Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults.
What is the role of temozolomide in the management of adult patients (aged 65 and under) with newly diagnosed glioblastoma? These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. Level I: Concurrent and post-irradiation Temozolomide (TMZ) in combination with radiotherapy and post-radiotherapy as described by Stupp et al. is recommended to improve both PFS and OS in adult patients with newly diagnosed GBM. There is no evidence that alterations in the dosing regimen have additional beneficial effect. Is there benefit to adjuvant temozolomide treatment in elderly patients (> 65 years old?). These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. Level III: Adjuvant TMZ treatment is suggested as a treatment option to improve PFS and OS in adult patients (over 70 years of age) with newly diagnosed GBM. What is the role of local regional chemotherapy with BCNU biodegradable polymeric wafers in adult patients with newly diagnosed glioblastoma? These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. Level III: There is insufficient evidence for the use of BCNU wafers following resection in patients with newly diagnosed glioblastoma who undergo the Stupp protocol after surgery. Further studies of higher quality are suggested to understand the role of BCNU wafer and other locoregional therapy in the setting of Stupp Protocol. What is the role of bevacizumab in the adult patient with newly diagnosed glioblastoma? These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. Level I: Bevacizumab in general is not recommended in the initial treatment of adult patients with newly diagnosed GBM. It continues to be strongly recommended that patients with newly diagnosed GBM be enrolled in properly designed clinical trials to assess the benefit of novel chemotherapeutic agents compared to standard therapy.


Impacts of climate change on nutrient and sediment loads from a subtropical catchment.
Climate change is predicted to significantly alter hydrological cycles across the world, affecting runoff, streamflow, and pollutant loads from diffuse sources. The objectives of this study were to examine the impacts of climate change on streamflow, total nitrogen (TN), total phosphorus (TP), and total suspended sediment (TSS) loads in the subtropical Logan-Albert catchment, Queensland, Australia. We calibrated the Soil Water Assessment Tool (SWAT) against event monitoring data in the Logan and Albert rivers, respectively. Hydrological and water quality effects of an ensemble of 11 dynamically downscaled high-resolution climate models were assessed with SWAT under high (Representative Concentration Pathway 8.5 - RCP8.5) and intermediate (RCP4.5) emission scenarios. Streamflow decreased most in winter and spring and decreased least in summer. This followed the predicted seasonal changes for precipitation, although decreases tended to be amplified due to increasing evaporative loss. TSS, TN, and TP loads showed a similar pattern to streamflow, with the largest decreases predicted for the dry season under RCP8.5 by the 2080s. Annual TSS load decreased by 34.3 and 54.2%, TN load decreased by 29.8 and 30.5%, and TP load by 24.9 and 4.4% for the Logan and Albert sites, respectively. The results of this study indicate that for subtropical river-estuary systems, climate warming may lead to lower streamflow and contaminant loads, reduced flushing, and greater relative importance of point source loads in urbanising catchments.


Neurotoxicity of apamin and MCD peptide upon central application.
Besides apamin, the structurally related MCD peptide (mast cell degranulating peptide; peptide 401) is another centrally acting peptide from bee venom. In contrast to apamin, it is hardly neurotoxic upon intravenous injection in mice. Following intraventricular injection, as little as 0.3 microgram/animal produce convulsions and respiratory arrest in mice. The clinical picture differs from that elicited by apamin, and apamin is about 10 times more potent than MCD peptide when given intraventricularly. Apamin and MCD peptide injected into the spinal cord of rats in nanogram amounts, produce circumscript hyperexcitation lasting more than one day, however with complete recovery following sublethal doses. Local apamin poisoning differs from local tetanus (elicited by the same way) by its faster time course.


Antibody responses of experimentally infected lambs to antigens collected during in vitro maintenance of the adult, metacestode or oncosphere stages of Taenia hydatigena and Taenia ovis with further observations on anti-oncospheral antibodies.
The antigenicity and specificity of crude antigens collected during the in vitro maintenance of Taenia hydatigena and T. ovis, excretory/secretory (ES) antigens, were assessed in a peroxidase microenzyme-linked immunosorbent assay (ELISA), using sera from lambs given experimental monospecific infections with T. hydatigena, T. ovis, Echinococcus granulosus or Fasciola hepatica. ES antigens of larval cysts of T. ovis and T. hydatigena were less reactive than those of adult or oncosphere stages. Strong interspecific cros-reactions occurred between all antigen preparations, and these antigens offered no better specificity than crude somatic extracts. IgG1 was the major immunoglobulin detected in sera from lambs experimentally infected with T. ovis or T. hydatigena using antigens prepared from sonicated oncospheres. Discrete peaks of anti-oncospheral antibodies were detected following initial and challenge infections with eggs (whether the homologous or heterologous species), when sera were assayed with a PBS sonicate or an ES antigen from oncospheres. However, when oncospheres solubilised with sodium deoxycholate were used, the antibody response was prolonged and resembled that reported previously when somatic extracts of adult and metacestode stages were used as antigen. The results showed that oncospheres share antigens in common with other life-cycle stages, but also support the notion that they may possess some unique stage-specific antigenic determinants.


Long-Noncoding RNA TUG1 Promotes Parkinson's Disease via Modulating MiR-152-3p/PTEN Pathway.
Long-noncoding RNA taurine upregulated gene 1 (TUG1) participates in nervous system diseases, but its function in Parkinson's disease (PD) remains unclear. This study explored the function and mechanism of TUG1 in PD. A PD model was constructed using SH-SY5Y cells induced by 1-methyl-4-phenylpyridinium (MPP+) in vitro and mice treated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo. The expressions of TUG1, miR-152-3p, phosphatase and tensin homologue (PTEN), tyrosine hydroxylase (TH), and Bcl-2, and cleaved caspase-3 expressions were determined by quantitative reverse transcription-PCR and Western blotting. The viability, apoptosis, reactive oxygen species, and release of inflammatory factors from SH-SY5Y cells and substantia nigra tissues were detected by commercial kits. The interaction between TUG1 and miR-152-3p was analyzed by dual-luciferase reporter assay. Hematoxylin/eosin and immunohistochemical staining was performed for assessing the pathological damage and proportion of TH-positive cells. In PD cell model and mice model, TUG1 expression was upregulated and that of miR-152-3p was downregulated. Further research showed that TUG1 sponged and regulated miR-152-3p expression. Silencing of TUG1 not only protected SH-SY5Y cells against cell apoptosis, oxidative stress, and neuroinflammation in vitro, pathological damage and neuroinflammation in vivo, but also suppressed the expressions of PTEN and cleaved caspase-3, and increased the expressions of TH and Bcl-2 in MPP+-treated SH-SY5Y cells. However, the protective role of siTUG1 in SH-SY5Y cells was significantly inhibited by the miR-152-3p inhibitor. Thus, knocking down TUG1 might have a protective effect on PD through the miR-152-3p/PTEN pathway.


Transcutaneous electrical stimulation of auricular branch of the vagus nerve effectively and rapidly modulates the EEG patterns in patients with possible electrographic status epilepticus.
Invasive vagal nerve stimulation (iVNS) is a known treatment approach for patients with refractory epilepsy. Transcutaneous auricular vagus nerve stimulation (tVNS) was developed to overcome the side effects and surgical complications of iVNS. tVNS is proven beneficial in refractory epilepsy. The effectiveness of tVNS, however, has never been studied in patients with Status Epilepticus. In this study, we explored the effect of tVNS in three patients with possible electrographic status epilepticus. To compare the EEG pattern before, during and after tVNS in three patients with possible electrographic status epilepticus. Three consecutive patients with possible electrographic status epilepticus were included after due consenting process. In addition to the standard care, tVNS was applied on the left ear over the cymba concha in two sessions, 6 h apart, with each session for 45 min. Continuous EEG monitoring was performed as standard of care and the findings before, during and after tVNS were documented. The duration of status epilepticus at the time of inclusion of Patients 1, 2, and 3 was 6 weeks, 7 days, and 5 days respectively. All were in coma and on multiple antiseizure medications. Patient 1 and 3 were on anesthetic infusions. Before stimulation, one patient had burst suppression pattern and two had generalized periodic discharges at 1 Hz frequency. We observed a significant reduction/resolution of ongoing EEG patterns in all three patients during the stimulation. The abnormal patterns re-emerged approximately 20 min post cessation of tVNS. No stimulation-related side effects were detected. There was no change in clinical status, but all three patients had severe underlying conditions. Transcutaneous auricular Vagus Nerve Stimulation (tVNS) is a potential noninvasive adjuvant therapy that can modulate EEG patterns in patients with Status epilepticus. Larger studies in early SE are needed to assess its clinical benefits.


Constructing maternal morbidity - towards a standard tool to measure and monitor maternal health beyond mortality.
Maternal morbidity is a complex entity and its presentation and severity are on a spectrum. This paper describes the conceptualization and development of a definition for maternal morbidity, and the framework for its measurement: the maternal morbidity matrix, which is the foundation for measuring maternal morbidity, thus, the assessment tool. We define maternal morbidity and associated disability as "any health condition attributed to and/or complicating pregnancy and childbirth that has a negative impact on the woman's wellbeing and/or functioning." A matrix of 121 conditions was generated through expert meetings, review of the International Classification of Diseases and related health problems (ICD-10), literature reviews, applying the definition of maternal morbidity and a cut-off of >0.1% prevalence. This matrix has three dimensions: identified morbidity category, reported functioning impact and maternal history. The identification criteria for morbidity include 58 symptoms, 29 signs, 44 investigations and 35 management strategies; these criteria are aimed at recognizing the medical condition, or the functional impact/disability component that will capture the negative impact experienced by the woman. The maternal morbidity matrix is a practical framework for assessing maternal morbidity beyond near-miss. In light of the emerging attention to Universal Health Coverage (UHC) as part of the post-2015 Sustainable Development Goals (SDGs) planning, a definition and standard identification criteria are essential to measuring its extent and impact.


Systematic Review of Literature on Eating Disorders During Pregnancy-Risk and Consequences for Mother and Child.
Background: Eating disorders (ED) are a diagnostic category that includes several nosological units such as anorexia nervosa (AN), bulimia nervosa (BN), or binge eating disorder (BED). This category most often concerns women, while the peak incidence falls on the reproductive age. Therefore the issue of ED during pregnancy is an interesting topic. Due to the creation of unrealistic ideal of "desired," slim figure both by the mass media and social media even during and right after gestation, more and more pregnant women introduce behaviours aimed at maintaining the "perfect" appearance. However in some cases it may have serious consequences for the health of both mother and child leading to the creation of the term "pregorexia" by the media to describe this issue. Aim: The aim of this paper was to conduct a systematic review of the literature dealing with eating disorders in pregnant women, with particular emphasis on pregorexia. Method: A systematic review of literature published within the last 5 years (2016-2021) in English or Polish and available through MEDLINE / PubMed, Google Scholar and Cochrane Library databases was conducted based on the previously assumed inclusion and exclusion criteria. Results: Initially, 634 publications were obtained during the review, of which 55 papers were selected in the course of the title analysis. After further evaluation of abstracts, 28 papers were qualified for full text analysis. Ultimately, 10 papers were selected for the final analysis. Conclusions: The issue of ED in pregnant women is a broad topic covering a heterogeneous group of women-both those with a previous history and those with the onset during pregnancy. The occurrence of ED symptoms during this period is associated with a high likelihood of negative consequences for both the mother and the child. The course of pregnancies and deliveries in these patients is more complicated. Therefore, it seems reasonable to develop a multidisciplinary screening strategy and standards of management and supervision over this group of patients.


Mutations in the genome of the highly pathogenic porcine reproductive and respiratory syndrome virus potentially related to attenuation.
A live-attenuated highly pathogenic porcine reproductive and respiratory syndrome (HP-PRRS) virus (HP-PRRSV) TJM vaccine strain was derived from the HP-PRRSV TJ strain by passage 92 times in the African green monkey kidney epithelial cell line Marc-145. We found that the virulence of the TJ strain to piglets was decreased greatly from passage 19. To identify mutations associated with attenuation of the TJM vaccine strain, we determined the nucleotide changes that arose during Marc-145 passage of the HP-PRRSV TJ virus. The TJM strain contains a 360 nucleotide (120 amino acids) deletion and a 118 nucleotide mutation that resulted in 48 amino acid changes. Analysis of the complete nucleotide sequences of intermediate passage-level viruses F19, F46 and F78 showed that 31 (64.6%) of the 48 amino acid mutations occurred in F19, 7 (14.6%) occurred in F46, 7 (14.6%) occurred in F78 and 3 (6.3%) occurred in F92. The 120 amino acid deletion occurred from F19 to TJM. Therefore, we hypothesized that the 31 amino acid mutations distributed in nsp1β, nsp2-nsp5, nsp7, nsp9, nsp10, GP4 and GP5 and the continuous 120 amino acid deletion in the nsp2 region from F19 provide a strong potential molecular basis for the observed attenuated phenotype.


Video-assisted thoracoscopic surgery for hydrothorax in peritoneal dialysis patients - check-air-leakage method.
Hydrothorax developing from pleuroperitoneal communication as a complication of peritoneal dialysis was first described in 1967 [Edward SR, Unger AM. Acute hydrothorax-a new complication of peritoneal dialysis. JAMA 1967; 199:853-5. ]. The incidence of hydrothorax is approximately 1.6-2% of continuous ambulatory peritoneal dialysis (CAPD) patients. The key to successful therapy is obliteration of the transdiaphragmatic route of dialysate leakage with video-assisted thoracoscopic surgery (VATS). The method in which air leakage is checked intraoperatively is the preferred choice and better than all other procedures.


Prevalence of depression in an elderly population in Finland.
The prevalence of depression by sex, age and certain sociodemographic variables was investigated in a sample of elderly Finns (60 years or over) living in the semi-industrialized municipality of Ahtäri (n = 1529). The study was carried out in two phases. In the first phase, depressive symptoms were screened with the Zung Self-rating Depression Scale (ZSDS). In the second phase, persons scoring greater than or equal to 40 points in the ZSDS and a random sample of persons scoring less than 40 ZSDS points were examined by a general practitioner. The prevalence of depression was determined on the basis of DSM-III criteria. The estimated prevalence for men was 22.4%, and for women 29.7%. The estimated prevalence for different categories of depression was as follows: dysthymic disorder, men 17.2% and women 22.9%; major depression, men 2.6% and women 4.5%; atypical depression, men 2.2% and women 2.5%; and cyclothymic disorder, men 0.4% and women 0%. No cases of bipolar disorder were found. A high risk of depression was associated with female sex, widowhood and being in long-term institutional care or receiving home nursing and/or home help. The occurrence of depression was not related to age, education or occupation.


Tutorial on large deviations for the binomial distribution.
We present, in an easy to use form, the large deviation theory of the binomial distribution: how to approximate the probability of k or more successes in n independent trials, each with success probability p, when the specified fraction of successes, a identical to k/n, satisfies 0 less than p less than a less than 1.


Diastereoselective one-pot Wittig olefination-Michael addition and olefin cross metathesis strategy for total synthesis of cytotoxic natural product (+)-varitriol and its higher analogues.
A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is detailed herein. The impressive biological activity and interesting structural features of natural (+)-varitriol fuelled us to undertake the synthesis of some higher analogues (1a-j) of this molecule. The key features of the synthetic strategy include one-pot Wittig olefination followed by a highly diastereoselective oxa-Michael addition to assemble stereochemically pure tetrasubstituted THF moiety of the natural varitriol and olefin cross metathesis to couple the aromatic part with tetrasubstituted THF moiety. The total synthesis of title natural product is efficient with 21.8% overall yield for 9 linear steps from D-ribose and thus facilitates the more scaled-up practical route for the synthesis of 1 and its analogues as well. The synthetic (+)-varitriol (1) and its analogues were screened for their cytotoxicity. The present synthetic approach paves the way for preparation of numerous analogues of the title natural product for drug development.


Prognostic relevance of androgen receptor detection in operable breast cancer.
Androgen receptor (AR) is relevant for prognostication in breast cancer. Different determination methods and cut-off levels hamper interpretation and comparisons of studies. Long-term prognostic evaluation of different AR assays in patients comprising operable breast cancers is scarce. AR was evaluated in 120 primary tumors using the dextran-coated charcoal method (charc-AR), and quantitative immunohistochemistry (IHC) on whole sections (WS) and tissue microarrays (TMA). Nuclear and cytoplasmic-AR localization was determined, and the prognostic importance of AR assays was assessed. Comparisons and correlations with the mitotic activity index (MAI), estrogen receptor (ERalpha), progesterone receptor (PR), HER-2, and histological grade (WHO I-III) were made. Nuclear-AR in WS, but not charc-AR, strongly correlated with MAI (P = 0.001). However, prognostic information appeared in univariate survival analyses only. Nuclear-AR in TMA was not prognostic. Charc-AR was independent prognostic in node positives both for relapse free survival (RFS) and breast cancer specific survival (BCSS). Both charc-AR and IHC cytoplasmic-AR provided independent prognostic survival information for BCSS in women <55 years. Methods that can detect AR localized in the cytoplasm yield important prognostic information, and further studies in patients with operable breast cancer are warranted.


Enzymatic synthesis of purine 2'-deoxyriboside and its properties as an inhibitor of adenosine deaminases from calf intestinal mucosa and Bacillus cereus.
Enzymatic synthesis of purine 2'-deoxyriboside was obtained by reacting purine with excess 2-deoxy-alpha-D-ribose-1-phosphate in the presence of commercial bovine nucleoside phosphorylase; the product was isolated by semipreparative reverse phase HPLC with an overall 62% yield. Purine 2'-deoxyriboside was shown to behave as a competitive inhibitor of adenosine deaminase from calf intestinal mucosa and Bacillus cereus, with apparent Ki values of 4.5 and 8.5 microM, respectively.


Does sex interact with the 2D:4D ratio or adult circulating hormones on the estimated glomerular filtration rate? A cross-sectional study in Ghana.
The 2D:4D ratio is the putative marker of prenatal hormone exposure and has been suggested as a correlate of adult circulating testosterone and estrogen. The study aimed to determine whether sexual dimorphism in the estimated glomerular filtration rate (eGFR) can be partly explained by the 2D:4D ratio or adult circulating testosterone or estrogen. The study was cross-sectional from June to December 2021 at the University for Development Studies. The study involved 206 healthy adults (Female = 93, Male = 113) between 18 and 30 years. The 2D:4D ratio was measured using computer-assisted analysis. Venous blood samples were collected and analyzed for testosterone, estradiol and creatinine using the ELISA technique and routine biochemical analysis. The adjusted eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (2021). The eGFR and the testosterone-to-estradiol ratio (TT:E2 ) were significantly higher in males than in females (p < 0.001). There was a significant interaction between sex and the TT:E2 on the eGFR (p < 0.001). Although the relationship between the eGFR and the TT:E2 was negative in both males and females, a unit change in the TT:E2 had a greater impact on the eGFR in females (B = -1.38) than in males (B = -0.01). Sexual dimorphism in the eGFR is influenced by both testosterone and estradiol. Although the sex difference in the eGFR may be influenced by the TT:E2 , estrogen seems to account for more variability in the eGFR than testosterone.


Changes in plasma concentrations of corticosterone and its precursors after ketoconazole administration in rats: An application of simultaneous measurement of multiple steroids using LC-MS/MS.
The adrenal gland is the most common toxicological target in the endocrine system, and inhibition of adrenal steroidogenesis by drugs can be fatal in humans. However, methods to evaluate the drug effect are limited. Recently, simultaneous measurement of multiple steroids, including precursors, has become possible. Here, we evaluated the usefulness of this simultaneous measurement for the evaluation of drug effects on adrenal steroidogenesis in vivo. For this purpose, we measured plasma concentrations of adrenal steroids in rats dosed with ketoconazole, a known inhibitor of adrenal steroidogenesis, and examined its relationship with the changes in histopathology and mRNA expression of steroidogenic enzymes in the adrenal gland. Ketoconazole (150mg/kg/day) was orally administered to male rats for 7 days. The adrenal weight was high, and the zona fasciculata/reticularis were hypertrophic with an accumulation of lipid droplets. mRNA expression of CYP11A1, a rate-limiting enzyme in adrenal steroidogenesis, was slightly high in the adrenal gland. Plasma concentration of deoxycorticosterone was markedly high, while there were no significant changes in that of corticosterone, progesterone, or pregnenolone. The changes in the adrenal gland and plasma concentration of steroids were thought to reflect inhibited metabolism of deoxycorticosterone to corticosterone through inhibition of CYP11B1, and compensatory reaction for the inhibition. The compensatory reaction was thought to have masked decrease of corticosterone. These results suggest that simultaneous measurement of multiple steroids can enable sensitive evaluation of drug effects on adrenal steroidogenesis in vivo, while providing insight into the underlying mechanism of the effect.


The gene and the RNA for the precursor to the plastid-located glycerol-3-phosphate acyltransferase of Arabidopsis thaliana.
The gene and the RNA from Arabidopsis thaliana for the plastid-located glycerol-3-phosphate acyltransferase (GPAT; EC 126.96.36.199) and their encoded product have been studied. The gene (designated ATS1) was isolated by screening a lambda DASH genomic library for cross-hybridization with a radiolabeled probe prepared from cDNA for GPAT from squash. cDNA clones representing the mRNA were isolated by screening a lambda ZAPII cDNA library for hybridization with a radiolabeled probe prepared from a DNA fragment of ATS1. The nucleotide sequences of the gene and the cDNA were determined, and the 5' end of the RNA was mapped by primer extension. Sequences similar to the TATA box, polyadenylation sequences and intron-splicing sequences were found at the expected locations. The pre-mRNA was 3288 nucleotides long and contained 5' and 3'-untranslated sequences of 57 and 442 nucleotides, respectively. The coding sequence of 1377 nucleotides was interrupted by 11 introns of 1412 nucleotides in total and the 3'-untranslated sequence contained another intron of 94 nucleotides. The open-reading frame encoded a polypeptide of 459 amino acid residues, the amino acid sequence of which was highly homologous to those of precursors to plastid-located GPATs from squash and pea. The enzymatic activity of a gene product that was over-produced in Escherichia coli confirmed the identity of the gene.


Activity-Friendly Built Environment Attributes and Adult Adiposity.
Physically-active and sedentary behaviors are determinants of adult weight gain and are associated with built-environment attributes. We reviewed recent evidence on built-environment attributes with adult adiposity. Of 41 relevant papers identified, 34 reported cross-sectional, six recorded prospective findings, and one included both cross-sectional and prospective designs. In 15 cross-sectional examinations of composite built environment indices (walkability; composite other), seven identified significant positive relationships in the expected direction; of 42 instances examining particular walkability elements (density, connectivity, land use mix), 13 were positive. Of 44 instances examining proximity of utilitarian and recreational destinations, there were 13 positive associations; and, of 41 instances examining pedestrian-environment attributes, 12 were positive. In the seven prospective studies, 20 sets of relationships were identified - nine were significant and in the expected direction. Evidence on built environment/adiposity relationships remains modest and could be strengthened through improvements in measurement methods and with further evidence from prospective studies.


Effectiveness of an alcohol-based hand hygiene programme in reducing nosocomial infections in the Urology Ward of Binh Dan Hospital, Vietnam.
To determine the effectiveness of hand hygiene in a developing healthcare setting in reducing nosocomial infections (NIs). Prospective study measuring NI rates in a urology ward in Ho Chi Minh City, Vietnam, before and after implementation of a hand hygiene programme with an alcohol-based decontaminant, and compliance rates of medical staff and carers with hand hygiene using standardised observation sheets. Incidence of NIs fell by 84%, from 13.1% to 2.1%, after implementation of the hand hygiene programme. Extended-spectrum beta-lactamase production was detected in 38.2%-50% of Enterobacteriaceae isolated from clinical samples. Length of patient stay and cost to the patient for antibiotics were reduced after implementation of the hand hygiene programme. The hand hygiene programme was effective in reducing incidence of NIs, leading to shorter inpatient stays and reduced treatment costs. Such programmes with measurable outcomes can be implemented at minimal cost in developing health contexts and should be promoted in all healthcare settings.


Two-year follow-up of percutaneous coronary intervention using EucaTax or Cypher.
The EucaTax stent (EUPES) is a coronary stent with biodegradable polymer and camouflage coating that has been developed to promote the complete elution of drugs and decrease the risk of late complications. The aim of this study was to evaluate the efficacy and safety of the double-coated EUPES in patients with stable angina versus sirolimus-eluting stent CYPHER (SES) with permanent polymer coating. The study included consecutive patient with at least 70% de novo coronary lesions in one or two native coronary arteries and who had undergone the coronary stenting using either EUPES or SES. We evaluated the 2-year major adverse cardiac events (MACE) rates, including total death (cardiac, non-cardiac), myocardial infarction (MI), target lesion revascularisation (TLR) and stent thrombosis. Between 2006 and 2009 this observational, prospective, single centre study included 602 patients (282 with EUPES and 320 with SES). At 2years, the rates of TLR (16.3% versus 6.25%; p=0.0001) and MACE (18.4% versus 7.8%; p=0.001) were significantly higher in the EUPES than in the SES group. The rate of TLR was significantly higher in the EUPES group compared with SES group in stenting of artery with a diameter less than 3mm, using stent length more than 18mm, as well as when the residual stenosis was more than 12%. We found that EUPES was inferior to SES during the 2-year follow-up with respect to rates of MACE and TLR that were significantly higher in the EUPES than in the SES group.


[Coercive measures in psychiatric clinics in Germany: current practice (2012)].
Due to the decisions of the German Constitutional Court on involuntary medication and the law on the prohibition of video surveillance in psychiatry in Nordrhine-Westfalia there has been an increasing discussion on coercive measures and how to conduct, supervise and prevent them. We conducted an online survey on the current practice of coercive measures in German psychiatric hospitals (2012). An online questionnaire was developed together with the working group for the prevention of violence and coercion in psychiatry and the regional association of psychiatry-experienced people in Baden-Wuerttemberg. The survey was conducted anonymously using the e-mail distribution lists of the psychiatric associations in Germany. A total of 88 questionnaires from hospitals with obligatory responsibility for a catchment area (19.7% of those addressed) could be analyzed. Of these 99% used internal or external guidelines, 97.5% conducted de-escalation training, 23% participated in external benchmarking on the use of coercive measures. All hospitals used mechanical restraint, approximately 50% seclusion and physical restraint was practiced in 7%. Most, but not all hospital directors reported that mechanical restraint and seclusion were continuously (24/7) monitored. Changes in practice in the years to come were expected by the majority. The survey revealed a high critical awareness concerning the use of coercive measures and the willingness to further change the practice.


Increased expression of PGRN protein in follicular fluid and mRNA in granulosa cells in overweight patients with polycystic ovary syndrome.
Obesity and low-grade chronic inflammation play critical roles in pathological process of PCOS. PGRN is an adipokine and was recently reported that it could induce a low-grade chronic inflammatory state and plays a functional role in insulin resistance associated with obesity. The overall goal of the present study was to evaluate the levels of PGRN in follicular fluid (FF) and the expression of PGRN in granulosa cells (GCs) with respect to the quality of the oocytes both in patients with PCOS and in the normal ovary during COH cycles. Ninety-two patients underwent IVF-ET were divided into four groups based on body mass index: normal-weight PCOS group; overweight PCOS group; non-overweight control group and overweight control group. FF samples and GCs were collected at the time of oocyte retrieval. The PGRN, TNF-α, IL-6 and MCP-1 levels were measured by ELISA, and the mRNA expression of PGRN in GCs was detected by real-time polymerase chain reaction. Analysis of PGRN expression revealed that PGRN levels in FF and the mRNA expression of PGRN in GCs were higher in patients with PCOS than in control patients, and higher in overweight patients than in the normal-weight patients; PGRN in FF of PCOS was positively correlate with basal testosterone and FF TNF-α,but negative correlation with retrieved oocytes number CONCLUSION: This study suggests that PGRN may be a crucial determinant of fertilization success for PCOS patients.


Periungual and subungual congenital melanocytic nevus on the foot: A rare case report.
A 5-year-old caucasian child is described with a congenital melanocytic periungual and subungual nevus on the right second toe. Histopathologic examination revealed a junctional nevus. Congenital subungual nevi in this location are rare. To the best of our knowledge, this represents the first case of lesion on the right second toe to be reported in the literature.


Biomarkers in Head and Neck Cancer an Update.
The study is aimed at establishing the purpose of tumour markers, their application, classification, diagnostic and therapeutic roles in the management of head and neck cancer. A literature review using Medline, Scopus, Google Scholar, the Cochrane Database of Systematic Reviews and the Cochrane central register of controlled trials for articles published between 1993 and 2016 on tumour markers and their role in head and neck cancer was performed. A broader search of prognostic markers in head and neck cancer was also carried out to avoid missing other pertinent markers. Natural history, tumour biology, stage and prognostic factors influence the outcome of management in patients with Head and Neck Squamous cell carcinoma (HNSCC). Evaluation of the cellular lineage and histogenic origin of diverse neoplasms can be done using tumour biomarkers. Identifying predictive tumour markers can lead to improvement in preventive management of HNSCC. There has been remarkable advancement in molecular technology with gene expression and proteomic profiling. Integration of specific tumour markers into routine clinical practice requires substantiation through well designed clinical trials. The investigation of tumour markers is imperative as they influence the prognosis of HNSCC and provide the potential to improve outcomes of treatment through targeted therapy. We have outlined recent tumour biomarkers in this review which have significant role in diagnosis, screening and prognostication in HNSCC. Recent advancement in clinical applications, therapeutic strategies of tumour markers has been highlighted.


A FORTRAN technique for correlating a circular environmental variable with a linear physiological variable in the sugar maple.
This paper deals with a computer program adapted to a statistical method for analyzing an unlimited quantity of binary recorded data of an independent circular variable (e.g. wind direction), and a linear variable (e.g. maple sap flow volume). Circular variables cannot be statistically analyzed with linear methods, unless they have been transformed. The program calculates a critical quantity, the acrophase angle (PHI, phi o). The technique is adapted from original mathematics [1] and is written in Fortran 77 for easier conversion between computer networks. Correlation analysis can be performed following the program or regression which, because of the circular nature of the independent variable, becomes periodic regression. The technique was tested on a file of approximately 4050 data pairs.


Comparison of chlortenoxicam and indomethacin on frusemide-induced diuresis.
A single oral dose of chlortenoxicam 4 mg, a new non-steroidal anti-inflammatory drug, significantly antagonized the diuretic and natriuretic actions of frusemide when compared with placebo in normal human volunteers. Indomethacin 50 mg significantly reduced the natriuretic, but not diuretic action of frusemide.


Continuity and change within an HIV epidemic. Injecting drug users in New York City, 1984 through 1992.
To examine trends in acquired immunodeficiency syndrome (AIDS) risk behavior and human immunodeficiency virus (HIV) seroprevalence among injecting drug users (IDUs) in New York City from 1984 through 1992. Comparisons were made between two surveys of IDUs at the same hospital-based New York City drug abuse detoxification program: 141 IDUs in 1984 and 974 IDUs in 1990 through 1992. National Death Registry, New York City Health Department, and drug treatment program records were also used. Persons attending detoxification program randomly selected for participation. Eligibility was based on injection within previous 2 months; 99% acceptance rates were obtained. Participants in the 1984 and 1990 through 1992 surveys were 66% and 79% men, 21% and 19% white, 33% and 34% African American, and 45% and 46% Latin American, respectively. Community-based AIDS prevention programs, including underground syringe exchanges. Acquired immunodeficiency syndrome risk behaviors; HIV serostatus; CD4+ cell counts; death rates among 1984 subjects; and injection and intranasal routes of drug administration. The HIV seroprevalence remained stable at slightly more than 50%. Mean CD4+ cell counts declined from 0.716 x 10(9)/L (716/microL) to 0.575 x 10(9)/L (P < .009). Annual death rate among 1984 subjects was 3%, with a significantly higher rate among HIV-seropositive subjects (relative risk, 2.57; 95% exact binomial confidence interval, 1.12 to 6.61). Large-scale declines were observed in AIDS risk behaviors, eg, use of potentially contaminated syringes declined from 51% to 7% of injections (P < .001). Recent additional risk reduction was associated with use of the underground syringe exchanges. Intranasal heroin use was the primary route of drug administration for 46% of heroin admissions to New York City drug treatment programs. The HIV seroprevalence has remained stable among this population of New York City IDUs for almost a decade. Continuation of current trends should lead to further reduction in HIV transmission, although reversal of the trend to intranasal use could lead to substantially increased transmission.


Peroxynitrite-dependent zinc release and inactivation of guanosine 5'-triphosphate cyclohydrolase 1 instigate its ubiquitination in diabetes.
Aberrant degradation of guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) with consequent deficiency of tetrahydrobiopterin is considered the primary cause for endothelial dysfunction in diabetes. How GTPCH1 becomes susceptible to the degradation remains unknown. We hypothesized that oxidation and release of the zinc ion by peroxynitrite (ONOO(-)), a potent oxidant generated by nitric oxide and superoxide anions, instigates GTPCH1 ubiquitination and degradation. Zinc contents, GTPCH1 ubiquitination, and GTPCH1 activity were assayed in purified GTPCH1, endothelial cells, and hearts from diabetic mice. Exogenous ONOO(-) dose-dependently released zinc, inhibited its activity, and increased the ubiquitin binding affinity of GTPCH1 in vitro and in endothelial cells. Consistently, high glucose (30 mmol/L) inhibited GTPCH1 activity with increased ubiquitination, which was inhibited by antioxidants. Furthermore, mutation of the zinc-binding cysteine (141) (C141R or C141A) significantly reduced GTPCH1 activity and reduced its half-life but increased GTPCH1 ubiquitination, indicating an essential role of the zinc ion in maintaining the catalytic activity and stability of GTPCH1. Finally, GTPCH1 ubiquitination and degradation markedly increased in parallel with decreased GTPCH1 activity in the aortas and hearts of diabetic mice, both of which were attenuated by the inhibitors of ONOO(-) in mice in vivo. Taken together, we conclude that ONOO(-) releases zinc and inhibits GTPCH1, resulting in its ubiquitination and degradation of the enzyme.


NMDA receptor antagonism does not inhibit induction of ischemic tolerance in gerbil brain in vivo.
Effects of high and moderate affinity uncompetitive NMDA receptor antagonists (+)MK-801 and memantine on ischemic tolerance were compared in relation to telemetrically controlled brain temperature. The tolerance to an injurious 3 min test of global forebrain ischemia in Mongolian gerbils was induced 48 h earlier by 2 min preconditioning ischemia. Normothermic preconditioning was virtually harmless, and greatly reduced neurodegeneration evoked by test ischemia. In hyperthermic animals it was injurious and failed to induce tolerance. Memantine (5 mg/kg) and (+)MK-801 (3 mg/kg) injected i.p. 1 h before preconditioning did not inhibit ischemic tolerance in the normothermic gerbils, while in hyperthermic animals treated with (+)MK-801 ischemic tolerance was partially restored. Subchronic 3 day infusion of memantine (30 mg/kg/day) significantly decreased neurodegeneration, and preconditioning in the normothermic gerbils further reduced neuronal damage. Hyperthermia exacerbated preconditioning ischemia and in this way reduced expression of tolerance, while (+)MK-801 partially reversed this effect. Our results do not confirm previous reports on the role of NMDA receptors in the induction of ischemic tolerance in gerbils.


Comparison of the haematoxylin basic fuchsin picric acid method and the fluorescence of haematoxylin and eosin stained sections for the identification of early myocardial infarction.
A retrospective study has been carried out on the necropsy material from 30 patients who have died after a clinically diagnosed myocardial infarction. This study has been undertaken to compare the reliability of the fluorescence of infarcted myocardium when stained by haematoxylin and eosin and an adjacent section stained by the haematoxylin basic fuchsin picric acid (HBFP) method to detect early ischaemia. The results showed that the fluorescence technique is reliable, reproducible and coincides with the findings obtained by HBFP stain.


Noradrenergic mediation of the positive reinforcing properties of ethanol: II. Extinction of ethanol-drinking behavior in laboratory rats by inhibition of dopamine-beta-hydroxylase. Implications for treatment procedures in human alcoholics.
Following stabilization of consumption of a 15% (v/v) ethanol solution in a free-choice with water, rats were presented with a forced-choice of ethanol for 10 consecutive alternate days. Prior to each forced-choice presentation experimental animals were injected with the non-toxic dopamine-beta-hydroxylase inhibitor FLA-57 (30 mg/kg i.p.) while control animals received only vehicle injections. At the termination of the injection phase when ethanol was again made available in a free-choice with water, ethanol consumption for the FLA-57 treated animals was markedly suppressed. These data are interpreted in terms of extinction resulting from the procedure whereby performance of the ethanol drinking response was perpetuated by force with the pharmacological reinforcing properties being blocked by FLA-57-induced depletions of norepinephrine. Applications of these procedures in the treatment of human alcoholics are discussed.


CXCL10 alters the tumour immune microenvironment and disease progression in a syngeneic murine model of high-grade serous ovarian cancer.
We recently established that high STAT1 expression and associated T helper type I tumour immune microenvironment (TME) are prognostic and chemotherapy response predictive biomarkers in high-grade serous ovarian cancer (HGSC). STAT1 induced chemokine CXCL10 is key to the recruitment of lymphocytes in the TME and is significantly highly expressed in the tumours from patients with longer survival. In the current study we therefore aimed to elucidate the role CXCL10 in disease progression and tumour immune transcriptomic alterations using the ID8 syngeneic murine model of HGSC. ID8 ovarian cancer cells were engineered for stable knockdown (KD) and overexpression (OX) of CXCL10. The OX and KD cell line derivatives, along with their respective vector controls, were implanted in immunocompetent C57BL/6 mice via intra-peritoneal injections. At end point, immune transcriptomic profiling of tumour tissues and multiplex cytokine profiling of ascites, was performed. Effect of CXCL10 expression on the tumour vasculature and tumour cell proliferation was evaluated by CD31 and Ki67 immunostaining, respectively. Increased CXCL10 expression led to decreased tumour burden and malignant ascites accumulation in the ID8 syngeneic murine model of HGSC. The ascites levels of IL-6 and VEGF were significantly reduced in OX mice compared to the vector controls. The OX tumours also showed reduced vasculature (CD31) and proliferative index (Ki67) compared to the control tumours. Significantly higher expression of genes associated with antigen processing, apoptosis and T cell function was observed in OX tumours compared to the controls. Reduced CXCL10 expression in tumours from KD mice led to increased ascites accumulation and disease progression compared to the controls. CXCL10 is a positive determinant of anti-tumour immune responses in HGSC TME and disease progression. These findings are foundational for future translational studies aimed at improving treatment response and survival in HGSC patients, via exploiting the TME.


A simplified cardiac damage staging predicts the outcome of patients undergoing TAVR-A multicenter analysis.
A significant number of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) suffer from extra-aortic cardiac damage. Few studies have investigated strategies to quantify cardiac damage and stratify patients accordingly in different risk groups. The aim of this retrospective multicenter study was to provide a user-friendly simplified staging system based on the proposed classification system of Généreux et al. as a tool to evaluate the prognosis of patients undergoing TAVR more easily. Moreover, we analyzed changes in cardiac damage after TAVR. We assessed cardiac damage in patients, who underwent TAVR at the Heart Center Bonn or Düsseldorf, using pre- and postprocedural transthoracic echocardiography. Patients were assigned to the staging system proposed by Généreux et al. according to the severity of their baseline cardiac damage. Based on the established system, we created a simplified staging system to facilitate improved applicability. Finally, we compared clinical outcomes between the groups and evaluated changes in cardiac damage after TAVR. A total of 933 TAVR patients were included in the study. We found a significant association between cardiac damage and 1-year all-cause mortality (stage 0: 0% vs. stage 1: 3% vs. stage 2: 6.6%; p < 0.009). In multivariate analysis, cardiac damage was an independent predictor of 1-year all-cause mortality (hazard ratio: 2.0, 95% confidence interval: 1.1-3.8; p = 0.03). In patients undergoing TAVR, cardiac damage is associated with enhanced mortality. A simplified staging system can help identify patients at high risk for an adverse outcome.


The potential of cystatin C as a predictive biomarker in pulmonary hypertension.
Cystatin C is a novel biomarker to identify renal dysfunction and cardiovascular risk. The aim of this study was to investigate the role of cystatin C in non-invasive risk prediction in a large cohort of patients with pre-capillary pulmonary hypertension (PH). We retrospectively analyzed pre-capillary PH patients with available cystatin C and hemodynamic data derived from right heart catheterization. A total of 398 consecutive patients with confirmed pre-capillary PH were recruited from Fuwai Hospital between November 2020 and November 2021. Over a median duration of 282 days, 72 (18.1%) of these patients experienced clinical worsening. Cystatin C levels significantly correlated with cardiac index (r = -0.286, P < 0.001), mixed venous oxygen saturation (r = -0.216, P < 0.001), and tricuspid annular plane systolic excursion (r = -0.236, P < 0.001), and high cystatin C levels independently predicted a poor prognosis after adjusting potential confounders in different models (all P < 0.05). A three-group non-invasive risk model was constructed based on the combined assessment of the cystatin C and WHO-FC using dichotomous cut-off value. Those patients with higher cystatin C (≥ 1.0 mg/L) and a worse WHO-FC experienced the highest risk of endpoint occurrence. The predictive capacity of this model was comparable to that of an existing invasive risk stratification model (area under curve: 0.657 vs 0.643, P = 0.619). Cystatin C levels were associated with disease severity and prognosis in patients with pre-capillary PH. A combination of high cystatin C and advanced WHO-FC identifies patients at particularly high risk of clinical deterioration.


Statistical geometry approach to the study of functional effects of human nonsynonymous SNPs.
The ability to predict the effect of nonsynonymous SNPs (nsSNPs) on protein function is important for the success of genetic disease association studies. Here we present a statistical geometry approach to nsSNP classification based on Delaunay tessellation, whereby the impact of nsSNPs on protein function is correlated with the change in the four-body statistical potential (DeltaQ) of the protein caused by the amino acid substitution. We observed that the DeltaQ of polymorphic proteins with disease-associated nsSNPs (daSNPs) was on average significantly lower than the DeltaQ of the proteins with neutral SNPs (ntSNPs). Clustering amino acid substitutions into conservative and nonconservative groups, and using a three-letter alphabet based on side-chain polarity showed significantly lower DeltaQ in nonconservative changes to daSNPs and when hydrophobic residues were substituted by charged or by polar residues. We also found that the daSNPs in the protein core caused much lower DeltaQ than surface daSNPs. This approach demonstrates a strong correlation between the computed DeltaQ and SNP classification. Integration of our approach with the existing models will help achieve a more precise recognition of nsSNPs that underlie polygenic diseases. All of the programs were written in Java and are available from the authors upon request.


Nutritional considerations in children undergoing bone marrow transplantation.
Bone marrow transplantation is often associated with multiple organ failure which is usually reversible. Oral mucositis and dysphagia, vomiting, diarrhoea, protein losing enteropathy, transient exocrine pancreatic impairment, hypoalbuminaemia, biochemical trace element and mineral deficiencies are all common following transplantation and have profound nutritional consequences. Malnutrition affects negatively the clinical outcome. Nutritional support is provided to malnourished patients and those who suffer deterioration in nutritional status despite the provision of dietetic counselling. Only a few randomised studies comparing enteral with parenteral nutrition after transplant exist. Both enteral tube feeding (in the absence of mucositis) and parenteral nutrition are effective in maintaining nutritional status. However, enteral nutrition is associated with a better nutritional response and fewer complications than parenteral. With existing enteral and parenteral nutrition regimens close monitoring of trace element and mineral status is required.


Loss of TSC2 confers resistance to ceramide and nutrient deprivation.
Nutrient stress that produces quiescence and catabolism in normal cells is lethal to cancer cells, because oncogenic mutations constitutively drive anabolism. One driver of biosynthesis in cancer cells is the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Activating mTORC1 by deleting its negative regulator tuberous sclerosis complex 2 (TSC2) leads to hypersensitivity to glucose deprivation. We have previously shown that ceramide kills cells in part by triggering nutrient transporter loss and restricting access to extracellular amino acids and glucose, suggesting that TSC2-deficient cells would be hypersensitive to ceramide. However, murine embryonic fibroblasts (MEFs) lacking TSC2 were highly resistant to ceramide-induced death. Consistent with the observation that ceramide limits access to both amino acids and glucose, TSC2(-/-) MEFs also had a survival advantage when extracellular amino acids and glucose were both reduced. As TSC2(-/-) MEFs were resistant to nutrient stress despite sustained mTORC1 activity, we assessed whether mTORC1 signaling might be beneficial under these conditions. In low amino acid and glucose medium, and following ceramide-induced nutrient transporter loss, elevated mTORC1 activity significantly enhanced the adaptive upregulation of new transporter proteins for amino acids and glucose. Strikingly, the introduction of oncogenic Ras abrogated the survival advantage of TSC2(-/-) MEFs upon ceramide treatment most likely by increasing nutrient demand. These results suggest that, in the absence of oncogene-driven biosynthetic demand, mTORC1-dependent translation facilitates the adaptive cellular response to nutrient stress.


Characteristics of gonorrhea and syphilis cases among the Roma ethnic group in Belgrade, Serbia.
The Roma ethnic group is the largest and most marginalized minority in Europe, believed to be vulnerable to sexually transmitted infections. The purpose of the study was to investigate frequency and characteristics of gonorrhea and syphilis among the Roma population in Belgrade. Data from the City Institute for Skin and Venereal Diseases to which all gonorrhea and syphilis cases are referred were analyzed. During the period of 2010-2014 sexually transmitted infections were more frequent among Roma than in rest of Belgrade population. Average percentages of Roma among all reported subjects with syphilis and those with gonorrhea were 9.6% and 13.5%, respectively, while the percentage of Roma in the total Belgrade population was about 1.6%. Roma with syphilis and gonorrhea were more frequently men (75%), most frequently aged 20-29 years (43.4%), never married (64.5%), with elementary school or less (59.2%), unemployed (80.3%), and heterosexual (89.5%). Among Roma 10.5% were sex workers and 68.4% did not know the source of their infection. Significant differences between Roma cases and other cases in Belgrade in all characteristics observed were in agreement with differences between Roma population and the total population of Serbia. The present study confirmed the vulnerability of the Roma population to sexually transmitted infections.


Heat shock proteins in mammalian development.
Mammalian development follows a defined but adjustable program, depending on the plasticity of embryonic cells 'response to environmental changes. Heat shock proteins (Hsp) are integral part of this developmental program and gene targeting experiments have started to unravel developmental processes, which exhibit specific requirements for Hsps (e.g. Hsp70.2 for spermatogenesis). In the present paper, we will review available data on Hsp function and discuss the roles of heat shock factors (HSF), their major regulators, in mammalian development.


Cerebral metabolic changes in a depression-like rat model of chronic forced swimming studied by ex vivo high resolution 1H magnetic resonance spectroscopy.
Many previous in vivo (1)H magnetic resonance spectroscopy (MRS) studies have shown that patients with major depressive disorder (MDD) are associated with perturbations of cerebral metabolism of neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA). In this study, we investigated the changes of cerebral metabolism in a depression-like rat model of chronic forced swimming stress (CFSS). The aims are to further understand the pathophysiological mechanisms underlying CFSS treatment, and to further establish the face and predictive validity of the CFSS model. The results showed that, relative to control, the CFSS rats had significantly reduced Glu, taurine and glutamate + glutamine (Glx) levels in the PFC, and significantly reduced N-acetyl aspartate (NAA) level, Glu level and Glu/GABA ratio in the hippocampus. Taking together, these results suggest that CFSS treatment can induce region-specific changes in the metabolism of Glu. The CFSS model might be used to study antidepressants specifically targeting the central glutamatergic system.


Agrobacterium tumefaciens-Mediated Stable Transformation of Daucus carota.
Daucus carota L. (carrot) is one of the ten most important vegetables cultivated and consumed worldwide and is a main source of provitamin A. Carrot storage root is rich in dietary fiber, antioxidants, and other nutrients but especially in carotenoids. It has been also used as plant model for studding embryogenesis, as well as the genetic and genomic evolution of carrots and for carotenoid synthesis regulation, among others. Research in carrot often needs genetic transformation. Here we describe a step-by-step protocol on the nuclear and stable transformation of carrot through Agrobacterium tumefaciens and somatic embryogenesis in vitro culture. Somatic embryos, induced by supplementation of Murashige-Skoog medium with the 2,4D hormone, develop into seedlings after 6 months approximately when plants are ready to be transferred to a greenhouse. The protocol has over 85% of transformation efficiency.


Further evidence for a major ancient mutation underlying myotonic dystrophy from linkage disequilibrium studies in the Japanese population.
The myotonic dystrophy (DM) mutation is an unstable (CTG)n repeat, present at a copy number of 5-37 repeats on normal chromosomes but amplified to 50-3000 copies on DM chromosomes. Previous findings in Caucasian populations of a DM founder chromosome raise a question about the molecular events involved in the expansion mutation. To investigate whether a founder chromosome for the DM mutation exists in the Japanese population, we genotyped families using polymorphic markers near the (CTG)n repeat region and constructed haplotypes. Six different haplotypes were found and DM alleles were always haplotype A. To find an origin of the (CTG)n repeat mutation and to investigate the mechanism of the expansion mutation in the Japanese population we have studied 90 Japanese DM families comprising 190 affected and 130 unaffected members. The results suggest that a few common ancestral mutations in both Caucasian and Japanese populations have originated by expansion of an ancestral n = 5 repeat to n = 19-37 copies. These data support multistep models of triplet repeat expansion that have been proposed for both DM and Friedreich's ataxia.


Suicidal ideation in Chinese adults with schizophrenia: associations with neurocognitive function and empathy.
Suicidal ideation is common among people diagnosed with schizophrenia spectrum disorders and may be related to neurocognitive, social cognitive, and clinical variables. This study aimed to investigate the relationships between suicidal ideation and both neurocognitive function and empathy. The sample for this cross-sectional study comprised 301 schizophrenic patients aged 18-44 years. All participants were administered the Beck Scale for Suicide Ideation-Chinese Version (BSI-CV), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Interpersonal Reactivity Index (IRI), and the Positive and Negative Syndrome Scale (PANSS). The demographic and clinical data of the patients were also collected. In total, 82 patients reported suicidal ideation. Compared to patients without suicidal ideation, patients with suicidal ideation showed significant differences in the IRI-Personal Distress subscale, PANSS-General Psychopathology symptom scores, and suicide attempts. Moreover, there were moderating effects of neurocognitive function and empathy on the relationship between suicide attempts and suicidal ideation. These results indicate that the personal distress component of empathy, general psychopathology symptoms and suicide attempts are independent risk factors for suicidal ideation in Chinese adults with schizophrenia. Moreover, neurocognitive function may also be related to suicidal ideation through a moderating relationship. In order to reduce suicidal ideation among patients with schizophrenia, early screening of empathy and neurocognitive function is essential.


Topical anti-inflammatory activity of Solenostemma argel leaves.
The topical anti-inflammatory activity of Solenostemma argel Hayne leaves was evaluated using the Croton oil ear test in mice. A bioassay-guided fractionation procedure led to a highly active chloroform extract: at 300 microg/cm(2), it induced 73% oedema reduction, while the reference drug indomethacin (100 microg/cm(2)) induced 56% reduction. The extract contained a new pregnene glycoside (1, solenoside A) and the known 14 beta,15 alpha-dihydroxy-Delta(4)pregnene-3,20 dione (2), kaempferol-3-O-glucoside (3) and kaempferol-3-O-rutinoside (4). Their structures were determined by ID and 2D NMR experiments as well as HRMS. Compounds 2 and 4 showed anti-inflammatory activity comparable to that of indomethacin.


Amyloid deposition in the nucleus basalis of Meynert complex: a topographic marker for degenerating cell clusters in Alzheimer's disease.
The deficiency of the cholinergic cortical projection system arising in the different basal forebrain structures collectively referred to as nucleus basalis of Meynert complex is a constant finding in Alzheimer's disease, a disorder which is neuro-pathologically characterised by the appearance of three intracerebral formes of twisted beta-pleated sheet (amyloid) fibrils, neurofibrillary tangles, amyloid-containing neuritic plaques and congophilic amyloid angiopathy. In the present study the quantitative relationship between these hallmarks of the disease, amyloid deposition and neuronal loss in the cholinergic basal forebrain system, was investigated in ten cases of Alzheimer's disease. Besides a constant involvement of the cerebral cortex and hippocampus, all cases of Alzheimer's disease show a large amount of amyloid in the medial septal nucleus, in the diagonal band nucleus and in the substantia innominata which is correlated with neuronal loss in these areas. These amyloid deposits in the basal forebrain are due to congophilic angiopathy associated with plaques and neurofibrillary tangles. The distribution of amyloid deposition in the basal forebrain is restricted entirely to those neuronal clusters which represent the origin of cholinergic innervation of the cerebral cortex and hippocampus. Immediately adjacent structures are not affected. These findings suggest a pathogenetic role of amyloid deposition in the mechanism of degeneration of the cholinergic basal forebrain system.


Using Ubiquitin Binders to Decipher the Ubiquitin Code.
Post-translational modifications (PTMs) by ubiquitin (Ub) are versatile, highly dynamic, and involved in nearly all aspects of eukaryote biological function. The reversibility and heterogeneity of Ub chains attached to protein substrates have complicated their isolation, quantification, and characterization. Strategies have emerged to isolate endogenous ubiquitylated targets, including technologies based on the use of Ub-binding peptides, such as tandem-repeated Ub-binding entities (TUBEs). TUBEs allow the identification and characterization of Ub chains, and novel substrates for deubiquitylases (DUBs) and Ub ligases (E3s). Here we review their impact on purification, analysis of pan or chain-selective polyubiquitylated proteins and underline the biological relevance of this information. Together with peptide aptamers and other Ub affinity-based approaches, TUBEs will contribute to unraveling the secrets of the Ub code.


Nucleoside transport in mammalian cell membranes. III. Kinetic and chemical modification studies of cytosine-arabinoside and uridine transport in hamster cells in culture.
Transport of the nucleoside analog cytosine-arabinoside (CAR) in transformed hamster cells in culture has been studied in conditions of minimal metabolic conversion. Uptake (zero-trans in) properties at 20 degrees C over a limited range of CAR concentrations were characterized by a Km of 350 micrometer and a maximal velocity (V) of 780 micrometer.min-1 (V/Km = 2.28 min-1). Equilibrium exhcange at 20 degrees C over a wider range of concentrations was best described by a saturable component with a Km of 500 micrometer and a v of 1230 micrometer.min-1 (V/Km = 2.26 min-1) and either a saturable component of high Km or a nonsaturable component of k = 0.3 min-1. For the saturable component, the v/Km values were similar in both procedures. CAR transport was inhibited by various metabolizable nucleosides. Uptake of some of these nucleosides was inhibited by CAR. CAR transport and uridine uptake were inhibited in a reversible but partially competitive fashion by high affinity probes like S-(p-nitrobenzyl-6-mercaptoinosine (NBMI) (Ki less than 0.5 nM) and in an irreversible fashion by SH reagents such as N-ethylmaleiimide (NEM). The organomercurial p-hydroxymercuribenzene sulfonate (pMBS) markedly stimulated transport of these nucleosides, but also markedly potentiated the inhibitory effects of either NBMI or NEM. The effects are interpreted either in terms of models which invoke allosteric properties or in terms of two transport systems which display distinct chemical susceptibilities to externally added probes.


Evaluation of the analgesic effect of vertebral cancellous bone infiltration anaesthesia during vertebroplasty.
To evaluate the analgesic effect of vertebral cancellous bone infiltration anaesthesia during percutaneous vertebroplasty (PVP). Patients treated with vertebral cancellous bone infiltration anaesthesia (intervention group) or local anaesthesia alone (control group) during PVP at our institution during 2016-2018 were reviewed. The visual analogue scale (VAS) score before the operation, during establishment of the puncture channel, during pressure changes in the vertebral body (e.g., when removing or inserting pushers or needle cores), during bone cement injection, immediately after the operation, and at 2 h and 1 day postoperatively were compared between the groups. The patient's satisfaction with the operation was recorded and compared between groups. A total of 112 patients were enrolled (59 cases in the intervention group and 53 cases in the control group). There was no difference in the VAS score between the groups before the operation or during establishment of the intraoperative puncture channel (P > 0.05). The VAS score in the intervention group was significantly lower than that in the control group during pressure changes in the vertebral body (removal or insertion of puncture needle cores or pushers) and bone cement injection (P < 0.05). Immediately after the operation and at 2 h postoperatively, the pain in the intervention group was also significantly lower than that in the control group (P < 0.05), but there was no significant difference between the groups at 1 day postoperatively (P > 0.05). The patient satisfaction rate was 88% (52/59) in the intervention group and 67% (35/53) in the control group (P < 0.05). Vertebral cancellous bone infiltration anaesthesia may effectively relieve intraoperative pain and improve the surgical experience of patients without affecting the clinical effect of surgery.


Empagliflozin ameliorates diabetic cardiomyopathy via regulated branched-chain amino acid metabolism and mTOR/p-ULK1 signaling pathway-mediated autophagy.
Empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), has been reported to significantly reduce the risk of heart failure in multiple clinical studies. However, the underlying mechanisms remain elusive. This study aimed to investigate the effect of empagliflozin on branched-chain amino acid (BCAA) metabolism in diabetic cardiomyopathy. Thirty male 8-week KK Cg-Ay/J mice were used to study diabetic cardiomyopathy; here, 15 were used as the model group, and the remaining 15 were administered empagliflozin (3.75 mg/kg/day) by gavage daily for 16 weeks. The control group consisted of fifteen male 8-week C57BL/6J mice, whose blood glucose and body weight were measured simultaneously with the diabetic mice until 16 weeks without additional intervention. Echocardiography and histopathology were performed to evaluate cardiac structure and function. Proteomic sequencing and biogenic analysis were performed on mouse hearts. Parallel Reaction Monitoring and western blotting were performed to validate the expression levels of differentially expressed proteins. The results showed that empagliflozin improved ventricular dilatation and ejection fraction reduction in diabetic hearts, as well as the elevation of myocardial injury biomarkers hs-cTnT and NT-proBNP. At the same time, empagliflozin alleviates myocardial inflammatory infiltration, calcification foci deposition, and fibrosis caused by diabetes. The results of the proteomics assay showed that empagliflozin could improve the metabolism of various substances, especially promoting the BCAA metabolism of diabetic hearts by up-regulating PP2Cm. Furthermore, empagliflozin could affect the mTOR/p-ULK1 signaling pathway by reducing the concentration of BCAA in diabetic hearts. When mTOR/p-ULK1 protein was inhibited, ULK1, the autophagy initiation molecule, increased. Moreover, autophagy substrate p62 and autophagy marker LC3B were significantly reduced, indicating that the autophagy activity of diabetes inhibition was reactivated. Empagliflozin may attenuate diabetic cardiomyopathy-related myocardial injury by promoting the catabolism of BCAA and inhibiting mTOR/p-ULK1 to enhance autophagy. These findings suggest that empagliflozin could be a potential candidate drug against BCAA increase and could be used for other cardiovascular diseases with a metabolic disorder of BCAA.


Bone marrow-derived mesenchymal stem cells promote hepatic regeneration after partial hepatectomy in rats.
Our goal was to study the ability of mesenchymal stem cells (MSCs) to stimulate liver regeneration after partial hepatectomy in rats. MSCs were isolated from bone marrow and cultured in vitro. Their characteristics were analyzed by flow cytometry. After 70% partial hepatectomy, Sprague-Dawley rats were randomly divided into three groups: a control group that was injected with saline, animals that received bone marrow-derived MSCs (BM-MSCs) by tail vein injection (the BM-MSC-TV group) and animals that received BM-MSCs by portal vein injection (the BM-MSC-PV group). The injected BM-MSCs were traced by labeling with 4',6-diamidino-2-phenylindole, and cell proliferations were determined by immunohistochemical staining with Ki-67 and 5-bromo-2'-deoxyuridine. After the third passage, the cultured BM-MSCs had a fibroblast-like morphology and expressed high levels of stem cell markers CD29 and CD90. The levels of albumin rose significantly in the BM-MSC-TV and BM-MSC-PV groups compared with the control group. The number of 4',6-diamidino-2-phenylindole-positive liver cells in the BM-MSC-PV group was significantly higher than in the BM-MSC-TV group. The levels of Ki-67 and 5-bromo-2'-deoxyuridine were significantly higher in the BM-MSC-TV and the BM-MSC-PV groups than in the controls. Taken together, these results indicate that BM-MSC injections enhance liver regeneration after partial hepatectomy in rats.


Molecular switches in troponin.
The contraction of vertebrate striated muscle contraction, and hence its work output, is controlled by Ca2+, which binds to troponin (Tn) associated with tropomyosin (TM) and actin in the thin filaments. Tn consists of three subunits: TnC, the Ca(2+)-receptor; TnI, an inhibitor of actomyosin activity; and TnT, anchoring Tn to TM. Of the four Ca(2+)-binding sites, I and II in the N-terminal domain are Ca-specific sites, while sites III and IV, the high affinity Ca-Mg sites, are in the C-domain. The former are recognized as the functionally important triggering sites. TnC, whose structure has been solved by X-ray crystallography and recently by high-resolution NMR, contains two homologous globular domains connected by an unusual single alpha-helix. The C-terminal domain exhibits an open hydrophobic area regardless of whether Ca2+ or Mg2+ is bound to sites III and IV. In contrast, the N-terminal domain is a closed structure that opens a hydrophobic patch upon Ca(2+)-binding to its two "triggering" sites producing a TnI binding area. Crosslinking and fragment binding studies indicate that, in the main, the two polypeptide chains run in opposite directions in the complex of TnC with Tn. A model of TnC-TnI interactions based on low angle X-ray and neutron scattering is discussed in light of biochemical and other physico-chemical studies. The opening of the structure in the N-terminal domain of TnC may be regarded as a molecular switch. It activates a molecular switch in TnI, reflected in the movement of portions of its C-terminal half, including Cys 133, away from actin and closer to TnC, as well as other structural changes in TnI. Finally the role of TnT in switching and transmitting the Ca(2+)-signal is discussed.


Fibrosis-associated gene expression in renal transplant glomeruli after acute renal allograft rejection.
Acute allograft rejection is thought to be a risk factor for chronic allograft nephropathy, the cardinal features of which are vasculopathy, interstitial fibrosis and glomerulosclerosis. Fibrosis-associated genes might act as ad interim surrogate markers for chronic allograft nephropathy. The aim of this study was to determine mRNA expression of fibrosis-associated genes in glomeruli plucked from protocol renal transplant biopsies, in patients with or without a history of acute rejection. A consecutive series of 52 patients (31 male, 21 female) was assessed. Donor categories were cadaveric, living related or asystolic. Transplant recipients received either cyclosporin- or tacrolimus-based immunosuppression. Patients routinely underwent percutaneous needle-core renal transplant biopsy at 1 week, and 3 and 6 months. Acute rejection episodes were confirmed histologically and treated with intravenous methylprednisolone, or antithymocyte globulin if steroid resistant. Individual glomeruli were plucked and total mRNA was extracted. Fibrosis-associated genes were amplified by reverse transcriptase-polymerase chain reaction (PCR) and quantified by enzyme-linked immunosorbent assay. The expression of both collagen type III (mean 0.42 versus 0.31 arbitrary units of PCR products corrected for a housekeeping gene) and collagen IV (mean 0.46 versus 0.42 arbitrary units) at 6 months did not differ between recipients who experienced acute rejection episodes and those who were free from rejection. There was also no significant difference between groups in terms of mRNA expression of collagen IValpha2, matrix metalloproteinase 2, tissue inhibitor of matrix metalloproteinases 1 and 2, transforming growth factor beta or tenascin. These results suggest that acute rejection episodes do not increase the expression of fibrosis-associated genes in glomeruli from renal transplant biopsies.


Nicotine exposure during a postnatal critical period alters NR2A and NR2B mRNA expression in rat auditory forebrain.
Chronic nicotine exposure (CNE) can alter brain development and is thought to produce deficits in auditory function. Previously, we found that CNE during the second postnatal week, but not before or after, increases the duration of excitatory postsynaptic potentials (EPSPs) mediated by N-methyl-D-aspartate receptors (NMDARs) in rat auditory cortex. It was proposed that a potential mechanism underlying increased EPSP duration could be over-stimulation of presynaptic nicotinic acetylcholine receptors, leading to prolonged glutamate release. Since glutamatergic activity regulates levels of postsynaptic NMDAR subunits, here we examine the effects of CNE on mRNA expression for the NR2A and NR2B subunits in auditory cortex and thalamus. Two days of CNE (postnatal days 8-9), produced no effects, but 5 days (postnatal days 8-12) enhanced cortical NR2A mRNA levels and reduced thalamic NR2B mRNA levels for up to 2 weeks. These effects are consistent with the hypothesis that CNE during a postnatal critical period disrupts auditory cortex development by over-stimulating glutamatergic synapses.


Visual Appearance of Chiral Nematic Cellulose-Based Photonic Films: Angular and Polarization Independent Color Response with a Twist.
Hydroxypropyl cellulose (HPC) is a biocompatible cellulose derivative capable of self-assembling into a lyotropic chiral nematic phase in aqueous solution. This liquid crystalline phase reflects right-handed circular polarized light of a specific color as a function of the HPC weight fraction. Here, it is demonstrated that, by introducing a crosslinking agent, it is possible to drastically alter the visual appearance of the HPC mesophase in terms of the reflected color, the scattering distribution, and the polarization response, resulting in an exceptional matte appearance in solid-state films. By exploiting the interplay between order and disorder, a robust and simple methodology toward the preparation of polarization and angular independent color is developed, which constitutes an important step toward the development of real-world photonic colorants.


Possible pathologenic role of interleukin-5 and eosino cationic protein in Henoch-Schönlein purpura nephritis.
The mechanism for the onset of Henoch-Schönlein purpura nephritis is unknown. In order to identify the pathogenesis of nephritis, laboratory findings and serum cytokines between Henoch-Schönlein purpura (HSP) patients without nephritis and with nephritis were investigated. We enrolled 32 patients who had been diagnosed with HSP from January 1993 to December 1998. These patients were divided into two groups. Group 1 consisted 12 patients without nephritis and group 2 consisted 20 patients with nephritis. We evaluated laboratory findings such as eosinophil counts, serum IgE, eosino cationic protein (ECP), and serum cytokine (interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-13 interferon-gamma and tumor necrotic factor-alpha) concentrations between both groups. At the acute phase, serum IL-5 and ECP concentrations in group 2 were higher than those in group 1 (59.4 +/- 32.7 pg/mL vs. 10.8 +/- 12.8 pg/mL, P < 0.05, 24.3 +/- 5.1 microg/L vs. 8.9 +/- 4.2 microg/L, P < 0.05, respectively). Serum IL-4 concentrations at the acute phase in group 1 were higher than those in group 2 (40.2 +/- 21.5 pg/mL vs. 10.7 +/- 5.4 pg/mL, P < 0.01). In group 2, serum IL-5 concentrations at the acute phase were higher than those at recovery phase. These findings suggest that IL-5 and eosinophil activation may be one of the factors involved in the mechanism for onset of nephritis.


The usefulness of super-selective computed tomography angiography (CTA) for diagnosing and localizing a small insulinoma.
Localization of insulinomas by preoperative imaging is critical for successful surgical resection. However, the visualization and localization of small insulinomas by recent imaging modalities still remains a challenge. Here, we report a 77-year-old woman with a small insulinoma successfully localized by performing arterial stimulation and venous sampling (ASVS), and subsequent super-selective CTA (SSCTA). It was not visualized by routine non-invasive imaging tests such as digital subtraction angiography (DSA). The small size (1.0 cm) of the surgically removed tumor supports the usefulness of SSCTA for localizing very small insulinomas.


Alpha-tocopherol quinine ameliorates spatial memory deficits by reducing beta-amyloid oligomers, neuroinflammation and oxidative stress in transgenic mice with Alzheimer's disease.
The pathologies of Alzheimer's disease (AD) is associated with soluble beta-amyloid (Aβ) oligomers, neuroinflammation and oxidative stress. Decreasing the levels of Aβ oligomer, glial activation and oxidative stress are potential therapeutic approaches for AD treatment. We previously found alpha-tocopherol quinine (α-TQ) inhibited Aβ aggregation and cytotoxicity, decreased the release of inflammatory cytokines and reactive oxygen species (ROS) in vitro. However, whether α-TQ ameliorates memory deficits and other neuropathologies in mice or patients with AD remains unknown. In this study, we reported that orally administered α-TQ ameliorated memory impairment in APPswe/PS1dE9 transgenic mice, decreased oxidative stress and the levels of Aβ oligomer in the brains of mice, prevented the production of inducible nitric oxide synthase and inflammatory mediators, such as interleukin-6 and interleukin-1β, and inhibited microglial activation by inhibiting NF-κB signaling pathway. These findings suggest that α-TQ has potential therapeutic value for AD treatment.


[Eclipse retinopathy : A case series after the partial solar eclipse on 20 March 2015].
Solar retinopathy refers to damage to the central macula caused by exposure to intense solar radiation, most frequently observed after a solar eclipse. Description of the morphological changes in spectral domain optical coherence tomography (SD-OCT) and the clinical course in patients with acute solar retinopathy. The study included a retrospective analysis of 12 eyes from 7 patients with solar retinopathy after the partial solar eclipse on 20 March 2015. Best corrected visual acuity, fundus changes and SD-OCT findings were analyzed. Out of the 7 patients 5 underwent treatment with 1 mg prednisolone per kg body weight. The average age of the patients was 30.1±13.1 years. Best corrected visual acuity was 0.65 at initial presentation. In the acute stage all affected eyes showed a small yellowish lesion in the centre of the fovea in the fundoscopic examination. In SD-OCT the continuity of all layers in the foveola appeared disrupted. In the follow-up examination these changes were partially resolved. After 2 months SD-OCT revealed a small defect of the ellipsoid zone. In one patient the defect could not be shown due to slightly excentric imaging sections. Best corrected visual acuity increased to 0.97. The SD-OCT is an appropriate tool to determine the exact localization of the site of damage and for follow-up examination in solar retinopathy. In the acute phase it shows a disruption of the continuity of all layers in the foveola. Despite good recovery of visual acuity a small central defect of the ellipsoid zone remains in the long term.


Intravenous drug use: not a barrier to achieving a sustained virological response in HCV infection.
Hepatitis C virus (HCV) is commonly transmitted by intravenous drug use (IDU) but drug users are under represented in many treatment cohorts, this is because of the assumption of lowered treatment success. We assessed HCV treatment outcomes in active intravenous drug users and patients on opiate substitution therapy. The Tayside HCV treatment database was retrospectively analysed for consecutively treated patients based on risk factor for acquisition of HCV. Primary end point was sustained virological response (SVR). Two hundred and ninety-one consecutively treated patients were assessed. The overall SVR rate was 55.3%. The SVR rates by risk factor were; Non-IDU 61.4%, Ex-IDU 54.8% and Active IDU 47.1% (P = n/s). In the groups G1 patients SVR was; Non-IDU 52.7%, Ex-IDU 30.7% and active IDU 35.4% (P = n/s). In the non-G1 patients: non-IDU 65.1%, Ex-IDU 76.7% and active IDU 53.5%. Ex-IDU had a significantly better SVR than active IDU, other differences were not significant. Our results demonstrate that SVR rates in the active drug users and those on opiate substitution therapy can be achieved which are comparable with non-IDU infected individuals. Intravenous drug use in those engaged with treatment services should not be seen as a barrier to treatment of HCV.


HIGHER MODIFIED BECK DEPRESSION INVENTORY SCORES ARE ASSOCIATED WITH BODY, EATING, AND EXERCISE COMPARISONS BUT DECREASED EXERCISE AMOUNTS.
Previous research has indicated that exercise can lead to decreased depression symptoms. The relationship of depression with right frontal lobe activity and self-image (body, eating, and exercise) were investigated as reasons why depressive symptoms might lead to decreased exercise. 120 college students (79 women) completed design fluency tasks followed by a set of questionnaires on depression and exercise. High (M = 23.03, SD = 5.92) and low quartiles (M = 3.11, SD = 1.59) were created using the Modified Beck Depression Inventory (mBDI) for primary analyses. The group with higher mBDI scores produced fewer unique designs (suggesting lower right frontal activity) and was more likely to make comparisons based on body shape, eating, and exercise. The group with higher mBDI scores reported significantly less strenuous and moderate exercise. These findings indicate that the relationship between exercise and depression could work in both directions. While exercise can be used as a potential treatment to decrease depression, increased depressive symptoms could be a hindrance to exercise.


Optical coherence tomography as a possible tool to monitor and predict disease progression in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes.
Optical coherence tomography (OCT) is an imaging technique used to obtain three-dimensional information on the retina. In this article, we evaluated the structural neuro-retinal abnormalities, especially the thickness in the ganglion cell complex (GCC), in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The GCC thickness in MELAS patients was significantly thinner than that in normal controls even when they had no history of transient homonymous hemianopia. There was a negative correlation between GCC thickness and disease duration. In conclusion, OCT may be an effective tool to monitor and predict disease progression in MELAS patients.


Expansion motions in the inner parts of the galaxy.
As well as the high velocity expansion features already known in the inner parts of the galaxy, there also seem to be expansion features at low velocities. Two new features with velocities of -27 km s(-1) and -14 km s(-1) at a distance of about 4.5 kpc are identified in this article and their relationship to the other expanding features is discussed.


Integrin-linked kinase mediates the hydrogen peroxide-dependent transforming growth factor-β1 up-regulation.
Transforming growth factor type-β1 (TGF-β1) has been recognized as a central mediator in many pathological events related to extracellular matrix (ECM) proteins accumulation, where their locally increased expression has been implicated in the fibrosis process of numerous organs, including glomerular fibrosis in the kidney. We and others have reported the TGF-β1 synthesis regulation by reactive oxygen species (ROS), and moreover we also described the implication of integrin-linked kinase (ILK) in the AP-1-dependent TGF-β1 up-regulation. Thus, we propose here that hydrogen peroxide (H2O2)-dependent TGF-β1 regulation may be mediated by ILK activation. First we confirmed the increase in TGF-β1 expression in human mesangial cells (HMC) after treatment with H2O2 or with an alternative H2O2-generating system such as the glucose-oxidase enzyme (GOX). By using immunoblotting, immunofluorescence, and ELISA techniques, we demonstrate that extracellular H2O2 up-regulates TGF-β1 transcription, as well as increases TGF-β1 promoter activity. Furthermore, catalase-decreased intracellular H2O2 abolished TGF-β1 up-regulation. The use of pharmacological inhibitors as well as knockdown of ILK with small interfering RNA (siRNA) demonstrated the implication of a PI3K/ILK/AKT/ERK MAPK signaling pathway axis in the H2O2-induced TGF-β1 overexpression. Finally, we explored the physiological relevance of these findings by treating HMC with angiotensin II, a known stimuli of H2O2 synthesis. Our results confirm the relevance of previous findings after a more physiological stimulus. In summary, our results provide evidence that ILK activity changes may act as a mechanism in response to different stimuli such as H2O2 in the induced TGF-β1 up-regulation in pathological or even physiological conditions.


Building a competency-based workplace curriculum around entrustable professional activities: The case of physician assistant training.
Competency-based medical education (CBME) is increasingly dominating clinical training, but also poses questions as to its practical implementation. There is a need for practical guidelines to translate CBME to the clinical work floor. This article aims to provide a practical model, based on the concept of entrustable professional activities (EPAs) to make this translation, derived from curriculum building for physician assistants (PAs). For the training of PAs at the Utrecht University of Applied Sciences, a three-step model was developed to guide competency-based curriculum development, teaching and assessment. It includes specific guidelines for the identification, systematic description and planning of EPAs. The EPA concept appeared to be a useful tool to build competency-based clinical workplace curricula. Implementation of the curriculum requires use of trainee portfolios and progress interviews, statements of rewarded responsibility and training of supervisors. The individualised approach and flexibility that true CBME implies is brought into practice with this model. The model may also be transferred to other domains of clinical training, among which postgraduate training for medical specialties.


Comparison of Conventional Versus Right Angled Fixation Technique in Management of Mandibular Angle Fractures - A Prospective Randomized Clinical Study.
The treatment of mandibular angle fractures ranges from observation to closed reduction with maxillomandibular fixation to open reduction and internal fixation. The study aims to compare the effectiveness of three different techniques (transoral, transbuccal, and right-angled fixation technique) for single adaptational monocortical upper border plating in mandibular angle fracture. The study conducted at our center was a prospective randomized study. The study duration was from November 2019 to August 2021. The three groups included in our study were transoral, transbuccal, and transoral approach using the right-angled drill. Patients who required open reduction and internal fixation of mandibular angle fracture were included in the study. Computer-generated randomization method was used to assign the participants among the 3 groups, ie, transoral, transbuccal, or right-angled fixation technique. The primary outcome clinical variables were mouth opening (MO), occlusion stability, scar or laceration, facial nerve weakness, infection, and the radiological variables were gap between the fracture segments and displacement of the fracture segment. The secondary outcome of our study is a comparison of the perioperative complications including plate exposure during the entire fracture healing period. The covariates of the study were age, sex, etiology, and tooth in line of fracture. Statistical analysis was done using ANOVA, post hoc Tukey test, and Pearson χ2 test. A P value less than 0.05 was considered statistically significant. A total of 48 patients were included in our study. According to randomization, each group was allotted 16 patients. In the study, 66.7% of the study population were male and 33.3% were female; 75% of the study population were victims of road traffic accidents, and 25% were injured due to assault. The mean and standard deviation for MO at 1 month were 31.3 ± 2.9 for the transoral group, 35.8 ± 1.7 for the transbuccal group, and 35.5 ± 1.3 for the right-angled fixation group. On intergroup comparison, statistically significant results were seen at the 1-month postoperative MO clinical parameter. The P value here was 0.02 which was statistically significant. The comparison of the right-angled fixation technique to transoral and transbuccal fixation methods have not been documented. Our study is the first of its kind to compare the right-angled fixation technique to various other approaches. Our study showed that the MO was better postoperatively with the transbuccal approach. The other variables showed no difference among the three techniques.


Removal of "black-line" margins and improving esthetics of porcelain-fused-to-metal crowns: update in technique.
A repair technique is presented for elimination of "black line" crown margins and extension of margins onto cervical surfaces. A resin bonding agent that adheres simultaneously to metal, porcelain, and dentin is utilized to expedite completion of the repair. The bonding resin is opaqued with a light-curing, filled resin and then covered with a suitable composite resin. This technique updates a previously published technique by eliminating glass-ionomer cement liners and liner etching and improves both efficiency and esthetics of the repair.


DNA damage triggers reprogramming of differentiated cells into stem cells in Physcomitrella.
DNA damage can result from intrinsic cellular processes and from exposure to stressful environments. Such DNA damage generally threatens genome integrity and cell viability1. However, here we report that the transient induction of DNA strand breaks (single-strand breaks, double-strand breaks or both) in the moss Physcomitrella patens can trigger the reprogramming of differentiated leaf cells into stem cells without cell death. After intact leafy shoots (gametophores) were exposed to zeocin, an inducer of DNA strand breaks, the STEM CELL-INDUCING FACTOR 1 (STEMIN1)2 promoter was activated in some leaf cells. These cells subsequently initiated tip growth and underwent asymmetric cell divisions to form chloronema apical stem cells, which are in an earlier phase of the life cycle than leaf cells and have the ability to form new gametophores. This DNA-strand-break-induced reprogramming required the DNA damage sensor ATR kinase, but not ATM kinase, together with STEMIN1 and closely related proteins. ATR was also indispensable for the induction of STEMIN1 by DNA strand breaks. Our findings indicate that DNA strand breaks, which are usually considered to pose a severe threat to cells, trigger cellular reprogramming towards stem cells via the activity of ATR and STEMINs.


Process chromatography: current constraints and future options for the adsorptive recovery of bioproducts.
A contemporary review of adsorption chromatography must embrace aspects of fixed-bed, batch suspension and fluidised-bed contacting of complex feedstocks with adsorbents chemically derivatised with ligands with binding specificities for target bioproducts. Advances in the design of adsorbents, ligands and contactors have facilitated opportunities for integrated processing of unclarified feedstocks to benefit purity and yield of macromolecular products. In the face of competition from apparently simpler, yet productive, technologies (e.g. precipitation, crystallisation and aqueous solvent extraction), further advances in chromatographic purification of macromolecules and nanoparticulates demand close collaboration between inventors and/or manufacturers of new products and the suppliers of chromatographic hardware and consumables.


Prevalence and incidence of neuromyelitis optica spectrum disorder and multiple sclerosis in Korea.
The epidemiology of neuromyelitis optica spectrum disorder and multiple sclerosis varies depending on the region and ethnicity. To estimate the prevalence and incidence of neuromyelitis optica spectrum disorder and multiple sclerosis in Korea during 2010-2016. We analyzed the National Health Insurance research database, which contains single-payer health insurance data collected in Korea. Neuromyelitis optica spectrum disorder was defined based on the 2006 Wingerchuk criteria (for 2010-2015), and the 2015 International Panel for Neuromyelitis Optica Diagnosis criteria (for 2016). Multiple sclerosis was defined by the 2005 International Panel criteria for multiple sclerosis. In 2016, the age-standardized prevalence per 100,000 persons was 2.56 (95% confidence interval: 2.43-2.7) for neuromyelitis optica spectrum disorder and 3.23 (95% confidence interval: 3.08-3.39) for multiple sclerosis. The age-standardized incidence of neuromyelitis optica spectrum disorder and multiple sclerosis were 0.73 (95% confidence interval: 0.66-0.8) and 0.50 (95% confidence interval: 0.44-0.56) per 100,000 persons in 2016. The prevalence of neuromyelitis optica spectrum disorder and multiple sclerosis have increased over time during 2010-2016 (18.5% and 5.4% annually; both p-trend < 0.001). The incidence of neuromyelitis optica spectrum disorder increased annually (10.0%, p-trend < 0.001), while the incidence of multiple sclerosis remained stable. While the prevalence of neuromyelitis optica spectrum disorder and multiple sclerosis are comparable in Korea, the incidence of neuromyelitis optica spectrum disorder is higher than that of multiple sclerosis. Both the prevalence and incidence of neuromyelitis optica spectrum disorder are rapidly increasing in Korea.


[Axial myopia--computed tomography and magnetic resonance tomography findings].
The case of a 44-year-old women suffering from amblyopia of the left eye with unilateral proptosis caused by axial (progressive) myopia is presented. The clinical and radiological findings were discussed in reference to the literature. The diagnosis was established by ruling out neoplastic, inflammatory or endocrine causes for the exophthalmos. CT and MR scans revealed an enlarged left globe without evidence of orbital masses. The findings were regarded as typical for the diagnosis of axial myopia.