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Non-steroidal anti-inflammatory drugs (NSAIDs) are known to be risk factors for a systemic inflammatory syndrome in viral infections. Innate immune cells are likely to represent the preferential targets for the deleterious effects of NSAIDs in patients with viral infections. We therefore examined whether various classes of NSAIDs could selectively inhibit cytokine production by innate immune cells. NSAIDs selectively inhibited interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production by natural killer (NK) and gammadelta T cells with each NSAID displaying its own unique pattern of inhibition, while sparing that by acquired immune cells. These inhibitions were independent on cyclooxygenase inhibition. These NSAIDs directly inhibited the cytokine production by the purified gammadelta T-cell population without involving other cell populations. The selective inhibition of the early generation of IFN-gamma and TNF-alpha from NK and gammadelta T cells by NSAIDs may serve to drive the subsequent acquired immune responses towards a Th2 phenotype, leading to the aggravation of allergic symptoms. Our results provide a mechanism to explain the deleterious effects of NSAIDs on clinical symptoms of viral infections and allergic diseases and suggest more targeted use depending on the type of disease. | Bufexamac |
BACKGROUND: An important element in the experiences of people with autism is the key role played by therapeutic interventions. This paper examines the role of therapeutic intervention and the construction of individuals with autism in the therapeutic relationship. METHOD: The contributions to four online asynchronous discussion lists were analysed using discourse analysis over a 3-month period. FINDINGS: Two key themes identified in the data are presented. These comprise issues concerning therapeutic intervention and issues related to the employment opportunities of adults with autism. CONCLUSIONS: In this paper the notion that people with autism must change in order to accommodate the non-autistic world is discussed. The author seeks to present an alternative construction of autism as a difference rather than a deficit or deviance and to examine the negotiation of a place for a person with autism within a neurologically typical dominated society. | Employment, Supported |
BACKGROUND: Diverticula are localized in the right colon with a rate of 6.7-14% in Western countries. Two types of diverticula have been described in the right colon, on the basis of etiologic and pathological features: multiple diverticula and solitary diverticulum of the caecum. The most common clinical presentation of the right-sided colonic diverticula is an acute inflammatory complication, which is difficult to distinguish from other causes of right iliac fossa pain. METHODS: A survey of the literature is presented and personal experience relative to 4 cases of acute diverticulitis of the right colon observed over a 10-year period is described. RESULTS: In all the patients the preoperative diagnosis was acute appendicitis. In two cases the poor clinical conditions of the patients were associated with the free perforation of a solitary caecal diverticulum and diffuse faecal peritonitis. A temporary caecostomy was therefore required. In two cases a localized inflammatory mass was found around a perforated solitary diverticulum of the caecum. An ileocaecal resection was performed. CONCLUSIONS: The purpose of this study is to emphasize the epidemiological, etiologic and clinical features of right-sided colonic diverticula, and the diagnostic and therapeutic management of their complications. | Diverticulum, Colon |
PURPOSE: Neurally adjusted ventilatory assist (NAVA) is a ventilatory mode that tailors the level of assistance delivered by the ventilator to the electromyographic activity of the diaphragm. The objective of this study was to compare NAVA and pressure support ventilation (PSV) in the early phase of weaning from mechanical ventilation. METHODS: A multicentre randomized controlled trial of 128 intubated adults recovering from acute respiratory failure was conducted in 11 intensive care units. Patients were randomly assigned to NAVA or PSV. The primary outcome was the probability of remaining in a partial ventilatory mode (either NAVA or PSV) throughout the first 48 h without any return to assist-control ventilation. Secondary outcomes included asynchrony index, ventilator-free days and mortality. RESULTS: In the NAVA and PSV groups respectively, the proportion of patients remaining in partial ventilatory mode throughout the first 48 h was 67.2 vs. 63.3 % (P = 0.66), the asynchrony index was 14.7 vs. 26.7 % (P < 0.001), the ventilator-free days at day 7 were 1.0 day [1.0-4.0] vs. 0.0 days [0.0-1.0] (P < 0.01), the ventilator-free days at day 28 were 21 days [4-25] vs. 17 days [0-23] (P = 0.12), the day-28 mortality rate was 15.0 vs. 22.7 % (P = 0.21) and the rate of use of post-extubation noninvasive mechanical ventilation was 43.5 vs. 66.6 % (P < 0.01). CONCLUSIONS: NAVA is safe and feasible over a prolonged period of time but does not increase the probability of remaining in a partial ventilatory mode. However, NAVA decreases patient-ventilator asynchrony and is associated with less frequent application of post-extubation noninvasive mechanical ventilation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02018666." | Interactive Ventilatory Support |
A method of covering exposed noninfected episcleral implants after retinal detachment surgery using a graft of preserved sclera is described. Four of seven eyes have had the dehiscence covered for six months or more. In three eyes the dehiscence recurred. The procedure is simple and effective in eyes in which removal of the implant might cause redetachment of the retina. | Scleral Buckling |
Replication-competent (oncolytic) viruses (OV) as cancer immunotherapeutics have gained an increasing level of attention over the last few years while the clinical evidence of virus-mediated antitumor immune responses is still anecdotal. Multiple clinical studies are currently ongoing and more immunomonitoring results are expected within the next five years. All viruses can be recognized by the immune system and are therefore potential candidates for immune therapeutics. However, each virus activates innate immune system by using different combination of recognition receptors/pathways which leads to qualitatively different adaptive immune responses. This review summarizes immunological findings in cancer patients following treatment with replication-competent viruses. | Oncolytic Viruses |
INTRODUCTION: Metabotropic glutamate receptor 4 (mGlu(4)) is a group III GPCR and has been demonstrated to play a major role in a number of therapeutic areas within the CNS. As the orthosteric site of all glutamate receptors is highly conserved, modulating mGlu(4) via allosteric modulation has emerged as a very attractive mode-of-action and has been validated preclinically in a number of animal models for Parkinson's disease, anxiety, pain, and neuroinflammation. AREAS COVERED: In this review, the patent literature for mGlu(4)-positive allosteric modulators over the past 4 years will be provided. Patents from all companies are discussed and an overview of the chemical matter and relevant biological properties will be given. EXPERT OPINION: Although there has yet to be an mGlu(4)-positive allosteric modulator progressed into clinical trials, there is a wealth of preclinical data from the primary literature that shows the promise of this emerging target. A number of academic and industry laboratories have recently published exciting patent data covering a multitude of chemical matter. Positive allosteric modulation of mGlu(4) remains one of the more attractive non-dopaminergic therapies for Parkinson's disease, as well as emerging data for other indications such as pain, neuroinflammation, schizophrenia and diabetes, which could potentially make mGlu(4) a significant therapeutic target going forward." | Excitatory Amino Acid Agonists |
Iron deficiency anemia (IDA) is the most common nutritional deficiency worldwide. This deficiency could be solved by preparing stable, edible, and absorbable iron food ingredients using environmentally friendly methods. This study investigated enzymatic hydrolysis and microencapsulation process of goose blood. The physicochemical properties, stabilities of the microencapsulated goose blood hydrolysate (MGBH) and a supplement for rats with IDA were also evaluated. The results showed that the synergetic hydrolytic action of neutrase and alkaline protease significantly increased the heme-releasing efficiency. The heme was then microencapsulated using sodium caseinate, maltodextrin and carboxymethyl cellulose (CMC) as the edible wall material, and the encapsulation efficiency of the product reached 98.64%. Meanwhile, favorable thermal, storage and light stabilities were observed for the microencapsulation. It was found that MGBH can significantly improve the body weight and hematological parameters of IDA Wistar rat. | Heme |
Isolated fat tissue microvessels and lung, whose capillary endothelia express in situ specific binding sites for albumin, were homogenized and subjected to SDS-gel electrophoresis and electroblotting. The nitrocellulose strips were incubated with either albumin-gold (Alb-Au) and directly visualized, or with [125I]albumin (monomeric or polymeric) and autoradiographed. The extracts of both microvascular endothelium and the lung express albumin-binding proteins (ABPs) represented by two pairs of polypeptides with major components of molecular mass 31 and 18 kD. The ABP peptides have pIs 8.05 to 8.75. Rabbit aortic endothelium, used as control, does not express detectable amounts of ABPs. The ABPs subjected to electrophoresis bind specifically and with high affinity (Kd = approximately 60 X 10(-9)M) both monomeric and polymeric albumin: the binding is saturable at approximately 80 nM concentration and 50% inhibition is reached at 5.5 micrograms/ml albumin concentration. Sulfhydryl-reducing agents beta-mercaptoethanol and dithiothreitol do not markedly affect the ABPs electrophoretic mobility and binding properties. As indicated by cell surface iodination of isolated capillary endothelium followed by electroblotting, autoradiography, and incubation with Alb-Au, the bands specifically stained by this ligand are also labeled with radioiodine. | Receptors, Albumin |
Cholera is a communicable disease caused by consumption of contaminated food and water. This potentially fatal intestinal infection is characterised by profuse secretion of rice watery stool that can rapidly lead to severe dehydration and shock, thus requiring treatment to be given immediately. Epidemic and pandemic cholera are exclusively associated with Vibrio cholerae serogroups O1 and O139. In light of the need for rapid diagnosis of cholera and to prevent spread of outbreaks, we have developed and evaluated a direct one-step lateral flow biosensor for the simultaneous detection of both V. cholerae O1 and O139 serogroups using alkaline peptone water culture. Serogroup specific monoclonal antibodies raised against lipopolysaccharides (LPS) were used to functionalize the colloidal gold nanoparticles for dual detection in the biosensor. The assay is based on immunochromatographic principle where antigen-antibody reaction would result in the accumulation of gold nanoparticles and thus, the appearance of a red line on the strip. The dry-reagent dipstick format of the biosensor ensure user-friendly application, rapid result that can be read with the naked eyes and cold-chain free storage that is well-suited to be performed at resource-limited settings. | Vibrio cholerae O139 |
The diuretic and saluretic effect of the benzothiadiazine derivative 3-(a-methylbenzyl)-6-chlore-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-diozide (bemetizide) and the pteridine derivative 2,4,7-triamino-6-phenylpteridine (triamterene) were compared with those of their combination in the animal experiment on rats. Dose-effect relationships at a ratio of 1:2. The combination displayed marked advantages over the individual substances. The mixing proportion of 1:2 may be considered suitable. | Triamterene |
OBJECTIVES: We examined the ways in which levels of preventive dental care and unmet dental needs varied among subgroups of low-income children. METHODS: Data were drawn from the 2002 National Survey of America's Families. We conducted bivariate and multivariate analyses, including logistic regression analyses, to assess relationships between socioeconomic, demographic, and health factors and receipt of preventive dental care and unmet dental needs. RESULTS: More than half of low-income children without health insurance had no preventive dental care visits. Levels of unmet dental needs among low-income children who had private health insurance coverage but no dental benefits were similar to those among uninsured children. Children of parents whose mental health was rated as poor were twice as likely to have unmet dental needs as other children. CONCLUSIONS: Additional progress toward improving the dental health of low-income children depends on identifying and responding to factors limiting both the demand for and the supply of dental services. In particular, it appears that expanding access to dental benefits is key to improving the oral health of this population. | Dental Care for Children |
OBJECTIVE: To study possible mechanisms for the inhibition of cytochrome P450 C21 (steroid 21-hydroxylase) enzyme activity by P450 C21 autoantibodies (Abs) in vitro. DESIGN: Two possible mechanisms for the inhibition of P450 C21 enzyme activity by P450 C21 Abs were studied: (a) conformational changes in the P450 C21 molecule induced by Ab binding and (b) the effects of Ab binding to P450 C21 on the electron transfer from the nicotinamide adenine dinucleotide phosphate reduced (NADPH) cytochrome P450 reductase (CPR) to P450 C21. METHODS: The effect of P450 C21 Ab binding on the conformation of recombinant P450 C21 in yeast microsomes was studied using an analysis of the dithionite-reduced CO difference spectra. The effect of P450 C21 Abs on electron transfer was assessed by analysis of reduction of P450 C21 in the microsomes in the presence of CO after addition of NADPH. RESULTS: Our studies confirmed the inhibiting effect of P450 C21 Abs on P450 C21 enzyme activity. Binding of the Abs did not induce significant change in the P450 C21 peak at 450nm (native form) and did not produce a detectable peak at 420 nm (denatured form) in the dithionite-reduced CO difference spectra. This indicated that conformation of P450 C21 around the heme was not altered compared with the native structure. However, incubation of the P450 C21 in yeast microsomes with P450 C21 Ab inhibited the fast phase electron transfer from the CPR to P450 C21. CONCLUSIONS: Our observations suggested that the mechanism by which P450 C21 Abs inhibit P450 C21 enzyme activity most likely involves inhibition of the interaction between the CPR and P450 C21. | Cytochrome P450 Family 21 |
Enzyme turnover numbers (k(cat)s) are essential for a quantitative understanding of cells. Because k(cat)s are traditionally measured in low-throughput assays, they can be inconsistent, labor-intensive to obtain, and can miss in vivo effects. We use a data-driven approach to estimate in vivo k(cat)s using metabolic specialist Escherichia coli strains that resulted from gene knockouts in central metabolism followed by metabolic optimization via laboratory evolution. By combining absolute proteomics with fluxomics data, we find that in vivo k(cat)s are robust against genetic perturbations, suggesting that metabolic adaptation to gene loss is mostly achieved through other mechanisms, like gene-regulatory changes. Combining machine learning and genome-scale metabolic models, we show that the obtained in vivo k(cat)s predict unseen proteomics data with much higher precision than in vitro k(cat)s. The results demonstrate that in vivo k(cat)s can solve the problem of inconsistent and low-coverage parameterizations of genome-scale cellular models. | Gene Knockout Techniques |
AIM: Research exploring alcohol consumption patterns and behaviour change among older adults is relatively scarce, often necessitating reliance on international evidence. To understand the degree to which findings may be generalizable across countries, this review compares recent epidemiological evidence from developed countries on the prevalence of abstention and potentially problematic alcohol consumption in older adults. METHODS: Medline, EMBASE, Web of Science and PsychInfo were searched for English language publications, identifying 21 peer-reviewed publications and six reports, including data from 17 national surveys and 10 general practice and community samples published since 2000. RESULTS: Of the developed countries for which data are available on adults aged over 50 years, rates of past 12-month abstention and former drinking are lowest in England and Finland, and highest in Korea and the USA. The prevalence of binge drinking varies widely between studies, whilst rates of alcohol dependence are broadly similar. CONCLUSIONS: Older adults in developed countries report different rates of abstention and alcohol consumption. This places obvious limitations on the extrapolation of results from specific research findings and policy strategies to other countries. | Alcohol Abstinence |
BACKGROUND: Anthrax is a bacterial zoonosis that occasionally causes human disease and is potentially fatal. Anthrax vaccines include a live-attenuated vaccine, an alum-precipitated cell-free filtrate vaccine, and a recombinant protein vaccine. OBJECTIVES: To evaluate the effectiveness, immunogenicity, and safety of vaccines for preventing anthrax. SEARCH STRATEGY: We searched the following databases (November 2008): Cochrane Infectious Diseases Group Specialized Register; CENTRAL (The Cochrane Library 2008, Issue 4); MEDLINE; EMBASE; LILACS; and mRCT. We also searched reference lists. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of individuals and cluster-RCTs comparing anthrax vaccine with placebo, other (non-anthrax) vaccines, or no intervention; or comparing administration routes or treatment regimens of anthrax vaccine. DATA COLLECTION AND ANALYSIS: Two authors independently considered trial eligibility, assessed risk of bias, and extracted data. We presented cases of anthrax and seroconversion rates using risk ratios (RR) and 95% confidence intervals (CI). We summarized immunoglobulin G (IgG) concentrations using geometric means. We carried out a sensitivity analysis to investigate the effect of clustering on the results from one cluster-RCT. No meta-analysis was undertaken. MAIN RESULTS: One cluster-RCT (with 157,259 participants) and four RCTs of individuals (1917 participants) met the inclusion criteria. The cluster-RCT from the former USSR showed that, compared with no vaccine, a live-attenuated vaccine (called STI) protected against clinical anthrax whether given by a needleless device (RR 0.16; 102,737 participants, 154 clusters) or the scarification method (RR 0.25; 104,496 participants, 151 clusters). Confidence intervals were statistically significant in unadjusted calculations, but when a small amount of association within clusters was assumed, the differences were not statistically significant. The four RCTs (of individuals) of inactivated vaccines (anthrax vaccine absorbed and recombinant protective antigen) showed a dose response relationship for the anti-protective antigen IgG antibody titre. Intramuscular administration was associated with fewer injection site reactions than subcutaneous injection, and injection site reaction rates were lower when the dosage interval was longer. AUTHORS' CONCLUSIONS: One cluster-RCT provides limited evidence that a live-attenuated vaccine is effective in preventing cutaneous anthrax. Vaccines based on anthrax antigens are immunogenic in most vaccinees with few adverse events or reactions. Ongoing randomized controlled trials are investigating the immunogenicity and safety of anthrax vaccines. | Anthrax Vaccines |
Cutis laxa (CL) is an extremely inherited or acquired connective tissue disorder characterised by a markedly reduced systemic elastin content. Genital abnormalities in patients with CL have been rarely reported. We report such a case in a 48-year-old CL patient affected by genital prolapse, focusing on immunohistological and molecular biology assessment of elastin and collagen type I, III, VI content in the main uterine ligaments. The woman was referred to our department for the onset of a rapidly progressing genital prolapse and urinary incontinence. The patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and sacrocolpopexy. Punch biopsies from both cardinal and uterosacral ligaments revealed a dramatic reduction in elastin and an increase in collagen type VI content. The present report seems to underline the central role exerted primarily by elastin in the supportive connective tissue and might contribute to the knowledge of extracellular matrix abnormalities at the basis of genital abnormalities in CL patients. | Uterine Prolapse |
Deregulation such as overexpression of adhesion molecules influences cancer progression and survival. Metastasis of malignant cells from their primary tumor site to distant organs is the most common reason for cancer-related deaths. Junctional adhesion molecule-C (JAM-C), a member of the immunoglobulin-like JAM family, can homodimerize and aid cancer cell migration and metastasis. Here we show that this molecule is dynamically expressed on multiple myeloma (MM) cells in the bone marrow and co-localizes with blood vessels within the bone marrow of patients and mice. In addition, upregulation of JAM-C inversely correlates with the downregulation of the canonical plasma cell marker CD138 (syndecan-1), whose surface expression has recently been found to dynamically regulate a switch between MM growth in situ and MM dissemination. Moreover, targeting JAM-C in a syngeneic in vivo MM model ameliorates MM progression and improves outcome. Overall, our data demonstrate that JAM-C might serve not only as an additional novel diagnostic biomarker but also as a therapeutic target in MM disease." | Junctional Adhesion Molecule C |
BACKGROUND: Klippel-Trenaunay syndrome (KTS) is a mixed mesenchymal malformation characterised by varicose veins, venous and capillary malformations, and hypertrophy of soft tissue and bone. The purpose of this study was to evaluate the surgical outcomes in KTS patients to provide standards for comparison with endovenous therapy. METHODS: The clinical data of consecutive patient with KTS who underwent open venous surgical treatment between January 1987 and December 2008 were reviewed. Demographics, clinical presentation, operative data, and clinical outcomes were recorded. Follow-up information was obtained from the medical records, mailed questionnaires and phone calls. Descriptive statistics, the Kaplan-Meier method and Log-rank statistics were used where appropriate. RESULTS: Twenty-seven females and 22 males, (mean age 26.5 years, range 7.7-55.8) were included in this study. All had varicose veins, 36 (73%) had limb hypertrophy, and 33 (67%) had capillary malformations, with two of three clinical features present in all. The most frequent symptom was pain (N = 43, 88%). Forty-nine patients underwent operations on 53 limbs. Stripping of the GSV, small and accessory saphenous and lateral embryonic veins was performed in 17 (32%), 10 (19%), 9 (17%), and 15 (28%) limbs, respectively. Two patients developed deep vein thrombosis, one had pulmonary embolism (PE), and one patient had peroneal nerve palsy. Freedom from disabling pain at 1, 3 and 5 years was 95%, 77% and 59%, respectively, and freedom from secondary procedures was 78% at 3 years, and 74% at 5 years. At the last follow-up visit, the venous clinical severity score had decreased from 9.48 +/- 3.27 to 6.07 +/- 3.20 (P < 0.001). CONCLUSIONS: In selected symptomatic patients with KT syndrome, open surgical treatment is safe and durable. Three-fourths of the patients remain free of disabling pain at five years, but secondary procedures are required in one-fourth of the patients. These data can serve as standards for comparison of endovenous therapy for KT syndrome." | Klippel-Trenaunay-Weber Syndrome |
We used light microscopy and computerized graphic reconstruction techniques to examine the endolymphatic duct and sac in 20 pairs of bones from patients with Meniere's disease and 21 bones from controls. The diameters of the endolymphatic duct and the proximal portion of the vestibular aqueduct were significantly smaller in Meniere's disease ears than in controls. Graphic reconstructions showed the Meniere's sacs to be smaller and to have fewer tubular epithelial structures in the intraosseous portion than in the control ears. The median volume of the sac in the Meniere's disease side was substantially lower than in the contralateral ear. The width of the external aperture of the vestibular aqueduct was significantly smaller in Meniere's disease ears than in controls. These findings indicate that the size not only of the vestibular aqueduct but also of the sac is reduced in Meniere's disease. The results may suggest that the endolymphatic sac is pathologically changed in Meniere's disease and that a reduced resorptive capacity of a small endolymphatic sac could result in endolymphatic hydrops. | Vestibular Aqueduct |
Three groups of products enriched with herbs were studied: (1) commercial herb honeys (n = 5) produced by bees fed a syrup with an herbal extract, (2) natural herbal honey (n = 3) produced by bees from the nectar of herbs, and (3) creamed multifloral honey with added dried herbs (n = 5). As a control, multifloral honey (n = 5) was used. The physicochemical parameters (i.e., sugar extract, water content, specific rotation, conductivity, hydroxymethylfurfural content, pH and acidity), sugar profiles (HPLC analysis), antioxidant activity and total phenolic compounds content of the studied samples were compared. Although great diversity in the basic properties of the studied products was observed, they were comparable to multifloral honey and complied with honey regulations. Significant differences in sugar composition were observed, and adversely positive rotation (excluding nettle herb honey) was detected in group 1, likely resulting from the change in bee feeding. The best antioxidant activity for creamed honeys with dried herbs (group 2) was investigated, whereas herb honeys (group 1) exhibited similar antioxidant properties as multifloral honey. The use of controlled feeding of bees appears to be an effective method of enriching honey with desirable plant bioactive components to create innovative bee products. | Furaldehyde |
OBJECTIVE: To compare experience of premature menopause (PM), information sources, treatments, depression, anxiety, body image, sexual function and self-efficacy, between women with premature ovarian failure (POF), surgically induced menopause (SIPM), chemically induced menopause (CIPM), and controls. DESIGN: Cross-sectional observational pilot study using validated and devised questionnaires in 77 Australian women (POF, n = 25; SIPM, n = 17; CIPM, n = 12; controls, n = 23). RESULTS: The average age of all women was 34.8 years (standard deviation (SD) +/- 5.7 years), and time since PM diagnosis was 3.8 years (SD +/- 4.4 years, p = 0.19). The gynecologist (69%) and internet (67%) were the best expected sources of information. Women with PM feared osteoporosis more than controls (p < 0.0001). Women with SIPM (p = 0.006) and POF (p = 0.01) had higher rates of depression compared to controls. SIPM women were more anxious than women with POF (p = 0.04) and both SIPM (p = 0.002) and CIPM (p = 0.02) women were more anxious than controls. Women with POF had higher health evaluation (p = 0.03), fitness evaluation (p = 0.01) and fitness orientation (p = 0.01) than women with SIPM. Controls had higher health evaluation than women with SIPM (p = 0.001) and CIPM (p = 0.04), higher fitness evaluation than women with SIPM (p = 0.02) and CIPM (p = 0.04), and higher fitness orientation than SIPM women (p < 0.0001). Sexual dysfunction (p < 0.0001) and dyspareunia (p = 0.001) were higher in CIPM women than controls. Controls were more sexually responsive than POF women (p = 0.008). SIPM (p = 0.008) and POF (p = 0.04) women reported decreased confidence to manage disease. CONCLUSION: Depression, anxiety, body image, sexual dysfunction and self-confidence are compromised for women across different groups of premature menopause. Understanding these differences is important to the development of individual management plans based on the needs of women. | Menopause, Premature |
BACKGROUND: Cervical mediastinoscopy is useful for diagnosing lung and mediastinal disease. Ultrasound is a safe real-time diagnostic tool widely employed in many surgical fields. Ultrasound was used in cervical mediastinoscopy in our cohort with satisfactory results. This study investigated the safety, feasibility, and availability of video-assisted mediastinoscopy (VAM) combined with ultrasound for mediastinal lymph node biopsy. METHODS: A total of 87 cases involving cervical mediastinal lymph node biopsy performed from November 2015 to May 2020, with complete clinical and pathological information, were retrospectively analyzed in the Department of Thoracic Surgery at Beijing Chaoyang Hospital. The cohort was divided into two groups: ultrasound-guided biopsy under video-assisted mediastinoscopy (UVAM) (44 cases) and routine VAM (43 cases). Operation time, biopsy number and nodal stations, postoperative complications, pathological conditions, and surgical difficulty were compared between the two nodal stations. RESULTS: UVAM was significantly shorter and more lymph node specimens were obtained than with VAM. There was one case of fatal bleeding and two cases of right recurrent laryngeal nerve injury in the VAM group, and no postoperative complications in the UVAM group. CONCLUSIONS: When used with cervical VAM, ultrasound guidance assists physicians assess the space between lymph nodes, surrounding tissues, and large vessels systematically, making biopsy safer and easier, improving lymph node sampling, and decreasing postoperative complications. Furthermore, surgeons can easily learn and master this method. KEY POINTS: Significant findings of the study: Ultrasound was used in combination with cervical mediastinoscopy and the results showed that ultrasound guidance makes biopsy in patients safer and easier, improves lymph node sampling, and decreases postoperative complications. WHAT THIS STUDY ADDS: Surgeons can easily learn and master this method. | Mediastinoscopy |
Objective: To investigate the prevalence and resistance changes of carbapenem-resistant Enterobacteriaceae (CRE) strains isolated from children patients of Chinese Bacterial Resistance Surveillance Network (CHINET) from 2005 to 2017. Methods: Antimicrobial susceptibility testing was carried out by disk diffusion method (KB method) and automated systems. Results were analyzed according to the Clinical and Laboratory Standards Institute (CLSI) 2017 edition standards. Results: Among the 4 481 CRE clinical strains, the overall prevalence of CRE in children was 6.4%, including 8.8% in neonatal period, 7.3% in infancy, 3.8% in early childhood, 4.0% in preschool, 4.7% at school age and 7.4% of puberty. The CRE prevalence of citrobacter spp. remained stable in 2005-2017, whereas other bacteria showed an upward trend, which was higher than that of the adult group (P<0.01). Among the 4 481 CRE strains, there were 2 905 strains of Klebsiella spp. (64.8%), 813 strains of Escherichia coli (18.1%), 549 strains of Enterobacter spp.(12.3%), and 65 strains of Citrobacter spp.(1.5%). Among the 4 481 CRE strains, 20.7%, 13.3%, and 11.8% were from the intensive care unit (ICU), neonatal department and internal medicine wards, respectively. Specimens were distributed as respiratory (42.8%), urine (26.3%), and blood (14.9%). The results of antimicrobial susceptibility testing exhibited that the CRE strains were highly resistant to most commonly used antimicrobial agents in clinical practice, such as imipenem, meropenem and ertapenem, as well as penicillins and cephalosporins, etc. Conclusion: The prevalence of CRE strains in children is increasing year by year, and their antimicrobial resistance to common antibacterial agents in clinical practice is extremely serious, to which serious attention needs to be paid. According to the results of antimicrobial susceptibility testings, the antibacterial agents should be rationally selected to effectively control the spread of CRE." | Carbapenem-Resistant Enterobacteriaceae |
The limited knowledge on the stability, removal, and the fate of bisphenol A analogues in the aqueous environment led us to assess the removal by hydrolysis, adsorption, biological treatment and UV photolysis of eighteen common bisphenol compounds (BPs). Hydrolysis of BPs does not occur. The main factor affecting their stability in wastewater samples is storage time, and safe storage conditions were found to be -20⯠degrees C or 4⯠degrees C for up to four weeks. The results also revealed no significant reduction in the levels of BPs standards when stored in either methanol or ultrapure water. BPE was found to be the most stable, followed by BPF isomers, BPS and BPF, while BP26DM was the least stable and BPM, BPPH, BPP, BPBP and BPFL were quickly adsorbed. For most BPs, the removal efficiency of biological treatment was >85%, and there was no difference between the suspended activated sludge and moving bed bioreactors. Different adsorption affinities of the BPs to biomass were observed and reflect the differences in their K(ow). In terms of degradability, direct UV photolysis in water produced three groups of BPs: (A) highly removable (REâ¯>â¯94%), (B) moderately removable (RE 50-80%) and (C) poorly removable (RE 25-45%). In nearly all cases degradation followed pseudo-first-order kinetics. | Photochemical Processes |
There is a dearth of studies comparing the efficacy of psoralen ultraviolet A (PUVA) and narrowband (NB)-UVB in psoriasis in South Asian patients. Patients having plaque psoriasis with > 20% body surface area involvement were randomly assigned to one of two groups (group A: NB-UVB, group B: PUVA). The response to treatment was assessed by the Psoriasis Area and Severity Index (PASI) at baseline and every 2 weeks thereafter. The maximum possible treatment duration was 16 weeks. In total, 43 patients (21 NB-UVB, 22 PUVA) completed the study. Marked improvement was seen in 80.9% of the patients in group A and 81.8% in group B (NS: P > 0.05). The mean +/- SD time taken to achieve marked improvement was 9.9 +/- 3.3 and 9.9 +/- 3.5 weeks, respectively. In total, 29 patients were available for the analysis of the remission data at 6 months after treatment completion; 26.7% of the patients in group A and 42.8% in group B were in remission (NS: P > 0.05). Both methods seem to be equally effective in achieving clearance and maintaining remission of severe chronic plaque psoriasis in patients with Fitzpatrick skin type 4 and 5. | Ultraviolet Therapy |
The inhibitory or negative Smads, Smad6 and Smad7, block TGFbeta superfamily signals of both the BMP and TGFbeta classes by antagonizing the intracellular signal transduction machinery. We report the cloning of one Smad6 and two Smad7 (Smad7a and Smad7b) chick homologs and their expression and regulation in the developing limb. Smad6 and Smad7a are expressed in dynamic patterns reflecting the domains of BMP gene expression in the limb. Activation and inhibition of the BMP signaling pathway in limb mesenchyme indicates that negative Smad gene expression is regulated, at least in part, by BMP family signals. | Smad6 Protein |
Recently it has been shown that some tumours require macrophage-derived growth factors for in vitro and in vivo proliferation, as well as tumour growth stimulation by macrophages. Furthermore, it has been reported that several biological response modifiers (BRM) stimulated some growth factor production in macrophages. In the present study we tried to define whether some BRM can modulate production of macrophage-derived growth factors for stimulating tumour cells. Results obtained indicate that: 1) growth stimulating activity of macrophages may be co-expressed with antitumor activity; 2) growth stimulating activity could prevail over antitumor effects in the outcome of tumour cell/macrophage interaction in vitro; 3) Some BRM and antitumor drugs can modulate the balance between antitumor and growth stimulating activity of macrophages. It is therefore proposed that growth factors modulation assessment is necessary for new BRM characterization. | Cytotoxicity, Immunologic |
Soluble forms of Fc gammaR type III (sFc gammaRIII or sCD16) are present in many biological fluids. Their main ligand is IgG in the form of complexes. In plasma, sCD16 essentially derive from cleavage of membrane CD16 (or Fc gammaRIII) present on neutrophils and, to a lesser extent, on NK cells. Determination of sCD16 serum level during monoclonal gammopathies has demonstrated markedly reduced levels in multiple myeloma and in monoclonal gammopathy of undetermined significance (MGUS) rapidly evolving to multiple myeloma, compared to stable MGUS or controls, indicating a prognostic value for this biological parameter. The biology and functions of sCD16 are described, together with the biological significance of modifications of the sCD16 serum level in monoclonal gammopathies. | Paraproteinemias |
Iris integrity is required to regulate both the amount of light reaching the retina and intraocular pressure (IOP), with elevated IOP being a major risk factor for glaucoma. Congenital microcoria (MCOR) is an extremely rare, autosomal dominant disease affecting iris development and hindering both of these functions. It is characterized by absent or underdeveloped dilator muscle fibers and immaturity of the iridocorneal angle-where the aqueous humor is drained-which play a central role in IOP regulation. The dilator muscle anomaly is manifested in pinhole pupils (<2 mm) and thin transilluminable irises, causing both hemeralopia and photoaversion. Axial myopia and juvenile open-angle glaucoma are very frequent (80% and 30% of all cases, respectively). It has been suggested that the immaturity of the chamber angle contributes to glaucoma, and myopia has been ascribed to photoaversion and elevated IOP. Though possible, these mechanisms are insufficient. The disease has been tied to chromosome 13q32.1 structural variations. In addition to compromising iris development, modification of the 13q32.1 architecture could alter signaling pathways for axial ocular length and IOP regulation. Here, we summarize the clinical, histological, and molecular features of this disease, and we discuss the possible etiology of associated anomalies. | Pupil Disorders |
Excess phosphate levels in water can lead to increased algal growth, eutrophication and reduced water quality. Phosphate levels in water are regulated by the EU through the Urban Waste Water Treatment Directive (annual mean total phosphorus concentrations of 1-2 mg/l) and the Water Framework Directive that will enforce good ecological and chemical status" by 2015. Legislation is therefore driving the need for increased monitoring of soluble phosphate in water, escalating the desire for a direct, label free approach that could provide remote, continuous monitoring in real-time. The standard method for measuring soluble phosphate in water is a colourimetric technique developed in the 1960s. This colourimetric approach is difficult to adapt for on-line measurements, uses specific reagents which require safe disposal and thus incurs significant costs to the water industry when carried out on a large scale. This review considers optical and electrochemical sensors plus recent advances with synthetic receptors and molecularly imprinted polymers. Progress in the development of phosphate sensors, designed for use in a variety of disciplines, is highlighted with a view to adapting successful approaches for use in the water sector. Additional considerations include the need for long term stability, low maintenance, specificity for phosphate and the capability of measuring total phosphorus concentrations down to at least 1 mg/l, as required by legislation. A sensor that could directly measure soluble, inorganic phosphate concentrations would draw significant interest from the environment sector and other disciplines, including the agricultural, detergent and bio-medical industries." | Phosphates |
BACKGROUND: Displaced olecranon fractures with a stable elbow joint are classified as Mayo type 2a or 2b and are commonly operated with tension band wiring, i.e. two K-wires and a cerclage. Retrospective studies have reported fewer reoperations and complications with cerclage fixation alone when compared to tension band wiring, though with similar long-term results. We decided to compare tension band wiring to cerclage fixation of displaced, stable olecranon fractures in adults in a randomized controlled trial. METHODS: All patients >/= 18 years old with Mayo type 2a and 2b fractures presenting at Skane University hospital will be eligible for study inclusion, unless exclusion criteria are met. Two hundred participants will be included and randomized 1:1 to cerclage fixation or tension band wiring. Outpatient physiotherapist follow-up appointments will be scheduled at 2 and 6 weeks and at 3, 12, and 36 months at the Dept. of Orthopaedics. A lateral view radiograph of the elbow will be analysed at 6 months. The primary outcome of our study is the rate of reoperations. Secondary outcomes are complication rates, severity of complications, and patient-reported outcome measures (QuickDASH, Short Musculoskeletal Function Assessment, pain level, and patient satisfaction). The sample size was calculated to give 80% power for detecting a statistically significant difference in reoperation rates (with alpha-value 0.05), based on a previous retrospective study. DISCUSSION: Reoperation and complication rates after tension band wiring of olecranon fractures are high. Treatment of these injuries is debated, and several ongoing trials compare tension band wiring with plate fixation, suture fixation, and non-operative treatment. As data from retrospective studies indicate that cerclage fixation may be superior to tension band wiring, we see a need for a randomized controlled trial comparing these methods. The WOW-OK Trial aims to obtain level-1 evidence that may influence treatment choice for this type of fracture. TRIAL REGISTRATION: ClinicalTrials.gov NCT05657899 . Registered on 16 November 2022. The trial complies with SPIRIT and CONSORT guidelines. The SPIRIT figure is found in Table 2. | Elbow Fractures |
We demonstrate the regression analysis of exposure determinants using cross-classified random effects in the context of lead exposures resulting from blasting surfaces in advance of painting. We had three specific objectives for analysis of the lead data, and observed: (1) high within-worker variability in personal lead exposures, explaining 79% of variability; (2) that the lead concentration outside of half-mask respirators was 2.4-fold higher than inside supplied-air blasting helmets, suggesting that the exposure reduction by blasting helmets may be lower than expected by the Assigned Protection Factor; and (3) that lead concentrations at fixed area locations in containment were not associated with personal lead exposures. In addition, we found that, on average, lead exposures among workers performing blasting and other activities was 40% lower than among workers performing only blasting. In the process of obtaining these analyses objectives, we determined that the data were non-hierarchical: repeated exposure measurements were collected for a worker while the worker was a member of several groups, or cross-classified among groups. Since the worker is a member of multiple groups, the exposure data do not adhere to the traditionally assumed hierarchical structure. Forcing a hierarchical structure on these data led to similar within-group and between-group variability, but decreased precision in the estimate of effect of work activity on lead exposure. We hope hygienists and exposure assessors will consider non-hierarchical models in the design and analysis of exposure assessments. | Inhalation Exposure |
Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299â¯cell, 18d exhibited excellent anti-proliferative potency with an IC(50) value of about 40â¯nM. Moreover, 18d demonstrated encouraging activities against wild-type ALK (19â¯nM), ROS1 (2.3â¯nM) as well as challenging crizotinib-resistant ALK(L1196M) and ALK(G1202R) mutants with IC(50) values of 45â¯nM and 22â¯nM, respectively. Additionally flow cytometric analysis indicates that 18d inhibited Karpas-299â¯cell viability via G1 phase arrest. Taken together, this work provided a promising ALK inhibitor to circumvent the clinical crizotinib-resistant mutants. | Aminopyridines |
INTRODUCTION: Physiologic alterations caused by oxidative stress can be assessed by measuring tissue malondialdehyde (MDA) levels, a biomarker for oxidative stress. The goal of this study is to determine the consequences of a twenty percent caloric restriction on the increased oxidative stress documented in tissues from rats exposed to simulated microgravity. MATERIALS/METHODS: Three groups of male SD rats (N=6 in each group) were used: Group 1, control; Group 2, food restricted (20% less food than control); and Group 3, food restricted with HLS. Group 3 was suspended after one week on the HLS-restricted diet and maintained for 14 days. Tissues harvested on day 14 were measured for MDA levels. RESULTS: The body weight gain of Group 2 and Group 3 was reduced as compared to that of Group 1 ( p <0.05) with no significant changes in water intakes. MDA levels in Group 2 were not different from those of the control group and were elevated only in liver tissues (p<0.05). In Group 3, MDA levels in the heart, liver, brain, and testes were significantly elevated (p<0.05) compared to the levels of Groups 1 and 2. CONCLUSIONS: Food restriction alleviated tissue oxidative response in all tissues except for the liver. Excessive stress resulting from HLS appeared to have been minimized by dietary restriction in all tissues except for the heart, liver, brain, and testes. | Weightlessness Simulation |
We report the reconstruction and characterization of a hemicornea (epithelialized stroma), using primary human cells, for use in research and as an alternative to the use of animals in pharmacotoxicology testing. To create a stromal equivalent, keratocytes from human corneas were cultured in collagen-glycosaminoglycan-chitosan foams. Limbal stem cell-derived epithelial cells were seeded on top of these, giving rise to hemi-corneas. The epithelium appeared morphologically similar to its physiological counterpart, as shown by the basal cell expression of p63 isoforms including, in some cases, the stem cell marker p63DeltaNalpha, and the expression of keratin 3 and 14-3-3sigma in the upper cell layers. In addition, the cuboidal basal epithelial cells were anchored to a basement membrane containing collagen IV, laminin 5, and hemidesmosomes. In the stromal part, the keratocytes colonized the porous scaffold, formed a network of interconnecting cells, and synthesized an ultrastructurally organized extracellular matrix (ECM) containing collagen types I, V, and VI. Electron microscopy showed the newly synthesized collagen fibrils to have characteristic periodic striations, with diameters and interfibril spacings similar to those found in natural corneas. Compared to existing models for corneal pharmacotoxicology testing, this new model more closely approaches physiological conditions by including the inducing effects of mesenchyme and cell-matrix interactions on epithelial cell morphogenesis. | Hemidesmosomes |
A 7-hour-old boy underwent an emergency operation with an anticipated diagnosis of total anomalous pulmonary venous connection. The precise diagnosis of common pulmonary vein atresia (CPVA) was made during the operation. A side-to-side anastomosis between the common pulmonary venous chamber and the left atrium was performed. All procedures were successfully carried out on the beating heart under the cardiopulmonary bypass. A tentative diagnosis of CPVA should always be borne in minds in neonates with clinical conditions such as deep cyanosis unresponsive to the oxygen therapy, stubborn acidosis, severe pulmonary venous congestion, and rapid deterioration. The corrective repair of CPVA with the heart beating appears to be the procedure of choice in the setting of seriously damaged myocardium of the immature heart. To the best of our knowledge, this is the youngest survivor of the corrective surgery for CPVA and operation at time of diagnosis is the important principle. | Pulmonary Veins |
(-)-beta-L-2',3'-Dideoxycytidine (L-ddC) and (-)-beta-L-2',3'-dideoxy-5-fluorocytidine (L-FddC) have been reported to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in vitro. In the present study, the 5'-triphosphates of L-ddC (L-ddCTP) and L-FddC (L-FddCTP) were demonstrated to competitively inhibit HIV-1 reverse transcriptase (RT), with inhibition constants (KiS) of 2 and 1.6 microM, respectively, when a poly(rI).oligo(dC)10-15 template primer was used; in comparison Ki values for beta-D-2',3'-dideoxycytidine 5'-triphosphate (D-ddCTP) and beta-D-2',3'-dideoxy-5-fluorocytidine 5'-triphosphate (D-FddCTP) were 1.1 and 1.4 microM, respectively. Use of the mutant RT at position 184 (substitution of methionine to valine [M184V]), which is associated with resistance to beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) and beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), resulted in significant increases (50- to 60-fold) in Ki values for L-ddCTP and L-FddCTP, whereas the elevation in Ki values for D-ddCTP and D-FddCTP was moderate (2-fold). L-ddCTP and L-FddCTP did not inhibit human DNA polymerases alpha and beta up to 100 microM. In contrast, D-ddCTP and D-FddCTP inhibited human DNA polymerase beta, with Ki values of 0.5 and 2.5 microM, respectively. By using sequencing analysis, L-ddCTP and L-FddCTP exhibited DNA chain-terminating activities toward the parental HIV-1 RT, whereas they were not a substrate for the mutant M184V HIV-1 RT.L-ddC and L-FddC did not inhibit the mitochondrial DNA content of human cells up to a concentration of 10 microM, whereas D-ddC and D-FddC decreased the mitochondrial DNA content by 90% at concentrations of 1 and 10 microM, respectively. All of these results suggest that further development of L-ddC, and L-FddC in particular, is warranted as a possible anti-HIV candidate. | Zalcitabine |
Within the last 15 years, members of the bacterial genus Acinetobacter have risen from relative obscurity to be among the most important sources of hospital-acquired infections. The driving force for this has been the remarkable ability of these organisms to acquire antibiotic resistance determinants, with some strains now showing resistance to every antibiotic in clinical use. There is an urgent need for new antibacterial compounds to combat the threat imposed by Acinetobacter spp. and other intractable bacterial pathogens. The essential processes of chromosomal DNA replication, transcription, and cell division are attractive targets for the rational design of antimicrobial drugs. The goal of this review is to examine the wealth of genome sequence and gene knockout data now available for Acinetobacter spp., highlighting those aspects of essential systems that are most suitable as drug targets. Acinetobacter spp. show several key differences from other pathogenic gammaproteobacteria, particularly in global stress response pathways. The involvement of these pathways in short- and long-term antibiotic survival suggests that Acinetobacter spp. cope with antibiotic-induced stress differently from other microorganisms. | Acinetobacter |
The absolute CD4+ T cell count in adults and CD4+ T cell percentage of lymphocytes (CD4%) in pediatrics compliment clinical history and physical examination to inform decisions about initiating antiretroviral therapy (ART). In addition, these immunologic markers predict host susceptibility to specific opportunistic infections, selected drug toxicities, and mortality. These benefits argue strongly for the availability of CD4+ T cell testing capacity in all settings where HIV infection is treated. Several currently available flow cytometry-based devices, and novel CD4+ T cell enumeration techniques such as the panleucogating CD4 are especially suitable for resource-constrained settings. At this time, unfortunately, the landscape of HIV care in sub-Saharan Africa is a mosaic characterized by large areas where CD4+ T cell testing capacity is limited or unavailable, and small, but growing, pockets where the capacity exists. Routine HIV quantification is currently unaffordable and unsustainable in the great majority of the region; therefore, a reliance on CD4+ T cell testing is inevitable for now. To this end, correcting the disparities in CD4+ T cell testing capacity and defining the minimum laboratory requirements for the safe use of antiretroviral drugs through well-designed clinical studies are some of the most urgent priorities of the ongoing global scale-up of ART. | CD4 Lymphocyte Count |
The number of helminths within a host can only increase by the host encountering additional infectious stages, so it is important to consider not only whether a host is infected, but also the severity of its infection. Stochastic models consider explicitly the number of parasites within the host and treat infection, death and other demographic events as random processes. I discuss stochastic helminth population models of increasing degrees of complexity, starting with the infection dynamics within a single host and finishing with the full parasite lifecycle among a population of hosts. I demonstrate the mathematical techniques that can help to analyse these models and discuss the insights into parasite population biology that these methods can bring. | Helminths |
OBJECTIVE: to know the relationship between the sensory function, gait ability, and cognitive function with dependency in older adults. METHOD: a descriptive cross-sectional design, 146 older adults took part. MEASUREMENTS: Snellen chart, Audiometer, Stereognosia tests, Semmes-Weinstein monofilament, basic aromas and flavors, GAITRite system, Montreal Cognitive Assessment Test, the Barthel Index, and the Lawton and Brody Index. RESULTS: sensory function, cognitive function and gait explain 25% dependence on basic activities of daily life and 21% dependence on instrumental activities of daily life. The variables that influence dependence on basic activities were taste (p=.029), gait speed (p=.009), cadence (p=.002) and step length (p=.001) and, in instrumental activities, gait speed (p=.049), cadence (p=.028) and step length (p=.010). CONCLUSION: gait speed, cadence and stride length are variables that influence both dependence on basic and instrumental activities of daily life. | Gait |
5-Hydroxytryptophan (5-HTP) was found to lower plasma 11-oxycorticoids and increase plasma growth hormone in anesthetized dogs. To determine whether these effects were mediated by release of serotonin, 5-HTP and L-tryptophan were injected intravenously alone and after treatment with various drugs. The decrease in corticoids produced by 5-HTP was unaffected by intravenous carbidopa and metergoline, but was abolished by intravenous benserazide in a dose that inhibits central 5-HTP and dopa decarboxylase, and by a small dose of phenoxybenzamine in the third ventricle. Adrenal sensitivity to ACTH was unaffected by 5-HTP. L-Tryptophan did not decrease plasma corticoids; instead it produced a small increase. The increase in plasma growth hormone produced by 5-HTP was potentiated by carbidopa and abolished by benserazide. L-Tryptophan did not increase plasma growth hormone; instead it produced no change or in some instances a decrease. Plasma growth hormone declined after administration of phenoxybenzamine in the third ventricle, and the decline continued after administration of 5-HTP. The data indicate that the effects of 5-HTP on ACTH and growth hormone secretion are not due to central release of serotonin and suggest that they are due instead to serotonin-induced release of catecholamines from catecholamine-secreting neurons. | Metergoline |
BACKGROUND: Phosphatidylcholine (PC) is intrinsically missing in intestinal mucus of patients with ulcerative colitis. Topical supplementation with delayed intestinal release PC formulations is assumed to compensate this lack. Three monocenter randomized controlled trials (RCTs) with a 30% PC-containing lecithin were successful, whereas 1 trial with >94% PC-containing lecithin failed. OBJECTIVES: Evaluation of 30% PC-containing lecithin provided in a delayed intestinal release formulation for treatment efficacy of ulcerative colitis was evaluated by meta-analysis of 3 RCTs. METHODS: Meta-analysis of 3 studies was performed using RevMan 5.3 software. Odds ratio (OR) and 95% Cl were calculated for remission, clinical and endoscopic improvement, histology, and life quality. p values <0.05 were accepted as significant. RESULTS: The meta-analysis of 3 RTCs with 160 included patients with ulcerative colitis verified that PC improved the rate of remission (OR = 9.68), as well as clinical (OR = 30.58) and endoscopic outcomes (OR = 36.73). Within the available patient population, also histology and quality of life became better. All effects were significant over placebo. Achieved remission was maintained in a higher percentage of patients under intestinal-release PC formulation than placebo. The profile of adverse events was identical to the placebo population. CONCLUSIONS: A 30% PC-containing lecithin in delayed intestinal release formulation improves clinical and endoscopic outcomes, histologic activity, and quality of life in patients with ulcerative colitis. For the patients, lack of adverse events is an important consideration. | Remission Induction |
Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations." | Leukemia, Megakaryoblastic, Acute |
An analysis of the anaesthesia caseload of the United Nations Military Hospital and its predecessors over the first 12 months of operation from September 1999 has been performed. Most patients were East Timorese civilians or Australian Military personnel. General anaesthesia using the ULCO Portable Field Anaesthesia Machine was most commonly administered." | Anesthesia Department, Hospital |
Obesity is associated with the growth and expansion of adipocytes which could be decreased via several mechanisms. Cissus Quadrangularis (CQ) extract has been shown to reduce obesity in humans; however, its effect on human white adipocytes (hWA) has not been elucidated. This study aimed to investigate the effects of CQ on obesity, lipolysis, and browning of hWA. CQ treatment in obese humans significantly decreased waist circumference at week 4 and week 8 when compared with the baseline values (p < 0.05 all) and significantly decreased hip circumference at week 8 when compared with the baseline and week 4 values (p < 0.05 all). Serum leptin levels of the CQ-treated group were significantly higher at week 8 compared to baseline levels (p < 0.05). In hWA, glycerol release was reduced in the CQ-treated group when compared with the vehicle-treated group. In the browning experiment, pioglitazone, the PPAR-gamma agonist, increased UCP1 mRNA when compared to vehicle (p < 0.01). Interestingly, 10, 100, and 1000 ng/ml CQ extract treatment on hWA significantly enhanced UCP1 expression in a dose-dependent manner when compared to pioglitazone treatment (p < 0.001 all). In conclusion, CQ decreased waist and hip circumferences in obese humans and enhanced UCP1 mRNA in hWA suggestive of its action via browning of hWA. | Cissus |
Pestiviruses isolated from sheep and goats in India thus far have been bovine viral diarrhoea virus 1 (BVDV-1) or BVDV-2. During routine genetic typing of pestiviruses in the years 2009-10, border disease virus (BDV) was detected in eight Indian sheep of a flock showing clinical signs of BD by real time RT-PCR. All the samples yielded positive virus isolates in cell culture but were found negative by a BVDV antigen ELISA. A representative BDV isolate was characterized at genetic and antigenic level. Phylogenetic analysis carried out in 5'-UTR, N(pro) and E2 regions of genome typed the Indian BDV isolate as BDV-3. A more detailed analysis in N(pro) and entire region coding structural proteins showed that the N(pro) (168), C (100 aa), E(rns) (227 aa), E1 (195 aa) and E2 (373 aa) proteins were of size characteristic for BDV reference strain X818. Antigenic differences were evident between the BDV-3 isolate and previously reported BDV-1, BDV-5 and BDV-7 strains. Although origin of BDV-3 in India is not clear, the results reflect probable introduction through trade in sheep between India and other countries or BDV-3 may be more widely distributed. Additionally, this study suggests that for diagnosis of BDV infection, the commercial BVDV Ag-ELISA should be used with caution. This is the first identification of BDV in sheep in India which highlights the need for continued pestivirus surveillance and assessing its impact on sheep and goat production. | Border disease virus |
Thirty-one limonoids and one tirucallane-type triterpenoid were isolated from the fruits of Melia azedarach (Meliaceae). The structures of 14 of these isolated compounds were elucidated on the basis of spectroscopic analyses and comparison with literature. All of these compounds were evaluated for their cytotoxic activities against HL60, A549, AZ521, and SK-BR-3 human cancer cell lines. Meliarachin C (IC50 0.65 muM) and 3-O-deacetyl-4'-demethyl-28-oxosalannin (IC50 2.8 muM) exhibited potent cytotoxic activity against HL60 cells, and this was demonstrated mainly due to the induction of apoptosis by flow cytometry. Western blot analysis suggested that both compounds induced apoptosis via both the mitochondrial and death receptor-mediated pathways. In addition, 25 compounds were evaluated for their inhibitory effects against the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. | Limonins |
Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1beta and an oxygen-regulated subunit HIF-1alpha (or its paralogs HIF-2alpha and HIF-3alpha). The stability and activity of the alpha subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1alpha trigger its association with pVHL E3 ligase complex, leading to HIF-1alpha degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1alpha subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy. | Hypoxia-Inducible Factor 1 |
We studied 28 Polish hereditary fructose intolerant (HFI) patients (26 unrelated) by direct sequencing of the ALDOB coding region/splice sites. Eight different mutations were found including two novel ones (each found in two unrelated individuals): c.250delC (frameshift) and c.522 C > G (p.Y174X). The most frequent mutation c.448 G > C (p.A150P, 67% of chromosomes) was screened for in a group of 1049 randomly selected unrelated individuals. Eight (1:131) carriers were found allowing to estimate the HFI prevalence in Poland as 1:31,000. | Fructose Intolerance |
Intestinal metaplasia is a well-established premalignant condition of the stomach that is characterized by mucin carbohydrate modifications defined by histochemical methods. The purpose of the present study was to see whether the expression of mucin core proteins was modified in the different types of intestinal metaplasia and to evaluate the putative usefulness of mucins as molecular markers" in this setting. We used a panel of monoclonal antibodies with well-defined specificities to MUC1, MUC2, MUC5AC, and MUC6 to characterize the expression pattern of mucins. In contrast to normal gastric mucosa, the complete form or type I intestinal metaplasia (n = 20) displayed little or no expression of MUC1, MUC5AC, or MUC6 in the metaplastic cells and strong expression of the intestinal mucin MUC2 in the goblet cells of all cases. The incomplete forms of intestinal metaplasia, type II (n = 25) and type III (n = 16), expressed MUC1 and MUC5AC in every case, both in goblet and in columnar cells. MUC6 was also expressed in 16 cases of type II intestinal metaplasia and in 11 cases of type III intestinal metaplasia. The intestinal mucin MUC2 was expressed in every case of incomplete intestinal metaplasia, mostly in goblet cells. The mucin expression profile in the different types of intestinal metaplasia allows the identification of two patterns: one defined by decreased levels of expression of "gastric" mucins (MUC1, MUC5AC, and MUC6) and expression of MUC2 intestinal mucin, which corresponds to type I intestinal metaplasia, and the other defined by coexpression of "gastric mucins" (MUC1, MUC5AC, and MUC6) together with the MUC2 mucin, encompassing types II and III intestinal metaplasia. Our results challenge the classical sequential pathway of intestinal metaplasia (from type I to type III via a type II intermediate step)." | Mucin-6 |
Fluoroscopic guided intra-articular hip injections generally utilize a standard anterior-posterior view. However, this approach can expose patients to inadvertent femoral nerve or vessel infiltration owing to the proximity of the neurovascular bundle to the joint space. This case-series study describes a novel technique using fluoroscopic ipsilateral oblique angulation and caudal tilt of the image intensifier. With this view, the clinician can advance the needle in a lateral to medial trajectory to obtain intra-articular access and minimize the risk of complications. This method was performed in five patients with refractory chronic hip osteoarthritis, which resulted in notable pain improvements and no reported adverse events. The suggested technique could provide a safer alternative to the anterior-posterior imaging technique for intra-articular hip injections by avoiding the femoral neurovascular bundle, limiting needle repositioning, and offering a satisfactory postprocedural analgesic effect. | Injections, Intra-Articular |
Leptospira was isolated from environmental water in central Japan using selective medium comprising five antibiotics, namely sulfamethoxazole, trimethoprim, amphotericin B, fosfomycin, and 5-fluorouracil. Of 100 water samples 57 (57%) were culture-positive and 50 pure cultures were isolated. Of the 50 cultures isolated from water 48 were classified into a saprophytic clade on the basis of 16S ribosomal RNA gene sequences. However, it was previously reported that isolates from soil in Japan belonged to pathogenic, intermediate, and saprophytic clades, the current findings suggest less diversity of Leptospira species in environmental water than that in soil in Japan. | Leptospira |
Progression from health to a classified autoimmune disease is an evolving process that can happen rapidly in some diseases, but usually takes years to develop. Specific immune alterations predate pathogenic autoimmunity and can be used as disease biomarkers to identify high-risk individuals for prevention studies applied in the pre-clinical state. Here we discuss recent findings that illuminate specific immune pathways that are altered in the earliest phases of pre-clinical autoimmunity as well as those mediators more closely associated with later clinically apparent and classified disease onset. | Seroconversion |
The genome of the hyperthermophilic and piezophilic euryarchaeaon Thermococcus barophilus Ch5 encodes three putative alcohol dehydrogenases (Tba ADHs). Herein, we characterized Tba ADH(547) biochemically and probed its catalytic mechanism by mutational studies. Our data demonstrate that Tba ADH(547) can oxidize ethanol and reduce acetaldehyde at high temperature with the same optimal temperature (75 degrees C) and exhibit similar thermostability for oxidization and reduction reactions. However, Tba ADH(547) has different optimal pH for oxidation and reduction: 8.5 for oxidation and 7.0 for reduction. Tba ADH(547) is dependent on a divalent ion for its oxidation activity, among which Mn(2+) is optimal. However, Tba ADH(547) displays about 20% reduction activity without a divalent ion, and the maximal activity with Fe(2+). Furthermore, Tba ADH(547) showcases a strong substrate preference for 1-butanol and 1-hexanol over ethanol and other alcohols. Similarly, Tba ADH(547) prefers butylaldehyde to acetaldehyde as its reduction substrate. Mutational studies showed that the mutations of residues D195, H199, H262 and H274 to Ala result in the significant activity loss of Tba ADH(547), suggesting that residues D195, H199, H262 and H274 are responsible for catalysis. Overall, Tba ADH(547) is a thermoactive ADH with novel biochemical characteristics, thereby allowing this enzyme to be a potential biocatalyst. | Thermococcales |
An ongoing discussion in the recognition-memory literature concerns the question of whether recognition judgments reflect a direct mapping of graded memory representations (a notion that is instantiated by signal detection theory) or whether they are mediated by a discrete-state representation with the possibility of complete information loss (a notion that is instantiated by threshold models). These 2 accounts are usually evaluated by comparing their (penalized) fits to receiver operating characteristic data, a procedure that is predicated on substantial auxiliary assumptions, which if violated can invalidate results. We show that the 2 accounts can be compared on the basis of critical tests that invoke only minimal assumptions. Using previously published receiver operating characteristic data, we show that confidence-rating judgments are consistent with a discrete-state account. (PsycINFO Database Record" | Signal Detection, Psychological |
Asthma is an inflammatory disease of the airways characterized by intermittent episodes of wheezing, chest tightness, and cough. Many of the inflammatory pathways implicated in asthma involve cytokines and growth factors that activate Janus kinases (JAKs). The discovery of the JAK/signal transducer and activator of transcription (STAT) signaling pathway was a major breakthrough that revolutionized our understanding of cell growth and differentiation. JAK inhibitors are under active investigation for immune and inflammatory diseases, and they have demonstrated clinical efficacy in diseases such as rheumatoid arthritis and atopic dermatitis. Substantial preclinical data support the idea that inhibiting JAKs will ameliorate airway inflammation and hyperreactivity in asthma. Here, we review the rationale for use of JAK inhibitors in different asthma endotypes as well as the preclinical and early clinical evidence supporting such use. We review preclinical data from the use of systemic and inhaled JAK inhibitors in animal models of asthma and safety data based on the use of JAK inhibitors in other diseases. We conclude that JAK inhibitors have the potential to usher in a new era of anti-inflammatory treatment for asthma. | Janus Kinase Inhibitors |
The article qualifies the nature of psychosociological perspective in analysing corruption in organizations. Corruption is analysed as a mental event and social conditions of corruption are investigated. In particular six social and organizational factors are identified as relevant in determining the diffusion of corruption: meaning, work wellbeing, consistency, social recognition, reflexivity, social relations. The main hypothesis explored in the article is that to take managerial care of the organisational factors above mentioned is a strong and active prevention of the risk of corruption. | Ethics, Institutional |
Microfibers are the most common type of microplastics in freshwater environments. Anthropogenic climate stressors, such as freshwater acidification (FA), can interact with plastic pollution to disrupt freshwater ecosystems. However, the underlying mechanisms responsible for the interactive effects of microfibers and FA on aquatic organisms remain poorly understood. In this study, we investigated individual Daphnia magna-microbiota interactions affected by interactions between microfibers and FA (MFA). We found that the accumulated amount of microfibers in pH-treatment groups was significantly higher than in the control groups, resulting in negative consequences on reproduction, growth, and sex ratio. We also observed that MFA interactions induced immunity- and reproduction-related biological processes. In particular, the abundance of pathogenic bacteria increased only in MFA groups, indicating that MFA interactions can cause intestinal damage. Our integrated analysis of microbiomes and host transcriptomes revealed that synergistic adverse effects of MFAs are closely related to changes in microbial communities, suggesting that D. magna fitness and the microbial community are causally linked. These finding may help elucidate the toxicity mechanisms governing the responses of D. magna to microfibers and acidification interactions, and to host-microbiome-environment interactions. | Cladocera |
Galectins are beta-galactoside-binding proteins. As carbohydrate-binding proteins, they participate in intracellular trafficking, cell adhesion, and cell-cell signaling. Accumulating evidence indicates that they play a pivotal role in numerous physiological and pathological activities, such as the regulation on cancer progression, inflammation, immune response, and bacterial and viral infections. Galectins have drawn much attention as targets for therapeutic interventions. Several molecules have been developed as galectin inhibitors. In particular, TD139, a thiodigalactoside derivative, is currently examined in clinical trials for the treatment of idiopathic pulmonary fibrosis. Herein, we provide an in-depth review on the development of galectin inhibitors, aiming at the dissection of the structure-activity relationship to demonstrate how inhibitors interact with galectin(s). We especially integrate the structural information established by X-ray crystallography with several biophysical methods to offer, not only in-depth understanding at the molecular level, but also insights to tackle the existing challenges. | Galectins |
The amphipathic flavoprotein NADH-cytochrome b5 reductase from steer liver was converted into the membrane-binding and soluble catalytic domains by controlled subtilisin proteolysis of vesicle-bound, externally oriented reductase. Amino acid analysis of the single nonpolar peptide which remained associated with the vesicles showed that it has a molecular weight of about 6400-6500 and that 65-66% of the amino acid residues are hydrophobic. Both the intact reductase and the nonpolar peptide were blocked to sequencing. Carboxypeptidase Y digestion of the holoenzyme and of a chymotryptically generated flavopeptide, which had lost membrane-binding capacity, released 1 residue of alanine and 2 residues of phenylalanine, indicating a common carboxyl terminus. Partial sequence analysis of the reductase placed the nonpolar peptide to the NH2-terminal side of the subtilisin-generated flavopeptide domain. Thus, the membrane-binding domain of cytochrome b5 reductase is localized at the NH2-terminus of the whole protein. The nonpolar peptide bound to vesicles contains a single fluorescent tryptophan with an emission maximum characteristic of a hydrophobic environment. | Cytochrome Reductases |
Defined DNA substrates containing discrete abasic sites or paired abasic sites set 1, 3, 5 and 7 bases apart on opposite strands were constructed to examine the reactivity of S1, mung bean and P1 nucleases towards abasic sites. None of the enzymes acted on the substrate containing discrete abasic sites. Under conditions where little or no non-specific DNA degradation was observed, all three nucleases were able to generate double-strand breaks when the bistranded abasic sites were 1 and 3 base pairs apart. However, when the abasic sites were further apart, the enzymes again failed to cleave the DNA. These results indicate that single abasic sites do not cause sufficient denaturation of the DNA to allow incision by these single-strand specific endonucleases. The reactivity of these enzymes was also investigated on DNA substrates that were nicked by DNasel or more site-specifically by endonuclease III incision at the discrete abasic sites. The three nucleases readily induced a strand break opposite such nicks." | Single-Strand Specific DNA and RNA Endonucleases |
The effect of phenoxybenzamine on in vitro contractile responses of human vasectomy tissues was investigated. Phenoxybenzamine (0.01-10 mumol l-1) produced a differential inhibition of contractions induced by noradrenaline (1-300 mumol l-1) in the human vas deferens in that it blocked the longitudinal but not the circular muscle. Contractions of both muscle types induced by noradrenaline (100 mumol l-1) were inhibited by either prazosin (0.01-10 mumol l-1), a competitive alpha 1-selective adrenoceptor antagonist or benextramine (0.01-10 mumol l-1), an irreversible alpha 1-adrenoceptor blocker, but were unaffected by chloroethylclonidine (0.1-100 mumol l-1), an irreversible alpha 1B-adrenoceptor blocker. In calcium-free/EGTA (1 mmol l-1) medium, contractions of the longitudinal but not circular muscle induced by noradrenaline (100 mumol l-1) were inhibited by phenoxybenzamine (0.01-1 mumol l-1). Chloroethylclonidine (10-100 mumol l-1) was ineffective on both muscle types in calcium-free medium, but, on readmission of calcium, in markedly inhibited the recovery of longitudinal but not the circular muscle. These results suggest a mechanism for the male contraceptive action of phenoxybenzamine by a selective blockade of longitudinal but not circular muscle contractions. The results are discussed in relation to (i) the possible involvement of receptor reserves for noradrenaline and of alpha 1-adrenoceptor subtypes coupled in the longitudinal and circular muscle to different mechanisms for increasing cytosolic calcium, (ii) a role in the longitudinal muscle for chloroethylclonidine-sensitive alpha 1-adrenoceptors in replenishment of a functional pool of intracellular calcium and (iii) the inhibition of sperm emission by phenoxybenzamine. | Cystamine |
Fingolimod is a first-in-class of sphingosine-1-phosphate (S1P) receptor modulator and is widely used a therapeutic drug for multiple sclerosis (MS), autoimmune disease in the central nervous system. About 25 year ago, a natural product, myriocin was isolated from culture broths of the fungus Isaria sinclairii. Myriocin, a rather complex amino acid having three successive asymmetric centers, was found to show a potent immunosuppressive activity in vitro; however, it induced a strong toxicity in vivo. To find out a less toxic immunosuppressive candidate, the chemical structure of myriocin was simplified to a nonchiral symmetric 2-substituted-2-aminoproane-1,3-diol framework. Finally, a highly potent immunosuppressant, fingolimod was found by the extensive chemical modification and pharmacological evaluation using skin allograft model in vivo. Throughout the analyses of the mechanism action of fingolimod, it is revealed that S1P receptor 1 (S1P(1)) plays an essential role in lymphocyte circulation and that the molecular target of fingolimod is S1P(1). Phosphorylated fingolimod acts as a functional" antagonist at S1P(1), modulates lymphocyte circulation, and shows a potent immunosuppressive activity. Fingolimod significantly reduced the relapse rate of MS in the clinical studies and has been approved as a new therapeutic drug for MS in more than 80 countries." | Fingolimod Hydrochloride |
Several genes have been related to late-onset Alzheimer's disease (LOAD). Phospholipases A2 (PLA2) influence the processing and secretion of the amyloid precursor protein, which gives rise to the beta-amyloid peptide, the major component of the amyloid plaque in AD. Hence, in the present study, polymorphisms of three genes encoding PLA2 enzymes group (cytosolic PLA2: BanI cPLA2 polymorphism; calcium-independent PLA2: AvrII iPLA2 polymorphism; PAFAH: Val279Phe PAFAH polymorphism) were analysed in a case-control sample using 58 patients with LOAD and 107 matched healthy controls. There was a genotypic association between the BanI cPLA2 polymorphism and LOAD (chi2=6.25, 2df, p=0.04), however there was no allelic association. There were no associations between AvrII iPLA2 and Val279Phe PAFAH polymorphisms and LOAD. These data suggest that the BanI cPLA2 polymorphism may play a role in the susceptibility for LOAD in our Brazilian sample. | Phospholipases A2, Cytosolic |
The Jamthund is the fourth most common breed in Sweden with approximately 1600 pups registered each year. Although it has been known that some adult dogs go blind, so they cannot hunt, the Jamthund dog has historically not been screened for hereditary eye diseases. This report describes nine Swedish Jamthund dogs with retinal degeneration. These dogs represent all Jamthund dogs diagnosed with progressive retinal atrophy (PRA) by the Swedish Eye Panel and registered with the Swedish Kennel Club from January 1998 to September 2008. The dogs were examined with indirect opthalmoscopy and slitlamp biomicroscopy. Additionally, electroretinograms (ERGs) following ECVO guidelines were performed in two dogs (one affected and one normal) and the eyes from three affected dogs were examined by light-microscopy postmortem. Typical findings were bilateral symmetric generalized retinal degeneration with tapetal hyper-reflectivity, attenuation of blood vessels and pigment clumping in the nontapetal fundus. These retinal findings progressed with time in two dogs after re-examination. Visual impairment, especially under dim light conditions, was observed in the affected dogs. ERG from one affected dog showed profoundly reduced rod responses, whereas cone responses were better preserved. Microscopic changes in the eyes from three dogs were characterized by a severe diffuse predominantly outer retinal degeneration and atrophy. Re-sequencing of the prcd-gene for eight of the nine investigated dogs revealed that none of the individuals carried disease allele that has been associated with prcd-PRA in other breeds. In conclusion, ophthalmoscopic, electroretinographic, and light-microscopic alterations observed in nine Jamthund dogs were compatible with PRA. The prcd mutation was excluded as a cause of this retinopathy. | Retinal Diseases |
The yield and chemical structures of exopolysaccharides (EPS) produced by many strains of Streptococcus thermophilus have been characterized. However, the kinetics (or production profile) for EPS during milk fermentation is not clear. In this study, we investigated whether any differences existed in the yield and molar mass of EPS when milk was fermented at the same acidification rate by 2 strains of S. thermophilus (St-143 and ST-10255y). The type of EPS produced by these 2 strains is different. Milk samples were analyzed for EPS concentration every 30 min during a fermentation period of 270 min (final pH 4.5) by using a modified quantification method, which was faster and validated for its recovery of added EPS. Rheological properties of milks during fermentation were also analyzed using small-strain dynamic oscillatory rheology. For the determination of molar mass, EPS extracts were isolated by ultrafiltration of whey obtained during fermentation of milk to pH values 5.2, 4.9, 4.7, and 4.5, and molar mass was analyzed using size-exclusion chromatography-multi-angle laser light scattering. During fermentation, both strains appeared to start producing significant amounts of EPS after about approximately 150 min, which corresponded to pH approximately 5.3, which was close to the point of gelation. During the remainder of the fermentation process (150-270 min), the EPS concentration from strains St-143 and ST-10255y significantly increased from 30 to 72 mg/L and from 26 to 56 mg/L, respectively. The quantity of EPS recovered by our modified method was estimated to represent approximately 60% of the total EPS added to milk. The molar mass of EPS produced by both strains appeared to slightly decrease during fermentation. At pH 5.2, EPS from St-143 and ST-10255y had molar masses of 2.9 x 10(6) and 1.4 x 10(6) g/mol, respectively, which decreased to 1.6 x 10(6) and 0.8 x 10(6) g/mol, respectively, when the pH of milk was 4.5. Distinct differences were apparent in the rheological properties of gels fermented by the 2 strains. At the end of fermentation, St-143 fermented milk had weaker gels with storage modulus (G') value at pH 4.6 of 26 Pa, whereas gels made with ST-10255y were stiffer with a G' value at pH 4.6 of 82 Pa. For St-143 gels, maximum loss tangent (LT(max)) values were higher (0.50) and occurred earlier (at a higher pH value) than the LT(max) values (0.46) for gels from ST-10255y strain. Because the fermentation conditions were identical for both strains, the observed changes in rheological properties could be due to the differences in chemical structures and molar mass of the EPS produced by these 2 S. thermophilus strains. | Streptococcus thermophilus |
Skin ageing is the result of intrinsic genetic and extrinsic lifestyle factors. However, there is no consensus on skin ageing phenotypes and ways to quantify them. In this systematic review, we first carefully identified 56 skin ageing phenotypes from multiple literature sources and sought the best photo-numeric grading scales to evaluate them. Next, we conducted a systematic review on all 44 Genome-wide Association Studies (GWAS) on skin ageing published to date and identified genetic risk factors (2349 SNPs and 366 genes) associated with skin ageing. We identified 19 promising SNPs found to be significantly (p-Value < 1E-05) associated with skin ageing phenotypes in two or more independent studies. Here we show, using enrichment analyses strategies and gene expression data, that (1) pleiotropy is a recurring theme among skin ageing genes, (2) SNPs associated with skin ageing phenotypes are mostly located in a small handful of 44 pleiotropic and hub genes (mostly on the chromosome band 16q24.3) and 32 skin colour genes. Since numerous genes on the chromosome band 16q24.3 and skin colour genes show pleiotropy, we propose that (1) genes traditionally identified to contribute to skin colour have more than just skin pigmentation roles, and (2) further progress towards understand the development of skin pigmentation requires understanding the contributions of genes on the chromosomal band 16q24.3. We anticipate our systematic review to serve as a hub to locate primary literature sources pertaining to the genetics of skin ageing and to be a starting point for more sophisticated work examining pleiotropic genes, hub genes, and skin ageing phenotypes. | Phenotype |
Traumatic injury remains an unfortunate and all-too-common event in the United States military population. Traumatic hemipelvectomy is a rare but devastating injury with few survivors recorded in the medical literature. We report a surviving case of traumatic hemipelvectomy and review an approach to management. | Hemipelvectomy |
This study aims to explore the protective effects of Picroside III, an active ingredient of Picrorhiza scrophulariiflora, on the intestinal epithelial barrier in tumor necrosis factor-alpha (TNF-alpha) induced Caco-2 cells and dextran sulfate sodium (DSS) induced colitis in mice. Results show that Picroside III significantly alleviated clinical signs of colitis including body weight loss, disease activity index increase, colon shortening, and colon tissue damage. It also increased claudin-3, ZO-1 and occludin expressions and decreased claudin-2 expression in the colon tissues of mice with colitis. In vitro, Picroside III also significantly promoted wound healing, decreased the permeability of cell monolayer, upregulated the expressions of claudin-3, ZO-1 and occludin and downregulated the expression of claudin-2 in TNF-alpha treated Caco-2 cells. Mechanism studies show that Picroside III significantly promoted AMP-activated protein kinase (AMPK) phosphorylation in vitro and in vivo, and blockade with AMPK could significantly attenuate the upregulation of Picroside III in ZO-1 and occludin expressions and the downregulation of claudin-2 expression in TNF-alpha treated Caco-2 cells. In conclusion, this study demonstrates that Picroside III attenuated DSS-induced colitis by promoting colonic mucosal wound healing and epithelial barrier function recovery via the activation of AMPK. | Picrorhiza |
A screening for siderophores produced by the ectomycorrhizal fungi Laccaria laccata and Laccaria bicolor in synthetic low iron medium revealed the release of several different hydroxamate siderophores of which four major siderophores could be identified by high resolution mass spectrometry. While ferricrocin, coprogen and triacetylfusarinine C were assigned as well as other known fungal siderophores, a major peak of the siderophore mixture revealed an average molecular mass of 797 for the iron-loaded compound. High resolution mass spectrometry indicated an absolute mass of m/z = 798.30973 ([M + H](+)). With a relative error of Delta = 0.56 ppm this corresponds to linear fusigen (C33H52N6O13Fe; MW = 797.3). The production of large amounts of linear fusigen by these basidiomycetous mycorrhizal fungi may possibly explain the observed suppression of plant pathogenic Fusarium species. For comparative purposes Fusarium roseum was included in this study as a well known producer of cyclic and linear fusigen. | Laccaria |
The more complex 3' UTR in higher organisms may have the function of increasing post-transcriptional gene regulation. Recent RNA sequencing technologies have provided us with the possibility to capture the complete 3' UTR landscape of different species and cells. However, no systematic analysis of sheep-related 3' UTR has been performed. Here, we conducted a detailed analysis of the 3' UTR with the primary goal of identifying intact 3' UTR landscapes in the sheep muscles of the three developmental stages. Based on strand-specific RNA sequencing (ssRNA-seq) data, we found that thousands of genes in sheep muscle are continuously transcribed after the UTR of the reference genome (Oar_v4.0). More than 66% of the 3' UTR extensions exhibit similar expression trends to their upstream gene exons. These 3' UTR extensions strongly enrich thousands of conserved microRNA binding sites. The 3' UTR extension-associated RNA of PFKM (PuaRNA) was predicted to be derived from the 3' UTR of PFKM. In sheep myocytes, myotubes and various tissues, the expression pattern of PuaRNA is positively correlated with that of PFKM. Taken together, these new 3' UTR annotations greatly extend the range of mammalian post-transcriptional regulatory networks, which have a particular impact on the regulation of sheep muscle development. | Sheep, Domestic |
Tandem transcription interference occurs when the act of transcription from an upstream promoter suppresses utilization of a co-oriented downstream promoter. Because eukaryal genomes are liberally interspersed with transcription units specifying long non-coding (lnc) RNAs, there are many opportunities for lncRNA synthesis to negatively affect a neighboring protein-coding gene. Here, I review two eukaryal systems in which lncRNA interference with mRNA expression underlies a regulated biological response to nutrient availability. Budding yeast SER3 is repressed under serine-replete conditions by transcription of an upstream SRG1 lncRNA that traverses the SER3 promoter and elicits occlusive nucleosome rearrangements. SER3 is de-repressed by serine withdrawal, which leads to shut-off of SRG1 synthesis. The fission yeast phosphate homeostasis (PHO) regulon comprises three phosphate acquisition genes - pho1, pho84, and tgp1 - that are repressed under phosphate-replete conditions by 5' flanking lncRNAs prt, prt2, and nc-tgp1, respectively. lncRNA transcription across the PHO mRNA promoters displaces activating transcription factor Pho7. PHO mRNAs are transcribed during phosphate starvation when lncRNA synthesis abates. The PHO regulon is de-repressed in phosphate-replete cells by genetic manipulations that favor 'precocious' lncRNA 3'-processing/termination upstream of the mRNA promoters. PHO lncRNA termination is governed by the Pol2 CTD code and is subject to metabolite control by inositol pyrophosphates." | Phosphoglycerate Dehydrogenase |
Intermittent parathyroid hormone (PTH) administration increases bone formation and bone mass and is being used as a therapy for osteoporosis. By contrast, chronic hyperparathyroidism results in the metabolic bone disease osteitis fibrosa characterized by local bone resorption and peritrabecular bone marrow fibrosis in humans. The animal models that can mimic the paradoxical effects of PTH provide the basis for further study of the functions of this hormone in skeletal tissues. In both rats and mice, the anabolic effects of PTH on bone can be achieved by daily injections subcutaneously and the catabolic effects can be achieved by continuous infusion with osmotic pumps. This chapter offers detailed information, such as the dosage and preparation of PTH, using the example of treatment of rats with PTH intermittently or continuously. High-quality, RT-PCR ready RNA is required for the analysis of gene expression. For the analysis of gene expression in bone, usually long bones are used for RNA extraction. Here we describe how to extract RNAs from the metaphyseal trabecular primary spongiosa of rat femur by a method based on two commercially available kits. This protocol can be used in other tissues with slight modification of the amount of reagent used according to the tissue size. | Parathyroid Hormone |
Use of the potent bronchodilators, beta 2-adrenoceptor agonists, has been a cornerstone of the treatment of obstructive lung disease, especially asthma, for the past 30 years. However, the occurrence of side effects and the development of tolerance have been discussed as limitations to their use. beta 2-Adrenoceptors are located on the surface of most cell types throughout the human body, and treatment with beta 2-agonists may exert effects in a wide variety of tissues. As with other pharmacological receptors, beta 2-adrenoceptors in most tissues develop tolerance as a result of continuous beta 2-stimulation. However, the bronchodilatory effect appears to be unaffected by the development of tolerance. Interestingly, most studies have yielded evidence suggesting tolerance development regarding protection against bronchoconstrictor stimuli such as methacholine, adenosine and exercise. Although the protective effect of a beta 2-agonist becomes attenuated with continuous treatment, this tolerance is partial and adequate residual protective effect remains. | Bronchodilator Agents |
2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-deazapteridines and four 2,4-diaminoquinazolines, each with an aryl groups attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH2NH, CH2N(CH3),CH2S, or CH2CH2), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 microM) with 14 compounds below 0.1 microM, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 microM). As inhibitors of T gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC50 values in the order of magnitude with those of piritrexim (0.017 microM) and trimetrexate (0.010 microM), and 17 compounds of this group gave IC50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 microM) and trimetrexate (0.042 microM). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC50 values of 0.10 microM or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC50 rat liver divided by IC50 T. gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose 6-substituent is CH2CH2C6H3(OCH3)2-2,5. This compound is over 10(3)-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH2NHC6H3(CH3)2-2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH2NH, CH2N(CH3), CH2CH2, and CH2S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia. | Trimetrexate |
The snake alarm call of Japanese tits prompts nesting adults to search for and mob the reptile until it is driven away. From playback experiments, Suzuki (2018) has inferred that the call provides an associative cue, evoking a searching image of the salient visual features of the predator-a novel approach to exploring visual attention and vocal communication in the wild. | Animal Communication |
We have analysed limit digests of mini-circles from kinetoplast DNA of Crithidia luciliae by gel electrophoresis. Endonucleases HapII and AluI cut the circles into at least 37 and 21 fragments, respectively, and leave no circles intact. In both cases the added molecular weights of the fragments, estimated from mobility in gels, exceeds 18 X 10(6), i.e. more than 12 times the molecular weight of the mini-circle DNA. Endonucleases HindII + III, EcoRI and HpaI cut only part of the circles. These results show that the mini-circles are heterogeneous in base sequence. Different sequence classes are present in different amounts. DNA-DNA renaturation analysis of mini-circle DNA yields a complexity of about 3 X 10(6), i.e. twice the molecular weight on one mini-circle. The delta tm of native and renatured duplexes is about 1 degree C, showing that the sequence heterogeneity is a micro-heterogeneity. Electron microscopy, gel electrophoresis and sedimentation analysis show that the circles that are not cut by endonucleases HindII + III remain catenated in very large associations. These associations lack the 'rosette' structures and the long edge loops characteristic of intact kinetoplast DNA. This suggests that the mini-circle classes cut by endonucleases HindII + III are present throughout the network and that the maxi-circle component of the network (see accompanying paper) is not essential to hold the network together. Prolonged electrophoresis on 1.5% or 2% agarose gels resolves the open mini-circles into three and linearized mini-circles into four bands, present in different amounts. We conclude that the mini-circles are also heterogeneous in size, the difference in size between the two extreme size classes being 4% of the contour length. Digestion with endonuclease HapII shows that at least three out of these four bands differ in sequence. Possible mechanisms that could account for the micro-heterogeneity in sequence of mini-circles are discussed. | Nucleic Acid Renaturation |
During a plant viral infection, host-pathogen interactions are critical for successful replication and propagation of the virus through the plant. RNA silencing suppressors (RSSs) are key players of this interplay, and they often interact with different host proteins, developing multiple functions. In the Potyviridae family, viruses produce two main RSSs, HCPro and type B P1 proteins. We focused our efforts on the less known P1b of cucumber vein yellowing virus (CVYV), a type B P1 protein, to try to identify possible factors that could play a relevant role during viral infection. We used a chimeric expression system based on plum pox virus (PPV) encoding a tagged CVYV P1b in place of the canonical HCPro. We used that tag to purify P1b in Nicotiana-benthamiana-infected plants and identified by mass spectrometry an importin-beta-like protein similar to importin 7 of Arabidopsis thaliana. We further confirmed the interaction by bimolecular fluorescence complementation assays and defined its nuclear localization in the cell. Further analyses showed a possible role of this N. benthamiana homolog of Importin 7 as a modulator of the RNA silencing suppression activity of P1b. | Potyviridae |
BACKGROUND: Croton oil (CO) is used by dermatologists and plastic surgeons in deep chemical peels. It is mixed with phenol, water, and a soap in Baker-Gordon's or Hetter's formulas. There is controversy as to whether CO or phenol is the active agent in the dermal effect of deep chemical peels. OBJECTIVE: To better clarify the role of CO in deep peels, by identification of active compounds in commercially available CO in the United States and biological effects in vivo. MATERIALS AND METHODS: Liquid chromatography-tandem mass spectrometry on CO and a domestic pig model experiment using 3 different formulas: G1: 5% Septisol (SEP), G2: 1.6% croton oil in 35% phenol with 5% SEP, and G3: 35% phenol with 5% SEP. RESULTS: Liquid chromatography-tandem mass spectrometry indicated the presence of phorbol esters. G1 was null overall. Extent of the coagulative necrosis: G2 > G3. Vascular ectasia: G2 > G3. Inflammation pattern: intense neutrophilic inflammatory band in G2 versus mild, sparse, perivascular mononuclear cell infiltrate in G3. Neocollagenesis: pronounced in G2, negligible in G3. CONCLUSION: Coagulative necrosis of the epidermis, superficial fibroblasts, and vasculature can be attributed to the action of phenol. Phorbol esters on CO could be responsible for the dense deep acute inflammation and the distinctive neocollagenesis. | Croton Oil |
Ingestion of aqueous 70% ethanol extract of Ballota nigra (400 mg/kg body weight for 7 days) by albino rats (n=10) was investigated to study its effects on glucose, total cholesterol, triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), troponin I (TnI), serum creatine kinase (CK), total protein, total bilirubin and blood urea. Ballota nigra extract caused a significant decrease in blood glucose, total serum cholesterol and CK levels. Blood levels of TnI, AST, ALT, triglycerides, total bilirubin, total protein and blood urea were unchanged. The hypoglycemic effect of Ballota nigra extract on albino rats was further investigated by conducting a glucose tolerance test intraperitoneally (IPGTT). Healthy rats that were fasting for 18 hours followed by administration of a dose of 400 mg/kg body weight of the crude extract of Ballota nigra, orally. A significant decrease in blood glucose levels (after 15, 30, and 45 minutes) with a significant increase in serum insulin level (after 15 and 30 minute) was noted. These results suggest that, the crude extract of Ballota nigra have hypoglycemic, insulin-releasing and cholesterol lowering effects in rats. | Ballota |
BACKGROUND AND PURPOSE: Sparing of the organs at risk is one of the primary end-points of radiotherapy. The effects of organ-at-risk delineation on the dosimetric parameters can be critical and can influence treatment planning and outcomes. The aim of our study was to provide anatomical boundaries for the identification and delineation of the following critical organs at risk in the head and neck district: brachial plexus, cochlea, pharyngeal constrictor muscles and optic chiasm. PATIENTS AND METHODS: One patient was initially selected to elaborate our atlas. This patient was subjected to a planning computed tomography of the brain and head and neck district; axial images of 3-mm thickness at 3-mm intervals were obtained. In the same set-up a magnetic resonance imaging study was also performed. The obtained images were fused based on anatomical landmarks and used by a radiation oncologist, supported by a neuroradiologist, to provide anatomo-radiological limits for the identification of the brachial plexus, cochlea, pharyngeal constrictor muscles and optic chiasm. These limits were further verified on three consecutive patients. RESULTS: A computed tomography-based atlas was developed with definition of cranial, caudal, medial, lateral, anterior and posterior limits for each organ considered. CONCLUSIONS: This study allows improvement of definitions of anatomic boundaries for the brachial plexus, cochlea, pharyngeal constrictor muscles and optic chiasm. Our multidisciplinary experience led to the production of an institutional reference tool that could represent a useful aid for radiation oncologists in clinical practice. | Optic Chiasm |
Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level. | MAP Kinase Kinase Kinase 4 |
Cytosolic sulfotransferases are a superfamily of enzymes that catalyze the transfer of the sulfonic group from 3'-phosphoadenosine-5'-phosphosulfate to hydroxy or amine groups in substrate molecules. The human cytosolic sulfotransferases that have been most studied, namely SULT1A1, SULT1A3, SULT1B1, SULT1E1 and SULT2A1, are expressed in different tissues of the body, including liver, intestine, adrenal, brain and skin. These sulfotransferases play important roles in the sulfonation of endogenous molecules such as steroid hormones and neurotransmitters, and in the elimination of xenobiotic molecules such as drugs, environmental chemicals and natural products. There is often overlapping substrate selectivity among the sulfotransferases, although one isoform may exhibit greater enzyme efficiency than other isoforms. Similarly, inhibitors or enhancers of one isoform often affect other isoforms, but typically with different potency. This means that if the activity of one form of sulfotransferase is altered (either inhibited or enhanced) by the presence of a xenobiotic, the sulfonation of endogenous and xenobiotic substrates for other isoforms may well be affected. There are more examples of inhibitors than enhancers of sulfonation. Modulators of sulfotransferase enzymes include natural products ingested as part of the human diet as well as environmental chemicals and drugs. This review will discuss recent work on such interactions. | Xenobiotics |
A novel 1,3,5-triamino-myo-inositol derivative is presented as a readily available scaffold for the design of tripodal siderophore mimetics. Based on this scaffold, various hexadentate catecholate-type siderophore analogs were synthesized by attaching the catechols to the inositol scaffold via spacer units of different structure and length. The potential to tune the polarity of the inositol containing siderophore analogs has also been demonstrated by varying the protection group strategy. The siderophore activity of the prepared siderophore analogs was examined by cross-feeding tests with various Gram-negative bacteria and mycobacteria. | Chelating Agents |
BACKGROUND: Many people from Burma have migrated to Dehong prefecture and married local residents during the past decades; however, little is known about HIV risk-taking behaviours and HIV prevalence among these mixed couples. We investigated factors correlated with HIV discordance and concordance within Chinese?Burmese mixed couples in Dehong prefecture, Yunnan province, China. METHODS: A cross-sectional study with face-to-face questionnaire interviews and HIV blood testing was conducted. RESULTS: Of 5742 couples, 1.6% couples were HIV-infected concordant, 2.2% were HIV serodiscordant with an HIV-infected male spouse and 0.9% were HIV serodiscordant with an HIV-infected female spouse. HIV discordance with an HIV-infected male spouse was significantly associated with characteristics of the male spouse, including being aged =30 years, non-Han ethnic minority, a marital relationship of <3 years, commercial sex and injection drug use by the male spouse. HIV discordance with an HIV-infected female spouse was significantly associated with an education level of primary school (v. illiterate); a marital status of being in their second marriage, widowed or divorced; a history of sexually transmissible infection diagnosis of the female spouse; noncommercial extramarital sex by the female spouse or by both spouses; and injection drug use by the male spouse. A marital relationship of =3 years was the only significant independent correlate of HIV-infected seroconcordance. CONCLUSIONS: The study findings underscore the importance of premarital HIV counselling and testing for this population, and the need for targeted interventions among HIV serodiscordant mixed couples to reduce secondary transmission as early as possible when the relationship begins. | Premarital Examinations |
Endometrial cancer (EC) is one of the most common and fatal gynecological cancers worldwide, but there is no effective treatment for the EC patients of progesterone resistance. Repurposing of existing drugs is a good strategy to discover new candidate drugs. In this text, perphenazine (PPZ), approved for psychosis therapy, was identified as a potential agent for the treatment of both progesterone sensitive and resistant endometrial cancer for the first time. Specifically, perphenazine exhibited good cell proliferation inhibition in Ishikawa (ISK) and KLE cell lines according to the CCK-8 assay and colony formation assay. It also reduced the cell migration of ISK and KLE cell lines in the light of the transwell migration assay. Annexin-V/PI double staining assay suggested that perphenazine could effectively induce ISK and KLE cell apoptosis. Moreover, results of western blot assay indicated perphenazine obviously inhibited the phosphorylation of Akt. Delightedly, PPZ also could significantly attenuate xenograft tumor growth at both 3 mg/kg and 15 mg/kg in mice without influencing the body weights. | Perphenazine |
From the rice-based culture of Malbranchea flavorosea, three new compounds namely flavoroseoside B (5-desoxy-5-chloro-flavoroseoside) (2), 4-hydroxy-2-O-alpha-ribofuranosyl-5-methylacetophenone (3), and (S)-3,4-dihydro-3-(1H-indol-3-ylmethyl)-4-methyl-1H-1,4-benzodiazepine-2,5-dione (4), along with three known compounds, rosigenin (5), massarilactone B (6), and riboxylarinol B (7) were obtained. The structures were determined by spectroscopic methods. Compound 4 and its synthetic analog 3,4-dihydro-3-(1H-indol-3-ylmethyl)-1-methyl-1H-1,4-benzodiazepine-2,5-dione (9) inhibited the activity of Ruminococus obeum alpha-glucosidase enzyme. Molecular docking and dynamic studies revealed that compounds 4 and 9 might bind to this alpha-glucosidase at the catalytic center. Phylogenetic analysis using internal transcribed spacer region revealed that Malbranchea flavorosea ATCC 34529 is related to Myxotrichum spp." | Glycoside Hydrolase Inhibitors |
Kyotorphin (KTP) is an endogenous peptide with analgesic properties when administered into the central nervous system (CNS). Its amidated form (l-Tyr-l-Arg-NH2; KTP-NH2) has improved analgesic efficacy after systemic administration, suggesting blood-brain barrier (BBB) crossing. KTP-NH2 also has anti-inflammatory action impacting on microcirculation. In this work, selected derivatives of KTP-NH2 were synthesized to improve lipophilicity and resistance to enzymatic degradation while introducing only minor changes in the chemical structure: N-terminal methylation and/or use of d amino acid residues. Intravital microscopy data show that KTP-NH2 having a d-Tyr residue, KTP-NH2-DL, efficiently decreases the number of leukocyte rolling in a murine model of inflammation induced by bacterial lipopolysaccharide (LPS): down to 46% after 30 min with 96 muM KTP-NH2-DL. The same molecule has lower ability to permeate membranes (relative permeability of 0.38) and no significant activity in a behavioral test which evaluates thermal nociception (hot-plate test). On the contrary, methylated isomers at 96 muM increase leukocyte rolling up to nearly 5-fold after 30 min, suggesting a proinflammatory activity. They have maximal ability to permeate membranes (relative permeability of 0.8) and induce long-lasting antinociception. | Dipeptidases |
OBJECTIVES: to understand the life stories and itineraries of transvestites and transsexuals in health services. METHODS: study with a qualitative approach, anchored in the methodological framework of Oral History. Interviews were conducted and thematically analyzed. RESULTS: two themes emerged: 1) gender and sexuality in life stories; and 2) the trajectories in health services. These revealed the challenges in the process of recognizing gender identity before the family and society. The reports show the dilemmas that transsexuals and transvestites face in health care, which ends up generating the removal of this population from services. FINAL CONSIDERATIONS: it has been demonstrated that Oral History can increase knowledge, especially about life histories and trajectories in the health services of transvestites and transsexuals; in addition, information was offered that can assist managers and health professionals in making decisions or caring for these people. | Transvestism |
A rapid cassette changer developed at Stanford University Hospital has been successfully used to record, radiographically, swift vascular flow and intrinsic motion of other hollow organs. This aids diagnosis of disease and study of normal physiologic motion. | X-Rays |
INTRODUCTION: Healthcare-associated infections are a common consequence of unsafe health care practices and are a major issue for patient safety. Health care workers play a key role in patient safety and the quality of care, with factors such as poor compliance with hygiene standards and poor knowledge of infection risks having a major impact. However, the role of health care workers in patient safety has been overlooked in the literature. The objectives of this study were i) to examine health care workers' awareness of infection risks and ii) to assess levels of hand hygiene compliance and barriers to patient safety. METHODS: A one-day cross-sectional survey was conducted in June 2011 at the Ziniare health district hospital. The study focused on the health care workers present on the day of the survey in hospital care units and involved interviews and observations. RESULTS: The study found that 30.04% of the health care workers knew the definition of healthcare-associated infections. Only 44.4% of the health care workers reported that the hands of health care workers (in the event of poor hand hygiene compliance) were the main mode of transmission of germs between patients in a care facility. In addition, only 21.43% (12/56) of the participants were aware of the main factors that increase the risk of health care-associated infections. The level of compliance with hygiene protocols was low (36.85%). CONCLUSION: The promotion of patient safety and quality of care requires a focus on training and behavior change among health care workers." | Infectious Disease Transmission, Patient-to-Professional |
Cyanobacteriochromes (CBCRs) are photoreceptor proteins that photoconvert between two parent states and thereby regulate various biological processes. An intriguing property is their variable ultraviolet-visible (UV-vis) absorption that covers the entire spectral range from the far-red to the near-UV region and thus makes CBCRs promising candidates for optogenetic applications. Here, we have studied Slr1393, a CBCR that photoswitches between red- and green-absorbing states (Pr and Pg, respectively). Using UV-vis absorption, fluorescence, and resonance Raman (RR) spectroscopy, a further orange-absorbing state O(600) that is in thermal equilibrium with Pr was identified. The different absorption properties of the three states were attributed to the different lengths of the conjugated pi-electron system of the phycocyanobilin chromophore. In agreement with available crystal structures and supported by quantum mechanics/molecular mechanics (QM/MM) calculations, the most extended conjugation holds for Pr whereas it is substantially reduced in Pg. Here, the two outer pyrrole rings D and A are twisted out of the plane defined by inner pyrrole rings B and C. For the O(600) state, the comparison of the experimental RR spectra with QM/MM-calculated spectra indicates a partially distorted ZZZssa geometry in which ring A is twisted while ring D and the adjacent methine bridge display essentially the same geometry as Pr. The quantitative analysis of temperature-dependent spectra yields an enthalpy barrier of approximately 30 kJ/mol for the transition from Pr to O(600). This reaction is associated with the movement of a conserved tryptophan residue from the chromophore binding pocket to a solvent-exposed position. | Phycobilins |
Introduction: Paroxysmal dyskinesias and episodic ataxias are often caused by mutations in genes related to cell membrane and synaptic function. Despite the exponential increase in publications of genetically confirmed cases, management remains largely clinical based on non-systematic evidence. Areas covered: The authors provide a historical and clinical review of the main types of paroxysmal dyskinesias and episodic ataxias, with recommendations for diagnosis and management of patients suffering from these conditions. Expert opinion: After secondary paroxysmal dyskinesias, the most common paroxysmal movement disorders are likely to be PRRT2-associated paroxysmal kinesigenic dyskinesias, which respond well to small doses of carbamazepine, and episodic ataxia type 2, which often responds to acetazolamide. Familial paroxysmal non-kinesigenic dyskinesias are largely caused by mutations in PNKD and have poor response to therapy but improve with age. Exercise-induced dyskinesias are genetically heterogeneous, caused by disorders of glucose transport, mitochondrial function, dopaminergic pathways or neurodegenerative conditions amongst others. GNAO1 and ADCY5 mutations can also cause paroxysmal movement disorders, often in the context of ongoing motor symptoms. Although a therapeutic trial is justified for classic cases and in limited resource settings, genetic testing may help direct initial or rescue therapy. Deep brain stimulation may be an option for severe cases. | Dyskinesias |
Wheat yellow striate virus (WYSV), which is found in wheat fields of Northwest China and transmitted by leafhopper vector Psammotettix alienus, is a tentative new species in the genus Nucleorhabdovirus. Although the insect vector and host range of WYSV have been characterized, many aspects of the acquisition and transmission processes by its insect vector have not been elucidated. Here, the transmission parameters of WYSV by P. alienus were determined using wheat cv. Yangmai 12 as the indicator plant under a controlled temperature (23 +/- 1 degrees C) and photoperiod (16 h of light). The results showed that the minimum periods for acquisition were 5 min and 10 min for inoculation access. The latent period for successful transmission was most commonly 16 to 20 days (minimum, 10 days; maximum, 22 days). The quantitative reverse-transcriptase PCR results indicated that the WYSV titer increased with time after acquisition, suggesting that WYSV can replicate in P. alienus. Notably, female P. alienus transovarially transmitted the virus to next generations at relatively high efficiency. Electron microscopy of the WYSV-infected leafhopper revealed bacilliform particles aggregated in the cytoplasm of the salivary gland and midgut tissues. Our present studies suggested that acquisition and transmission of WYSV by P. alienus is consistent with a propagative, circulative, and persistent mode of transmission. Details regarding transmission competencies and distribution of WYSV in P. alienus will provide a basis for designing preventive measures. | Rhabdoviridae |
Due to their persistence, haloaromatics are compounds of environmental concern. Aerobically, bacteria degrade these compounds by mono- or dioxygenation of the aromatic ring. The common intermediate of these reactions is (halo)catechol. Halocatechol is cleaved either intradiol (ortho-cleavage) or extradiol (meta-cleavage). In contrast to ortho-cleavage, meta-cleavage of halocatechols yields toxic metabolites. Dehalogenation may occur fortuitously during oxygenation. Specific dehalogenation of aromatic compounds is performed by hydroxylases, in which the halo-substituent is replaced by a hydroxyl group. During reductive dehalogenation, haloaromatic compounds may act as electron-acceptors. Herewith, the halosubstituent is replaced by a hydrogen atom. | Hydrocarbons, Halogenated |
A man in his 70s in a rehabilitation hospital, post cerebral infarct, became acutely short of breath with reduced oxygen saturations and an elevated d-dimer.Non-occlusive filling defects were noted on the CT pulmonary angiogram in the proximal left pulmonary arteries. There was associated hypoplasia of the distal pulmonary arterial tree in the left hemithorax with left pulmonary vein stenosis. Review of previous imaging suggested this oligaemia was longstanding.Although filling defects in the pulmonary arteries usually correspond to embolic material, in our patient they were too dense to represent thrombus and probably represented flow-related artefacts in the setting of chronic air trapping.Given the associated volume loss, bronchiectasis and bronchial wall thickening in the left hemithorax Swyer-James-McLeod syndrome was thought to be the most likely underlying cause. | Lung, Hyperlucent |
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal neoplasms worldwide and represents the vast majority of pancreatic cancer cases. Understanding the molecular pathogenesis and the underlying mechanisms involved in the initiation, maintenance, and progression of PDAC is an urgent need, which may lead to the development of novel therapeutic strategies against this deadly cancer. Here, we review the role of SET and MYND domain-containing protein 2 (SMYD2) in initiating and maintaining PDAC development through methylating multiple tumor suppressors and oncogenic proteins. Given the broad substrate specificity of SMYD2 and its involvement in diverse oncogenic signaling pathways in many other cancers, the mechanistic extrapolation of SMYD2 from these cancers to PDAC may allow for developing new hypotheses about the mechanisms driving PDAC tumor growth and metastasis, supporting a proposition that targeting SMYD2 could be a powerful strategy for the prevention and treatment of PDAC. | MYND Domains |
PURPOSE: To assess the variations in corneal topographic characteristics after removal of the epithelium in patients having myopic photorefractive keratectomy (PRK). SETTING: Rothschild Foundation, Paris, France. METHODS: Forty-four eyes of 25 patients with myopia had corneal topography examination with the Orbscan II device (Bausch & Lomb) before removal of the corneal epithelium preoperatively and after removal of the corneal epithelium during PRK. On each examination, elevation, curvature, and pachymetry parameters were recorded and analyzed (paired 2-sided Student t test). RESULTS: The mean difference in central pachymetry between preoperative and epithelial removal was 37.84 mum +/- 9.82 (SD) (range 19 to 58 mum). The mean best-fit spherical surface radius was 7.75 +/- 0.28 mm (range 7.25 to 8.42 mm) before removal of the epithelium and 7.92 +/- 0.29 mm (range 7.39 to 9.16 mm) after removal of the epithelium (P<.0001). The mean simulated K-value difference increased from 0.75 +/- 0.55 diopter (D) (range 0.1 to 4.7 D) before removal to 1.21 +/- 0.66 D (range 0.2 to 4.7 D) after removal (P<.0001). The mean simulated value decreased from 43.77 +/- 1.83 D (range 40.25 to 47.00 D) to 42.44 +/- 1.73 D (range 37.05 to 45.50 D), respectively. The mean power (3.0 mm) decreased from 44.42 +/- 1.59 D (range 40.4 to 47.2 D) before removal to 43.46 +/- 1.37 D (range 39.7 to 46.9 D) after removal. The mean irregularity index increased from 1.07 +/- 0.35 D (range 0.5 to 2.5 D) to 2.03 +/- 0.38 D (range 1.3 to 3.3 D), respectively (P<.0001). The mean asphericity value (Q) changed from -0.44 +/- 0.14 (range -0.72 to -0.20) to -0.65 +/- 0.46 (range -1.04 to 0.14), respectively (P = .003). CONCLUSIONS: The epithelium affected the topographic properties of the cornea by significantly reducing corneal topographic astigmatism and irregularity. This might prove to be important in the assessment of patient candidacy for and treatment planning in refractive surgery. | Epithelium, Corneal |
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