Examining trabecular morphology and chemical composition of peri-scaffold osseointegrated bone.
Porous titanium alloy scaffold fabricated by 3D printing technology could induce osseointegration well to repair bone defect during early postoperative period. However, trabecular histomorphological features and chemical compositions of ingrowth bone in the long term after surgery still lacked in-depth research. Fourteen New Zealand rabbits were divided into two groups (7 rabbits in surgery group and 7 rabbits in control group). A 3D-printed porous titanium alloy scaffold was implanted into right femoral condyle of each rabbit in the surgery group. Preload was produced at the surface between bone tissue and scaffold through interference assembly during implantation process. Rabbits in the control group were feed free. All rabbits were sacrificed to extract femoral condyles at week 12 after surgery. All right femoral condyles were performed micro-CT scanning to test bone mineral density (BMD) and trabecular histomorphological parameters, including bone volume fraction (BV/TV), bone surface/volume ratio (BS/BV), bone surface density (BS/TV), structure model index (SMI), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), porosity (PO), connectivity density (Conn.Dn), and degree of anisotropy (DA). Scanning electron microscope was used to observe osteogenesis peri-scaffold. Fourier transform infrared spectroscopy (FTIR) scanning was performed to analyze chemical compositions of peri-scaffold trabeculae. All trabecular morphological parameters and BMDs were statistically analyzed between surgery group and control group. The pores of scaffold were filled with ingrowth bone tissues after 12 weeks osseointegration. However, the mean BMD peri-scaffold in surgery group was 800 ± 20 mg/cm3, which was 18.37% lower than that in the control group. There was a significant decrease in BV/TV, Tb.N, and BS/TV, and there was a significant increase in Tb.Sp and PO between the surgery group and control group (p < 0.05). There were no significant differences in Tb.Th, SMI, Conn.Dn, BS/BV, and DA. Although ingrowth of bone tissue was very effective, some fragmented connective tissues were still found instead of bone tissues on the partial beams of scaffolds through SEM images. It was found from FTIR that there was no significant hydroxyapatite peak signal in surgery group. Collagen in the control group mainly existed as cross-link structure, while non-cross-link structure in the surgery group. Preload could promote the same good osseointegration ability as chemical surface modification method in the early term after surgery, and better osseointegration effect than chemical surface modification method in the mid-long term after surgery. However, histomorphological features of peri-scaffold trabeculae were still in deterioration and low collagen maturity caused by stress shielding. It was suggested from this study that extra physical training should be taken to stimulate the bone remodeling process for recovering to a healthy level.


Comprehension of Spatial Demonstratives in Mandarin-speaking Children on the Autism Spectrum: The Roles of Theory of Mind and Executive Function.
The present study aimed to examine whether Mandarin-speaking children on the autism spectrum showed differences in comprehending spatial demonstratives ("this" and "that", and "here" and "there"), as compared to typically developing (TD) children. Another aim of this study was to investigate the roles of theory of mind (ToM) and executive functions (EF) in the comprehension of spatial demonstratives. Twenty-seven autistic children (mean age 6.86) and 27 receptive-vocabulary-matched TD children (mean age 5.82) were recruited. Demonstrative comprehension was assessed based on participants' ability to place objects in certain locations according to experimenters' instructions which involved these demonstratives in three different conditions (same-, opposite-, and spectator-perspective conditions). Four false-belief tasks were administered to measure ToM, and the word-span task and the dimensional change card sort task were used to measure two subcomponents of EF - working memory and mental flexibility - respectively. Children on the autism spectrum were found to score below TD children in the comprehension of spatial demonstratives. In addition, the results showed that ToM and working memory were conducive to the correct interpretation of spatial demonstratives. The two cognitive abilities mutually influenced their respective roles in spatial demonstrative comprehension in the three different conditions. The findings suggest that the comprehension of spatial demonstratives comprehension is an area of need in Mandarin-speaking children on the autism spectrum, and it might be linked to their differences in cognitive abilities.


Efficacy of parent-delivered behavioral therapy for primary complex motor stereotypies.
Primary complex motor stereotypies (CMS) are persistent, patterned, repetitive, rhythmic movements in young people with typical development. This study evaluated the efficacy of an instructional DVD as a home-based, parent-administered, behavioral therapy for primary CMS. Eighty-one children with primary CMS were enrolled. Primary outcome measures included the Stereotypy Severity Scale (SSS) - Motor and Impairment scores, and Stereotypy Linear Analog Scale (SLAS). Mean CMS onset was 13.4 months (SD 13.1). Eligibility required observed CMS. Psychiatric disorders were not exclusionary and a stable medication regimen was required. Intellectual disability, neurological disorder, autism spectrum disorder, and tics were exclusionary. Initial assessments were completed via REDCap before receipt of the DVD. Fifty-four of the 81 children (34 male, 20 female; mean age 8y 2mo, SD 1.42, range 7-14y) completed assessments at 1, 2, or 3 months after receiving the DVD. Reductions (baseline to last assessment) in SSS Motor, SSS Impairment, and SLAS scores (all p<0.001) represented change ratios of -15%, -24%, and a -20% respectively. Greatest relative treatment benefit was observed by younger children (ages 7-8y), and by 1 month after receipt of DVD, while a parent global assessment scale showed progressive improvement throughout the study. An instructional DVD for parent-delivered behavioral therapy was a safe, effective intervention for primary CMS.


Professional reimbursement and professional behavior: emerging issues and research challenges.
The decisions and actions of health care professionals have a major impact on such health care outcomes as cost, quality and equity. It is widely believed that professional behavior is determined, in part by how and how much they are paid. Professionals can respond to reimbursement incentives at both the individual level (treatment decisions, referral patterns, specialty choice, etc.) and at the level of the professional association. Health care analysts usually identify and discuss three principal reimbursement modes: salary, capitation, and fee-for-service. Mixed systems are proliferating and need to be evaluated. Payment levels are determined by a mix of equity, market, and political considerations. They are believed by many to influence the behavior of providers, who are thought to act so as to preserve target incomes. The target income hypothesis has been tested for the case of physicians operating in a fee-for-service environment. The impact of changes in reimbursement levels on the behavior of other groups of professionals and on the behavior of professionals working in other reimbursement modes remains unclear. Both policy-makers and researchers need to broaden the way in which they think about professional reimbursement. To date, the field has been dominated by economists, inquiry has focused heavily on physicians, and empirical work has emphasized those dimensions of outcome which are most easily measured. Changes in the organization of health services and in society-at-large intensify the need for a broader view.


Vitamin E attenuates liver injury induced by exposure to lead, mercury, cadmium and copper in albino mice.
Water pollution is the contamination of water resources by harmful wastes or toxins. Both community and private sources of drinking water are susceptible to a myriad of chemical contaminants. Heavy metals pollution of surface water can create health risks. The present study was aimed to investigate the effect of vitamin E supplementation on male mice exposed to a mixture of some heavy metals (lead, mercury, cadmium and copper) in their drinking water for seven weeks. Significant increases of blood alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) were detected in heavy metals-treated mice. Histopathologically, the liver sections from heavy metals-treated mice showed severe changes including disarrangement of hepatic strands, rupture in hepatocytes, advanced hepatocellular necrosis, dilation and congestion of blood vessels with hemorrhage, dense lymphocytic infiltration round the central vein and dark stained hepatocytic nuclei indicating cell pycnosis. Administration of vitamin E at a dose of 50 IU/kg body weight, five times weekly improved the observed biochemical and histopathological changes induced by these heavy metals intoxication. Hence, the results of this study suggest that vitamin E protects against these heavy metals-induced liver injury and the attenuating effect of vitamin E may be due to its antioxidant activity.


Secondary rifampin resistance following multi-drug therapy--a case report.
This is the first report of secondary resistance to rifampin following MDT in a patient with prolonged, but irregular treatment. Repeated mouse foot-pad studies demonstrated resistance to dapsone after several years of monotherapy, and following subsequent MDT the studies demonstrated the development of resistance to rifampin.


Relationship of bacterioplankton production with primary production and respiration in a shallow estuarine system (Ria de Aveiro, NW Portugal).
The response of bacterial growth to phytoplankton production and planktonic respiration (RESP) variation was examined over different stations and dates in the shallow estuarine system Ria de Aveiro. The temporal and spatial profiles of bacterial productivity (2.7-744.2mg Cm(-3)d(-1)) did not coincide with those of primary production (PP) (0.2-19.1 g Cm(-3)d(-1)) and RESP (0.1-8.2 g Cm(-3) d(-1)). The bacterioplankton production/PP ratio varied differently, depending on the season and location. The heterotrophic zones, with the lowest values of PP, exhibited the most intense bacterial secondary production. Moreover, the variation of PP in the system was rather small when compared with that of bacterial secondary production. These suggest that, in a large extension of the lagoon and throughout the year, bacterioplankton growth is largely dependent on non-phytoplanktonic carbon sources. Benthic PP and/or allochtonous organic matter from land have a fundamental role in the dynamics of the planktonic compartment of the estuarine system.


Differential degradation rates of the G protein alpha o in cultured cardiac and pituitary cells.
Signal transduction in biological membranes is modulated by a family of GTP-binding proteins termed G proteins. Differences in the tissue-specific expression of G protein subtypes suggest that the levels of individual G proteins may be an important determinant of the hormonal response in a given cell type. We have used a polyclonal antibody raised against the purified G protein, alpha o to study alpha o in the rat pituitary cell line GH4 and in primary rat cardiocytes in culture by quantitative immunoprecipitation. Biosynthetic labeling and specific immunoprecipitation of alpha o in pulse-chase experiments demonstrated that the t1/2 for alpha o degradation is 28 +/- 7 h (n = 4) in GH4 pituitary cells and is greater than 72 h (n = 4) in cardiocytes. The steady-state level of alpha o protein is similar in both cell types as measured by Western blots. Northern blots of poly(A)-selected mRNA from these two cell types were probed with labeled alpha o cDNA and showed they have similar alpha o mRNA levels. The observation of different degradation rates, but similar steady-state protein levels, suggests that the rate of alpha o synthesis is different in GH4 cells and cardiocytes. Since mRNA levels are approximately equal in both, our studies imply that protein translation controls may be important determinants of G protein alpha subunit concentrations in biological membranes.


The ethanolic extract of Salvia lachnostachys Benth is not maternotoxic, does not alter reproductive performance, but has teratogenic potential.
Salvia lachnostachys Benth is native to Brazil and has anti-inflammatory, anti-arthritic, cytotoxic, antitumor, and antihyperalgesic activities. The population, including pregnant women, consume this plant to treat pain, inflammation, flu, spasms, insomnia, and depression, mainly. There are no safety reports on the use of this plant during pregnancy. The present study aimed to evaluate the effects of S. lachnostachys ethanolic extract (EESl) on reproductive performance, embryofetal development, and DNA integrity of pregnant female mice. Pregnant females were randomly divided into three experimental groups (n = 10): The Control group was treated with a vehicle, and treatment groups were administered with EESl at 100 and 1000 mg/kg, respectively. Treatment occurred by gavage throughout the gestational period until day 18. Afterward, reproductive performance, embryofetal development, and DNA integrity parameters were evaluated. The results indicated that EESl did not alter any reproductive performance parameters. However, it changed embryofetal outcome through reduced placental weight (EESl 100 mg/kg), decreased fetal weight (EESl 100 and 1000 mg/kg), and increased frequency of small for gestational age fetuses (EESl 1000 mg/kg). In addition, EES1 increased the frequency of external, visceral, and skeletal malformations. Because of the above, it is considered that EESl is not maternotoxic, does not alter reproductive performance, but does alter embryofetal development. Its use in the gestational period is not indicated due to its teratogenic potential.


Prolonging Treatment Window of Photodynamic Therapy with Self-Amplified H2 O2 -Activated Photodynamic/Chemo Combination Therapeutic Nanomedicines.
Photodynamic therapy (PDT) is a promising approach to cancer therapy. However, the relatively short tumor retention time of photosensitizers (PSs) makes it difficult to catch the optimal treatment time and restricts multiple PDT within a single injection. In this study, a tumor-specific phototheranostic nanomedicine (DPPa NP) is developed for photodynamic/chemo combination therapy with a prolonged PDT treatment window. DPPa NP is prepared via encapsulating a hydrophobic oxidized bovine serum albumin (BSA-SOH)-conjugatable PS DPPa with amphiphilic H2 O2 -activatable chlorambucil (CL) prodrug mPEG-TK-CL. The released CL under H2 O2 treatment can not only kill tumor cells but also upregulate reactive oxygen species levels within tumor cells, leading to the almost full release of cargoes. The released DPPa may conjugate with overexpressed BSA-SOH, which results in the recovery of the fluorescence signal and photodynamic effect. More importantly, such conjugation transfers DPPa from a small molecule PS into a macromolecular PS with a long tumor retention time and treatment window of PDT, which enables multiple PDT. This study thus provides an effective strategy to prolong the treatment window of PDT and enables tumor-specific fluorescence imaging-guided combination therapy.


Comparison of ANA endpoint dilution using the PolyTiter immunofluorescent titration system and conventional serial dilution.
The PolyTiter immunofluorescent titration system (PolyTiter system), an attachment for conventional fluorescent microscopes, facilitates immunofluorescent antinuclear antibody (IFA-ANA) testing by using calibrated light attenuation to determine the semiquantitative endpoint dilution or titer of ANA-positive specimens. The objective of this study was to compare the determination of ANA titer using the PolyTiter system to that of the conventional serial dilution method. A total of 172 consecutive ANA-IFA positive serum specimens, including the four most common pattern types, were evaluated in parallel by two readers to determine the dilution endpoint. The two methods produced equal dilution endpoints in 78 specimens (45%), within 1-dilution endpoint in 121 specimens (70%), and within 2-dilutions endpoint in 158 specimens (92%). The conventional method consistently produced a more conservative dilution endpoint than the PolyTiter system for three of the four patterns evaluated (i.e., centromere, nucleolar, and speckled vs. homogeneous). The PolyTiter system demonstrated satisfactory performance in comparison to the current standard for determining ANA dilution endpoints, while significantly reducing operator labor, time, and materials usage.


Female testosterone, dominance rank, and aggression in an Ethiopian population of hybrid baboons.
Studies on the relationship between female testosterone (T) measures and behavior, particularly in free-ranging primate populations, remain scant. In this study we used fecal steroid analysis to examine the effects of seasonal, reproductive, and social factors on female T in a group of free-ranging hybrid baboons (Papio sp.) in the Awash National Park of Ethiopia. We collected behavioral and hormonal data from 25 adult females across an 11-month period. Solid phase extraction and radioimmunoassay (RIA) techniques were used to quantify T in 776 fecal samples collected weekly from each female. The results indicate that 1) the females had elevated T during pregnancy and during the wet season relative to other periods, 2) female dominance rank was positively related to T measures, and 3) female T and aggression were positively related within subjects but not across subjects. Higher T concentrations during pregnancy are consistent with other published profiles of pregnancy in primates. In combination with data on foraging, wet season increases in T may indicate contest competition for females. The rank-T relationship may be mediated by supplants or aggression. Finally, we discuss the different interpretations of the hormone-behavior relationship based on within- and across-subject analyses.


Refractive error in Chinese with type 2 diabetes and its association with glycaemic control.
The aim of this study was to determine the prevalence of refractive errors and their association with glycaemic control among adults with type 2 diabetes mellitus (T2DM) in eastern China. A community-based survey, including 913 adults with T2DM aged 30 to 89 years, was conducted. Refractive error was assessed by autorefraction, after which subjective refraction was performed. Ocular biometric parameters were measured by non-contact partial coherence laser interferometry. Myopia was defined as spherical equivalent (SE) less than -0.50 dioptres (D), high myopia as SE less than -5.00 D, hyperopia as SE greater than 0.50 D and astigmatism as cylinder less than -0.50 D. After excluding participants who had undergone cataract surgery, 839 were included in the data analyses and 96.1 per cent were found to have refractive errors. The overall prevalences of myopia, high myopia, hyperopia and astigmatism were 28.2 per cent (95 per cent confidence interval [CI] 25.2-31.3), 6.3 per cent (95 per cent CI 4.7-8.0), 46.4 per cent (95 per cent CI 43.0-49.7) and 81.0 per cent (95 per cent CI 78.4-83.7) with no gender differences observed (all p > 0.10). In multivariate analysis, myopia was associated with decreasing age (odds ratio [OR] = 0.86, p = 0.01; per year increase), higher blood levels of haemoglobin A1c (HbA1c ) (OR = 1.12, p = 0.05; per unit increase), higher education levels (OR = 5.10, p < 0.001; university or college versus illiterate or primary school) and the presence of nuclear cataract (OR = 2.36, p < 0.001). Refractive errors may be associated with glycaemic control among T2DM patients. Longitudinal analyses are warranted to examine the relationship between changes in HbA1c and the development of refractive errors.


Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-β1.
Psoriasis vulgaris is a chronic inflammatory skin disease affecting millions of people. Its pathophysiology is complex and involves a skin compartment with epidermal and immune cells which produce cytokines, e.g. belonging to the IL-23-Th17-cell axis. Glucocorticoids (GCs) are the most common therapeutics used in cutaneous inflammatory disorders and GC-induced leucine zipper (GILZ) has emerged as a mediator of GCs due to its anti-inflammatory actions, theoretically lacking GC side-effects. We evaluated whether GILZ may provide a better therapeutic index in comparison to GCs during the onset and progression of psoriasis by generating and characterizing a mouse model with generalized overexpression of this protein (GILZ-Tg mice) and the imiquimod (IMQ) psoriasis model. Unexpectedly, in GILZ-Tg mice, the severity of IMQ-induced psoriasis-like skin lesions as well as induction of cytokines commonly up-regulated in human psoriasis (Il-17, Il-22, Il-23, Il-6, S100a8/a9, and Stat3) was significantly more pronounced relative to GILZ-Wt mice. The increased susceptibility to IMQ-induced psoriasis of GILZ-Tg mice was significantly associated with skin-specific over-activation of TGF-β1-mediated signaling via SMAD2/3. Our findings demonstrate that GILZ may behave as pro-inflammatory protein in certain tissues and that, similar to prolonged GC therapy, GILZ as an alternative treatment for psoriasis may also have adverse effects.


Prediction of salt effects on protein phase behavior by HIC retention and thermal stability.
In the biopharmaceutical industry it is mandatory to know and ensure the correct protein phase state as a critical quality attribute in every process step. Unwanted protein precipitation or crystallization can lead to column, pipe or filter blocking. In formulation, the formation of aggregates can even be lethal when injected into the patient. The typical methodology to illustrate protein phase states is the generation of protein phase diagrams. Commonly, protein phase behavior is shown in dependence of protein and precipitant concentration. Despite using high-throughput methods for the generation of phase diagrams, the time necessary to reach equilibrium is the bottleneck. Faster methods to predict protein phase behavior are desirable. In this study, hydrophobic interaction chromatography retention times were correlated to crystal size and form. High-throughput thermal stability measurements (melting and aggregation temperatures), using an Optim(®)2 system, were successfully correlated to glucose isomerase stability. By using hydrophobic interaction chromatography and thermal stability determinations, glucose isomerase conformational and colloidal stability were successfully predicted for different salts in a specific pH range.


Molecular modeling of the cytoskeleton.
Molecular modeling techniques have truly come of age in recent decades, and here we cover several of the most commonly used techniques, namely molecular dynamics, Brownian dynamics, and molecular docking. In each case, we explain the physical basis and limitations of the various techniques and then illustrate their application to various problems related to the cytoskeleton. This set of studies covers a relatively wide range of examples and is comprehensive enough to clearly see how these techniques could be applied to other systems. Finally, we cover several related methodologies that expand on these basic techniques to allow for more detailed and specific simulation and analysis.


The evolution of cell types in animals: emerging principles from molecular studies.
Cell types are fundamental units of multicellular life but their evolution is obscure. How did the first cell types emerge and become distinct in animal evolution? What were the sets of cell types that existed at important evolutionary nodes that represent eumetazoan or bilaterian ancestors? How did these ancient cell types diversify further during the evolution of organ systems in the descending evolutionary lines? The recent advent of cell type molecular fingerprinting has yielded initial insights into the evolutionary interrelationships of cell types between remote animal phyla and has allowed us to define some first principles of cell type diversification in animal evolution.


Can a urinary tract symptom score predict the development of postoperative urinary retention in patients undergoing lower limb arthroplasty under spinal anaesthesia? A prospective study.
There is no general consensus amongst orthopaedic surgeons on how best to manage the urinary tract and its complications after lower limb arthroplasty. This prospective audit investigates whether postoperative urinary retention can be predicted pre-operatively using the validated International Prostate Symptom Severity score (IPSS). A total of 182 patients undergoing lower limb arthroplasty under spinal anaesthetic were given the IPSS questionnaire to complete pre-operatively and an audit into numbers catheterised postoperatively was performed. Overall, 69% of males and 39% of females required catheterisation. Following logistic regression analysis there was 0.85 predicted probability that males over 70 years would require catheterisation. The IPSS score was not useful in predicting retention in either sex at any age. We propose that all males over 70 years undergoing this type of surgery should be catheterised pre-operatively and all other patients should be catheterised postoperatively with close monitoring of bladder volumes to prevent established urinary retention.


Healthcare utilization and costs among patients with chronic migraine, episodic migraine, and tension-type headache enrolled in commercial insurance plans.
To quantify and compare healthcare utilization and costs for patients with chronic migraine (CM), episodic migraine (EM), and tension-type headache (TTH) enrolled in US commercial health plans. This retrospective cohort study used the Optum Clinformatics® Data Mart database from January 2015 to December 2018. Adult patients with a diagnosis of EM, CM or TTH and at least 12 months of continuous enrollment before and after diagnosis were included. Inverse probability of treatment weighting was used to adjust for baseline differences among the three groups. Patient demographic and clinical characteristics at baseline, and healthcare utilization and costs during follow-up, were described and compared between the three groups. A total of 45,849 patients were included: 8955 with CM, 31,961 with EM, and 4933 with TTH. The total all-cause annual direct medical costs of patients with CM ($17,878) were 1.38 times higher (95% CI: 1.31-1.44) than those with EM ($12,986), and 2.26 times higher (95% CI: 2.08-2.47) than those with TTH ($7902). The annual migraine/TTH-related costs of patients with CM ($1869) were 4.19 times higher (95% CI: 3.92-4.48) than those with EM ($446), and 11.90 times (95% CI: 10.59-13.52) higher than those with TTH ($157). In the adjusted analyses, for all service categories (emergency department, inpatient, outpatient, and prescriptions), the expected costs in the migraine groups were higher than in the TTH group (all p < 0.001), while controlling for covariates. Main findings were consistent in both weighted and unweighted samples, and with both unadjusted and adjusted analyses. This study provides an updated assessment of healthcare utilization and expenditures for adult patients with primary headache disorders. Compared to TTH, migraine is associated with higher resource use and direct medical costs, especially for those with a chronic condition. Future studies are needed to understand the indirect medical costs (productivity loss) and humanistic burden (quality of life) between migraine and TTH.


Loss of metabolic adaptation in lean MAFLD is driven by endotoxemia leading to epigenetic reprogramming.
Lean patients with MAFLD have an initial adaptive metabolic response characterised by increased serum bile acids and Farnesoid X Receptor (FXR) activity. How this adaptive response wanes resulting in an equal or perhaps worse long-term adverse outcome compared to patients with obese MAFLD is not known. We show that patients with lean MAFLD have endotoxemia while their macrophages demonstrate excess production of inflammatory cytokines in response to activation by Toll-like receptor (TLR) ligands when compared to healthy subjects. Alterations of the lean MAFLD macrophage epigenome drives this response and suppresses bile acids signalling to drive inflammation. Our data suggests that selectively restoring bile acids signalling might restore adaptive metabolic responses in patients with MAFLD who are lean.


Structural determinants for the strict monomethylation activity by trypanosoma brucei protein arginine methyltransferase 7.
Trypanosoma brucei protein arginine methyltransferase 7 (TbPRMT7) exclusively generates monomethylarginine (MMA), which directs biological consequences distinct from that of symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). However, determinants controlling the strict monomethylation activity are unknown. We present the crystal structure of the TbPRMT7 active core in complex with S-adenosyl-L-homocysteine (AdoHcy) and a histone H4 peptide substrate. In the active site, residues E172, E181, and Q329 hydrogen bond the guanidino group of the target arginine and align the terminal guanidino nitrogen in a position suitable for nucleophilic attack on the methyl group of S-adenosyl-L-methionine (AdoMet). Structural comparisons and isothermal titration calorimetry data suggest that the TbPRMT7 active site is narrower than those of protein arginine dimethyltransferases, making it unsuitable to bind MMA in a manner that would support a second turnover, thus abolishing the production of SDMA and ADMA. Our results present the structural interpretations for the monomethylation activity of TbPRMT7.


Prognostic significance of cyclin D1 expression in colorectal cancer: a meta-analysis of observational studies.
Cyclin D1 plays a vital role in cancer cell cycle progression and is overexpressed in many human cancers, including colorectal cancer (CRC). However, the prognostic value of cyclin D1 overexpression in colorectal cancer is conflicting and heterogeneous. We conducted a meta-analysis to more precisely evaluate its prognostic significance. A comprehensive literature search for relevant studies published up to January 2014 was performed using PubMed, EMBASE, and ISI Web of Science. The pooled hazard ratio (HR) with 95% confidence intervals (CI) was used to estimate the effects. 22 studies with 4150 CRC patients were selected to evaluate the association between cyclin D1 and overall survival (OS), disease-free survival (DFS) and clinicopathological parameters. In a random-effects model, the results showed that cyclin D1 overexpression in CRC was significantly associated with both poor OS (HR = 0.73, 95% CI: 0.63-0.85, P<0.001) and DFS (HR = 0.60, 95% CI: 0.44-0.82, P = 0.001). Additionally, cyclin D1 overexpression was significantly associated with more relative older patients (≥ 60 years) (OR 0.62, 95% CI 0.44-0.89, P = 0.009), T3,4 tumor invasion (OR 0.70, 95% CI 0.57-0.85, P<0.001), N positive (OR 0.75, 95% CI 0.60-0.95, P = 0.016) and distant metastasis (OR 0.60, 95% CI 0.36-0.99, P = 0.047) of CRC. The meta-analysis results indicated that cyclin D1 is an unfavorable prognostic factor for CRC. Cyclin D1 overexpression might be associated with poor clinical outcome and some clinicopathological factors such as age, T category, N category and distant metastasis in CRC patients.


Serum lipids and coronary heart disease in heterozygous familial hypercholesterolemia in the Hokuriku District of Japan.
The serum cholesterol and triglyceride levels and the incidence of ischemic heart disease were studied in 122 (55 men and 67 women) consecutive heterozygous familial hypercholesterolemic patients in the Hokuriku district of Japan. (1) The mean +/-SD of serum cholesterol level was 354.0 +/- 71.0 mg/100 ml, which was lower than those of the Western countries by about 60--70 mg/100 ml. (2) The mean +/-SD of serum triglyceride level was 116.5 +/- 54.0 mg/100 ml. (3) The average serum cholesterol values in the 20--50-year-old group showed no differences from those of the Western countries. However, in the above 50 years of age group the serum cholesterol levels were much lower than those in the United States. (4) The occurrence of ischemic heart disease in 83 heterozygous familial hypercholesterolemic patients was 43.3%. The incidence of myocardial infarction was 20.5%. Thus, familial hypercholesterolemia is as highly atherogenic as that of the Western countries even in Japan where the low incidence of coronary heart disease in the general population has been attributed to the low level of serum cholesterol.


Multiple steroid receptors in male breast carcinomas.
Specific cytosol receptors for estradiol, progesterone and dihydrotestosterone were detected in human male breast carcinomas. Competition studies with excess unlabelled steroids showed that the receptors were distinct binding proteins. The properties and binding specificity of the estradiol receptor in a male breast carcinoma were very similar to those found in female breast tumors. The possible clinical significance of the presence of steroid receptors in male breast tumors is discussed.


What are the relations between Lewy body disease and AD?
Several hospital based autopsy series indicate dementia with Lewy bodies (DLB) to be the second most common pathological subtype of degenerative dementia in elderly subjects. The majority of DLB cases have high densities of beta amyloid senile plaques, whereas neocortical neurofibrillary tangle density is only slightly increased above age-matched normal control values and over tenfold lower than the average in Alzheimer's disease. The interpretation of this Alzheimer type pathology is problematic, reflecting in part changing views about the neuropathological diagnosis of AD itself. AD is characterised by hyperphosphorylation of the microtubular associated protein tau, and DLB by neurofilament abnormalities including phosphorylation, ubiquitination, proteolysis, and cross-linking of constituent proteins. The two diseases appear therefore to be distinct at an ultrastructural and molecular level, a conclusion which is consistent with the fact that the clinical syndromes associated with DLB and AD are sufficiently differentiated to allow for accurate antemortem diagnosis.


Differential expression of peroxisome proliferator-activated receptor subtypes during the differentiation of human keratinocytes.
The expression of mRNA encoding peroxisome proliferator-activated receptor (PPAR) subtypes in human keratinocytes was determined by semiquantitative reverse transcriptase-polymerase chain reaction. When normal human keratinocytes were induced to differentiate by shifting the culture medium to high Ca2+ concentration, the expression of PPAR-alpha and -gamma mRNA was increased, whereas that of PPAR-delta remained unchanged. At the protein level, the expression of PPAR in cultured human keratinocytes was demonstrated by a DNA mobility shift assay and the functionality of the receptor subtypes was assessed by transactivation experiments. In epidermis reconstructed in vitro, the level of PPAR-alpha and -gamma mRNA was also associated with keratinocyte differentiation. In lesional compared with nonlesional psoriatic epidermis, the expression of PPAR-alpha and -gamma mRNA was reduced, indicating that these two subtypes are tightly linked to the epidermal differentiation process.


Stereoselective high-performance liquid chromatography and analytical method characterization of evacetrapib using a brush-type chiral stationary phase: a challenging isomeric separation requiring a unique eluent system.
Using HPLC chiral separation screening, various columns representing the polysaccharide, macrocyclic antibiotic and brush classes were assessed in multiple chromatographic modes for the separation of evacetrapib, a potential cardiovascular drug, from its enantiomer, two diastereomers and several impurities. Screening data consistently pointed to the brush-type Whelk-O 1 chiral column as most promising for this task. A systematic separation optimization process is outlined using the (S,S) Whelk-O 1 chiral column, first for the resolution of the isomers, and later including six potential impurities. A relatively complex yet rugged separation system was eventually identified that effectively resolves all compounds within a reasonable analysis time, and should serve as an adequate tool for evacetrapib bulk drug enantiopurity measurement.


Restructuring of the Diabetes Day Centre: a pilot lean project in a tertiary referral centre in the West of Ireland.
Diabetes is a chronic disease amenable to management in the community and outpatient setting. The increasing incidence of diabetes places outpatient endocrinology services under pressure to provide a quality service in a timely manner. Our aim was to apply lean thinking to the diabetes clinic in a tertiary referral centre in the West of Ireland to improve flow, as reflected in reduced patient journey times. The project lasted 6 months, from January to June 2011. An introductory seminar on lean thinking was arranged to inform and motivate the Diabetes Day Centre staff. Two 'rapid improvement events' took place. Value stream mapping (VSM) was the predominant lean tool employed. Patient journeys were mapped and quantified (minutes) using timesheets allocated to each step in the process at baseline, and following intervention. Data were analysed using Minitab V.16.0. VSM allowed the value-adding and problem-causing steps in the patient journey through the diabetes clinic process to be identified and addressed. Total patient journey time through the clinic was significantly reduced from 118 (± 38.02) min to 58 (± 18.30) min (p<0.001). This project reflects the successful application of VSM as a lean tool in a pilot study at our institution as evidenced by improved patient flow and a significant reduction in patient journey time through the clinic. Through the incorporation of Lean into the ethos of the hospital, we have the potential to deliver excellent care in a safe environment and in an efficient manner, while benefiting the patient, employees and tax-payer.


[Comparative analysis of deterioration products in bio-waste oil and vegetable oils].
To analyze the difference of deterioration products in bio-waste oil and vegetable oils. The changes of species and abundance of deterioration products were analyzed through observing the differences in Raman spectra during the process of deterioration and refining. The deterioration contents produced during heating, cooking, frying and wasting, instead of storage, were significantly more abundant than normal contents. Through the refining process, the deterioration products abundance was reduced in vegetable oils while increased in bio-waste oils. Due to the distinct deteriorating processes, the species and abundance of deterioration products are remarkably different in bio-waste oil and vegetable oils. The deterioration products in vegetable oils would be mostly removed, but those in bio-waste oils are concentrated instead of eliminated during the refining procedure.


Mathematical modelling of Mycobacterium tuberculosis VNTR loci estimates a very slow mutation rate for the repeats.
Minisatellites are highly variable tandem repeats used for over 20 years in humans for DNA fingerprinting. In prokaryotes fingerprinting techniques exploiting VNTR (variable number of tandem repeats) polymorphisms have become widely used recently in bacterial typing. However although many investigations into the mechanisms underlying minisatellite variation in humans have been performed, relatively little is known about the processes that mediate bacterial minisatellite polymorphism. An understanding of this is important since it will influence how the results from VNTR experiments are interpreted. The minisatellites of Mycobacterium tuberculosis are well characterized since they are some of the few polymorphic loci in what is otherwise a very homogeneous organism. Using VNTR results from a well-defined and characterized set of M. tuberculosis strains we show that the repeats at a locus are likely to evolve by stepwise contraction or expansion in the number of repeats. A stochastic continuous-time population mathematical model was developed to simulate the evolution of the repeats. This allowed estimation of the tendency of the repeats to increase or decrease and the rate at which they change. The majority of loci tend to lose rather than gain repeats. All of the loci mutate extremely slowly, with an average rate of 2.3 x 10(-8), which is 350 times slower than that of a set of VNTR repeats with similar diversity observed experimentally in Escherichia coli. This suggests that the VNTR profile of a strain of M. tuberculosis will be indicative of its clonal lineage and will be unlikely to vary in epidemiologically-related strains.


A Single-Center Analysis of the Treatment and Prognosis of Patients With Thymic Carcinoma.
The low incidence of thymic carcinoma has precluded the development of randomized clinical trials, and present knowledge is based on small retrospective studies. We performed this single-center retrospective analysis to evaluate the clinical characteristics, treatments, and prognosis in patients with pathologically confirmed thymic carcinoma. Data regarding clinicopathologic characteristics, treatment protocols, toxicities, and survival were collected from 135 patients who attended our institution between January 1980 and January 2010. Survival was assessed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the log-rank test and Cox proportional hazards model. The 135 patients (88 men) were with a median age of 48 years, and 123 patients were diagnosed with Masaoka stage III to IV disease. R0 resection was performed in 35 patients. Treatment comprised radiotherapy in 121 patients and chemotherapy in 60. The median follow-up time was 12.5 years. At 5 and 10 years, local-regional relapse free survivals were 81.4% and 54.4%, overall survivals were 42.2% and 15.4%, progression-free survivals were 29.7% and 8.0%, and distant metastasis-free survivals were 35.9% and 25.6%, respectively. R0 resection was the only independent prognosticator of overall survival, progression-free survival, and distant metastasis-free survival in univariate and multivariate analyses. Thymic carcinoma was frequently diagnosed at Masaoka stage III to IV with a poor prognosis. Surgical resection is still the predominant treatment. Radiotherapy may increase local-regional relapse free survival with mild toxicities in advanced-stage patients.


DRESS with delayed onset acute interstitial nephritis and profound refractory eosinophilia secondary to Vancomycin.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a relatively rare clinical entity; even more so in response to vancomycin. Case report. We present a severe case of vancomycin-induced DRESS syndrome, which on presentation included only skin, hematological and mild liver involvement. The patient further developed severe acute interstitial nephritis, eosinophilic pneumonitis, central nervous system (CNS) involvement and worsening hematological abnormalities despite immediate discontinuation of vancomycin and parenteral corticosteroids. High-dose corticosteroids for a prolonged period were necessary and tapering of steroids a challenge due to rebound-eosinophilia and skin involvement. Patients with DRESS who are relatively resistant to corticosteroids with delayed onset of certain organ involvement should be treated with a more prolonged corticosteroid tapering schedule. Vancomycin is increasingly being recognized as a culprit agent in this syndrome.


Phacoanaphylactoid reaction in persistent hyperplastic primary vitreous.
Three cases of persistent hyperplastic primary vitreous (PHPV) showing a ruptured lens capsule and a phacoanaphylactoid reaction are presented. In two cases, there was evidence that the lens had been clinically clear in the presence of a ruptured capsule and posterior cortical granulomatous reaction. The capsular rupture and granulomatous reaction can begin in utero, as shown by the third case, a premature who died at one day of age. It is suggested that a phacoanaphylactoid reaction can contribute to the lens swelling, cataract, and anterior chamber narrowing which often initiate the downhill course in eyes with PHPV. The immunological implications of this reaction are discussed.


Precision targeting in prediction for rTMS clinical outcome in depression: what about sgACC lateralization, metabolic connectivity, and the potential role of the cerebellum?
Predicting clinical response to repetitive transcranial magnetic stimulation (rTMS) in medication-resistant depression (MRD) has gained great importance in recent years. Mainly, the right subgenual anterior cingulate cortex (sgACC) functional connectivity has been put forward as biomarker in relation to rTMS clinical outcome. Even though the left and right sgACC may have different neurobiological functions, little is known about the possible lateralized predictive role of the sgACC in rTMS clinical outcome. In 43 right-handed antidepressant-free MRD patients, we applied a searchlight-based interregional covariance connectivity approach using the baseline 18FDG-PET scan-collected from two previous high-frequency (HF)-rTMS treatment studies delivering stimulation to the left dorsolateral prefrontal cortex (DLPFC)-and investigated whether unilateral or bilateral sgACC glucose metabolism at baseline would result in different predictive metabolic connectivity patterns. Regardless of sgACC lateralization, the weaker the sgACC seed-based baseline metabolic functional connections with the (left anterior) cerebellar areas, the significantly better the clinical outcome. However, the seed diameter seems to be crucial. Similar significant findings on sgACC metabolic connectivity with the left anterior cerebellum, also unrelated to sgACC lateralization, in relation to clinical outcome were observed when using the HCPex atlas. Although we could not substantiate that specifically right sgACC metabolic connectivity would predict HF-rTMS clinical outcome, our findings suggest considering the entire sgACC in functional connectivity predictions. Given that the interregional covariance connectivity results were significant only when using the Beck Depression Inventory (BDI-II) and not with the Hamilton Depression Rating Scale (HDRS), our sgACC metabolic connectivity observations also suggest the possible involvement of the (left) anterior cerebellum involved in higher-order cognitive processing as part of this predictive value.


Eosinophilic granuloma of the orbit with spontaneous healing.
A 13-year-old boy presented with a 2-month history of swelling of the right upper eyelid and displacement of the right eye. Computed tomography (CT) showed a tumor in the right orbit and a large osteolytic defect of the orbital frontal bone. At surgery a yellowish-tan mass was found replacing the orbital roof and abutting the dura. Incisional biopsy established the diagnosis of eosinophilic granuloma. In the absence of further therapy, the mass resolved, and the bony defect completely reossified within 14 months. During more than 2 years of follow-up, there has been no evidence of local recurrence or systemic disease. This case demonstrates that eosinophilic granuloma may resolve spontaneously with healing of bony defects, thus eliminating the need for adjunctive resection or radiation therapy in selected patients.


Cytochemical localization of glutaraldehyde-resistant NAD(P)H-oxidase in rat hepatocytes.
NAD(P)H-oxidase activity was demonstrated in glutaraldehyde-fixed rat hepatocytes by a cerium technique. The activity was observed exclusively on the bile-canalicular plasma membrane of hepatocyte. No reaction product was formed in the absence of NAD(P)H as the substrate. The reaction was inhibited by pCMB (surface sulfhydryl group specific reagent), by heating, by anaerobic incubation and by catalase (H2O2 scavenger), but it was not inhibited by KCN or NaN3. The present results show that bile-canalicular plasma membrane produces H2O2 and the cerium technique for demonstration of H2O2 is therefore an useful method for the subcellular localization of NAD(P)H-oxidase activity in the glutaraldehyde-fixed hepatocyte.


[The treatment of cross-bites in the Angle Class I cases with modular 3 D lingual appliances].
Anterior cross-bites which involve one tooth or a group of teeth is commonly seen in every age groups. Removable or fixed appliances are used in the treatment of these cases. Both of these appliances have some advantages and disadvantages. The objective of this study is to evaluate the effectiveness of the Modular 3 D Adapter in the treatment of the anterior cross-bites. All of the 14 patients aged between 10 years 1 month and 24 years 2 months showed Angle Class I anterior Cross-bite malocclusion. Only the first molar tooth or teeth were banded, then 0.025 inch Adapter appliance was used Lingually. By applying a force between 60-70 grams, the normal occlusions were gained after 2 months.


Retroperitoneal colopexy for adult rectal procidentia. A new procedure.
Nonresective fixation procedures are superior to resections in the management of rectal procidentia. A new operative procedure of retroperitoneal fixation of the redundant rectum and sigmoid after mobilization of the rectum up to the pelvic floor is described. The procedure was performed in 32 patients. In a follow-up ranging up to 11 years, only one recurrence of mucosal prolapse was seen. Rectal, bladder, and sexual functions were normal. There was a low wound infection rate and no mortality. The procedure appears superior to conventional operations for rectal procidentia and, at the same time, avoids usage of prosthetic materials for fixation with their known risk of complications.


Hemoptysis and pulmonary aspergilloma: operative versus nonoperative treatment.
The clinical experience with 42 patients with pulmonary aspergilloma evaluated at the Vanderbilt University Affliated Hospitals in a 22-year period was reviewed to determine the necessity and advisability of pulmonary resection. Twenty-nine patients (69%) had sustained one or more episodes of gross hemoptysis. Eleven of the 42 patients were treated operatively with lobectomy, wedge resection, or cavernostomy. Five of them had had hemoptysis preoperatively, but in only 1 patient was massive hemoptysis the primary indication for operation. The single death among these 11 patients occurred in the patient undergoing operation for control of massive hemoptysis. Nonoperative treatment was selected in 31 patients because of advanced chronic lung disease. Twenty-four of these 31 patients experienced 41 episodes of gross hemoptysis during observation periods up to 8 years (average, 32 months). Superimposed bacterial infection usually accompanied the episodes of hemoptysis, and medical therapy with bedrest, antibiotics, and postural drainage was successful in controlling the hemorrhage in 40 of the 41 episodes. One patient died from massive hemoptysis. On the basis of this experience, pulmonary resection for aspergilloma in patients with hemoptysis seems rarely indicated.


A validation study of a clinical prediction rule for screening asymptomatic chlamydia and gonorrhoea infections among heterosexuals in British Columbia.
One component of effective sexually transmitted infections (STIs) control is ensuring those at highest risk of STIs have access to clinical services because terminating transmission in this group will prevent most future cases. Here, we describe the results of a validation study of a clinical prediction rule for identifying individuals at increased risk for chlamydia and gonorrhoea infection derived in Vancouver, British Columbia (BC), against a population of asymptomatic patients attending sexual health clinics in other geographical settings in BC. We examined electronic records (2000-2012) from clinic visits at seven sexual health clinics in geographical locations outside Vancouver. The model's calibration and discrimination were examined by the area under the receiver operating characteristic curve (AUC) and the Hosmer-Lemeshow (H-L) statistic, respectively. We also examined the sensitivity and proportion of patients that would need to be screened at different cut-offs of the risk score. The prevalence of infection was 5.3% (n=10 425) in the geographical validation population. The prediction rule showed good performance in this population (AUC, 0.69; H-L p=0.26). Possible risk scores ranged from -2 to 27. We identified a risk score cut-off point of ≥8 that detected cases with a sensitivity of 86% by screening 63% of the geographical validation population. The prediction rule showed good generalisability in STI clinics outside of Vancouver with improved discriminative performance compared with temporal validation. The prediction rule has the potential for augmenting triaging services in STI clinics and enhancing targeted testing in population-based screening programmes.


Comparing dual-stream and standard cardiopulmonary bypass in pigs.
Dual-stream (DS) and standard cardiopulmonary bypass (CPB) were compared. A DS catheter inserted into the distal ascending aorta across the arch pumps blood through an upper lumen (maximum 2.25 L/min) directed by a bloodstreaming baffle toward the arch vessels. A separate lower lumen pumps blood (maximum 3.75 L/min) into the aorta caudad to the inflated baffle. The baffle is flat and horizontal along the catheter. When the baffle is collapsed the heart or both lumens may perfuse all organs. For 30 minutes 8 randomized CPB pigs had corporeal cooling to 32 degrees C and for 30 minutes had rewarming to 36 degrees C. Eight randomized DS pigs had 25 degrees C upper lumen cooling for 60 minutes. Lower lumen blood flow was streamed at 32 degrees C for 30 minutes, then rewarmed to 36 degrees C for 30 minutes. The change in relative lower lumen to brain blood flow as determined by brain-counted microspheres (15 micron) injected into the ascending aorta was less for DS brains than controls during full flow (DS 63.4+/-129.5 versus CPB 2,585.4+/-250.8, p < 0.001), and when injected into the ejecting-heart left atrium just after weaning off only lower lumen blood flow (DS 250.8+/-297.3 versus CPB 1,159.1+/-782.3, p < 0.001). DS brain temperatures were lower at an equal pump-off core temperature of 36 degrees C+/-0.5 degrees C (DS 31.6 degrees C+/-3.2 degrees C versus CPB 36.5 degrees C+/-1.7 degrees C, p < 0.025). Jugular O2 saturations were not different. DS-CPB prioritizes pump-filtered separate cold blood flow to the brain over a blood-streaming baffle to wash away potentially surgery related air and particulate matter arising from the heart or ascending aorta.


Comprehensive analysis of novel three-long noncoding RNA signatures as a diagnostic and prognostic biomarkers of human triple-negative breast cancer.
Currently, traditional predictors of prognosis (tumor size, nodal status, progesterone receptor [PR], estrogen receptor [ER], or human epidermal growth factor receptor-2 [HER2]) are insufficient for precise survival prediction for triple-negative breast cancer (TNBC). Long noncoding RNAs (lncRNAs) have been observed to exert critical functions in cancer, including in TNBC. Nevertheless, systematically tracking expression-based lncRNA biomarkers based on the sequence data for the prediction of prognosis in TNBC has not yet been investigated. To ascertain whether biomarkers exist that can distinguish TNBC from adjacent normal tissue or nTNBC, we implemented a comprehensive analysis of lncRNA expression profiles and clinical data of 1097 BC samples from The Cancer Genome Atlas database. A total of 1510 differentially expressed lncRNAs in normal and TNBC samples were extracted. Similarly, 672 differentially expressed lncRNAs between nTNBC and TNBC samples were detected. The receiver operating characteristic curve analysis indicated that three upregulated lncRNAs (AC091043.1, AP000924.1, and FOXCUT) may be of strong diagnostic value for predicting the existence of TNBC in the training and validation sets (area under the curve (AUC > 0.85). Kaplan-Meier analysis demonstrated that the other three lncRNAs (AC010343.3, AL354793.1, and FGF10-AS1) were associated with the prognosis of TNBC patients (P < 0.05). We used the three overall survival (OS)-related lncRNAs to establish a three-lncRNA signature. Multivariate Cox regression analysis suggested that the three-lncRNA signature was a prognostic factor independent of other clinical variables ( P < 0.01) for predicting OS in TNBC patients that could be utilized to classify patients into high- or low-risk subgroups. Our results might provide efficient signatures for clinical diagnosis and prognostic evaluation of TNBC.


Mechanical thrombectomy of occluded hemodialysis native fistulas and grafts using a hydrodynamic thrombectomy catheter: preliminary experience.
The purpose of this study was to evaluate the efficacy and safety of a new hydrodynamic percutaneous thrombectomy catheter in the treatment of thrombosed hemodialysis fistulas and grafts. Twenty-two patients (median age: 47 years; range: 31-79 years) underwent mechanical thrombectomy for thrombosed hemodialysis fistulas or polytetrafluoroethylene (PTFE) grafts. In all cases, an Oasis hydrodynamic catheter was used. Five patients had native fistulas and 17 had PTFE grafts. Six patients required repeat procedures. All patients with native fistulas and 15 of the 17 with PTFE grafts also underwent angioplasty of the venous limb following the thrombectomy. Major outcome measures included technical success, clinical success, primary and secondary patency, and complication rates. Twenty-eight procedures were performed in total. The technical success rate was 100% and 90% and clinical success was 86% and 76% for native fistulas and grafts, respectively. The primary patency at 6 months was 50% and 59% for fistulas and grafts, respectively, and the secondary patency at 6 months was 75% and 70% for fistulas and grafts, respectively. Two patients died of unrelated causes during the follow-up period. The Oasis catheter is an effective mechanical device for the percutaneous treatment of thrombosed hemodialysis access. Our initial success rate showed that the technique is safe in the treatment of both native fistulas and grafts.


Human amniotic mesenchymal stem cells promote endometrium regeneration in a rat model of intrauterine adhesion.
Human amniotic transplantation has been proposed to improve the therapeutic efficacy of intrauterine adhesions (IUAs). Human amniotic mesenchymal stem stromal cells (hAMSCs) can differentiate into multiple tissue types. This study aimed to investigate the mechanism by which hAMSCs transplantation promotes endometrial regeneration. The rat models with IUA were established through mechanical and infective methods, and PKH26-labeled hAMSCs were transplanted through the tail vein (combined with/without estrogen). Under three different conditions, hAMSCs differentiated into endometrium-like cells. HE and Mason staining assays, and immunohistochemistry were used to compare the changes in rat models treated with hAMSCs and/or estrogen transplantation. To define the induction of hAMSCs to endometrium-like cells in vitro, an induction medium (cytokines, estrogen) was used to investigate the differentiation of hAMSCs into endometrium-like cells. qRT-polymerase chain reaction (PCR) and western blotting were performed to detect the differentiation of hAMSCs into endometrium-like cells. A greater number of glands, fewer endometrial fibrotic areas, and stronger expression of vascular endothelial growth factor and cytokeratin in the combined group (hAMSCs transplantation combined with estrogen) than in the other treatment groups were observed. hAMSCs could be induced into endometrium-like cells by cytokine treatment (TGF-β1, EGF, and PDGF-BB). Transplantation of hAMSCs is an effective alternative for endometrial regeneration after injury in rats. The differentiation protocol for hAMSCs will be useful for further studies on human endometrial regeneration.


Raman spectroscopic evaluation of aging and long-wave UV exposure in the guinea pig lens: a possible model for human aging.
The laser Raman optical dissection technique makes it possible to study individual points of minute volumes (2 X 10(-3) microliter) in the intact living lens in vitro. This technique was used to measure the sulfhydryl and disulfide content of 21 distinct points along the visual axis of the guinea-pig lens after aging and long-wave ultraviolet exposure (9-month duration in vivo). To facilitate comparison between different lenses, data was compiled as the intensity ratio of sulfhydryl (2580 cm-1) to a protein reference signal (2731 cm-1) or disulfide (508 cm-1) to phenylalanine (622 cm-1). These 21 ratios for each experiment were plotted as a function of the distance of the point from the nuclear center of the lens to give a visual axis profile. From these profiles we have found that the loss of sulfhydryl can be accelerated in the guinea-pig lens by in vivo ultraviolet exposure (353 nm peak from an incoherent source) for nine months. There is also a subsequent uniform increase in the disulfide content across the visual axis after UV exposure suggesting a direct sulfhydryl to disulfide conversion in the guinea-pig lens.


Quinolizidine alkaloids from Sophora tonkinensis and their anti-inflammatory activities.
Two new quinolizidine-based alkaloids (2 and 12), along with ten known ones (1, 3-11) were isolated from the roots of S. tonkinensis. Their structures were determined by spectroscopic data (including NMR, MS, IR, and UV), X-ray single crystal diffraction, electronic circular dichroism analyses (ECD), and comparing with related literatures. Compounds 1, 3-12 at non-toxic concentrations exhibited potent anti-inflammatory activities according to in vitro and in vivo anti-inflammatory tests. Among them, (-)-anagyrine (4), sophocarpine (8), 14β-hydroxymatrine (10), and 7β-sophoramine (12) showed more potent in vitro anti-inflammatory activities, and 5α,14β-dihydroxymatrine (2), (-)-anagyrine (4), sophocarpine (8), and 5α-hydroxymatrine (9) exhibited better in vivo anti-inflammatory effects.


Association of prior outpatient diabetes screening with cardiovascular events and mortality among people with incident diabetes: a population-based cohort study.
Outcomes of diabetes screening in contemporary, multi-ethnic populations are unknown. We examined the association of prior outpatient diabetes screening with the risks of cardiovascular events and mortality in Ontario, Canada. We conducted a population-based cohort study using administrative databases among adults aged ≥ 20 years with incident diabetes diagnosed during 2014-2016. The exposure was outpatient diabetes screening performed within 3 years prior to diabetes diagnosis. The co-primary outcomes were (1) a composite of all-cause mortality and hospitalization for myocardial infarction, stroke, coronary revascularization, and (2) all-cause mortality (followed up until 2018). We calculated standardized rates of each outcome and conducted cause-specific hazard modelling to determine the adjusted hazard ratio (HR) of the outcomes, adjusting for prespecified confounders and accounting for the competing risk of death. We included 178,753 Ontarians with incident diabetes (70.2% previously screened). Individuals receiving prior screening were older (58.3 versus 53.4 years) and more likely to be women (49.6% versus 40.0%) than previously unscreened individuals. Individuals receiving prior screening had relatively lower standardized event rates than those without prior screening across all outcomes (composite: 12.8 versus 18.1, mortality: 8.2 versus 11.1 per 1000 patient-years). After multivariable adjustment, prior screening was associated with 34% and 32% lower risks of the composite (HR 0.66, 0.63-0.69) and mortality (0.68, 0.64-0.72) outcomes. Among those receiving prior screening, a result in the prediabetes range was associated with lower risks of the composite (0.82, 0.77-0.88) and mortality (0.71, 0.66-0.78) outcomes than a result in the normoglycemic range. Previously screened individuals with diabetes had lower risks of cardiovascular events and mortality versus previously unscreened individuals. Better risk assessment tools are needed to support wider and more appropriate uptake of diabetes screening, especially among young adults.


A randomized comparison of alternative methods of information provision on the acceptability of elective single embryo transfer.
The purpose of this study was to assess the effect of alternative ways of providing information about the risks of twins on couples' perceptions about elective single embryo transfer (eSET). Couples undergoing IVF were randomized into three groups. Group 1 received a standard information pack, group 2 an extra information leaflet about twin pregnancy, and group 3 an additional discussion session. The primary outcome measure was acceptability of a hypothetical policy of eSET. Data were collected by means of a questionnaire. eSET was acceptable to 17 (27%), 20 (30%) and 24 (32%) couples in groups 1, 2 and 3, if it meant a slight reduction in pregnancy rates, and to 51 (82%), 55 (83%) and 53 (87%) couples, respectively, if pregnancy rates were unchanged. A fixed charge for all fresh and frozen embryo transfers following a single oocyte retrieval led to acceptability rates of 35 (57%), 36 (55%) and 38 (65%). Additional information, involving an extra information leaflet and face to face discussion, did not changes couples' attitudes towards eSET. Maintaining existing rates of pregnancy and offering a fixed charge for all embryo transfers resulting from an oocyte recovery may encourage more couples to consider eSET.


Oxidation of lactose with bromine.
Oxidation of lactose by bromine in an aqueous buffered solution was conducted as a model experiment to examine the glycosidic linkage cleavage occurring during the oxidation of oligosaccharides and polysaccharides. The resulting oxidation products, after reduction with sodium borodeuteride, were characterized by GLC-MS analyses of the per-O-methyl or per-O-Me3Si derivatives. Most of the products were carboxylic acids, of which lactobionic acid was major. Minor products, identified after partial fractionation on a BioGel P-2 column, comprised oxalic acid; glyceric acid; threonic and erythronic acids; tartaric acid; lyxonic, arabinonic, and xylonic acids; galactonic and gluconic acids; galactosylerythronic acid; galactosylarabinonic acid; galactosylarabinaric acid; galacturonosylarabinonic acid; and galactosylglucaric acid. No keto acids were identified. Galactose was detected as 1-deuteriogalactitol, the presence of which, together with the C6 aldonic acids, supported a galactosidic bond cleavage. Galactosylarabinonic acid was the major constituent (7.5%) among minors, and others constituted 0.2-3.7% of the principal lactobionic acid. These products together comprised 29% of the lactobionic acid, more than half (17%) of which were accounted for by the galactosidic linkage cleavage, supporting the significant decrease in molecular weight seen earlier in the bromine-oxidized polysaccharides by glycosidic cleavage.


Benzylidene rhodanines as novel inhibitors of UDP-N-acetylmuramate/L-alanine ligase.
Benzylidene rhodanines are novel inhibitors of UDP N-acetylmuramate/L-alanine ligase. They showed selective whole-cell activity against the Gram-positive MRSA but not against the Gram-negative Escherichia coli. Their cytotoxic effect on mammalian CHO cells was also evaluated.


Computational study of the mechanical influence of lacunae and perilacunar zones in cortical bone microcracking.
The mechanical behavior of cortical bone is influenced by microstructural components such as osteons, Haversian canals, and osteocyte lacunae that arise from biological remodeling processes. This study takes a computational approach to investigate the role of the perilacunar zones formed by the local remodeling processes of lacunar-dwelling osteocytes by utilizing phase-field finite element models based on histological imaging of human bone. The models simulated the microdamage accumulation that occurs in cortical bone under transverse compression in bone without lacunae, with lacunae, and with a perilacunar zone surrounding lacunae in order to investigate the role of these features. The results of the simulations found that while lacunae create stress concentration which initiate further damage, perilacunar regions can delay or prevent the emergence and growth of microcracks.


Effects of pulse strength and pulse duration on in vitro DNA electromobility.
Interstitial transport of DNA is a rate-limiting step in electric field-mediated gene delivery in vivo. Interstitial transport of macromolecules, such as plasmid DNA, over a distance of several cell layers, is inefficient due to small diffusion coefficient and inadequate convection. Therefore, we explored electric field as a novel driving force for interstitial transport of plasmid DNA. In this study, agarose gels were used to mimic the interstitium in tissues as they had been well characterized and could be prepared reproducibly. We measured the electrophoretic movements of fluorescently labeled plasmid DNA in agarose gels with three different concentrations (1.0%, 2.0% and 3.0%) subjected to electric pulses at three different field strengths (100, 200 and 400 V/cm) and four different pulse durations (10, 50, 75, 99 ms). We observed that: (1) shorter pulses (10 ms) were not as efficient as longer pulses in facilitating plasmid transport through agarose gels; (2) plasmid electromobility reached a plateau at longer pulse durations; and (3) plasmid electromobility increased with applied electric energy, up to a threshold, in all three gels. These data suggested that both pulse strength and duration needed to be adequately high for efficient plasmid transport through extracellular matrix. We also found that electric field was better than concentration gradient of DNA as a driving force for interstitial transport of plasmid DNA.


Alzheimer's disease and alcoholism: possible interactions.
The purpose of this investigation was to test the hypothesis that chronic exposure to alcohol may accelerate Alzheimer's disease (AD), either by independently adding receptor losses or by accelerating the AD disease process itself. Muscarinic [3H]quinuclidinyl benzilate and benzodiazepine [3H]-flunitrazepam receptor binding in homogenates of human autopsy brains were determined in four nonalcoholic and seven alcoholic AD brains and in histologically normal brains from 20 alcoholics and 20 nonalcoholics. Muscarinic binding was decreased in alcoholic AD compared with nonalcoholic AD in the parahippocampal region of frontal cortex, premotor temporal cortex, and amygdala, but not in the hippocampus. Benzodiazepine receptors were lost from the temporal cortex and amygdala, but the difference in the amygdala was not statistically significant. Plaque counts considered a marker of the severity of AD were not increased in the brains of alcoholics compared with nonalcoholics. Larger receptor losses in some alcoholic AD were associated with low plaque counts. Since all of these patients were severely demented, it is tentatively suggested that the receptor losses resulting from alcoholism may have contributed to the dementia in these AD patients.


Bacteriuria in appendicitis.
The value of bacteriologic findings in patients with acute appendicitis was studied. Routine urinary culture specimens were taken preoperatively from 194 children (mean age 11 +/- 3 years) undergoing emergency appendectomy. Bacteria were found in culture specimens of urine from 26 of 156 patients with acute appendicitis. The bacteriuria was correlated to the position of the appendix, the duration of disease, and the degree of inflammatory changes in the appendix. The results suggest direct spread of bacteria from the inflamed appendix to the urinary tract due to close anatomic relationship and to the severity of the inflammatory changes. That this spread of bacteria can have clinical significance cannot be excluded. Urinary sedimentation study is of no use in the diagnosis of acute appendicitis.


Association of FTO and near MC4R variants with obesity measures in urban and rural dwelling Sri Lankans.
To investigate the association between the fat mass and obesity related (FTO) gene rs9939609 and near melanocortin-4-receptor (MC4R) gene rs17782313 polymorphisms with obesity measures and metabolic parameters in urban and rural dwelling Sri Lankans. 535 subjects (60.9% female) from the general adult population (ages 18-70 years) representative of both urban (28.4%) and rural areas of residence were recruited by multi-stage random sampling. Body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) was obtained by standard methods. DNA extracted from whole blood was genotyped using real-time PCR. The FTO risk genotypes (AA+AT) were associated with higher BMI (p=0.03) and WC (p=0.05) measures as well as categorical obesity (BMI ≥27.5kgm-2 definition) (OR 1.69 95% CI 1.11-2.56, p=0.01). The near MC4R risk genotypes (CC+CT) were associated with greater BMI (p=0.03) as well as categorical obesity (BMI ≥25kgm-2 definition) (OR 1.57 95% CI 1.11-2.22, p=0.01). In addition the MC4R risk genotype carriers (CC+CT) had significantly higher fasting blood sugar (FBS) levels compared to the 'TT' genotype carriers independent of BMI (p=0.05). Urban living was associated with significantly greater BMI values for FTO risk genotypes compared to rural living (p=0.02). FTO and near MC4R variants are associated with obesity measures in Sri Lankan populations whilst urban living accentuates the obesogenic effect of the FTO polymorphism.


Is There Still a Survival Advantage to Bypass Surgery Over Percutaneous Intervention in the Modern Era?
The method of revascularization for multi-vessel coronary artery disease (MVD) has traditionally been coronary artery bypass grafting (CABG), however, due to recent advances in the field of percutaneous coronary intervention (PCI), this latter technique has gained in popularity and its role in guidelines has been promoted. This review aims to address the current data available for the treatment of patients with complex coronary disease, including the specific disease subset in those with diabetes mellitus, focusing on the importance of risk stratification and review by the 'Heart Team'. The concept of complete versus incomplete revascularization and the assessment of lesions utilizing functional techniques are discussed. Over recent years, PCI has grown to become the most frequently performed therapeutic intervention in medicine and continues to grow. There are encouraging data that this is an effective and safe treatment option in selected patients, however, neither strategy alone can provide a solution for the entire spectrum of patients with MVD.


Chronic subdural hematomas in Finnish patients with Huntington's disease.
Many features of Huntington's disease (HD) make these patients susceptible to subdural hematomas (SDH), but there are no previous reports on the epidemiology of SDH in this population. We investigated the incidence and risk factors of chronic SDH. A national cohort of 192 Finnish patients with HD was investigated. Information was gathered from medical records and administrative registries. The incidence rate of SDH was 68.3/100,000 person-years among the 192 patients. Seven patients were identified with a chronic SDH at or after the diagnosis of HD. Their age was 58.5 ± 15.0 years (mean ± SD) at the time of diagnosis of HD and 60.9 ± 14.1 years at the time of diagnosis of SDH. The incidence rate of chronic SDH after the diagnosis of HD was 4.7/1000 person-years and by 8.3 years of follow-up the cumulative risk was 5.4 %. Review of the patient charts revealed only a few of the common risk factors for chronic SDH, but the rate of reoperations was high. The incidence of chronic SDH was higher in patients with HD than that in the general population. Incidence of chronic SDH began to increase at the time of expected motor onset of HD. Common risk factors of SDH were scarce aside from fall-related head injuries.


Hepatitis E in Sub Saharan Africa - A significant emerging disease.
Hepatitis E is an emerging endemic disease found across the African continent, but there are clear differences in epidemiology between North Africa and countries south of the Sahara. In this systematic review, Google scholar and PubMed databases were searched for peer-reviewed articles on HEV epidemiology. Publications meeting our inclusion criteria were critically reviewed to extract consistent findings and identify knowledge gaps. Hepatitis E has been reported in 25 of the 49 countries in Sub Saharan Africa. Mortality rates of 1-2% in the general population and ~ 20% in pregnant women. Outbreaks were closely linked to refugees and Internally Displaced Persons in camps which accounted for 50% of reported outbreaks. There was very little research and concrete evidence for sources of contamination and transmission routes. There are indications of zoonotic transmission of Hepatitis E Virus infection but further research in these fields is required.


Dementia risk after major elective surgery based on the route of anaesthesia: A propensity score-matched population-based cohort study.
Whether the route of anaesthesia is an independent risk factor for dementia remains unclear. Therefore, we conducted a propensity score-matched (PSM) population-based cohort study to compare dementia incidence among surgical patients undergoing different routes of anaesthesia. The inclusion criteria were being an inpatient >20 years of age who underwent major elective surgery, defined as those requiring GA without or with inhalation anaesthetics or regional anaesthesia, and being hospitalised for >1 day between Jan 1, 2008 and Dec 31, 2019 in Taiwan. Patients undergoing major elective surgery were categorised into three groups according to the type of anaesthesia administered: noninhalation anaesthesia, inhalation anaesthesia, and regional anaesthesia, matched at a 1:1 ratio. The incidence rate (IR) of dementia was determined. PSM yielded 63,750 patients (21,250 in the noninhalation anaesthesia group, 21,250 in the inhalation anaesthesia group, and 21,250 in the regional anaesthesia group). In the multivariate Cox regression analysis, the adjusted hazard ratios (aHRs; 95% confidence intervals) of dementia for the inhalation and noninhalation anaesthesia groups compared with the regional anaesthesia group were 20.16 (15.40-26.35; p < 0.001) and 18.33 (14.03-24.04; p < 0.001), respectively. The aHR of dementia for inhalation anaesthesia compared with noninhalation anaesthesia was 1.13 (1.03-1.22; p = 0.028). The IRs of dementia for the inhalation, noninhalation, and regional anaesthesia groups were 3647.90, 3492.00, and 272.99 per 100,000 person-years, respectively. In this population based cohort study, the incidence of dementia among surgical patients undergoing general anaesthesia was higher than among those undergoing regional anaesthesia. Among patients undergoing general anaesthesia, inhalation anaesthesia was associated with a higher risk of dementia than noninhalation anaesthesia. Our results should be confirmed in a randomised controlled trial. The study was partially supported by Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital (Funding Number: 10908, 10909, 11001, 11002, 11003, 11006, and 11013).


Comparison of biosorption properties of different kinds of fungi for the removal of Gryfalan Black RL metal-complex dye.
Three kinds of filamentous fungi (Rhizopus arrhizus, Trametes versicolor, Aspergillus niger) were tested for their ability to adsorb Gryfalan Black RL metal-complex dye as a function of pH, temperature and dye concentration. R. arrhizus and T. versicolor exhibited the maximum dye uptake at pH 2.0 and at 25 degrees C while A. niger performed the highest dye biosorption at pH 1.0 and at 35 degrees C. Sorption capacity of each biosorbent increased with increasing initial dye concentration. Among the three fungi, R. arrhizus was the most effective biosorbent showing a maximum dye uptake of 666.7 mg g(-1). The Langmuir model described the equilibrium data of each dye-fungus system accurately in the concentration and temperature ranges studied. Kinetic analysis indicated that both adsorption kinetics and internal diffusion played an important role on controlling the overall adsorption rate for each fungus. Thermodynamic analysis verified that A. niger biosorption was endothermic while the others were exothermic.


Factors influencing the exudation recurrence after cataract surgery in patients previously treated with anti-vascular endothelial growth factor for exudative age-related macular degeneration.
To investigate factors influencing exudation recurrence following cataract surgery in patients already treated with anti-vascular endothelial growth factor (VEGF) agents for exudative age-related macular degeneration (AMD). A retrospective review of medical records was performed for patients who underwent cataract surgery and had been previously treated with anti-VEGF for exudative AMD. Visual acuity was examined before surgery and 1 and 6 months after surgery. The time between diagnosis and surgery, and the exudation-free period before surgery were examined and compared between patients who had exudation recurrence and those that did not. Thirty-nine eyes of 39 patients were included in analyses. The logarithm of the minimum angle of resolution visual acuity was 1.02 ± 0.58 and had significantly improved 1 month (0.81 ± 0.62, P < 0.001) and 6 months (0.85 ± 0.64, P = 0.001) following surgery. Both the diagnosis-to-surgery period (P = 0.001) and the preoperative exudation-free period (P < 0.001) were significantly longer in patients without recurrence than in patients with recurrence. Cataract surgery was beneficial in patients previously treated with anti-VEGF for exudative AMD. Our data suggests that cataract surgery should be performed after a sufficiently long exudation-free period to minimize exudation recurrence. But larger prospective studies are required to draw definitive clinical guidelines.


In-sample derivatization-solid-phase microextraction of amphetamines and ecstasy related stimulants from water and urine.
A solid-phase microextraction (SPME) method for the determination of five amphetamine type stimulants (ATSs) in water and urine samples is presented. Analytes were simultaneously derivatized with iso-butyl chloroformate (iBCF) in the aqueous sample while being extracted, improving in this way the extractability of ATSs and permitting their determination by gas chromatography-mass spectrometry (GC-MS). The SPME procedure was carefully optimized in order to achieve adequate limits of detection (LODs) for environmental concentrations. Hence, different operational parameters were considered: type of SPME coating, ionic strength, basic catalyzer and derivatizing agent amount, extraction time and temperature. The final SPME procedure consists into the extraction of 100mL of sample containing 2 g of dipotassium monohydrogen phosphate trihydrate and 100 μL of iBCF (1:1 in acetonitrile), for 40 min at 60°C with a polydimethylsiloxane-divinylbenzene (PDMS-DVB) fiber. Under these conditions, LODs in wastewater ranged from 0.4 to 2 ng L(-1), relative recoveries in the 84-114% range and relative standard deviations (RSD) lower than 15% were obtained. The application of the method to wastewater and river water samples showed the ecstasy ATS, 3,4-methylenedioxymethamphetamine (MDMA), as the most frequently detected, followed by methamphetamine, in concentrations around 20 ng L(-1). Finally, the method was downscaled and also validated with urine samples, proving its good performance with this matrix too: RSD<11%, recoveries in the 98-110% range and LODs lower than 0.1 μg L(-1).


Idiopathic intrahepatic arterioportal fistula treated by hepatectomy assisted by balloon-occluded retrograde transvenous obliteration: Report of an elderly case.
An 80-year-old woman with hepatic encephalopathy and esophagogastric varices was admitted. Doppler sonography and arteriography demonstrated an arterioportal fistula in the right anterior superior segment of the liver. Two attempts at transcatheter arterial embolization failed to manage the fistula and portacaval collaterals. We carried out hepatectomy and balloon-occluded retrograde transvenous obliteration, by which the portal flow changed from hepatofugal to hepatopetal. The resected specimen demonstrated multiple small holes in the right portal vein, which are arterioportal fistula. The underlying liver was normal. After treatment, esophagogastric varices and hepatic encephalopathy were markedly improved. Hepatectomy is useful as a reliable therapy for arterioportal fistula in case of failure of transarterial embolization.


Echovirus-associated polyarthritis. Report of a case with synovial fluid and synovial histologic characterization.
A patient with fever, myalgias, and acute polyarthritis in whom echovirus 9 was isolated from throat and rectal swab specimens is described. All symptoms resolved spontaneously over a one week period except for the arthritis which required three months for complete recovery. A mildly inflammatory synovial fluid and histologic picture were observed. Attempts to isolate the virus from synovial fluid and synovium during acute illness were unsuccessful.


Direct thrombin inhibition with dabigatran attenuates pressure overload-induced cardiac fibrosis and dysfunction in mice.
The multifunctional serine protease thrombin exerts proinflammatory and profibrotic cellular effects that may contribute to cardiac remodeling. This study was designed to investigate whether direct thrombin inhibition with dabigatran attenuates myocardial injury in the setting of pressure overload-induced heart failure. Transverse aortic constriction (TAC) surgery was performed on C57Bl/6J male mice to elicit cardiac hypertrophy. TAC, or sham, mice were randomly assigned to receive chow supplemented with the oral anticoagulant, dabigatran etexilate, or placebo. Dabigatran did not affect cardiac hypertrophy, as measured by heart weight-to-body weight or the heart weight-to-tibia length, although a non-significant reduction in myocardial hypertrophic markers (ANP, BNP and MHC) occurred. Dabigatran reduced perivascular fibrosis by 25%, interstitial fibrosis by 54%, and the expression of myocardial fibrosis markers collagen I & III, MMP9, SMA, and PAR-1. These changes were associated with significant improvement in both coronary flow reserve and global left ventricular function. In cultured cardiac fibroblasts, dabigatran decreased thrombin and PAR-1-mediated collagen deposition by 30% and 37%, respectively. Dabigatran attenuates cardiac fibrosis in the setting of pressure overload and improves coronary flow reserve and global cardiac function possibly by inhibiting thrombin activity and down-regulating PAR-1 expression in the absence of an effect on cardiomyocyte hypertrophy.


Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity.
Trafficking of cargo through the endosomal system depends on endosomal fusion events mediated by SNARE proteins, Rab-GTPases, and multisubunit tethering complexes. The CORVET and HOPS tethering complexes, respectively, regulate early and late endosomal tethering and have been characterized in detail in yeast where their sequential membrane targeting and assembly is well understood. Mammalian CORVET and HOPS subunits significantly differ from their yeast homologues, and novel proteins with high homology to CORVET/HOPS subunits have evolved. However, an analysis of the molecular interactions between these subunits in mammals is lacking. Here, we provide a detailed analysis of interactions within the mammalian CORVET and HOPS as well as an additional endosomal-targeting complex (VIPAS39-VPS33B) that does not exist in yeast. We show that core interactions within CORVET and HOPS are largely conserved but that the membrane-targeting module in HOPS has significantly changed to accommodate binding to mammalian-specific RAB7 interacting lysosomal protein (RILP). Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome-associated mutations in VPS33B selectively disrupt recruitment to late endosomes by RILP or binding to its partner VIPAS39. Within the shared core of CORVET/HOPS, we find that VPS11 acts as a molecular switch that binds either CORVET-specific TGFBRAP1 or HOPS-specific VPS39/RILP thereby allowing selective targeting of these tethering complexes to early or late endosomes to time fusion events in the endo/lysosomal pathway.


Pathogenicity of Fusarium spp. isolates and phenomenon of interaction between isolates and different genotypes of winter wheat.
Pathogenicity of 74 Fusarium spp. isolates was studied. Isolates munifested significant variation of the parasitic ability. The phenomenon of interaction between some isolates and different wheat varieties was found.


Viewing distance dependence of the vestibulo-ocular reflex during translation: extra-otolith influences.
Despite nearly perfect gaze stability during natural head movements, the amplitude of the vestibulo-ocular reflex during passive head and body translation (TVOR) has been consistently reported to be undercompensatory during near target viewing. Here we have compared the rhesus monkey TVOR during pure head and body translation with the eye movements generated during eccentric yaw rotations, where both semicircular canal and otolith signals are activated. We found a significant increase in both the near target TVOR amplitude and its viewing distance dependence during eccentric rotations, as compared to pure translations. We conclude that the simultaneous activation of the horizontal semicircular canals result in an improvement of the viewing distance-dependence of the rhesus monkey TVOR.


Quantification of plasma remdesivir and its metabolite GS-441524 using liquid chromatography coupled to tandem mass spectrometry. Application to a Covid-19 treated patient.
A method based on liquid chromatography coupled to triple quadrupole mass spectrometry detection using 50 µL of plasma was developed and fully validated for quantification of remdesivir and its active metabolites GS-441524. A simple protein precipitation was carried out using 75 µL of methanol containing the internal standard (IS) remdesivir-13C6 and 5 µL ZnSO4 1 M. After separation on Kinetex® 2.6 µm Polar C18 100A LC column (100 × 2.1 mm i.d.), both compounds were detected by a mass spectrometer with electrospray ionization in positive mode. The ion transitions used were m/z 603.3 → m/z 200.0 and m/z 229.0 for remdesivir, m/z 292.2 → m/z 173.1 and m/z 147.1 for GS-441524 and m/z 609.3 → m/z 206.0 for remdesivir-13C6. Calibration curves were linear in the 1-5000 μg/L range for remdesivir and 5-2500 for GS-441524, with limit of detection set at 0.5 and 2 μg/L and limit of quantification at 1 and 5 μg/L, respectively. Precisions evaluated at 2.5, 400 and 4000 μg/L for remdesivir and 12.5, 125, 2000 μg/L for GS-441524 were lower than 14.7% and accuracy was in the [89.6-110.2%] range. A slight matrix effect was observed, compensated by IS. Higher stability of remdesivir and metabolite was observed on NaF-plasma. After 200 mg IV single administration, remdesivir concentration decrease rapidly with a half-life less than 1 h while GS-441524 appeared rapidly and decreased slowly until H24 with a half-life around 12 h. This method would be useful for therapeutic drug monitoring of these compounds in Covid-19 pandemic.


Overexpression of mammalian phenylalanyl-tRNA synthetase upon phenylalanine restriction.
The effect of phenylalanine restriction on the level of expression of phenylalanyl-tRNA synthetase from cultured Chinese hamster ovary cells was investigated. By lowering the phenylalanine concentration from 200 to 2 microM, cell growth was arrested, tRNAPhe aminoacylation level was rapidly and specifically decreased and phenylalanyl-tRNA synthetase was derepressed. The progressive 2-fold elevation of phenylalanyl-tRNA synthetase level was determined by activity measurement and immunotitration. None of the other aminoacyl-tRNA synthetases tested were significantly affected.


Application of endoscopy to the surgical management of craniopharyngiomas.
The purpose of this study was to evaluate the efficacy of a minimally invasive/endoscopic approach to craniopharyngiomas (CPGs) given that the surgical aim was a complete excision of the tumor as a single stage procedure. The endoscope can be used with both a subfrontal and a transsphenoidal approach. This study is a retrospective review of 36 operative patients who were seen by one surgeon. All patients had attempted complete excision. Patients were divided into three groups according to their preoperative status. Those in group 1 had no previous treatment and fared well, although all developed postoperative diabetes insipidus. Those in group 2 had previous surgery only and also did well with repeat surgery. Those in group 3 had been treated previously with surgery and radiotherapy and, apart from a single exception, did poorly. The endoscopic, minimally invasive approach is versatile and effective in the surgical management of both first-time and repeat cases of CPG. It offers superior visualization of surrounding neurovascular structures and allows a more complete resection of tumor. It can be used for a cranial or a nasal approach to these tumors. Sadly, it failed to prevent postoperative endocrinopathy.


Acute toxic effects of oxamyl in the rat.
The effects of single acute oral doses of 1, 2.1, and 3.5 mg/kg oxamyl (a carbamate insecticide) on selected biochemical parameters in male Sprague-Dawley rats were investigated. The animals exhibited significantly decreased weight gain when compared to control animals. The compound inhibited brain and blood acetylcholinesterase significantly in the first few hours of exposure. Liver glucose-6-phosphatase was inhibited substantially after 7 and 4 days at the levels of 2.1 and 3.5 mg/kg, respectively. Maximum inhibition of liver succinic acid dehydrogenase was noted after 1 day at the level of 1 mg/kg and after 6 hr at the level of 2.1 and 3.5 mg/kg. Significant changes in serum total lipids and glucose were observed when oxamyl was given at 2.1 and 3.5 mg/kg, but serum protein was not affected at any dose level. However, the absence of statistically significant effects between Days 7 and 14 in most of the investigated parameters is indicative of an overall moderate degree of toxicity of oxamyl following acute oral administration of the selected doses.


Iodinated melatonin mimics melatonin action and reveals discrete binding sites in fetal brain.
Iodinated melatonin was used to study melatonin sites of action in brain. Iodomelatonin mimicked the effects of melatonin on reproductive development in Djungarian hamster fetuses. 125I-melatonin injected into the dam was recovered from fetal brain. In vitro autoradiographic studies revealed a remarkably discrete distribution of competitive 125I-melatonin-binding sites in the fetal brain, with binding in median eminence/arcuate nucleus area greater than suprachiasmatic nucleus greater than pineal gland much greater than anterior pituitary gland much greater than preoptic area. 125I-melatonin promises to be a useful tool for understanding the sites and mechanism of action of melatonin.


Selective surface enhanced Raman detection and effective photocatalytic degradation of sulfonamides antibiotic based on a flexible three-dimensional chitosan/carbon nitride/silver substrate.
The prevalence of sulfonamide residues in aquatic environments poses serious environmental risks, and the sensitive detection and effective degradation of sulfonamides have attracted widespread attention. Here, the environmentally friendly chitosan (CS)/carbon nitride (CN) with three-dimensional porous structure is fabricated by freeze-drying method, and subsequently a new bifunctional flexible substrate (CS/CN/Ag) is prepared by anchoring of small sized AgNPs (6 ∼ 12 nm) on CS/CN. Importantly, the CS/CN/Ag substrate shows high adsorption capacity (∼ 83.06%) for sulfamethoxazole (SMX) solution within 20 mins and the limit of detection can be as low as 7.46 × 10-9 mol·L-1 with an enhancement factor of 3.3 × 105. Also, the CS/CN/Ag substrate displays highly selective for surface-enhanced Raman spectroscopy (SERS) detection of sulfonamides and also shows excellent SERS response for SMX in hospital wastewater samples. In addition, the photocatalytic degradation efficiency of SMX could reach as high as 99.22% within 20 mins of irradiation and the CS/CN/Ag still maintains outstanding photocatalytic performance after six cycles. Moreover, the Ag content in the CS/CN/Ag substrate is only 2.35%, and also the CS/CN/Ag exhibits good uniformity, repeatability, recyclability and stability. Therefore, this flexible and cost-effectively substrate of CS/CN/Ag shows great potential for the simultaneous SERS detection and photocatalytic degradation of pollutants in actual wastewater samples.