Self-collected oral flocked swabs to measure prevalence of Epstein-Barr Virus antibodies and DNA amongst university students.
Epstein-Barr Virus (EBV) exposure and illness is common in undergraduate university students and may affect academic achievement, social life, and quality of life. We designed a study to measure EBV exposure (EBV-IgG, either Epstein-Barr nuclear antigen 1 (EBNA-1)-IgG or viral capsid antigen (VCA)-IgG) and current viral shedding (EBV-DNA) using self-collected oral swabs among university undergraduate students. Of 184 students enrolled, 129 (70.1%) tested positive for EBV-IgG. Salivopositivity was associated with being in a current relationship, but not with enrollment year. Forty (21.7%) of the participants tested positive for EBV-DNA, which was associated with all symptom scores, including history of sore throat, fever, swollen glands, muscle weakness, and fatigue in the previous 6 months. Our findings suggest that noninvasive, self-collected oral flocked swabs are feasible and potentially valuable for measuring EBV IgG antibodies and DNA.


Outcomes of stage 1-5 chronic kidney disease in Mainland China.
This study aims to quantify and compare the risks of death and end stage renal disease (ESRD) in a prospective cohort of patients with chronic kidney disease (CKD) stages 1-5 under renal management clinic at Peking University Third Hospital and to evaluate the risk factors associated with these two outcomes. This was a prospective cohort study. Finally, 1076 patients at CKD stage 1-5 short of dialysis were recruited from renal management clinic. Patients were monitored for up to Dec, 2011 or until ESRD and death. Glomerular filtration rate was estimated (eGFR) according to the using the CKD Epidemiology Collaboration (CKD-EPI) formula. At the end of follow-up, 111 patients (10.1%) developed ESRD (initiated dialysis or kidney transplantation (ESRD)) and 24 patients (2.2%) had died. There were more ESRD occurrence rate in patients with baseline diabetic nephropathy, lower eGFR, hemoglobin <100 g/L and 24 h urinary protein excretion ≥ 3.0 g. By multivariate Cox regression model, having heavy proteinuria and CKD stage were the risk factors of ESRD. For all-cause mortality, the most common cause was cardiovascular disease, followed by infectious disease and cancer. But we failed to conclude any significant variable as risk factors for mortality in multivariate analysis. Our study indicated that baseline diabetic nephropathy, lower hemoglobin level, lower baseline GFR and heavy proteinuria were the risk factors of ESRD. In this CKD cohort, patients were more likely to develop ESRD than mortality, and cardiovascular mortality was the leading cause of death, and then followed by infectious diseases and cancer in this population.


Assessment of Smartphone Addiction in Indian Adolescents: A Mixed Method Study by Systematic-review and Meta-analysis Approach.
There is a considerable debate on addiction and abuse to Smartphone among adolescents and its consequent impact on their health; not only in a global context, but also specifically in the Indian population; considering that Smartphone's, globally occupy more than 50% of mobile phones market and more precise quantification of the associated problems is important to facilitate understanding in this field. As per PRISMA (2009) guidelines, extensive search of various studies in any form from a global scale to the more narrow Indian context using two key search words: "Smartphone's addiction" and "Indian adolescents" was done using websites of EMBASE, MEDLINE, PubMed, Global Health, Psyc-INFO, Biomed-Central, Web of Science, Cochrane Library, world library - World-Cat, Indian libraries such as National Medical Library of India from 1 January, 1995 to March 31, 2014 first for systematic-review. Finally, meta-analysis on only Indian studies was done using Med-Calc online software capable of doing meta-analysis of proportions. A total of 45 articles were considered in systematic-review from whole world; later on 6 studies out of these 45 related to Smartphone's addiction in India were extracted to perform meta-analysis, in which total 1304 participants (range: 165-335) were enrolled. The smartphone addiction magnitude in India ranged from 39% to 44% as per fixed effects calculated (P < 0.0001). Smartphone addiction among Indian teens can not only damage interpersonal skills, but also it can lead to significant negative health risks and harmful psychological effects on Indian adolescents.


Reinitiation of spermatogonial mitotic differentiation in inactive old BDF1 mouse seminiferous tubules transplanted to W/Wv mouse testis.
The seminiferous epithelia of old mice (33 mo of age) are composed of spermatogonia and Sertoli cells. Histochemical examination using the anti-c-kit monoclonal antibody demonstrated that the number of differentiating type A spermatogonia decreases with age. To elucidate the differential activity of old mouse spermatogonia, we transplanted extremely thin seminiferous epithelia of old BDF, mice into W/Wv mouse testes and examined whether or not they could reinitiate differentiation. Artificially cryptorchid mice were used as the control. At 2 wk after transplantation, spermatocytes and round spermatids were detected in transplanted seminiferous tubules of the control, whereas the most advanced spermatogenic cells in those of old mice were spermatocytes. At 4 wk after transplantation, although elongated spermatids were detected in transplanted tubules of the control, haploid cells (spermatids) were still undetectable in those derived from old mice. Thus, meiosis was never restored, although spermatogonia of old mice can reinitiate differentiation into spermatocytes under suitable testicular conditions. Since it has been reported in several mammalian species that age-related changes in the testicular microenvironment lead to the gerontal cessation of spermatogenesis, the present results suggest that both a defective extratubular environment and a defective intratubular environment may cause the cessation of spermatogenesis in old BDF, mice.


Comparison of clinical-radiological and molecular findings in hypochondroplasia.
Hypochondroplasia is an autosomal dominant skeletal dysplasia characterized by disproportionate short stature. A mutation (N540K) in the fibroblast growth factor receptor 3 (FGFR3) gene was described in some patients with this condition. The aims of the study were to identify the frequency of the FGFR3 gene mutation, to define the salient clinical and radiological abnormalities of the affected subjects, and to verify the contribution of molecular findings to the clinical and radiological definition of hypochondroplasia. Based on the most common radiological criteria, we selected 18 patients with a phenotype compatible with hypochondroplasia. Height, sitting height, and cranial circumference were measured in all patients. Radiographs of the lumbar spine, left leg, pelvis, and left hand were also obtained. The presence of the N540K mutation was verified by restriction enzyme digestions. Half of our patients carried the N540K mutation. Although similar in phenotype to the patients without the mutation, they showed in addition relative macrocephaly. The association of the unchanged/narrow interpedicular distance with the fibula longer than the tibia was more common in patients with gene mutation. Although we did not find a firm correlation between genotype and phenotype, in our study the N540K mutation was most often associated with disproportionate short stature, macrocephaly, and with radiological findings of unchanged/narrow interpedicular distance and fibula longer than tibia.


Improved sensitivity and precision in multicentre diffusion MRI network analysis using thresholding and harmonization.
To investigate if network thresholding and raw data harmonization improve consistency of diffusion MRI (dMRI)-based brain networks while also increasing precision and sensitivity to detect disease effects in multicentre datasets. Brain networks were reconstructed from dMRI of five samples with cerebral small vessel disease (SVD; 629 patients, 166 controls), as a clinically relevant exemplar condition for studies on network integrity. We evaluated consistency of network architecture in age-matched controls, by calculating cross-site differences in connection probability and fractional anisotropy (FA). Subsequently we evaluated precision and sensitivity to disease effects by identifying connections with low FA in sporadic SVD patients relative to controls, using more severely affected patients with a pure form of genetically defined SVD as reference. In controls, thresholding and harmonization improved consistency of network architecture, minimizing cross-site differences in connection probability and FA. In patients relative to controls, thresholding improved precision to detect disrupted connections by removing false positive connections (precision, before: 0.09-0.19; after: 0.38-0.70). Before harmonization, sensitivity was low within individual sites, with few connections surviving multiple testing correction (k = 0-25 connections). Harmonization and pooling improved sensitivity (k = 38), while also achieving higher precision when combined with thresholding (0.97). We demonstrated that network consistency, precision and sensitivity to detect disease effects in SVD are improved by thresholding and harmonization. We recommend introducing these techniques to leverage large existing multicentre datasets to better understand the impact of disease on brain networks.


Heterogeneity of growth-hormone receptors detected with monoclonal antibodies to human growth hormone.
The specificity of hormone-receptor interactions has been examined with the aid of monoclonal antibodies (MABs) (EB1, EB2, QA68 and NA71) defining four non-overlapping antigenic determinants on human growth hormone (hGH). The results indicate that growth-hormone receptors in liver obtained from different sources differ with regard to their affinities and relative numbers; they may also differ with respect to the region of the growth-hormone molecule to which they bind. Antibody NA71 effectively inhibited hormone binding to all receptor preparations tested, although with various degrees of potency. Monoclonal antibody EB1 demonstrated a graded inhibition with respect to its ability to block 125I-hGH binding to receptors from various sources, the maximum inhibition being seen in receptor preparations from mouse and ovine liver and the minimum in rat liver. MABs EB2 and QA68 also showed various abilities to inhibit hormone-receptor interaction, depending on the origin of the receptor preparation. Furthermore, the receptor-binding characteristics of hormone-antibody complexes were dependent on whether the binding-site preparation was derived from pregnant, lactating or 'normal' animals. A particularly striking difference between the ability of hormone-MAB complexes to bind to receptors from different sources was seen for microsomes (microsomal fractions) derived from livers of animals of the 'Little' mouse strain. These animals become progressively obese, and it was shown that MABs were considerably more effective in inhibiting 125I-labelled hGH binding to microsomes from phenotypically obese mice than to those derived from their non-obese littermates. The results can be explained by the presence of multiple receptor types for GH, the relative proportions of which vary according to the physiological state of the animal, and possibly between species.


Information seeking and evaluation: a multi-institutional survey of veterinary students.
To practice evidence-based medicine, clinicians must be competent in information literacy (IL). Few studies acknowledge the critical role that reading strategies play in IL instruction and assessment of health professional students. The purpose of this study was to understand the information-seeking and evaluation behaviors of doctor of veterinary medicine (DVM) students in regard to scientific papers. The authors studied DVM student behaviors across eight programs in North America using a web-based survey of closed- and open-ended questions about finding and evaluating scientific papers, including a task to read a linked scientific paper and answer questions about it. A total of 226 individuals responded to the survey. The sections of a scientific paper that were most commonly read were the abstract, introduction, and conclusions. Students who reported reading a higher proportion of scientific papers were more likely to feel confident in their abilities to interpret them. A third of respondents answered open-ended questions after the paper reading task. Respondents felt the least amount of confidence with one of the final steps of evidence-based medicine, that of interpreting the significance of the paper to apply it in veterinary medicine. DVM students may lack the skills needed to evaluate scientific literature and need more practice and feedback in evaluating and interpreting scientific papers. Librarians who support DVM students can (1) help DVM students to efficiently evaluate scientific literature, (2) seek training opportunities in alternative modes of teaching and learning IL skills, and (3) partner with veterinary faculty and clinicians to provide students with practice and feedback in information evaluation.


Glutamine Blocks Interleukin-13-Induced Intestinal Epithelial Barrier Dysfunction.
Impaired intestinal epithelial barrier function is a hallmark of a variety of pathological conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). IBD patients with IBS-like symptoms show higher interleukin-13 (IL-13) serum levels and poor psychological well-being. Supplementary glutamine reduced the daily bowel movement frequency, improved the stool form, and normalized intestinal hyperpermeability. This study was aimed at assessing the effects of IL-13 and supplementary glutamine on human intestinal epithelial function in vitro. Caco-2 cells were grown on TranswellTM inserts. -IL-13 was added to the basolateral compartment, and transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) labeled-dextran permeability measured. Effects of glutamine or the phosphatidylinositol-3-kinase inhibitor LY294002 were assessed. Involvement of tight junction proteins was assessed using Western blotting and immunofluorescence staining. IL-13 significantly decreased TEER and increased FITC labeled-dextran epithelial permeability. IL-13 stimulation decreased the claudin-1 expression and increased the claudin-2 expression. Glutamine alleviated IL-13-induced decrease of TEER and increase of FITC labeled-dextran permeability. Further, the phosphatidylinositol-3-kinase inhibitor showed this alleviating effect while the signal transducer and activator of transcription 6 inhibitor did not. IL-13 induced barrier integrity impairment by decreasing claudin-1 and increasing claudin-2. Glutamine alleviated IL-13-induced barrier dysfunction by increasing claudin-1 expression, via disruption of the phosphatidylinositol-3-kinase/Akt signaling pathway.


Children's dietary diversity and related factors in Rwanda and Burundi: A multilevel analysis using 2010 Demographic and Health Surveys.
One of the reported causes of high malnutrition rates in Burundi and Rwanda is children's inadequate dietary habits. The diet of children may be affected by individual characteristics and by the characteristics of the households and the communities in which they live. We used the minimum dietary diversity of children (MDD-C) indicator as a proxy of diet quality aiming at: 1) assess how much of the observed variation in MDD-C was attributed to community clustering, and 2) to identify the MDD-C associated factors. Data was obtained from the 2010 Demographic and Health Surveys of Burundi and Rwanda, from which only children 6 to 23 months from rural areas were analysed. The MDD-C was calculated according to the 2007 WHO/UNICEF guidelines. We computed the intra-class coefficient to assess the percentage of variation attributed to the clustering effect of living in the same community. And then we applied two-level logit regressions to investigate the association between MDD-C and potential risk factors following the hierarchical survey structure of DHS. The MDD-C was 23% in rural Rwanda and 16% in rural Burundi, and a 29% of its variation in Rwanda and 17% in Burundi was attributable to community clustering. Increasing age and living standards were associated with higher MDD-C in both countries, and only in Burundi also increasing level of education of the mother's partner. In Rwanda alone, the increasing ages of the head of the household and of the mother at first birth were also positively associated with it. Despite the identification of an important proportion of the MDD-C variation due to clustering, we couldn't identify any community variable significantly associated with it. We recommend further research using hierarchical models, and to integrate dietary diversity in holistic interventions which take into account both the household's and the community's characteristics the children live in.


Surgery in the Neonatal Intensive Care Unit in Indian Scenario: Should It be "The New State of the Art" or Just "The Need of the Hour"?
Critically ill surgical neonates are physiologically challenged and delicately poised on ventilator and inotropic support systems. They experience significant stress in the event of surgery. Shifting them poise further addition to this stress. We here share our experience of operating such surgical neonates for certain conditions in the neonatal intensive care unit (NICU). We retrospectively analyzed the data of operated patients in the NICU. We collected the demographic data, diagnosis, and preoperative stability of the patient, ventilator and inotropic requirements, need for extra anesthetic drugs, procedures performed, complications, and outcome. Operations were performed at bedside in the NICU in critically ill, unstable neonates who needed emergency surgery, neonates of very low birth weight (<1000 g), and neonates on special equipment such as high-frequency ventilators. We excluded minor routine procedures such as drain placement, central line placement, ventricular taps, incision and drainage, and intercostal drainage procedures. We performed seven surgical procedures in the NICU. These included bowel resections and stoma creation, fistula ligation, lung biopsies, and ventricular reservoir placement. Gestational age ranged between 24 and 34 weeks (mean, 28 weeks). Birth weights ranged between 800 and 2500 g (mean, 1357 g). Age at surgery was between 2 and 18 days (mean, 10.2 days). All our patients were on inotropic support and were intubated and mechanically ventilated. Doing surgery for critically ill neonates in the NICU definitely has a place. It was the need of the hour based on the condition of the neonates; however, we feel that neonatal surgery in the NICU should be the norm as it can improve survival. Surgery in the NICU can give a fighting chance to these patients; however, operation theaters in the NICU would be an ideal setting.


Enhanced protein kinase C activity correlates with the growth rate of malignant gliomas in vitro.
Direct measurement of protein kinase C (PKC) activity in vitro revealed a significant increase in the activity of the enzyme in all human malignant glioma lines examined and the rat C6 tumor in comparison with control nonneoplastic astrocyte and mixed glial cultures. The total and particulate PKC activity in these cell types correlated strongly [r = 0.98 (P less than 0.001) and 0.94 (P = 0.002), respectively] with the maximal growth rates as measured by 3H-thymidine incorporation in each of the samples. An alteration in the growth rate of an individual glioma line (A172) by varying the serum concentration in the growth medium produced comparative changes in the measured PKC activity. The addition of the phorbol ester phorbol-12-myristate-13-acetate to this tumor line under high serum conditions produced down-regulation of the enzyme, which was accompanied by a corresponding reduction in thymidine incorporation. The administration of the PKC inhibitor staurosporine produced a dose-related decrease in the basal proliferation rate of glioma lines A172 and C6, as measured by 3H-thymidine uptake and confirmed by flow cytometry, indicating that the high intrinsic PKC activity is amenable to pharmacological manipulation. Cytofluorometric deoxyribonucleic acid cell cycle analysis of the tumors treated with PKC modulators demonstrated that reduced proliferation rates were caused by an inhibition of entrance into the deoxyribonucleic acid synthesis (S) phase (decrease in proliferative index), supporting the evidence that these modulators are not slowing the tumor growth in a nonspecific cytotoxic manner.(ABSTRACT TRUNCATED AT 250 WORDS)


[Reactions of neurons of the primary somatosensory cortex in cats to stimulation of different vibrissae].
Extracellular and intracellular reactions of 57 neurons from the vibrissal projection region in SI cortical zone were studied in cats. Intensity of both excitatory and inhibitory reactions decreased when stimulation of the receptive field was shifted from the centre to the periphery. A relative role of inhibition of vibrissal stimulation in inhibition/excitation interactions increased during such shift. Neurons recorded in the same microelectrode track had a common centre in the receptive field, but the dimensions of the receptive fields could differ substantially. Units with primary inhibition to the vibrissal stimulation were met.


The use of ornithine salts of branched-chain ketoacids in portal-systemic encephalopathy.
In eight patients with chronic portal-systemic encephalopathy who were symptomatic despite protein restriction and lactulose, a double-blind crossover comparison was conducted of branched-chain amino acids (68 mmol/d) versus ornithine salts of branched-chain ketoacids (34 mmol/d), both mixtures being administered orally for 7 to 10 days, after control periods, during a single hospitalization. Ornithine salts of branched-chain ketoacids markedly improved electroencephalographic abnormalities and clinical grade of encephalopathy; branched-chain amino acids had significantly lesser effects, which were of borderline statistical significance. To ascertain whether ornithine or branched-chain ketoacids were responsible for the improvement observed, we administered to six patients calcium salts of branched-chain ketoacids (34 mmol/d) after control periods; only slight improvement was seen.. Four patients received a daily dose of ornithine alpha-ketoglutarate containing the same quantity of ornithine; one did not change and three deteriorated rapidly. We conclude that the combination of ornithine and branched-chain ketoacids improves chronic portal-systemic encephalopathy more than its components given separately and more than branched-chain amino acids at twice the molar dose.


[Risk of convulsions due to the use of bupropion as an aid for smoking cessation].
Bupropion is a new aid in smoking cessation. Since marketing of this product in the Netherlands (from December 1999 on), 7 cases of (possible) convulsions have been reported. In 3 cases there was a contraindication in the form of a history of epilepsy. The four other cases concerned tonic-clonic epileptic seizures in patients with no history of epilepsy and no combination with other medication. In view of the seriousness of this, already known, side effect of bupropion, physicians ought to be sensitive to situations with increased risk of this side effect. In addition it is advised to explain to the patient the proper use of bupropion, which is not comparable to nicotine chewing gum and should be swallowed whole due to the slow release properties of the tablet.


E-cigarette use and adverse respiratory symptoms among adolescents and Young adults in the United States.
E-cigarette use among adolescents and young adults has been associated with adverse respiratory symptoms, including symptoms of asthma and bronchitis. This investigation examined whether such associations differ by primary type of e-cigarette device used. This cross-sectional study included data from four study populations in California and Connecticut, United States, ages 13-21 years (N = 10,483), who self-reported their tobacco use behaviors and health status from 2018 to 2020. Adverse respiratory symptoms were grouped as bronchitis, asthma exacerbation, and shortness of breath. Associations with e-cigarette use were examined by frequency of e-cigarette use (regardless of device type) and most-frequently use device type in the past 30 days (pod, pen/tank, disposable, or mod). Multivariable modeling accounted for demographic variables and use of other tobacco and cannabis. Results were pooled at the study level via random-effects meta-analysis. Across the four studies, e-cigarette use >5 days/month versus never use was associated with bronchitic symptoms (summary odds ratio, sOR: 1.56; 95% confidence interval, CI: 1.37, 1.77) and shortness of breath (sOR: 1.68; 95% CI: 1.35, 2.08) but not statistically significantly with asthma exacerbations (sOR: 1.36; 95% CI; 0.95, 1.95). Among past 30-day e-cigarette users, associations with respiratory symptoms did not differ by device type. In these populations, e-cigarette use was positively associated with symptoms of bronchitis and shortness of breath, but adjusted odds of symptoms did not differ meaningfully by device type. These findings suggest that risk of these respiratory outcomes is elevated among more frequent e-cigarette users regardless of device type used.


Anger attacks are associated with persistently elevated irritability in MDD: findings from the EMBARC study.
This report tests the association of self-reported symptoms of irritability with overt behavior of anger attacks (uncharacteristic sudden bouts of anger that are disproportionate to situation and associated with autonomic activation). Participants of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care study who completed Massachusetts General Hospital Anger Attacks questionnaire were included (n = 293). At each visit, the 17-item Hamilton Depression Rating Scale and the 16-item Concise Associated Symptom Tracking scale were used to measure depression, anxiety, and irritability. In those with anger attacks present v. those without anger attacks, separate t tests and mixed model analyses compared afore-mentioned symptoms at baseline and changes with treatment respectively. As anger attacks may occur without aggressive behaviors, analyses were repeated based only on the presence of aggressive behaviors. At baseline, those with anger attacks (n = 109) v. those without anger attacks (n = 184) had similar levels of depression but higher levels of irritability [effect size (d) = 0.80] and anxiety (d = 0.32). With acute-phase treatment, participants with anger attacks experienced a greater reduction in irritability (p < 0.001) but not in depression (p = 0.813) or anxiety (p = 0.771) as compared to those without anger attacks. Yet, irritability levels at week-8 were higher in those with anger attacks (d = 0.32) than those without anger attacks. Similar results were found in participants with aggressive behaviors. The presence of anger attacks in outpatients with major depressive disorder may identify a sub-group of patients with persistently elevated irritability.


High prevalence of esophageal dysmotility in asymptomatic obese patients.
Obesity is an important health problem affecting >500 million people worldwide. Esophageal dysmotility is a gastrointestinal pathology associated with obesity; however, its prevalence and characteristics remain unclear. Esophageal dysmotilities have a high prevalence among obese patients regardless of gastrointestinal symptoms. To identify the prevalence of esophageal dysmotility among obese patients. The secondary goals were to characterize these pathologies in obese patients and identify risk factors. A prospective study from January 2009 to March 2010 at the University of Montreal Hospital Centre (Montreal, Quebec) was performed. Every patient scheduled for bariatric surgery underwent preoperatory esophageal manometry and was included in the study. Manometry was performed according to a standardized protocol with the following measures: superior esophageal sphincter - coordination and release during deglutition; esophageal body - presence, propagation, length, amplitude and type of esophageal waves of contraction; lower esophageal sphincter - localization, tone, release, intragastic pressure and intraesophageal pressure. All reference values were those used in the digestive motility laboratory. A gastrointestinal symptoms questionnaire was completed on the day manometry was performed. Chart reviews were performed to identify comorbidities and treatments that could influence the results. A total of 53 patients were included (mean [± SD] age 43 ± 10 years; mean body mass index 46 ± 7 kg/m; 70% female). Esophageal manometry revealed dysmotility in 51% (n=27) of the patients. This dysmotility involved the esophageal body in 74% (n=20) of the patients and the inferior sphincter in 11% (n=3). Mixed dysmotility (body and inferior sphincter) was found in 15% (n=4) of cases. The esophageal body dysmotilities were hypomotility in 85% (n=23) of the patients, either from insignificant waves (74% [n=20]), nonpropagated waves (11% [n=3]) or low-amplitude waves (33% [n=9]). Gastroesophageal symptoms were found in 66% (n=35) of obese patients, including heartburn (66% [n=23]), regurgitation (26% [n=9]), dysphagia (43% [n=15]), chest pain (6% [n=2]) and dyspepsia (26% [n=9]). Among symptomatic patients, 51% (n=18) had normal manometry and 49% (n=17) had abnormal manometry (statistically nonsignificant). Among asymptomatic patients (n=18), 44% (n=8) had normal manometry and 56% (n=10) had abnormal manometry (statistically nonsignificant). Furthermore, no statistical differences were found between the normal manometry group and the abnormal manometry group with regard to medication intake or comorbidities. Esophageal dysmotilities had a high prevalence in obese patients. Gastrointestinal symptoms cannot predict the presence of esophageal dysmotility. Hypomotility of the esophageal body is the most common dysmotility, especially from the absence of significant waves.


Sanitation-related psychosocial stress: A grounded theory study of women across the life-course in Odisha, India.
While sanitation interventions have focused primarily on child health, women's unique health risks from inadequate sanitation are gaining recognition as a priority issue. This study examines the range of sanitation-related psychosocial stressors during routine sanitation practices in Odisha, India. Between August 2013 and March 2014, we conducted in-depth interviews with 56 women in four life stages: adolescent, newly married, pregnant and established adult women in three settings: urban slums, rural villages and indigenous villages. Using a grounded theory approach, the study team transcribed, translated, coded and discussed interviews using detailed analytic memos to identify and characterize stressors at each life stage and study site. We found that sanitation practices encompassed more than defecation and urination and included carrying water, washing, bathing, menstrual management, and changing clothes. During the course of these activities, women encountered three broad types of stressors-environmental, social, and sexual-the intensity of which were modified by the woman's life stage, living environment, and access to sanitation facilities. Environmental barriers, social factors and fears of sexual violence all contributed to sanitation-related psychosocial stress. Though women responded with small changes to sanitation practices, they were unable to significantly modify their circumstances, notably by achieving adequate privacy for sanitation-related behaviors. A better understanding of the range of causes of stress and adaptive behaviors is needed to inform context-specific, gender-sensitive sanitation interventions.


Utilization of the Medical Research Council evaluation framework in the development of technology for symptom management: the ASyMS-YG Study.
Technology is becoming an important medium for supporting patients in health care. However, successful application depends on user acceptability. The Advanced Symptom Management System (ASyMS) involves patients reporting cancer chemotherapy-related symptoms using mobile phone technology. The aim of this article was to report a study of how young people were involved in the development of ASyMS using the Medical Research Council framework for evaluating complex interventions. A convenience sample of young people aged 13 to 18 years undergoing cancer chemotherapy were recruited from 2 principal cancer treatment centers in London. In phase 1, young people selected 5 symptoms from an adapted version of the Memorial Symptom Assessment Scale that were most important to them. In phase 2, young people completed the ASyMS-YG PDA (personal digital assistant) questionnaire daily on days 1 to 14 of a cycle of chemotherapy and pre/post-use questionnaires. In phase 1, 5 young people chose diarrhea, nausea, vomiting, constipation, and weight loss as the most important symptoms. In phase 2, 25 young people reported positively to using PDA technology, found ASyMS-YG simple and easy to complete, and liked that they were monitored at home. In addition to the 5 core symptoms, the ASyMS-YG reports showed the number (n = 37) of other symptoms young people experienced. This early development work indicates the acceptability of ASyMS-YG and has informed an exploratory trial (phase 3) and randomized controlled trial (stage 4). This study reaffirms the importance of promoting communication between young people and health professionals.


Decreased expression of Gab2 in patients with temporal lobe epilepsy and pilocarpine-induced rat model.
Growth factor receptor bound protein-2 associated binding protein-2 (Gab2) is widely expressed in the central nervous system, and participates in multiple signaling pathways. Recent studies showed that Gab2 was involved in the pathogenesis of Alzheimer's disease (AD). Gab2 reduces tau phosphorylation levels and is associated with cellular apoptosis and differentiation. However, whether Gab2 was also involved in the pathogenesis of epilepsy, remains unknown. This study aimed to investigate the expression pattern of Gab2 protein in brains with temporal lobe epilepsy (TLE) and in pilocarpine-induced rat model of TLE. Western blot, immunohistochemistry, and immunofluorescence were used to assess the location and the expression level of Gab2 in the neocortex of the temporal lobe in patients with TLE and in rat model of epilepsy. Results showed that Gab2 protein was expressed mainly in the membranes and cytoplasm of neurons in the cortex and hippocampus. Gab2 protein expression was remarkably reduced in temporal neocortex of TLE patients. In hippocampus and adjacent cortex in rat epilepsy model, Gab2 expression was decreased at different time points after kindling compared with the controls, and the lowest level of Gab2 expression occurred at 1 week. Thus, significant reductions of Gab2 protein in both TLE patients and epilepsy rats suggest that Gab2 may play an important role in the pathogenesis of TLE.


Psoralea glandulosa as a potential source of anticancer agents for melanoma treatment.
With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on melanoma cancer, the present study was undertaken to investigate the biological activity of the resinous exudate of aerial parts from Psoralea glandulosa, and its active components (bakuchiol (1), 3-hydroxy-bakuchiol (2) and 12-hydroxy-iso-bakuchiol (3)) against melanoma cells (A2058). In addition, the effect in cancer cells of bakuchiol acetate (4), a semi-synthetic derivative of bakuchiol, was examined. The results obtained show that the resinous exudate inhibited the growth of cancer cells with IC50 value of 10.5 μg/mL after 48 h of treatment, while, for pure compounds, the most active was the semi-synthetic compound 4. Our data also demonstrate that resin is able to induce apoptotic cell death, which could be related to an overall action of the meroterpenes present. In addition, our data seem to indicate that the apoptosis correlated to the tested products appears, at least in part, to be associated with an increase of reactive oxygen species (ROS) production. In summary, our study provides the first evidence that P. glandulosa may be considered a source of useful molecules in the development of analogues with more potent efficacy against melanoma cells.


Design considerations for narrow-band dielectric resonant grating reflection filters of finite length
An interference-waveguide approach is developed to predict the response of a resonant grating reflection filter and to provide a better understanding of the resonant process. An expression for the reflected field that accounts for all internal boundary reflections within the filter is developed. Under the assumption of an anti-reflective design, expressions characterizing the line shape of a filter of infinite length are first developed; then the effects of finite length on the response are determined. Expressions relating the length of the filter to the peak reflection efficiency and line width are developed. The degradation of the response as a function of filter length is evaluated. An equivalent waveguide representation is used to determine the location of the resonance as well as the spectral and angular linewidths of the filter. The minimum obtainable spectral linewidth for a filter of given length is determined to be on the order of deltalambda approximately lambda2/L. Rigorous analysis is used to verify the interference-waveguide approach.


Activation of adenylate cyclase in human platelet membranes by guanosine 5'-[beta gamma-imido]triphosphate is inhibited by cyclic-AMP-dependent phosphorylation. Slow activation occurs in the absence of ATP.
Incubation of platelet membranes with guanosine 5'-[beta gamma-imido]triphosphate causes a slow increase in GS (stimulatory GTP-binding protein) activation of adenylate cyclase. Mg2+ is necessary for this slow activation. This process is inhibited in the presence of ATP, and inhibition is greater if cyclic AMP is also included in the incubation. Adenosine 5'-[beta gamma-imido]triphosphate instead of ATP in the incubation facilitates the slow activation in the presence of cyclic AMP, and incubation of membranes with cyclic-AMP-dependent protein kinase inhibitor decreased inhibition of the slow activation of adenylate cyclase by ATP and cyclic AMP. A protein of 45 kDa in platelet membranes is phosphorylated in a cyclic-AMP-dependent manner. The transition from a reversibly activated form of GS to an irreversibly activated form is substantially slower in the presence of ATP and cyclic AMP. We propose that guanosine 5'-[beta gamma-imido]triphosphate-activated GS may exist in phosphorylated or non-phosphorylated forms, and that the non-phosphorylated form is the more active of the two species. The non-phosphorylated form of GS may correspond to the irreversibly activated state.


Roles of Ca2+ in human neutrophil responses to receptor agonists.
Previous studies have concluded that cytosolic Ca2+ [( Ca2+]i) transients are essential for neutrophils (PMN) to degranulate and make superoxide anion when challenged with the receptor agonists N-formyl-methionyl-leucyl-phenylalanine, platelet-activating factor and leukotriene B4. This view is based on the profound unresponsiveness of PMN that have their [Ca2+]i fixed at resting levels by removing storage Ca2+ and loading the cells with greater than or equal to 20 microM of a Ca2+ chelator, quin2 AM. We too observed this unresponsive state in PMN loaded with 10-32 microM-quin2 AM, fura-2 AM or 1,2-bis-(2-aminophenoxy) ethane-NNN'N'-tetra-acetic acid (BAPTA). When loaded with less than or equal to 1 microM fura-2 AM, however, Ca(2+)-depleted PMN failed to alter [Ca2+]i appreciably, yet still had substantial degranulation and superoxide-anion-generating responses to the receptor agonists. Function thus did not require [Ca2+]i transients. Moreover, Ca(2+)-depleted PMN had 20-35% decreases in receptor numbers for each of the three agonists, and chelator loading of these cells decreased receptor availability by 30-50%. All receptor losses were reversed by incubating PMN with Ca2+ at 37 degrees C, but not at 4 degrees C, and agonist binding at 4 degrees C was not influenced by the presence or absence of extracellular Ca2+. Ca2+ thus caused PMN to up-regulate their agonist receptors at 37 degrees C, and the effect persisted at 4 degrees C regardless of ambient Ca2+. We conclude that Ca2+ acts in at least three ways to regulate responses to receptor agonists. First, some pool of (probably cellular) Ca2+ maintains receptor expression. Second, [Ca2+]i transients potentiate, but are not required for, function. The [Ca2+]i pool may or may not be the same as that influencing receptors. Finally, another pool(s) of Ca2+ signals or permits responses. This last pool, rather than [Ca2+]i transients, appears essential for the bioactions of standard Ca(2+)-mobilizing stimuli.


An iterative algorithm for X-ray CT fluoroscopy.
X-ray computed tomography fluoroscopy (CTF) enables image guidance of interventions, synchronization of scanning with contrast bolus arrival, and motion analysis. However, filtered backprojection (FB), the current method for CTF image reconstruction, is subject to motion and metal artifacts from implants, needles, or other surgical instruments. Reduced target lesion conspicuity may result from increased image noise associated with reduced tube current. In this report, we adapt the row-action expectation-maximization (EM) algorithm for CTF. Because time-dependent variation in images is localized during CTF, the row-action EM-like algorithm allows rapid convergence. More importantly, this iterative CTF algorithm has fewer metal artifacts and better low-contrast performance than FB.


Assessment of workers' exposure to aromatic hydrocarbons in a paint industry.
A factory survey was conducted in a paint industry in Tehran-Iran. The time-weighted average of toluene and xylene concentration in breathing zone and environmental air were monitored by charcoal tube samplers and GC-FID. The results showed that the tank cleaners had the highest exposure to toluene and xylene (1.5-5.4 times of TLV), while the workers in packaging workshops had the lowest. However, environmental concentration did not show significant differences in workshops and their levels were all lower than the TLV.


Effects of progesterone on hyperoxia-induced damage in mouse C8-D1A astrocytes.
The birth of most mammals features a dramatic increase in oxygen while placenta-derived hormones such as β-estradiol and progesterone plummet. In experimental newborn animals, transiently elevated oxygen concentrations cause death of neurons, astrocytes, and oligodendrocyte precursors. High oxygen has been associated with cerebral palsy in human preterm infants while progesterone is being used to prevent preterm delivery and investigated as a neuroprotective agent. In this study, we investigated the effects of hyperoxia (80% O2 for 24, 48, and 72 h) on cultured C8-D1A astrocytes in the presence or absence of progesterone at concentrations ranging from 10(-9) to 10(-5) mol/L. Hyperoxia measured by methytetrazolium assay (MTT) reduced cell viability, increased release of lactate dehydrogenase (LDH), reduced carboxyfluorescein diacetate succinimidyl ester (CFSE)-assessed cell proliferation, and downregulated Cylin D2 expression. Progesterone did not affect any of these hyperoxia-mediated indicators of cell death or malfunctioning. Real-time PCR analysis showed that hyperoxia caused downregulation of the progesterone receptors PR-AB und PR-B. Our experiments showed that there was no protective effect of progesterone on hyperoxia-inducted cell damage on mouse C8-D1A astrocytes. Down regulation of the progesterone receptors might be linked to the lack of protective effects.


Introduction to correlation microwave thermography.
Correlation microwave thermography, a new process based on a coherent detection of noise, is able to improve the localization of the thermal gradients in the tissues. We explain the principles of this method and describe the first system which has been built and tested. Several experiments point out that with this process better spatial resolution and flexibility can be expected.


Lupeol, a Pentacyclic Triterpene, Promotes Migration, Wound Closure, and Contractile Effect In Vitro: Possible Involvement of PI3K/Akt and p38/ERK/MAPK Pathways.
Skin wound healing is a dynamic and complex process involving several mediators at the cellular and molecular levels. Lupeol, a phytoconstituent belonging to the triterpenes class, is found in several fruit plants and medicinal plants that have been the object of study in the treatment of various diseases, including skin wounds. Various medicinal properties of lupeol have been reported in the literature, including anti-inflammatory, antioxidant, anti-diabetic, and anti-mutagenic effects. We investigated the effects of lupeol (0.1, 1, 10, and 20 μg/mL) on in vitro wound healing assays and signaling mechanisms in human neonatal foreskin keratinocytes and fibroblasts. Results showed that, at high concentrations, Lupeol reduced cell proliferation of both keratinocytes and fibroblasts, but increased in vitro wound healing in keratinocytes and promoted the contraction of dermal fibroblasts in the collagen gel matrix. This triterpene positively regulated matrix metalloproteinase (MMP)-2 and inhibited the NF-κB expression in keratinocytes, suggesting an anti-inflammatory effect. Lupeol also modulated the expression of keratin 16 according to the concentration tested. Additionally, in keratinocytes, lupeol treatment resulted in the activation of Akt, p38, and Tie-2, which are signaling proteins involved in cell proliferation and migration, angiogenesis, and tissue repair. These findings suggest that lupeol has therapeutic potential for accelerating wound healing.


A Law for Loudness Discrimination.
A law for loudness is proposed which implies detection and averaging in a general nonlinear device with excitation by a complex signal-noise wave form. This law provides a mechanistic explanation for subjective intensity in the general time varying case. Mathematical solutions to the general law may be obtained in certain elementary cases, the well-known power-law characteristic being an example. A modified Weber law is derived which is in good agreement with experiments at both small and moderate stimulus intensities.


Spironolactone-associated digoxin radioimmunoassay interference.
Apparent digoxin was measured in the serum of 21 patients receiving spironolactone and in 21 controls, by use of a sequential-saturation 3H-radioimmunoassay (RIA) and an equilibrium 125I-RIA. No patient had been given digoxin for at least four weeks. "Digoxin" values in the former group were significantly (p less than 0.05) higher than in the control group, and often were in or near the "therapeutic" range by the equilibrium 125I-RIA, but not by the sequential-saturation 3H-RIA. Canrenone (a major active metabolite of spironolactone) in the serum of the former group was measured by a newly developed liquid-chromatographic technique and correlated (r = 0.73) with "digoxin" concentrations by the 125I-RIA. However, external addition of canrenone to control serum in comparable concentrations did not cause appreciable "digoxin" values by the 125I-RIA. These findings suggest that other metabolites of spironolactone are responsible for the assay interference, the degree of which appears to depend on antibody specificity. Therefore, assay specificity should be established in clinical laboratories by using digoxin-free serum from patients ingesting spironolactone, and not by using spironolactone- or canrenone-fortified digoxin-free serum.


Chronic headache and comorbidities: a two-phase, population-based, cross-sectional study.
Studies using resources of a public family health program to estimate the prevalence of chronic daily headaches (CDH) are lacking. To estimate the 1-year prevalence of CDH, as well as the presence of associated psychiatric and temporomandibular disorders (TMD) comorbidities, on the entire population of a city representative of the rural area of Brazil. This was a cross-sectional, population-based, 2-phase study. In the first phase, health agents interviewed all individuals older than 10 years, in a rural area of Brazil. In the second stage, all individuals who reported headaches on 4 or more days per week were then evaluated by a multidisciplinary team. CDH were classified according to the second edition of the International Classification of Headache Disorders (ICHD-2). Medication overuse headache was diagnosed, as per the ICHD-2, after detoxification trials. Psychiatric comorbidities and TMD were diagnosed based on the DSM-IV and on the Research Diagnostic Criteria for Temporomandibular Disorders criteria, respectively. A total of 1631 subjects participated in the direct interviews. Of them, 57 (3.6%) had CDH. Chronic migraine was the most common of the CDH (21, 36.8%). Chronic tension-type headache (10, 17.5%), medication overuse headache (13, 22.8%) and probable medication overuse headache (10, 17.5%) were also common. Psychiatric disorders were observed in 38 (67.3%) of the CDH subjects. TMD were seen in 33 (58.1)% of them. The prevalence of CDH in the rural area of Brazil is similar to what has been reported in previous studies. A significant proportion of them have psychiatric comorbidities and/or TMD. In this sample, comorbidities were as frequent as reported in convenience samples from tertiary headache centers.


Care of the newborn in perinatal units in New Brunswick.
A survey of 23 perinatal units in New Brunswick hospitals was conducted by means of a mailed questionnaire to determine the type of care provided to newborns. The results showed various degrees of conformity with published guidelines for the care of newborns. Deficiencies were noted in several areas of care: failing to give or improperly giving vitamin K1 prophylaxis (in 7 of the units), flushing the eyes after silver nitrate prophylaxis (in 10), using hexachlorophene to bathe newborns (in 11) and delaying the first feeding up to 12 hours (in 3). It is essential to provide appropriate support to newborns as they adjust to a new environment and to ensure that alternative practices are in keeping with current scientific knowledge.


Design of a one-tube hemi-nested PCR for detection of Toxoplasma gondii and comparison of three DNA purification methods.
The aims of the present study were to design an easy and sensitive DNA amplification method for detection of Toxoplasma gondii with low risk of accidental contamination, and to find a rapid method for purification of clinical samples containing potential inhibitors of the amplification reaction. With a pair of primers amplifying a 619-bp fragment of the B1 gene of this parasite it was possible to detect DNA equivalent to 10 parasites. When a third primer was added to the same tube, sensitivity increased to 0.1 parasite. In a comparison of different DNA purification methods, the High Pure PCR Template Preparation Kit (Boehringer Mannheim, Germany) gave the best results. With this purification method and the one-tube hemi-nested PCR, T. gondii DNA was detected in 14 (87.5%) of 16 clinical specimens (amniotic fluid, broncho-alveolar lavage, bone marrow, blood, liver biopsy) in which the parasite was demonstrated by cell culture.


ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response.
On-treatment anemia is associated with higher sustained virological response (SVR) rates during peginterferon plus ribavirin (RBV) therapy. Inosine triphosphatase (ITPA) variants causing ITPase deficiency have been shown to protect against RBV-induced anemia. However, ITPase activity has not been associated with SVR. To study this discrepancy, we examined the relationships between ITPase activity, on-treatment anemia, SVR, and RBV levels in hepatitis C virus genotype 1 (HCV-1) patients from the CHARIOT study. ITPA genotype (rs7270101, rs1127354) was used to define ITPase activity in 546 patients. Plasma RBV levels were measured using high-performance liquid chromatography (HPLC). Relationships between ITPase activity, on-treatment hemoglobin (Hb) levels, RBV levels, and SVR were tested using regression modeling, survival analysis, and locally weighted scatterplot smoothing (LOWESS) plot analysis. Hb decline was independently associated with SVR (P<0.0001). ITPase deficiency was present in 35%. ITPase deficiency strongly protected against Hb decline (P<0.0001), but was not associated with SVR (P=0.28). The probability of SVR increased with lower nadir Hb for both wild-type and deficient ITPase activity, but the association curve shifted to describe a parallel relationship at higher Hb levels in patients with ITPase deficiency. In a subset (n=203), we tested the hypothesis that the association between Hb decline and SVR reflected RBV levels rather than actual Hb level. RBV levels were associated with on-treatment Hb decline and SVR, but not ITPase activity. In regression models, adjustment for RBV levels attenuated the association between Hb decline and SVR. ITPase deficiency protects against RBV-induced anemia, but is not associated with SVR. Our data suggest that the relationship between Hb decline and SVR is not mechanistic, but is linked to RBV levels.


Pulmonary function tests in school children.
Pulmonary Function tests were measured in 261 healthy boys and 254 healthy girls in the age group of 6 to 15 years with standard Benidects Roth type recording spirometer and Wrights Peak Flow Meter. The values of Pulmonary Functions were found to be increased with increase in age. For vital capacity this relation was curvilinear. All values were higher in boys than girls. There was significant positive correlation between pulmonary Function Tests Vital Capacity, (VC), Maximum Voluntary Ventilation (MV), peak Expiratory Flow Rate (PEFR) and anthropometric parameters like height, weight and body surface area. Equations were formed for prediction of V.C., M.V.V. and PEFR values in relation to the height. The values of Pulmonary Functions were lower when compared with Western Standards, but were comparable with different Indian Studies.


The 86-kD subunit of Ku autoantigen mediates homotypic and heterotypic adhesion of multiple myeloma cells.
Previous studies have shown that triggering multiple myeloma (MM) cells via CD40 induces IL-6-mediated autocrine growth as well as increased expression of cell surface adhesion molecules including CD11a, CD11b, CD11c, and CD18. In this study, we generated the 5E2 mAb which targets an antigen that is induced upon CD40 ligand (CD40L) activation of MM cells. Immunofluorescence, immunoprecipitation, and protein sequencing studies identified the target antigen of 5E2 mAb as the 86-kD subunit of the Ku autoantigen. We demonstrate that increased cell surface expression of Ku on CD40L-treated cells is due to migration of Ku from the cytoplasm to the cell surface membrane. Moreover, cell surface Ku on CD40L-treated MM cells mediates homotypic adhesion of tumor cells, as well as heterotypic adhesion of tumor cells to bone marrow stromal cells and to human fibronectin; and 5E2 mAb abrogates IL-6 secretion triggered by tumor cell adherence to bone marrow stromal cells. These data suggest that CD40L treatment induces a shift of Ku from the cytoplasm to the cell surface, and are the first to show that Ku functions as an adhesion molecule. They further suggest that cell surface Ku may play a role in both autocrine and paracrine IL-6-mediated MM cell growth and survival.


Psychiatry's role in the dehumanization of health care.
Contemporary health care systems have been criticized as being insensitive to patients' affective needs. Although the mental health care disciplines have assumed the guardianship of medical humanism, psychiatrists and behavioral scientists have unintentionally played a role in the development of this insensitivity. Preclinical psychiatric curricula and the role models presented by clinician-teachers often neglect the technologic aspects of humanistic medicine. This has encouraged a schism between the affective and cognitive components of medical practice. Alterations of psychiatric teaching and practice that may foster humanistic medical practice are suggested.


Possible quantum critical behavior revealed by the critical current density of hole doped high-Tc cuprates in comparison to heavy fermion superconductors.
The superconducting critical current density, Jc, in hole doped cuprates show strong dependence on the doped hole content, p, within the copper oxide plane(s). The doping dependent Jc mainly exhibits the variation of the intrinsic depairing critical current density as p is varied. Jc(p) tends to peak at p ~ 0.185 in copper oxide superconductors. This particular value of the hole content, often termed as the critical hole concentration, has several features putative to a quantum critical point (QCP). Very recently, the pressure dependences of the superconducting transition temperature (Tc) and the critical current (Ic) in pure CeRhIn5 and Sn doped CeRhIn5 heavy fermion compounds have been reported (Nature Communications (2018) 9:44, https://doi.org/10.1038/s41467-018-02899-5 ). The critical pressure demarcates an antiferromagnetic quantum critical point where both Tc and Ic are maximized. We have compared and contrasted this behavior with those found for Y1-xCaxBa2Cu3O7-δ in this brief communication. The resemblance of the systematic behavior of the critical current with pressure and hole content between heavy fermion systems and hole doped cuprates is significant. This adds to the circumstantial evidence that quantum critical physics probably plays a notable role behind the unconventional normal and superconducting state properties of copper oxide superconductors.


The Hybrid Orthodontic Treatment System (HOTS).
This paper describes the Hybrid Orthodontic Treatment System (HOTS), an innovative method used in first premolar extraction cases. It comprises the following three components: (1) a miniscrew, (2) dual-dimension wires, and (3) multiloop edgewise archwires. HOTS consists of four clearly defined treatment steps: (1) setup, (2) leveling, (3) separate but simultaneous anterior and canine teeth retraction, and (4) final adjustment. HOTS achieves a predictable treatment outcome with a shorter treatment time.


Design and Fabrication of a Device for Reducing Hand Tremor in Parkinson Patients during Eating.
In this paper, the method of designing a noninvasive device for eliminating hand tremors in Parkinson's patients is presented. The designed device measures the tremors of the patient's hand and implements the tremor control accordingly. Since Parkinson's disease reduces patients' abilities to perform daily activities, this device is designed as an electronic spoon. The inertial measurement units are used to measure hand tremors. The signals got from motion sensors are passed through Butterworth's second order low pass filters to attenuate signals amplitude at frequencies higher than the human hand's natural frequency. The signals are sent to a proposed Proportional Integral (PI) fuzzy controller as a set point signal, and appropriate control signals are applied to two actuators installed orthogonal. Besides motion sensors, a microcontroller is installed inside the spoon handle that implements a PI fuzzy controller and provides control signals for two high speed servo motors installed perpendicularly. As such, the spoon can minimize the tremor effect. In this system, no damper or mass is added to the hand, and the patients are not required to wear an orthosis. The contribution of this paper is twofold. First, we use sensor data fusion to increase measurement accuracy. In this paper, we use accelerometer and gyroscope sensors. Second, we proposed a robust PI fuzzy controller to compensate for the uncertainties and reduce the tremor. The test results show that the hand tremor of Parkinson's patients during eating is reduced up to 75% using this method.


Daily life of patients with chronic renal failure receiving hemodialysis treatment.
This analytical descriptive study aimed at assessing the perception of people with chronic renal failure in relation to their daily and occupational activities. The sample was formed by 35 men and 35 women receiving hemodialysis treatment with ages between 17 and 60 years. The instrument used was the SAOF (Self Assessment of Occupational Functioning). The data were submitted to statistical analysis and the areas with greater choice of the alternative "need to improve" were habits (20%) and values (20.5%). In these areas, the proportion related with difficulties was more evident regarding organization of the daily life, the changes of routines and the expectations about the future. Therefore, occupational therapy, as it presents instrumental resources to reorganize daily life of these patients, can contribute for their care as well as with information for nursing.


On tests of treatment-covariate interactions: An illustration of appropriate power and sample size calculations.
The appraisals of treatment-covariate interaction have theoretical and substantial implications in all scientific fields. Methodologically, the detection of interaction between categorical treatment levels and continuous covariate variables is analogous to the homogeneity of regression slopes test in the context of ANCOVA. A fundamental assumption of ANCOVA is that the regression slopes associating the response variable with the covariate variable are presumed constant across treatment groups. The validity of homogeneous regression slopes accordingly is the most essential concern in traditional ANCOVA and inevitably determines the practical usefulness of research findings. In view of the limited results in current literature, this article aims to present power and sample size procedures for tests of heterogeneity between two regression slopes with particular emphasis on the stochastic feature of covariate variables. Theoretical implications and numerical investigations are presented to explicate the utility and advantage for accommodating covariate properties. The exact approach has the distinct feature of accommodating the full distributional properties of normal covariates whereas the simplified approximate methods only utilize the partial information of covariate variances. According to the overall accuracy and robustness, the exact approach is recommended over the approximate methods as a reliable tool in practical applications. The suggested power and sample size calculations can be implemented with the supplemental SAS and R programs.


Shared and unique features of evolutionary diversification.
A fundamental question in evolutionary biology asks whether organisms experiencing similar selective pressures will evolve similar solutions or whether historical contingencies dominate the evolutionary process and yield disparate evolutionary outcomes. It is perhaps most likely that both shared selective forces as well as unique histories play key roles in the course of evolution. Consequently, when multiple species face a common environmental gradient, their patterns of divergence might exhibit both shared and unique elements. Here we describe a general framework for investigating and evaluating the relative importance of these contrasting features of diversification. We examined morphological diversification in three species of livebearing fishes across a predation gradient. All species (Gambusia affinis from the United States of America, Brachyrhaphis rhabdophora from Costa Rica, and Poecilia reticulata from Trinidad) exhibited more elongate bodies, a larger caudal peduncle, and a relatively lower position of the eye in predator populations. This shared response suggests that common selective pressures generated parallel outcomes within three different species. However, each species also exhibited unique features of divergence, which might reflect phylogenetic tendencies, chance events, or localized environmental differences. In this system, we found that shared aspects of divergence were of larger magnitude than unique elements, suggesting common natural selective forces have played a greater role than unique histories in producing the observed patterns of morphological diversification. Assessing the nature and relative importance of shared and unique responses should aid in elucidating the relative generality or peculiarity in evolutionary divergence.


PerSort Facilitates Characterization and Elimination of Persister Subpopulation in Mycobacteria.
Mycobacterium tuberculosis (MTB) generates phenotypic diversity to persist and survive the harsh conditions encountered during infection. MTB avoids immune effectors and antibacterial killing by entering into distinct physiological states. The surviving cells, persisters, are a major barrier to the timely and relapse-free treatment of tuberculosis (TB). We present for the first time, PerSort, a method to isolate and characterize persisters in the absence of antibiotic or other pressure. We demonstrate the value of PerSort to isolate translationally dormant cells that preexisted in small numbers within Mycobacterium species cultures growing under optimal conditions but that dramatically increased in proportion under stress conditions. The translationally dormant subpopulation exhibited multidrug tolerance and regrowth properties consistent with those of persister cells. Furthermore, PerSort enabled single-cell transcriptional profiling that provided evidence that the translationally dormant persisters were generated through a variety of mechanisms, including vapC30, mazF, and relA/spoT overexpression. Finally, we demonstrate that notwithstanding the varied mechanisms by which the persister cells were generated, they converge on a similar low-oxygen metabolic state that was reversed through activation of respiration to rapidly eliminate persisters fostered under host-relevant stress conditions. We conclude that PerSort provides a new tool to study MTB persisters, enabling targeted strategies to improve and shorten the treatment of TB.IMPORTANCE Mycobacterium tuberculosis (MTB) persists and survives antibiotic treatments by generating phenotypically heterogeneous drug-tolerant subpopulations. The surviving cells, persisters, are a major barrier to the relapse-free treatment of tuberculosis (TB), which is already killing >1.8 million people every year and becoming deadlier with the emergence of multidrug-resistant strains. This study describes PerSort, a cell sorting method to isolate and characterize, without antibiotic treatment, translationally dormant persisters that preexist in small numbers within Mycobacterium cultures. Characterization of this subpopulation has discovered multiple mechanisms by which mycobacterial persisters emerge and unveiled the physiological basis for their dormant and multidrug-tolerant physiological state. This analysis has discovered that activating oxygen respiratory physiology using l-cysteine eliminates preexisting persister subpopulations, potentiating rapid antibiotic killing of mycobacteria under host-relevant stress. PerSort serves as a new tool to study MTB persisters for enabling targeted strategies to improve and shorten the treatment of TB.


Endothelin-1 potentiates cholinergic nerve-mediated contraction in human isolated bronchus.
That endothelin-1(ET-1) plays a mediator role in asthma is consistent with reports of ET-1-induced potentiation of cholinergic nerve-mediated contraction in airways from various animal species. This study examined the effect of ET-1 on cholinergic contractions in human isolated bronchus. Macroscopically nondiseased human bronchial tissue was obtained from 23 patients with respiratory tumours. An electrical field stimulation (EFS) frequency that produced one third of the contraction at 30 Hz (EFS30) was estimated. The effect of ET-1 on these EFS-evoked contractions was assessed. EFS-evoked contractions were frequency-dependent and abolished by either atropine or tetrodotoxin. Thus, EFS-induced contractions were mediated by acetylcholine from cholinergic nerves. ET-1 (3 nM) potentiated EFS-evoked contractions by 10+/-2% EFS30 (p<0.05) without any significant effect on contractions induced by exogenous acetylcholine. Neither the ET(A) receptor-selective antagonist BQ-123 (3 microM) nor the ET(B) receptor-selective antagonist BQ-788 (10 microM) alone significantly altered ET-1-induced potentiation of EFS-evoked contractions. However, in the combined presence of both BQ-123 and BQ-788, ET-1-induced potentiation of EFS-evoked contractions was abolished. Thus, prejunctional endothelinA and endothelinB receptors appear to mediate endothelin-1-induced potentiation of electrical field stimulation-evoked cholinergic contractions in human bronchus. This suggests another potentially important mechanism through which endothelin-1 could increase bronchial tone in asthma.


Service industries, globalization, and urban restructuring within the Asia-Pacific: new development trajectories and planning responses.
While industralization programmes have been central to the development of Asia-Pacific states and city-regions over the past half-century, service industries are increasingly important as instruments of urban growth and change. The purpose of this paper is to establish service industries as increasingly significant aspects of urban development within the Asia-Pacific, and to propose a conceptual and analytical framework for scholarly investigation within this important research domain. To this end the paper explores a sequence of related themes and issues, concerning the larger developmental implications of urban services growth (or tertiarization), the facets of urban transformation associated with tertiarization, and a preliminary typology of urban service functions which acknowledges the rich diversity of service vocations and stages of development within the Asia-Pacific. The paper concludes that "advanced services"-specialized, intermediate service industries, advanced-technology services, and creative service industries-will be quite crucial to the development of city-regions within the Asia-Pacific, with respect to employment growth and human capital formation, to the urban economic (or export) base, to the operation of flexible production systems, and to competitive advantage. The development of these urban service poles will require innovative policy commitments and regulatory adjustments, as will the multi-centred specialized urban service corridors which function as engines of regional economic growth, and which provide platforms for national modernization and responses to the pressures (and opportunities) of globalization. To date, urban and regional development strategies for service industries within the Asia-Pacific have privileged globalization, industrial restructuring, and modernization aims, but there is also an encouraging record of more progressive planning experimentation in some jurisdictions, incorporating principles of sustainability and co-operative development. There is also increasing interest in policies to support cultural and creative industries among Asia-Pacific city-regions, informed by some recent urban policy experimentation in this domain. These experiences can offer models for further policy and programmatic innovation in the 21st century, as service industries continue to play larger roles in urban and regional development within the Asia-Pacific.


Judgment of the Quality of Restorative Care as Predictors of Restoration Retreatment: Findings from the National Dental PBRN.
The primary aim of this study was to test the hypothesis that a patient's subjective assessments of the dentist's technical competence, quality of care, and anticipated restoration longevity during a restorative visit are predictive of restoration outcome. This prospective cohort study involved 3,326 patients who received treatment for a defective restoration in a permanent tooth, participated in a baseline patient satisfaction survey, and returned for follow-up. Of the 4,400 restorations that were examined by 150 dentists, 266 (6%) received additional treatment after baseline. Reporting satisfaction with the technical skill of the dentist or quality of the dental work at baseline was not associated with retreatment after baseline. However, patients' views at baseline that the fee was reasonable (odds ratio [OR], 1.6) was associated with retreatment after baseline, whereas satisfaction at baseline with how long the filling would last (OR, 0.6) was associated with less retreatment. These findings suggest that retreatment occurs more often for patients who at baseline are satisfied with the cost or who at baseline have less confidence in the restoration. The authors found no associations between restoration retreatment and the patients' baseline evaluations of the technical skills of their dentists or perceptions of quality care. Dental patients' ratings of their dentist's skills were not related to a restoration needing retreatment. Patients focus on other aspects of the dental visit when making this judgment.


Family caregiving and all-cause mortality: findings from a population-based propensity-matched analysis.
Previous studies have provided conflicting evidence on whether being a family caregiver is associated with increased or decreased risk for all-cause mortality. This study examined whether 3,503 family caregivers enrolled in the national Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study showed differences in all-cause mortality from 2003 to 2012 compared with a propensity-matched sample of noncaregivers. Caregivers were individually matched with 3,503 noncaregivers by using a propensity score matching procedure based on 15 demographic, health history, and health behavior covariates. During an average 6-year follow-up period, 264 (7.5%) of the caregivers died, which was significantly fewer than the 315 (9.0%) matched noncaregivers who died during the same period. A proportional hazards model indicated that caregivers had an 18% reduced rate of death compared with noncaregivers (hazard ratio = 0.823, 95% confidence interval: 0.699, 0.969). Subgroup analyses by race, sex, caregiving relationship, and caregiving strain failed to identify any subgroups with increased rates of death compared with matched noncaregivers. Public policy and discourse should recognize that providing care to a family member with a chronic illness or disability is not associated with increased risk of death in most cases, but may instead be associated with modest survival benefits for the caregivers.


Plant Kinesin-Like Calmodulin Binding Protein Employs Its Regulatory Domain for Dimerization.
Kinesin-like calmodulin binding protein (KCBP), a Kinesin-14 family motor protein, is involved in the structural organization of microtubules during mitosis and trichome morphogenesis in plants. The molecular mechanism of microtubule bundling by KCBP remains unknown. KCBP binding to microtubules is regulated by Ca(2+)-binding proteins that recognize its C-terminal regulatory domain. In this work, we have discovered a new function of the regulatory domain. We present a crystal structure of an Arabidopsis KCBP fragment showing that the C-terminal regulatory domain forms a dimerization interface for KCBP. This dimerization site is distinct from the dimerization interface within the N-terminal domain. Side chains of hydrophobic residues of the calmodulin binding helix of the regulatory domain form the C-terminal dimerization interface. Biochemical experiments show that another segment of the regulatory domain located beyond the dimerization interface, its negatively charged coil, is unexpectedly and absolutely required to stabilize the dimers. The strong microtubule bundling properties of KCBP are unaffected by deletion of the C-terminal regulatory domain. The slow minus-end directed motility of KCBP is also unchanged in vitro. Although the C-terminal domain is not essential for microtubule bundling, we suggest that KCBP may use its two independent dimerization interfaces to support different types of bundled microtubule structures in cells. Two distinct dimerization sites may provide a mechanism for microtubule rearrangement in response to Ca(2+) signaling since Ca(2+)- binding proteins can disengage KCBP dimers dependent on its C-terminal dimerization interface.


Epigenome-wide epidemiologic studies of human immunodeficiency virus infection, treatment, and disease progression.
Despite significant advances in the treatment and care of people with HIV (PWH), several challenges remain in our understanding of disease pathogenesis to improve patient care. HIV infection can modify the host epigenome and as such can impact disease progression, as well as the molecular processes driving non-AIDS comorbidities in PWH. Epigenetic epidemiologic studies including epigenome-wide association studies (EWAS) offer a unique set of tools to expand our understanding of HIV disease and to identify novel strategies applicable to treatment and diagnosis in this patient population. In this review, we summarize the current state of knowledge from epigenetic epidemiologic studies of PWH, identify the main challenges of this approach, and highlight future directions for the field. Emerging epigenetic epidemiologic studies of PWH can expand our understanding of HIV infection and health outcomes, improve scientific validity through collaboration and replication, and increase the coverage of diverse populations affected by the global HIV pandemic. Through this review, we hope to highlight the potential of EWAS as a tool for HIV research and to engage more investigators to explore its application to important research questions.


Cucurbitacin D Overcomes Gefitinib Resistance by Blocking EGF Binding to EGFR and Inducing Cell Death in NSCLCs.
In this study, the mechanism of the anticancer effect through which cucurbitacin D (CuD) can overcome gefitinib resistance in NSCLC was investigated. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide assay, and cell migration and growth were observed by wound healing and colony formation assays, respectively. Levels of EGFR family members, protein kinase B, extracellular signal-regulated kinase, poly(ADP-ribose) polymerase, and G2/M phase-related proteins were detected by Western blot analysis. Immunofluorescence analysis was used to detect the intracellular expression of p-EGFR. Induction of apoptosis and cell cycle arrest was measured by flow cytometry. Solid-phase binding assays were used to determine binding to the EGFR family. CuD inhibits the phosphorylation of EGFR in gefitinib-resistant NSCLC cells and induces cell death via cell cycle arrest and apoptosis. CuD treatment or EGFR knockdown also suppressed the growth of gefitinib-resistant NSCLC cells. In addition, CuD overcame resistance by blocking EGF binding to EGFR in gefitinib-resistant NSCLC cells. In conclusion, we demonstrate that CuD overcomes gefitinib resistance by reducing the activation of EGFR-mediated survival in NSCLC and by inhibiting the combination of EGF and EGFR.


Reproducibility and Precision of CT Scans to Evaluate Tibial Component Rotation.
Component rotation likely plays a greater role on the survivorship and outcomes of total knee arthroplasties than is currently known. Our goal was to evaluate the precision, interobserver reliability, and intrarater reliability of tibial component rotation as measured by computed tomography (CT) scan, regardless of measurement technique. Three fellowship-trained, academic arthroplasty surgeons independently measured tibial component rotation on CT scans of 62 total knee arthroplasties using their methods of choice. Measurements were repeated at least 2 weeks after the initial measurement. The precision of the measurements was assessed using a formal 8-step protocol as the gold standard. Intraclass correlation coefficients (ICCs) were calculated to evaluate precision, interobserver agreement, and intrarater reliability RESULTS: The interobserver agreement between the 3 surgeons for tibial component rotation was also moderate (ICC = 0.52). The intrarater reliability of tibial rotation was excellent (ICC = 0.81). Comparison of surgeons' measurement to a validated gold standard revealed only moderate precision for tibial component rotation (ICC = 0.64). Practicing surgeons measuring tibial rotation were internally consistent, but failed to demonstrate satisfactory precision and interobserver agreement. We support the adoption of standardized criteria for the measurement of tibial component rotation on CT scans.


Atypical symptoms of depression in a sample of depressed child and adolescent outpatients.
To examine the presence of symptoms of atypical depression among children and adolescents with a major depressive disorder (MDD). One thousand forty-six youths (aged 6-19 years) meeting DSM-III-R criteria for MDD were included in the study. All subjects had presented at an outpatient clinic seeking treatment and were identified as having MDD via clinical interviews using the semistructured Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Episode (K-SADS-P) with the youngster themselves and a parent/guardian. A diagnosis of atypical depression was derived from the symptoms of depression assessed in the K-SADS-P and required the presence of mood reactivity and at least one the following symptoms: hypersomnia, increased appetite, weight gain, or psychomotor retardation (substituted for leaden paralysis). One hundred sixty-two (15.5%) of the depressed youths met criteria for atypical depression. The symptoms of atypical depression were found to correlate marginally, and the diagnosis of atypical depression had marginal construct validity for both children and adolescents. The findings from this large sample of depressed children and adolescents suggest that atypical features of depression occur in this age group. However, the diagnosis of atypical depression appears to have only marginal construct validity for both children and adolescents.


Protein-tyrosine phosphatase 1B (PTP1B) is a novel regulator of central brain-derived neurotrophic factor and tropomyosin receptor kinase B (TrkB) signaling.
Neuronal protein-tyrosine phosphatase 1B (PTP1B) deficiency in mice results in enhanced leptin signaling and protection from diet-induced obesity; however, whether additional signaling pathways in the brain contribute to the metabolic effects of PTP1B deficiency remains unclear. Here, we show that the tropomyosin receptor kinase B (TrkB) receptor is a direct PTP1B substrate and implicate PTP1B in the regulation of the central brain-derived neurotrophic factor (BDNF) signaling. PTP1B interacts with activated TrkB receptor in mouse brain and human SH-SY5Y neuroblastoma cells. PTP1B overexpression reduces TrkB phosphorylation and activation of downstream signaling pathways, whereas PTP1B inhibition augments TrkB signaling. Notably, brains of Ptpn1(-/-) mice exhibit enhanced TrkB phosphorylation, and Ptpn1(-/-) mice are hypersensitive to central BDNF-induced increase in core temperature. Taken together, our findings demonstrate that PTP1B is a novel physiological regulator of TrkB and that enhanced BDNF/TrkB signaling may contribute to the beneficial metabolic effects of PTP1B deficiency.


Effect of diethylcarbamazine citrate and anti-inflammatory drugs on experimental onchocercal punctate keratitis.
Subconjunctivally injected Onchocerca lienalis microfilariae (Mf) migrate into the guinea pig cornea, resulting, when the microfilariae die, in punctate stromal opacities resembling those of human onchocerciasis. Administration of diethylcarbamazine citrate (DEC-C) following subconjunctival injection of Mf increased the proportion of dead Mf in the cornea, the number of punctate opacities and the extent of peripheral corneal neovascularization. Betamethasone (a synthetic steroid) and lodoxamide tromethamine (an inhibitor of mediator release from mast cells) inhibited the formation of punctate opacities. Chlorpheniramine maleate and cimetidine (H1 and H2 histamine receptor antagonists), given together, did not alter the formation of punctate opacities but inhibited the peripheral corneal neovascularization. These observations suggest that mast cell mediators other than histamine may be of importance in the formation of the corneal punctate opacities.


Human embryonic gastric xenografts in nude mice: a new model of Helicobacter pylori infection.
In vitro or animal models have been used to investigate the pathogenesis of Helicobacter pylori infection. However, extrapolation to humans of results obtained with these heterologous models remains difficult. We have developed a new model for the study of H. pylori infection that uses human entire embryonic stomachs engrafted in nude mice. At 80 days after implantation, 22 of these xenografts, which exhibited a mature gastric epithelium, were inoculated with 10(7) to 10(8) CFU of either H. pylori LB1, a freshly isolated H. pylori strain (n = 12), or H. pylori ATCC 49503 (n = 10). After 12-week examination, H. pylori LB1 persistently colonized the antrum of all inoculated grafts, as assessed by culture (mucus and mucosa), immunohistochemistry (mucosa), and a rapid urease test (mucus). H. pylori ATCC 49503, either before or after in vivo passage, permitted only a transient 2-week colonization in one of the five inoculated grafts in both groups. Colonization was always associated with an increase of gastric juice pH. A mild neutrophil infiltration of the gastric mucosa was noted solely in infected grafts. Transmission electron microscopy showed adherence of H. pylori organisms to epithelial cell surface. In six animals, intracytoplasmic location of this bacterium was observed in the antrum or the fundus. These results allow us to propose this model as a new ex vivo model for the study of specific H. pylori-gastric cell interactions.


[Clinical guides in Mexico, emission of the Academia Mexicana de Cirugia].
Today, these exist worldwide organizations related with the practice of medicine that are interested in marking recommendations and in formulating guidelines for better performance of physicians and health professionals. These organizations are headed by universities, associations, colleges, research center, and work groups and are made up of well-known physicians with academic prestige from the private and public sectors. This report presents a brief overview concerning the development of three clinical guides related with illnesses frequently observed in the physician's office: rhinosinusitis gastroesophageal reflux diseases (GERD), and prostate benign hyperplasia. These guides are issued by one of the most important academic institutions in the country. In the above-mentioned works, the efforts of specialist who are opinion leaders in these topics form different states of the country converge. Likewise, critical points to consider for producing clinical guides are provided mechanisms of diffusion, consultation, feedback and updating of these documents, have already been provided and focus on national medical practice quality of services, and the manner in which to carry out diagnosis and therapy at the different levels of medical care, with emphasis on preventing complications.


Seipin deficiency increases chromocenter fragmentation and disrupts acrosome formation leading to male infertility.
The Berardinelli-Seip congenital lipodystrophy type 2 (Bscl2, seipin) gene is involved in adipogenesis. Bscl2-/- males were infertile but had normal mating behavior. Both Bscl2-/- cauda epididymis sperm count and sperm motility were ~20×less than control. Bscl2-/- seminiferous tubules had relatively normal presence of spermatogonia and spermatocytes but had reduced spermatids and sperm. Spatiotemporal expression analyses in Bscl2+/+ testes demonstrated prominent Bscl2 transcriptional activity in spermatocytes with a plateau reached around postnatal day 28. Seipin protein localization was most abundant in postmeiotic spermatids, suggesting translational repression of Bscl2 mRNA in spermatocytes. In situ end-labeling plus detected increased spermatid apoptosis in Bscl2-/- testis and annexin V detected increased percentage of positive Bscl2-/- round spermatids compared with control. Immunofluorescence of marker proteins synaptonemal complex proteins 3 and 1 (SYCP3 and SYCP1), and H3K9me3 (histone H3 trimethylated at lysine 9) in germ cell spreads detected normal meiotic chromosome pairing and homologous chromosome synapsis in Bscl2-/- spermatocytes, but significantly increased percentages of round spermatids with chromocenter fragmentation and late spermatids and sperm with chromatin vacuoles, indicating defective chromatin condensation in Bscl2-/- spermatids. Bscl2-/- late spermatids were disorganized within the seminiferous epithelium, despite normal appearance of Sertoli cells detected by vimentin immunofluorescence. Peanut agglutinin staining revealed various abnormalities of acrosomes in Bscl2-/- late spermatids, including the absence, irregular-shaped, and fragmented acrosomes, indicating defective acrosome formation in Bscl2-/- late spermatids, which may affect late spermatid orientation in the seminiferous epithelium. Mitotracker strongly stained the midpiece of control sperm but only very weakly labeled the midpiece of Bscl2-/- sperm, indicating defective mitochondrial activity that most likely contributed to reduced Bscl2-/- sperm motility. These data demonstrate novel roles of seipin in spermatid chromatin integrity, acrosome formation, and mitochondrial activity. Increased spermatid apoptosis, increased chromocenter fragmentation, defective chromatin condensation, abnormal acrosome formation, and defective mitochondrial activity contributed to decreased sperm production and defective sperm that resulted in Bscl2-/- male infertility.


Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative syndrome characterized by the systemic loss of motor neurons with prominent astrocytosis and microgliosis in the spinal cord and brain. Astrocytes play an essential role in maintaining extracellular microenvironments that surround motor neurons, and are activated by various insults. Growing evidence points to a non-cell autonomous neurotoxicity caused by chronic and sustained astrocytic activation in patients with neurodegenerative diseases, including ALS. However, the mechanisms that underlie the harmful effects of astrocytosis in patients with ALS remain unresolved. We focused on bone morphogenetic proteins as a major soluble factor that promotes astrocytogenesis and its activation in the adult spinal cord. In a transgenic rat model with ALS-linked mutant Cu/Zn superoxide dismutase gene, BMP4 was progressively up-regulated in reactive astrocytes of the spinal ventral horns, whereas the BMP-antagonist noggin was decreased in association with neuronal degeneration. Continuous intrathecal noggin supplementation after disease onset significantly ameliorated motor dysfunction symptoms, neurogenic muscle atrophy, and extended survival of symptomatic ALS model rats, despite lack of deterrence against neuronal death itself. The exogenous noggin inhibited astrocytic hypertrophy, astrocytogenesis, and neuroinflammation by inactivating both Smad1/5/8 and p38 mitogen-activated protein kinase pathways. Moreover, intrathecal infusion of a Bmp4-targeted antisense oligonucleotides and provided selective Bmp4 knockdown in vivo, which suppressed astrocyte and microglia activation, reproducing the aforementioned results by noggin treatment. Collectively, we clarified the involvement of BMP4 in the processes of excessive gliosis that exacerbate the disease progression of the ALS model rats. Our study demonstrated that BMP4, with its downstream signaling, might be a novel therapeutic target for disease-modifying therapies in ALS.


The Malpighi lecture. Vascular permeability--the consequence of Malpighi's hypothesis.
The permeability of microvessels to water and small hydrophilic solutes varies considerably between different vascular beds and even between individual vessels in the same vascular bed. Provided the tissues are undamaged, the filtering properties of vessel walls to macromolecules are relatively constant and an analysis of the variations in hydraulic conductances and permeabilities to small ions between different endothelia suggests that the channels for hydrophilic molecules are similar in a wide range of vessels. In undamaged tissues, variations in permeability may be accounted for by variations in the frequency of channels per unit area of vessel wall. The permeability of vessel walls to water and small hydrophilic molecules and their ability to sieve macromolecules are consistent with the molecular filter being a lattice of fibrous molecules which covers and fills the channels through the endothelium. Direct and indirect evidence indicate that globular proteins are part of the molecular filter and it is suggested that they bind the fibrous molecules into a more uniform lattice (the fibre matrix) which greatly increases its selectivity. The question of how the contraction of adjacent endothelial cells might widen the intercellular clefts and thus regulate permeability is discussed. Preliminary experiments show that the permeability of frog capillaries can be varied by varying concentrations of Mg2+ (rather than Ca2+) in the presence of the ionophore A23187 and suggest an interesting line of investigation.


Polydispersity of normal human conjunctival mucins.
To isolate all constituent mucins from human conjunctival mucus. Mucins were extracted from human conjunctiva in guanidine hydrochloride and protease inhibitors. The mucins were isolated by density gradient centrifugation, gel filtration, and ion exchange chromatography. Throughout purification, the mucin profile was monitored by agarose electrophoresis and vacuum blotting. Blots were probed for peptide and carbohydrate epitopes. The latter included IE3 and TKH2 specific for Tn and sialyl-Tn, respectively, considered tumor-related antigens. In vivo impression cytology specimens of normal conjunctival goblet cells also were probed with the same reagents. Oligosaccharides were released from isolated mucins by alkaline beta-elimination and then size fractionated. Human conjunctival mucins consist of at least three size populations; the largest is excluded on Sepharose CL2B. The two largest populations are polydisperse. Their overall electrophoretic pattern is conserved between individuals. Similar charge distributions were detected in different buoyant density ranges from the density gradient centrifugation: a less charged population containing three components and a highly charged population with two components on agarose electrophoresis. Cross-reaction with IE3 and TKH2 was detected throughout purification in the largest mucins, which were presumably mature, and in impression cytology. Oligosaccharides from mucins in each buoyant density were largely in the monosaccharide and disaccharide range, consistent with Tn and sialyl-Tn standards. Secreted human conjunctival mucins are polydisperse, with discrete components appearing consistently in pooled and individual samples. They have a unique oligosaccharide pattern containing Tn and sialyl-Tn. This indicates normal roles in normal human ocular mucins for these antigens, which are disease markers in other tissues.


Outbreak of Legionnaires' disease associated with a supermarket mist machine.
An outbreak of Legionnaires' disease affected 12 customers of a supermarket in a town in Catalonia, Spain, between August and November 2006. An epidemiological and environmental investigation was undertaken. Preliminary investigation showed that all patients had visited the same supermarket in this town where a mist machine was found in the fish section. Water samples were collected from the machine and from the supermarket's water distribution system when high-risk samples were excluded. Environmental samples from the mist machine and clinical samples from two patients tested positive for L. pneumophila serogroup 1 and had the same molecular pattern. The PFGE pattern detected in the clinical and mist-machine isolates had never previously been identified in Catalonia prior to the outbreak and has not been identified since. Four days after turning off the machine, new cases ceased appearing. Molecular study supports the hypothesis that the mist machine from the fish section of the supermarket was the source of infection. We believe it is essential to include exposure to mist machines in any legionellosis epidemiological survey.


Multiparametric magnetic resonance imaging for prostate cancer: A review and update for urologists.
Recently, imaging of prostate cancer has greatly advanced since the introduction of multiparametric magnetic resonance imaging (mpMRI). mpMRI consists of T2-weighted sequences combined with several functional sequences including diffusion-weighted imaging, dynamic contrast-enhanced imaging, and/or magnetic resonance spectroscopy imaging. Interest has been growing in mpMRI because no single MRI sequence adequately detects and characterizes prostate cancer. During the last decade, the role of mpMRI has been expanded in prostate cancer detection, staging, and targeting or guiding prostate biopsy. Recently, mpMRI has been used to assess prostate cancer aggressiveness and to identify anteriorly located tumors before and during active surveillance. Moreover, recent studies have reported that mpMRI is a reliable imaging modality for detecting local recurrence after radical prostatectomy or external beam radiation therapy. In this regard, some urologic clinical practice guidelines recommended the use of mpMRI in the diagnosis and management of prostate cancer. Because mpMRI is the evolving reference standard imaging modality for prostate cancer, urologists should acquire cutting-edge knowledge about mpMRI. In this article, we review the literature on the use of mpMRI in urologic practice and provide a brief description of techniques. More specifically, we state the role of mpMRI in prostate biopsy, active surveillance, high-risk prostate cancer, and detection of recurrence after radical prostatectomy.