Prevalence of obesity in korean adolescents and its relationship with the weekly frequency of the physical education classes.
The purpose of this study was to investigate differences in the prevalence of obesity among Korean adolescents and to determine the relationship of obesity prevalence with weekly frequency of physical education (PE) classes. In 2009, 72,399 students from grades 7 to 12 participated in the fifth Korea Youth Risk Behavior Web-based Survey (KYRBWS-V) project. Body mass index (BMI) and the frequency of PE classes attended were assessed by the KYRBWS- V. BMI was computed to classify the participants as underweight, normal weight, overweight, and obese. The association between the frequency of PE classes and BMI were examined using one-way ANOVA and logistic regression analysis. The differences in the weekly frequency of PE classes and the BMI values among both the boys and girls were significant (p < 0.001). A post-hoc test showed that underweight boys and girls attended the PE classes more frequently (p < 0.001), and overweight girls attended these classes less frequently (p < 0.01) than the other groups did; moreover, obese boys and girls, compared to boys and girls in the other groups, attended less number of PE classes per week while at school (p < 0.05). Besides, the odds ratio (95% confidence interval, CI) for normal-weight vs. underweight boys attending 1 PE class, 2 PE classes, and ≥ 3 PE classes per week were 1.168 (1.011-1.349, p = 0.035), 1.621 (1.450-1.812, p < 0.001), and 3.023 (2.704-3.381, p < 0.001), respectively, compared with those for boys who did not attend PE classes. The OR (95% CI) of normal-weight vs. obese boys attending ≥ 3 PE classes attended across normal vs. obese boys was 0.862 (0.762-0.974, p = 0.017), compared with those of boys who did not attend PE classes. The OR (95% CI) for normal-weight vs. underweight girls who attended 2 PE classes and ≥ 3 PE classes per week were 1.235 (1.131-1.349, p < 0.001) and 2.238 (2.048-2.446, p < 0.001), respectively, compared with those of girls who did not attend PE classes. The OR (95% CI) of for normal-weight vs. overweight girls who attended ≥ 3 PE classes per week were 0.886 (0.787- 0.997, p = 0.045) and 0.772 (0.679-0.878, p < 0.001), respectively, compared with those of girls who did not attend PE classes. The OR (95% CI) for normal-weight vs. obese girls who attended 2 PE classes and ≥ 3 PE classes per week were 0.788 (0.675-0.919, p = 0.002) and 0.709 (0.599-0.838, p < 0.001), respectively, compared with those of girls who did not attend the PE class. Increase in the frequency of PE classes should be considered in any attempt for curbing weight-related problems in Korean adolescents. Key pointsIncrease in the frequency of PE classes is a factor that should be considered to improve weight status.


Spouses' physical and psychological symptoms during pregnancy and the postpartum.
This cross-sectional descriptive study investigated the type and frequency of physical and psychological symptoms experienced by pregnant and postpartal women and their spouses. The sample of 70 married couples included 23 pairs in an early pregnancy group, 24 in a late pregnancy group, and 23 in a postpartum group. Both spouses completed a symptoms checklist of 20 physical and 3 psychological symptoms and the Beck Depression Inventory. Findings indicate that both spouses experienced some physical and psychological symptoms during pregnancy and the postpartum, although the women reported many more symptoms than did the men. Women in the late pregnancy group reported the highest number of physical symptoms; those in the postpartum group, the lowest number. No differences, however, in reports of psychological symptoms were found among the three groups of women. No significant differences in reports of either physical or psychological symptoms were found among the three groups of men.


Reproductive-aged women's knowledge and attitudes regarding infant-feeding practices: an experimental evaluation.
Using an experimental design, this study assessed knowledge, attitudes, and intentions regarding infant feeding practices among Canadian female university undergraduates (N = 285). Participants completed a survey of knowledge, attitudes, and intentions with respect to infant-feeding practices. Two versions of the survey were randomly distributed to participants: one containing a photograph of a woman breastfeeding her infant (n = 131) and the other containing a photograph of the same women bottle-feeding her infant (n = 154). Findings indicated that the majority of the sample had been breastfed (84%) and intend to breastfeed their own offspring (97%). The intention to breastfeed future offspring was predicted by knowledge, attitudes, and perceptions of social norms. Participants reported more positive attitudes toward visual depictions of breastfeeding compared with bottle-feeding but less positive views of breastfeeding in public compared with bottle-feeding in public. Participants also significantly underestimated the health benefits and optimal duration of breastfeeding. The findings highlight gaps in knowledge that may contribute to premature cessation of breastfeeding among Canadian women and suggest the need for breastfeeding education.


Association of chronic kidney disease and cerebral small vessel disease with cognitive impairment in elderly patients with type 2 diabetes.
In recent years, the relationship between chronic kidney disease (CKD) and cognitive impairment has been attracting attention. Cerebral small vessel disease (SVD) is also associated with an increased risk of cognitive impairment. However, it is still unknown whether CKD markers are associated with cognitive impairment independently of SVD in elderly diabetic patients. Seventy-nine type 2 diabetic patients (mean age, 76.0 years) were enrolled in the present study. CKD was defined as the presence of albuminuria and/or a low estimated glomerular filtration rate (eGFR <60 ml/min/1.73 m(2)). SVD was evaluated by the presence and severity of silent brain infarcts (SBIs) and white matter lesions (WMLs) on brain magnetic resonance imaging. Neuropsychological tests were assessed using four validated cognitive instruments. In multiple linear regression analyses, albuminuria was associated with worse modified Stroop Color Word scores (β = 0.284, p = 0.017) and low eGFR was associated with reduced Digit Symbol Substitution scores (β = -0.224, p = 0.026) after adjustment for age, sex, education years, diabetes duration, hypertension, multiple SBIs, and advanced WMLs. In contrast, there were no significant associations between CKD markers and Mini-Mental State Examination or Word Recall scores. Our findings suggest that albuminuria and low eGFR are associated with frontal lobe dysfunction independently of SVD in elderly type 2 diabetic patients.


Omicron: A Heavily Mutated SARS-CoV-2 Variant Exhibits Stronger Binding to ACE2 and Potently Escapes Approved COVID-19 Therapeutic Antibodies.
The new SARS-CoV-2 variant of concern "Omicron" was recently spotted in South Africa and spread quickly around the world due to its enhanced transmissibility. The variant became conspicuous as it harbors more than 30 mutations in the Spike protein with 15 mutations in the receptor-binding domain (RBD) alone, potentially dampening the potency of therapeutic antibodies and enhancing the ACE2 binding. More worrying, Omicron infections have been reported in vaccinees in South Africa and Hong Kong, and that post-vaccination sera poorly neutralize the new variant. Here, we investigated the binding strength of Omicron with ACE2 and monoclonal antibodies that are either approved by the FDA for COVID-19 therapy or undergoing phase III clinical trials. Computational mutagenesis and free energy perturbation could confirm that Omicron RBD binds ACE2 ~2.5 times stronger than prototype SARS-CoV-2. Notably, three substitutions, i.e., T478K, Q493K, and Q498R, significantly contribute to the binding energies and almost doubled the electrostatic potential (ELE) of the RBDOmic-ACE2 complex. Omicron also harbors E484A substitution instead of the E484K that helped neutralization escape of Beta, Gamma, and Mu variants. Together, T478K, Q493K, Q498R, and E484A substitutions contribute to a significant drop in the ELE between RBDOmic-mAbs, particularly in etesevimab, bamlanivimab, and CT-p59. AZD1061 showed a slight drop in ELE and sotrovimab that binds a conserved epitope on the RBD; therefore, it could be used as a cocktail therapy in Omicron-driven COVID-19. In conclusion, we suggest that the Spike mutations prudently devised by the virus facilitate the receptor binding, weakening the mAbs binding to escape the immune response.


Strengthening national, regional and global health capacity through the WHO Western Pacific Region's Field Epidemiology Fellowship Programme.
The World Health Organization's (WHO's) Field Epidemiology Fellowship Programme in the Western Pacific Region aims to strengthen countries' capacities for surveillance and risk assessment and build a workforce to tackle public health emergencies. A survey was conducted to assess the on-the-job training experience of the Regional Fellows, evaluate the strengths of the Programme and gain feedback on areas for improvement. Between 25 September and 25 October 2018, an online survey was sent to Regional Fellows who had participated in the Programme between July 2006 and September 2018. The survey was shared with WHO country offices in the Western Pacific Region and directly with graduates of the Programme. Responses were recorded electronically and analysed. A total of 53 former Regional Fellows responded (54% response rate; 53/98). At the time of Programme participation, the Fellows' median age was 35, 62% (33/53) were female and 72% (38/53) were affiliated with a national or subnational health department. Fellows gained experience in event-based surveillance and risk assessment and worked among a diverse group of professionals in various Member States. Altogether, 77% (41/53) of respondents believed that the Programme had helped them move into a better career position with greater responsibility. Ninety-four percent (50/53) would recommend the Programme to their colleagues. Alumni from the Western Pacific Region's Field Epidemiology Fellowship Programme perform key health security roles, particularly within governmental systems, and directly contribute to managing health emergencies in their countries, in the Region and globally. The Programme is building a workforce with surge capacity to ensure that public health events in the Region can be addressed. Furthermore, connections developed through the Programme are helping to develop an alumni network, and enhance communications among Member States and between Member States and WHO.


Fluorescent detection and isolation of DNA variants using stabilized RecA-coated oligonucleotides.
Extract: The information generated by the genome sequencing initiatives is being gathered, cataloged and evaluated. These databases will provide fertile ground for the development of new technologies in the areas of functional genomics and molecular diagnostics. Concurrent use of these data sets, however, presents an ethical dilemma. Genomic sequence data reveals a substantial amount of sequence diversity within a population; therefore, confidentiality must be maintained so that an individual is not exposed to the risk of "genetic" discrimination. In addition, as nucleic acid tests enter this diagnostic arena, the obtaining of a high degree of accurate and reliable data from the assays will become essential for decision making in healthcare. Genotyping methodologies, which aim to identify genetic variants in large populations often rely heavily on the use of PCR to amplify the designated template DNA. By its very nature, PCR requires a denaturation step that produces the substrates for primer annealing and template amplification. In some cases, nucleic acid denaturation and the number of processing steps in the PCR reaction can introduce errors into the template, mistakes that are then amplified logarithmically creating a sequence bias. In addition, specimen handling of PCR samples and/or products provides the basis for a certain degree of user contamination. Considering the importance of producing exact genotypic IDs for individuals and its real life implications, new techniques that reduce the potential for mistakes at any stage of the processes resulting in data for analysis should be pursued vigorously.


Environmental and sensitization variations among asthma and/or rhinitis patients between 2008 and 2018 in China.
Little is known about the changes in allergen sensitization in China secondary to the environmental variations over the past decade. We aimed at investigating the variations in sensitization among asthma and/or rhinitis patients in China between 2008 and 2018. This study analyzed cross-sectional data from national surveys conducted in China in 2008 and 2018. After finishing the questionnaire, participants underwent serum specific IgE measurements. A total of 2322 and 2798 patients were enrolled in 2008 and 2018, respectively. The significance of differences in sensitization rates among four regions of China were assessed. Correlation analysis was used to identify the associations of sensitization with climate change and planting of Artemisia desertorum between the two surveys. Compared with 2008, the general sensitization rate to mites significantly increased in 2018, which ranked highest among all tested allergens. Sensitization to pollens, especially Artemisia vulgaris, showed the greatest increase in the north. The annual mean temperature, rainfall and relative humidity in all four regions, and the Artemisia desertorum coverage in the northeastern area, increased significantly in 2018 as compared with 2008. From 2008 to 2018, an increase in Dermatophagoides pteronyssinus sensitization was significantly associated with an increase in relative humidity (r = 0.54, p = 0.037). The increase in A. vulgaris sensitization was significantly associated with the increase in the A. desertorum planting area (r = 0.67, p = 0.006) and with a decrease in rainfall (r = -0.59, p = 0.021). House dust mites remain the most important allergen in Chinese individuals with asthma and/or rhinitis. Pollen sensitization dramatically increased in northern China. Increases in sensitization to dust mites and Artemisia were related to the increases in humidity and planting area of A. desertorum.


[Traumatic thrombosis of the internal carotid artery].
Two cases of post-traumatic thrombosis of the internal carotid artery are presented, which are of interest because of their relative rarity. A detailed understanding of the pathogenesis and variety of clinical presentations, an adequate appraisal of the diverse proposed treatments, and an improvement in the prognosis, which is poor even in young patients-these await further enquiry and research.


The National Library of Medicine and interlibrary loan.
The National Library of Medicine was a pioneer in the development of the interlibrary loan system. In 1957, the Library instituted the policy of combining loan and photocopy which it follows to this day. There has been a steady rise in the demand for photocopies from the NLM; hence, the advantage of making fuller use of local resources before approaching NLM is stressed. The criteria the Library observes to strike a balance between the national public interest expressed in the Library's statutory mission, and private interests protected by the Copyright Act, are described; but NLM will always be obliged to provide materials difficult to obtain elsewhere. Developing programs under the Medical Library Assistance Act should have considerable impact on the local availability of medical library resources.


Efficacy of Endoscopic Interventions for the Management of Obesity: a Meta-analysis to Compare Endoscopic Sleeve Gastroplasty, AspireAssist, and Primary Obesity Surgery Endolumenal.
Novel endoscopic procedures (endoscopic sleeve gastroplasty (ESG), AspireAssist (AA), and primary obesity surgery endolumenal (POSE)) have been developed for treatment of obesity. We aimed to conduct a systematic review and meta-analysis to evaluate and compare the efficacy of these three endoscopic procedures. Main outcomes of interest were percent excess weight loss (%EWL) and percent total body weight loss (%TBWL). Weighted pooled means (WPMs) were calculated and analyzed using random effects model. Mean differences (MDs) were calculated to compare these procedures. Twelve studies with 1149 patients were included. WPMs for %EWL at 6 and 12 months with ESG were 49.67 (45.67, 53.66) and 52.75 (43.52, 61.98), respectively, while %TBWLs at 6 and 12 months with ESG were 16.01 (15.10, 16.92) and 17.41 (17.08, 17.74), respectively. WPMs for %EWL at 6 and 12 months with POSE were 43.79 (40.17, 47.42) and 44.91 (40.90, 48.92), respectively. WPM for %EWL at 12 months with AA was 50.85 (46.03, 55.68). While comparing ESG and POSE, at 6 months and 12 months, MD for %EWL was 6.17 (1.07, 11.26; P = 0.01) and 7.84 (- 2.05, 17.71; P = 0.06) in favor of ESG. No difference in %EWL was observed while comparing ESG with AA (P = 0.29). Likewise, MD for %EWL to compare AA and POSE was not significant (P = 0.68). During a follow-up of 6-12 months, both AA and ESG had excellent efficacy in achieving significant and sustained weight loss; however, ESG was found to be superior in terms of weight loss when compared with POSE.


Comparison between operative findings on malignant glioma by a fluorescein surgical microscopy and histological findings.
Using a fluorescein surgical microscope that we developed, we performed surgery on 30 cases of malignant glioma. Operative findings and histological findings were then compared in five of these cases. Fluorescein sodium was systemically administered intravenously as a fluorescent dye. About 20 min after intravenous administration, fluorescein activity in the blood decreased, and the fluorescence was observed only in the area lacking the blood-brain barrier function, such as tumors; then, resection of the tumor was started. The fluorescent regions coincided with the enhanced regions on CT and MRI. Fluorescein spread to the surrounding brain edematous region with time, but its intensity was very different from the tumor-associated one. In the histological examination of intensely fluorescent regions, abnormal tumor blood vessels with a thick wall and a small caliber, or with a thin wall and a large caliber, were observed. Dense tumor cells were found in these regions. On the other hand, in regions with weak or no fluorescence, infiltration of tumor cells was scant, and no abnormal blood vessels were found. Fluorescence was not observed in necrotic regions of the tumor center. These histological findings coincided with those obtained in large surgical specimen or autopsy, and tumor-cell rich regions seemed to be removed by resecting abnormal vascular regions (fluorescent regions). Enhanced regions on CT and MRI disappeared after operation by resecting intensely fluorescent regions. These results indicate that the fluorescein surgical microscope developed by us is a useful aid in operations on malignant glioma.


Structural characterization of lipid membranes from clear and cataractous human lenses.
Lipid composition related structural changes in human cataractous lenses was explored by characterizing the hydrophobic hydrocarbon chains in lipid membranes corresponding to twelve Indian cataractous lenses and eight American clear lenses of similar age. The nuclear-lipid phase transitions corresponding to the clear lenses exhibited significantly higher average transition temperatures (nucleus 33 degrees C, cortex 26.3 degrees C) and cooperativities, 38.1, as compared to the value of 24.1 for the cortical-lipid phase transitions. At 36 degrees C, the phase transitions corresponding to cortical and nuclear lipids indicate a similar degree of disorder, 63%, in the hydrocarbon chains, i.e., similar relative amounts of gauche and trans rotomers. The twelve cataractous lenses investigated all had nuclear opacities, four were brunescent and four had cortical opacities. No significant differences were observed in the phase transition parameters (temperature, cooperativity, magnitude, enthalpy) evaluated for the nuclear-lipid membranes corresponding to the different types of cataracts. Furthermore, for the cataractous membranes, the phase transition parameters obtained for the nuclear lipids were comparable to those evaluated for the cortical lipid membranes. However, the cortical lipids exhibited the highest order in membranes from nuclear cataracts without cortical opacity. The cortical lipids from clear, non-cataractous lenses had the lowest level of order. At 36 degrees C, the degree of order in the cortical lipid from clear lenses was comparable to that from nuclear cataractous lenses without cortical opacity. The transition temperature, and cooperativity were significantly higher for cortical lipids from cataractous lenses as compared to those from clear lenses. At 36 degrees C, the degree of order in the cortical lipid membranes was lower for all cataract types vs. clear lens fractions. Our results suggest the possibility that lipid-lipid interactions could be different in cataractous lens membranes. Lipid compositional and chemical differences must account for these altered lipid interactions. These studies will provide a basis for studying lipid-protein interactions and structure-function relationships in the lens membrane.


Trypanosomatids Associated in the Alimentary Canal of Bagrada hilaris (Hemiptera: Pentatomidae).
Bagrada hilaris (Burmeister) is an invasive pest of economically important crops in the United States. During physiological investigations of B. hilaris, a flagellated protozoan was discovered in the alimentary canal of many specimens. This manuscript characterizes the morphology and molecular identification of the trypanosomatid, which appears similar to trypanosomatids identified in other stink bug species. It has been identified as a species in the Blastocrithidia genus based on morphological characteristics and molecular analyses.


A natural S-equol supplement alleviates hot flushes and other menopausal symptoms in equol nonproducing postmenopausal Japanese women.
The objective of this clinical trial was to examine the efficacy of a supplement containing natural S-(-)equol, a daidzein metabolite, in reducing menopausal symptoms. In this multicenter, double-blind placebo-controlled trial, 160 equol nonproducing, postmenopausal Japanese women who experienced at least 1 hot flush/day were randomly assigned to consume 10 mg/day S-(-)equol (n=77 women) or placebo (n=83 women) for 12 weeks. Participants completed a standardized menopausal symptom checklist and rated five common menopause symptoms by a visual analog scale at baseline, week 12, and week 18 (6-week postintervention). Physical, blood, and urine examinations were conducted. One hundred twenty-six women completed the study. At baseline, daily hot flush frequency was 2.9±2.1 for the S-(-)equol group and 3.2±2.4 for the placebo group. After the 12-week intervention, the S-(-)equol group had a greater decrease from baseline in hot flush frequency compared with the placebo group (-1.9±1.8/day, -58.7%, vs. -1.0±2.0/day, -34.5%, p=0.009). The severity of hot flushes and neck or shoulder muscle stiffness significantly decreased in the S-(-)equol group compared with the placebo group. No changes in clinical parameters or serious adverse effects were reported. This is the first trial to show beneficial effects of a 10-mg natural S-(-)equol supplement consumed daily for 12 weeks on major menopausal symptoms, specifically, hot flushes and neck or shoulder muscle stiffness, in postmenopausal Japanese women. This supplement offers a promising alternative for management of menopausal symptoms.


The Protective Effect of Sulodexide on Acute Lung Injury Induced by a Murine Model of Obstructive Jaundice.
The effect of sulodexide (SLX) on obstructive jaundice- (OJ-) induced acute lung injury (ALI) in rats was examined in this study. In this study, 48 rats were randomly assigned to one of six groups: sham, OJ, OJ+saline, OJ+SLX (0.5 mg/ml/d), OJ+SLX (1 mg/ml/d), and OJ+SLX (2 mg/ml/d). The pathological lung injury was assessed by histological analysis and lung injury grading. ELISA kits were used to evaluate the expression of IL-6, IL-1, TNF-α, and syndecan-1 (SDC-1) in bronchoalveolar lavage fluids (BALFs). Commercial assay kits were performed to evaluate malondialdehyde (MDA) production and catalase (CAT) activity in lung tissues. The apoptosis was assessed by TUNEL assay. The lung microvascular permeability was investigated using Evans blue leakage, lung wet/dry weight (W/D) ratio, and lung permeability index (LPI). SDC-1, claudin-5, ZO-1, and VE cadherin expression levels in lung tissues were measured using Western blot. The OJ-induced ALI rats showed severe lung injury. The value of IL-6, IL-1β, TNF-α, and SDC-1 in BALFs was remarkedly increased in the OJ group. MDA content, apoptotic area, apoptotic molecules, and SDC-1 level were all higher in the OJ group's lung tissues than in the sham group. CAT activity, Evans blue leakage, W/D ratio, LPI, and expression of claudin-5, ZO-1, and VE cadherin were all lower in the OJ group compared to the sham group. The degenerative alterations in lung tissue improved after 7 days of treatment with 2 mg/ml SLX. The BALFs had lower amounts of IL-6, IL-1, TNF-α, and SDC-1. The SLX therapy reduced MDA levels while restoring CAT activity. In lung tissues, SLX reduced apoptotic area and SDC-1 expression. SLX reduced lung microvascular permeability by raising the expression of Claudin-5, ZO-1, and VE-cadherin in lung tissue when compared to the OJ group. The results suggested that SLX attenuates OJ-induced ALI in rats by protecting the pulmonary microvascular endothelial barrier.


Usefulness of a Simple Immunohistochemical Staining Technique to Differentiate Anti-p200 Pemphigoid From Other Autoimmune Blistering Diseases: A Report of 2 Cases.
Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease characterized by the presence of circulating immunoglobulin G antibodies directed against laminin gamma-1, a 200-kDa protein located in the lamina lucida of the basement membrane. We review the clinical, histopathological and immunological characteristics of the first 2 cases described in Spain. Anti-p200 pemphigoid shares histopathological and immunopathological findings with epidermolysis bullosa acquisita, the main entity in the differential diagnosis. However, its management follows the same guidelines as those used for bullous pemphigoid. The diagnosis is confirmed by immunoblotting, which is a complex technique available in few centers. We propose the immunohistochemical detection of collagen type IV on the floor of the blister, combined with standard immunofluorescence techniques, as a simple, accessible alternative to differentiate anti-p200 pemphigoid from epidermolysis bullosa acquisita.


Study of referral pattern to ophthalmology outpatient department from various departments in the medical college.
The study was aimed at finding out the pattern of referrals to ophthalmology outpatient department (OPD) in a teaching hospital and to provide guidelines for the improvement. Patients referred from various departments of a medical college situated in central India for ophthalmic evaluation were scrutinised for age, sex, diagnosis and the referring OPD. Out of 730 patients referred, 350 (47.95%) were males and 380 (52.02%) were females. The highest referral was found in the age group 45-64 years (22.60%). The highest referral was from the medicine OPD (58.22%) and the lowest was from psychiatry (2.05%). Maximum patients were referred for fundus examination (27.40%). While there were 280 patients (38.36%) who had refractive error, no diagnosis was established in 147 cases (20.14%). Ophthalmic opinion definitely helped patients as well as physician in the management of the patients. The study also stresses on some areas deficient, when unnecessary referrals could be avoided by arranging short annual refreshers courses to acquire basic skills in ophthalmology like visual acuity testing, colour vision, ophthalmoscopy and the diagnosis of common ocular conditions. We believe this kind of activity will help to make our services more efficient and cost effective.


Microbial Growth in Surimi and Mince made from Atlantic Pollock.
Surimi preparation from minced Atlantic pollock decreased protein, fat, and NaCl levels and increased moisture and carbohydrate levels of the mince. Aerobic plate counts and psychrotrophic counts of samples from three trials stored at 5 and 13°C were initially similar, but reached higher levels in surimi with time. The pH of surimi tended to decrease relative to that of mince during storage at both temperatures. Careful handling and storage are equally important for both products if micro-biological quality is to be maintained.


Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans.
"On-target off-tumor" toxicity is a major challenge to the use of chimeric antigen receptor (CAR)-engineered T cells in the treatment of solid malignancies, because of the expression of target antigens in normal tissues. Mesothelin overexpression is associated with poor prognosis of multiple solid tumors, and would therefore appear to be a suitable antigen target. To understand the risk of toxicity to different organs on anti-mesothelin CAR T cell therapy, single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems were analyzed in this study, including the respiratory, cardiovascular, digestive, and urinary systems. According to scRNA-seq datasets, the organs were stratified into high or low risk based on the level of mesothelin expression. We report that the proportion of mesothelin-positive cells was 7.71%, 2.40% and 2.20% of myocardial cells, pulmonary cells and stomach cells, respectively, indicating that these organs could be at high risk of "on-target off-tumor" toxicity on anti-mesothelin CAR T cell therapy. By contrast, esophagus, ileum, liver, kidney and bladder exhibited low mesothelin expression (<1%). Therefore, these organs could be regarded as at low risk. Thus, the risk of toxicity to different organs and tissues in anti-mesothelin CAR T cell therapy may be predicted by these scRNA-seq data.


Mildly oxidized low-density lipoprotein acts synergistically with angiotensin II in inducing vascular smooth muscle cell proliferation.
Considerable attention has been focused on both mildly oxidized low-density lipoprotein (mox-LDL) and highly oxidized LDL (ox-LDL) as important risk factors for cardiovascular disease. Further, angiotensin II (Ang II) appears to play a crucial role in the development of hypertension and atherosclerosis. We assessed the effect of oxidatively modified LDL and its major oxidative components, i.e., hydrogen peroxide (H2O2), lysophosphatidylcholine (LPC), and 4-hydroxy-2-nonenal (HNE) and their interaction with Ang II on vascular smooth muscle cell (VSMC) DNA synthesis. Growth-arrested rabbit VSMCs were incubated in serum-free medium with different concentrations of native LDL, mox-LDL, ox-LDL, H2O2, LPC, or HNE with or without Ang II. DNA synthesis in VSMCs was measured by [3H]thymidine incorporation. Ang II stimulated DNA synthesis in a dose-dependent manner with a maximal effect at a concentration of 1 micromol/l (173%). Ang II (0.5 micromol/l) amplified the effect of native LDL at 500 ng/ml, ox-LDL at 100 ng/ml, and mox-LDL at 50 ng/ml on DNA synthesis (108 to 234%, 124 to 399%, 129 to 433%, respectively). H2O2 had a maximal effect at a concentration of 5 micromol/l (177%), LPC at 15 micromol/l (156%), and HNE at 0.5 micromol/l (137%). Low concentrations of H2O2 (1 micromol/l), LPC (5 micromol/l), or HNE (0.1 micromol/l) also acted synergisitically with Ang II (0.5 micromol/l) in inducing DNA synthesis to 308, 304, or 238%, respectively. Synergistic interactions of Ang II (0.5 micromol/l) with mox-LDL, ox-LDL (both 50 ng/ml), H2O2 (1 micromol/l), LPC (5 micromol/l), or HNE (0.1 micromol/l) on DNA synthesis were completely reversed by the combined use of probucol (10 micromol/l), a potent antioxidant and candesartan (0.1 micromol/l), an AT1 receptor antagonist. Our results suggest that mox-LDL, ox-LDL, and their major components H2O2, LPC, and HNE act synergistically with Ang II in inducing VSMC DNA synthesis. A combination of antioxidants with AT1 receptor blockade may be effective in the treatment of VSMC proliferative disorders associated with hypertension and atherosclerosis.


GTP-cyclohydrolase I gene mutations in hereditary progressive amd dopa-responsive dystonia.
Recently, mutations of the GTP-cyclohydrolase I (GTP-CH I) gene, which catalyzes the first step in the tetrahydrobiopterin (BH4) biosynthesis, were discovered in Japanese patients with hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD). However, it has not been confirmed that non-Japanese patients also contain mutations in the same gene, or whether these mutations are specific to HPD/DRD. In this study, two novel nonsense mutations in exon I of the GTP-CH I gene and a new mutation at the splice acceptor site of intron I were identified in an autopsied case of English-Irish descent and 2 Japanese patients with HPD/DRD. In the latter, cerebrospinal fluid (CSF) neopterin levels (which may reflect the GTP-CH I activity in the brain) were reduced to 18% and 37% of controls. A therapeutic trial of oral BH4 was ineffective, however, in a genetically proven patient. In contrast, no mutations in any exons of the GTP-CH I gene were found in 2 patients with early-onset parkinsonism with dystonia (EOP-D) who developed dopa-responsive parkinsonism and dystonia at 6 and 8 years old, respectively. Neopterin levels in CSF were well preserved in 6 EOP-D patients. These data suggest that, among patients of different racial backgrounds, the pathogenesis of HPD/DRD, unlike EOP-D, involves partial reduction of the brain GTP-CH I activity consequent to mutations in the GTP-CH I gene. Measurement of CSF neopterin concentration may be useful for the differential diagnosis between HPD/DRD and EOP-D.


Decomposition of socioeconomic inequalities in child vaccination in Ethiopia: results from the 2011 and 2016 demographic and health surveys.
Monitoring and addressing unnecessary and avoidable differences in child vaccination is a critical global concern. This study aimed to assess socioeconomic inequalities in basic vaccination coverage among children aged 12-23 months in Ethiopia. Secondary analyses of cross-sectional data from the two most recent (2011 and 2016) Ethiopia Demographic and Health Surveys were performed. This analysis included 1930 mother-child pairs in 2011 and 2004 mother-child pairs in 2016. Completion of basic vaccinations was defined based on whether a child received a single dose of Bacille Calmette-Guerin (BCG), three doses of diphtheria, tetanus toxoids and pertussis (DTP), three doses of oral polio vaccine and one dose of measles vaccine. The concentration Curve and Concentration Indices (CCIs) were used to estimate wealth related to inequalities. The concentration indices were also decomposed to examine the contributing factors to socioeconomic inequalities in childhood vaccination. From 2011 to 2016, the proportion of children who received basic vaccination increased from 24.6% (95% CI 21.4% to 28.0%) to 38.6% (95% CI 34.6% to 42.9%). While coverage of BCG, DTP and polio immunisation increased during the study period, the uptake of measles vaccine decreased. The positive concentration index shows that basic vaccination coverage was pro-rich (CCI=0.212 in 2011 and CCI=0.172 in 2016). The decomposition analysis shows that use of maternal health services such as family planning and antenatal care, socioeconomic status, exposure to media, urban-rural residence and maternal education explain inequalities in basic vaccination coverage in Ethiopia. Childhood vaccination coverage was low in Ethiopia. Vaccination was less likely in poorer than in richer households. Addressing wealth inequalities, enhancing education and improving maternal health service coverage will reduce socioeconomic inequalities in basic vaccination uptake in Ethiopia.


[MiR-486 Regulates the Glycometabolism of Hematopoietic Cells by Targeting Sirt1].
To investigate the effect and mechanism of miR-486 on glycometabolism of hematopoietic cells. qRT-PCR was applied to detect the expression of miR-486 or Sirt1 on TF-1 cells under hypoxia. Lentivirus was used to mediate the overexpression or inhibition of miR-486 on TF-1 cells and qRT-PCR was used to detect the expressions of Sirt1, glucose transporter 1(Glut1) and glucose transporter 4(Glut4). Lentivirus-mediated Sirt1-shRNA transduction was used to knockdown Sirt1 expression which was detected by qRT-PCR and Western blot. The expressions of Glut1 and Glut4 were determined by qRT-PCR. Hypoxia promoted the expression of miR-486 and inhibited the expression of Sirt1. MiR-486 overexpression could inhibit the expression of Sirt1 and promote the expressions of Glut1 and Glut4, whereas miR-486 silencing upregulated the sirt1 expression and inhibited the expressions of Glut1 and Glut4. And inhibition of Sirt1 expression increased the expressions of Glut1 and Glut4. MiR-486 can regulate the glycometabolism of hematopoietic cells by targeting Sirt1.


[Screening of Serum Peptidome-Based Biomarker for Multiple Myeloma Renal Impairment].
To screen serum peptide associated with renal impairment in patients with multiple myeloma(MM) and search early biomarker of MM renal impairment. The weak cation exchange magnetic bead combined with matrix assisted laser desorption/ionization time of flight mass spectrometry was used to compare and analyze serum peptidome of MM with or without renal impairment. There were 18 peptide peaks with statistical significance in the molecular weight range from 700 to 10 000 Da(P<0.05), among them 7 peptides were upregulated and 11 were downregulated. The Quick Classifier diagnostic model composed of 3 peptides, which can strongly distinguish MM patients with or without renal impairment by means of Embedded Software. Its sensitivity and specificity were 97.14% and 94.12%, respectively. Peptides with molecular weight of 3908.85 Da and 3216.06 Da were significantly upregulated in MM patients with renal impairment, while the peptide with molecular weight of 2990.08 Da was significantly downregulated in MM patients with renal impairment. Peptides associated with MM renal impairment obtained by serum peptidome technology can provide a new clue for early assessment and diagnosis of clinical MM renal impairment.


HOXA11 silencing and endogenous HOXA11 antisense ribonucleic acid in the uterine endometrium.
Hoxa11 is an essential regulator of embryonic uterine development and the cyclic development of the adult uterine endometrium. Hoxa11 is required for female fertility, as evidenced by targeted mutation. Here we demonstrate a naturally occurring Hoxa11 (mouse)/HOXA11 (human) antisense transcript present in the adult mouse and human endometrium. HOXA11 antisense transcript levels varied during the menstrual cycle, with peak antisense RNA levels occurring in the midproliferative phase, varying inversely with mRNA expression levels. HOXA11 protein levels correlated temporally with peak mRNA levels. In primary stromal cell culture, progesterone down-regulated HOXA11 antisense transcription, and this was followed by up-regulation of HOXA11 mRNA, suggesting a possible role for the antisense transcript in regulating mRNA expression. Attempts to block Hoxa11 function by transfection of the murine uterus with Hoxa11 antisense oligonucleotides failed to interrupt normal uterine function, suggesting that Hoxa11 antisense does not regulate Hoxa11 mRNA by formulation of sense/antisense duplexes. We propose that HOXA11 antisense functions by transcriptional interference, repressing HOXA11 expression by competing for transcription of the common gene, rather than by sense/antisense interaction.


Effectiveness of mitomycin C in reducing reformation of adhesions following surgery for restrictive strabismus.
To evaluate the efficacy of mitomycin C in reducing reformation of adhesions following surgery for restrictive strabismus. Sixteen patients with restrictive strabismus resulting from trauma, retinal detachment surgery, and multiple squint surgeries were randomized to either a mitomycin group (8 patients) or a control group (8 patients). Mitomycin C (0.2 mg/mL) was applied intraoperatively for 5 minutes after release of adhesions. Range of passive ductions was scored for comparison. Postoperative follow-up ranged from 3-18 months. Compared to controls, the mitomycin C group had better range of passive ductions. There were no complications related to the cornea, intraocular pressure, uveitis, or muscle disinsertion in the mitomycin C group. Intraoperative application of mitomycin C (0.2 mg/mL for 5 minutes) is a safe and effective adjunct to surgery in the treatment of restrictive strabismus.


Changing mesophilic wastewater sludge digestion into thermophilic operation at Terminal Island Treatment Plant.
This paper describes the progress up to June 2000 for thermophilic digestion of wastewater sludge at the Los Angeles, California, Bureau of Sanitation's Terminal Island Treatment Plant. The development of the microorganism culture has followed a course similar to that seen at other successful plants for establishment of a stable, well-balanced thermophilic culture in a large digester, but at an accelerated pace. This study began with rapid heating, increasing the temperature of the 4500 m3 (1.2 mil. gal) digester to the target temperature of 55 degrees C at approximately 3 degrees C/d. A method of feeding to maximize the rate of culture development was used as feeding accelerated to approximately 400 m3/d (0.1 mgd). An initial rise of acid concentration (primarily acetate) was seen. Within two weeks, acid concentration declined and stabilized, indicating that acidogenic and methanogenic microbial communities came into balance. Coliform data indicate that digester disinfection was stably effective from the middle of April. The salmonella tests done to date satisfy the U.S. Environmental Protection Agency (U.S. EPA) class A specification. Testing with helminth ova and enteric viruses before and after the digester shows satisfaction of class A standard for those organisms. The present combination of low volatile fatty acids and low hydrogen sulfide is good news for odor control. The data show increases in volatile solids destruction and estimated gas production, compared with the previous mesophilic operation; however, large uncertainties have been calculated from the data. As the digester is now operating successfully at the current feed rate, there seems to be no barriers to processing the entire sludge production of the plant. Other results indicate that the U.S. EPA requirements for exceptional quality class A biosolids are likely to be achieved.


The Role of Oxidative Stress in Intervertebral Disc Degeneration.
Intervertebral disc degeneration is a very common type of degenerative disease causing severe socioeconomic impact, as well as a major cause of discogenic low back pain and herniated discs, placing a heavy burden on patients and the clinicians who treat them. IDD is known to be associating with a complex process involving in extracellular matrix and cellular damage, and in recent years, there is increasing evidence that oxidative stress is an important activation mechanism of IDD and that reactive oxygen and reactive nitrogen species regulate matrix metabolism, proinflammatory phenotype, autophagy and senescence in intervertebral disc cells, apoptosis, autophagy, and senescence. Despite the tremendous efforts of researchers within the field of IDD pathogenesis, the proven strategies to prevent and treat this disease are still very limited. Up to now, several antioxidants have been proved to be effective for alleviating IDD. In this article, we discussed that oxidative stress accelerates disc degeneration by influencing aging, inflammation, autophagy, and DNA methylation, and summarize some antioxidant therapeutic measures for IDD, indicating that antioxidant therapy for disc degeneration holds excellent promise.


Mecp2 regulates tnfa during zebrafish embryonic development and acute inflammation.
Mutations in MECP2 cause Rett syndrome, a severe neurological disorder with autism-like features. Duplication of MECP2 also causes severe neuropathology. Both diseases display immunological abnormalities that suggest a role for MECP2 in controlling immune and inflammatory responses. Here, we used mecp2-null zebrafish to study the potential function of Mecp2 as an immunological regulator. Mecp2 deficiency resulted in an increase in neutrophil infiltration and upregulated expression of the pro- and anti-inflammatory cytokines Il1b and Il10 as a secondary response to disturbances in tissue homeostasis. By contrast, expression of the proinflammatory cytokine tumor necrosis factor alpha (Tnfa) was consistently downregulated in mecp2-null animals during development, representing the earliest developmental phenotype described for MECP2 deficiency to date. Expression of tnfa was unresponsive to inflammatory stimulation, and was partially restored by re-expression of functional mecp2 Thus, Mecp2 is required for tnfa expression during zebrafish development and inflammation. Finally, RNA sequencing of mecp2-null embryos revealed dysregulated processes predictive for Rett syndrome phenotypes.


Promoting Effects of Streptozotocin-induced Diabetes on Induction of Hepatic Preneoplastic Lesions by Diethylnitrosamine in Rats.
The effects of streptozotocin (STZ)-induced diabetes on induction of hepatic preneoplastic lesions by diethylnitrosamine (DEN) were investigated in male Fischer rats. A single dose of STZ was injected intravenously either 2 weeks before or after initiation with DEN. The blood glucose levels were significantly elevated from 1 week after STZ-injection until autopsy. The numbers of GST-P positive foci at 1 week after DEN administration in the STZ-injected rats were similar to those in the non-diabetic rats. In contrast, both the numbers and areas of GST-P positive foci > 2 mm in diameter 8 weeks after DEN administration were increased significantly in the rats treated with STZ after DEN exposure compared with the non-diabetic control rats. The results suggest that hepatic preneoplastic lesions initiated with DEN are promoted by STZ treatment-inducing diabetes.


Neurosecretory cells in Diptera.
The neurosecretory cells were studied in 20 dipteran species belonging to three suborders. The NSC are localized in (a) the frontal ganglion (in 10 of the 20 species studied), (b) the pars intercerebralis region of the protocerebrum (in the median and lateral groups), (c) the tritocerebral region of the brain (in 8 of the 20 species studied) and (d) the suboesophageal ganglion. In one species, NSC were also seen in the prothoracic ganglion. The NSC were classified as types A, B and C/D. The NSC of the median group of the pars intercerebralis were unusually large compared with the size of the brain. The number, size and distribution of the cells are discussed.


[Uptake of radioactive precursors for the evaluation of sensitivity of anticancer drugs against cancer cells].
An in vitro drug sensitivity test was developed to estimate the lethal effects of drugs on cancer cells. Cancer cells we incubated in the presence of radioactive precursors and anticancer drugs. The drug effects were estimated from the changes in rates of incorporation of precursors into DNA, RNA, and protein. Handling of a large number of samples became possible using a microtiter plate and a multiple automatic cell harvester. Incorporation of radioactive precursor showed linear correlation with drug-induced lethality. The results of this test were also correlated well with in vivo regression of tumors of mice. This test appeared to be more reliable than other similar test of cell lethality in vitro. For utilization in clinical studies, a test plate was simplified and 25 human cancers were tested. The results demonstrated the generally good correlation between in vitro and in vivo tumor sensitivities.


Circasemidian sleep propensity and the phase-amplitude maintenance model of human sleep/wake regulation.
Evidence for circasemidian sleep/wake regulation is briefly reviewed with respect to protocols used to quantify sleep propensity. Existing models of sleep/wake regulation are examined in view of their ability to accommodate data which demonstrate an afternoon sleep period. Finally, a modelling approach is briefly outlined which emphasizes the maintenance of the phase and amplitude characteristics of the circadian rhythm of body (and brain) temperature and predicts the circasemidian phenomena.


Instability of succinate dehydrogenase in SDHD polymorphism connects reactive oxygen species production to nuclear and mitochondrial genomic mutations in yeast.
Mitochondrial succinate dehydrogenase (SDH) is an essential complex of the electron transport chain and tricarboxylic acid cycle. Mutations in the human SDH subunit D frequently lead to paraganglioma (PGL), but the mechanistic consequences of the majority of SDHD polymorphisms have yet to be unraveled. In addition to the originally discovered yeast SDHD subunit Sdh4, a conserved homolog, Shh4, has recently been identified in budding yeast. To assess the pathogenic significance of SDHD mutations in PGL patients, we performed functional studies in yeast. SDHD protein expression was reduced in SDHD-related carotid body tumor tissues. A BLAST search of SDHD to the yeast protein database revealed a novel protein, Shh4, that may have a function similar to human SDHD and yeast Sdh4. The missense SDHD mutations identified in PGL patients were created in Sdh4 and Shh4, and, surprisingly, a severe respiratory incompetence and reduced expression of the mutant protein was observed in the sdh4Δ strain expressing shh4. Although shh4Δ cells showed no respiratory-deficient phenotypes, deletion of SHH4 in sdh4Δ cells further abolished mitochondrial function. Remarkably, sdh4Δ shh4Δ strains exhibited increased reactive oxygen species (ROS) production, nuclear DNA instability, mtDNA mutability, and decreased chronological lifespan. SDHD mutations are associated with protein and nuclear and mitochondrial genomic instability and increase ROS production in our yeast model. These findings reinforce our understanding of the mechanisms underlying PGL tumorigenesis and point to the yeast Shh4 as a good model to investigate the possible pathogenic relevance of SDHD in PGL polymorphisms.


Acoustic streaming in two-dimensional freely suspended smectic liquid crystal films.
We study horizontal streaming excited by means of a low-frequency and low-intensity acoustic wave in 2D freely suspended films of thermotropic smectic liquid crystals. Acoustic pressure induces fast periodic transverse oscillations of the film, which produce in-plane stationary couples of vortices slowly rotating in opposite directions owing to hydrodynamic nonlinearity. The parameters of the vortices are measured using a new method, based on tracking solidlike disk-shaped islands. The horizontal motion occurs only when the amplitude of the acoustic pressure exceeds the threshold value, which can be explained by Bingham-like behavior of the smectic film. The measurements above threshold are in good agreement with existing theoretical predictions. We demonstrate experimentally that in-plane flow is well controlled by changing the acoustic pressure, excitation frequency, and geometry of the film. The observations open the way to using the phenomenon in nondisplay applications.


Effects of permissive hypercapnia on transient global cerebral ischemia-reperfusion injury in rats.
Permissive hypercapnia is a widely practiced protective ventilatory strategy that has significant protective effects on several models of in vitro and in vivo neuronal injury. However, conclusive effects of permissive hypercapnia on cerebral ischemia are still unknown. One hundred sixty male Wistar rats were divided into five groups: S group (control), ischemia-reperfusion (I/R) group, P1 group, P2 group, and P3 group. I/R was induced by bilateral occlusion of the common carotid arteries, combined with controlled hypotension for 15 min. In groups P1, P2, and P3, the rats inhaled carbon dioxide for 2 h during reperfusion to keep Paco2 within the ranges of 60-80 mmHg, 80-100 mmHg, and 100-120 mmHg, respectively. After 24 and 72 h, neurologic deficit scores, ultrastructural changes, apoptotic neurons, and brain wet-to-dry weight ratios were observed. Caspase-3 and aquaporin-4 protein expression and caspase-3 activity were analyzed. Compared with groups I/R and P3, groups P1 and P2 had better neurologic deficit scores and fewer ultrastructural histopathologic changes. I/R-induced cerebral apoptosis was also significantly reduced. The neuroprotective effect was significantly increased in the P2 group compared with the P1 group. There was a significant increase of brain water content and of aquaporin-4 levels in the P3 group. Mild to moderate hypercapnia (Paco2 60-100 mmHg) is neuroprotective after transient global cerebral I/R injury. Such a protection might be associated with apoptosis-regulating proteins. In contrast, severe hypercapnia (Paco2 100-120 mmHg) increased brain injury, which may be caused by increased brain edema.


Mesenchymal Stromal Cell Secretome: Immunomodulation, Tissue Repair and Effects on Neurodegenerative Conditions.
Mesenchymal stromal cells (MSCs) have emerged as a modern development in therapeutics for a wide variety of diseases. Secreted paracrine factors constitute the principal components harboring the restorative promise of MSCs. Recent studies demonstrate that MSC-derived secretomes are composed of several molecules targeting a variety of biological processes that impact tissue repair, growth and immunomodulation. Indeed, secretomes interact with immune cells, activating regulatory anti-inflammatory phenotypes. In this review, we discuss the action of MSC-derived secretomes in promoting tissue regeneration, opposing the inflammatory response in context-specific cases, and treating neurodegenerative diseases, resulting from chronic neuroinflammation.


[Cyclic changes of S100A10 expression in human endometrium].
To explore the cyclic changes of S100A10 expression in human endometrium. The gene and protein expression of S100A10 in human endometrium was examined by real-time polymerase chain reaction (PCR), immunohistochemical staining and Western blot. S100A10 protein was predominantly expressed in cytoplasm and cytomembrane of luminal and glandular epithelia. The S100A10 protein was continuously expressed from proliferative phase to secretory phase of menstrual cycle. However the expression in the secretory phase was much higher than in the proliferative phase (2.26 ± 0.17, 3.75 ± 0.22, 2.65 ± 0.20 vs 1.17 ± 0.11, 1.32 ± 0.14, both P < 0.05). Specifically, the highest level of S100A10 expression occurred during the mid-secretory phase. Then real-time PCR was used to analyze the mRNA expression of S100A10 in human endometrial samples at various points during the menstrual cycle. And the results confirmed the corresponding changes at the genetic level (0.50 ± 0.05, 1.02 ± 0.10, 0.55 ± 0.05 vs 0.25 ± 0.02, 0.30 ± 0.03, both P < 0.05). The endometrial expression of S100A10 increases during the window of embryo implantation. It suggests that it may increase the endometrial receptivity of uterine epithelial cells for embryos.


Vaginoplasty by inverted perineal and labia minora flaps-a retrospective study.
Absence of the vagina occurs most frequently in the Rokitansky-Küster-Mayer (RKM) syndrome. Since Küster has reviewed the literature in 1910 many techniques have been described to create a neovagina. We describe a technique in which both a part of the labia minora and of the perineal skin are used as flaps to cover the neovagina and report on the long-term outcome in a series of 16 patients with RKM syndrome treated with this technique. No intra-operative or immediate postoperative complications were recorded. The average depth of the neovagina was 8 cm, at the end of the operation and 1 year later. After 3 months the neovagina was completely lined with vaginal epithelium. In six out of 16 patients scar formation and polypoid formation was observed at the apex of the neovagina. This could be successfully handled by excision and coagulation in all six cases. Ten patients reported a satisfactory sexual life. The technique is simple and easy to perform. The anatomical result and sexual gratification was outstanding in two-thirds of the patients. We conclude that flaps derived from the genital region offer the most physiological tissue for construction of a neovagina.


Genetic inhibition of PKCε attenuates neurodegeneration after global cerebral ischemia in male mice.
Global cerebral ischemia that accompanies cardiac arrest is a major cause of morbidity and mortality. Protein Kinase C epsilon (PKCε) is a member of the novel PKC subfamily and plays a vital role in ischemic preconditioning. Pharmacological activation of PKCε before cerebral ischemia confers neuroprotection. The role of endogenous PKCε after cerebral ischemia remains elusive. Here we used male PKCε-null mice to assess the effects of PKCε deficiency on neurodegeneration after transient global cerebral ischemia (tGCI). We found that the cerebral vasculature, blood flow, and the expression of other PKC isozymes were not altered in the PKCε-null mice. Spatial learning and memory was impaired after tGCI, but the impairment was attenuated in male PKCε-null mice as compared to male wild-type controls. A significant reduction in Fluoro-Jade C labeling and mitochondrial release of cytochrome C in the hippocampus was found in male PKCε-null mice after tGCI. Male PKCε-null mice expressed increased levels of PKCδ in the mitochondria, which may prevent the translocation of PKCδ from the cytosol to the mitochondria after tGCI. Our results demonstrate the neuroprotective effects of PKCε deficiency on neurodegeneration after tGCI, and suggest that reduced mitochondrial translocation of PKCδ may contribute to the neuroprotective action in male PKCε-null mice.


Single brain metastasis from a minute, well differentiated, but invading beyond the tunica muscularis mucosa rectal carcinoid.
We report the case of a 48-year-old woman with small-sized (< 10 mm), highly differentiated, aggressive rectal carcinoid, who developed a solitary distant metastasis to the brain. The primary lesion, initially removed by conventional polypectomy, invaded the mucosa/tunica muscularis mucosa and had positive resection margins. Afterwards, an assessment of 5-hydroxyindoloacetic acid (5-HIAA) 24 h urine excretion revealed a significantly increased level. Thus, a partial rectal resection was performed. Because of constantly elevated carcinoid markers: serum chromogranin A (CGA) and 5-HIAA, a somatostatin receptor scintigraphy was performed, which disclosed a focus of pathological marker accumulation in the left frontal area. The pathological finding after neurosurgical excision was meningioma. An unexpected normalization of the biochemical markers prompted us to verify this diagnosis. The final histopathological report was a well-differentiated neuroendocrine brain metastasis. Our case shows that in well differentiated, of diameter < 10 mm rectal carcinoids, an invasion even beyond the mucosa/tunica muscularis mucosa seems to be an independent factor predicting a malignant metastatic potential of these tumors. Hence, in such cases, behind the endoscopic submucosal resection with ligation device a more radical surgery should be considered. Additionally, a systematic CGA and 5-HIAA follow-up assessment and whole body somatostatin receptor scintigraphy, if necessary, are required.


Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers.
Glucose uptake has been found to be increased in cancer cells. Previous work has shown increased expression of the human erythrocyte glucose transporter (Glut1) mRNA in some human cancers, indicating that Glut1 may play a significant role in glucose uptake by these tumors. The distribution of Glut1 protein in normal and malignant human tissues is still largely unknown. Using immunohistochemistry, we found that Glut1 is largely undetectable in normal epithelial tissues and benign epithelial tumors but is expressed in a significant proportion of a variety of human carcinomas. We hypothesize that Glut1 expression by human carcinomas indicates an increased glucose uptake, and probably increased utilization of energy, which may correlate with an aggressive behavior. The biological significance of Glut1 expression needs to be determined.


[Eye damage and lighting among workers in the beer industry].
A cross-sectional study was realized to determine the occurrence of visual pathology in 143 male workers of the bottling area of a beer industry, in Zulia state, Venezuela; and it was compared with a control group of 143 male workers of the administrative area, similar in age, weight and height, with different periods of occupational exposure. A medical history, visual acuity, astigmatism, stereopsis, phoria, occupational visual capacity and tonometry tests, were realized. The risks in the occupational environment were identified through an industrial hygiene survey and inspection of the work sites. Lighting was measured according to the established COVENIN 2249-85 norm. The workers of the bottling area presented a greater frequency of pathological antecedents (conjunctivitis and foreign bodies); occupational and non-occupational antecedents; smaller frequency of pterygium and near sightedness; smaller values for the visual acuity in workers older than 40 years (p < 0.05); greater frequency of astigmatism, steropsis, phoria, below average visual capacity; and abnormal intraocular pressure. The point prevalence of the clinical findings was greater in the bottling area workers and the disparity reason corresponded to a non-significant causative association. The mean lighting measures were greater in the bottling area (p < 0.05); however, with the exception of the bottle washing area, they were below recommended levels. This study suggests the influence of occupational risks factors in the visual system and the need to implement prevention and control measures.


Development and Validation of a Stability-Indicating Liquid Chromatographic Method for Estimating Vilazodone Hydrochloride in Pharmaceutical Dosage Form Using Quality by Design.
A stability-indicating liquid chromatographic method was developed employing the principles of quality by design (QbD) to quantify vilazodone hydrochloride (VLN) in pharmaceutical dosage form. A Box-Behnken experimental design was employed to establish optimum conditions including method robustness by selecting organic phase proportion (%), mobile phase flow rate (mL/min) and pH of buffer as the factors, to study their effect on plate number as the response variable. Chromatography was performed on a C-18 column using methanol:phosphate buffer of pH 7.0 (85:15, v/v) as the mobile phase at a flow rate of 1.2 mL/min with photo diode array (PDA) detection at 285 nm. Calibration curve was linear over 5-80 µg/mL with values of accuracy within 99.4-100.8%. The limit of detection and quantification were found to be 1.5 and 5.0 µg/mL, respectively. The developed method revealed high specificity for VLN and its degradation products formed during forced degradation conditions. Furthermore, control strategies were developed based on system suitability test result. The QbD-based developed liquid chromatographic method was found suitable for routine analysis of VLN in bulk drug and pharmaceutical dosage form.


Mechanism for enterohepatic injury caused by circulatory disturbance of hepatic vessels in the rat.
We reported previously that a transient occlusion followed by reperfusion of the portal vein and the hepatic artery of the rat significantly decreased the transhepatic transport of a cholephilic compound, and that this decrease was prevented by pretreating animals with poly(styrene co-maleic acid butyl ester)-conjugated superoxide dismutase (SM-SOD). To elucidate the mechanism for oxidative injury of the liver and the site for the generation of superoxide radicals, the effect of a portosystemic bypass on the liver function was examined in the rat whose hepatic vessels were temporarily occluded. A portosystemic bypass inhibited the reperfusion-induced decrease in hepatic transport of bromosulfophthalein as effectively as did SM-SOD. Kinetic analysis using 125I-labeled albumin revealed that the permeability of the small intestine markedly increased after a transient occlusion. The increase in intestinal permeability was also inhibited either by SM-SOD or by the portosystemic bypass. Xanthine oxidase activity in portal plasma markedly increased during occlusion and reperfusion, while it remained within normal ranges in the bypassed group. Thus, superoxide radical, and/or its metabolite(s), might play a critical role in increasing the intestinal permeability and in the pathogenesis of reperfusion-induced liver injury.


Treatment of the depressive phase of bipolar affective disorder: a review.
Bipolar disorder is a chronic mood disorder which usually has its onset in adolescence and young adulthood. The disorder is typified by a remitting and relapsing course. While remissions are often partial in nature, relapses are frequent and manifested as manic, mixed, hypomanic and depressive episodes. Rapid cycling is a particularly disabling form of bipolar disorder, characterised by four or more episodes in a 12-month period. Bipolar disorder inevitably causes impairment in social and occupational functioning. Many patients experience severe hopelessness and suicidal ideation and the disorder is associated with one of the highest mortality rates of all psychiatric disorders. The treatment of bipolar depression is particularly challenging and numerous patients achieve incomplete benefit even with complex psychopharmacological strategies. In recent years, many new pharmacological options have become available for the treatment of bipolar depression and the field has seen significant progress. In order to achieve better outcome for the patients, it is mandatory that treating physicians have an up to date knowledge of recent advances in the management of this condition.


Trisetum paniceum (wild oats) pollen counts and aeroallergens in the ambient air of Madrid, Spain.
Madrid has a short but intensive grass pollen season, in which 79% of the total grass pollen load is released from the middle of May to the middle of June. The main objectives of this study were to quantify Trisetum paniceum (wild oats) aeroallergen in the atmosphere in Madrid from February to December 1996 and to correlate the aeroallergen concentrations with grass pollen counts. Two different samplers were used to assess allergen exposure; a Burkard spore trap was used to collect pollen grains and a high-volume air sampler to collect airborne particles. A total of 182 air filters were collected and extracted in 1 ml of PBS and analysed by ELISA inhibition, using pooled sera from highly allergic individuals. T. paniceum aeroallergens were detected not only during the grass pollen season, but also before and after. Wild oat allergens had two main peaks of 1 and 1.9 microg/m(3), occurring in late May and July, respectively. The time series analysis established the existence of lags between the two main variables pollen counts and aeroallergen activity. Analysis of the data by the Spearman rank test and linear regression showed a weak correlation between grass allergenic activity and grass pollen counts (Spearman's rho = 0.29). Data obtained from time series analysis demonstrated that grass allergenic activity correlated strongly with current and 5-week-old grass pollen grain counts (r(2) = 0.73). Wild oats allergenic activity was detected during the entire year and not only during the pollen season. This fact is an important aspect to be considered in the clinical follow-up and treatment of grass pollen-sensitised patients in Madrid.


Sequence and expression analyses of the UL37 and UL38 genes of Aujeszky's disease virus.
Previously, we sequenced the HSV-1 Ul39-Ul40 homologue genes of Aujeszky's disease virus (ADV), also designated as pseudorabies virus (Kaliman et al., 1994a, b). Now we report the nucleotide sequence of the adjacent DNA that encodes Ul38, the 5'-region (750 bp) of Ul37, and the promoter regions between these divergently arranged two genes. The ADV Ul38 gene encodes a protein of 368 amino acids. Amino acid sequence comparison of ADV Ul38 with that of other herpesviruses revealed significant structural homology. In a transcription study using RNase protection assay and Northern blot hybridization, we found that the Ul38 gene had one initiation site, but the Ul37 gene was initiated at two transcription sites with two potential initiator AUGs, one of which was dominant. Comparison of ADV Ul37, Ul38 and ribonucleotide reductase gene expression showed that these genes belong to the same temporal class with early kinetics. Data of structural and transcriptional studies suggest that regulation of the expression of these two ADV genes could differ from that of the HSV-1 virus.


Retroviral infection can abrogate the factor-dependency of hematopoietic cells by autocrine and non-autocrine mechanisms depending on the presence of a functional viral oncogene.
The mechanisms responsible for abrogation of the growth factor-dependency of a hematopoietic cell line were investigated. FDC-P1 cells were infected with retroviral constructs containing the neo gene and either a wild-type or a temperature-sensitive v-src oncogene. v-srcwt abrogated the factor-dependency of these cells since each G418r colony gave rise to factor-independent cells and no autocrine growth factor activity was detected. Moreover, the vast majority (< 99%) of cells infected with the v-srcts mutant gave rise to conditional factor-independent cells. Therefore a functional v-src gene product was required for growth factor-independence which occurred by a non-autocrine mechanism. A minority of factor-independent cells which arose after v-srcts infection, grew at the non-permissive temperature and one-half secreted granulocyte/macrophage-colony stimulating factor (GM-CSF) which supports the growth of the parental cells. Since the v-srcts viral stock contained a helper virus, Murine Leukemia Virus (MuLV), the ability of this virus to relieve factor-dependency was examined. A low frequency of factor-independent transformants was recovered after MuLV infection and one-half secreted GM-CSF. Therefore, retroviruses such as MuLV which lack an oncogene, can transform cells by stimulating autocrine growth factor secretion. Subsequent experiments performed with helper-free v-src preparations indicated that they could abrogate factor-dependency directly by a non-autocrine mechanism. These results demonstrate that a hematopoietic cell line can be transformed by two different mechanisms after retroviral infection and may be relevant for understanding hematopoietic cell transformation after persistent viral infection.


Clinical Impact of Combined Modified Glasgow Prognostic Score and C-Reactive Protein/Albumin Ratio in Patients with Colorectal Cancer.
The prognostic impact of the combination of the modified Glasgow prognostic score (mGPS) and C-reactive protein/albumin ratio (CAR) in colorectal cancer (CRC) is unclear. We aimed to investigate the clinical usefulness of this combination as a predictor of survival in CRC patients. We retrospectively evaluated 769 CRC patients who had undergone surgery between January 2006 and March 2014. The CAR and mGPS within 1 month postoperation were examined. The integrated area under the curve (iAUC) was compared among mGPS, CAR, and the combined classification (CC). The optimal CAR cut-off for discriminating overall survival was 0.14. Based on this cut-off, the mGPS 0 group was divided into the mGPS 0 with low CAR and the mGPS 0 with high CAR groups, whereas all mGPS 1 and 2 patients were classified into the high CAR group. CC was an independent prognostic factor, and its iAUC value (0.587, 95% CI 0.553-0.624) was superior to those of the mGPS (0.544, 95% CI 0.516-0.576) (bootstrap iAUC mean difference = 0.043; 95% CI = 0.015-0.072) and CAR (0.578, 95% CI 0.545-0.613) (bootstrap iAUC mean difference = 0.009; 95% CI = 0.002-0.017), respectively. In conclusion, the combination of mGPS and CAR has a synergistic effect and has a higher prognostic accuracy than mGPS or CAR alone in patients with CRC.


The effect of abnormal colour vision on the ability to identify and outline coloured clinical signs and to count stained bacilli in sputum.
To determine if medical practitioners with congenital colour vision deficiencies (CCVD) are less able to identify and delineate the extent of coloured abnormal signs than those with normal colour vision. Twenty-two medical practitioners with CCVD and 17 with normal colour vision, matched for age and gender, were shown 10 photographs. They were asked to identify and outline the extent of the clinical sign in eight that were of vomit or stool (six of these showing fresh blood), one of a skin rash and for one to mark the position of bacilli in sputum stained by the Ziehl-Neelsen method. There were statistically significant differences between the CCVD practitioners and those with normal colour vision in their ability to outline abnormalities in five of the six photographs that showed fresh blood, in the photograph of a rash and in marking the position of bacilli in the photograph of a stained slide. Medical practitioners with CCVD are handicapped in their evaluation of the presence and extent of coloured clinical signs. Medical schools should ensure that students with CCVD are aware of their deficiency and know its severity, so they can take special care in clinical practice.


Recurrent primary spinal subarachnoid neurocysticercosis.
Case description. To describe a patient with a recurrent primary spinal subarachnoid neurocysticercosis (NCC) that was successfully treated with surgical decompression and medical therapy at our center. Spinal subarachnoid NCC is thought to be the secondary result from larval migration through the ventricular system into the spinal subarachnoid space. However, this entity can develop as a primary infection through blood stream or direct larval migration. It can result in high recurrence and severe neurologic morbidity if it is not treated in an appropriate manner. A 50-year-old woman with treatment history of spinal NCC presented with back pain and radicular pain. The lumbar magnetic resonance imaging showed a cystic lesion with septation and slight rim enhancement after gadolinium administration at the L4-S1 area. We performed surgical removal of this lesion and postoperative medical therapy for complete eradication of the parasite. The histopathology was diagnostic for a cysticercal cyst. Adjuvant medical therapy with albendazole was administered for 30 days after surgery. The patient remained symptom-free for 1 year after surgery without any evidence of recurrence. We report a rare case of recurrent primary spinal subarachnoid NCC at L4-S1 area. In cases of primary spinal subarachnoid NCC can be treated by adequate combined approach with surgery and medical therapy. Spinal subarachnoid NCC should be added to the differential diagnosis of primary spinal intradural cysts, because this lesion can occur primarily.


Chronic suppurative otitis media: complicated versus uncomplicated disease.
To determine prognostic factors in patients with chronic otitis media who develop suppurative complications, we performed a retrospective study of all patients with chronic suppurative otitis media who underwent mastoid surgery between the years 1981 and 1989. Patients who developed complications were compared with those who did not with respect to six prognostic variables. The results indicated that patients with complications were younger (p less than 0.001), had shorter duration of ear discharge (p less than 0.001), were more likely to have pars tensa perforations (p less than 0.05), and had a higher degree of mastoid sclerosis in the operated and contralateral ears (p less than 0.001). The presence of cholesteatoma and the sex of the patient were of no prognostic value. Bacteriology of CSF and pus specimens from patients who developed intracranial complications mostly revealed mixed flora (62.9%). Proteus species was the most frequent isolate (34%) and anaerobes were present in 21.3% of specimens. Mastoid abscess occurred in more than half the patients in the complicated group. Brain abscess (57.4%) was the most frequent intracranial complication. On the basis of our findings we recommend that risk factors in patients with chronic suppurative otitis media be identified early to enable effective measures to be taken to eradicate the disease.


Statement on nursing: a personal perspective.
Contemporary nursing is based on a conglomerate of theoretical nursing models. These models each incorporate four central concepts: person, health, environment, and nursing. By defining these concepts, nurses develop an individual framework from which they base their nursing practice. As an aspiring nurse practitioner in the gastroenterology field, I have retrospectively assessed my personal definitions of person, health, environment, and nursing. From these definitions, I am able to incorporate specific theoretical frameworks into my personal belief system, thus formulating a basis for my nursing practice. This foundation is comprised of the influence of nursing theorists Jean Watson, Sister Callista Roy, Kolcaba, Florence Nightingale, and Ida J. Orlando; the Perioperative Patient-Focused Model; Watson's Theory of Human Caring; theories regarding transpersonal human caring and healing; and feminist theories. Therefore, this article describes self-examination of nursing care by defining central nursing concepts, acknowledging the influence of nursing theorists and theories, and developing a personal framework from which I base my nursing practice.


Cause and effect between concentration-dependent tissue damage and temporary cell proliferation in rat stomach mucosa by NaCl, a stomach tumor promoter.
This study was designed to test whether concentration or dose of NaCl was responsible for the initial tissue damage (after 1 min) and resulting temporary cell proliferation at 17 h in stomach mucosa of male F344 rats after gastric intubation of 0.65, 1.3, 2.6 and 3.7 M NaCl. Histological damage was studied by dual staining combining horseradish peroxidase-labeled Griffonia simplicifolia agglutinin-II staining (HRP-GSA-II) and periodic acid cold thionin-Schiff reaction (PATS). Cell proliferation was studied by measuring replicative DNA synthesis with liquid scintillation counting and by BrdU staining. NaCl at the same overall dose of 0.8 g/kg body weight induced different degrees of response depending on the concentration. For 4 ml of 0.65 M NaCl, there was no tissue damage after 1 min nor any increase in replicative DNA synthesis after 17 h in the pyloric mucosa. Administration of 1.3 M NaCl (2 ml), 2.6 M NaCl (1 ml) and 3.7 M NaCl (0.7 ml) induced concentration-dependent damage of the surface mucous cell layer after 1 min and increased replicative DNA synthesis after 17 h (P<0.05). Concentration-dependent increase in replicative DNA synthesis at 17 h was also induced with the same volume (1 ml) of 1.3, 2.6, and 3.7 M NaCl, while a volume-dependent increase in replicative DNA synthesis at 17 h was induced with 0.4, 0.7 and 1 ml of 3.7 M NaCl. However, a greater increase in replicative DNA synthesis was always observed when using higher NaCl concentrations at the same dose. Liquid scintillation counting was well-correlated with BrdU staining. These results suggest that a high concentration of NaCl is responsible for the initial tissue damage and resulting temporary cell proliferation during stomach tumor promotion.


Ethanol sclerosis: one of the best treatments for thymic cyst in very elderly patients?
An 83-year-old female patient with a giant thymic cyst that was successfully treated by percutaneous aspiration and ethanol injection. The patient had complained of coughing and chest discomfort for several years. A chest X-ray film revealed the shadow of a large abnormal mass in the anterior mediastinum. We diagnosed it as a thymic cyst. The patient refused surgery because of her age. We chose a less invasive therapy, namely, ethanol sclerosis of the cyst. The cyst was successfully treated without any complications, and no recurrence was found at the one-year follow-up. This therapy may be one of the best treatments for thymic cysts, especially in very elderly patients.


[Isokinetic torque of quadriceps in patients with untreated anterior cruciate ligament injury of the knee joint].
In order to study the role of muscle strength in patients with untreated anterior cruciate ligament (ACL) injury of the knee joint, the torque of the quadriceps was isokinetically measured during concentric contraction (CC) and passive eccentric contraction (PEC). The results were compared with those in normal individuals and sports players. Ninety patients with untreated ACL injury were subjected for the study. There were 50 men and 40 women. The normal group consisted of 20 students and the sports player group consisted of 20 soccer players. The peak torque and the torque at 30 degrees flexion of the quadriceps were isokinetically measured during CC and PEC by using a BIODEX machine. In patients with ACL injury, the peak torque was smaller in the injured side as compared with the uninjured side. At the same angle velocity, decrease of PEC in the injured side was larger than that of CC. These results were compared with the normal group and the sports player group. There was significant difference in the peak torque per body weight among each groups. But, the torque per body weight at 30 degrees flexion was almost consistent in these three groups. A considerable quadriceps atrophy occurs following ACL injury. In our experience, patients with functional absence of ACL are much more difficult to return to vigorous sports which require explosive eccentric contraction than to return to endurance sports which require repetitive concentric contractile efforts of the quadriceps. In the present study, decrease of the passive eccentric contraction in the injured side was more pronounced than that of the concentric contraction. From these results, the significantly decreased passive eccentric torque in the patients with untreated ACL injury can be a factor to cause instability of the knee joint in active daily life as well as in sports activities.


Functional role of gangliotetraosylceramide in epithelial-to-mesenchymal transition process induced by hypoxia and by TGF-{beta}.
The epithelial-to-mesenchymal transition (EMT) is a basic cellular process that plays a key role in normal embryonic development and in cancer progression/metastasis. Our previous study indicated that EMT processes of mouse and human epithelial cells induced by TGF-β display clear reduction of gangliotetraosylceramide (Gg4) and ganglioside GM2, suggesting a close association of glycosphingolipids (GSLs) with EMT. In the present study, using normal murine mammary gland (NMuMG) cells, we found that levels of Gg4 and of mRNA for the UDP-Gal:β1-3galactosyltransferase-4 (β3GalT4) gene, responsible for reduction of Gg4, were reduced in EMT induced by hypoxia (∼1% O(2)) or CoCl(2) (hypoxia mimic), similarly to that for TGF-β-induced EMT. An increase in the Gg4 level by its exogenous addition or by transfection of the β3GalT4 gene inhibited the hypoxia-induced or TGF-β-induced EMT process, including changes in epithelial cell morphology, enhanced motility, and associated changes in epithelial vs. mesenchymal molecules. We also found that Gg4 is closely associated with E-cadherin and β-catenin. These results suggest that the β3GalT4 gene, responsible for Gg4 expression, is down-regulated in EMT; and Gg4 has a regulatory function in the EMT process in NMuMG cells, possibly through interaction with epithelial molecules important to maintain epithelial cell membrane organization.


Toward a Rosetta stone for the stem cell genome: stochastic gene expression, network architecture, and external influences.
We review literature relating to three types of factors known to influence stem cell behavior. These factors are stochastic gene expression, regulatory network architecture, and the influence of external signals, such as those emanating from the niche. Although these factors are considered separately, their shared evolutionary history necessitates integration. Stochastic gene expression pervades network components; network architecture controls, modulates, or exploits this noise while performing additional computation; and such complexity also interplays with factors external to cells. Adequate understanding of each of these components, and how they interact, will lead to a conceptual model of the stem cell regulatory system that can be used to drive hypothesis-driven research and facilitate interpretation of experimental data.


Contractile characteristics of rat mesenteric artery after organ culture.
Organ culture of blood vessels is a useful technique to analyze long-term effects of drugs. Various growth factors are responsible for structural and functional changes during vascular remodeling. We investigated 1) basic contractile characteristics in organ-cultured rat mesenteric arteries (MA) in serum-free condition and 2) long-term effects of fetal bovine serum (FBS). Rat isolated MA with [E (+)] or without [E (-)] endothelium were divided into 1) freshly isolated (fresh), 2) cultured for 3 days without FBS (control) or 3) with 10% FBS (FBS). In E (+) control, maximal contraction by noradrenaline (NA), endothelin (ET)-1 and 5-hydroxytriptamine (5-HT) was similar to that in fresh. In E (-) control, maximal contraction by NA decreased whereas that by ET-1 and 5-HT didn't change from fresh. In E (+) FBS, maximal contraction by NA, ET-1, and 5-HT increased from control. In E (-) FBS, maximal contraction by NA and ET-1 decreased whereas that by 5-HT increased. In E (+) or E (-) control and FBS, sensitivity to NA and ET-1 increased from fresh. In E (+) and E (-) control, sensitivity to 5-HT decreased from fresh, and that in FBS further decreased from control. Three-day organ-cultured rat MA in serum-free condition preserved enough contraction to enable analysis for long-term effects of drug. In FBS, maximal contractions by NA and ET-1 increased in E (+) and decreased in E (-) from control, while those by 5-HT increased in both E (+) and E (-).


[Deep Veins: Hybrid Procedure for Treatment of Iliofemoral Obstruction].
Background Endovascular recanalisation of chronic obstruction of iliofemoral or caval veins gives very good patency. However, patency decreases if the common femoral vein and its side branches are also involved. Endophlectomy during a hybrid procedure can improve outcome and avoid early reocclusion due to restored inflow. The review presents the technical details and the published results of this technique. Results The hybrid procedure combines venous recanalisation and stent angioplasty with endophlebectomy. There have only been 4 studies with more than 10 patients and follow-up between 6 and 24 months. Primary and secondary patency ranges from 0 to 70% and 30 to 93%, respectively, but most patients showed clinical benefit. Conclusion Although there have only been a few studies on the hybrid procedure with endophlebectomy, this technique seems to improve the outcome of venous recanalisation if femoral inflow is disturbed.


Extracellular cysteines of the corticotropin-releasing factor receptor are critical for ligand interaction.
The corticotropin-releasing factor receptor (CRF-R) contains six conserved cysteines in its amino-terminal domain (C30, C44, C54, C68, C87, and C102) and one cysteine in its first and second extracellular loops (C188 and C258, respectively). Additionally, several other cysteines are located in the transmembrane domains (C128, C211, C233, and C364) and first intracellular loop (C150). Reduction of disulfide bonds with DTT decreased CRF binding to detergent-solubilized membranes, suggesting an important role for disulfide bonds in ligand recognition. Therefore, site-directed mutagenesis was used to introduce single and paired Cys (C) to Ser (S) or Ala (A) mutations. A silent nine amino acid tag from c myc was introduced in the amino terminus of the mouse CRF-R. With the exception of C258S and C188S/C258S mutations, all C to S or to A receptor mutants had good surface expression that was at least 52.5% of control. C30S, C54S, and C30S/C54S mutations had good CRF binding and CRF-stimulated cAMP accumulation. No CRF binding was detected for the C44S, C68S, C87S, C102S, C188S, C258S, C30S/C44S, C30S/C68S, C54S/C68S, C87S/C102S, and C188S/C258S mutants, while CRF-stimulated cAMP accumulation occurred with high EC50 values. In particular, receptors carrying double mutations, C44S/C102S and C68S/C87S, had an improved signaling property as compared to receptors carrying the respective single cysteine mutations. These data, together with the effects of DTT on CRF binding, indicate that disulfide bridges are important for receptor functions. Functional data from single and paired cysteine mutations suggest potential pairings between C44 and C102, C68 and C87, and C188 and C258 that are critical for ligand-receptor interactions.


A drug from poison: how the therapeutic effect of arsenic trioxide on acute promyelocytic leukemia was discovered.
It is surprising that, while arsenic trioxide (ATO) is now considered as "the single most active agent in patients with acute promyelocytic leukemia (APL)", the most important discoverer remains obscure and his original papers have not been cited by a single English paper. The discovery was made during the Cultural Revolution when most Chinese scientists and doctors struggled to survive. Beginning with recipes from a countryside practitioner that were vague in applicable diseases, Zhang TingDong and colleagues proposed in the 1970s that a single chemical in the recipe is most effective and that its target is APL. More than 20 years of work by Zhang and colleagues eliminated the confusions about whether and how ATO can be used effectively. Other researchers, first in China and then in the West, followed his lead. Retrospective analysis of data from his own group proved that APL was indeed the most sensitive target. Removal of a trace amount of mercury chloride from the recipe by another group in his hospital proved that only ATO was required. Publication of Western replication in 1998 made the therapy widely accepted, though neither Western, nor Chinese authors of English papers on ATO cited Zhang's papers in the 1970s. This article focuses on the early papers of Zhang, but also suggests it worth further work to validate Chinese reports of ATO treatment of other cancers, and infers that some findings published in Chinese journals are of considerable value to patients and that doctors from other countries can benefit from the clinical experience of Chinese doctors with the largest population of patients.


Bayesian data fusion: Probabilistic sensitivity analysis for unmeasured confounding using informative priors based on secondary data.
Bayesian causal inference offers a principled approach to policy evaluation of proposed interventions on mediators or time-varying exposures. Building on the Bayesian g-formula method introduced by Keil et al., we outline a general approach for the estimation of population-level causal quantities involving dynamic and stochastic treatment regimes, including regimes related to mediation estimands such as natural direct and indirect effects. We further extend this approach to propose a Bayesian data fusion (BDF), an algorithm for performing probabilistic sensitivity analysis when a confounder unmeasured in a primary data set is available in an external data source. When the relevant relationships are causally transportable between the two source populations, BDF corrects confounding bias and supports causal inference and decision-making within the main study population without sharing of the individual-level external data set. We present results from a simulation study comparing BDF to two common frequentist correction methods for unmeasured mediator-outcome confounding bias in the mediation setting. We use these methods to analyze data on the role of stage at cancer diagnosis in contributing to Black-White colorectal cancer survival disparities.


Association Between Advanced Care Management and Progression of Care Needs Level in Long-Term Care Recipients: Retrospective Cohort Study.
Long-term care insurance systems in Japan started a special senior care program overseen by qualified care managers (also known as advanced care managers). However, the relationship between advanced care management and outcomes in long-term care recipients remains unknown. We aimed to compare the outcome of long-term care recipients using facilities with advanced care management and conventional care management, in terms of care needs level progression. We conducted a retrospective cohort study using the Survey of Long-Term Care Benefit Expenditures in Japan. We identified those aged ≥65 years who were newly designated a care need level of 3, and received long-term care services between April 2009 and March 2014 in Tokyo. We compared survival without progression of care needs level between the groups, with and without advanced care management, using the Kaplan-Meier method. Factors affecting the outcomes were determined using a multivariable logistic regression model fitted with a generalized estimating equation. Of 45,330 eligible persons, 12,903 (28.46%) received long-term care based on advanced care management. The average duration of progression-free survival was 17.4 (SD 10.2) months. The proportions of five-year cumulative progression-free survival were 41.2% and 32.8% in those with and without advanced care management, respectively. The group with advanced care management had significantly lower care needs levels (odds ratio 0.77, 95% CI, 0.72-0.82, P<.001). Advanced care management was significantly associated with improved care needs levels.


Effect of Fosfomycin on Cyclosporine Nephrotoxicity.
Fosfomycin (Fos) has emerged as a potential treatment against multidrug-resistant organisms, however, there has been little work done on its influence on calcineurin inhibitor nephrotoxicity (CIN). This study was designed to evaluate the effect of Fos in combination with cyclosporine (CsA) on CIN. Two sets of experiments were undertaken. In the first, Wistar rats received different doses of Fos: 0, 62.5, 125, 250, and 500 mg/kg. In the second, rats were divided into four groups: control, CsA 15 mg/kg s.c., CsA + fosfomycin 62.5 mg/kg (CsA + LF), and CsA + Fos 500 mg/kg (CsA + HF). CsA was administrated daily for 14 days, whereas Fos administration started on the ninth day followed by two more doses, delivered 48 h apart. The administration of different Fos doses did not alter renal function. In contrast, CsA induced arteriolopathy, hypoperfusion, a reduction in the glomerular filtration rate, and downregulation of eNOS, angiotensinogen, and AT1R mRNA levels. Lower doses of Fos did not modify CIN. Instead, the CsA + HF group exhibited greater hypoperfusion, arteriolopathy, and oxidative stress, and increased mRNA levels of pro-inflammatory cytokines. This study shows that Fos administered by itself at different doses did not cause renal injury, but when it was given repeatedly at high dosages (500 mg/kg) in combination with CsA, it increased CIN through the promotion of greater oxidative stress and renal inflammation.


Posttraumatic orbital emphysema: a numerical model.
Orbital emphysema is a common symptom accompanying orbital fracture. The pathomechanism is still not recognized and the usually assumed cause, elevated pressure in the upper airways connected with sneezing or coughing, does not always contribute to the occurrence of this type of fracture. Observations based on the finite model (simulating blowout type fracture) of the deformations of the inferior orbital wall after a strike in its lower rim. Authors created a computer numeric model of the orbit with specified features-thickness and resilience modulus. During simulation an evenly spread 14400 N force was applied to the nodular points in the inferior rim (the maximal value not causing cracking of the outer rim, but only ruptures in the inferior wall). The observation was made from 1 · 10(-3) to 1 · 10(-2) second after a strike. Right after a strike dislocations of the inferior orbital wall toward the maxillary sinus were observed. Afterwards a retrograde wave of the dislocation of the inferior wall toward the orbit was noticed. Overall dislocation amplitude reached about 6 mm. Based on a numeric model of the orbit submitted to a strike in the inferior wall an existence of a retrograde shock wave causing orbital emphysema has been found.