Increased expression of importin13 in endometriosis and endometrial carcinoma.
Importin13 (IPO13) is a novel potential marker of corneal epithelial progenitor cells. We investigated the expression and localization of IPO13 in endometrial, endometriotic and endometrial carcinoma tissue. IPO13 expression in endometrial, endometriotic and endometrial carcinoma tissue was examined by immunohistochemistry, qPCR and Western blot. Immunohistochemistry studies showed that IPO13 protein was expressed mainly in cytoplasm of glandular epithelial cell and stromal cells. The rate of importin13-positive cells in proliferative phase endometrium was higher (by about 6-fold) than that in secretory endometrium (P<0.05) and the rate of importin13-positive cells in endometriosis and endometrial carcinoma was higher than that in normal secretory phase endometrial tissues (by about 4- and 9-fold, respectively). Immunofluorescence microscopy revealed co-localization of IPO13 with CD34, CD45, c-kit, telomerase, CD90 and CD146. QPCR revealed significantly increased IPO13 mRNA in endometriosis and endometrial carcinoma versus secretory phase endometrium (by about 2- and 10-fold, respectively). Western blot analysis showed that IPO13 protein is enhanced in endometriosis and endometrial carcinoma versus secretory phase endometrium (p<0.05). These results demonstrate an increased expression of IPO13 in endometriosis and endometrial carcinoma, which could be involved in the pathogenesis of endometriosis and endometrial carcinoma; IPO13 can serve as an endometrial progenitor/stem cell marker.


A pharmacological appraisal of medicinal plants with antidiabetic potential.
Diabetes mellitus is a complicated metabolic disorder that has gravely troubled the human health and quality of life. Conventional agents are being used to control diabetes along with lifestyle management. However, they are not entirely effective and no one has ever been reported to have fully recovered from diabetes. Numerous medicinal plants have been used for the management of diabetes mellitus in various traditional systems of medicine worldwide as they are a great source of biological constituents and many of them are known to be effective against diabetes. Medicinal plants with antihyperglycemic activities are being more desired, owing to lesser side-effects and low cost. This review focuses on the various plants that have been reported to be effective in diabetes. A record of various medicinal plants with their established antidiabetic and other health benefits has been reported. These include Allium sativa, Eugenia jambolana, Panax ginseng, Gymnema sylvestre, Momrodica charantia, Ocimum sanctum, Phyllanthus amarus, Pterocarpus marsupium, Trigonella foenum graecum and Tinospora cordifolia. All of them have shown a certain degree of antidiabetic activity by different mechanisms of action.


A TOR-YAK1 signaling axis controls cell cycle, meristem activity and plant growth in Arabidopsis.
TARGET OF RAPAMYCIN (TOR) is a conserved eukaryotic phosphatidylinositol-3-kinase-related kinase that plays a major role in regulating growth and metabolism in response to environment in plants. We performed a genetic screen for Arabidopsis ethylmethane sulfonate mutants resistant to the ATP-competitive TOR inhibitor AZD-8055 to identify new components of the plant TOR pathway. We found that loss-of-function mutants of the DYRK (dual specificity tyrosine phosphorylation regulated kinase)/YAK1 kinase are resistant to AZD-8055 and, reciprocally, that YAK1 overexpressors are hypersensitive to AZD-8055. Significantly, these phenotypes were conditional on TOR inhibition, positioning YAK1 activity downstream of TOR. We further show that the ATP-competitive DYRK1A inhibitor pINDY phenocopies YAK1 loss of function. Microscopy analysis revealed that YAK1 functions to repress meristem size and induce differentiation. We show that YAK1 represses cyclin expression in the different zones of the root meristem and that YAK1 is essential for TOR-dependent transcriptional regulation of the plant-specific SIAMESE-RELATED (SMR) cyclin-dependent kinase inhibitors in both meristematic and differentiating root cells. Thus, YAK1 is a major regulator of meristem activity and cell differentiation downstream of TOR.


Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo'.
On 21 February 2020, a resident of the municipality of Vo', a small town near Padua (Italy), died of pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection1. This was the first coronavirus disease 19 (COVID-19)-related death detected in Italy since the detection of SARS-CoV-2 in the Chinese city of Wuhan, Hubei province2. In response, the regional authorities imposed the lockdown of the whole municipality for 14 days3. Here we collected information on the demography, clinical presentation, hospitalization, contact network and the presence of SARS-CoV-2 infection in nasopharyngeal swabs for 85.9% and 71.5% of the population of Vo' at two consecutive time points. From the first survey, which was conducted around the time the town lockdown started, we found a prevalence of infection of 2.6% (95% confidence interval (CI): 2.1-3.3%). From the second survey, which was conducted at the end of the lockdown, we found a prevalence of 1.2% (95% CI: 0.8-1.8%). Notably, 42.5% (95% CI: 31.5-54.6%) of the confirmed SARS-CoV-2 infections detected across the two surveys were asymptomatic (that is, did not have symptoms at the time of swab testing and did not develop symptoms afterwards). The mean serial interval was 7.2 days (95% CI: 5.9-9.6). We found no statistically significant difference in the viral load of symptomatic versus asymptomatic infections (P = 0.62 and 0.74 for E and RdRp genes, respectively, exact Wilcoxon-Mann-Whitney test). This study sheds light on the frequency of asymptomatic SARS-CoV-2 infection, their infectivity (as measured by the viral load) and provides insights into its transmission dynamics and the efficacy of the implemented control measures.


Pediatric burns--2 year survey of cases admitted to the Chang Gung Memorial Hospital.
A total of 722 patients were admitted to the Burn Unit of Chang Gung Memorial Hospital over a 2-year period, of these 285 (39.5%) were under 15 years of age. The major cause of pediatric burns was scalding, 236 (82.8%). Most of the patients under age of 15 years had total burn surface under 20% (199 patients, 70%), and were discharged from the hospital within one month (263 patients, 91%). Treatments included debridement done in 98 patients (41.5%) and skin grafting in 81 patients (28%). Oxacillin-Resistant Staphylococcus Aureus infections were the most common complication (5.3%). The mortality rate was 5.3%.


Valuing QALYs in Relation to Equity Considerations Using a Discrete Choice Experiment.
To judge whether an intervention offers value for money, the incremental costs per gained quality-adjusted life-year (QALY) need to be compared with some relevant threshold, which ideally reflects the monetary value of health gains. Literature suggests that this value may depend on the equity context in which health gains are produced, but the value of a QALY in relation to equity considerations has remained largely unexplored. The objective of this study was to estimate the social marginal willingness to pay (MWTP) for QALY gains in different equity subgroups, using a discrete choice experiment (DCE). Both severity of illness (operationalized as proportional shortfall) and fair innings (operationalized as age) were considered as grounds for differentiating the value of health gains. We obtained a sample of 1205 respondents, representative of the adult population of the Netherlands. The data was analysed using panel mixed multinomial logit (MMNL) and latent class models. The panel MMNL models showed counterintuitive results, with more severe health states reducing the probability of receiving treatment. The latent class models revealed distinct preference patterns in the data. MWTP per QALY was sensitive to severity of disease among a substantial proportion of the public, but not to the age of care recipients. These findings emphasize the importance of accounting for preference heterogeneity among the public on value-laden issues such as prioritizing health care, both in research and decision making. This study emphasises the need to further explore the monetary value of a QALY in relation to equity considerations.


Two decades of research on autoimmune liver disease in Turkey.
Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are the 3 main autoimmune liver diseases (AILDs). The epidemiology of AILD in Turkey is not known. To determine the scientific status, we performed a scientometric analysis of AILD-related original articles that originated from Turkey. We searched the Web of Science database, the Science Citation Index Expanded (SCI-E), and the Social Sciences Citation Index (SSCI) by using the keywords "autoimmune hepatitis," "primary biliary cholangitis/primary biliary cirrhosis," and "primary sclerosing cholangitis" in conjunction with "Turkey." A scientometric analysis was done on the search results. We identified 117 AILD-related papers that were published in Turkey from 1997 to 2019. Among these, 70 case reports, letters, and reviews and 2 original articles that were not cited in SCI-E/SSCI were excluded. The remaining 45 original articles were further analyzed. These studies were related to AIH (n=22), PBC (n=7), PSC (n=9), PBC-AIH overlap (n=5), and others (n=2). Four of the publications originated in pediatric settings; 9 of 45 papers were published from 1997 to 2008 and 36 papers were published from 2009 to 2019. Most papers (75%) were reported from 5 centers; 9 papers (20%) were published in journals with an impact factor of 3 or higher. The overall number and quality of AILD-related papers in Turkey are unexpectedly low, although a number of papers have received considerable international recognition. More epidemiologic, prospective, and multicenter research projects are warranted to advance AILD knowledge and to produce high-quality research from Turkey.


An instrument to measure atrial fibrillation knowledge in Chinese patients: validation of the Jessa Atrial fibrillation Knowledge Questionnaire.
Background: There is no validated tool to assess patients' knowledge of oral anticoagulant therapy in atrial fibrillation in China. Methods: Using a standard translation program, the Jessa Atrial fibrillation Knowledge Questionnaire (JAKQ) was translated into Chinese. The reliability of the JAKQ was assessed by internal consistency (Cronbach's α coefficient), repeatability (test-retest reliability), and sensitivity tests. Effectiveness was assessed by hypothesizing that a lower JAKQ score was a risk factor for bleeding. A total of 447 patients with atrial fibrillation (AF) who were hospitalized between July 2019 and December 2021 were studied and followed up. Participants were followed up 1, 3, 6, and 12 months after enrollment. Bleeding during follow-up was recorded. Data were obtained from hospital databases and telephone follow-up. Result: A total of 447 patients with AF completed JAKQ. The mean age of patients was 67.7 ± 10.2 years. The median JAKQ score was 31.3% (12.5-43.8). The Cronbach's α coefficient of JAKQ was 0.616-0.637, and the test-retest reliability value was 0.902 (p < 0.001). Multivariate logistic regression showed that the higher knowledge level of AF was associated with secondary education or above, an income of more than 2000 yuan, and a history of AF of more than 1 year. Bleeding was associated with a lower JAKQ score, hypertension, and a history of bleeding. Non-bleeding patients on VKA had a better understanding of how often INR should be monitored and what to do if an OAC dose was missed. Conclusion: The Chinese version of JAKQ shows good reliability and validity, indicating that it is a valuable tool for AF and oral anticoagulation (OAC) knowledge assessment. It can be used in clinical practice to guide educational activities and improve the effectiveness and safety of treatment. It was shown that Chinese patients with AF have insufficient knowledge about AF and OAC. Lower JAKQ scores are associated with bleeding, so targeted education is necessary. Targeted educational efforts should focus on patients recently diagnosed with AF and those with lower formal education and income.


Parental Influences on Preschoolers' TV Viewing Time: Mediation Analyses on Australian and Belgian Data.
Television viewing is highly prevalent in preschoolers (3-5 years). Because of the adverse health outcomes related to this behavior, it is important to investigate associations and mediators of young children's television viewing time. This study investigated whether parental rules regarding television viewing time and parental concerns about screen viewing activities mediated the association between parents' and preschoolers' television viewing time. Mediation analyses were performed with the product-of-coefficient test on data derived from the Australian HAPPY study (n = 947) and the Belgian sample of the ToyBox-study (n = 1527). Parents reported their own and their child's television viewing time, their rules regarding television viewing and concerns about their child's screen viewing activities. Parents' television viewing time was directly associated with preschoolers' television viewing time and parental rule for television viewing time mediated this association in both samples (14.4% and 8.1% in the Australian and Belgian samples, respectively). This study is unique in examining the mediating pathway of parental television viewing and a rule limiting TV viewing time and whether this is consistent in different samples. Due to the consistent importance, both parents' television viewing time and rules should be targeted in interventions to decrease preschoolers' television viewing time.


Eighth International Meeting of the European Laboratory Working Group on Diphtheria and the Diphtheria Surveillance Network--June 2004: progress is needed to sustain control of diphtheria in European Region.
The Eighth International Meeting of the European Laboratory Working Group on Diphtheria (ELWGD) and the Diphtheria Surveillance Network (DIPNET) was held and co-organised with the WHO Regional Office for Europe, Copenhagen, Denmark, in June 2004. This article provides an international updated review of progress in clinical, epidemiological and microbiological aspects of diphtheria in the European region as presented at the meeting. It highlights the need for improved immunisation coverage, surveillance and epidemiological studies to sustain control of diphtheria in European Region.


Reducing Dog Relinquishment to Rescue Centres Due to Behaviour Problems: Identifying Cases to Target with an Advice Intervention at the Point of Relinquishment Request.
Behaviour problems are a leading reason for dogs being relinquished to rescue centres across the world every year. The aim of this study was to investigate whether free behavioural advice would be accepted at the point of an owner requesting to relinquish their dog for behavioural reasons. The call records of 1131 relinquishment requests were reviewed and analysed to establish if the offer of free behaviour advice was accepted. The results showed that advice was accepted in 24.4% of relinquishment requests and behavioural problem was a significant predictor of whether advice was accepted (p < 0.001). The odds of advice being accepted were 5.755 times (95% CI: 2.835-11.681; p < 0.001) greater for a relinquishment request due to problems with general management behaviours compared to aggression between dogs in the home, representing 4.2% and 20.2% of overall relinquishment requests. These data suggest that owners are prepared to accept behaviour advice at the point of relinquishment request, so advice interventions could have potential to impact the levels of dog relinquishment to rescue centres. The impact of an intervention offering behaviour advice may be limited by overall levels of advice acceptance by owners and therefore complimentary proactive solutions to reduce behavioural relinquishments should also be considered.


Effects of acute ingestion of caffeinated chewing gum on performance in elite judo athletes.
Previous investigations have found positive effects of acute ingestion of capsules containing 4-to-9 mg of caffeine per kg of body mass on several aspects of judo performance. However, no previous investigation has tested the effectiveness of caffeinated chewing gum as the form of caffeine administration for judoists. The main goal of this study was to assess the effect of acute ingestion of a caffeinated chewing gum on the results of the special judo fitness test (SJFT). Nine male elite judo athletes of the Polish national team (23.7 ± 4.4 years, body mass: 73.5 ± 7.4 kg) participated in a randomized, crossover, placebo-controlled and double-blind experiment. Participants were moderate caffeine consumers (3.1 mg/kg/day). Each athlete performed three identical experimental sessions after: (a) ingestion of two non-caffeinated chewing gums (P + P); (b) a caffeinated chewing gum and a placebo chewing gum (C + P; ~2.7 mg/kg); (c) two caffeinated chewing gums (C + C; ~5.4 mg/kg). Each gum was ingested 15 min before performing two Special Judo Fitness Test (SJFT) which were separated by 4 min of combat activity. The total number of throws was not different between P + P, C + P, and C + C (59.66 ± 4.15, 62.22 ± 4.32, 60.22 ± 4.08 throws, respectively; p = 0.41). A two-way repeated measures ANOVA indicated no significant substance × time interaction effect as well as no main effect of caffeine for SJFT performance, SJFT index, blood lactate concentration, heart rate or rating of perceived exertion. The results of the current study indicate that the use of caffeinated chewing gum in a dose up to 5.4 mg/kg of caffeine did not increase performance during repeated SJFTs.


Comparison of enhanced Mycobacterium tuberculosis amplified direct test with COBAS AMPLICOR Mycobacterium tuberculosis assay for direct detection of Mycobacterium tuberculosis complex in respiratory and extrapulmonary specimens.
The new Roche COBAS AMPLICOR Mycobacterium tuberculosis Assay was compared to the Gen-Probe enhanced Mycobacterium tuberculosis Amplified Direct Test (AMTDII). A total of 486 specimens (296 respiratory and 190 extrapulmonary) collected from 323 patients were tested in parallel with both assays. Results were compared with those of acid-fast staining and culture, setting the combination of culture and clinical diagnosis as the "gold standard." After resolution of discrepant results, the sensitivity, specificity, and positive and negative predictive values for AMTDII were 85.7, 100, 100, and 90.4% for respiratory specimens and 82.9, 100, 100, and 95. 5% for extrapulmonary specimens, respectively. The corresponding values for AMPLICOR were 94.2, 100, 100, and 96.6% for respiratory specimens and 85, 100, 100, and 96.1% for extrapulmonary specimens, respectively. No significant differences were observed between the results of both assays or, within each one, between respiratory and extrapulmonary specimens. The difference between AMTDII and AMPLICOR sensitivities was related to the presence of inhibitory samples, which the former assay, lacking an internal amplification control (IAC), could not detect. The overall inhibition rate for the AMPLICOR assay was 3.9% (19 specimens). It is concluded that, although both amplification assays proved to be rapid and specific for the detection of M. tuberculosis complex in clinical samples, AMPLICOR, by a completely automated amplification and detection procedure, was shown to be particularly feasible for a routine laboratory setting. Finally, AMTDII is potentially an excellent diagnostic technique for both respiratory and extrapulmonary specimens, provided that an IAC is included with the assay.


Factors associated with breastfeeding continuation for 12 months or more among working mothers in a general hospital.
This article aims to identify factors associated with breastfeeding continuation for at least 12 months among working mothers in a hospital in the south of Brazil. We conducted a cross-sectional study, interviewing 251 women who breastfed after returning to work. Eligibility criteria included non-twin biological children aged between 12 and 36 months and the absence of an illness (mother and/or child) that could affect breastfeeding. The association between breastfeeding continuation and the exposure variables was tested using Poisson multivariate regression. Only one work-related variable showed a significant association with the outcome. Working only during the day increased the prevalence of BF continuation for at least 12 months by 37%. The following non-work-related factors showed a positive association with the outcome: mothers without a college degree; mothers with at least 12 months' prior breastfeeding experience; child not given milks other than breast milk when the mother returned to work, and not using a pacifier. The following variables showed a negative association with the outcome: older maternal age; older gestational age; mother receiving support from the child's caregiver; and mother receiving professional breastfeeding support. Non-work-related factors had a greater influence on breastfeeding continuation for at least 12 months among working mothers.


The pathology of the external ear canal in dogs and cats.
A survey of factors which predispose the canine ear to otitis externa is presented. In resected ear specimens of 106 dogs, otitis externa without tumour was found on 58 occasions. In 46 dogs tumours were diagnosed in 15 cases with an otitis externa. In two dogs an inflammatory polyp was found. In the resected ear specimens of 48 cats, otitis externa was diagnosed 27 times, in 6 cases combined with an inflammatory polyp. In 21 cases neoplasia was present. The otitis externa was mainly a chronic proliferative inflammation characterised by hyperkeratinization, hyperplasia of the sebaceous and ceruminous glands, fibrosis and infiltration with plasma cells, lymphocytes and macrophages, often containing ceroid pigment.


Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection.
We investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) administered by the subcutaneous route, first alone and then alternating with azidothymidine (AZT), in leukopenic patients with severe human immunodeficiency virus (HIV) infection. Ten patients with acquired immunodeficiency syndrome (AIDS) or related disorders, five of whom could not tolerate conventional doses of AZT, were administered rGM-CSF subcutaneously for 12 days. They then were administered an alternating regimen using AZT for 1 week, followed by 5 days of subcutaneous rGM-CSF and 2 days without any medication. During the initial 12 days of GM-CSF administration, there was an increase in the mean white blood cell (WBC) value. In addition, rGM-CSF stimulated circulating monocytes as evidenced by an increase in superoxide anion production and expression of surface HLA-DR antigen. However, at the same time rGM-CSF increased the serum HIV p24 antigen in each of the six evaluable patients from 189 x/divided by 2.02 pg/mL (geometric mean x/divided by SEM) at entry to 375 x/divided by 2.11 pg/mL (P less than .05). During the subsequent period of alternating AZT and rGM-CSF treatment, serum HIV p24 antigen fell below the day 14 value in most patients, particularly after the weeks of AZT administration. The mean T4 cell value increased in patients who had not previously received AZT, but generally did not change in those who had prior AZT exposure. Hematologic toxicity appeared to be somewhat reduced compared with continuous full-dose AZT therapy, and two patients with previous AZT hematologic toxicity tolerated this alternating regimen for 25 weeks. Additional regimens simultaneously combining these two agents are worth exploring.


Transforming growth factor beta1 regulates the expression of cyclooxygenase in cultured cortical astrocytes and neurons.
The hypothesis that transforming growth factor beta1 (TGFbeta1) regulates the synthesis of prostaglandins by CNS tissue was tested by using purified cultures of cortical astrocytes or neurons that were obtained from rat pups on postnatal day 4 or 5 or fetuses on gestational day 16, respectively. The cells were exposed to TGFbeta1 for 2 days. The synthesis of prostaglandins depends upon the production and conversion of arachidonic acid, steps that are catalyzed by phospholipase A2 (PLA2) and cyclooxygenase (COX), respectively. Prostaglandin E2 (PGE2) concentration was determined by radioimmunoassay. The expression of cytosolic PLA2 and COX (the constitutive COX1 and the inducible COX2) was assessed by using immunohistochemical and quantitative immunoblotting procedures. Astrocytes produced much more PGE2 than neurons, suggesting that glial cells are an important source of PGE2 in the CNS. TGFbeta1 increased the production of PGE2 by astrocytes and neurons in a concentration-dependent manner. Furthermore, TGFbeta1 enhanced COX activity; the inhibitor indomethacin completely blocked TGFbeta1-mediated PGE2 synthesis. Cultured astrocytes and neurons expressed the three enzymes: cytosolic PLA2, COX1, and COX2. Cytosolic PLA2 expression was unaffected by TGFbeta1 treatment. In contrast, COX expression was altered by TGFbeta1 treatment in a concentration-dependent fashion. COX1 was increased by TGFbeta1, but only in astrocytes. TGFbeta1 increased COX2 expression in astrocytes and neurons. Thus, TGFbeta1-induced increases in PGE2 concentration are regulated by COX. This study suggests that TGFbeta1 is an important regulator of immune and inflammatory processes in the CNS.


CD3-CD20-positive nodal lymphoma with cross-lineage rearrangement in a dog.
A 7-y-old mixed-breed male dog was presented with a history of generalized lymphadenopathy. Fine-needle aspirates of the enlarged peripheral lymph nodes were suggestive of lymphoma. Histologic examination of a retromandibular lymph node was suggestive of high-grade, medium large-cell lymphoma. Immunohistochemistry revealed concurrent expression of CD3 and CD20. The co-localization of the 2 antigens was confirmed by immunofluorescence. PCR for antigen receptor gene rearrangements (PARR) detected clonal rearrangements for both T-cell receptor gamma and B-cell receptor. The final diagnosis was CD3-CD20-positive anaplastic lymphoma with cross-lineage rearrangement.


Antiproliferation, antioxidation and induction of apoptosis by Garcinia mangostana (mangosteen) on SKBR3 human breast cancer cell line.
This study was designed to determine the antiproliferative, apoptotic and antioxidative properties of crude methanolic extract (CME) from the pericarp of Garcinia mangostana (family Guttiferae) using human breast cancer (SKBR3) cell line as a model system. SKBR3 cells were cultured in the presence of CME at various concentrations (0-50 microg/ml) for 48 h and the percentage of cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-di phenyl tetrazolium bromide (MTT) assay. CME showed a dose-dependent inhibition of cell proliferation with ED(50) of 9.25+/-0.64 microg/ml. We found that antiproliferative effect of CME was associated with apoptosis on breast cancer cell line by determinations of morphological changes and oligonucleosomal DNA fragments. In addition, CME at various concentrations and incubation times were also found to inhibit ROS production. These investigations suggested that the methanolic extract from the pericarp of Garcinia mangostana had strong antiproliferation, potent antioxidation and induction of apoptosis. Thus, it indicates that this substance can show different activities and has potential for cancer chemoprevention which were dose dependent as well as exposure time dependent.


Hemophagocytic Lymphohistiocytosis and Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis Possibly Caused by Enterococcus faecalis Infective Endocarditis: A Case Report.
Infection can induce hemophagocytic lymphohistiocytosis (HLH) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We herein report a 52-year-old man who had HLH and AAV simultaneously, possibly caused by Enterococcus faecalis infective endocarditis. The HLH diagnosis was based on the HLH-2004 criteria. AAV was diagnosed based on a positive result for proteinase-3 ANCA and necrotizing vasculitis of the small vessels on a skin biopsy. He eventually died and was sent for autopsy after combination treatment of valve replacement, antibiotics, and immunosuppressants, including corticosteroids. This case involved a challenging diagnosis and treatment of HLH with various complications in an adult.


The p16(INK4A) tumor suppressor regulates cellular oxidative stress.
Mutations or deletions in the cyclin-dependent kinase inhibitor p16(INK4A) are associated with multiple cancer types, but are more commonly found in melanoma tumors and associated with familial melanoma predisposition. Although p16 is thought to function as a tumor suppressor by negatively regulating the cell cycle, it remains unclear why the genetic compromise of p16 predisposes to melanoma over other cancers. Here we describe a novel role for p16 in regulating oxidative stress in several cell types, including melanocytes. Expression of p16 was rapidly upregulated following ultraviolet-irradiation and in response to H₂O₂-induced oxidative stress in a p38 stress-activated protein kinase-dependent manner. Knockdown of p16 using small interfering RNA increased intracellular reactive oxygen species (ROS) and oxidative (8-oxoguanine) DNA damage, which was further enhanced by H₂O₂ treatment. Elevated ROS levels were also observed in p16-depleted human keratinocytes and in whole skin and dermal fibroblasts from Cdkn2a-deficient mice. Aberrant ROS and p38 signaling in Cdkn2a-deficient fibroblasts was normalized by expression of exogenous p16. The effect of p16 depletion on ROS was not recapitulated by the knockdown of retinoblastoma protein (Rb) and did not require Rb. Finally, p16-mediated suppression of ROS could not be attributed to the potential effects of p16 on cell cycle phase. These findings suggest a potential alternate Rb-independent tumor-suppressor function of p16 as an endogenous regulator of carcinogenic intracellular oxidative stress. Compared with keratinocytes and fibroblasts, we also found increased susceptibility of melanocytes to oxidative stress in the context of p16 depletion, which may explain why the compromise of p16 predisposes to melanoma over other cancers.


Voyager 2 in the uranian system: imaging science results.
Voyager 2 images of the southern hemisphere of Uranus indicate that submicrometersize haze particles and particles of a methane condensation cloud produce faint patterns in the atmosphere. The alignment of the cloud bands is similar to that of bands on Jupiter and Saturn, but the zonal winds are nearly opposite. At mid-latitudes (-70 degrees to -27 degrees ), where winds were measured, the atmosphere rotates faster than the magnetic field; however, the rotation rate of the atmosphere decreases toward the equator, so that the two probably corotate at about -20 degrees . Voyager images confirm the extremely low albedo of the ring particles. High phase angle images reveal on the order of 10(2) new ringlike features of very low optical depth and relatively high dust abundance interspersed within the main rings, as well as a broad, diffuse, low optical depth ring just inside the main rings system. Nine of the newly discovered small satellites (40 to 165 kilometers in diameter) orbit between the rings and Miranda; the tenth is within the ring system. Two of these small objects may gravitationally confine the e ring. Oberon and Umbriel have heavily cratered surfaces resembling the ancient cratered highlands of Earth's moon, although Umbriel is almost completely covered with uniform dark material, which perhaps indicates some ongoing process. Titania and Ariel show crater populations different from those on Oberon and Umbriel; these were probably generated by collisions with debris confined to their orbits. Titania and Ariel also show many extensional fault systems; Ariel shows strong evidence for the presence of extrusive material. About halfof Miranda's surface is relatively bland, old, cratered terrain. The remainder comprises three large regions of younger terrain, each rectangular to ovoid in plan, that display complex sets of parallel and intersecting scarps and ridges as well as numerous outcrops of bright and dark materials, perhaps suggesting some exotic composition.


Effects of competition on hospital quality: an examination using hospital administrative data.
This paper investigates the effects of competition on hospital quality using hospital administration data from the State of Victoria, Australia. Hospital quality is measured by 30-day mortality rates and 30-day unplanned readmission rates. Competition is measured by Herfindahl-Hirschman index and the numbers of competing public and private hospitals. The paper finds that hospitals facing higher competition have lower unplanned admission rates. However, competition is related negatively to hospital quality when measured by mortality, albeit the effects are weak and barely statistically significant. The paper also finds that the positive effect of competition on quality as measured by unplanned readmission differs greatly depending on whether the hospital is publicly or privately owned.


Sugar consumption and dental caries experience in Kenya.
There have been claims that dental caries experience and prevalence in Kenya has been increasing as a result of increased sugar consumption. A review of the literature in 1986 failed to link dental caries experience with an increase in gross national sugar consumption. Subsequently, a number of studies were conducted, necessitating further review to examine trends in dental caries experience and to relate this to changes in per capita sugar consumption. Studies conducted since 1980 for children 3-15 years of age were examined. Dental caries prevalence and experience for 3-5 years' (deciduous teeth) and 12 years' (permanent teeth) age groups were analysed. Calculation of per capita sugar consumption was performed using gross national annual sugar consumption for 1969-2009 national population census years. There was a gradual increase in per capita sugar consumption, from 35.5 g/day in 1969 to 60.8 g/day in 2009. Dental caries experience in deciduous teeth for children 3-5 years of age increased from a decayed, missing and filled teeth/decayed and filled teeth (dmft/dft) index of 1.5 in the 1980s to 2.95 in the 2000s. At 12 years of age, caries experience for permanent teeth increased from a DMFT of 0.2 to a DMFT of 0.92 over the same period. Dental caries prevalence for both deciduous and permanent teeth also increased with time. These observations suggest that dental caries prevalence and experience increased with time, in parallel to an increase in per capita sugar consumption. However, a clearer understanding can be derived from longitudinal studies, based on actual household age-specific sugar consumption and dental caries incidence.


p63 Transcriptionally regulates BNC1, a Pol I and Pol II transcription factor that regulates ribosomal biogenesis and epithelial differentiation.
The p53-family member, p63 is a transcription factor that influences cellular adhesion, motility, proliferation, survival and apoptosis, and has a major role in regulating epithelial stem cells. Expression of p63 is often dysregulated in squamous cell carcinomas of the head and neck. In this study we show that p63 induces the expression of the basal epithelial transcription factor, Basonuclin 1. Basonuclin 1 is an unusual transcription factor that interacts with a subset of promoters of genes that are transcribed by both RNA polymerase-I and -II and has roles in maintaining ribosomal biogenesis and the proliferative potential of immature epithelial cells. Chromatin immunoprecipitation and reporter assays demonstrate that Basonuclin 1 is a direct transcriptional target of p63 and we also show that up-regulation of Basonuclin 1 is a common event in squamous cell carcinomas of the head and neck. These data identify a new transcriptional programme mediated by p63 regulation of the Basonuclin 1 transcription factor in squamous cell carcinomas and provide a novel link of p63 with the regulation of ribosomal biogenesis in epithelial cancer.


Variation in estimates of urinary incontinence prevalence in the community: effects of differences in definition, population characteristics, and study type.
Prevalence estimates for urinary incontinence among community-dwelling adults vary from 2 to 55%. A review of the literature was undertaken to investigate the degree to which differences in definitions of incontinence, age, and gender of the populations studied, response rates, measurement techniques, or location could explain differences in reported prevalences. A literature search was conducted to locate all studies published in English reporting the prevalence of urinary incontinence in a population-based sample of adults. Information was abstracted for study size, response rate, type of survey, definition of urinary incontinence, and prevalence of incontinence by age group and gender. Prevalence by type of incontinence was also abstracted where available. Stratification was used to obtain prevalence estimates specific for age, gender, and frequency of incontinence. Data were examined for associations between prevalence and survey type, response rate, year, and location of survey. A total of 21 studies met inclusion criteria. Stratification of reported prevalence by frequency, gender, and age substantially reduced the variation in prevalence estimates. For older women, the estimated prevalence of urinary incontinence ranged from 17 to 55% (median = 35%, pooled mean = 34%), and for daily incontinence it ranged from 3 to 17% (median = 14%, pooled mean = 12%). For older men, incontinence prevalence was estimated to be 11 to 34% (median = 17%, pooled mean = 22%), and 2 to 11% reported daily incontinence (median = 4%, pooled mean = 5%). Within studies, the prevalence of any incontinence was 1.3 to 2.0 times greater for older women than for older men. Among middle-aged and younger adults, prevalence of incontinence ranged from 12 to 42% (median = 28%, pooled mean = 25%) for women and from 3 to 5% (median = 4%, pooled mean = 5%) for men. The ratio of prevalence of any incontinence for women to men in this age group ranged from 4.1 to 4.5. Stress incontinence predominated in younger women, whereas urge and mixed incontinence predominated in older women. There was a tendency for studies using in-person interviews to report higher prevalences. An accurate estimate of the prevalence of urinary incontinence depends on specifying the definition of incontinence and the age and gender groups of interest.


Effects of a Healthy Diet on Reducing Symptoms of Premenstrual Syndrome and Improving Quality of Life among Omani Adolescents: A Randomized Controlled Open-Label Trial.
Premenstrual syndrome (PMS) continues to impact the health outcomes and emotional well-being of reproductive-age women, globally. Several studies have provided conflicting evidence concerning the role of dietary approaches in improving PMS symptoms. Accordingly, this study aimed to evaluate the possible influence of a healthy diet and motivational strategies on PMS symptoms and health-related quality of life among Omani adolescents. This open-label, randomized, prospective controlled trial was conducted at two randomly selected secondary schools, in Al Seeb Willayah, in Muscat region. Adolescents with PMS symptoms, who were in grade 10 or 11, aged 16 years or above, had regular menstrual cycles, and were not known to have psychiatric disorder were included in this study. Participants in the intervention group received an individual face-to-face dietary consultation and motivational phone consultation. The health outcomes, including the PMS symptoms in both groups, and quality of life, were recorded using the Daily Record of Severity of Problems questionnaire (DRSP) and the 14-item Self-Reporting-Based Perceived Stress Scale tools, respectively. The primary outcome was the difference in the mean premenstrual symptom scores between the two groups. Secondary outcomes included the quality of life and stress levels of participants. The study period was from 1 February and ended 30 June 2021. SPSS was used to analyze the data, and intention-to-treat analysis was utilized. A total of 72 adolescents with PMS were randomized into intervention and control groups (n = 36 each). Both groups were similar at baseline (p-value > 0.05). No significant association was found between a healthy diet and PMS symptoms (p-value > 0.05). In addition, no significant association was found between a healthy diet and quality of life at follow-up (p-value = 0.216). The outcomes of this study refuted any possible relationships between a healthy diet and PMS symptoms. Accordingly, dietary consultations may not facilitate the clinical management of PMS symptoms in adolescent females.


Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes.
Enzymes catalyze organic transformations with exquisite levels of selectivity, including chemoselectivity, stereoselectivity, and substrate selectivity, but the types of reactions catalyzed by enzymes are more limited than those of chemical catalysts. Thus, the convergence of chemical catalysis and biocatalysis can enable enzymatic systems to catalyze abiological reactions with high selectivity. Recently, we disclosed artificial enzymes constructed from the apo form of heme proteins and iridium porphyrins that catalyze the insertion of carbenes into a C-H bond. We postulated that the same type of Ir(Me)-PIX enzymes could catalyze the cyclopropanation of a broad range of alkenes with control of multiple modes of selectivity. Here, we report the evolution of artificial enzymes that are highly active and highly stereoselective for the addition of carbenes to a wide range of alkenes. These enzymes catalyze the cyclopropanation of terminal and internal, activated and unactivated, electron-rich and electron-deficient, conjugated and nonconjugated alkenes. In particular, Ir(Me)-PIX enzymes derived from CYP119 catalyze highly enantio- and diastereoselective cyclopropanations of styrene with ±98% ee, >70:1 dr, >75% yield, and ∼10,000 turnovers (TON), as well as 1,2-disubstituted styrenes with up to 99% ee, 35:1 dr, and 54% yield. Moreover, Ir(Me)-PIX enzymes catalyze cyclopropanation of internal, unactivated alkenes with up to 99% stereoselectivity, 76% yield, and 1300 TON. They also catalyze cyclopropanation of natural products with diastereoselectivities that are complementary to those attained with standard transition metal catalysts. Finally, Ir(Me)-PIX P450 variants react with substrate selectivity that is reminiscent of natural enzymes; they react preferentially with less reactive internal alkenes in the presence of more reactive terminal alkenes. Together, the studies reveal the suitability of Ir-containing P450s to combine the broad reactivity and substrate scope of transition metal catalysts with the exquisite selectivity of enzymes, generating catalysts that enable reactions to occur with levels and modes of activity and selectivity previously unattainable with natural enzymes or transition metal complexes alone.


Model-based classification of CPT data and automated lithostratigraphic mapping for high-resolution characterization of a heterogeneous sedimentary aquifer.
Cone penetration testing (CPT) is one of the most efficient and versatile methods currently available for geotechnical, lithostratigraphic and hydrogeological site characterization. Currently available methods for soil behaviour type classification (SBT) of CPT data however have severe limitations, often restricting their application to a local scale. For parameterization of regional groundwater flow or geotechnical models, and delineation of regional hydro- or lithostratigraphy, regional SBT classification would be very useful. This paper investigates the use of model-based clustering for SBT classification, and the influence of different clustering approaches on the properties and spatial distribution of the obtained soil classes. We additionally propose a methodology for automated lithostratigraphic mapping of regionally occurring sedimentary units using SBT classification. The methodology is applied to a large CPT dataset, covering a groundwater basin of ~60 km2 with predominantly unconsolidated sandy sediments in northern Belgium. Results show that the model-based approach is superior in detecting the true lithological classes when compared to more frequently applied unsupervised classification approaches or literature classification diagrams. We demonstrate that automated mapping of lithostratigraphic units using advanced SBT classification techniques can provide a large gain in efficiency, compared to more time-consuming manual approaches and yields at least equally accurate results.


Literature analysis of artificial intelligence in biomedicine.
Artificial intelligence (AI) refers to the simulation of human intelligence in machines, using machine learning (ML), deep learning (DL) and neural networks (NNs). AI enables machines to learn from experience and perform human-like tasks. The field of AI research has been developing fast over the past five to ten years, due to the rise of 'big data' and increasing computing power. In the medical area, AI can be used to improve diagnosis, prognosis, treatment, surgery, drug discovery, or for other applications. Therefore, both academia and industry are investing a lot in AI. This review investigates the biomedical literature (in the PubMed and Embase databases) by looking at bibliographical data, observing trends over time and occurrences of keywords. Some observations are made: AI has been growing exponentially over the past few years; it is used mostly for diagnosis; COVID-19 is already in the top-3 of diseases studied using AI; China, the United States, South Korea, the United Kingdom and Canada are publishing the most articles in AI research; Stanford University is the world's leading university in AI research; and convolutional NNs are by far the most popular DL algorithms at this moment. These trends could be studied in more detail, by studying more literature databases or by including patent databases. More advanced analyses could be used to predict in which direction AI will develop over the coming years. The expectation is that AI will keep on growing, in spite of stricter privacy laws, more need for standardization, bias in the data, and the need for building trust.


Can we see enough? A comparative study of film-screen vs digital radiographs in small lesions in rheumatoid arthritis.
The aim of this study was to evaluate the performance of digital radiography in the detection of early very small erosions and joint space narrowing in the hands and feet in rheumatoid arthritis. Fifty-three sets of film-screen and digital radiographs of the same hands and feet with very small and sometimes questionable lesions (possible erosions and cysts) were scored independently two times by four investigators. The percentage of lesions found in exactly the same position for each investigator was calculated. Intra-observer agreement between first and second reading in film-screen radiography was 64-76 % (mean 67 %), and in digital radiographs 60-71 % (mean 64 %). Agreement between film-screen and digital radiographs ranged from 54 to 64 % (mean 58 %) in the first reading and from 56 to 66 % (mean 62 %) in the second reading. Overall agreement between both techniques between first and second reading ranged between 62 and 73 % (mean 65 %). Digital radiography of the hands and feet can be used in patients suspected of rheumatoid arthritis and in follow-up of those patients, because small and early erosions can be seen equally well with the digital technique as compared with the conventional film-screen technique.


Diastereoselective Petasis-Borono-Mannich Crotylation Reactions of Chiral α-Heteroatom (F, OBz, OH) Aldehydes: Rapid Access to Valuable Mono and Bicyclic Heterocyclic Scaffolds.
The crotylation reactions of chiral α-F, α-OBz and α-OH aldehydes under Petasis-borono-Mannich conditions using (E)- or (Z)-crotylboronates and primary amines resulted in γ-addition products in high dr and high er. α-F and α-OBz aldehydes gave 1,2-anti-2,3-syn and 1,2-anti-2,3-anti, products, respectively while an α-OH aldehyde gave 1,2-syn-2,3-syn products. The stereochemical outcomes of reactions of the former aldehydes can be explained using a six-membered ring transition state (TS) model in which a Cornforth-like conformation around the imine intermediate is favoured resulting in 1,2-anti products. The 2,3-stereochemical outcome is dependent upon the geometry of the crotylboronate. These TS models were also supported by DFT calculations. The stereochemical outcomes of reactions employing an α-OH aldehyde can be rationalised as occurring via an open-TS involving H-bonding in the imine intermediate between the α-OH group and the imine N atom. Representative products were converted to highly functionalized 1,2,3,6-tetrahydropyridines and 3H-oxazolo[3,4-a]pyridine-3-ones which will be valuable scaffolds in synthesis.


RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo.
Transforming growth factor (TGF)-beta is the key molecule implicated in impaired immune function in human patients with malignant gliomas. Here we report that patients with glioblastoma, the most common and lethal type of human glioma, show decreased expression of the activating immunoreceptor NKG2D in CD8(+) T and natural killer (NK) cells. TGF-beta is responsible for the down-regulation of NKG2D expression in CD8(+) T and NK cells mediated by serum and cerebrospinal fluid of glioma patients in vitro. Moreover, TGF-beta inhibits the transcription of the NKG2D ligand MICA. Interference with the synthesis of TGF-beta1 and TGF-beta2 by small interfering RNA technology prevents the down-regulation of NKG2D on immune cells mediated by LNT-229 glioma cell supernatant and strongly enhances MICA expression in the glioma cells and promotes their recognition and lysis by CD8(+) T and NK cells. Furthermore, TGF-beta silencing results in a less migratory and invasive glioma cell phenotype in vitro. LNT-229 glioma cells deficient in TGF-beta exhibit a loss of subcutaneous and orthotopic tumorigenicity in nude mice, and NK cells isolated from these mice show an activated phenotype. RNA interference targeting TGF-beta1,2 results in a glioma cell phenotype that is more sensitive to immune cell lysis and less motile in vitro and nontumorigenic in nude mice, strongly confirming TGF-beta antagonism as a major therapeutic strategy for the future treatment of malignant gliomas.


[Various aspects of blood cells in the 19th century].
Although the erythrocytes are known since the 17th century, their quantification and their way of production could only be described in the 19th century. As the result of the first cytological and histological colorations at that time, the different types of leucocytes were discovered and the first clinico-cytological descriptions of leukemia and of ganglionic disturbances could be made. The platelets were also identified, the knowledge of their functions and of their pathological aspects, however, was still very fragmentary.


Changing the current health system's vision for disease prevention and health promotion.
Using the case of Israel, we examine the confluence of current philosophies of health care along with the historical trends of health promotion/disease prevention services to consider strategies for increasing inclusiveness and for updating and improving their service delivery. Health services in Israel are at a crossroads. Plans to integrate the historic, nurse-operated, nationwide programme, providing health promotion/disease prevention services to pregnant women and young children for all residents (Tipat Halav) into the National Health Service System's existing Sickness Funds are under discussion. Using a discourse approach, this paper examines the current and historical context of health promotion/disease prevention services. Our history shows an increasingly treatment-based perspective and dwindling support for inclusive services. In the current health system, Tipat Halav nurses solely provide inclusive health promotion/disease prevention services to pregnant women and young children. Informed by the World Health Organization, a reorientation to health promotion/disease prevention is essential in an ageing society where chronic rather than infectious diseases are the reigning health problems. Israel needs to reorganize the health system using a public health approach that both incorporates existing structures and establishes new ones, such as creating a network to elicit community input, and instituting nurse-operated clinics designed to provide health promotion/disease prevention services for all ages and all residents. The newly created health system framework demands activism among all health professionals to legislate for an inclusive, holistic orientation. Master's level clinical programmes in community health nursing are vital to ensure the provision of optimal health promotion/disease prevention services.


Principal component analysis to assess the efficiency and mechanism for enhanced coagulation of natural algae-laden water using a novel dual coagulant system.
A novel dual coagulant system of polyaluminum chloride sulfate (PACS) and polydiallyldimethylammonium chloride (PDADMAC) was used to treat natural algae-laden water from Meiliang Gulf, Lake Taihu. PACS (Aln(OH)mCl3n-m-2k(SO4)k) has a mass ratio of 10 %, a SO4 (2-)/Al3 (+) mole ratio of 0.0664, and an OH/Al mole ratio of 2. The PDADMAC ([C8H16NCl]m) has a MW which ranges from 5 × 10(5) to 20 × 10(5) Da. The variations of contaminants in water samples during treatments were estimated in the form of principal component analysis (PCA) factor scores and conventional variables (turbidity, DOC, etc.). Parallel factor analysis determined four chromophoric dissolved organic matters (CDOM) components, and PCA identified four integrated principle factors. PCA factor 1 had significant correlations with chlorophyll-a (r=0.718), protein-like CDOM C1 (0.689), and C2 (0.756). Factor 2 correlated with UV254 (0.672), humic-like CDOM component C3 (0.716), and C4 (0.758). Factors 3 and 4 had correlations with NH3-N (0.748) and T-P (0.769), respectively. The variations of PCA factors scores revealed that PACS contributed less aluminum dissolution than PAC to obtain equivalent removal efficiency of contaminants. This might be due to the high cationic charge and pre-hydrolyzation of PACS. Compared with PACS coagulation (20 mg L(-1)), the removal of PCA factors 1, 2, and 4 increased 45, 33, and 12 %, respectively, in combined PACS-PDADMAC treatment (0.8 mg L(-1) +20 mg L(-1)). Since PAC contained more Al (0.053 g/1 g) than PACS (0.028 g/1 g), the results indicated that PACS contributed less Al dissolution into the water to obtain equivalent removal efficiency.


Vascular remodeling in coronary artery disease.
Traditionally, the diagnosis of significant coronary atherosclerotic disease has relied on angiographic techniques. Both histologic analyses and, more recently, intravascular ultrasonography techniques have revealed that a significant atherosclerotic plaque load may be present in epicardial coronary arteries without significant luminal narrowing, consistent with compensatory vessel enlargement or remodeling. In patients with coronary atherosclerosis, more limited structural changes are present in the smaller resistance arterioles, whereas a decrease in luminal area with an increase in wall thickness and perivascular fibrosis are the characteristic structural changes observed in resistance arteries in the presence of systemic hypertension. Further, functional changes, such as impairment of endothelium-mediated vasodilation, are present in epicardial and resistance vessels of patients with coronary atherosclerosis and may influence the progression of this disease and development of ischemic syndromes. The introduction of two-dimensional intravascular and Doppler ultrasonography enables us to study in vivo these morphologic and functional changes. In this article, the knowledge acquired in humans on the mechanisms and clinical relevance of vascular remodeling with the use of these two ultrasonography-based techniques is reviewed. The possibility of using pharmacologic interventions to improve or normalize the vascular response to endothelium-dependent and independent vascular interventions is discussed, with special attention to the efficacy of the inhibition of the angiotensin-converting enzyme.


[Epidemiological aspects and organization of ecological expertise of project data].
The necessity of organizing the ecological evaluation of projects, the interrelation of measures for the protection of nature and ecological forecasting, the importance of introducing the section of ecological forecasting into every project are discussed. Changes in the ecological systems, occurring due to different kinds of human intervention, and their consequences for human health are shown. The organization of the ecological evaluation of project plans and specifications at different administrative levels of the sanitary and epidemiological service and at institutes is proposed , which must ensure the elimination-of consequences, unfavorable for human health.


[Influence of glutamic acid, histidine and arginine on dietary intake. Chemical structure and body mass composition of rats].
100 male rats, aged 30 +/- 1 days were investigated by means of 28 days study. The influence of the supplementation of glutaminic acid, histidine and arginine to the diet on dietary intake, weight gain and chemical composition was determined. It was casein that was used as the source of protein. We investigated the application of 4 kinds of diet during each experiment and the composition of the diets was based on the Miller-Bend non-protein diet model. The casein control diet contained 20g of casein per 100 g of diet. The diet with the supplementation of glutaminic acid contained 15 g of casein and 5 g of glutaminic acid per 100 g of diet. The histidine diet contained 15 g casein and 5 g of histidine per 100 g of diet. The arginine diet contained 15 g of casein and 5 g arginine per 100 g of diet. The addition of glutaminic acid, histidine and arginine to the diet caused the substantial decrease of diet intake weight gain and its ingredients. The addition of histidine to the diet reduced the nitrogen/total water contain ratio. This resulted in the inhibition of the chemical maturation of rat tissue and simultaneously decreased the percentage contain of fat in rat body.


Efficacy and Safety of Whey Protein Supplements on Vital Sign and Physical Performance Among Athletes: A Network Meta-Analysis.
Introduction: Athletes train physically to reach beyond their potential maximum aerobic threshold. Whey protein supplements (WPS) are often used in conjunction with physiotherapy and psychotherapy to regain better vital sign and physical performances. This review aimed to explore the clinical evidence on the efficacy and safety of WPS in sports performance and recovery among athletes. Methodology: A comprehensive literature search was performed to identify relevant randomized control trials (RCTs) that investigated the efficacy and safety of WPS on the vital sign and physical performance among athletes. The Cochrane Risk of Bias (ROB) Assessment tools were used to assess the quality of the studies. Meta-analysis was conducted using the frequentist model with STATA version 14.2®. Results: A total of 333,257 research articles were identified out of which 20 RCTs were included for qualitative synthesis and network meta-analysis with 351 participants. Among the studies, 7 had low ROB and 3 RCTs had high ROB. Of these 20 trials, 16 trials were randomized clinical trials which compared whey protein supplements (WPS) with various comparators i.e., L-alanine, bovine colostrum, carbohydrate, casein, leucine, maltodextrin, rice, protein + caffeine were compared with placebo. Analysis from the pairwise meta-analysis revealed that for respiratory exchange ratio (RER) WPS was found to be significantly improving compared to maltodextrin (WMD = 0.012; 95%CI = 0.001, 0.023). Similarity to RPE (Rate Perceived Exertion), slight difference between WPS and the comparators, however, when the estimation was favorable to the comparators, there was moderate-high heterogeneity. For VO 2max, high heterogeneity appeared when WPS compared to maltodextrin with the I 2 = 97.8% (WMD = 4.064; 95% CI = -4.230, 12.359), meanwhile bovine colostrum (WMD = -2.658; 95%CI = -6.180, 0.865) only comparator that was better than WPS. According to the estimated effect of the supplements on physical performance outcome results, maximum power (8 studies, 185 athletes), highest ranked was bovine colostrum (SUCRA = 70.7%) and the lowest ranked was placebo (SUCRA = 17.9%), yet all insignificant. Then again, on average power (nine studies, 187 athletes), WPS was the highest ranked (SUCRA = 75.4 %) about -112.00 watt (-187.91, -36.08) and most of the estimations were significant. Body mass was reported in 10 studies (171 athletes), carbohydrate may be at the highest ranked (SUCRA = 66.9%) but it is insignificant. Thought the second highest ranked was WPS (SUCRA = 64.7%) and it is significant (WMD = -6.89 kg; CI = -8.24, -5.54). Conclusion: The findings of this review support the efficacy and safety of WPS as an ergogenic aid on athletes' sports performance and recovery. The overall quality of clinical evidence was found to be valid and reliable from the comprehensive search strategy and ROB assessment.


Upregulation of vascular ET(B) receptor gene expression after chronic ET(A) receptor blockade in prediabetic NOD mice.
In the aorta of prediabetic non-obese diabetic mice, a model of human type 1 diabetes, we investigated gene expression of the endothelin receptors and contractility to big endothelin-1 and endothelin-1 at the ages of 10 and 16 weeks. A subgroup of 10- week-old animals was treated with the endothelin ETA receptor antagonist LU461314 (30 mg/kg per day for 6 weeks). Blood glucose levels were normal in all animals. Real-time polymerase chain reaction analysis revealed that vascular ETB receptor expression was higher in 10-week-old non-obese diabetic (NOD) mice compared with controls. In 16-week-old NOD mice, but not in control mice, ETB receptor mRNA was twofold lower (P < 0.05 vs 10-week-old NOD mice). In all groups ETA receptor expression was unaffected by age or treatment. Contractions to big endothelin-1 and endothelin-1 were lower in 10-week-old NOD mice compared with controls. Treatment with LU461314 increased ETB receptor expression in 16-week-old NOD mice, but had no effect on vascular contractility. These data indicate that dysregulation of ETB receptor expression and a decreased contractile response to big endothelin-1 and endothelin-1 are present in the prediabetic state of a model of human type 1 diabetes. These alterations occur independent of glucose levels. Furthermore, ETA receptor blockade is effective in increasing ETB receptor gene expression, suggesting a potential role for endothelin ETA antagonists in the treatment of type 1 diabetes.


Coordinative Modulation of Chlorothricin Biosynthesis by Binding of the Glycosylated Intermediates and End Product to a Responsive Regulator ChlF1.
Chlorothricin, isolated from Streptomyces antibioticus, is a parent member of spirotetronate family of antibiotics that have long been appreciated for their remarkable biological activities. ChlF1 plays bifunctional roles in chlorothricin biosynthesis by binding to its target genes (chlJ, chlF1, chlG, and chlK). The dissociation constants of ChlF1 to these genes are ∼ 102-140 nm. A consensus sequence, 5'-GTAANNATTTAC-3', was found in these binding sites. ChlF1 represses the transcription of chlF1, chlG, and chlK but activates chlJ, which encodes a key enzyme acyl-CoA carboxyl transferase involved in the chlorothricin biosynthesis. We demonstrate that the end product chlorothricin and likewise its biosynthetic intermediates (demethylsalicycloyl chlorothricin and deschloro-chlorothricin) can act as signaling molecules to modulate the binding of ChlF1 to its target genes. Intriguingly, a correlation between the antibacterial activity and binding ability of signaling molecules to the regulator ChlF1 is clearly observed. These features of the signaling molecules are associated with the glycosylation of spirotetronate macrolide aglycone. The findings provide new insights into the TetR family regulators responding to special structure of signaling molecules, and we reveal the regulatory mini-network mediated by ChlF1 in chlorothricin biosynthesis for the first time.


Hepatitis C virus and autoimmunity.
Hepatitis C virus infection is associated with several extrahepatic manifestations. About 60% of patients infected with HCV develop at least one extrahepatic manifestation. The majority of these diseases seem to be triggered through autoimmune mechanisms, such as autoantibody production, autoreactive T cells and complex autoimmune mechanisms leading to systemic autoimmune disorders. In this review we categorize these diseases into three groups according to the main pathogenetic process involved, in particular B-cell-mediated, T-cell-mediated and complex autoimmune systemic diseases.


Music Intervention With Reminiscence Therapy and Reality Orientation for Elderly People With Alzheimer Disease Living in a Nursing Home: A Pilot Study.
The purpose of this study was to investigate the effect of an 8-week nursing intervention consisting of 2 weekly sessions of music and reminiscence therapy together with the application of reality orientation techniques. Our expectation at the onset of the study was that listening to music that was familiar and connected with the memory of past events would, due to the music's emotional impact, stimulate memory associations, leading, in turn, to a positive effect on depression and anxiety in people living with dementia. We carried out a pre-/posttest intervention design with a sample of 19 patients divided into 2 groups-a 10-patient control group and a 9-patient intervention group-in a nursing home in Spain. Goldberg tests for depression and anxiety have been assessed at baseline and postintervention in both groups. Our results confirm the valuable effect of music therapy and reminiscence therapy together with reality orientation techniques on depression in patients with mild Alzheimer disease. Our study may constitute an important starting point for further research on nursing interventions based on the provision of music and/or reminiscence therapy together with reality orientation techniques that is implemented on a daily basis in nursing homes.


Evaluation of phenoxymethylpenicillin treatment of acute otitis media in children aged 2-16.
To study the clinical recovery from acute otitis media (AOM) in children, 2-16 years of age, managed with or without treatment with phenoxymethylpenicillin (PcV). An open, prospective randomized trial. Children aged between 2 and 16 years, presenting with one- or double-sided AOM (without perforation) with symptom duration of less than four days, were included. The children were randomized to PcV for five days or to no primary antibiotic treatment. A health score and compliance were registered on a daily basis for seven days. A total of 32 health centres and 72 GPs in south-east Sweden. Subjects. Children aged 2-16 presenting with earache. Recovery time, symptom duration, frequency of complications (up to three months) and consumption of healthcare services independent of treatment with or without antibiotics. A total of 179 patients carried out the trial; 92 were randomized to PcV, 87 to no primary antibiotic treatment. The median recovery time was four days in both groups. Patients who received PcV had less pain (p <0.001) and used fewer analgesics. There were no significant differences in the number of middle-ear effusions or perforations at the final control after three months. Children randomized to PcV treatment consulted less (p <0.001) during the first seven days. Our investigation supports that PcV treatment of AOM does not affect the recovery time or complication rates. PcV provided some symptomatic benefit in the treatment of AOM in otherwise healthy children, aged 2-16 years.


RNA interference in ageing research--a mini-review.
The search for genetic mechanisms affecting life-span and ageing represents an important part of ageing research, especially since the discovery of single-gene mutations with dramatic effects on these traits. Due to its relative ease of use and its power to specifically target arbitrary genes, RNA interference (RNAi) has rapidly been adopted as a technique for silencing gene expression. The feasibility of genome-wide RNAi screens potentially much simplifies the identification of novel ageing-related genes. In a review of applications of RNAi in ageing research with a focus on the model organisms Caenorhabditis elegans and Drosophila melanogaster and discussing recent technical developments, we aim to highlight the current and future impact of this technology in the field. We show how RNAi has successfully been used to complement classic mutant studies. Moreover, we discuss the novel opportunities and challenges of an application of RNAi in genome-wide screens in D. melanogaster, which has become possible with the recent availability of a comprehensive transgenic RNAi library for the fly. We highlight, in particular, how the flexible control of RNAi induction can support the study of dynamic processes like ageing through specific experiments and the development of matching computational methods. In an overview of complementary approaches we discuss the challenge of extracting insight from the high-dimensional measurement datasets that are required for the study of dynamic effects and interaction dependencies. RNAi has emerged as a powerful tool for the study of ageing, allowing the further characterization of the roles of specific genes in the ageing process as well as the efficient identification of new genes implicated. RNAi has contributed to our understanding of age-related diseases especially by making genes amenable to manipulation for which mutants were not easily available. Recent developments enable genome-wide screens with unprecedented temporal and spatial control of RNAi induction. Specific RNAi time-course experiments provide an opportunity for the analysis of high-resolution gene expression profiles capturing the dynamics of ageing-relevant processes and gene interactions. Research exploiting new avenues opened by the growing RNAi toolbox will considerably contribute to the next steps in researching the genetics of ageing and age-related diseases.


Political (Meta-)Dehumanization in Mental Representations: Divergent Emphases in the Minds of Liberals Versus Conservatives.
We conducted two reverse-correlation studies, as well as two pilot studies reported in the online supplement (total N = 1,411), on the topics of (a) whether liberals and conservatives differ in the types of dehumanization that they cognitively emphasize when mentally representing one another, and if so, (b) whether liberals and conservatives are sensitive to how they are represented in the minds of political outgroup members. Results suggest that partisans indeed differ in the types of dehumanization that they cognitively emphasize when mentally representing one another: whereas conservatives' dehumanization of liberals emphasizes immaturity (vs. savagery), liberals' dehumanization of conservatives more strongly emphasizes savagery (vs. immaturity). In addition, results suggest that partisans may be sensitive to how they are represented. That is, partisans' meta-representations-their representations of how the outgroup represents the ingroup-appear to accurately index the relative emphases of these two dimensions in the minds of political outgroup members.


Use of a choice survey to identify adult, adolescent and parent preferences for vaccination in the United States.
Adult and adolescent vaccination rates are far below coverage targets in the United States. Our objective was to identify the most influential factors related to vaccine uptake among adults, adolescents, and parents of adolescents (parents) in the United States. We used a fractional factorial design to create a binary choice survey to evaluate preferences for vaccination. The national survey was fielded to a sample of adults, adolescents ages 13-17 years, and parents, using a national probability-based online research panel in November 2015. Respondents were presented with 5 profiles of a hypothetical vaccine and asked in a series of questions whether they would accept each vaccine. We analyzed the binary choice data using logistic regression in STATA v13 (College Station, TX) to calculate the odds that a participant would choose to accept the vaccine. We received completed responses from 334 (51%) of 652 adults, 316 (21%) of 1516 adolescents, and 339 (33%) of 1030 parents. Respondents were generally representative of the U.S. Vaccine effectiveness was the most influential factor in the choice to vaccinate for all groups. Other most influential factors were primary care provider (PCP) recommendation and the out-of-pocket cost of the vaccine. Other factors such as risk of illness, risk of vaccine side effects, vaccination location, and time for vaccination were not important in the decision to get vaccinated. Adults, adolescents, and parents are most sensitive to vaccine effectiveness, PCP recommendation, and out-of-pocket cost for vaccination in their decision to get vaccinated. Strong PCP recommendations that focus on vaccine effectiveness and health care policies that minimize out-of-pocket costs for vaccinations may increase vaccine uptake by adults and adolescents.


MG132 enhances the radiosensitivity of lung cancer cells in vitro and in vivo.
Radiotherapy is a common treatment modality for lung cancer, however, radioresistance remains a fundamental barrier to attaining the maximal efficacy. Cancer cells take advantage of the ubiquitin-proteasome system (UPS) for increased proliferation and decreased apoptotic cell death. MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal‑H), a specific and selective reversible inhibitor of the 26S proteasome, has shown anticancer effect in multiple types of cancers. Previously, we have reported that MG132 enhances the anti‑growth and anti-metastatic effects of irradiation in lung cancer cells. However, whether MG132 can enhance the radiosensitivity in lung cancer cells in vitro and in vivo is still unknown. In this study, we found that MG132 increased apoptosis and dicentric chromosome ratio of A549 and H1299 cells treated by irradiation. Radiation-induced NF-κB expression and IκBα phosphorylation was attenuated in MG132 plus irradiation-treated cells. The in vivo model of H1299 xenografts of nude mice showed that the tumor size of MG132 plus irradiation treated xenografts was smaller than that of irradiation, MG132 or the control group. Moreover, MG132 plus irradiation group showed significant reduced Ki67 expression. Taken together, these results demonstrate that MG132 enhances the radiosensitivity through multiple mechanisms in vitro and in vivo.


Depressive Symptom Trajectories Across Adolescence and Adulthood Among Individuals With Asthma.
Individuals with asthma experience increased depressive symptoms, which is associated with deleterious health outcomes. No studies have examined depressive symptom trajectories among individuals with asthma despite increased risk. This study expanded prior literature by identifying the following: (1) depressive symptoms trajectories for individuals with and without asthma and (2) predictors of baseline levels and changes in symptoms across time for individuals with asthma. Adolescents with (N = 965) and without (N = 7,392) asthma self-reported on depressive symptoms (CESD-9) across development. Covariates included: demographics and persistence of asthma. Latent growth curve modeling (LGCM) was used to identify depressive symptom trajectories and their predictors. A multigroup LCGM identified no significant differences between depressive symptom trajectories of individuals with and without asthma. Depressive symptoms followed a quadratic shape across time for individuals with asthma (Mintercept = 5.73, p < .00; Mlinear = -0.38,p < .001; Mquad = 0.03, p < .001), with a linear deceleration in depressive symptoms during adolescence and an acceleration of symptoms into adulthood. Next predictors of depressive trajectories among individuals with asthma were examined. Female sex (B = 0.58, p < .001), lower parent education (B = -0.57, p < .001), older age (B = 0.19, p < .001), and identifying as Black (B = 0.31, p = .04) were associated with greater baseline depressive symptoms. Older individuals exhibited faster linear symptom decelerations (B = -0.56, p < .001) and faster symptom accelerations (B = 0.73, p < .001). American Indian (AIAN) individuals exhibited faster linear symptom decelerations (B = -1.98, p = .005) and faster quadratic accelerations (B = 3.33, p = .007). Our results suggest that the depressive symptom trajectories of individuals with asthma are curvilinear and similar to individuals without asthma. When examining predictors of depressive symptom trajectories for those with asthma, socioeconomic disadvantage and racial marginalization were associated with greater baseline depressive symptoms. Although AIAN youth demonstrated more favorable trajectories in adolescence, they also exhibited worse trajectories across young adulthood and adulthood. Findings suggest the need to better understand the impact of multilevel risk and protective factors on depressive symptoms trajectories for individuals with asthma, especially marginalized populations.


Effect of tamsulosin on ejaculatory function in BPH/LUTS.
This study was undertaken to determine the impact on ejaculatory function of tamsulosin (0.2 mg) given once daily (OD) for 12 weeks and to identify risk factors for ejaculatory dysfunction in patients undergoing this treatment. Males with an International Prostatic Symptom Score (IPSS) ≥8 were enrolled in this study. All participants completed questionnaires, including the IPSS and the Male Sexual Health Questionnaire (MSHQ), and serum prostate-specific antigen, transrectal ultrasound and uroflowmetry with post-void residual were measured. After initiating 0.2 mg OD tamsulosin, patients were re-evaluated on the fourth and twelfth weeks of medication. The chi-squared test, the independent t-test and one-way ANOVA were used to compare means. Binary logistic regression analysis was used to calculate the odds ratio for all risk factors. A total of 177 men constituted the study cohort. No significant difference was observed between baseline and follow-up for the erectile function, ejaculatory function, satisfaction, sexual activity and desire domains (EFD, EjFD, SDA and ADD) or for erectile or ejaculatory bother mean scores. After 12 weeks, the overall incidence of ejaculatory dysfunction (EjD) was 13.4%. Incidences of the seven different types of EjD (decreased frequency, delay, dryness, decreased strength/force, decreased volume, decreased pleasure and pain at ejaculation) were 2.4%, 3.1%, 3.9%, 3.9%, 6.3%, 7.1% and 3.1%, respectively. Baseline EjFD scores were higher for IPSS responders than for non-responders (26.09 vs. 24.06, P=0.03). An EjFD score reduction was more frequent in IPSS responders. The incidence of EjD was small, but not negligible and was more frequent in patients with less lower urinary tract symptoms, a smaller prostate, higher baseline MSHQ totals and higher EjFD scores.


AMS analyses of I-129 from the Fukushima Daiichi nuclear accident in the Pacific Ocean waters of the Coast La Jolla--San Diego, USA.
This paper presents the results of an experimental study we performed by using the Accelerator Mass Spectrometry (AMS) method with iodine 129 (T1/2 = 15.7 My), to determine the increase of the radionuclide content in the USA West Pacific Coast waters, two years after the March 2011 Fukushima Daiichi nuclear power plant accident. The collection of the water samples took place between April and July 2013 at regular intervals of time, from the Pacific Ocean, at the cove of La Jolla, San Diego, USA. The results of the experiments showed a significant increase of the radionuclide concentration during the late spring of 2013. Compared to the isotopic ratio (129)I/(127)I, measured at a 40 km distance, offshore of Fukushima and immediately after the accident, our results show an increase on the USA West Coast that was more than a 2.5 factor higher. Also, compared with the pre-Fukushima background values, our results show an isotopic ratio of about two orders of magnitude higher. A distinct feature of the reconstructed radioactive plume was that it traveled with a speed of 12 cm s(-1), which we estimated and is consistent with the zonal speed in the Pacific. We coupled our (129)I results with the measurements from the June 2011 KOK cruise and we derived the levels of activity for (3)H and (137)Cs. On the USA West Coast, they did not exceed the international regulatory limits.


Impact of Acid ("Progressive Brush") and Alkaline Straightening on the Hair Fiber: Differential Effects on the Cuticle and Cortex Properties.
Glyoxylic acid has emerged as a safe alternative to formol (formaldehyde) use as a hair straightener/relaxer. However, the possible damage to the hair fiber after its application is low known and/or published in the literature. This work aims to characterize hair locks treated with glyoxylic acid compared to traditional alkaline straighteners such as sodium and guanidine hydroxide and ammonium thioglycolate. The morphology of the hair cuticles was observed by scanning electron microscopy. Protein loss was assessed by the Lowry method modified by Peterson and as mechanical properties that were expressed in terms of tensile strength. All products (sodium and guanidine hydroxides and ammonium thioglycolate) caused protein loss of about 2.5 μg/g, except glyoxylic acid that caused the worst damage (3.5 μg/g), in relation to the untreated (virgin) hair (1.12 μg/g), indicating that the chemical treatments can cause hair damage in both cuticles and cortex. The force to break the fibers treated with traditional straighteners based on sodium hydroxide, guanidine hydroxide, and ammonium thioglycolate was statistically the same. The treatment with glyoxylic acid showed rupture tensile statistically equivalent to the alkaline straighteners. The mechanism of action of glyoxylic acid does not appear to be based on breaking and rearrangement of disulfide bridges, but altered them, that influenced the hair strength. However, it is also essential to consider other factors relevant: technical application technique, reaction time, and interval of reapplication of the product, as this can change the pattern of the results obtained.


Mass vaccination as a complementary tool in the control of a severe outbreak of bovine brucellosis due to Brucella abortus in Extremadura, Spain.
We report the evolution of an outbreak of bovine brucellosis (Brucella abortus) in the region of Extremadura (Spain) involving more than 1000 herds and nearly 40,000 animals. S19 vaccination of young cattle combined with a test and slaughter strategy did not result in a rapid decrease in herd prevalence and animal incidence; these parameters showed a constant decreasing trend only when a combination of restriction of cattle movements, increased test frequency, S19 vaccination and mass RB51 vaccination (with yearly revaccinations) were applied to all susceptible populations. These measures were applied for 5 years; abortions following RB51 vaccination of pregnant cows were limited to the first inoculation and the involvement of the vaccine strain could only be demonstrated in 78 out of 897 abortions. Our results demonstrate the usefulness - and lack of significant side effects - of RB51 mass vaccination as a complementary tool to control bovine brucellosis outbreaks in areas where the disease cannot be contained using more conservative approaches.


Neoflavonoids and related constituents from Nepalese propolis and their nitric oxide production inhibitory activity.
A methanolic extract of Nepalese propolis yielded 10 new open-chain neoflavonoids (1-10), a new chalcone (11), and eight previously reported compounds (12-19). Their structures were determined on the basis of spectroscopic data and chemical conversion. The isolated compounds other than 5, 8, and 16 showed dose-dependent inhibitory activities on nitric oxide production in lipopolysaccharide-activated macrophage-like J774.1 cells and were more active than a positive control, N(G)-monomethyl-L-arginine (IC(50), 27.1 microM). The most potent activities, of 6 and 7 (IC(50), 0.5 microM), were greater than another positive control, caffeic acid phenethyl ester (IC(50), 4.8 microM).


Noise correlations in neural ensemble activity limit the accuracy of hippocampal spatial representations.
Neurons in the CA1 area of the mouse hippocampus encode the position of the animal in an environment. However, given the variability in individual neurons responses, the accuracy of this code is still poorly understood. It was proposed that downstream areas could achieve high spatial accuracy by integrating the activity of thousands of neurons, but theoretical studies point to shared fluctuations in the firing rate as a potential limitation. Using high-throughput calcium imaging in freely moving mice, we demonstrated the limiting factors in the accuracy of the CA1 spatial code. We found that noise correlations in the hippocampus bound the estimation error of spatial coding to ~10 cm (the size of a mouse). Maximal accuracy was obtained using approximately [300-1400] neurons, depending on the animal. These findings reveal intrinsic limits in the brain's representations of space and suggest that single neurons downstream of the hippocampus can extract maximal spatial information from several hundred inputs.


[Microscopic myocardial changes and their significance for forensic medical diagnosis].
Morphological myocardial changes essential for diagnosis in forensic medical medicine are listed as well as alterations in the vessels of the myocardium, cardiac muscular fibers and cardiomyocytes important for diagnosis of death of ischemic heart disease, acute alcohol poisoning, alcohol cardiomyopathy, closed cardiac lesions. Changes induced by reflex impacts on the heart and postmortem alterations are also shown.


The Role of the Pediatric Pharmacist in Precision Medicine and Clinical Pharmacogenomics for Children.
With the initiatives by the National Institutes of Health and the US Food and Drug Administration, pharmacogenomics is transitioning from the laboratory to patient care. Nearly 200 drug products now contain pharmacogenomic information as part of their labeling; many of these products are commonly used in the pediatric population. Because pharmacogenomic testing can provide patient-specific predictors for drug response, pharmacists are positioned to assume a leadership role in pharmacogenomic testing, clinical interpretation of results, and recommendations for individualization of drug therapy. Opportunities for pharmacists exist in both inpatient and outpatient settings, such as pharmacist-managed clinical pharmacogenomics consultation services and educating patients and families about pharmacogenomic testing. Given the potential for genetic and age-dependent factors to influence drug selection and dosing, pediatric pharmacists should be involved in the development of dosing recommendations and interprofessional practice guidelines regarding pharmacogenomic testing in pediatric patients. Opportunities to become knowledgeable and competent in pharmacogenomics extend from coursework as part of the pharmacy curriculum to postgraduate education (e.g., residencies, fellowship, continuing education). The Pediatric Pharmacy Advocacy Group acknowledges a need for increased education of both students and practicing pharmacists with consideration for infants and children.


Assessment of islet isolation efficacy in dogs.
The outcome of islet isolation is considered uncertain because of the large variability of islet and insulin yield, but comparison of the isolated and native islet population has not been attempted. We therefore addressed the efficacy of collagenase digestion, and density gradient purification of islets from the splenic dog pancreas (n = 31) by morphometry of the islet volume and size distribution, and by extraction of insulin and amylase, in samples from the pancreas, the digest, and gradient fractions. In contrast to a approximately 90% recovery of pancreatic insulin and amylase after digestion, islet yield amounted to 50% of the islet content of the pancreas. After density separation, islets were mainly found in the purified fractions, while half of the recovered insulin was located in the acinar fraction of the gradients-indicating a substantial proportion of islets entrapped in acinar fragments. The islet and insulin content of the pancreas correlated well with islet and insulin yield after digestion (r = 0.7, p < .0001). The insulin content of digest suspensions did neither correlate with islet nor insulin recovery in the purified fraction of the gradients (r = 0.4) as opposed to the islet content of digest suspensions, which correlated with both (r = 0.7, p < .0001). After density separation near 100% purity was obtained, and no loss of insulin from isolated islets was demonstrated by extraction and microscopy. Size distributions of native and isolated islets demonstrated no fragmentation. We conclude that the variability of isolation outcome may be attributed to a large extent to the variability of the native endocrine pancreas. Isolation efficacy was best documented by morphometry, because insulin extraction did not discriminate between free and entrapped islets. However, assessment by both morphometry and extraction allowed the quantitation of entrapped islets, and demonstrated preservation of beta-cell granulation. Similar studies should facilitate the analysis of other factors affecting islet isolation in man.


Preferential localization of a vesicular monoamine transporter to dense core vesicles in PC12 cells.
Neurons and endocrine cells have two types of secretory vesicle that undergo regulated exocytosis. Large dense core vesicles (LDCVs) store neural peptides whereas small clear synaptic vesicles store classical neurotransmitters such as acetylcholine, gamma-aminobutyric acid (GABA), glycine, and glutamate. However, monoamines differ from other classical transmitters and have been reported to appear in both LDCVs and smaller vesicles. To localize the transporter that packages monoamines into secretory vesicles, we have raised antibodies to a COOH-terminal sequence from the vesicular amine transporter expressed in the adrenal gland (VMAT1). Like synaptic vesicle proteins, the transporter occurs in endosomes of transfected CHO cells, accounting for the observed vesicular transport activity. In rat pheochromocytoma PC12 cells, the transporter occurs principally in LDCVs by both immunofluorescence and density gradient centrifugation. Synaptic-like microvesicles in PC12 cells contain relatively little VMAT1. The results appear to account for the storage of monoamines by LDCVs in the adrenal medulla and indicate that VMAT1 provides a novel membrane protein marker unique to LDCVs.


Rheumatoid arthritis patients fulfilling Korean National Health Insurance reimbursement guidelines for anti-tumor necrosis factor-α treatment and comparison to other guidelines.
The aim of this study was to compare anti-tumor necrosis factor-α (TNFα) treatment status in rheumatoid arthritis (RA) patients with the Korean National Health Insurance (KNHI) reimbursement eligibility criteria and with American College of Rheumatology (ACR) recommendations, Japan College of Rheumatology (JCR) guidelines and British Society for Rheumatology (BSR) guidelines. Between December 2011 and August 2012, outpatients from 17 South Korean general hospitals diagnosed with RA according to the 1987 ACR criteria were enrolled into a noninterventional, cross-sectional, observational study. Of 1700 patients (1414 female (83.2 %), mean age of 56.6 ± 12.0, mean disease duration 97.9 ± 91.8 months), 306 (18.0 %) had used anti-TNFα agents, and 224 (13.2 %) were currently using an anti-TNFα agent. Of 1394 anti-TNFα-naive patients, 32 (2.3 %) met KNHI reimbursement guidelines, 148 (10.6 %) met ACR recommendations, and 127 (9.1 %) and 126 (9.0 %) were considered eligible for anti-TNFα agents according to JCR and BSR guidelines, respectively. The main discrepancy was the higher active joint count required by the KNHI eligibility criteria. In the opinion of treating rheumatologists, the KNHI reimbursement criteria ineligibility accounted for 15.3 % (n = 213) of the reasons for not initiating anti-TNFα agents in anti-TNFα-naive group. The anti-TNFα user group showed significantly higher disease activity than the anti-TNFα-naive group based on DAS28 score. In comparison with the ACR recommendations and JCR and BSR guidelines, fewer patients met KNHI reimbursement eligibility criteria for anti-TNFα agents. The current amendment of the KNHI criteria based on DAS28 score will improve an access to biologic agents including anti-TNFα treatment for South Korean patients with active RA.


Modified sliding trochanteric osteotomy in revision total hip arthroplasty.
Traditional trochanteric sliding osteotomy preserves the lateral aspect of the greater trochanter, the abductors, and vastus lateralis in continuity. Our modification uses a lateral approach to the hip and osteotomy immediately anterior to the insertion of the posterior capsule and external rotators onto the greater trochanter. The osteotomy and attached abductors and vastus lateralis are translated anteriorly, leaving the posterior capsule and external rotators attached to the proximal femur. This surgical approach preserves the posterior soft-tissue stabilizing structures that resist posterior dislocation of the hip. In a retrospective review of 2 consecutive 2-year series of acetabular component revisions only between 1997 and 2001, 4 of 27 acetabular revisions using a traditional trochanteric slide subsequently dislocated; only 1 of 30 subsequent cases using a modified sliding trochanteric osteotomy dislocated. Modified sliding trochanteric osteotomy facilitated surgical exposure and produced a trend toward a lower dislocation rate that did not reach statistical significance with the small numbers of patients available.


The environmental health of children: priorities in Europe.
To evaluate existing research on the environmental health of children and provide a prioritised list of risk factors and policy recommendations for action, the Policy Interpretation Network on Children's Health and Environment (PINCHE) was set up within EU FP5 (QLK4-2002-02395). The project focused on air pollutants, carcinogens, neurotoxicants and noise. PINCHE was a multidisciplinary and multinational network of representatives from science, industry, NGOs, and consumer and patient organisations in Europe. A literature search was performed using the Pubmed, Embase and Toxline databases. The quality of the gathered articles was assessed and their information and relevance was interpreted within a systematic framework. Information related to exposure, epidemiology, and toxicology was analysed separately and then a risk evaluation of particular environmental factors was made. Socioeconomic factors were specifically taken into account. The results were compiled, and considering the present regulatory situation, policy recommendations for action were made. Finally, the risk factors and policy recommendations were prioritised through a process of discussion between all the partners. PINCHE concluded that outdoor air pollutants (especially traffic-related), environmental tobacco smoke, allergens, and mercury were high priorities with an urgent need for action. Brominated flame retardants, lead, PCBs and dioxins, ionising and solar radiation, and some noise sources were classified as being of medium priority. Some toxins were given low priority, based on few exposed children, relatively mild health effects or an improving situation due to past policy measures. We recognise the shortcomings of such a prioritisation and, though some measures are more urgent than others, emphasise that ideally all policy measures should be carried out without delay for all toxins. This priority list must be continuously revised, the precautionary principle should be central to all decisions, and the focus should be on safe exposure levels for children.