Conformational freedom in tight binding enzymatic transition-state analogues.
Transition-state analogues of bacterial 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidases (MTANs) disrupt quorum-sensing pathways in Escherichia coli and Vibrio cholerae, demonstrating the potential to limit pathogenicity without placing bacteria under intense selective pressure that leads to antibiotic resistance. Despite the similarity of the crystal structures of E. coli MTAN (EcMTAN) and V. cholerae MTAN (VcMTAN) bound to DADMe-Immucillin-A transition-state (TS) analogues, EcMTAN demonstrates femtomolar affinity for BuT-DADMe-Immucillin-A (BDIA) whereas VcMTAN possesses only picomolar affinity. Protein dynamic interactions are therefore implicated in this inhibitor affinity difference. We conducted molecular dynamics simulations of both EcMTAN and VcMTAN in complex with BDIA to explore differences in protein dynamic architecture. Simulations revealed that electrostatic and hydrophobic interactions with BDIA are similar for both enzymes and thus unlikely to account for the difference in inhibitor affinity. The EcMTAN-BDIA complex reveals a greater flexibility and conformational freedom of catalytically important atoms. We propose that conserved motions related to the EcMTAN transition state correlate with the increased affinity of BDIA for EcMTAN. Transition-state analogues permitting protein motion related to formation of the transition state are better mimics of the enzymatic transition state and can bind more tightly than those immobilizing catalytic site dynamics.


Is the efficacy of oxytocin for autism diminished at higher dosages or repeated doses?: Potential mechanisms and candidate solutions.
No approved pharmacological intervention currently exists to address the core symptoms of autism spectrum disorder, a prevalent neurodevelopmental condition. However, there is a growing body of empirical evidence highlighting oxytocin's modulatory effects on social and communicative behaviors. Numerous single-dose trials have consistently demonstrated the efficacy of oxytocin in ameliorating behavioral and neural measurements associated with the core symptoms of autism spectrum disorder. Nevertheless, prior investigations involving the repeated administration of oxytocin have yielded disparate findings concerning its effectiveness, particularly in relation to clinical measures of the core symptoms of autism spectrum disorder. Recent studies have also raised the possibility of diminishing efficacy of oxytocin over time, particularly when higher or recurrent dosages of oxytocin are administered. This review article aims to provide an overview of previous studies examining this issue. Furthermore, it aims to discuss the potential mechanisms underlying these effects, including the interaction between oxytocin and vasopressin, as well as potential strategies for addressing the challenges mentioned. This review's overall objective is to provide insights into the potential development of innovative therapeutics to mitigate the core symptoms of autism spectrum disorder, representing potential breakthroughs in the treatment of this complex neurodevelopmental condition.


Inhibitory effects of cranberry polyphenols on formation and acidogenicity of Streptococcus mutans biofilms.
Cranberry fruit is a rich source of polyphenols, and has shown biological activities against Streptococcus mutans. In the present study, we examined the influence of extracts of flavonols (FLAV), anthocyanins (A) and proanthocyanidins (PAC) from cranberry on virulence factors involved in Streptococcus mutans biofilm development and acidogenicity. PAC and FLAV, alone or in combination, inhibited the surface-adsorbed glucosyltransferases and F-ATPases activities, and the acid production by S. mutans cells. Furthermore, biofilm development and acidogenicity were significantly affected by topical applications of PAC and FLAV (P<0.05). Anthocyanins were devoid of any significant biological effects. The flavonols are comprised of mostly quercetin glycosides, and the PAC are largely A-type oligomers of epicatechin. Our data show that proanthocyanidins and flavonols are the active constituents of cranberry against S. mutans.


Observational pain assessment in older persons with dementia in four countries: Observer agreement of items and factor structure of the Pain Assessment in Impaired Cognition.
Recognition of pain in people with dementia is challenging. Observational scales have been developed, but there is a need to harmonize and improve the assessment process. In EU initiative COST-Action TD1005, 36 promising items were selected from existing scales to be tested further. We aimed to study the observer agreement of each item, and to analyse the factor structure of the complete set. One hundred and ninety older persons with dementia were recruited in four different countries (Italy, Serbia, Spain and The Netherlands) from different types of healthcare facilities. Patients represented a convenience sample, with no pre-selection on presence of (suspected) pain. The Pain Assessment in Impaired Cognition (PAIC, research version) item pool includes facial expressions of pain (15 items), body movements (10 items) and vocalizations (11 items). Participants were observed by health professionals in two situations, at rest and during movement. Intrarater and interrater reliability was analysed by percentage agreement. The factor structure was examined with principal component analysis with orthogonal rotation. Health professionals performed observations in 40-57 patients in each country. Intrarater and interrater agreement was generally high (≥70%). However, for some facial expression items, agreement was sometimes below 70%. Factor analyses showed a six-component solution, which were named as follows: Vocal pain expression, Face anatomical descriptors, Protective body movements, Vocal defence, Tension and Lack of affect. Observation of PAIC items can be done reliably in healthcare settings. Observer agreement is quite promising already without extensive training. In this international project, promising items from existing observational pain scales were identified and evaluated regarding their reliability as an alternative to pain self-report in people with dementia. Analysis on factor structure helped to understand the character of the items. Health professionals from four countries using four different European languages were able to rate items reliably. The results contributed to an informed reduction of items for a clinical observer scale (Pain Assessment in Impaired Cognition scale with 15 items: PAIC15).


Early predictors of juvenile sacroiliitis in enthesitis-related arthritis.
To identify early predictors of sacroiliac (SI) involvement in a cohort of patients with enthesitis-related arthritis (ERA). During a 7-year followup period, all consecutive patients fulfilling the ILAR classification criteria for ERA were enrolled. Data collected included demographic, clinical and laboratory variables at disease onset, at the onset of inflammatory back pain, and at the last available followup visit. Pelvis radiographs and dynamic magnetic resonance imaging (MRI) scans for SI joints were obtained simultaneously in all patients who developed inflammatory back pain. Fifty-nine children with ERA were studied; 40 male, 19 female; median age at disease onset 9 years 4 months (range 6 yrs 6 mo - 13 yrs 3 mo). At a median interval after disease onset of 1 year 3 months, 21 children reported symptoms of inflammatory back pain. In all cases, radiographs of SI joints were negative, while dynamic MRI revealed acute sacroiliitis in 17 cases. Multivariate analysis showed that the early predictors of SI were the number of active joints (p < 0.03) and the number of active entheses (p < 0.001) at onset. In our cohort, roughly 30% of children with ERA/juvenile idiopathic arthritis develop clinical and MRI evidence of sacroiliitis, detectable with dynamic MRI as early as 1 year after disease onset. Additional data from larger case series are needed to assess the specificity and sensitivity of this technique in the early phase of the disease and to confirm the rate of SI involvement reported in this cohort.


[Serum and secretory immunoglobulins in allergic diseases].
A total of 158 patients with pollinosis, bronchial asthma, urticaria and Quincke's edema were examined. The immunoglobulin and C3 levels in sera and the immunoglobulin and albumin levels in saliva were determined by the method of single radial immunodiffusion with the corresponding monospecific antisera. In all the groups of patients subjected to examination the presence of polyclonal hypergammaglobulinemia was detected, which was manifested by a rise in the levels of IgG, IgA and especially IgM; the level of IgD was low. A decrease in the level of C3 was detected in pollinosis patients in the absence of the exacerbation of the disease. No circulating immune complexes were detected. An essential increase in the level of IgG in saliva was revealed, which was due to the local synthesis of this immunoglobulin. In winter the level of salivary IgA in pollinosis patients was found to be essentially below normal, but at the period of exacerbation it increased twofold, probably in response to local stimulation with antigen-allergen. Patients with bronchial asthma and pollinosis were found to have a high level of free secretory component (SC); in pollinosis the level of free SC sharply increased during the stage of exacerbation, which was due to the increase of its synthesis and secretion by the epithelial cells of the mucous membranes. The importance of these data for the pathogenesis of allergic diseases are discussed.


Intramolecular excimer formation in hexakis(pyrenyloxy)cyclotriphosphazene: photophysical properties, crystal structure, and theoretical investigation.
A hexakis(pyrenyloxy)cyclotriphosphazene is synthesized by the reaction of N3P3Cl6 with 2-hydroxypyrene, and its excimer emission through intramolecular interactions in solution and in the solid state has been investigated by fluorescence spectroscopy and X-ray crystallography. Thermal and electrochemical properties were investigated. A DFT benchmark study has been performed to evaluate the intramolecular interactions and molecular orbital levels by comparing with the experimental results.


Dietary supplements and bariatric surgery.
Bariatric surgery or weight loss surgery has been in practice for achieving significant weight loss in patients who have failed to achieve weight loss after pharmacological interventions. The rising cases of obesity are a triggering factor for more bariatric surgeries worldwide. Interestingly, sustained weight loss achieved post-bariatric surgery offers metabolic advantages, and patients show improved glucose and lipid metabolisms. Bariatric surgery is directly linked to higher incidences of vitamin, mineral, and trace element deficiencies, thus making patients susceptible to anemia, osteoporosis, and cardiomyopathy. Reduced nutrient absorption capacity, dietary changes, dietary restriction, and altered gastrointestinal tract morphology are some reasons for nutritional deficiency observed in post-bariatric surgery procedures. Micro-and-macronutrient deficiency observed in patients during the postoperative phase requires continuous monitoring of nutritional parameters. Therefore, adequate multivitamin and mineral supplements become essential to prevent/overcome micronutrient deficiencies. Bariatric surgery also raises the risk of small for gestational age (SGA) babies. Hence, a 12 - 24 months gap is recommended between bariatric surgery and pregnancy to achieve desired weight loss targets. The topic of this review is the impact of bariatric surgery procedures on vitamin and mineral absorption and the role of dietary supplements in maintaining a healthy nutritional balance during the postoperative phase.


A randomized, controlled clinical evaluation of a synthetic gel membrane for guided bone regeneration around dental implants: clinical and radiologic 1- and 3-year results.
The objective of this study was to determine whether a synthetic bioresorbable polyethylene glycol (PEG) hydrogel membrane could provide similar clinical and radiographic outcomes as a standard collagen membrane, both in combination with a membrane-supporting material, during follow-up periods of 1 and 3 years. This study enrolled patients requiring implant treatment with an expected osseous defect in the posterior maxilla or mandible. Defects around the implants were grafted with deproteinized bovine bone mineral and covered with either a collagen membrane or a PEG hydrogel membrane, which is applied as a liquid and becomes a solid gel in situ. Surgical re-entry was performed after 6 months, and fixed partial dentures were inserted subsequently. Patients were examined clinically and radiographically 1 and 3 years after loading. Thirty-six of the 37 included patients were reexamined in the third year. The implant survival rate at 3 years was 100%. The peri-implant tissues were healthy, with no differences between the two groups. Compared to the time of surgery, the mean changes in the distance between the first bone-to-implant contact to the transition point (ie, rough implant surface to polished neck portion) were 0.43 ± 0.56 mm (PEG) and 0.21 ± 0.36 mm (collagen) at 1 year and 0.61 ± 0.89 mm (PEG) and 0.33 ± 0.64 mm (collagen) at 3 years. The respective differences between groups were 0.13 mm (1 year) and 0.31 mm (3 years), which were not significant at either time point (analysis of covariance). The tested PEG hydrogel was as successful as a standard collagen membrane for the treatment of bony dehiscence defects around dental implants after follow-up periods of 1 and 3 years.


Novel 2-alkythio-4-chloro-N-[imino(heteroaryl)methyl]benzenesulfonamide Derivatives: Synthesis, Molecular Structure, Anticancer Activity and Metabolic Stability.
A series of novel 2-alkythio-4-chloro-N-[imino-(heteroaryl)methyl]benzenesulfonamide derivatives, 8-24, were synthesized in the reaction of the N-(benzenesulfonyl)cyanamide potassium salts 1-7 with the appropriate mercaptoheterocycles. All the synthesized compounds were evaluated for their anticancer activity in HeLa, HCT-116 and MCF-7 cell lines. The most promising compounds, 11-13, molecular hybrids containing benzenesulfonamide and imidazole moieties, selectively showed a high cytotoxic effect in HeLa cancer cells (IC50: 6-7 μM) and exhibited about three times less cytotoxicity against the non-tumor cell line HaCaT cells (IC50: 18-20 μM). It was found that the anti-proliferative effects of 11, 12 and 13 were associated with their ability to induce apoptosis in HeLa cells. The compounds increased the early apoptotic population of cells, elevated the percentage of cells in the sub-G1 phase of the cell cycle and induced apoptosis through caspase activation in HeLa cells. For the most active compounds, susceptibility to undergo first-phase oxidation reactions in human liver microsomes was assessed. The results of the in vitro metabolic stability experiments indicated values of the factor t½ for 11-13 in the range of 9.1-20.3 min and suggested the hypothetical oxidation of these compounds to sulfenic and subsequently sulfinic acids as metabolites.


[Epidemiology of drug use during the first three months of life in a urban area of southern Brazil].
The few studies on the use of medicines in children point to excessive use, and in these studies, physicians are those mainly responsible for the prescription of medicines. In order to get to know the patterns of consumption medicines better, a study was made in children in their first three months of life, according to social biological, food pattern and use of health services of variables. The patterns of the use of medicines during the first three months of life in 655 urban children born in Pelotas, Brazil, in 1993, were described. Information on the use of medicines was collected during a two-week period in the first and third month of life. The use of medicines was reported by 65% of mothers at the 1st and 69% at the 3rd month of life. Seventeen per cent of children consumed three or more different medicines during those periods. Fixed combinations of three or more components-which was taken as an indicator of the poor of medicines quality-were consumed by 14% of the children at the 1st and 19% at the 3rd months of life. At the latter age, 20% of children had used a given medicine for one month or more. At the first month follow-up, Benzalkonium Chloride + Normal Saline Solution (nasal drops), Nystatin Mixture and Dimethicone + Homotropine were the most frequently used medicines. At the third month they were, Aspirin, Benzalkonium Chloride + Normal Saline Solution and Dimethicone + Homatropine. The main reasons for taking medicines were cramps at the first month and colds at the third. At the first month follow-up, children with three or more siblings used 64% less medicines than the older ones. Children who were not breast-fed at the end of the first month showed a 75% greater risk of use of medicines. Similar results were observed at the third month follow-up. Some of the medicines used were not recommendable for children. Since early age children are submitted to an intense use of medicines for almost every conceivable reason, with the risk of potential side-effects and the possible lead to medicine or other drugs addiction.


Measurement of HCI absorption coefficients with a DF laser.
Absorption coefficients in the fundamental P-branch of HCl at several DF laser transitions from 2439.02 cm(-1) to 2862.87 cm(-1) have been measured experimentally. The 2-1 P(3) DF laser transition has been shown to overlap the P(6) HCl(37) absorption line within the halfwidth of an atmospherically broadened line. The absorption coefficient k was measured to be 5.64 +/- 0.28 (atm-cm)cm(-1) for a 0.27% mixture of HCl in N(2) at a total pressure of 760 Torr. A theoretical and experimental comparison of the pressure dependence of k showed that the 2-1 P(3) DF transition lies 1.32 +/- 0.15 GHz from the center of the P(6) HCl absorption line. This line separation is in good agreement with published positions for this DF laser transition and the HCl absorption line. At least four other DF laser transitions in the spectral interval measured are reported showing measurable absorption (>/=10%) for a 10.2% mixture of HCl in N(2) across a 1-m pathlength. Applications of these results to differential absorption lidar (DIAL) and to heterodyne detection are also discussed.


Patient Decision-making and Predictors of Genital Satisfaction Associated With Testicular Prostheses After Radical Orchiectomy: A Questionnaire-based Study of Men With Germ Cell Tumors of the Testicle.
To better understand patient decision-making and genital satisfaction associated with postorchiectomy testicular prosthesis (TP) implantation in patients with germ cell tumors of the testicle. An electronic survey to assess TP decision-making and genital satisfaction was distributed to patients via an institutional database (n = 70) and social media outlets (n = 167). Statistical analyses were performed using chi-square tests for categorical variables, Wilcoxon-Mann-Whitney tests for continuous variables, and multivariate regression analyses to identify independent predictors of receiving a prosthesis, genital satisfaction, and prosthesis satisfaction. 24.9% of respondents elected to receive a TP, but 42% of men without a prosthesis reported never being offered one. Identifying as a heterosexual man (2.86) and receiving a TP (odds ratio = 3.29) were both positive predictors of overall genital satisfaction. Having the orchiectomy performed at an academic institution (odds ratio = 2.87) was a positive predictor of testicular prosthesis TP placement. 89.8% of TP recipients were satisfied with the look of their prosthetic, but only 59.3% of respondents were satisfied with prosthetic feel. There are high levels of genital satisfaction in those who elect to receive a TP postorchiectomy. Associations between TP placement, genital satisfaction, and sexuality merit further investigation. Our results also indicate that patients who pursue an orchiectomy at an academic institution are more likely to receive a TP. The use of social media to recruit study participants in urology should be explored further.


E-cigarette use and associated changes in population smoking cessation: evidence from US current population surveys.
Objective To examine whether the increase in use of electronic cigarettes in the USA, which became noticeable around 2010 and increased dramatically by 2014, was associated with a change in overall smoking cessation rate at the population level.Design Population surveys with nationally representative samples.Setting Five of the US Current Population Survey-Tobacco Use Supplement (CPS-TUS) in 2001-02, 2003, 2006-07, 2010-11, and 2014-15.Participants Data on e-cigarette use were obtained from the total sample of the 2014-15 CPS-TUS (n=161 054). Smoking cessation rates were obtained from those who reported smoking cigarettes 12 months before the survey (n=23 270). Rates from 2014-15 CPS-TUS were then compared with those from 2010-11 CPS-TUS (n=27 280) and those from three other previous surveys.Main outcome measures Rate of attempt to quit cigarette smoking and the rate of successfully quitting smoking, defined as having quit smoking for at least three months.Results Of 161 054 respondents to the 2014-15 survey, 22 548 were current smokers and 2136 recent quitters. Among them, 38.2% of current smokers and 49.3% of recent quitters had tried e-cigarettes, and 11.5% and 19.0% used them currently (every day or some days). E-cigarette users were more likely than non-users to attempt to quit smoking, 65.1% v 40.1% (change=25.0%, 95% confidence interval 23.2% to 26.9%), and more likely to succeed in quitting, 8.2% v 4.8% (3.5%, 2.5% to 4.5%). The overall population cessation rate for 2014-15 was significantly higher than that for 2010-11, 5.6% v 4.5% (1.1%, 0.6% to 1.5%), and higher than those for all other survey years (range 4.3-4.5%).Conclusion The substantial increase in e-cigarette use among US adult smokers was associated with a statistically significant increase in the smoking cessation rate at the population level. These findings need to be weighed carefully in regulatory policy making regarding e-cigarettes and in planning tobacco control interventions.


Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities.
Mutant p53 (mtp53) is an oncogene that drives cancer cell proliferation. Here we report that mtp53 associates with the promoters of numerous nucleotide metabolism genes (NMG). Mtp53 knockdown reduces NMG expression and substantially depletes nucleotide pools, which attenuates GTP-dependent protein activity and cell invasion. Addition of exogenous guanosine or GTP restores the invasiveness of mtp53 knockdown cells, suggesting that mtp53 promotes invasion by increasing GTP. In addition, mtp53 creates a dependency on the nucleoside salvage pathway enzyme deoxycytidine kinase for the maintenance of a proper balance in dNTP pools required for proliferation. These data indicate that mtp53-harbouring cells have acquired a synthetic sick or lethal phenotype relationship with the nucleoside salvage pathway. Finally, elevated expression of NMG correlates with mutant p53 status and poor prognosis in breast cancer patients. Thus, mtp53's control of nucleotide biosynthesis has both a driving and sustaining role in cancer development.


Polymorphisms in the interleukin-6 receptor gene are associated with bone mineral density and body mass index in Spanish postmenopausal women.
Osteoporosis and obesity are complex diseases with a strong genetic component. Bone mineral density (BMD) and body mass index (BMI) linkage studies identified a locus at 1q21-23, where the interleukin-6 receptor (IL6R) gene is located. The IL6R and the gp130 receptors are the mediators of IL6 action. Serum levels of IL6 and sIL6R (the soluble form of IL6R) are higher in several diseases such as osteoporosis or obesity. Variants at IL6R have been associated with BMI and obesity. However, IL6R is an as-yet-unexplored osteoporosis candidate gene. In the present study we analysed two polymorphisms in the IL6R promoter, -1435 C/T (rs3887104) and -208 G/A (rs4845617), and the Asp358Ala polymorphism (rs8192284), in relation to both BMD and BMI in a cohort of 559 postmenopausal Spanish women. The promoter polymorphisms, -1435 C/T and -208 G/A were associated with femoral neck (FN) BMD (P=0.011 and P=0.025 respectively). The C-A and T-G promoter haplotypes were also associated with FN BMD. Additionally, the Asp358Ala variant was associated with lumbar spine BMD (P=0.038). Finally, the -208 G/A polymorphism and the C-G and C-A haplotypes were associated with BMI and obesity, where GG was the risk genotype (P=0.033 for BMI; P=0.010 for obesity). These data suggest that variants in the IL6R gene are not only involved in the determination of BMI but also relevant for the determination of BMD. The IL6R gene may belong to the growing list of genes known to be involved in both phenotypes.


The Impact of Oral Promethazine on Human Whole-Body Motion Perceptual Thresholds.
Despite the widespread treatment of motion sickness symptoms using drugs and the involvement of the vestibular system in motion sickness, little is known about the effects of anti-motion sickness drugs on vestibular perception. In particular, the impact of oral promethazine, widely used for treating motion sickness, on vestibular perceptual thresholds has not previously been quantified. We examined whether promethazine (25 mg) alters vestibular perceptual thresholds in a counterbalanced, double-blind, within-subject study. Thresholds were determined using a direction recognition task (left vs. right) for whole-body yaw rotation, y-translation (interaural), and roll tilt passive, self-motions. Roll tilt thresholds were 31 % higher after ingestion of promethazine (P = 0.005). There were no statistically significant changes in yaw rotation and y-translation thresholds. This worsening of precision could have functional implications, e.g., during driving, bicycling, and piloting tasks. Differing results from some past studies of promethazine on the vestibulo-ocular reflex emphasize the need to study motion perception in addition to motor responses.


Implications of nonshivering thermogenesis for energy balance regulation in humans.
The incidence of the metabolic syndrome has reached epidemic levels in the Western world. With respect to the energy balance, most attention has been given to reducing energy (food) intake. Increasing energy expenditure is an important alternative strategy. Facultative thermogenesis, which is the increase in energy expenditure in response to cold or diet, may be an effective way to affect the energy balance. The recent identification of functional brown adipose tissue (BAT) in adult humans promoted a renewed interest in nonshivering thermogenesis (NST). The purpose of this review is to highlight the recent insight in NST, general aspects of its regulation, the major tissues involved, and its metabolic consequences. Sustainable NST in adult humans amounts to 15% of the average daily energy expenditure. Calculations based on the limited available literature show that BAT thermogenesis can amount to 5% of the basal metabolic rate. It is likely that at least a substantial part of NST can be attributed to BAT, but it is possible that other tissues contribute to NST. Several studies on mitochondrial uncoupling indicate that skeletal muscle is another potential contributor to facultative thermogenesis in humans. The general and synergistic role of the sympathetic nervous system and the thyroid axis in relation to NST is discussed. Finally, perspectives on BAT and skeletal muscle NST are given.


Female genital cosmetic surgery.
To provide Canadian gynaecologists with evidence-based direction for female genital cosmetic surgery in response to increasing requests for, and availability of, vaginal and vulvar surgeries that fall well outside the traditional realm of medically-indicated reconstructions. Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2011 and 2012 using appropriate controlled vocabulary and key words (female genital cosmetic surgery). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2012. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). Recommendations 1. The obstetrician and gynaecologist should play an important role in helping women to understand their anatomy and to respect individual variations. (III-A) 2. For women who present with requests for vaginal cosmetic procedures, a complete medical, sexual, and gynaecologic history should be obtained and the absence of any major sexual or psychological dysfunction should be ascertained. Any possibility of coercion or exploitation should be ruled out. (III-B) 3. Counselling should be a priority for women requesting female genital cosmetic surgery. Topics should include normal variation and physiological changes over the lifespan, as well as the possibility of unintended consequences of cosmetic surgery to the genital area. The lack of evidence regarding outcomes and the lack of data on the impact of subsequent changes during pregnancy or menopause should also be discussed and considered part of the informed consent process. (III-L) 4. There is little evidence to support any of the female genital cosmetic surgeries in terms of improvement to sexual satisfaction or self-image. Physicians choosing to proceed with these cosmetic procedures should not promote these surgeries for the enhancement of sexual function and advertising of female genital cosmetic surgical procedures should be avoided (III-L) 5. Physicians who see adolescents requesting female genital cosmetic surgery require additional expertise in counselling adolescents. Such procedures should not be offered until complete maturity including genital maturity, and parental consent is not required at that time. (III-L) 6. Non-medical terms, including but not restricted to vaginal rejuvenation, clitoral resurfacing, and G-spot enhancement, should be recognized as marketing terms only, with no medical origin; therefore they cannot be scientifically evaluated. (III-L).


To what extent do site-based training, mentoring, and operational research improve district health system management and leadership in low- and middle-income countries: a systematic review protocol.
District health managers play a key role in the effectiveness of decentralized health systems in low- and middle-income countries. Inadequate management and leadership skills often hamper their ability to improve quality of care and effectiveness of health service delivery. Nevertheless, significant investments have been made in capacity-building programmes based on site-based training, mentoring, and operational research. This systematic review aims to review the effectiveness of site-based training, mentoring, and operational research (or action research) on the improvement of district health system management and leadership. Our secondary objectives are to assess whether variations in composition or intensity of the intervention influence its effectiveness and to identify enabling and constraining contexts and underlying mechanisms. We will search the following databases: MEDLINE, PsycInfo, Cochrane Library, CRD database (DARE), Cochrane Effective Practice and Organisation of Care (EPOC) group, ISI Web of Science, Health Evidence.org, PDQ-Evidence, ERIC, EMBASE, and TRIP. Complementary search will be performed (hand-searching journals and citation and reference tracking). Studies that meet the following PICO (Population, Intervention, Comparison, Outcome) criteria will be included: P: professionals working at district health management level; I: site-based training with or without mentoring, or operational research; C: normal institutional arrangements; and O: district health management functions. We will include cluster randomized controlled trials, controlled before-and-after studies, interrupted time series analysis, quasi-experimental designs, and cohort and longitudinal studies. Qualitative research will be included to contextualize findings and identify barriers and facilitators. Primary outcomes that will be reported are district health management and leadership functions. We will assess risk of bias with the Cochrane Collaboration's tools for randomized controlled trials (RCT) and non RCT studies and Critical Appraisal Skills Programme checklists for qualitative studies. We will assess strength of recommendations with the GRADE tool for quantitative studies, and the CERQual approach for qualitative studies. Synthesis of quantitative studies will be performed through meta-analysis when appropriate. Best fit framework synthesis will be used to synthesize qualitative studies. This protocol paper describes a systematic review assessing the effectiveness of site-based training (with or without mentoring programmes or operational research) on the improvement of district health system management and leadership. PROSPERO CRD42015032351.


An overview of the digital solutions for helping people with aphasia through bibliometric analysis.
This paper gives insights into recent research developments in the field of digital solutions for people with aphasia and tries to analyse its impact on their rehabilitation. A bibliometric research approach is used for data collection. Relevant studies were extracted from seven major academic databases from years 2000 to 2019 inclusive. The systematic process resulted in 986 studies. The average growth in this field is 4%, which is less compared to other research areas. However, the average citations per paper is 7.27, which represents a medium level of publication quality. Scopus and Web of Science are leading databases for the number of studies (379 and 264) and quality of publications (P-Index: 49.26 and 32.85), respectively. The USA, with 42% of publications, leads this research field, followed by the UK with 15%. Both countries have national aphasia strategies in place through charities (not government level strategies), which potentially contributed to their research leadership. The results show that recent advances in digital solutions have the potential to support people with aphasia. However, further work is needed at both academic and government levels to deliver more research contributions and funding for the rehabilitation of people with aphasia.


The associations between self-consciousness and internalizing/externalizing problems among Chinese adolescents.
Self-consciousness is considered as a multifaceted and hierarchical construct that includes self-evaluation, self-experience, and self-control. This study assumes that self-consciousness is a preventative factor of internalizing and externalizing problems among Chinese adolescents. 1202 Chinese adolescents from grade 7 to grade 12 participated in this study by completing a battery of questionnaires that assessed self-consciousness and internalizing/externalizing problems. The results showed that, after controlling demographic variables, some lower-order factors (i.e., sense of satisfaction, sense of anxiety, social self, self-restraint, self-esteem, and self-monitoring) and higher-order subscales (i.e., self-evaluation and self-experience) of self-consciousness significantly predicted internalizing problems, while externalizing problems were predicted by several lower-order factors (i.e., self-restraint, sense of satisfaction, and self-monitoring) and higher-order subscales (i.e., self-control and self-experience). In conclusion, this study demonstrates that Chinese adolescents' internalizing and externalizing problems are related with different aspects of self-consciousness, which sheds light on the prevention into adolescents' problem behaviors.


An in vivo model to study and manipulate the hematopoietic stem cell niche.
Because the microenvironment that supports hematopoietic stem cell (HSC) proliferation and differentiation is not fully understood, we adapted a heterotopic bone formation model as a new approach for studying the HSC microenvironment in vivo. Endogenous HSCs homed to tissue-engineered ossicles and individually sorted HSCs from ossicles were able to reconstitute lethally irradiated mice. To further explore this model as a system to study the stem cell niche, ossicles were established with or without anabolic parathyroid hormone (PTH) treatment during the 4-week course of bone development. Histology and micro-computed tomography showed higher bone area-to-total area ratios, thicker cortical bone and trabecular bone, significantly higher bone mineral density and bone volume fraction in PTH-treated groups than in controls. By an in vivo competitive long-term reconstitution assay, HSC frequency in the ossicle marrow was 3 times greater in PTH groups than in controls. When whole bone marrow cells were directly injected into the ossicles after lethal irradiation, the PTH-treated groups showed an enhanced reconstitution rate compared with controls. These findings suggest the residence of HSCs in heterotopic bone marrow and support the future use of this ossicle model in elucidating the composition and regulation of the HSC niche.


Disorder in milk proteins: caseins, intrinsically disordered colloids.
This article opens a series of reviews on the abundance and roles of intrinsic disorder in milk proteins. The focus of this introductory article on caseins is symbolic, since caseins were among the first recognized functional unfolded proteins and since they are definitely the most disordered, the most abundant, and the most studied of all milk proteins. In eutherian milks, the casein family includes at least three and usually four major members (αs1-, αs2-, β-, and κ-caseins) that are unrelated in sequence. However, in some species, two different αS2-casein genes are active, and therefore the total number of caseins can be as high as five. These proteins have found a number of uses in food industry. The functional repertoire of caseins ranges from nutritional function to involvement in the improving and/or maintaining cardiovascular health, to crucial contribution to the milk capacity to transport calcium phosphate, to serve as molecular chaperones, and to protect the mother's mammary gland against amyloidoses and ectopic calcification. An intricate feature of caseins is their ability to assemble to colloidal protein particles, casein micelles, serving to sequester and transport amorphous calcium phosphate. These and many other functions of caseins are obviously dependent on their intrinsically disordered nature and are controlled by various posttranslational modifications. Since various aspects of casein structure and function are rather well studied and since several recent reviews emphasized the functional roles of caseins' intrinsic disorder, the major goal of this article is to show how intrinsic disorder is encoded in the amino acid sequences of these proteins.


The effects of iron fertilization on carbon sequestration in the Southern Ocean.
An unresolved issue in ocean and climate sciences is whether changes to the surface ocean input of the micronutrient iron can alter the flux of carbon to the deep ocean. During the Southern Ocean Iron Experiment, we measured an increase in the flux of particulate carbon from the surface mixed layer, as well as changes in particle cycling below the iron-fertilized patch. The flux of carbon was similar in magnitude to that of natural blooms in the Southern Ocean and thus small relative to global carbon budgets and proposed geoengineering plans to sequester atmospheric carbon dioxide in the deep sea.


A complete set of material properties of single domain 0.26Pb(In(12)Nb(12))O(3)-0.46Pb(Mg(13)Nb(23))O(3)-0.28PbTiO(3) single crystals.
Pb(In(12)Nb(12))O(3)-Pb(Mg(13)Nb(23))O(3)-PbTiO(3) (PIN-PMN-PT) single crystals have been developed recently, which can increase the operating temperature by at least 20 degrees C compared to PMN-PT crystals. We have measured a complete set of material properties of single domain PIN-PMN-PT crystal, which is urgently needed in theoretical studies and electromechanical device designs using this crystal. Because the rotated values of d33*=1122 pCN and k33*=89% along [001](c) calculated using the single domain data obtained here are in good agreement with the [001](c) poled multidomain PIN-PMN-PT crystals, one may conclude that the physical origin of the ultrahigh piezoelectric properties mainly come from orientation effect.


Analysis of Temporobasal Vein with Short Subdural Segment for Anterior Transpetrosal Approach.
The anterior transpetrosal approach (ATPA) is applied to petroclival and brainstem lesions. Although neurosurgeons need to minimize the risk of neurologic complications, brain retraction is necessary for procedures of ATPA. Bridging veins (BVs) limit mobility of the temporal lobe. In the present study, BVs around the petrous bone were analyzed, focusing on the dural entrance and termination points. The relationship between subdural and meningeal segments of temporobasal veins (TBVs) was analyzed by preoperative computed tomography venography in 102 patients who underwent ATPA. TBVs were classified by the dural entrance and termination points. TBVs mainly entered the transverse sinus and rarely entered transverse-sigmoid sinus (T-S) junction and superior petrosal sinus (SPS). TBVs entered a dural sinus either directly or indirectly through a meningeal vein. The changes in vascular diameter of the lumen, shape, and course were identified between the subdural and meningeal segments. Generally, BVs with long subdural segment do not limit mobility of the temporal lobe. TBVs draining into the T-S junction and SPS tended to be shorter than those draining into the transverse sinus. Furthermore, a few TBVs indirectly entered the dural sinuses through the meningeal vein (early dural entrance). The subdural segment of these TBVs was much shorter. TBVs entering the T-S junction or SPS with short subdural segment may limit the mobility of the temporal lobe. Changes in vascular diameter, shape, and course were detected by computed tomography venography, which was helpful to detect the subdural-meningeal transition.


The safety and immunogenicity of two novel live attenuated monovalent (serotype 2) oral poliovirus vaccines in healthy adults: a double-blind, single-centre phase 1 study.
Use of oral live-attenuated polio vaccines (OPV), and injected inactivated polio vaccines (IPV) has almost achieved global eradication of wild polio viruses. To address the goals of achieving and maintaining global eradication and minimising the risk of outbreaks of vaccine-derived polioviruses, we tested novel monovalent oral type-2 poliovirus (OPV2) vaccine candidates that are genetically more stable than existing OPVs, with a lower risk of reversion to neurovirulence. Our study represents the first in-human testing of these two novel OPV2 candidates. We aimed to evaluate the safety and immunogenicity of these vaccines, the presence and extent of faecal shedding, and the neurovirulence of shed virus. In this double-blind, single-centre phase 1 trial, we isolated participants in a purpose-built containment facility at the University of Antwerp Hospital (Antwerp, Belgium), to minimise the risk of environmental release of the novel OPV2 candidates. Participants, who were recruited by local advertising, were adults (aged 18-50 years) in good health who had previously been vaccinated with IPV, and who would not have any contact with immunosuppressed or unvaccinated people for the duration of faecal shedding at the end of the study. The first participant randomly chose an envelope containing the name of a vaccine candidate, and this determined their allocation; the next 14 participants to be enrolled in the study were sequentially allocated to this group and received the same vaccine. The subsequent 15 participants enrolled after this group were allocated to receive the other vaccine. Participants and the study staff were masked to vaccine groups until the end of the study period. Participants each received a single dose of one vaccine candidate (candidate 1, S2/cre5/S15domV/rec1/hifi3; or candidate 2, S2/S15domV/CpG40), and they were monitored for adverse events, immune responses, and faecal shedding of the vaccine virus for 28 days. Shed virus isolates were tested for the genetic stability of attenuation. The primary outcomes were the incidence and type of serious and severe adverse events, the proportion of participants showing viral shedding in their stools, the time to cessation of viral shedding, the cell culture infective dose of shed virus in virus-positive stools, and a combined index of the prevalence, duration, and quantity of viral shedding in all participants. This study is registered with EudraCT, number 2017-000908-21 and ClinicalTrials.gov, number NCT03430349. Between May 22 and Aug 22, 2017, 48 volunteers were screened, of whom 15 (31%) volunteers were excluded for reasons relating to the inclusion or exclusion criteria, three (6%) volunteers were not treated because of restrictions to the number of participants in each group, and 30 (63%) volunteers were sequentially allocated to groups (15 participants per group). Both novel OPV2 candidates were immunogenic and increased the median blood titre of serum neutralising antibodies; all participants were seroprotected after vaccination. Both candidates had acceptable tolerability, and no serious adverse events occurred during the study. However, severe events were reported in six (40%) participants receiving candidate 1 (eight events) and nine (60%) participants receiving candidate 2 (12 events); most of these events were increased blood creatinine phosphokinase but were not accompanied by clinical signs or symptoms. Vaccine virus was detected in the stools of 15 (100%) participants receiving vaccine candidate 1 and 13 (87%) participants receiving vaccine candidate 2. Vaccine poliovirus shedding stopped at a median of 23 days (IQR 15-36) after candidate 1 administration and 12 days (1-23) after candidate 2 administration. Total shedding, described by the estimated median shedding index (50% cell culture infective dose/g), was observed to be greater with candidate 1 than candidate 2 across all participants (2·8 [95% CI 1·8-3·5] vs 1·0 [0·7-1·6]). Reversion to neurovirulence, assessed as paralysis of transgenic mice, was low in isolates from those vaccinated with both candidates, and sequencing of shed virus indicated that there was no loss of attenuation in domain V of the 5'-untranslated region, the primary site of reversion in Sabin OPV. We found that the novel OPV2 candidates were safe and immunogenic in IPV-immunised adults, and our data support the further development of these vaccines to potentially be used for maintaining global eradication of neurovirulent type-2 polioviruses. Bill & Melinda Gates Foundation.


Comparative Subsequence Sets Analysis (CoSSA) is a robust approach to identify haplotype specific SNPs; mapping and pedigree analysis of a potato wart disease resistance gene Sen3.
Standard strategies to identify genomic regions involved in a specific trait variation are often limited by time and resource consuming genotyping methods. Other limiting pre-requisites are the phenotyping of large segregating populations or of diversity panels and the availability and quality of a closely related reference genome. To overcome these limitations, we designed efficient Comparative Subsequence Sets Analysis (CoSSA) workflows to identify haplotype specific SNPs linked to a trait of interest from Whole Genome Sequencing data. As a model, we used the resistance to Synchytrium endobioticum pathotypes 2, 6 and 18 that co-segregated in a tetraploid full sib population. Genomic DNA from both parents, pedigree genotypes, unrelated potato varieties lacking the wart resistance traits and pools of resistant and susceptible siblings were sequenced. Set algebra and depth filtering of subsequences (k-mers) were used to delete unlinked and common SNPs and to enrich for SNPs from the haplotype(s) harboring the resistance gene(s). Using CoSSA, we identified a major and a minor effect locus. Upon comparison to the reference genome, it was inferred that the major resistance locus, referred to as Sen3, was located on the north arm of chromosome 11 between 1,259,552 and 1,519,485 bp. Furthermore, we could anchor the unanchored superscaffold DMB734 from the potato reference genome to a synthenous interval. CoSSA was also successful in identifying Sen3 in a reference genome independent way thanks to the de novo assembly of paired end reads matching haplotype specific k-mers. The de novo assembly provided more R haplotype specific polymorphisms than the reference genome corresponding region. CoSSA also offers possibilities for pedigree analysis. The origin of Sen3 was traced back until Ora. Finally, the diagnostic power of the haplotype specific markers was shown using a panel of 56 tetraploid varieties. CoSSA is an efficient, robust and versatile set of workflows for the genetic analysis of a trait of interest using WGS data. Because the WGS data are used without intermediate reads mapping, CoSSA does not require the use of a reference genome. This approach allowed the identification of Sen3 and the design of haplotype specific, diagnostic markers.


Trabecular and cortical bone structure of the talus and distal tibia in Pan and Homo.
Internal bone structure, both cortical and trabecular bone, remodels in response to loading and may provide important information regarding behavior. The foot is well suited to analysis of internal bone structure because it experiences the initial substrate reaction forces, due to its proximity to the substrate. Moreover, as humans and apes differ in loading of the foot, this region is relevant to questions concerning arboreal locomotion and bipedality in the hominoid fossil record. We apply a whole-bone/epiphysis approach to analyze trabecular and cortical bone in the distal tibia and talus of Pan troglodytes and Homo sapiens. We quantify bone volume fraction (BV/TV), degree of anisotropy (DA), trabecular thickness (Tb.Th), bone surface to volume ratio (BS/BV), and cortical thickness and investigate the distribution of BV/TV and cortical thickness throughout the bone/epiphysis. We find that Pan has a greater BV/TV, a lower BS/BV and thicker cortices than Homo in both the talus and distal tibia. The trabecular structure of the talus is more divergent than the tibia, having thicker, less uniformly aligned trabeculae in Pan compared to Homo. Differences in dorsiflexion at the talocrural joint and in degree of mobility at the talonavicular joint are reflected in the distribution of cortical and trabecular bone. Overall, quantified trabecular parameters represent overall differences in bone strength between the two species, however, DA may be directly related to joint loading. Cortical and trabecular bone distributions correlate with habitual joint positions adopted by each species, and thus have potential for interpreting joint position in fossil hominoids.


Combination drug treatment in patients with non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) includes simple steatosis, a benign condition, and non-alcoholic steatohepatitis, a condition that beyond TG accumulation also includes necroinflammation and fibrosis. An association between NAFLD and cardiovascular disease (CVD) has been recently suggested. NAFLD patients usually have an increased CVD risk profile. NAFLD is also associated with metabolic syndrome (MetS) and is considered as the hepatic component of MetS by some authors. Currently, the only established treatment of NAFLD is gradual weight loss. However, multifactorial treatment of NAFLD risk factors may be needed to reduce the increased CVD risk of NALFD patients. Drug combinations that include antiobesity drugs (such as orlistat and sibutramine) and target CVD risk factors may be a good approach to NAFLD patients. Our group has investigated the orlistat-fenofibrate combination treatment in obese patients with MetS and the orlistat-ezetimibe and sibutramine-antihypertensive combination treatment in obese patients with hyperlipidaemia with promising results in CVD risk factor reduction and improvement of liver function tests. Small studies give promising results but double-blind, randomized trials examining the effects of such multifactorial treatment in hard CVD endpoints in NAFLD patients are missing.


Marine vessels as substitutes for heavy-duty trucks in Great Lakes freight transportation.
This paper applies a geospatial network optimization model to explore environmental, economic, and time-of-delivery tradeoffs associated with the application of marine vessels as substitutes for heavy-duty trucks operating in the Great Lakes region. The geospatial model integrates U.S. and Canadian highway, rail, and waterway networks to create an intermodal network and characterizes this network using temporal, economic, and environmental attributes (including emissions of carbon dioxide, particulate matter, carbon monoxide, sulfur oxides, volatile organic compounds, and nitrogen oxides). A case study evaluates tradeoffs associated with containerized traffic flow in the Great Lakes region, demonstrating how choice of freight mode affects the environmental performance of movement of goods. These results suggest opportunities to improve the environmental performance of freight transport through infrastructure development, technology implementation, and economic incentives.


Electrocardiogram of young diabetic subjects.
Standard 12-lead electrocardiogram patterns were studied in 100 Type I diabetic subjects aged 15-40 years and in 100 control subjects of the same age. Neither study group had evidence of clinical ischaemic heart disease or other systemic diseases which might affect cardiac function. The diabetic subjects had higher heart rates, lower electrocardiographic voltages and more T wave inversions than the controls. The diabetic women had longer QT intervals corrected for heart rate than the control women. The R-R interval variability (mean +/- S.D.) in the ECG was smaller in the diabetic subjects than in the controls (13 +/- 11 vs. 17 +/- 11%, p less than 0.05). Its magnitude was related to the heart rate variation in deep breathing, a measure of autonomic nervous function (r = 0.54, n = 50). The diabetic subjects with vagal autonomic neuropathy had an R-R interval variability of only 0-6%. The standard electrocardiograms of young asymptomatic diabetic subjects appear to differ in many respects from the those of healthy subjects in the same age group. The differences may reflect the presence of preclinical diabetic cardiovascular complications at an early age. A small or absent R-R interval variability helps to select patients for closer evaluation of autonomic function.


The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications.
PTEN/PI3K/AKT constitutes an important pathway regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation and cell growth. PTEN is a dual protein/lipid phosphatase which main substrate is the phosphatidyl-inositol,3,4,5 triphosphate (PIP3), the product of PI3K. Increase in PIP3 recruits AKT to the membrane where it is activated by other kinases also dependent on PIP3. Many components of this pathway have been described as causal forces in cancer. PTEN activity is lost by mutations, deletions or promoter methylation silencing at high frequency in many primary and metastatic human cancers. Germ line mutations of PTEN are found in several familial cancer predisposition syndromes. Activating mutations which have been reported for PI3K and AKT, in tumours are able to confer tumourigenic properties in several cellular systems. Additionally, the binding of PI3K to oncogenic ras is essential for the transforming properties of ras. In summary, the data strongly support the view of the PTEN/PI3K/AKT pathway as an important target for drug discovery.


Primary malt lymphoma of the tongue.
Primitive malignant lymphoma mucosa associated lymphoid tissue (MALT) on the tongue are rare entities. We report here a case of an old woman (80 years old) with a tumor in the dorsum of the tongue, which was histologically diagnosed as an extra-nodal marginal B cell lymphoma. An inflammatory reaction resembling myoepithelial sialoadenitis was observed in the minor salivary glands adjacent at the tumour, suggesting a possible derivation of the lymphoma from a previous reactive process of unknown origin.


Excessive daytime sleepiness and fatigue in depressed patients and therapeutic response of a sedating antidepressant.
Although sleepiness and fatigue are common symptoms in depressed patients, the relationships among sleepiness, fatigue and treatment of depression have not been fully elucidated. The main objective of this study was to investigate the therapeutic effects of a sedating antidepressant on sleepiness and fatigue in patients with depression. Forty-two depressed patients, who met DSM-IV diagnostic criteria, and 32 matched healthy controls participated in the baseline measurements. Sixteen of the depressed patients were treated with mirtazapine. At baseline, daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS) and Stanford Sleepiness Scale (SSS), and fatigue was assessed using the Fatigue Severity Scale (FSS) and Fatigue Impact Scale (FIS). During treatment, Multiple Sleep Latency Test (MSLT), ESS and SSS were used to measure daytime sleepiness, and the FIS, FACES Checklist-Fatigue subscale (FAF) and Fatigue Assessment Instrument (FAI) were used to measure fatigue. At baseline, there were significant group differences between the depressed and healthy controls on the ESS (P = 0.001), SSS (P<0.001), FSS (P < 0.001) and FIS (P < 0.001). Significant improvement of sleepiness and fatigue measures was seen after treatment with mirtazapine on the MSLT (P = 0.011), ESS (P = 0.021), SSS (P = 0.001), FIS (P = 0.002) and FAF (P = 0.004). Open-label treatment and relatively small sample size. Daytime sleepiness and fatigue are significant symptoms in depressed patients. Slightly paradoxically, a sedating antidepressant may alleviate these symptoms.


[Operational tests of "MOST", a new membrane oxygenator].
Functional and service characteristics of a Soviet membrane oxygenator are determined and compared with analogous foreign models. Results of hygienic examinations including medico-chemical and toxicological trials made it possible to evaluate oxygenator effects on a living organism.


Potassium-rich diet and risk of stroke: updated meta-analysis.
Recently a few prospective population studies provided additional and heterogeneous information concerning the reported statistical associations between potassium (K) intake and stroke risk. Therefore, we updated our previous meta-analysis of K intake and risk of cerebrovascular events. Three studies were added to the previous analysis, and the results of the comparison between the event rate in the two extreme categories of K intake were used. Pooled analysis of 14 cohorts (overall 333,250 participants and 10,659 events) showed an inverse and significant association between K intake and risk of stroke (Relative Risk: 0.80; 95% CI: 0.72-0.90). Our results indicated a favorable effect of higher K intake on risk of stroke. These results confirm the appropriateness of worldwide recommendations for a population increased consumption of potassium-rich foods to prevent cardiovascular disease.


Loss of Muscle Mass and Strength After Hip Fracture: an Intervention Target for Nutrition Supplementation.
To summarize what is known about the deleterious effect of hip fracture on muscle mass and strength as well as the scientific evidence for post-surgical nutrition supplementation to maintain muscle and improve function. This review provides a discussion of the relationship between muscle mass, strength, and physical function following hip fracture, briefly describes the approaches to measuring lean mass, discusses prevalence of sarcopenia and malnutrition among older men and women with hip fracture, and reviews the effects of essential amino acids on muscle. Loss of muscle mass and strength following hip fracture is substantial with consequences for recovery of functional independence. EAA-based nutrition supplementation, which directly effects muscle, has potential to improve outcomes.


Metastases From Colorectal Cancer Avid on 68Ga-PSMA PET/CT.
Ga-PSMA PET/CT is currently used for detection of prostate cancer including metastases, even at low prostate-specific antigen values. A grown number of reports have shown increased uptake of PSMA in neovessels of nonprostatic malignancies including lung cancer, and recently a case report has demonstrated increased PSMA uptake in colorectal adenocarcinoma. In this case report, we demonstrate increased Ga-PMSA uptake on PET/CT in metastases from previously treated colon adenocarcinoma, and it illustrates the importance of histology of suspicious lesions on Ga-PSMA PET/CT.


[One-stage extracapsular cataract extraction with sinusotrabeculotomy in patients with combined glaucoma and cataract].
The paper deals with the question about surgical treatment of patients with glaucoma associated with cataract. A new technique of one-stage extracapsular cataract extraction with sinusotrabeculotomy is proposed. Its main point is a change in the sequence of stages: stage I--opening of anterior lens capsule, stage II--antiglaucomatous operation, stage III--extraction of lenticular nucleus and masses through a corneal incision. The operation was made in 30 patients (31 ages). The follow-up period was 2 years. Normalization of intraocular pressure was achieved in all patients, in one eye--miotics had to be used. All patients showed a rise of visual functions: in 21 of 31 eyes vision rose to 0.3 and higher. In one patient vision fell after a year because of progression of the glaucomatous process in the presence of normal intraocular pressure. One-stage extracapsular cataract extraction with sinusotrabeculotomy can be made at any stage of glaucoma. By the authors' data, contraindications can be a rise of intraocular pressure above 40.0 mm Hg as well as the presence of a single eye and severe course of hypertonic disease.


Development and application of a multimodal contrast agent for SPECT/CT hybrid imaging.
Hybrid or multimodality imaging is often applied in order to take advantage of the unique and complementary strengths of individual imaging modalities. This hybrid noninvasive imaging approach can provide critical information about anatomical structure in combination with physiological function or targeted molecular signals. While recent advances in software image fusion techniques and hybrid imaging systems have enabled efficient multimodal imaging, accessing the full potential of this technique requires development of a new toolbox of multimodal contrast agents that enhance the imaging process. Toward that goal, we report the development of a hybrid probe for both single photon emission computed tomography (SPECT) and X-ray computed tomography (CT) imaging that facilitates high-sensitivity SPECT and high spatial resolution CT imaging. In this work, we report the synthesis and evaluation of a novel intravascular, multimodal dendrimer-based contrast agent for use in preclinical SPECT/CT hybrid imaging systems. This multimodal agent offers a long intravascular residence time (t(1/2) = 43 min) and sufficient contrast-to-noise for effective serial intravascular and blood pool imaging with both SPECT and CT. The colocalization of the dendritic nuclear and X-ray contrasts offers the potential to facilitate image analysis and quantification by enabling correction for SPECT attenuation and partial volume errors at specified times with the higher resolution anatomic information provided by the circulating CT contrast. This may allow absolute quantification of intramyocardial blood volume and blood flow and may enable the ability to visualize active molecular targeting following clearance from the blood.


Computed tomographic findings in cerebral arterial ectasia.
The computed tomographic findings in 15 patients with angiographically documented cerebral arterial ectasia are reported. In addition to demonstrating the majority of pathologic arterial segments, computed tomography also documents the presence and extent of associated intracranial abnormalities. In this study these included cerebral atrophy (10 patients), infarction (three patients), and subarachnoid hemorrhage (one patient).


Endothelin-1 up-regulates p115RhoGEF in embryonic rat cardiomyocytes during the hypertrophic response.
In cardiomyocytes, certain extracellular stimuli that activate heterotrimeric G protein-coupled receptors (GPCRs) can induce hypertrophy by regulating gene expression and increasing protein synthesis. We investigated if rat embryonic cardiomyocytes (H9c2) underwent variations in the expression levels and subcellular distribution of key components of GPCR-activated signaling pathways during endothelin-1 (ET-1)-induced hypertrophic response. A significant increase of p115RhoGEF protein level was evident in ET-1-treated cells. Real-time quantitative PCR showed RhoGEF mRNA levels were significantly increased. Inhibition of the Rho-associated kinase (ROCK) caused a significant decrease of p115RhoGEF protein in the nuclear fraction, whereas an inhibitor of PKC induced a redistribution of the protein between membrane/organelle and nuclear fractions. The ROCK inhibitor also decreased H9c2 cell hypertrophic response. These results indicate that ROCK and its downstream target molecules, which are involved in inducing the hypertrophic response, are also implicated in signaling the up-regulation of the p115RhoGEF protein.


Autistic traits and mental health in women with the fragile-X premutation: maternal status versus genetic risk.
Research on women with the fragile-X premutation (FX-p) has been underrepresented within the field of behavioural phenotypes. To understand whether the FX-p confers risk for autistic traits, depression and anxiety, independent of maternal status. In study 1, mothers of children with fragile-X syndrome (M-FXp; n = 51, mean age 43 years (s.d. = 5.80)) were compared with mothers of autistic children (M-ASD; n = 59, mean age 42 (s.d. = 5.80)), mothers of children with Smith-Magenis syndrome (M-SMS; n = 27, mean age 39 (s.d. = 7.20)) and mothers of typically developing children (M-TD; n = 44, mean age 40 (s.d. = 4.90)). In study 2, the M-FXp group were compared with non-mothers with the FX-p (NM-FXp; n = 17, mean age 32 (s.d. = 9.20)), typically developed non-mothers (NM-TD; n = 28, mean age 31 (s.d. = 6.80)) and the M-TD group. All participants completed an online survey, including measures of IQ, autistic traits, anxiety, depression and positive affect. In study 1: the M-FXp group reported more autistic traits than the M-TD group (P < 0.05, η2 = 0.046). Anxiety and parental stress were elevated in the M-FXp, M-SMS and M-ASD groups relative to the M-TD group (all P ≤ 0.003, η2 = 0.079-0.322). In study 2: a main effect of premutation status indicated that women with the FX-p report elevated autistic traits and anxiety (P ≤ 0.007, η2 = 0.055-0.060); this did not interact with maternal status. The findings indicate that women with the FX-p show an increased risk for autistic traits and anxiety. This risk is specific to the presence of the FX-p and is not fully accounted for by maternal status or the stress of caring for children with neurodevelopmental disorders.


Redox equilibria in hydroxylamine oxidoreductase. Electrostatic control of electron redistribution in multielectron oxidative processes.
We report results of continuum electrostatics calculations of the cofactor redox potentials, and of the titratable group pK(a) values, in hydroxylamine oxidoreductase (HAO). A picture of a sophisticated multicomponent control of electron flow in the protein emerged from the studies. First, we found that neighboring heme cofactors strongly interact electrostatically, with energies of 50-100 mV. Thus, cofactor redox potentials depend on the oxidation state of other cofactors, and cofactor redox potentials in the active (partially oxidized) enzyme differ substantially from the values obtained in electrochemical redox titration experiments. We found that, together, solvent-exposed heme 1 (having a large negative redox potential) and heme 2 (having a large positive redox potential) form a lock for electrons generated during the oxidation reaction The attachment of HAO's physiological electron transfer partner cytochrome c(554) results in a positive shift in the redox potential of heme 1, and "opens the electron gate". Electrons generated as a result of hydroxylamine oxidation travel to heme 3 and heme 8, which have redox potentials close to 0 mV versus NHE (this result is in partial disagreement with an existing experimental redox potential assignment). The closeness of hemes 3 and 8 from different enzyme subunits allows redistribution of the four electrons generated as a result of hydroxylamine oxidation, among the three enzyme subunits. For the multielectron oxidation process to be maximally efficient, the redox potentials of the electron-accepting cofactors should be roughly equal, and electrostatic interactions between extra electrons on these cofactors should be minimal. The redox potential assignments presented in the paper satisfy this general rule.


Genotype-phenotype relationships as prognosticators in Rett syndrome should be handled with care in clinical practice.
Rett syndrome (RTT; OMIM 312750) is an X-linked dominant neurodevelopmental disorder leading to cognitive and motor impairment, epilepsy, and autonomic dysfunction in females. Since the discovery that RTT is caused by mutations in MECP2, large retrospective genotype-phenotype correlation studies have been performed. A number of general genotype-phenotype relationships were confirmed and specific disorder profiles were described. Nevertheless, conflicting results are still under discussion, partly due to the variability in classification of mutations, assessment tools, and structure of the data sets. The aim of this study was to investigate relationships between genotype and specific clinical data collected by the same experienced physician in a well-documented RTT cohort, and evaluate its prognostic value in counseling young parents with a newly diagnosed RTT girl regarding her future outcome. The Maastricht-Leuven Rett Syndrome Database is a register of 137 molecularly confirmed clinical RTT cases, containing both molecular and clinical data on examination and follow up by the same experienced physician. Although the general genotype-phenotype relationships were confirmed, the clinical severity was still found to be very variable. We therefore recommend caution in using genotype-phenotype data in the prognosis of outcome for children in Rett syndrome. Early diagnosis, early intervention, and preventive management are imperative for better outcomes and better quality of daily life for RTT females and their families.


Treatment of dentine hypersensitivity by lasers: a review.
Since the development of the ruby laser by Maiman in 1960, a variety of papers on potential applications for lasers in dentistry have been published. The purpose of this paper is to summarise laser applications for the treatment of dentine hypersensitivity. The effects of laser on pulp tissue and problems on laser treatment are also reviewed. This article reviews the role of lasers for the treatment of dentine hypersensitivity since 1985, summarises many research reports from the last decade, and surmises what the future may hold for lasers in this treatment. To date, 4 kinds of lasers have been used for the treatment of dentine hypersensitivity, and the effectiveness ranged from 5.2 to 100%, which was dependent on the laser type and parameters used. The mechanism involved in laser treatment of dentine hypersensitivity are relatively unknown. These require clarification to result in safely effective treatment optimization. In general, the efficiency for the treatment of dentine hypersensitivity using lasers is higher than other methods, but in severe cases, it is less effective. It is necessary to consider the severity of dentine hypersensitivity before laser use.


Dose ingested, vomiting, and outcome in patients ingesting a standard paraquat 20SL formulation.
FAO specifications for liquid paraquat dichloride SL formulations require the use of an emetic agent to stimulate vomiting within 30 min of ingestion. To date, there is no high-quality evidence of efficacy, despite use of the PP796 emetic since 1979. We first examined the validity of patients' self-reported dose of paraquat ingested by examining the relationship with blood paraquat concentration and time to death for patients ingesting the standard paraquat SL formulation in a Sri Lankan cohort. As a secondary outcome, we assessed whether ingestion resulted in vomiting within 30 min and whether vomiting was associated with good outcome. Patients presenting with paraquat SL self-poisoning were prospectively studied in ten Sri Lankan hospitals in 2003-08. Data on reported dose ingested, incidence and timing of vomiting after ingestion, treatment received, plasma paraquat concentration, and outcome were collected prospectively on presentation to hospital. Time between ingestion and blood sampling was incorporated by covariate adjustment. 441 patients were recruited to the case series, presenting a median (IQR) of 3.0 (1.5-8.1] h post ingestion. Outcome was known for 435 patients of whom 322 (74.0%) died within 42 days, a median of 1.3 (0.6-4.4) days post ingestion. Median reported dose ingested was 15 to <30 mL. There was a highly significant linear trend between log plasma paraquat and reported dose ingested (p < .001); adjustment for the log of the time from ingestion to sampling further improved the model fit. Case fatality and median time to death also showed good agreement with estimated ingestion amount. 347/438 patients (79.2%) were stated to have vomited before reaching the study hospital with 300 (68.5%) vomiting within 30 min of ingestion; time to vomiting was unknown for a further 12 (2.7%). The proportion vomiting was strongly associated with reported dose ingested (p < .001); of note the proportion vomiting within 30 min only increased to 83.3% for the highest ingestion group. Patients vomiting within 30 min had higher plasma paraquat concentrations (p = .008), and higher hazard ratio in the adjusted Cox regression model of 2.01 (95% CI 1.45-2.77) compared to those who did not. Vomiting within 30 min was associated with a higher case fatality (241/295 [81.7%] vs 68/125 [54.4%], p < .001). Forty-three (47.3%) of the 91 patients who did not vomit before reaching hospital died (one had unknown outcome). Importantly, we found good agreement between reported dose ingested and plasma paraquat concentration, case fatality, and time to death, suggesting that the reported dose is a valid marker for the dose ingested. Vomiting occurred within 30 min for 68.5% of patients, exceeding the characteristics for a purported effective emetic in the FAO specifications. However, vomiting within 30 min was associated with approximately double the risk of death compared to those who did not vomit, larger paraquat ingestions, and higher blood paraquat concentrations. In addition, death occurred in many patients who did not vomit, and the proportion vomiting within 30 min only reached 82.1% for the highest ingested dose group. Overall, we found no evidence of benefit resulting from incorporation of the emetic, suggesting that the current FAO specification is not effective at preventing deaths after ingestion of the paraquat SL formulation.


High-concentration nitrous oxide for procedural sedation in children: adverse events and depth of sedation.
Nitrous oxide is an attractive agent for procedural sedation and analgesia in the emergency department; however, there are limited safety data for high-concentration continuous-flow nitrous oxide (50%-70%) and its use in young children. We set out to characterize the depth of sedation and incidence of adverse events associated with various concentrations of nitrous oxide used in a pediatric emergency department. This was a prospective observational study of nitrous oxide use for procedural sedation and analgesia in a tertiary children's hospital emergency department. Nitrous oxide concentration, adverse events, and sedation depth were recorded. Adverse events were categorized as mild or serious. Sedation depth was recorded on a sedation scale from 0 to 6. A total of 762 patients who were aged 1 to 17 years received nitrous oxide during the 2-year study period. A total of 548 (72%) received nitrous oxide 70%, and 101 (13%) received nitrous oxide 50%. Moderate or deep sedation with scores of < or = 2 occurred in 3% of patients who had received nitrous oxide 70% and no patients who had received nitrous oxide 50%. Mean sedation scores were 4.4 at nitrous oxide 70% and 4.6 at nitrous oxide 50%. Sixty-three (8.3%) patients sustained 70 mild and self-resolving adverse events, most of which were vomiting (5.7%); 2 (0.2%) patients had serious adverse events. There was no significant difference in adverse events rates between nitrous oxide 70% (8.4%) and nitrous oxide 50% (9.9%). There was no significant difference in the percentage of deep sedation when children who were < or = 3 years of age (2.9%) were compared with older children (2.8%). In this largest prospective emergency department series, high-concentration continuous-flow nitrous oxide (70%) was found to be a safe agent for procedural sedation and analgesia when embedded in a comprehensive sedation program. Nitrous oxide also seems safe in children aged 1 to 3 years.


The effects of coal dust on photosynthetic performance of the mangrove, Avicennia marina in Richards Bay, South Africa.
Richards Bay, on the northern KwaZulu-Natal coast, is the largest coal exporting port in South Africa. The coal is stored at the Richards Bay Coal Terminal (RBCT) prior to export. Dust from coal operations is a major problem in the Richards Bay area. In this study, we tested the hypothesis that coal dust adversely affects photosynthetic performance of Avicennia marina (Forssk.) Vierh., the dominant mangrove species in the harbour. Photosynthetic performance was determined on 10 trees by measuring carbon dioxide uptake and chlorophyll fluorescence parameters at two elevation sites and on upper and lower leaf surfaces that were covered or uncovered with coal dust. Measurements were made on five clear, sunny days at saturating light (>1,000 micromol m(-2)s(-1)) and high temperature (28-30 degrees C). Coal dust significantly reduced carbon dioxide exchange of upper and lower leaf surfaces by 17-39%, the reduction being generally greater on the lower leaf surface that is covered by a dense mat of trichomes and salt glands. The reduction in carbon dioxide exchange by coal dust was higher at the high elevation site that supported isolated dwarfed trees. The chlorophyll fluorescence data indicated that leaves coated with dust exhibited significantly lower photosystem II (PS II) quantum yield, lower electron transport rate (ETR) through PSII and reduced quantum efficiency of PSII (FvFm). The chlorophyll fluorescence data supported the gas exchange measurements and are consistent with reduced photosynthetic performance of leaves coated with coal dust.


Aging-Related Behavioral, Adiposity, and Glucose Impairments and Their Association following Prenatal Alcohol Exposure in the C57BL/6J Mouse.
People that experience prenatal alcohol exposure (PAE) may have behavioral and metabolic impairments, and it is unclear whether these remain stable or change with age. We assessed behavioral and metabolic endpoints across the lifespan in a mouse model of fetal alcohol spectrum disorder (FASD). Pregnant C57BL/6J mice received alcohol (ALC; 3 g/kg) or maltose-dextrin (control, CON) daily from embryonic day 8.5 to 17.5. Offspring were tested on accelerating rotarod, Y-maze, novel object recognition, and fear conditioning at 6 weeks and 10 and 17 months; females were also tested at 24 months. Body composition, fasting glucose, and glucose clearance were assessed at 18 months. Female but not male ALC mice had greater adiposity than age-matched CON from 7 months onward. At 18 months, male but not female ALC mice had reduced glucose clearance and ALC mice were more likely to have elevated fasting glucose. In the rotarod training session, ALC females performed worse than CON. In the Y-maze, significant exposure-age interactions affected ALC performance in both sexes versus age-match CON. For fear conditioning, all animals acquired the task and froze more at older ages. In both the context and cued tasks, there were exposure-age interactions and ALC animals frozen less than CON at 10 months. Correlation analysis revealed that fasting glucose and glucose clearance correlated with % of body fat in ALC but not in CON mice. Additionally, glucose intolerance and % body fat negatively correlated with performance in the rotarod, context learning, and novel object recognition tasks in ALC but not CON mice. All mice exhibit worsening of behavioral performance as they age, and PAE did not further exacerbate this. ALC but not CON mice displayed adiposity and glucose intolerance that correlate with their cognitive impairments, suggesting that these may be mechanistically related in PAE. Findings emphasize that FASD should be considered a whole-body disorder.


[Long-acting nitrate-induced changes in microcirculation and tissue oxygen balance in patients with coronary heart disease].
A total of 56 patients with Functional Class II angina pectoris and 25 healthy subjects were examined. Long-acting nitrates were ascertained to result in profound venular dilatation, slight arteriolar dilatation, moderately decreased erythrocyte aggregation and improvement of tissue oxygen supply. The most marked increase in exercise tolerance and reduction in the frequency of anginal attacks were noted in patients with normal and narrowed venules. There were no significant changes in microcirculation and exercise tolerance in patients with baseline dilated venules. It is concluded that the microvasculature may be one of the criteria for applying long-acting nitrates in patients with coronary heart disease on an individual basis.


IV access in bleeding trauma patients: a performance review.
Exsanguinating haemorrhage is a leading cause of death in severely injured trauma patients. Management includes achieving haemostasis, replacing lost intravascular volume with fluids and blood, and treating coagulopathy. The provision of fluids and blood products is contingent on obtaining adequate vascular access to the patient's venous system. We sought to examine the nature and timing of achieving adequate intravenous (IV) access in trauma patients requiring uncrossmatched blood in the trauma bay. We performed a retrospective chart review of all patients admitted to our trauma centre from 2005 to 2009 who were transfused uncrossmatched blood in the trauma bay. We examined the impact of IV access on prehospital times and time to first PRBC transfusion. Of 208 study patients, 168 (81%) received prehospital IV access, and the on-scene time for these patients was 5 min longer (16.1 vs 11.4, p<0.01). Time to achieving adequate IV access in those without any prehospital IVs occurred on average 21 min (6.6-30.5) after arrival to the trauma bay. A central venous catheter was placed in 92 (44%) of patients. Time to first blood transfusion correlated most strongly with time to achieving central venous access (Pearson correlation coefficient 0.94, p<0.001) as opposed to time to achieving adequate peripheral IV access (Pearson correlation coefficient 0.19, p=0.12). We found that most bleeding patients received a prehospital IV; however, we also found that obtaining prehospital IVs was associated with longer EMS on-scene times and longer prehospital times. Interestingly, we found that obtaining a prehospital IV was not associated with more rapid initiation of blood product transfusion. Obtaining optimal IV access and subsequent blood transfusion in severely injured patients continues to present a challenge.


A pilot study to test the feasibility of salt restriction in a community.
Index subjects were selected from the population of Milton studied in the May 1981 survey. Index subjects aged 64 or less with a systolic blood pressure 138-179 mmHg (18.35/23.8 kPa), including those on antihypertensive treatment, were invited to participate with their families. Index subjects were divided into two matched groups. One group was randomly assigned to be the control group and the other to be the salt-restriction group. Age, weight, height and 24-hour urinary excretion of sodium, potassium and creatinine at the start of the study in August 1981 were similar for the control and salt-restriction groups. When tested in November 1981, the salt-restriction group had achieved a reduction in 24-hour sodium excretion to a mean of 84 mmol for men and 70 mmol for women; corresponding values for the control groups were 150 and 120 mmol. A further test in March 1982 showed little further change. Potassium output changed very little. Attitudes to the low-salt diet varied, but 87 percent found it tolerable or actually preferable. There is no doubt that major reductions in sodium intake are feasible. However, if these are to be achieved on a large scale, food, manufacturers will need to offer a variety of low-sodium foods.


The Influence of State Anxiety on Fear Discrimination and Extinction in Females.
Formal theories have linked pathological anxiety to a failure in fear response inhibition. Previously, we showed that aberrant response inhibition is not restricted to anxiety patients, but can also be observed in anxiety-prone adults. However, less is known about the influence of currently experienced levels of anxiety on inhibitory learning. The topic is highly important as state anxiety has a debilitating effect on cognition, emotion, and physiology and is linked to several anxiety disorders. In the present study, healthy female volunteers performed a fear conditioning task, after being informed that they will have to perform the Trier Social Stress Test task (n = 25; experimental group) or a control task (n = 25; control group) upon completion of the conditioning task. The results showed that higher levels of state anxiety corresponded with a reduced discrimination between a stimulus (CS+) typically followed by an aversive event and a stimulus (CS-) that is never followed by an aversive event both during the acquisition and the extinction phase. No effect of state anxiety on the skin conductance response associated with CS+ and CS- was found. Additionally, higher levels of state anxiety coincided with more negative valence ratings of the CSs. The results suggest that increased stress-induced state anxiety might lead to stimulus generalization during fear acquisition, thereby impairing associative learning.


Cnidium officinale Makino: Phytology, Phytochemistry, Toxicology, Pharmacology and Prescriptions.
Cnidium officinale Makino (COM), a perennial herbaceous plant in the Apiaceous family, widely distribute in Eastern Asia and Asia-Temperate. It has a long history application as a traditional medicine for invigorating the blood and removing blood stasis, and also has been employed to diet, pesticide, herbal bathing materials, the cosmetic and skin care industry. However, there has been no associated review of literature in the past half a century (1967-2023). By searching the international authoritative databases and collecting 229 literatures closely related to COM, herewith a comprehensive and systematic review was conducted. The phytology includes plant distribution and botanical characteristics. The phytochemistry covers 8 major categories, 208 compounds in total, and the quantitative determination of 14 monomer compounds, total polyphenols and total flavonoids. Theclinical trial in pregnant woman and toxic experments mice, the pharmacology of 7 aspects and 82 frequently used prescriptions are summarized. It is expected that this paper will provide forward-looking scientific thinking and literature support for the further modern research, development and utilization of COM.


Liquid crystalline salen manganese(III) complexes. Mesomorphic and catalytic behaviour.
Several salen manganese(III) complexes displaying stable columnar mesophases in a wide range of temperatures have been synthesized. In condensed phases the molecules are assembled into dimers through intermolecular manganese-oxygen interactions and the columnar structure of the mesophases consist of the stacking of supramolecular discs formed by the association of two or three dimers, depending on the number and location of alkoxy chains in the complex. The catalytic activity of the complexes in solution has been studied, and they behave as efficient homogeneous catalysts in the epoxidation of styrene with iodosylbenzene as oxidant.


CD44 plays a functional role in Helicobacter pylori-induced epithelial cell proliferation.
The cytotoxin-associated gene (Cag) pathogenicity island is a strain-specific constituent of Helicobacter pylori (H. pylori) that augments cancer risk. CagA translocates into the cytoplasm where it stimulates cell signaling through the interaction with tyrosine kinase c-Met receptor, leading cellular proliferation. Identified as a potential gastric stem cell marker, cluster-of-differentiation (CD) CD44 also acts as a co-receptor for c-Met, but whether it plays a functional role in H. pylori-induced epithelial proliferation is unknown. We tested the hypothesis that CD44 plays a functional role in H. pylori-induced epithelial cell proliferation. To assay changes in gastric epithelial cell proliferation in relation to the direct interaction with H. pylori, human- and mouse-derived gastric organoids were infected with the G27 H. pylori strain or a mutant G27 strain bearing cagA deletion (∆CagA::cat). Epithelial proliferation was quantified by EdU immunostaining. Phosphorylation of c-Met was analyzed by immunoprecipitation followed by Western blot analysis for expression of CD44 and CagA. H. pylori infection of both mouse- and human-derived gastric organoids induced epithelial proliferation that correlated with c-Met phosphorylation. CagA and CD44 co-immunoprecipitated with phosphorylated c-Met. The formation of this complex did not occur in organoids infected with ∆CagA::cat. Epithelial proliferation in response to H. pylori infection was lost in infected organoids derived from CD44-deficient mouse stomachs. Human-derived fundic gastric organoids exhibited an induction in proliferation when infected with H. pylori that was not seen in organoids pre-treated with a peptide inhibitor specific to CD44. In the well-established Mongolian gerbil model of gastric cancer, animals treated with CD44 peptide inhibitor Pep1, resulted in the inhibition of H. pylori-induced proliferation and associated atrophic gastritis. The current study reports a unique approach to study H. pylori interaction with the human gastric epithelium. Here, we show that CD44 plays a functional role in H. pylori-induced epithelial cell proliferation.


CT-assessed large airway involvement and lung function decline in eosinophilic asthma: The association between induced sputum eosinophil differential counts and airway remodeling.
Eosinophilic asthma (EA) is a distinct clinical phenotype characterized by eosinophilic airway inflammation and airway remodeling. Few studies have used computed tomography (CT) scanning to assess the association between sputum eosinophil differential counts and airway involvement. We aimed to investigate the clinical characteristics and airway involvement of EA, and to examine the correlation between induced sputum eosinophil differential counts and CT-assessed airway remodeling. We retrospectively divided 63 patients with stable asthma receiving inhaled corticosteroids into 2 groups: 26 patients with EA (sputum eosinophil >3%) and 37 patients with non-eosinophilic asthma (NEA). Clinical measurements such as spirometry, fractional exhaled nitric oxide levels (FeNO), and CT-assessed indices of airway involvement were compared between the groups. Multivariate analysis was performed to identify determinants of the percentage of wall area (WA%). The EA group had significantly longer asthma duration, lower pulmonary function, and higher FeNO than the NEA group. Also, the EA group had higher WA% and smaller airway luminal area than the NEA group. Sputum eosinophil differential counts and WA% were positively correlated. The multivariate linear regression analysis showed that the factors associated with WA% included sputum eosinophil differential counts, age, and body mass index. However, asthma duration was not associated with WA%. Our CT-assessed findings demonstrated large airway involvement in EA, and we observed a positive association between induced sputum eosinophil differential counts and WA%. The findings indicate that induced sputum eosinophil differential counts may be associated with airway remodeling in patients with stable asthma.


Restorative neurosurgery of the cortex: resections of pathologies of the central area can improve preexisting motor deficits.
Different pathologies such as tumors or focal dysplasias can be removed from eloquent areas without subsequent functional deficits. What has not yet been established is the removal of structural abnormalities in sensorimotor area associated with substantial neurological deficits performed in order to accomplish functional improvement. Neurosurgical resections in highly eloquent areas thus hold promise to open a new field--achievement of functional restitution even in cases with long-standing deficits. We present four exemplary cases where the removal of different structural abnormalities led to an impressive improvement of motor deficits. One patient had bilateral ischemic lesion resulting from perinatal hypoxia, one cavernoma, and two focal cortical dysplasias. All presented with motor or sensorimotor deficits and three had long-standing therapy refractory focal seizures. The extent of safe lesionectomy was determined using fMRI, fiber tracking, and PET studies and performed with intraoperative functional neuronavigation guidance and cortical stimulation. The achievement of the planned amount of resection was verified with an intraoperative MR examination. New persisting neurological deficits after surgery were not registered. One patient had temporary worsening of the right hand weakness that rapidly resolved. One patient was completely seizure free, and in two patients, the seizures' frequency, duration, and severity were significantly reduced. The preoperatively disturbed motor function improved in all four cases in the course of days or weeks. In summary, pathological processes affecting the sensorimotor area may cause focal seizures and/or compromise sensorimotor functions. Lesionectomy may accomplish not only the amelioration of focal seizures but also substantial functional improvement.


In vitro soluble CD30 levels in patients with chronic stable coronary artery disease.
The CD30 antigen seems to play a costimulatory role in maintaining the physiological balance between T-helper (Th)1/Th2 immune responses. In this study, plasma and in vitro soluble CD30 (sCD30) secretion was investigated in patients with coronary artery disease (CAD) as a plausible marker of dysregulated immune response.Twenty one patients with angiographically confirmed CAD and 31 healthy controls took part in this study. The levels of the activation marker sCD30 were determined in plasma and phytohaemagglutinin (PHA)-stimulated and unstimulated peripheral blood mononuclear cell cultures by ELISA. Plasma sCD30 levels did not differ significantly between the patients and controls. However, spontaneous sCD30 secretion was significantly lower in patients with CAD compared to controls (p < 0.001). The soluble CD30 levels were significantly increased in the supernatant of PHA-stimulated PBMCs compared to unstimulated cultures in both groups of patients and controls (p < 0.001). PHA-stimulated sCD30 secretion was found to be lower in patients compared to controls; however, the difference was not statistically significant. Plasma sCD30 levels were not statistically different in patients with chronic stable CAD, a well-known Th1-mediated disease, compared to controls; whereas decreased spontaneous and PHA-stimulated sCD30 secretion in patients with CAD might indicate the progressive shift towards a Th1 immune response.


Neuropeptides and the Nodes of Ranvier in Cranial Headaches.
The trigeminovascular system (TGV) comprise of the trigeminal ganglion with neurons and satellite glial cells, with sensory unmyelinated C-fibers and myelinated Aδ-fibers picking up information from different parts of the head and sending signals to the brainstem and the central nervous system. In this review we discuss aspects of signaling at the distal parts of the sensory fibers, the extrasynaptic signaling between C-fibers and Aδ-fibers, and the contact between the trigeminal fibers at the nerve root entry zone where they transit into the CNS. We also address the possible role of the neuropeptides calcitonin gene-related peptide (CGRP), the neurokinin family and pituitary adenylyl cyclase-activating polypeptide 38 (PACAP-38), all found in the TGV system together with their respective receptors. Elucidation of the expression and localization of neuropeptides and their receptors in the TGV system may provide novel ways to understand their roles in migraine pathophysiology and suggest novel ways for treatment of migraine patients.