[THE STUDY OF ANXIOLYTIC PROPERTIES OF NEW PYRAZOLO[C]PYRIDINE DERIVATIVE GIZH-72].
It was studied the anxiolytic properties of 4,6-dimethyl-2-(4-chlorophenyl)-2,3-dihydro-1Í-pyrazolo[4,3-c]pyridin-3-one chloralhydrate (GIZh-72, 20 mg/kg, i.p.) and afobazole (1 mg/kg, i.p.) in comparison to fluoxetine (20 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) in open-field and marble burying tests on male mice of inbred strains BALB/C and C57BL/6. It is established that GIZh-72 administered both 30 min and 24 h before testing produces anxiolytic effect in the open-field test. The open field anxiety response patterns following GIZh-72 administration differed from these in diazepam or afobazole treated BALB/C mice. This drug also decreased the number of buried marbles in both BALB/C and C57BL/6 mice, the effect being comparable to that of afobazole and fluoxetine. In operant drug discrimination liquid-reinforcement paradigm in male Wistar rats, GIZh-72 failed to antagonize or substitute for the interoceptive stimulus cues of pentylenetetrazole evoking the saline-like responses in the latter case, which was evidence for the absence of properties of a ligand bearing positive modulator sites of GABA-A receptor.


Influences of alkaline ionized water on milk electrolyte concentrations in maternal rats.
We previously reported that body weight on day 14 after birth in male offspring of rats given alkaline ionized water (AKW) was significantly heavier than that in offspring of rats given tap water (TPW), but no significant difference was noted in milk yield and in suckled milk volume between the two groups. Additionally, the offspring in the AKW group and TPW group were given AKW and TPW, respectively, at weaning, and unexpectedly, the necrotic foci in the cardiac muscle were observed at the 15-week-old age in the AKW group, but not in the TPW group. The present study was designed to clarify the factors which are involved in that unusual increase of body weight and occurrence of cardiac necrosis. Eight dams in each group were given AKW or TPW (control) from day 0 of gestation to day 14 of lactation. The milk samples were collected on day 14 of lactation and analyzed for concentrations of calcium (Ca), sodium (Na), potassium (K), magnesium (Mg) and chloride (Cl). The AKW and TPW were also analyzed. Ca, Na and K levels in milk were significantly higher in the AKW group compared to the TPW group. No significant difference was noted in the Mg and Cl levels between the two groups. These data suggested that the Ca cation of AKW enriched the Ca concentration of the milk and accelerated the postnatal growth of the offspring of rats given AKW.


Label-free characterization of exosome via surface enhanced Raman spectroscopy for the early detection of pancreatic cancer.
Pancreatic cancer is a highly lethal malignancy. Lack of early diagnostic markers makes timely detection of pancreatic cancer a highly challenging endeavor. Exosomes have emerged as information-rich cancer specific biomarkers. However, characterization of tumor-specific exosomes has been challenging. This study investigated the proof of principle that exosomes could be used for the detection of pancreatic cancer. Label-free analysis of exosomes purified from normal and pancreatic cancer cell lines was performed using surface enhanced Raman Spectroscopy (SERS) and principal component differential function analysis (PC-DFA), to identify tumor-specific spectral signatures. This method differentiated exosomes originating from pancreatic cancer or normal pancreatic epithelial cell lines with 90% accuracy. The cell line trained PC-DFA algorithm was next applied to SERS spectra of serum-purified exosomes. This method exhibited up to 87% and 90% predictive accuracy for HC and EPC individual samples, respectively. Overall, our study identified utility of SERS spectral signature for deciphering exosomal surface signature.


A mission-oriented approach to cancer in Europe: a joint mission/vision 2030.
By combining innovative prevention and treatment strategies in a sustainable state-of-the-art virtual European cancer centre/infrastructure, it will be possible by 2030 to achieve a long-term survival of 3 out of 4 cancer patients in countries with well-developed healthcare systems. Furthermore, the proposed concerted actions will pave the way to handling the economic and social inequalities in countries with less developed systems. These efforts will also ensure that in the long-run, science-driven and social innovations reach patients across the healthcare systems in Europe.


The Malevolent Side of Human Nature.
The term dark triad refers to the constellation of narcissism, Machiavellianism, and psychopathy. Over the past few years, the concept has gained momentum, with many researchers assuming that the dark triad is a prominent antecedent of transgressive and norm-violating behavior. Our purpose in this meta-analytic review was to evaluate (a) interrelations among narcissism, Machiavellianism, and psychopathy; (b) gender differences in these traits; (c) how these traits are linked to normal personality factors; and (d) the psychosocial correlates of the dark triad. Our findings show that dark triad traits are substantially intercorrelated, somewhat more prevalent among men than women, predominantly related to the Big Five personality factor of agreeableness and the HEXACO factor of honesty-humility, and generally associated with various types of negative psychosocial outcomes. We question whether dark triad traits are sufficiently distinct and argue that the way they are currently measured is too simple to capture the malevolent sides of personality. Because most research in this domain is cross-sectional and based on self-reports, we recommend using a cross-informant approach and prospective, longitudinal research designs for studying the predictive value of dark triad features.


Month of Conception and Learning Disabilities: A Record-Linkage Study of 801,592 Children.
Learning disabilities have profound, long-lasting health sequelae. Affected children born over the course of 1 year in the United States of America generated an estimated lifetime cost of $51.2 billion. Results from some studies have suggested that autistic spectrum disorder may vary by season of birth, but there have been few studies in which investigators examined whether this is also true of other causes of learning disabilities. We undertook Scotland-wide record linkage of education (annual pupil census) and maternity (Scottish Morbidity Record 02) databases for 801,592 singleton children attending Scottish schools in 2006-2011. We modeled monthly rates using principal sine and cosine transformations of the month number and demonstrated cyclicity in the percentage of children with special educational needs. Rates were highest among children conceived in the first quarter of the year (January-March) and lowest among those conceived in the third (July-September) (8.9% vs 7.6%; P < 0.001). Seasonal variations were specific to autistic spectrum disorder, intellectual disabilities, and learning difficulties (e.g., dyslexia) and were absent for sensory or motor/physical impairments and mental, physical, or communication problems. Seasonality accounted for 11.4% (95% confidence interval: 9.0, 13.7) of all cases. Some biologically plausible causes of this variation, such as infection and maternal vitamin D levels, are potentially amendable to intervention.


The problem of scale in the prediction and management of pathogen spillover.
Disease emergence events, epidemics and pandemics all underscore the need to predict zoonotic pathogen spillover. Because cross-species transmission is inherently hierarchical, involving processes that occur at varying levels of biological organization, such predictive efforts can be complicated by the many scales and vastness of data potentially required for forecasting. A wide range of approaches are currently used to forecast spillover risk (e.g. macroecology, pathogen discovery, surveillance of human populations, among others), each of which is bound within particular phylogenetic, spatial and temporal scales of prediction. Here, we contextualize these diverse approaches within their forecasting goals and resulting scales of prediction to illustrate critical areas of conceptual and pragmatic overlap. Specifically, we focus on an ecological perspective to envision a research pipeline that connects these different scales of data and predictions from the aims of discovery to intervention. Pathogen discovery and predictions focused at the phylogenetic scale can first provide coarse and pattern-based guidance for which reservoirs, vectors and pathogens are likely to be involved in spillover, thereby narrowing surveillance targets and where such efforts should be conducted. Next, these predictions can be followed with ecologically driven spatio-temporal studies of reservoirs and vectors to quantify spatio-temporal fluctuations in infection and to mechanistically understand how pathogens circulate and are transmitted to humans. This approach can also help identify general regions and periods for which spillover is most likely. We illustrate this point by highlighting several case studies where long-term, ecologically focused studies (e.g. Lyme disease in the northeast USA, Hendra virus in eastern Australia, Plasmodium knowlesi in Southeast Asia) have facilitated predicting spillover in space and time and facilitated the design of possible intervention strategies. Such studies can in turn help narrow human surveillance efforts and help refine and improve future large-scale, phylogenetic predictions. We conclude by discussing how greater integration and exchange between data and predictions generated across these varying scales could ultimately help generate more actionable forecasts and interventions. This article is part of the theme issue 'Dynamic and integrative approaches to understanding pathogen spillover'.


Effectiveness of antimicrobial-coated sutures for the prevention of surgical site infection: a review of the literature.
Surgical site infections (SSIs) are the third most common hospital-acquired infections and account for 14% to 16% of all such infections, and suture material may play a role in SSI rate. Given this risk of infection, sutures with antimicrobial activity have been developed. Both in vitro and in vivo experiments have shown that triclosan-coated sutures (TCS) are effective in the prevention of SSIs. Our aim is to analyze currently available RCTs, comparing the effect of antimicrobial-coated suture (ACS) with uncoated suture on the occurrence of SSIs following surgical procedures, we highlighted major contributions of most significant studies and evaluate the current "state of the art" on antimicrobial-coated sutures. We reviewed 15 RCTs comparing antimicrobial-coated sutures with conventional sutures and assessing the clinical effectiveness of antimicrobial sutures to decrease the risk for SSIs. We focused our attention on each variable in all the analyzed study. Our selected RCTs, produced controversial results: 7 RCTs demonstrated a significant benefit, on the contrary, 8 RCTs presented a comparison in which there was no difference. On the basis of our selected trial results and the heterogeneous findings of our 7 selected meta-analyses, we conclude that even though the question of whether TCSs could reduce the occurrence of SSI remains still open, the antimicrobial suture was effective in decreasing the risk for postoperative SSIs in a broad population of patients undergoing surgery. Alternative substances are becoming clinically relevant, such as Chlorhexidine (CHX) coated sutures and only 6 in vivo scientific studies evaluated them. In vivo studies, large and comparative clinical research trials are necessary to validate the efficacy of CHX-coated sutures thus allowing their use in clinical practice.


[Aspects of hemodynamics in thyroid dysfunction].
Quantitative electrocardiography, echocardiography and variation pulsometry were used in examination of 231 patients with thyroid dysfunction of various degree. Changes in the central and pulmonary hemodynamics, clinical course, ECG depended on thyroid and thyrotropic blood activity, sympathetic and parasympathetic components of autonomic nervous system. Thyrotoxicosis patients had hemodynamic disorders of the greater and lesser circulation, hypothyroidism patients had only the former.


Interactions among Drosophila nuclear envelope proteins lamin, otefin, and YA.
The nuclear envelope plays many roles, including organizing nuclear structure and regulating nuclear events. Molecular associations of nuclear envelope proteins may contribute to the implementation of these functions. Lamin, otefin, and YA are the three Drosophila nuclear envelope proteins known in early embryos. We used the yeast two-hybrid system to explore the interactions between pairs of these proteins. The ubiquitous major lamina protein, lamin Dm, interacts with both otefin, a peripheral protein of the inner nuclear membrane, and YA, an essential, developmentally regulated protein of the nuclear lamina. In agreement with this interaction, lamin and otefin can be coimmunoprecipitated from the vesicle fraction of Drosophila embryos and colocalize in nuclear envelopes of Drosophila larval salivary gland nuclei. The two-hybrid system was further used to map the domains of interaction among lamin, otefin, and YA. Lamin's rod domain interacts with the complete otefin protein, with otefin's hydrophilic NH2-terminal domain, and with two different fragments derived from this domain. Analogous probing of the interaction between lamin and YA showed that the lamin rod and tail plus part of its head domain are needed for interaction with full-length YA in the two-hybrid system. YA's COOH-terminal region is necessary and sufficient for interaction with lamin. Our results suggest that interactions with lamin might mediate or stabilize the localization of otefin and YA in the nuclear lamina. They also suggest that the need for both otefin and lamin in mediating association of vesicles with chromatin might reflect the function of a protein complex that includes these two proteins.


[The clinical diagnostic importance of detection of vascular endothelial growth factor in evaluation of progression of pyelonephritis in children].
The article deals with evaluation of clinical diagnostic importance of detection of vascular endothelial growth factor under pyelonephritis in children. The study was implemented on sampling of 60 patients with various degree of compensation process. The level of vascular endothelial growth factor increased significantly in patients proportionally to severity of process and its value correlated with velocity of glomerular filtration and vascularization of kidney.


[Experience in using the indirect hemagglutination test to detect Shigella Sonnei in market milk].
The results obtained by analyzing 231 samples of market milk during the period of 1977-1978 are presented. The microbial index, E. coli titer, the presence of pathogenic and opportunistic microflora, as well as the presence of Sh. sonnei antigen were determined. In 39.3% of the milk samples the microbial index was found to be 4 x 10(6), and E. coli titer was 0.001 and lower. No pathogenic microflora was detected in bacteriological assays, but the indirect hemagglutination test with the use of diagnostic antibody reagent revealed the presence of Sh. sonnei antigen in 12 samples. The examination of 28 members of the families which had supplied this milk to the market revealed 3 cases of dysentery infection. The authors propose to widely use the indirect hemagglutination test with diagnostic antibody reagent as an express method for the detection of Sh. sonnei in milk.


Emergence of scholarship in the American Journal of Occupational Therapy.
We undertook a content analysis of 192 American Journal of Occupational Therapy articles published from 1947 to 2010 to understand and explicate the emergence of scholarship within the profession. Scholarship includes scientific inquiry, empirical research, and other forms of inquiry. We identified and coded three aspects of the development of scholarship: argument, methodological rigor, and occupational focus. All three aspects increased over the evaluated period, during which substantial changes occurred in the profession's practice and access to higher education. We see the development of scholarship as aligned with the claiming of the profession's independence and voice.


Substrate mediated enzyme prodrug therapy.
Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug administration and site-specific, implant mediated drug delivery. Specifically, SMEPT offers the flexibility of delivering multiple drugs - individually as monotherapy, in sequence, or as a combination therapy, all of which is also accomplished in a site-specific manner. This technology is also unique for site-specific synthesis of drugs with short half-life, such as nitric oxide. This review presents historical development of SMEPT from early reports to the most recent examples, and also outlines potential avenues for subsequent development of this platform.


The proliferation of cervical cancer is promoted by miRNA-125b through the regulation of the HMGA1.
It has been reported that miRNA-125b is associated with carcinogenesis and development of several different kinds of cancers. Nevertheless, there is no clarity regarding the significance and mechanism of action of miR-125b in clinical practice for cervical cancer (CC). In the current investigation, the expression of miR-125b in cervical clinical specimens and CC cell lines was analyzed via real-time quantitative PCR, and the relationship of miR-125b with the chromatin-associated protein high mobility group A (HMGA1) expression and clinicopathological parameters of CC patients was explored. The results indicated that miR-125b expression was remarkably upregulated in CC cell lines as well as in the tissues of humans. miR-125b overexpression was significantly related to a decrease in HMGA1 expression, progression-free survival, overall survival, and prognosis as well. Besides, knockdown of miR-125b inhibited proliferation and colony formation in SW756 and C4-1 cells, where the 3'-UTR of HMGA1 mRNA was directly targeted. Moreover, PI3K/Akt pathway was regulated by miR-125b through suppression of HMGA1. These findings illustrated that a new regulatory role of HMGA1 is involved in the progression of CC. Our data demonstrated that miR-125b could play a critical role in the carcinogenesis and progression of CC, revealing that miR-125b might serve as a potential new target for treating CC.


Myosin Vb and Rab11a regulate phosphorylation of ezrin in enterocytes.
Microvilli at the apical surface of enterocytes allow the efficient absorption of nutrients in the intestine. Ezrin activation by its phosphorylation at T567 is important for microvilli development, but how such ezrin phosphorylation is controlled is not well understood. We demonstrate that a subset of kinases that phosphorylate ezrin closely co-distributes with apical recycling endosome marker Rab11a in the subapical domain. Expression of dominant-negative Rab11a mutant or depletion of the Rab11a-binding motor protein myosin Vb prevents the subapical enrichment of Rab11a and these kinases and inhibits ezrin phosphorylation and microvilli development, without affecting the polarized distribution of ezrin itself. We observe a similar loss of the subapical enrichment of Rab11a and the kinases and reduced phosphorylation of ezrin in microvillus inclusion disease, which is associated with MYO5B mutations, intestinal microvilli atrophy and malabsorption. Thus, part of the machinery for ezrin activation depends on recycling endosomes controlled by myosin Vb and Rab11a which, we propose, might act as subapical signaling platforms that enterocytes use to regulate development of microvilli and maintain human intestinal function.


Structural and functional profiling of the lateral gate of the Sec61 translocon.
The evolutionarily conserved Sec61 translocon mediates the translocation and membrane insertion of proteins. For the integration of proteins into the membrane, the Sec61 translocon opens laterally to the lipid bilayer. Previous studies suggest that the lateral opening of the channel is mediated by the helices TM2b and TM7 of a pore-forming subunit of the Sec61 translocon. To map key residues in TM2b and TM7 in yeast Sec61 that modulate lateral gating activity, we performed alanine scanning and in vivo site-directed photocross-linking experiments. Alanine scanning identified two groups of critical residues in the lateral gate, one group that leads to defects in the translocation and membrane insertion of proteins and the other group that causes faster translocation and facilitates membrane insertion. Photocross-linking data show that the former group of residues is located at the interface of the lateral gate. Furthermore, different degrees of defects for the membrane insertion of single- and double-spanning membrane proteins were observed depending on whether the mutations were located in TM2b or TM7. These results demonstrate subtle differences in the molecular mechanism of the signal sequence binding/opening of the lateral gate and membrane insertion of a succeeding transmembrane segment in a polytopic membrane protein.


Crossover from Femoral to Radial Access During Mechanical Thrombectomy of Large Vessel Occlusion Stroke.
Challenging arterial anatomy may prevent timely endovascular treatment (EVT) of acute ischemic stroke (AIS) through a transfemoral approach prompting the use of alternative access routes. We determined the crossover rate from femoral to radial access during EVT of AIS due to large vessel occlusion and identified its radiological predictors and clinical outcomes. Retrospective review of all AIS patients who underwent EVT at a single institution from January 2016 to March 2021 was performed. A primary and a secondary radial group depending on whether the radial approach was used primarily or secondary to failure of transfemoral approach were compared. A total of 358 consecutive AIS patients with large vessel occlusion underwent EVT. Radial approach was used primarily in 6 patients (primary radial [PR]) and secondarily in 16 patients (secondary radial [SR]). The rate of femoral to radial crossover was 4.7%. Type III arch and bovine arch configurations were the most common characteristic in the crossover group. Radial access was successful to secure intracranial access in all cases of PR and in 87% of crossover cases. There was no significant difference between the rates of successful reperfusion (53.3% SR, 83% PR, P = 0.20), National Institutes of Health Stroke Scale score on discharge (19 SR, 18 PR group, P = 0.90), or good outcome defined as modified Rankin Scale score 0-2 (13.3% SR, 33.3% PR, P = 0.29). A radial approach can be considered during EVT of AIS due to large vessel occlusion either primarily or secondarily with a lower threshold to switch from the femoral approach in cases of challenging anatomy.


International cooperation on health and medical care for viral hepatitis: 30 years of activities on comprehensive viral hepatitis control of the JICA group training program for developing countries.
The National Hospital Organization Kumamoto Medical Center has conducted a group training course for health care workers (HCW) from developing countries on viral hepatitis and its related diseases in cooperation with the Japan International Cooperation Agency, for 30 years. In the first 10 years, the course included acquired immunodeficiency syndrome (AIDS), adult T-cell leukemia/lymphoma (ATL), and hepatitis. Following the discovery of the hepatitis C virus and the genotype of the hepatitis B virus, and development of treatments for hepatitis, viral-related cirrhosis, and cancer, the course was divided into two courses. In 2015, the hepatitis training course was renewed as the "Comprehensive Countermeasure for Virus Hepatitis", which ended its role in February 2018. Between 1998 and 2017, 175 HCW from 43 countries, including 36 participants from Egypt, participated. Between October 11 and 20, 2019, we conducted a follow-up survey of the results of the training and conducted a field visit on hepatitis control in Egypt.


[Effect of polarization of the frontal cortex on the resistance of the subcortical centers to ether].
Chronic experiments on unanesthetized rabbits have demonstrated that frontal cortex polarization with a constant anode current (5 mkA) elevates the resistance of bioelectrical activity to ether of the ipsilateral supervisual nucleus of the hypothalamus and midbrain reticular formation as well as the general endurance of the body. As compared with controls, the lifespan of experimental animals increases by 59.85 min, that is by 67.7% (P less than 0.01). In the awakening phase the restoration processes in bioelectrical activity of the cortex and subcortex centers of animals under polarization conditions are accelerated.


Comparison of Insulin Detemir and Insulin Glargine for Hospitalized Patients on a Basal-Bolus Protocol.
BACKGROUND: The primary purpose of this study is to determine whether insulin detemir is equivalent to insulin glargine in controlling hyperglycemia for the adult hospitalized patient on a basal-bolus treatment regimen. METHODS: A retrospective study was conducted at two acute care hospitals within the same health system. Patients from both facilities who were initiated on a basal-bolus subcutaneous insulin regimen were included in the study. The basal-bolus regimen consisted of three components: basal, bolus, and corrective insulin with only the data from the first seven days analyzed. Once the basal-bolus protocol was initiated, all previous glycemic agents were discontinued. The target glycemic goal of the study was 100-180 mg/dL. RESULTS: In both groups, 50% of the patients had achieved the target glycemic control goal (100-180 mg/dL) by day 2 (p = 0.3). However, on the seventh or last day of basal-bolus treatment, whichever came first, 36.36% of patients receiving insulin detemir (n = 88) achieved the blood glucose reading goal compared to 52.00% in patients receiving insulin glargine (n = 100) (p = 0.03). This corresponded to an adjusted odds ratio of 2.12 (1.08 to 4.15), p = 0.03. The adjusting variables were provider type, whether the patient was hospitalized within 30 days prior and diagnosis of stroke. The mean blood glucose readings for the insulin glargine and the insulin detemir groups while on basal-bolus therapy were 200 mg/dL and 215 mg/dL, respectively (p = 0.05). The total number of blood glucose readings less than 70 mg/dL and less than 45 mg/dL was very low and there were no differences in number of episodes with hypoglycemia between the two groups. CONCLUSION: There was not a statistical difference between the two groups at 2 days, however there was on the seventh day or the last day of basal-bolus treatment. There were nonsignificant hypoglycemia events between basal insulin groups and the results for the last or seventh day of treatment may not be clinically significant in practice.


Improving outcomes of preschool language delay in the community: protocol for the Language for Learning randomised controlled trial.
Early language delay is a high-prevalence condition of concern to parents and professionals. It may result in lifelong deficits not only in language function, but also in social, emotional/behavioural, academic and economic well-being. Such delays can lead to considerable costs to the individual, the family and to society more widely. The Language for Learning trial tests a population-based intervention in 4 year olds with measured language delay, to determine (1) if it improves language and associated outcomes at ages 5 and 6 years and (2) its cost-effectiveness for families and the health care system. A large-scale randomised trial of a year-long intervention targeting preschoolers with language delay, nested within a well-documented, prospective, population-based cohort of 1464 children in Melbourne, Australia. All children received a 1.25-1.5 hour formal language assessment at their 4th birthday. The 200 children with expressive and/or receptive language scores more than 1.25 standard deviations below the mean were randomised into intervention or 'usual care' control arms. The 20-session intervention program comprises 18 one-hour home-based therapeutic sessions in three 6-week blocks, an outcome assessment, and a final feed-back/forward planning session. The therapy utilises a 'step up-step down' therapeutic approach depending on the child's language profile, severity and progress, with standardised, manualised activities covering the four language development domains of: vocabulary and grammar; narrative skills; comprehension monitoring; and phonological awareness/pre-literacy skills. Blinded follow-up assessments at ages 5 and 6 years measure the primary outcome of receptive and expressive language, and secondary outcomes of vocabulary, narrative, and phonological skills. A key strength of this robust study is the implementation of a therapeutic framework that provides a standardised yet tailored approach for each child, with a focus on specific language domains known to be associated with later language and literacy. The trial responds to identified evidence gaps, has outcomes of direct relevance to families and the community, includes a well-developed economic analysis, and has the potential to improve long-term consequences of early language delay within a public health framework. Current Controlled Trials ISRCTN03981121.


Evaluating chronic pain impact among patients in primary care: further validation of a brief assessment instrument.
To evaluate the psychometric properties of the Profile of Chronic Pain: Screen (PCP:S) in primary care. The PCP:S is a brief assessment device designed to gauge pain severity, interference, and emotional burden. Questionnaire survey with short-term reliability and validity follow-up. Two hundred and forty-four outpatients (52% female) with chronic pain recruited from five primary care settings completed the 15-item PCP:S at an initial testing session. Approximately 1 week later, two subgroups participated in a retest reliability and validity follow-up. The battery of follow-up questionnaires included a measure of social desirability response bias and several instruments designed to provide convergent validity for the PCP:S. Retest reliability, internal consistency, factor structure, and social desirability bias were all found to be acceptable. Likewise, preliminary evidence suggests that, by virtue of its correlation with established measures of pain adjustment, the PCP:S is a valid pain assessment device. Although the PCP:S was initially developed and validated using a national community sample of adults with chronic pain who provided data via telephone interviews, the present findings support its use as a brief and psychometrically sound paper-and-pencil measure for the assessment of three key components of chronic pain in primary care.


Prevalence and Associated Factors of Early Cessation of Exclusive Breastfeeding Practice in Noakhali, Bangladesh: A Mixed-Method Study.
Though the benefits of exclusive breastfeeding (EBF) till the age of six months are unanimously perceived and ubiquitously accepted, there are several factors that impede this great practice all over the world, and Bangladesh is no exception. A clinic-based, mixed-method, cross-sectional study was conducted to investigate the EBF practice and the possible causes of early cessation in Noakhali district, Bangladesh. The Kaplan-Meier survival curve with a log-rank test was used to compare the survival differences of recommended and observed EBF practices. The life table for EBF practice was also presented, and the multivariate cox proportional regression model was used to identify the predictors of EBF duration. Two focus group discussions were conducted to generate qualitative data on EBF cessation. The mean duration of EBF was five months; only 30% of mothers did not complete EBF, and the cumulative survival curve showed a sharp fall after four months of breastfeeding. However, factors such as mother's advanced age (30 years or above; AHR: 0.376, 90% CI: 0.158-0.893) and low level of education increase the risk of the EBF cessation, while being housewife mothers, preceding birth interval of more than 2 years and living in urban areas decreases the risk of EBF termination. Perceived inadequacy of breast milk and some cultural norms were among the cessation factors revealed in qualitative analysis. Although the completion rates of EBF practice seem to be high in this study population, some socio-cultural issues remain to be addressed, and further promotional efforts should be made to continue and improve the EBF practice.


Applications of the rep-PCR DNA fingerprinting technique to study microbial diversity, ecology and evolution.
A large number of repetitive DNA sequences are found in multiple sites in the genomes of numerous bacteria, archaea and eukarya. While the functions of many of these repetitive sequence elements are unknown, they have proven to be useful as the basis of several powerful tools for use in molecular diagnostics, medical microbiology, epidemiological analyses and environmental microbiology. The repetitive sequence-based PCR or rep-PCR DNA fingerprint technique uses primers targeting several of these repetitive elements and PCR to generate unique DNA profiles or 'fingerprints' of individual microbial strains. Although this technique has been extensively used to examine diversity among variety of prokaryotic microorganisms, rep-PCR DNA fingerprinting can also be applied to microbial ecology and microbial evolution studies since it has the power to distinguish microbes at the strain or isolate level. Recent advancement in rep-PCR methodology has resulted in increased accuracy, reproducibility and throughput. In this minireview, we summarize recent improvements in rep-PCR DNA fingerprinting methodology, and discuss its applications to address fundamentally important questions in microbial ecology and evolution.


Regulation of the stability of P-glycoprotein by ubiquitination.
Ubiquitination plays a crucial role in regulating protein turnover. Here we show that ubiquitination regulates the stability of the MDR1 gene product, P-glycoprotein, thereby affecting the functions of this membrane transporter that mediates multidrug resistance. We found that P-glycoprotein was constitutively ubiquitinated in drug-resistant cancer cells. Transfection of multidrug-resistant cells with wild-type ubiquitin or treatment with an N-glycosylation inhibitor increased the ubiquitination of P-glycoprotein and increased P-glycoprotein degradation. Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG-132), a proteasome inhibitor, induced accumulation of ubiquitinated P-glycoprotein, suggesting the involvement of the proteasome in the turnover of the transporter. Treatment of multidrug-resistant cells with 12-O-tetradecanoylphorbol-13-acetate, a phorbol ester that increases the phosphorylation of P-glycoprotein through activation of protein kinase C, or substituting phosphorylation sites of P-glycoprotein by nonphosphorylatable residues did not affect the ubiquitination of the transporter. Enhanced ubiquitination of P-glycoprotein resulted in a decrease of the function of the transporter, as demonstrated by increased intracellular drug accumulation and increased cellular sensitivity to drugs transported by P-glycoprotein. Our results indicate that the stability and function of P-glycoprotein can be regulated by the ubiquitin-proteasome pathway and suggest that modulating the ubiquitination of P-glycoprotein might be a novel approach to the reversal of drug resistance.


Hepatic Hodgkin Lymphoma Presenting as Solitary Hepatic Mass Following Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder in a Patient With Rheumatoid Arthritis.
Lymphoproliferative disorders (LPDs) occur frequently in patients with rheumatoid arthritis (RA) under methotrexate treatment. Some LPDs spontaneously regressed after methotrexate discontinuation, but classic Hodgkin lymphoma (CHL)-type LPDs frequently relapse, and chemotherapy is usually required for the treatment. CHL usually spreads in contiguous lymph nodes and then infiltrates in organs at an advanced stage. Thus, hepatic Hodgkin lymphoma (HHL) without lymphadenopathy is extremely rare at diagnosis. We present a case of methotrexate-associated LPDs associated with systemic lymphadenopathy and hepatosplenic mass in a 71-year-old woman with RA under methotrexate treatment over 10 years. Although spontaneous remission occurred after methotrexate discontinuation, she developed HHL presenting as a solitary hepatic mass without lymphadenopathy 3 years after spontaneous regression. She received brentuximab vedotin (BV) combination chemotherapy without bleomycin to avoid pulmonary toxicity. Complete metabolic response was achieved after four courses of BV combination chemotherapy, and the activity of RA was kept to be in remission. Our case suggested that the recurrence lesions of LPDs may present at unexpected site, which is not coincide with the primary site, and BV combination chemotherapy is a promising regimen for limited-stage CHL-type LPDs in patients with RA owing to its anti-lymphoma effect on CHL-type LPDs and a possible targeted therapy for RA.


Mindfulness and music interventions in the workplace: assessment of sustained attention and working memory using a crowdsourcing approach.
Occupational stress has huge financial as well as human costs. Application of crowdsourcing might be a way to strengthen the investigation of occupational mental health. Therefore, the aim of the study was to assess Danish employees' stress and cognition by relying on a crowdsourcing approach, as well as investigating the effect of a 30-day mindfulness and music intervention. We translated well-validated neuropsychological laboratory- and task-based paradigms into an app-based platform using cognitive games measuring sustained attention and working memory and measuring stress via. Cohen's Perceived Stress Scale. A total of 623 healthy volunteers from Danish companies participated in the study and were randomized into three groups, which consisted of a 30-day intervention of either mindfulness or music, or a non-intervention control group. Participants in the mindfulness group showed a significant improvement in the coefficient of sustained attention, working memory capacity and perceived stress (p < .001). The music group showed a 38% decrease of self-perceived stress. The control group showed no difference from pre to post in the survey or cognitive outcome measures. Furthermore, there was a significant correlation between usage of the mindfulness and music app and elevated score on both the cognitive games and the perceived stress scale. The study supports the nascent field of crowdsourcing by being able to replicate data collected in previous well-controlled laboratory studies from a range of experimental cognitive tasks, making it an effective alternative. It also supports mindfulness as an effective intervention in improving mental health in the workplace.


Isolated and contiguous glycerol kinase gene disorders: a review.
Glycerol kinase deficiency (GKD) is an X-linked recessive disorder. There are two types. an isolated form and a complex form. We review the clinical, biochemical and molecular genetic features of GKD. The clinical and biochemical phenotype of isolated GKD may vary from a life-threatening childhood metabolic crisis to asymptomatic adult 'pseudohypertriglyceridaemia', resulting from hyperglycerolaemia. To date 38 patients from 24 families with isolated GKD have been reported. At least 7 of these patients had a metabolic crisis during a catabolic condition. The complex GKD is an Xp21 contiguous gene syndrome involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Clinical features of a patient with complex GKD depend on the loci that are involved. Approximately 100 patients from 78 families with a complex GKD have been reported. Seventeen patients with complex GKD (AHC-GKD-DMD or AHC-GKD) died in the neonatal period or early childhood because of unrecognized or inappropriate management of adrenal dysfunction. Since the outcome of the crisis in GKD is highly dependent on the physicians' knowledge of the disease, we devised an algorithmic approach to the diagnosis. From molecular genetic investigations of isolated GKD, 7 missense mutations, 2 splice site mutations, I nonsense mutation, 1 Alu Sx insertion and 2 small deletions were reported for isolated GKD in 13 unrelated families. In 4 families consisting of more than one patient with the same biochemical and genetic defect, the phenotypic variability of the isolated GKD was remarkable. The clinical variability in isolated GKD cannot be explained by biochemical or by molecular heterogeneity. Isolated GKD patients showed a tendency towards hypoglycaemia with hyperketonaemia; whether the clinical symptoms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis needs to be investigated further.


Building capacity for rigorous controlled trials in autism: the importance of measuring treatment adherence.
Research groups across Europe have been networking to share information and ideas about research on preschool children with autism. The paper describes preliminary work to develop capacity for future multi-site randomized controlled trials of early intervention, with a specific focus on the need to measure treatment adherence where parents deliver therapy. The paper includes a review of randomized and controlled studies of parent-mediated early intervention from two sources, a recent Cochrane Collaboration review and a mapping of European early intervention studies in autism published since 2002. The data extracted focused on methods for describing parent adherence, that is, how and to what extent parents carry out the strategies taught them by therapists. Less than half of the 32 studies reviewed included any measure of parent adherence. Only seven included a direct assessment method. The challenges of developing pan-European early intervention evaluation studies are discussed, including choice of intervention model and of important outcomes, the need for translation of measurement tools and achievement of joint training to reliability of assessors. Measurement of parent-child interaction style and of adherence to strategies taught need further study.


PRECiS (Patient Reported Evaluation of Cognitive State): psychometric evaluation of a new patient reported outcome measure of the impact of stroke.
Determine the psychometric properties of PRECiS (Patient Reported Evaluation of Cognitive State): A new patient-centred, patient reported outcome measure for perceived impact of cognitive problems, developed through qualitative work, systematic review and service user consultation. An observational study exploring acceptability, internal consistency, construct validity, inter-rater reliability and test-retest reliability, with opportunistic qualitative data on sensitivity to change. Home visits in the community. Stroke survivors with self-reported cognitive difficulties and informal carers. The 27 item PRECiS was self-completed with support, and proxy completed by informal carers. We collected descriptive cognitive screening test data, and measures of overall stroke impact, mood and activities of daily living to explore construct validity. Data were collected from 159 (visit 1) and 66 (visit 2) stroke survivors and 86 informal carers. PRECiS showed good acceptability (no missing values or floor/ceiling effects, minimal skewness); high internal consistency (α = 0.94, indicative of potential redundancy); with moderate to strong construct correlations in the directions hypothesised (0.40 to 0.74). An intraclass correlation coefficient of 0.85 indicated good test-retest reliability. Where self-reported change had occurred from visit 1 to 2, PRECiS appeared sensitive. Using carers as proxy respondents is not supported by this analysis (inter-rater ICC = 0.43). PRECiS is a patient-centred, practical and reliable measure assessing perceived impact of cognitive problems from the unique perspective of stroke survivors.


Giant mediastinal mass: thymolipoma.
A 26-year-old man presented with shortness of breath on exertion that was gradually getting worse. His history revealed a mass in the left hemithorax that had been growing on follow-ups. Physical examination only showed that the respiratory sounds were fainter on the left. Thoracic computerized tomography was performed to elucidate the left hemithorax lesion seen on chest x-ray and a giant mass of lipid density extending from the anterior mediastinum to the diaphragm and filling almost the entire left hemithorax was observed. Total excision of the 25 × 21 × 8 cm mass weighing 1580 g was performed with a left thoracotomy. The histopathology investigation of the mass was reported as thymolipoma. The case was presented because it is a rare mediastinal mass.


Implications of gambling problems for family and interpersonal adjustment: results from the Quinte Longitudinal Study.
To evaluate (1) whether gambling problems predict overall trajectories of change in family or interpersonal adjustment and (2) whether annual measures of gambling problems predict time-specific decreases in family or interpersonal adjustment, concurrently and prospectively. The Quinte Longitudinal Study (QLS) involved random-digit dialling of telephone numbers around the city of Belleville, Canada to recruit 'general population' and 'at-risk' groups (the latter oversampling people likely to develop problems). Five waves of assessment were conducted (2006-10). Latent Trajectory Modelling (LTM) estimated overall trajectories of family and interpersonal adjustment, which were predicted by gambling problems, and also estimated how time-specific problems predicted deviations from these trajectories. Southeast Ontario, Canada. Community sample of Canadian adults (n = 4121). The Problem Gambling Severity Index (PGSI) defined at-risk gambling (ARG: PGSI 1-2) and moderate-risk/problem gambling (MR/PG: PGSI 3+). Outcomes included: (1) family functioning, assessed using a seven-point rating of overall functioning; (2) social support, assessed using items from the Non-support subscale of the Personality Assessment Inventory; and (3) relationship satisfaction, measured by the Kansas Marital Satisfaction Scale. Baseline measures of ARG and MR/PG did not predict rates of change in trajectories of family or interpersonal adjustment. Rather, the annual measures of MR/PG predicted time-specific decreases in family functioning (estimate: -0.11, P < 0.01), social support (estimate: -0.28, P < 0.01) and relationship satisfaction (estimate: -0.53, P < 0.01). ARG predicted concurrent levels of family functioning (estimate: -0.07, P < 0.01). There were time-lagged effects of MR/PG on subsequent levels of family functioning (estimate: -0.12, P < 0.01) and social support (estimate: -0.24, P < 0.01). In a longitudinal study of Canadian adults, moderate-risk/problem gambling did not predict overall trajectories of family or interpersonal adjustment. Rather, the annual measures of moderate-risk/problem gambling predicted time-specific and concurrent decreases in all outcomes, and lower family functioning and social support across adjacent waves.


Treatment Interventions for the Management of Intestinal Permeability: A Cross-Sectional Survey of Complementary and Integrative Medicine Practitioners.
Objectives: This study aims to explore the treatment interventions complementary and integrative medicine (CIM) practitioners use in the management of an emerging health condition, increased intestinal permeability (IP), and the association these methods have on the observed time to resolve this condition. Design and setting: A cross-sectional survey of Australian naturopaths, nutritionists, and Western herbal medicine practitioners was undertaken (n = 227) through the Practitioner Research and Collaboration Initiative (PRACI) network. Outcome measures: Frequencies and percentages of the treatment methods, including chi-square analysis to examine the associations between treatment methods and observed time to resolve IP. Results: Thirty-six CIM practitioners responded to the survey (response rate 15.9%). CIM practitioners were found to use a multimodal approach in the management of IP with 92.6% of respondents using three or more categories of treatment interventions (nutritional, herbal, dietary, and lifestyle) with a mean total of 43.0 ± 24.89 single treatment interventions frequently prescribed. The main treatments prescribed in the management of IP were zinc (85.2%), probiotics: multistrain (77.8%), vitamin D (75.0%), glutamine (73.1%), Curcuma longa (73.1%), and Saccharomyces boulardii (70.4%). CIM practitioners also advocate patients with IP to reduce alcohol (96.3%), gluten (85.2%), and dairy (75.0%) consumption. Evaluation of antibiotics (75.0%) and nonsteroidal anti-inflammatory drugs (73.1%) prescriptions were frequently advised by CIM practitioners. A longer observed time to resolve IP was seen in CIM practitioners who did not reduce intense exercise in the management of IP (p = 0.02). Conclusions: This study represents the first survey of the treatments prescribed by CIM practitioners for IP and suggests that CIM practitioners use numerous integrative treatment methods for the management of IP. The treatment interventions frequently prescribed by CIM practitioners align with preclinical research, suggesting that CIM practitioners prescribe in accordance with the published literature. The findings of this study contribute to the implementation of clinical research in the management of IP, which considers multiple concurrent treatments.


Classification of spontaneous cerebrospinal fluid middle ear effusion: review of forty-nine cases.
This article presents a classification system of spontaneous cerebrospinal fluid middle ear effusion to facilitate early diagnosis and lesion localization for surgical correction. Thirty-eight articles containing case histories of 45 patients with spontaneous cerebrospinal fluid middle ear effusion reported in the English literature from 1913 to 1983 were reviewed. Four additional personal cases, representing the largest single series, are described in detail. Classification of these cases into the following three types has been possible: (type I, abnormal connections through the otic capsule; type II, abnormal connections adjacent to the otic capsule; and type III, abnormal connections distant from the otic capsule. The diagnostic and therapeutic implications of each type are unique. Age, auditory and vestibular test results, and computerized or hypocycloidal tomography differentiate the three.


[Carcinoma of the stomach. Role of imaging for primary diagnosis and preoperative tumor staging].
The aim of imaging of gastric carcinoma has to be to diagnose the carcinoma as early as possible and to sort out the tumors that are resectable. At the same time imaging of gastric carcinoma should reduce the number of futile laparotomies in patients with advanced, non-resectable tumors to a minimum. Today, endoscopy is the method of choice to diagnose gastric carcinoma. Endosonography is advantageous if small carcinomas have to be judged for depth of tumor infiltration (early gastric carcinoma vs. advanced gastric carcinoma) because high resolution images of the gastric wall are obtained. Staging of large carcinomas that have grown beyond the gastric wall is best performed by hydro-CT because CT scans most accurately delineate infiltrations of surrounding organs/structures and help to plan surgery. Nowadays MRI is not suited for gastric imaging. MRI, however, has the highest potential to fundamentally improve staging of gastric carcinoma if high resolution imaging of the gastric wall is combined with screening for metastases in one examination.


A randomized combined modality trial in small cell carcinoma of the lung: comparison of combination chemotherapy-radiation therapy versus cyclophosphamide-radiation therapy effects of maintenance chemotherapy and prophylactiv whole brain irradiation.
A randomized trial of combined modality therapy employing combination chemotherapy (cyclophosphamide (CTX) and methotrexate (MTX), CTX, MTX and Vincristine (VCR) and CTX, VCR and high-dose MTX with citrovorum rescue) and radiation therapy was compared to cyclophosphamide and radiation therapy in 258 patients with pulmonary small cell carcinoma. Patients were also rendomized: 1) to determine the effects of prophylactic whole brain irradiation; and 2) to establish the effects of maintenance chemotherapy. Survival, frequency of response and site of relapse were different in patients with limited disease (LD) (disease confined to lung, mediastinum and supraclavicular lymph nodes) when compared with disease spread beyond these sites (extensive disease) (ED). No survival advantage was seen in LD when combination chemotherapy was employed, although the frequency of complete remission was greater with three drugs than with one or two drugs (40% vs. 32%). In ED frequency of response was greater for three drugs than for one and two drugs (60% vs. 40%), but there was no survival advantage. The median survival time for complete responders was similar for limited or extensive disease (12.1 months), but 23.8% were alive at 24 months with LD compared to none with ED. Maintenance chemotherapy significantly prolonged survival by 16.8 months with 33% alive at 24 months compared to 9% who were unmaintained. Prophylactic while brain irradiation prevented brain metastases with only 4% developing this complication as compared to 18% of control subjects, but did not influence survival.


Vaccination of dogs in an African city interrupts rabies transmission and reduces human exposure.
Despite the existence of effective rabies vaccines for dogs, dog-transmitted human rabies persists and has reemerged in Africa. Two consecutive dog vaccination campaigns took place in Chad in 2012 and 2013 (coverage of 71% in both years) in the capital city of N'Djaména, as previously published. We developed a deterministic model of dog-human rabies transmission fitted to weekly incidence data of rabid dogs and exposed human cases in N'Djaména. Our analysis showed that the effective reproductive number, that is, the number of new dogs infected by a rabid dog, fell to below one through November 2014. The modeled incidence of human rabies exposure fell to less than one person per million people per year. A phylodynamic estimation of the effective reproductive number from 29 canine rabies virus genetic sequences of the viral N-protein confirmed the results of the deterministic transmission model, implying that rabies transmission between dogs was interrupted for 9 months. However, new dog rabies cases appeared earlier than the transmission and phylodynamic models predicted. This may have been due to the continuous movement of rabies-exposed dogs into N'Djaména from outside the city. Our results show that canine rabies transmission to humans can be interrupted in an African city with currently available dog rabies vaccines, provided that the vaccination area includes larger adjacent regions, and local communities are informed and engaged.


[Tracheobronchial foreign body in the laryngectomized patient].
We report a case of aspiration of a foreign body in the left tracheobronchial tree occurring in a laryngectomy, operated one year previously. The accident presented by fracture of the inner tracheostomy cannula. The literature is reviewed in order to explain possible causes of tracheostomy tube components breakage and to suggest methods for preventing such complications.


Revisiting adverse effects of cross-hybridization in Affymetrix gene expression data: do they matter for correlation analysis?
This work was undertaken in response to a recently published paper by Okoniewski and Miller (BMC Bioinformatics 2006, 7: Article 276). The authors of that paper came to the conclusion that the process of multiple targeting in short oligonucleotide microarrays induces spurious correlations and this effect may deteriorate the inference on correlation coefficients. The design of their study and supporting simulations cast serious doubt upon the validity of this conclusion. The work by Okoniewski and Miller drove us to revisit the issue by means of experimentation with biological data and probabilistic modeling of cross-hybridization effects. We have identified two serious flaws in the study by Okoniewski and Miller: (1) The data used in their paper are not amenable to correlation analysis; (2) The proposed simulation model is inadequate for studying the effects of cross-hybridization. Using two other data sets, we have shown that removing multiply targeted probe sets does not lead to a shift in the histogram of sample correlation coefficients towards smaller values. A more realistic approach to mathematical modeling of cross-hybridization demonstrates that this process is by far more complex than the simplistic model considered by the authors. A diversity of correlation effects (such as the induction of positive or negative correlations) caused by cross-hybridization can be expected in theory but there are natural limitations on the ability to provide quantitative insights into such effects due to the fact that they are not directly observable. The proposed stochastic model is instrumental in studying general regularities in hybridization interaction between probe sets in microarray data. As the problem stands now, there is no compelling reason to believe that multiple targeting causes a large-scale effect on the correlation structure of Affymetrix gene expression data. Our analysis suggests that the observed long-range correlations in microarray data are of a biological nature rather than a technological flaw.


State-to-state time-of-flight measurements of NO scattering from Au(111): direct observation of translation-to-vibration coupling in electronically nonadiabatic energy transfer.
Translational motion is believed to be a spectator degree of freedom in electronically nonadiabatic vibrational energy transfer between molecules and metal surfaces, but the experimental evidence available to support this view is limited. In this work, we have experimentally determined the translational inelasticity in collisions of NO molecules with a single-crystal Au(111) surface-a system with strong electronic nonadiabaticity. State-to-state molecular beam surface scattering was combined with an IR-UV double resonance scheme to obtain high-resolution time-of-flight data. The measurements include vibrationally elastic collisions (v = 3→3, 2→2) as well as collisions where one or two quanta of molecular vibration are excited (2→3, 2→4) or de-excited (2→1, 3→2, 3→1). In addition, we have carried out comprehensive measurements of the effects of rotational excitation on the translational energy of the scattered molecules. We find that under all conditions of this work, the NO molecules lose a large fraction (∼0.45) of their incidence translational energy to the surface. Those molecules that undergo vibrational excitation (relaxation) during the collision recoil slightly slower (faster) than vibrationally elastically scattered molecules. The amount of translational energy change depends on the surface temperature. The translation-to-rotation coupling, which is well-known for v = 0→0 collisions, is found to be significantly weaker for vibrationally inelastic than elastic channels. Our results clearly show that the spectator view of the translational motion in electronically nonadiabatic vibrational energy transfer between NO and Au(111) is only approximately correct.


Cytotoxic and apoptotic effects of synthetic benzochromene derivatives on human cancer cell lines.
With the aim of discovering potential cytotoxic agents, a series of benzochromene derivatives were screened for their cytotoxic activity against seven human cancer cell lines by standard 3-(4, 5-dimethyl thiazol)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptosis, as the mechanism of cell death, was investigated morphologically by acridine orange/ethidium bromide staining and cell surface expression assay of phosphatidylserine by Annexin V-PE/7-AAD technique. The effects of compounds on reactive oxygen species (ROS) and nitric oxide (NO) generations in three human breast cancer cell lines were also studied. All compounds showed significant cytotoxic activity with inhibitory concentration (IC50) values in the micromolar range (4.6-21.5 μM). The results of apoptosis evaluation suggested that the cytotoxic activity of these compounds in breast cancer cells occurs via apoptosis. MCF-7 cell line showed higher levels of ROS and NO production after treatment with compounds. The increase in ROS production after 4 and 24 h indicated that one of the ways that these compounds can induce apoptosis is by increasing ROS generation. Cytotoxic and apoptotic effects of these compounds in human cancer cells indicated that they can be a good candidate for further pharmacological studies to discover effective anticancer agents.


[Combined therapy in non-insulin-dependent diabetes mellitus].
In recent years an improved understanding of potential complications associated with hyperinsulinemia has led to a growing interest in alternatives to insulin monotherapy for patients with non-insulin-dependent diabetes mellitus, who have failed on a regimen of diet and sulphonylureas. These patients typically present normal or elevated levels of insulin. This problem which has been attributed to insulin resistance, is superimposed on the peripheral hyperinsulinemia resulting from subcutaneous insulin delivery. A plethora of clinical trials have reported on the efficacy of combining therapy in limiting insulin requirements while achieving better glycemic control. This paper attempts a critical review of the pros and cons with respect to combining therapy and provides guidelines for its practical use.


Appropriateness of testing for serious bacterial infection in children hospitalized with bronchiolitis.
The goal of this study was to evaluate provider practice patterns for evaluation of serious bacterial infection (SBI) in patients hospitalized with bronchiolitis and to assess the association of SBI testing with length of stay and antibiotic use. This was a retrospective chart review of hospitalized patients <24 months of age with a discharge diagnosis of bronchiolitis from 2 separate study sites during 2004 to 2008. Patient characteristics, laboratory testing, antibiotic use, and clinical outcomes were assessed in relation to SBI testing. A total of 1233 charts met inclusion criteria. The incidence of urinary tract infections in patients who underwent urine testing was 2.3%. Of the 367 patients undergoing blood culture testing, all 13 positive-result blood cultures were contaminated specimens. There were no cases of meningitis. In total, 64.5% of patients tested for SBI had a blood culture obtained, 45.0% had an urinalysis or urine culture, and 16.3% had a cerebral spinal fluid culture obtained. Of those patients who underwent SBI testing, 53.8% received antibiotics versus 19.1% who did not (P < .0001). Length of stay for patients undergoing SBI testing was 3.4 days versus 2.3 days for those without SBI testing (P < .0001). There was no significant difference in readmission rates. SBI is uncommon in children hospitalized for bronchiolitis, and urinary tract infection is the most common diagnosis. In the evaluation of SBI in bronchiolitis, providers more frequently obtain blood cultures than urinalysis and/or urine cultures. Evaluation for SBI is associated with increased antibiotic use and increased LOS.


Identification of a promoter region generating Sry circular transcripts both in germ cells from male adult mice and in male mouse embryonal gonads.
The mouse testis determining gene Sry is expressed in somatic cells of the differentiating male gonad as a linear transcript, encoding a transcription factor containing an HMG box. In the adult mouse testis, Sry expression occurs in meiotic and postmeiotic germ cells. The mouse genomic Sry locus is characterized by two arms of a large inverted repeat, flanking a unique region that, between an acceptor and a donor splice site, contains a single exon encoding the Sry protein. In germ cells from the adult mouse testis, Sry RNA is a circular molecule, which is generated by an inverted splicing event that utilizes the above-mentioned splice sites. Thus, a circular exon is spliced out starting from a large linear RNA precursor containing both arms of the inverted repeat, which pair and generate a large stem-loop structure. Using reverse transcription-polymerase chain reaction and an RNase protection assay, we have now mapped the 5' end of this precursor RNA in the 5' arm of the inverted repeat. Gel mobility shift assay and in vitro transcription with nuclear extracts from adult germ cells further confirm that a region immediately 5' upstream of two transcriptional initiation sites of the precursor RNA contains a promoter sequence in which two consensus Sry binding sequences are specifically recognized by nuclear factors present in adult germ cells but not in Sertoli cells. We also show that the linear precursor of the Sry circular transcript and its splicing product are specifically expressed not only in adult germ cells but also in male embryonal gonads between 11.5 and 13.5 days postcoitum, immediately after the expression of the linear transcript starting from the unique region.


Telomere dynamics in rhesus monkeys: no apparent effect of caloric restriction.
The role of telomere attrition in limiting the replicative capacity of cells in culture is well established. In humans, epidemiologic evidence suggests telomere length (TL) in leukocytes is highly variable at birth and inversely related to age. Although calorie restriction (CR) significantly increases life span in most rodent models, its association with TL is unknown. Using linear regression analysis, TLs (as measured by Southern blot analysis) of skeletal muscle (a postmitotic tissue that largely represents early development TL), fat, leukocytes, and skin were tested for effects of age, sex, and diet in 48 control and 23 calorie restriction rhesus monkeys. After controlling for the individual's muscle mean TL, differences between leukocytes muscle and skin muscle were significantly associated with age (p = .002; p = .002) and sex (p = .003; p = .042), but not calorie restriction (p = .884; p = .766). Despite an age-dependent shortening of TL in leukocytes and skin, calorie restriction did not significantly affect TL dynamics in these samples.


Inherited renal tubular dysgenesis may not be universally fatal.
Inherited renal tubular dysgenesis (RTD) is caused by mutations in the genes encoding components of the renin-angiotensin cascade: angiotensinogen, renin, angiotensin-converting enzyme (ACE), and angiotensin ΙΙ receptor type 1. It is characterized by oligohydramnios, prematurity, hypotension, hypocalvaria, and neonatal renal failure. The histological hallmark is the absence or poor development of renal proximal tubules. Except for a few cases, the prognosis has been thought to be universally poor, with patients dying either in utero or shortly after birth. We report a 3-year-old infant diagnosed clinically with RTD. The infant survived the neonatal period after 2 weeks of anuria subsequently subsiding. Hypotension and hyperkalemia normalized eventually with administration of fludrocortisone. A revision of renal tissue obtained from a sibling that died shortly after birth revealed normal glomeruli and distal tubules but no identifiable proximal tubules. A novel mutation in the ACE gene was found in the surviving child, who remains with stage 4 chronic kidney disease and normal neurodevelopment. As the number of surviving cases of RTD increases, it should be emphasized to the parents and the neonatal care team that it may not be universally fatal as previously reported. A trial of fludrocortisone may correct hyperkalemia and hypotension.


Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis: A Randomized, Controlled Trial.
To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS). In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set. Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0-6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI -292 to 491 ng/L). MBP in CSF decreased in the treatment group (-182 ng/L, 95% CI -323 to -41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups. Dimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment. Clinicaltrials.gov identifier NCT02959658. This study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.


Donor site morbidity using the buccinator myomucosal island flap.
The objective of this study was to analyze our experience with donor site morbidity after harvesting a buccinator myomucosal island flap (BUMIF) for reconstructing surgical defects involving the tongue and floor of the mouth after oncological resections in 15 consecutive patients. Donor site morbidity was evaluated using 5 parameters: mouth opening, oral commissure symmetry, inner vestibule restoration, cheek mucosal lining, and the esthetic result. The clinical evaluation was performed by a blinded panel of 2 clinicians and the patient him- or herself, assessing each parameter with a score ranging from 0 to 3. The 3 scores for each parameter were summed to obtain a score reflecting the overall parameter assessment. The mean mouth opening score was 8.6 out of a maximum of 9 (range, 6-9). The mean commissure symmetry was 8.6 (range, 7-9), the mean inferior vestibule score was 8 (range, 6-9), the mean cheek lining score was 8.2 (range, 7-9), and the mean final esthetic score was 8.5 (range, 6-9). The results of this retrospective evaluation demonstrate that when special care is taken in the management of the BUMIF donor site, its morbidity is extremely low, allowing optimal functional and cosmetic results and confirming the major role of this flap in reconstructing moderate-size defects following tongue and floor of the mouth resections.


Ammonia monitoring at trace level using photoacoustic spectroscopy in industrial and environmental applications.
An ammonia traces analyser based on photoacoustic spectroscopy is described. The system uses a CO(2) laser and a properly designed resonant photoacoustic cell to achieve ammonia detection at sub-parts-per-billion (ppb) level. The instrument features unattended automatic on-line monitoring of ammonia with a detection limit of 0.1 ppb. Interferences from atmospheric CO(2) and H(2)O are efficiently suppressed by a careful selection of the laser wavelength and a compensation of the water vapour signal made with a high-precision hygrometer. The cell design enables continuous measurement at high flow rates (up to 5 l/min), which guarantees a fast response time of the system for the monitoring of ammonia, a sticky polar molecule that adheres to most surfaces. Various examples of applications of the instrument in the semiconductor industry and for atmospheric pollution monitoring are presented. They demonstrate the excellent performances of the system and its suitability for these applications.


Angiopoietin-Like Protein 2 Is Increased in Obese Mouse Models of Lung Injury.
To investigate the regulatory role of angiopoietin-1ike protein 2 (Angptl 2) in the pathogenesis of acute respiratory distress syndrome (ARDS). A high-fat diet (HFD) and tail vein injection of 0.1 ml/kg oleic acid were used to induce acute lung injury (ALI) and ARDS models, and male Kunming mice were randomly divided into four groups: control group (injected with normal saline), ALI group (injected with oleic acid), HFD group (injection of normal saline), and ARDS group (HFD+injection of oleic acid). The degree of lung injury was assessed by lung histopathology score and lung injury index. At the same time, the mRNA and protein expression levels of Angptl 2 in lung tissue were also detected to determine the relationship between Angptl 2 and ARDS. Lee's index of the HFD group and ARDS group was significantly higher than that of the control group and ALI group (P < 0.05), and the lung injury index of the ARDS group was significantly higher than that of the ALI group. The expression of Angptl 2 in the lung tissue of the ALI group and ARDS group was significantly different, and the Angptl 2 mRNA level was the highest in the ARDS group. Immunohistochemistry showed that the alveolar walls of the ALI group and ARDS group were severely collapsed, and the ARDS group had the greatest Angptl 2 aggregation at the site of edema exudation. Collectively, obesity might be mediated by Angptl 2 and promotes lung injury. Immunohistochemistry analysis showed that the expression of the receptor on alveolar walls was correlated with Angptl 2, which increased alveolar wall permeability, edema fluid exudation, and alveolar wall collapse. Thus, Angptl 2 might be a target for improving the treatment of ARDS.


Resource allocation for cellular data services using multiagent schemes.
Because the radio spectrum is limited, managing the limited amount of resources is an important issue, especially for high-speed data applications. This paper presents a distributed multiagent scheme (DMAS) that was developed for supporting resource allocation in a customer-accepted and cost-effective fashion. The scheme consists of a collection of problem-solving agents with three modules built into the scheme: the knowledge source, the blackboard system, and the control engine. Through operations and cooperation among the active agents, an allocation policy is selected and a customer-accepted schedule that meets the specified quality of service (QoS) is generated. A comparison of the performance between the DMAS scheme and other references previously proposed was derived using a 55 microcell model. It was found that the proposed scheme gave the highest quality of service satisfaction (around 90% at light loading and 60% at heavy loading).


Effects of stimulus presentation level on stop consonant identification in normal-hearing and hearing-impaired listeners.
The purpose of the present study was to determine whether varying the presentation level of stop consonant stimuli resulted in similar phonetic boundary shifts for listeners with normal and impaired hearing. Sixteen normal-hearing and 16 hearing-impaired listeners categorized synthetic speech stimuli as /b/, /d/, or /g/. The onset frequency of F2 varied from 900 to 2300 Hz (100-Hz steps), and the presentation level varied from 92 to 62 dB SPL (10-dB steps) for each stimulus presentation. Hearing-impaired listeners had significantly more missing boundary values than normal-hearing listeners; however, the correlation between the number of missing boundary values and hearing sensitivity was not significant. Comparison of boundary shift with level demonstrated that hearing-impaired listeners had a smaller boundary shift with increasing level than normal-hearing listeners. The amount of boundary shift was not correlated with audibility. The results of the current study suggest that increasing the presentation level of a signal does not result in performance similar to that of listeners with normal hearing.


Cigarette smoking is associated with thinner cingulate and insular cortices in patients with severe mental illness.
Magnetic resonance imaging (MRI) studies show reduced cortical thickness in patients with schizophrenia and bipolar disorder. These subtle brain abnormalities may provide insight into illness mechanisms. However, environmental and lifestyle-related factors, such as cigarette smoking, may contribute to brain structure changes. Cigarette smoking is highly prevalent in patients with severe mental illness. In nonpsychiatric samples, smoking has been associated with reduced thickness in the anterior (ACC) and posterior cingulate cortices, the insular cortex (INS), the dorsolateral prefrontal cortex and the orbitofrontal cortex. We examined MRI scans from patients with schizophrenia, other psychotic disorders or bipolar disorder and healthy controls using FreeSurfer. We included 506 patients (49% smokers) and 237 controls (20% smokers) in our study. We found reduced cortical thickness in the left rostral ACC and the left INS in smoking patients compared with nonsmoking patients, but this difference was not found among healthy controls. No dose-response relationship was found between amount of smoking and cortical thickness in these regions. Among patients, maps of thickness along the whole cortical surface revealed reduced insular thickness but no effects in other regions. Among healthy controls, similar analyses revealed increased age-related cortical thinning in the left occipital lobe among smokers compared with nonsmokers. The causal direction could not be determined owing to the cross-sectional design and lack of detailed data on smoking addiction and smoking history. The effect of cigarette smoking should be considered in MRI studies of patients with severe mental illness.


Failure of gel filtration and HPLC purification to increase levels of immunoreactive TRH in rat brain extracts.
It has recently been reported [4] that purification of acidified methanol extracts of rat cerebellum by gel filtration and high performance liquid chromatography (HPLC) caused a fifty-fold increase in immunoreactive thyrotrophin-releasing hormone (ir-TRH). However either using Sephadex LH20 or SepPak separation prior to HPLC we have failed to find a significant increase in ir-TRH in rat cerebellar or hypothalamic extracts. We conclude that it is valid to measure TRH by radioimmunoassay in unpurified methanolic extracts of brain tissue.


Acute Liver Failure of Indeterminate Etiology: A Comprehensive Systematic Approach by An Expert Committee to Establish Causality.
In the United States, the Acute Liver Failure Study Group (ALFSG) registry lists approximately 11% of cases as of indeterminate etiology (IND-ALF) as determined by the respective local site principal investigator (PI). Traditionally, IND-ALF has prompted concern that other viruses or toxins might be implicated. We hypothesized that many IND- ALF cases would have an identifiable etiology upon further investigation. Improving the identification process should reduce the number of truly indeterminate cases. Specific definitions for each etiology ("etiology-specific algorithms") were developed by a Causality Adjudication Committee that included six reviewers (each with 20 or more years of experience). Of 2718 patients with ALF, 303 initially deemed IND-ALF by site PIs underwent committee review guided by the algorithms. Acetaminophen (APAP) protein adducts were measured in sera when available, additional HEV testing was performed, and viral sequences sought by microarray analysis and metagenomic next-generation sequencing (mNGS). Study sites were asked to provide liver biopsy and/or explant reports and to update serological findings not reported previously. Nearly half (142, 46.9%) of the 303 IND-ALF cases could be reassigned to a single, defined etiology and rated as highly likely or probable; 11 additional cases, upon review, did not meet ALF criteria. Amongst reassigned etiologies, 45 were previously unrecognized APAP, 34 autoimmune hepatitis (AIH), 24 drug-induced liver injury (DILI), 13 various viral causes, 12 ischemia, and 14 miscellaneous other etiologies. The remaining 150, deemed true IND-ALF, represented just 5.5%. The indeterminate etiology in ALF includes patients with a diagnosis that is discernible after closer examination. Revision of etiologic diagnoses of indeterminate cases using added testing and expert opinion is useful in understanding all aspects of ALF.


Functional Integrity of the Inferior Vestibular Nerve and Posterior Canal BPPV.
The functional integrity of the inferior vestibular nerve (IVN) may be evaluated by the cervical vestibular evoked myogenic potential (cVEMP) response, which requires signal transmission via the nerve. As functional integrity of the IVN innervating the posterior semicircular canal is required to produce the typical positioning vertigo and nystagmus characterizing posterior canal benign paroxysmal positional vertigo (PCBPPV), we hypothesized that normal cVEMPs would be found in most PCBPPV patients. Twenty-four PCBPPV patients participated in a prospective cohort study. All were treated by canal repositioning maneuver and had air-conduction cVEMP and videonystagmography (VNG). Follow-up evaluations including history and otoneurological bedside examination were carried out 1, 3, 6, and 12 months after the initial treatment. At the last follow-up, the patients filled the Dizziness Handicap Inventory (DHI) questionnaire. Normal cVEMPs were recorded in 19 (79%) and were absent in 5 (21%) of the subjects. The average DHI in the patients with normal cVEMP was 16.42 ± 17.99 vs. 0.4 ± 0.89 among those with pathological cVEMP (p < 0.04, Mann-Whitney test). Thirteen (54%) patients experienced recurrent PCBPPV (rPCBPPV). The average DHI score was significantly higher among patients having recurrence (22.15 ± 18.61) when compared to those with complete cure (2.36 ± 5.98; p < 0.003, Mann-Whitney test). Ten (77%) of the subjects with rPCBPPV had normal and 3 (23%) had pathological cVEMP as compared to 9 (82%) and 2 (18%) subjects in the non-recurrent (nrPCBPPV) group (Fisher's exact test-not significant). cVEMP p13 and n23 wave latencies and amplitudes, inter-aural differences in p13-n23 peak-to-peak amplitudes, and response thresholds did not differ between the groups. No differences were found between the rPCBBPV and nrPCBBPV groups in VNG caloric lateralization and directional preponderance values. We have found that in most cases, PCBPPV symptoms and signs are associated with normal cVEMP response supporting the role of IVN functional integrity. The absent cVEMPs in the minority of patients, although having similar clinical presentation, raise the possibility that the ipsilateral saccule is affected by the same pathology causing degeneration of the utricle macula. Alternatively, lacking inhibitory stimuli from the involved ipsilateral utricle or partial degeneration of the IVN and ganglion could explain the diminished cVEMP response. Clinical Trial Registration: The study was registered in ClinicalTrials.gov Internet site (study ID-NCT01004913; https://clinicaltrials.gov/ct2/show/NCT01004913?cond=BPPV&cntry=IL&draw=2&rank=3).


Structures of the dI2dIII1 complex of proton-translocating transhydrogenase with bound, inactive analogues of NADH and NADPH reveal active site geometries.
Transhydrogenase couples the redox reaction between NADH and NADP+ to proton translocation across a membrane. The enzyme comprises three components; dI binds NAD(H), dIII binds NADP(H), and dII spans the membrane. The 1,4,5,6-tetrahydro analogue of NADH (designated H2NADH) bound to isolated dI from Rhodospirillum rubrum transhydrogenase with similar affinity to the physiological nucleotide. Binding of either NADH or H2NADH led to closure of the dI mobile loop. The 1,4,5,6-tetrahydro analogue of NADPH (H2NADPH) bound very tightly to isolated R. rubrum dIII, but the rate constant for dissociation was greater than that for NADPH. The replacement of NADP+ on dIII either with H2NADPH or with NADPH caused a similar set of chemical shift alterations, signifying an equivalent conformational change. Despite similar binding properties to the natural nucleotides, neither H2NADH nor H2NADPH could serve as a hydride donor in transhydrogenation reactions. Mixtures of dI and dIII form dI2dIII1 complexes. The nucleotide charge distribution of complexes loaded either with H2NADH and NADP+ or with NAD+ and H2NADPH should more closely mimic the ground states for forward and reverse hydride transfer, respectively, than previously studied dead-end species. Crystal structures of such complexes at 2.6 and 2.3 A resolution are described. A transition state for hydride transfer between dihydronicotinamide and nicotinamide derivatives determined in ab initio quantum mechanical calculations resembles the organization of nucleotides in the transhydrogenase active site in the crystal structure. Molecular dynamics simulations of the enzyme indicate that the (dihydro)nicotinamide rings remain close to a ground state for hydride transfer throughout a 1.4 ns trajectory.


GmPep914, an eight-amino acid peptide isolated from soybean leaves, activates defense-related genes.
Only a handful of endogenous peptide defense signals have been isolated from plants. Herein, we report a novel peptide from soybean (Glycine max) leaves that is capable of alkalinizing the media of soybean suspension cells, a response that is generally associated with defense peptides. The peptide, DHPRGGNY, was synthesized and found to be active at 0.25 nM and requiring only 5 to 10 min to obtain a maximal pH change. The peptide is located on the carboxy-terminal end of a 52-amino acid precursor protein (Glyma12g00990) deduced from the soybean genome project. A search of the soybean databank revealed a homolog (Glyma09g36370) that contained a similar peptide, DLPRGGNY, which was synthesized and shown to have identical activity. The peptides, designated GmPep914 (DHPRGGNY) and GmPep890 (DLPRGGNY), were capable of inducing the expression of both Glyma12g00990 (GmPROPEP914) and Glyma09g36370 (GmPROPEP890) in cultured soybean suspension cells within 1 h. Both peptides induced the expression of defense genes, including CYP93A1, a cytochrome P450 gene involved in phytoalexin synthesis, chitinaseb1-1, a chitinase involved in pathogen defense, and Glycine max chalcone synthase1 (Gmachs1), chalcone synthase, involved in phytoalexin production. Both GmPROPEP914 and GmPROPEP890 were highly expressed in the roots, relative to the aerial portions of the plant. However, treatment of the aerial portion of soybean plants with hormones involved in elicitation of defense responses revealed a significant increase in expression levels of GmPROPEP914 and GmPROPEP890. A search of gene databases revealed homologous sequences in other members of the Fabales and also in the closely related Cucurbitales but not in any other order of plants.


Modulation of the Mucosa-Associated Microbiome Linked to the PTPN2 Risk Gene in Patients with Primary Sclerosing Cholangitis and Ulcerative Colitis.
Gut microbiota appears to be involved in the pathogenesis of primary sclerosing cholangitis (PSC). The protein tyrosine phosphatase nonreceptor 2 (PTPN2) gene risk variant rs1893217 is associated with gut dysbiosis in inflammatory bowel disease (IBD), and PTPN2 was mentioned as a possible risk gene for PSC. This study assessed the microbial profile of ulcerative colitis (UC) patients with PSC and without PSC (non-PSC). Additionally, effects of the PTPN2 risk variant were assessed. In total, 216 mucosal samples from ileum, colon, and rectum were collected from 7 PSC and 42 non-PSC patients, as well as 28 control subjects (non-IBD). The microbial composition was derived from 16S rRNA sequencing data. Overall, bacterial richness was highest in PSC patients, who also had a higher relative abundance of the genus Roseburia compared to non-PSC, as well as Haemophilus, Fusobacterium, Bifidobacterium, and Actinobacillus compared to non-IBD, as well as a lower relative abundance of Bacteroides compared to non-PSC and non-IBD, respectively. After exclusion of patients with the PTPN2 risk variant, Brachyspira was higher in PSC compared to non-PSC, while, solely in colon samples, Eubacterium and Tepidimonas were higher in PSC vs. non-IBD. In conclusion, this study underlines the presence of gut mucosa-associated microbiome changes in PSC patients and rather weakens the role of PTPN2 as a PSC risk gene.


Short-course drug therapy for tuberculosis.
The cost, patient compliance considerations, and toxicity of short-course chemotherapy (SCC) and conventional 18- to 24-month treatment regimens for pulmonary tuberculosis are compared; studies of the efficacy of SCC regimens are evaluated; and the future of SCC in the United States is examined. SCC is defined as treatment for nine months or less. A definite advantage of SCC over conventional therapy in terms of cost, patient compliance, or adverse effects has not been established. A series of studies conducted by the East African-British Medical Research Council documented the efficacy of various six-month, multiple-drug regimens that contain rifampin and verified the sterilizing activity of pyrazinamide during the first two months of therapy. The studies of the Hong Kong Chest Service and British Medical Research Council documented the efficacy of several intermittent drug regimens. Acceptable relapse rates were achieved with streptomycin, isoniazid, and pyrazinamide given two or three times a week for four or six months, preceded by a two-month, multiple-drug, daily regimen, and various four-drug, pyrazinamide-containing intermittent regimens. The benefit of pyrazinamide in reducing the relapse rate with SCC was confirmed by studies of the British Thoracic and Tuberculosis Association. Few studies of SCC have been conducted in the United States. Treatment practices in the United States are becoming more uniform, and SCC is being used more frequently for uncomplicated pulmonary tuberculosis. SCC will probably be used more widely in the future. Current guidelines of the Centers for Disease Control recommend treatment for nine months with isoniazid and rifampin, plus ethambutol in areas where resistance to isoniazid is common. In vitro data suggest that the addition of pyrazinamide may be more effective, but clinical experience with this drug in the United States is limited.


The impact evaluation of physical therapy on the quality of life of cerebrovascular stroke patients.
This study aimed to evaluate the impact of physical therapy on the quality of life of patients presenting with a motor deficit caused by ischemic stroke at the median cerebral artery. Physical therapeutic intervention consisted of three sessions per week of conventional kinesiotherapy; 50 min each, for three consecutive months. The sample comprised 18 patients aged between 18 and 72 years old, evaluated according to the Stroke Impact Scale. There was a significant difference for the following domains: strength (P < 0.001), daily life activities (P < 0.001), mobility (P = 0.001), manual function (P = 0.004) and social participation (P=0.001). We were able to conclude that physical therapy, performed for up to three 50-min weekly sessions for 3 consecutive months, resulted in the reduction of motor deficits and functional improvement, consequently promoting favorable effects on the quality of life of patients presenting with motor deficit due to ischemic stroke.


[Studies on the benefits of using assistants in the dental clinic].
We've analysed the systematization in odontological assistance in fifty dental clinics placed in our area. The variables examined: Working hours per day, working days per week, weeks of holiday per year, patients treated per year, number of dental assistants, number of operatories room. We've calculated a series of formulas and compared them with ideal values.


The Microbial Composition of Bacteroidetes Species in Ulcerative Colitis Is Effectively Improved by Combination Therapy With Fecal Microbiota Transplantation and Antibiotics.
We previously reported that fresh fecal microbiota transplantation (FMT) after triple-antibiotic therapy (amoxicillin, fosfomycin, and metronidazole [AFM]; A-FMT) synergistically contributed to the recovery of phylum Bacteroidetes composition associated with the endoscopic severity and treatment efficacy of ulcerative colitis (UC). Here, we performed further microbial analyses using a higher-resolution method to identify the key bacterial species in UC and determine whether viable Bacteroidetes species from donor feces were successfully colonized by A-FMT. The taxonomic composition of Bacteroidetes in 25 healthy donors and 27 UC patients at baseline was compared at the species level using a heat-shock protein (hsp) 60-based microbiome method. Microbiota alterations before and after treatment of UC patients were also analyzed in 24 cases (n = 17 A-FMT; n = 3 mono-AFM; n = 4 mono-FMT). We found species-level dysbiosis within the phylum Bacteroidetes in UC samples, which was associated with reduced species diversity, resulting from hyperproliferation and hypoproliferation of particular species. Moreover, in responders treated with A-FMT, diversity was significantly recovered at 4 weeks after a fresh round of FMT, after which high degrees of similarity in Bacteroidetes species composition among recipients and donors were observed. A-FMT alleviated intestinal dysbiosis, which is caused by the loss of Bacteroidetes species diversity in patients with UC. Eradication of dysbiotic indigenous Bacteroidetes species by AFM pretreatment might promote the colonization of viable Bacteroidetes cells, thereby improving the intestinal microbiota dysbiosis induced by UC. Our findings serve as a basis for further investigations into the mechanisms of FMT.


Aspartate transcarbamoylase from Phaseolus aureus. Partial purification and properties.
1. Aspartate transcarbamoylase from 4-day-old radicles of Phaseolus aureus was purified 190-fold by (NH(4))(2)SO(4) fractionation, DEAE-cellulose and DEAE-Sephadex chromatography and Sephadex-gel filtration. The partially purified enzyme, which required P(i) for maximum stability, had an apparent molecular weight of 83000+/-5000. 2. Uridine nucleotides were found to inhibit the activity; UMP was the most potent inhibitor, followed by UDP and UTP. No other nucleotide was found to affect the enzyme, nor could UMP inhibition be overcome by adding another nucleotide. Aspartate gives a hyperbolic substrate-saturation curve, both with and without UMP. The nucleotide inhibitor is non-competitive with respect to this substrate. Carbamoyl phosphate also yields a hyperbolic substrate-saturation curve in the absence of feedback inhibitor, but when UMP is added a sigmoidal pattern results, and the inhibition is competitive with carbamoyl phosphate. 3. The degree of inhibition by UMP is not affected by p-chloromercuribenzoate, urea, mild heat pretreatment or change in pH over the range 8.5-10.5, but is affected by temperature. 4. The aspartate analogue, succinate, both activates and inhibits the reaction, depending on the concentrations of aspartate and succinate used. 5. Kinetic studies with the partially purified enzyme showed that the K(m) for carbamoyl phosphate (0.091 mm) is much lower than that for aspartate (1.7mm). A sequential reaction mechanism was inferred from product-inhibition kinetics, with carbamoyl phosphate binding to the enzyme before aspartate, and the product, carbamoylaspartate, being released ahead of P(i). Initial-velocity studies gave a set of parallel reciprocal plots, compatible with an essentially irreversible step occurring before the binding of aspartate.


Developing a model for hospital inherent safety assessment: Conceptualization and validation.
Paying attention to the safety of hospitals, as the most crucial institute for providing medical and health services wherein a bundle of facilities, equipment, and human resource exist, is of significant importance. The present research aims at developing a model for assessing hospitals' safety based on principles of inherent safety design. Face validity (30 experts), content validity (20 experts), construct validity (268 examples), convergent validity, and divergent validity have been employed to validate the prepared questionnaire; and the items analysis, the Cronbach's alpha test, ICC test (to measure reliability of the test), composite reliability coefficient have been used to measure primary reliability. The relationship between variables and factors has been confirmed at 0.05 significance level by conducting confirmatory factor analysis (CFA) and structural equations modeling (SEM) technique with the use of Smart-PLS. R-square and load factors values, which were higher than 0.67 and 0.300 respectively, indicated the strong fit. Moderation (0.970), simplification (0.959), substitution (0.943), and minimization (0.5008) have had the most weights in determining the inherent safety of hospital respectively. Moderation, simplification, and substitution, among the other dimensions, have more weight on the inherent safety, while minimization has the less weight, which could be due do its definition as to minimize the risk.