic factor-1, which distinguishes the gonadotrope progenitor cells, around embryonic d 14. Gonadotrope maturation is marked by the onset of LHbeta-gene expression 2 d later. The alphaT3-1 and LbetaT2 immortalized mouse pituitary cell lines correspond to these later sequential stages of gonadotrope differentiation. In addition to the early markers of the gonadotrope lineage present in alphaT3-1 cells, LbetaT2 cells also express markers of a mature gonadotrope, including LHbeta and FSHbeta. Using transient transfections to compare expression among gonadotrope and nongonadotrope-derived cell types, we show that the rat 1.8-kb LHbeta promoter directs reporter gene expression specifically to the mature gonadotrope LbetaT2 cell line. Promoter truncation and mutagenesis analyses indicate that the homeodomain (HD) element located at approximately -100 bp relative to the transcriptional start site is essential for this selectivity to LbetaT2 cells when compared with alphaT3-1 cells. In EMSAs, this HD site binds a protein present in LbetaT2 but not other gonadotrope-derived cells. Antibody supershift and competition experiments indicate that this LbetaT2 nuclear protein is a K50 HD protein related to the Otx family, though it is not a known pituitary homeobox transcription factor protein. These studies indicate a role for a novel Otx-related HD protein in gonadotrope maturation during development.


Clinicoradiological Risk Factors Associated with Inability to Achieve Minimum Clinically Important Difference in Operated Cases of Cervical Spondylotic Myelopathy.
This is a retrospective cohort study. This study aimed to identify the clinicoradiological risk factors associated with the inability to achieve minimum clinically important difference (MCID) on the modified Japanese Orthopaedic Association (mJOA) Scale in operated cases of cervical spondylotic myelopathy (CSM). Only a few studies have evaluated the outcomes of surgery performed for CSM using MCID on the mJOA scale. We analyzed 124 operated CSM cases from March 2019 to April 2021 for preoperative clinical features, cervical sagittal radiographic parameters, and magnetic resonance imaging (MRI) signal intensities (SI). The risk factors associated with missing the MCID (poor outcome) on mJOA at the final follow-up were identified using binary logistic regression. Multivariate analysis was used to find significant risk factors, and odds ratios (OR) were computed. A total of 110 men (89.2%) and 14 women (10.8%) with an average age of 53.5±13.2 years were included in the analysis. During the last follow-up, 89 cases (72.1%) achieved MCID (meaningful gains following surgery) while 35 (27.9%) could not. The final model identified the following parameters as significant risk factors for poor outcome: increased duration of symptoms (OR, 6.77; p=0.001), lower preoperative mJOA scale (OR, 0.75; p=0.029), the presence of multilevel T2-weighted (T2W) MRI SI (OR, 4.79; p=0.004), and larger change in cervical sagittal vertical axis (ΔcSVA) (OR, 1.06; p=0.013). Also, an increase in cSVA postoperatively correlated with a reduced functional recovery rate (r=-0.4, p<0.001). Surgery for CSM leads to significant functional benefits. However, poorer outcomes are observed in cases of greater duration of symptoms, higher preoperative severity with multilevel T2W MRI SI, and a larger increase in the postoperative cSVA (sagittal imbalance).


Development and validation of UPLC method for WST-1 cell viability assay and its application to MCTT HCE™ eye irritation test for colorful substances.
WST-1 [Water Soluble Tetrazolium-1; 2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt)] is widely used in the cell viability assays replacing MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). A water-soluble formazan dye (4-[1-(4-Iodophenyl)-5-(4-nitrophenyl)formaz-3-yl]-1,3-benzene disulfonate, disodium salt) is produced from the reduction of WST-1 tetrazolium, of which optical density at 450 nm is measured to evaluate cell viability. Colorful substances may interfere with spectrometric measurement, and a method to specifically detect WST-1 formazan is required. Here, a simple, rapid, sensitive, and specific ultra-performance liquid chromatography coupled to UV detector (UPLC-UV) was developed and validated for the WST-1 formazan. For the application to cell viability assay, the supernatant from WST-1 assay was injected without sample preparation procedure and a single run was completed within 5 min. Chromatographic separation was achieved on BEH C18 column (1.7 μm, 2.1 × 50 mm) using gradient elution with the mobile phase of water and acetonitrile. The standard curves were linear over the concentration range of 2.5-120 μg/mL WST-1 formazan, which encompasses WST-1 formazan concentrations from 2% cell viability to 2 fold of 100% cell viability. The intra- and inter-day precisions were measured to be below 5% and accuracies were within the range of 91.8-104.9%. The validated method was successfully applied to the test of colorful substances in vitro eye irritation test with a human cornea-like epithelium, and in vitro cytotoxicity in HaCaT, human keratinocyte cell line.


Shoshin beriberi: an unusual complication of prolonged parenteral nutrition.
After 4 weeks of total parenteral nutrition (TPN), a 12-yr-old girl exhibited an acute heart failure with high cardiac output, anuria, and severe lactic acidosis. The clinical, hemodynamic, and biological data suggested the diagnosis of shoshin beriberi which was proved by the low erythrocyte transketolase activity with elevated "TPP effect" and by the dramatic improvement of the patient after thiamin administration. Thiamin deficiency and severe neurological disorders have been described during long-term parenteral nutrition. To our knowledge, this is the first report of the cardiovascular complication of this vitamin deprivation in long-term TPN.


Quantitative trait loci mapping and transcriptome analysis reveal candidate genes regulating the response to ozone in Arabidopsis thaliana.
As multifaceted molecules, reactive oxygen species (ROS) are known to accumulate in response to various stresses. Ozone (O3 ) is an air pollutant with detrimental effect on plants and O3 can also be used as a tool to study the role of ROS in signalling. Genetic variation of O3 sensitivity in different Arabidopsis accessions highlights the complex genetic architecture of plant responses to ROS. To investigate the genetic basis of O3 sensitivity, a recombinant inbred line (RIL) population between two Arabidopsis accessions with distinct O3 sensitivity, C24 (O3 tolerant) and Te (O3 sensitive) was used for quantitative trait loci (QTL) mapping. Through analysis of QTL mapping combined with transcriptome changes in response to O3 , we identified three causal QTLs and several potential candidate genes regulating the response to O3 . Based on gene expression data, water loss and stomatal conductance measurement, we found that a combination of relatively low stomatal conductance and constitutive activation of salicylic acid (SA)-mediated defence signalling were responsible for the O3 tolerance in C24. Application of exogenous SA prior to O3 exposure can mimic the constitutive SA signalling in C24 and could attenuate O3 -induced leaf damage in the sensitive Arabidopsis accessions Te and Cvi-0.


Role of N-acetylglutamate turnover in urea synthesis by rats treated with the thyroid hormone.
We determined whether the synthesis and degradation of N-acetylglutamate would regulate urea synthesis when the thyroid status was manipulated. Experiments were done on three groups of rats, each being given 6-propyl-2-thiouracil (PTU, a thyroid inhibitor) without a triiodothyronine (T3) treatment, treated with PTU + T3, or receiving neither PTU nor T3 (control). The plasma concentration and urinary excretion of urea, the liver concentration of N-acetylglutamate, and the liver N-acetylglutamate synthesis in rats given PTU alone were each significantly higher than in the control rats. Compared with the control rats, the liver N-acetylglutamate degradation was significantly lower in those rats given PTU without the T3 treatment. Treatment of the PTU-treated rats with T3 reversed the effects of PTU to the values of the control rats. N-Acetylglutamate synthesis in the liver was closely correlated with the excretion of urea, and inverse correlation between the liver N-acetylglutamate degradation and urea excretion was found. These results suggest that the greater synthesis and lower degradation of N-acetylglutamate in the hypothyroid (PTU alone) rats would be likely to increase the hepatic concentration of this compound and stimulate urea synthesis.


Decrease in pulmonary function and oxygenation after lung resection.
Respiratory deficits are common following curative intent lung cancer surgery and may reduce the patient's ability to be physically active. We evaluated the influence of surgery on pulmonary function, respiratory muscle strength and physical performance after lung resection. Pulmonary function, respiratory muscle strength (maximal inspiratory/expiratory pressure) and 6-min walk test (6MWT) were assessed pre-operatively, 2 weeks post-operatively and 6 months post-operatively in 80 patients (age 68±9 years). Video-assisted thoracoscopic surgery was performed in 58% of cases. Two weeks post-operatively, we found a significant decline in pulmonary function (forced vital capacity -0.6±0.6 L and forced expiratory volume in 1 s -0.43±0.4 L; both p<0.0001), 6MWT (-37.6±74.8 m; p<0.0001) and oxygenation (-2.9±4.7 units; p<0.001), while maximal inspiratory and maximal expiratory pressure were unaffected. At 6 months post-operatively, pulmonary function and oxygenation remained significantly decreased (p<0.001), whereas 6MWT was recovered. We conclude that lung resection has a significant short- and long-term impact on pulmonary function and oxygenation, but not on respiratory muscle strength. Future research should focus on mechanisms negatively influencing post-operative pulmonary function other than impaired respiratory muscle strength.


p185neu is phosphorylated on tyrosine in human primary breast tumors which overexpress neu/erbB-2.
A series of primary human breast tumors was analysed by immunoblotting with anti-neu antibodies. Overproduction of the neu protein-tyrosine kinase, p185neu, was observed in 23 of 56 malignant tumor samples. 29 of these tumors were also immunoblotted with antiphosphotyrosine antibodies. A single prominent phosphotyrosine-containing protein, which co-migrated with p185neu was identified in 11 of the 29 tumors examined. There was an exact concordance between the tumors with a 185kDa phosphotyrosine-containing protein, and those with elevated p185neu. These results indicate that overexpressed p185neu in primary human breast cancer is phosphorylated on tyrosine, most likely by autophosphorylation, and by inference is enzymatically activated as a protein-tyrosine kinase. Aberrant tyrosine phosphorylation may therefore be important in the development of a substantial fraction of breast cancers.


On the Wrong Track: Process and Content in Moral Psychology.
According to Joshua Greene's influential dual process model of moral judgment, different modes of processing are associated with distinct moral outputs: automatic processing with deontological judgment, and controlled processing with utilitarian judgment. This article aims to clarify and assess Greene's model. I argue that the proposed tie between process and content is based on a misinterpretation of the evidence, and that the supposed evidence for controlled processing in utilitarian judgment is actually likely to reflect, not 'utilitarian reasoning', but a form of moral deliberation which, ironically, is actually in serious tension with a utilitarian outlook. This alternative account is further supported by the results of a neuroimaging study showing that intuitive and counterintuitive judgments have similar neural correlates whether or not their content is utilitarian or deontological.


Enhanced Recovery After Surgery (ERAS) protocols for spine surgery - review of literature.
Enhanced Recovery After Surgery (ERAS) is a multidisciplinary approach that uses a combination of evidence-based methods to improve patient care. Different ERAS protocols are used in various surgical fields but for spine surgery there is no widely used standard ERAS protocol. We compiled and examined the multiple available publications on ERAS protocols for spine surgery. Some general commonalities exist between ERAS protocols; however, a great deal of variety is observed in the granularity of important details such as differing drug choices or specific dosing. To assess and relate the different available ERAS protocols, we conducted a comprehensive narrative literature review focused on comparing commonalities and differences among the following aspects of ERAS protocols: mechanisms of action, post-surgery pain levels, opioid consumption, utilization of muscle relaxants, use of anti-inflammation drugs, and ambulation after surgery. Our goal in this project was to simplify the search process for institutions who review the literature. In this review, certain ERAS elements such as early ambulation, blood loss, pain management, and patient positioning are further explored in more depth.


Abnormal bile acid pool and composition in neonates of spontaneously diabetic Wistar BB rats and its change during development.
Streptozotocin-induced diabetes during pregnancy in rats causes a decrease in primary bile acid pool in neonates. To rule out direct drug effect on the fetus as the basis for this change, studies of bile acid pool and composition at birth and during subsequent development was carried out in neonates of spontaneously diabetic Wistar BB rats and compared to control neonates. The cholic acid pool in neonates of diabetic rats was lower when compared to control neonates at birth. The pool of secondary bile acids was markedly increased in neonates of diabetic rats, with increases in lithocholic and 3 beta,12 alpha-dihydroxycholanoic acid. With age, the cholic acid pool of neonates from diabetic rats was increased and at 3 months of age it was actually higher than in control neonates. The pool of chenodeoxycholic at diabetes onset age was lower in neonates of diabetic rats. HDL-cholesterol was lower in neonates of diabetic rats at 1 week, but this reversed at 3 months of age. These studies firmly establish that neonates of diabetic rats have abnormal bile acid pool and composition at birth which changes to adult diabetic pattern with age.


Quantification and prediction of the detoxifying properties of humic substances related to their chemical binding to polycyclic aromatic hydrocarbons.
Effects of 27 different humic materials on the toxicity of polycyclic aromatic hydrocarbons (PAH) were studied for crustacean Daphnia magna. Sources included isolated humic acids, fulvic acids, and their combination from soil, peat, and freshwater. The PAH used were pyrene, fluoranthene, and anthracene. The observed reduction in toxicity of PAH in the presence of humic substances (HS) was shown to be a result of the detoxification effect caused by the chemical binding of PAH to HS and of the direct effect of HS on D. magna. An approach was developed to quantify the detoxifying impact of humic materials related to their chemical binding to PAH with a use of the "constant of detoxification" or "toxicological partition coefficient" K(oc)D. The latter was proposed to determine by fitting the experimental relationships of the detoxification effect versus concentration of HS. The obtained K(oc)D values were well tracked by the corresponding partition coefficients determined by the fluorescence quenching technique (K(oc)fq): K(oc)D=b x K(oc)fq, b (mean+/-Cl, n=26, P=95%)=2.6+/-0.3, 4.6+/-0.6, and 6.0+/-1.4 for pyrene, fluoranthene, and anthracene, respectively. The predictive relationships between the structure and detoxifying properties of humic materials in relation to PAH were developed. It was shown that the magnitude of the K(oc)D values correlated closely with the aromaticity of humic materials characterized with the 13C NMR descriptors (sigma(C)Ar, sigma(C)Ar/sigma(C)Alk) and atomic H/C ratio. The obtained relationships showed the highest detoxifying potential of the humic materials enriched with aromatics and allowed a conclusion on the chemical binding as the governing mechanism of the mitigating action of HS on the toxicity of PAH.


Involvement of insulin resistance in normoglycaemic obese patients with periodontitis: A cross-sectional study.
We explored the association between obesity and periodontitis with the aim of determining the possible role of insulin resistance (IR) in this relationship. A total of 212 subjects-110 obese and 102 lean individuals-were evaluated for periodontal disease and divided according to IR: a lean group without IR (LWIR), an obese group without IR (OWIR), and an obese group with IR (OIR). Anthropometric, metabolic, inflammatory and periodontal parameters were evaluated. Periodontitis was more prevalent in obese (80.9%) than in lean subjects (41.2%), with the former group showing a risk of periodontitis sixfold that of the latter. Obese subjects as a whole displayed higher diastolic blood pressure, TNFα and hsCRP and lower HDL cholesterol than lean subjects. OIR had higher systolic blood pressure, glucose, insulin, HOMA-IR, A1c, triglycerides and number of teeth with PD ≥ 4 mm than OWIR, while other periodontal variables remained unaltered. The multivariable regression model showed that probing depth, bleeding on probing and HOMA-IR were independent predictors of number of teeth with PD ≥ 4 mm. Our data support an association between obesity and periodontitis, and point to a central role of IR. Periodontitis tends to be more extensive in obese patients with IR.


One of early maladaptive schemas' causal relationship through metacognitive beliefs with borderline and antisocial personality patterns.
This study aimed at determining the causal relationship of metacognitive beliefs as a mediator between one of early maladaptive schemas including (emotional deprivation, abandonment, mistrust/abuse, social isolation/alienation and defectiveness/shame) and borderline and antisocial personality patterns. The study type has been relational and seeking causal modeling of path analysis has been used. The population used in this study included outpatients in counseling, psychological and psychiatric centers in 2012-2013. We randomly distributed 350 questionnaires in five centers out of three parts in Isfahan, and finally 230 valid questionnaires were evaluated and analyzed. Data collection tool has been Millon Clinical Multiaxial Inventory-III's (MCMI-III's) personality questionnaire, Yang's schema questionnaire (75 items), Metacognition Questionnaire-30 (30 items). Reliability of the Yang's Schema Questionnaire in this study was calculated by Cronbach's alpha (α =96%), and that of metacognition was calculated the same way (α =87%). Data analysis has been done using MCMI-III's software for Millon's personality questionnaire, and SPSS-16 and AMOS-18 software. We used path analysis method for testing each model in statistical data analysis. The results of this study suggest a possible causal relationship between the number of one of the early maladaptive schemas and the patterns of anti-social and borderline personalities through some metacognitive beliefs. This study showed that cognitive beliefs can be activators of the early schema and continuation's coping behaviors in personality patterns.


Antibiotic Sensitivity of Clostridium perfringens Isolated From Faeces in Tabriz, Iran.
Clostridium perfringens, a Gram-positive, anaerobic bacterium that produces at least 16 virulence factors including 12 toxins (α-ν), enterotoxin, hemolysin and neuraminidase, can create variable pathogenic condition, ranging from a food poisoning to life-threatening myonecrosis. Among C. perfringens strains, resistance to the drug choices such as penicillin as well as to alternatives of penicillin like metronidazole and clindamycin has also been observed. The aim of this study was to determine the resistance of isolated toxigenic and non-toxigenic C. perfringens strains against common antimicrobial agents. In this descriptive study, a total of 136 stool specimens were collected. At first, cooked meat medium enrichment method was performed on samples at 45°C. Thereafter, a loopful of the enriched culture was transferred to blood agar and incubated anaerobically at 37°C for 24-72 hours. Colonies with double zone of hemolysis were identified by different biochemical tests such as phospholipase C (lecithinase) test, indole and urease production. The Minimum Inhibitory Concentration (MIC) for common antibiotics was determined by Etests (Epsilometer) and duplex Polymerase Chain Reaction (PCR) reaction was performed with specific primers for amplification of cpe (426 bp) and plc (283 bp) Genes. Of 136 stool samples including diarrhea [48] and non-diarrhea [88] ones, 83 (61.02%) C. perfringens were cultured. Of these 83, 79 C. perfringens isolates showed the alpha-toxin (phospholipase C) production gene by PCR. Respectively, 3 (9.09%) and 2 (4.34%) cpe genes were present in diarrhea and non-diarrhea samples. Of 79 isolates of C. perfringens, 34 (43.03%) cases showed no resistance, 18 (22.78%) had one resistance and 27 (34.17%) isolates had multiple resistance to imipenem, metronidazole, ceftriaxone, clindamycin, chloramphenicol, and penicillin. Periodic evaluation of antimicrobial susceptibility for C. perfringens should be performed. Harboring of enterotoxigenic C. perfringens in individuals not necessarily results in diarrhea.


Spatial mobility and reasons for migration of Japanese women.
This paper discloses, istly, the spatial mobility of Japanese women and its change mainly between 1970 and 1980, through comparison with the men's mobility, in respect of distance of movement, age patterns, and labor force status, using population census data. Secondly, the chief reasons for the migration of women by types of migratory flows are examined using the data derived from the survey on reasons for migration conducted in 1981 by the Land Agency of the Government of Japan. Results show that the spatial mobility of Japanese women is smaller than that of men in long distance movements but is almost the same in short distance moves, and that the age pattern of spatial mobility of the women is nearly the same between both distances of movement. Also, it is disclosed that the mobility of women not in the labor force is higher for the whole country but lower in metropolitan areas than that for men. The prime reason for the migration of women is employment, the as same as that for men for the whole nation, but this varies between the types of migratory flows.


Role of arginine and its methylated derivatives in cancer biology and treatment.
Both L-arginine supplementation and deprivation influence cell proliferation. The effect of high doses on tumours is determined by the optical configuration: L-arginine is stimulatory, D-arginine inhibitory. Arginine-rich hexapeptides inhibited tumour growth. Deprivation of L-arginine from cell cultures enhanced apoptosis. The pro-apoptotic action of NO synthase inhibitors, like NG-monomethyl-L-arginine, is manifested through inhibition of the arginase pathway. NG-hydroxymethyl-L-arginines caused apoptosis in cell cultures and inhibited the growth of various transplantable mouse tumours. These diverse biological activities become manifest through formaldehyde (HCHO) because guanidine group of L-arginine in free and bound form can react rapidly with endogenous HCHO, forming NG-hydroxymethylated derivatives. L-arginine is a HCHO capturer, carrier and donor molecule in biological systems. The role of formaldehyde generated during metabolism of NG-methylated and hydroxymethylated arginines in cell proliferation and death can be shown. The supposedly anti-apoptotic homozygous Arg 72-p53 genotype may increase susceptibility of some cancers. The diverse biological effects of L-arginine and its methylated derivatives call for further careful studies on their possible application in chemoprevention and cancer therapy.


Improving deep convolutional neural networks with mixed maxout units.
Motivated by insights from the maxout-units-based deep Convolutional Neural Network (CNN) that "non-maximal features are unable to deliver" and "feature mapping subspace pooling is insufficient," we present a novel mixed variant of the recently introduced maxout unit called a mixout unit. Specifically, we do so by calculating the exponential probabilities of feature mappings gained by applying different convolutional transformations over the same input and then calculating the expected values according to their exponential probabilities. Moreover, we introduce the Bernoulli distribution to balance the maximum values with the expected values of the feature mappings subspace. Finally, we design a simple model to verify the pooling ability of mixout units and a Mixout-units-based Network-in-Network (NiN) model to analyze the feature learning ability of the mixout models. We argue that our proposed units improve the pooling ability and that mixout models can achieve better feature learning and classification performance.


The efficacy and safety of growth hormone therapy in children with noonan syndrome: a review of the evidence.
Noonan syndrome is a genetic disorder associated with short stature. We reviewed 15 studies in which growth hormone (GH) therapy was used in children with Noonan syndrome. Data show consistent increases in mean height standard deviation score (SDS), with first-year changes of up to 1.26 SDS. Among studies reporting adult or near-adult height, GH therapy over 5-7 years resulted in adult height SDS from -0.6 to -2.1, with up to 60% of subjects in some studies achieving adult height within 1 SDS of mid-parental height. GH treatment results in an acceleration of bone age, likely reflecting normalization from the retarded bone age common in Noonan syndrome patients at the start of therapy. BMI is not affected by GH treatment, but favorable changes in fat mass and body composition are achievable. Longer-term studies and observational studies suggest a waning of the effect of GH therapy over time, as is seen in other GH-treated conditions, and early initiation of therapy and prepubertal status are important predictors of response. GH treatment does not appear to be associated with adverse cardiac or metabolic effects, and data on malignancy during GH treatment give no cause for concern, although they are limited.


Enteroatmospheric fistula: from soup to nuts.
Enteroatmospheric fistula (EAF), a special subset of enterocutaneous fistula (ECF), is defined as a communication between the gastrointestinal (GI) tract and the atmosphere. It is one of the most devastating complications of "damage control" laparotomy (DCL) and results in significant morbidity and mortality. The published incidence of EAF ranges from 5%-19% of patients who have undergone DCL and survived long enough to develop complications. Their etiology is complex and ranges from persistent abdominal infection, anastomotic leakage, adhesions of the bowel to itself or fascia, and repeated bowel manipulation during return trips to the operating room or dressing changes. Prevention is clearly the best treatment strategy but may be difficult to achieve. Once an EAF occurs, immediate management consists of treatment of sepsis if present; nutrition, fluid, and electrolyte support in the form of parenteral nutrition (PN); and wound/effluent control and protection of surrounding tissues and exposed bowel. It should be noted that EAF almost never close spontaneously, and definitive repair usually requires major surgical intervention and abdominal wall reconstruction 6 to 12 months after the original insult. Enteral feeding should be attempted once the anatomy of the EAF is defined and reliable enteral access is obtained. Most patients can tolerate some amount of enteral and even oral feeding and do not need to be maintained on PN alone. Professional judgment, experience, and teamwork are key to successfully managing the patient with EAF.


A three-dimensional vocal fold posturing model based on muscle mechanics and magnetic resonance imaging of a canine larynx.
In this work, a high-fidelity three-dimensional continuum model of the canine laryngeal framework was developed for simulating laryngeal posturing. By building each muscle and cartilage from magnetic resonance imaging (MRI), the model is highly realistic in anatomy. The muscle mechanics is modeled using the finite-element method. The model was tested by simulating vocal fold postures under systematic activations of individual as well as groups of laryngeal muscles, and it accurately predicted vocal fold posturing parameters reported from in vivo canine larynges. As a demonstration of its application, the model was then used to investigate muscle controls of arytenoid movements, medial surface morphology, and vocal fold abduction. The results show that the traditionally categorized adductor and abductor muscles can have opposite effects on vocal fold posturing, making highly complex laryngeal adjustments in speech and singing possible. These results demonstrate that a realistic comprehensive larynx model is feasible, which is a critical step toward a causal physics-based model of voice production.


Quantum dynamics with curvilinear coordinates: models and kinetic energy operator.
In order to simplify the numerical solution of the time-dependent or time-independent Schrödinger equations associated with atomic and molecular motions, the use of well-adapted coordinates is essential. Usually, this set of curvilinear coordinates leads to a Hamiltonian operator that is as separable as possible. Although their corresponding kinetic energy operator (KEO) expressions can be derived analytically for small systems or special kinds of coordinates, a numerical and exact approach allows one to compute them in terms of sophisticated curvilinear coordinates. Furthermore, the numerical approach enables one to easily define reduced-dimensionality or constrained models. We present here a recent implementation of this numerical approach that allows nested coordinate transformations, therefore leading to great flexibility in the definition of the curvilinear coordinates. Furthermore, this implementation has no limitations in terms of numbers of atoms or coordinate transformations. The quantum dynamics of the cis-trans photoisomerization of part of the retinal chromophore illustrates the construction of the coordinates and KEO part of a three-dimensional model. This article is part of the theme issue 'Chemistry without the Born-Oppenheimer approximation'.


Complete genome sequence of Achromobacter insolitus type strain LMG 6003T, a pathogen isolated from leg wound.
Achromobacter insolitus is a newly described, Gram-negative, small (1-2 mm long) and coccoid pathogen that has been isolated from leg wound. Due to its potential threat to human beings, the type strain of this species LMG 6003T was completely sequenced in this study. The genomic analysis revealed that the genome of LMG 6003T consists of one circular DNA chromosome of 6 492 697 bp with a GC content of 65.10%. The entire genome contains 6208 predicted coding genes, 61 tRNAs and 13 rRNA genes. Comparative genome analysis between LMG 6003T and another selected 10 sequenced Achromobacter revealed that 725 genes only exist in LMG 6003T. In particular, these genes include several important pathogenic-related genes such as Type IV prepilin peptidase (TadV/CpaA), Type VI secretion lipoprotein (VasD) and type 1 fimbriae major subunit (FimA). Genomic island (GI) analysis also suggests the existence of GIs in LMG 6003T. All these results strongly suggest the unique genomic features in LMG 6003T against other Achromobacter species. This report will provide us with an extended understanding of A. insolitus at the genomic level and would be helpful for understanding the evolution of the Achromobacter genus.


Sleep and Inflammation During Adolescents' Transition to Young Adulthood.
This study investigated the extent to which multiple sleep dimensions are associated with inflammation during adolescents' transition to young adulthood, a developmental period when sleep difficulties and systemic inflammation levels are on the rise. Additionally, the moderating roles of socioeconomic status (SES) and ethnicity were explored. A total of 350 Asian American, Latino, and European American youth participated at two-year intervals in wave 1 (n = 316, Mage = 16.40), wave 2 (n = 248 including 34 new participants to refresh the sample, Mage = 18.31), and wave 3 (n = 180, Mage = 20.29). Sleep duration (weekday and weekend) and variability in duration (nightly and weekday/weekend) were obtained from eight nights of wrist actigraphy. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index. Levels of C-reactive protein (CRP), a biomarker of systemic inflammation, were assayed from dried blood spots obtained from finger pricks. Multilevel models demonstrated that greater weekday/weekend sleep variability and worse sleep quality were associated with higher CRP; shorter weekend duration was associated with higher CRP only at younger ages. Shorter weekday duration was associated with higher CRP only among high-SES youth, whereas greater nightly variability was associated with higher CRP only among European American youth. Aspects of poor sleep may contribute to the rise of CRP during adolescents' transition to young adulthood, especially in earlier years. In addition, some sleep-CRP associations may vary as a function of youth's SES and ethnicity.


Comprehensive and computational analysis of genes in human umbilical vein endothelial cells responsive to X-irradiation.
Radiation exposure such as A-bomb or radiation therapy is considered a major health-risk factor for cardiovascular disease. In order to understand the molecular mechanisms underlying the inflammatory reaction frequently encountered in the vascular system after exposure to ionizing radiation, we carried out a global scale microarray and computational gene expression analyses on human umbilical endothelial cells (HUVECs) exposed to X-ray (2.5 Gy). The gene ontology analysis revealed that the down-regulated genes were associated with cell cycle regulation, whereas the up-regulated genes were associated with inflammatory responses, in particular, the type 1 interferon response. The computational analysis using ingenuity pathway analysis also identified a gene network containing the interferon response factor 7 (IRF7) and its transcriptional targets such as interferon-induced transcripts (IFITs) and Mx1, which have been known to be associated with inflammation in endothelial cells. The up-regulated genes and the gene network identified here may explain the inflammatory response induced by X-irradiation. These findings uncover part of the molecular basis of the mechanism(s) of the inflammatory disorder in response to X-irradiation in HUVECs. The dataset is publicly available at the Gene Expression Omnibus (GEO) repository (http://www.ncbi.nlm.nih.gov/geo/) with accession number GSE76484.


Probing the Structural Topology and Dynamic Properties of gp28 Using Continuous Wave Electron Paramagnetic Resonance Spectroscopy.
Lysis of Gram-negative bacteria by dsDNA phages is accomplished through either the canonical holin-endolysin pathway or the pinholin-SAR endolysin pathway. During lysis, the outer membrane (OM) is disrupted, typically by two-component spanins or unimolecular spanins. However, in the absence of spanins, phages use alternative proteins called Disruptin to disrupt the OM. The Disruptin family includes the cationic antimicrobial peptide gp28, which is found in the virulent podophage φKT. In this study, EPR spectroscopy was used to analyze the dynamics and topology of gp28 incorporated into a lipid bilayer, revealing differences in mobility, depth parameter, and membrane interaction among different segments and residues of the protein. Our results indicate that multiple points of helix 2 and helix 3 interact with the phospholipid membrane, while others are solvent-exposed, suggesting that gp28 is a surface-bound peptide. The CW-EPR power saturation data and helical wheel analysis confirmed the amphipathic-helical structure of gp28. Additionally, course-grain molecular dynamics simulations were further used to develop the structural model of the gp28 peptide associated with the lipid bilayers. Based on the data obtained in this study, we propose a structural topology model for gp28 with respect to the membrane. This work provides important insights into the structural and dynamic properties of gp28 incorporated into a lipid bilayer environment.