A multimodal assessment of the genetic control over working memory.
Working memory performance is significantly influenced by genetic factors. Here, we assessed genetic contributions to both working memory performance and neuroimaging measures focused on the network of brain regions associated with working memory by using a sample of 467 human participants from extended families. Imaging measures included diffusion tensor imaging indices in major white matter tracts thought to be associated with working memory and structural magnetic resonance imaging measures of frontal and parietal gray matter density. Analyses directly addressed whether working memory performance and neural structural integrity are influenced by common genetic factors (e.g., pleiotropy). While all cognitive measures, gray matter regions, and white matter tracts assessed were heritable, only performance on a spatial delayed response task and integrity of the superior longitudinal fasciculus (a primary fronto-parietal connection) shared genetic factors. As working memory may be a core component of other higher level processes, such as general intelligence, this finding has implications for the heritability of complex cognitive functions, as well as for our understanding of the transmission of cognitive deficits in mental and neurological disorders.


Protective Effect of Bioactivity Guided Fractions of Ziziphus jujuba Mill. Root Bark against Hepatic Injury and Chronic Inflammation via Inhibiting Inflammatory Markers and Oxidative Stress.
The tribal communities of North Eastern India rely on herbal medicine to cure various disease conditions. Ziziphus jujuba Mill. (Rhamnaceae) is one of such medicinal plants used for curing liver ailments, insomnia, anemia, diarrhea, diabetic complications, cancer, and loss of appetite. The present study was aimed to describe the protective ability of Z. jujuba root bark (ZJRB) against hepatic injury and chronic inflammation. Bioactivity guided fractionation of Z. jujuba methanol extract (ZJME) was performed using different solvents of increasing polarity viz. hexane (ZJHF), chloroform (ZJCF), ethyl acetate (ZJEAF), water (ZJWF), and residue (ZJMR). In vitro antioxidant results revealed that both ZJME and ZJWF possess strong antioxidant activity among all the fractions and mother extract tested. Further, ZJME and ZJWF showed significant protection against CCl4 intoxicated HepG2 cell lines by means of increased cell viability and decreased LDH levels compared to control group. ZJME at 200, 400 mg/kg and ZJWF at 50, 100 mg/kg inhibited the lipid peroxidation and significantly restored the liver function markers (AST, ALT, ALP, LDH, SOD, and CAT) and cytokine levels (TNF-α, Il-1β, and Il-10) in CCl4 induced acute liver damage in rats. All the results were comparable with standard drug silymarin which was further confirmed by histopathology analysis of liver. Similarly, inflammation and increase inflammatory cytokines levels of carrageenan induced paw edema in rats have been refurbished to normal levels on par with the standard drug indomethacin. ZJWF demonstrated potent response than ZJME in all the biological tests conducted. The results of the study signify the ability of ZJRB as good therapeutic agent for liver toxicity and chronic inflammation.


A Pilot Study to Examine the Effects of an Anti-inflammatory Supplement on Eicosanoid Derivatives in Patients with Chronic Kidney Disease.
Chronic kidney disease (CKD) is a progressive disease with an inverse relationship between kidney function and levels of inflammation and oxidative stress. Curcumin and Boswellia serrata have been reported to exert anti-inflammatory effects on the cyclooxygenase and lipoxygenase pathways. Therefore, the purpose of this study was to study the effects of a supplement containing curcumin and B. serrata on eicosanoid derivatives in early stage CKD patients who had not initiated hemodialysis. Sixteen patients with stage 2 and stage 3 CKD (56.0 ± 16.0 years, 171.4 ± 11.9 cm, 99.3 ± 20.2 kg) were randomized into a treatment group with curcumin and B. serrata or a placebo group. The dependent variables prostaglandin E2 (PGE2), 5-hydroxyicosatetraenoic acid, 12-hydroxyicosatetraenoic acid, 15-hydroxyicosatetraenoic acid, and 13-hydroxyoctadecadienoic acid were measured both before and after 8 weeks of supplementation. Results were analyzed by using a repeated-measures analysis of covariance for compliance and body-mass index. A significant group effect (p = 0.05), and a trend for Group × Time interaction (p = 0.056) were detected for PGE2. No significant differences were observed for any other variables. This is the first article of baseline levels of the dependent variables in early stage CKD, and the first article to show a significant effect of these supplements on PGE2 in early stage CKD. Further studies are needed to determine whether curcumin and B. serrata may be effective means to reduce inflammation in patients with CKD.


An orally active non-selective endothelin receptor antagonist, bosentan, markedly reduces injury in a rat model of colitis.
Activation of endothelial cells by vasoactive mediators, such as endothelins, may be an early, strategically important step in the initiation of inflammation in the intestine. In view of recent evidence that inflammatory bowel disease is associated with elevated intestinal concentrations of endothelins and upregulated expression of endothelin receptors on vascular endothelium in intestine, endothelins may become therapeutic targets in inflammatory bowel disease. The recent availability of an orally active, mixed endothelin receptor antagonist, bosentan, allowed us to examine the role of endothelins in a rat model of colitis. Colitis was induced by intra-rectal administration of trinitrobenzene sulphonic acid. In each treatment group, rats were treated with bosentan (10-60 mg/kg p.o.) 24 and 2 h prior to (pre-dose) or 1 h after the induction (post-induction) of colitis and all animals were treated every 24 h thereafter for 5 days. On day 6, stool consistency and the presence of adhesions in the peritoneal cavity were accessed. Colonic tissue samples were removed for determination of macroscopic and microscopic tissue injury, and myeloperoxidase activity. Colitis was typified by tissue ulceration in the distal colon and a corresponding 35-fold increase in myeloperoxidase activity compared to non-inflamed controls. Daily treatment with bosentan dose-dependently reduced colonic damage and myeloperoxidase activity when bosentan was given prior to induction of colitis. In the pre-dose group, the greatest beneficial effect of bosentan was observed at 60 mg/kg; colonic damage and granulocyte infiltration were attenuated by > 80%. A partial therapeutic effect of bosentan was also observed at 60 mg/kg when the pre-treatment regimen was excluded. These findings demonstrate that an orally active, mixed endothelin receptor antagonist has marked protective and therapeutic effects in an animal model of colitis.


Extended-spectrum [beta]-lactamase producing Escherichia coli: changing epidemiology and clinical impact.
This review discusses the recent findings (July 2008-January 2010) on extended-spectrum [beta]-lactamase (ESBL)-producing Escherichia coli, mainly focussed on the epidemiology and clinical impact of infections owing to this pathogen. CTX-M-producing E. coli, mainly the CTX-M-15 producers, has emerged and disseminated worldwide as an important cause of both nosocomial and community-onset infections. The clonal spread of the ST131 epidemic E. coli strain is linked not only to the CTX-M-15 pandemia but also to other ESBLs types. The most commonly reported risk factors for community-onset ESBL-producing E. coli infections are contact with healthcare centres, recent use of antimicrobial agents, and presence of comorbidities. But infections owing to ESBL-producing E. coli in patients without obvious risk factors can occur, probably related to the increase of healthy carriers colonized with this pathogen. The main significant predictor of mortality caused by ESBL-producing E. coli is inadequate initial antimicrobial therapy. Alternatives of treatment of severe ESBL-producing E. coli infections included carbapenems, amikacin, tigecycline, and [beta]-lactam/[beta]-lactamase inhibitor combinations; with some of them enough clinical evidence is lacking (tigecycline, [beta]-lactam/[beta]-lactamase inhibitor combinations). For urinary tract infections, fosfomycin and nitrofurantoin could be useful. The worldwide emergence of multiresistant ESBL-producing E. coli raises key therapeutic problems; interventions addressed to their quick detection and early appropriate antibiotic treatment and prevention are urgently needed.


Prospective computerized simulation of breast cancer: comparison of computer predictions with nine sets of biological and clinical data.
A computer program which accepts clinically relevant information can be used to predict breast cancer growth, response to chemotherapy, and disease-free survival. The computer output is patient individualized because the program is highly iterative and simulates up to 2500 patients with exactly the same clinical presentation. Computer predictions have been compared to a broad spectrum of breast cancer data, and a high degree of correlation has been established. There are numerous significant clinical implications which can be derived from the computer model. Among these are the following. (a) Breast cancer tumors do not grow continuously but may have up to five growth plateaus each lasting from a small fraction of a year up to approximately 8 yr. (b) Adjuvant chemotherapy, such as 6-mo treatment with cyclophosphamide-methotrexate-5-fluorouracil, does not eradicate tumors but just reduces the number of viable cells by a factor of 10 to 100 and sets the eventual growth back by several years. This may partially explain why the age-adjusted death rate from breast cancer has not changed in the past 50 yr. (c) The computer model challenges the underlying principles in support of short-term intensive adjuvant chemotherapy, namely Gompertzian kinetics and genetically acquired tumor resistance to drugs. (d) The computer model questions the evidence opposing long-term maintenance chemotherapy protocols and suggests that maintenance protocols should be reexamined.


The SF-36 Offers a Strong Measure of Mental Health Symptoms in Survivors of Acute Respiratory Failure. A Tri-National Analysis.
Survivors of acute respiratory failure commonly experience long-term psychological sequelae and impaired quality of life. For researchers interested in general mental health, using multiple condition-specific instruments may be unnecessary and inefficient when using the Medical Outcomes Study Short Form (SF)-36, a recommended outcome measure, may suffice. However, relationships between the SF-36 scores and commonly used measures of psychological symptoms in acute survivors of respiratory failure are unknown. Our objective is to examine the relationship of the SF-36 mental health domain (MH) and mental health component summary (MCS) scores with symptoms of depression, anxiety, and post-traumatic stress disorder (PTSD) evaluated using validated psychological instruments. We conducted a cross-sectional analysis of 1,229 participants at 6- and 12-month follow-up assessment using data from five studies from the United States, the United Kingdom, and Australia. Symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS), Depression Anxiety Stress Scales, the Davidson Trauma Scale, Impact of Event Scale (IES), and IES-Revised (IES-R). At 6-month assessment there were moderate to strong correlations of the SF-36 MH scores with HADS depression and anxiety symptoms (r = -0.74 and -0.79) and with IES-R PTSD symptoms (r = -0.60) in the pooled analyses. Using the normalized population mean of 50 on the SF-36 MH domain score as a cut-off, positive predictive values were 16 and 55% for substantial depression; 20 and 68% for substantial anxiety (Depression Anxiety Stress Scales and HADS, respectively); and 40, 44, and 67% for substantial PTSD symptoms (IES-R, IES, and Davidson Trauma Scale, respectively). Negative predictive values were high. The area under the receiver operating characteristics curve of the SF-36 MH score was high for depression, anxiety, and PTSD symptoms (0.88, 0.91, and 0.84, respectively). All results were consistent for the MCS, across the individual studies, and for the 12-month assessment. For researchers interested in general mental health status, the SF-36 MH or MCS offers a strong measure of psychological symptoms prevalent among survivors of acute respiratory failure. For researchers interested in specific conditions, validated psychological instruments should be considered.


Clinical outcomes after initial treatment of methicillin-resistant Staphylococcus aureus infections.
To evaluate the clinical outcomes associated with anti-methicillin-resistant Staphylococcus aureus (MRSA) antimicrobials. We reviewed a prospective database of 247 consecutive patients with clinically and microbiologically confirmed MRSA infections, hospitalized in 7 Japanese hospitals between April 2014 and March 2015, and treated with anti-MRSA pharmaceuticals. Survival was measured at 30 days. We examined the relationships between initial antimicrobial administered and survival and organ toxicity. HR and 95% CIs were calculated. Overall 30-day mortality was 12%. The lungs were infected in 105 (41%), skin and soft tissue in 73 (30%), and bones and joints in 21 (9%) patients. Bacteremia complicated the illness in 69 patients (28%). Among 5 pharmaceuticals, vancomycin was prescribed to 174 (71%), linezolid to 38 (16%), teicoplanin to 22 (9%), and daptomycin to 11 (5%) patients. Vancomycin tended to be associated with the lowest survival (HR=2.47; 95% CI=0.93-6.51; P=0.067), particularly in the lung-infected subgroup (HR=4.85; 95% CI=1.12-20.94; P=0.034) after adjustments for baseline illness severity. The incidence of renal dysfunction tended to be higher in patients with trough serum concentrations of vancomycin >15 mg/dL. In this observational study reflecting real-world conditions, vancomycin was associated with higher 30-day mortality and incidence of kidney dysfunction than other anti-MRSA agents. The significance of the differences observed among antimicrobials other than vancomycin is uncertain.


Evaluation of inflammatory cell biomarkers in chronic venous insufficiency.
Objective Inflammation has been implicated as a factor that may contribute to chronic venous insufficiency. The purpose of this study is to compare readily available inflammatory cell biomarkers, with an emphasis on neutrophil count, lymphocyte count, and neutrophil lymphocyte ratio, in patients with chronic venous insufficiency. We hypothesized that circulating leukocyte counts would be higher in the peripheral blood of patients with severe compared to mild chronic venous insufficiency. Methods We performed a retrospective medical record review of patients discharged from Ruby Memorial Hospital (Morgantown, WV, USA) with a primary diagnosis of chronic venous insufficiency. Patients were organized into two groups-mild and severe chronic venous insufficiency-based on the Clinical, Etiologic, Anatomic, and Pathophysiological classification system, and inflammatory cell counts were compared between groups. Results We observed a significantly higher neutrophil count ( p = .002) and neutrophil-lymphocyte ratio ( p = .005) in patients with severe chronic venous insufficiency compared to mild. Further, the neutrophil-lymphocyte ratio may be a useful predictor of chronic venous insufficiency severity. Conclusions We reported significant differences in inflammatory cell biomarkers between mild and severe chronic venous insufficiency, as well as provided support for the use of the neutrophil-lymphocyte ratio as a predictor of chronic venous insufficiency severity. These results may provide clinicians with additional insight to manage chronic venous insufficiency in patients and provide a framework for the development of novel treatment options targeting the immune system in chronic venous insufficiency.


More than Just a Game? Combat-Themed Gaming Among Recent Veterans with Posttraumatic Stress Disorder.
This article examines recent combat veterans' experiences of "first-person shooter" (FPS) gaming and its relationship to posttraumatic stress disorder (PTSD). Current PTSD treatment approaches increasingly use virtual reality (VR) technologies, which have many similarities with FPS games. To explore these similarities, this article presents six case studies from recently separated veterans in New York City who reported both current PTSD symptoms and regular use of combat-themed FPS games. In open-ended interviews, participants discussed a range of benefits as well as the importance of regulating use and avoiding particular contextual dimensions of gaming to maintain healthy gaming habits. Findings demonstrate the need for more comprehensive study and dissemination of best-practices information about FPS gaming in the context of combat-related PTSD symptomatology.


Accidental late PEG dislodgment in 3 cases with a narrow stoma: Bougie dilatation rescue.
Percutaneous Endoscopic Gastrostomy (PEG) is a simple and effective method of enteral nutrition in many patients who cannot take oral food. The accidental dislodgement of the PEG tube after the maturation of the gastro-cutaneous fistula (stoma) is called late dislodgement. If it is not detected early, the stoma lumen gets narrower; and does not permit the passage of the replacement tube. In this case, the commonly followed method is to continue enteral nutrition by opening a new gastro-cutaneous fistula after the complete closing of the original stoma. Here, we present a stoma-saving bougie dilatation method in 3 cases with severely narrowed stomas after late accidental dislodgement of the PEG tube.


Incorporation of curcumin in liquid nanodomains embedded into polymeric films for dermal application.
Liquid nanovehicles are gaining interest in drug delivery because of the high solubilization capacity of bioactives at their interface and enhanced permeation of compounds across physiological membranes. However, the dermal application of liquid nanovehicles is still limited. The goal of this research is to develop a dermal delivery system based on embedding of liquid nanovehicles into polymeric films, which will allow controlled release of the nanodroplets with the solubilized drug. In this study, we describe the incorporation of empty and curcumin-loaded nanodomains into polymeric film. The novel technology results in formation of homogeneous, transparent and elastic films with high (up to 85 wt%) loading capacity of nanodomains. The fundamental structural characterizations show that nanodomain structures embedded in the dry film are spontaneously reformed during the dermal application with similar droplets size of 10 nm. Ex-vivo release studies were performed on Franz diffusion cells and demonstrated a significant permeation of curcumin through the pig skin. This novel film technology can serve as a "solid platform reservoir" for liquid nanovehicles which enables controlled release of nanodroplets with solubilized bioactive.


Arrested development of bovine Ostertagia spp. and Cooperia spp. in New Zealand. Effect of temperature and duration of storage on infective larvae.
Infective larvae of Ostertagia spp. and Cooperia spp. derived from naturally infected dairy calves were subjected to periods of storage of up to 16 weeks at 4 degrees C or 15 degrees C to determine if this treatment would influence their propensity for arrested development in previously worm-free calves. Results showed no significant increase in the propensity of Ostertagia spp. for arrested development in response to the treatments, but a small increase in the case of Cooperia spp.


Histochemistry of aortic elastin in patients with nonspecific abdominal aortic aneurysmal disease.
Histochemical studies of nine aneurysmal aortas revealed a conspicuous deficiency of iron hematoxylin-reactive elastin in four specimens, in comparison with eight atherosclerotic control specimens. A fibrillar matrix that morphologically resembled elastin was demonstrated in these same specimens under ultraviolet light. The phenomenon of substantial preservation of features of medial architecture suggests that, if the pathogenetic mechanism is enzymatic destruction, the process is highly selective. Comparisons with differences in human fetal vs newborn aortas and in Blotchy mouse vs normal mouse aortas suggest superficial similarities. These latter observations suggest that a hypothesis of maturation arrest might be considered as an alternative to enzymatic destruction. Definitive experiments to test the relative importance of maturation arrest vs enzymatic destruction in the pathogenesis of aneurysmal disease will require further studies.


Temperature accounts for the biodiversity of a hyperdiverse group of insects in urban Los Angeles.
The urban heat island effect is a worldwide phenomenon that has been linked to species distributions and abundances in cities. However, effects of urban heat on biotic communities are nearly impossible to disentangle from effects of land cover in most cases because hotter urban sites also have less vegetation and more impervious surfaces than cooler sites within cities. We sampled phorid flies, one of the largest, most biologically diverse families of true flies (Insecta: Diptera: Phoridae), at 30 sites distributed within the central Los Angeles Basin, where we found that temperature and the density of urban land cover are decoupled. Abundance, richness, and community composition of phorids inside urban Los Angeles were most parsimoniously accounted for by mean air temperature in the week preceding sampling. Sites with intermediate mean temperatures had more phorid fly individuals and higher richness. Communities were more even at urban sites with lower minimum temperatures and sites located further away from natural areas, suggesting that communities separated from natural source populations may be more homogenized. Species composition was best explained by minimum temperature. Inasmuch as warmer areas within cities can predict future effects of climate change, phorid fly communities are likely to shift nonlinearly under future climates in more natural areas. Exhaustive surveys of biotic communities within cities, such as the one we describe here, can provide baselines for determining the effects of urban and global climate warming as they intensify.


[Reconstructive surgeries on deep femoral artery in chronic critical limb ischemia].
Possibilities of revascularisation of the lower extremity through the deep femoral artery in elderly and aged patients with chronic critical limb ischemia were evaluated. Forty-nine patients with high surgical risk were studied. Safety of the extremity, decrease of ischemia degree and level of amputation were the main problems in surgical treatment. Deep-femoral-popliteal index was very important. If this index was less 0.3 surgeries on deep femoral artery were effective. If index was 0.3-0.5 results of surgery were questionable. Index more than 0.5 is the factor of unsuccessful revascularisation through the deep femoral artery.


The molecular epidemiology of respiratory viruses associated with asthma attacks: A single-center observational study in Japan.
Few reports have described the significance of viral respiratory infections (VRIs) in exacerbation of asthma in adult patients. The aim of this study was to elucidate the profiles of VRIs in adult patients with asthma along with their molecular epidemiology.A cross-sectional observational study was conducted at Kyorin University Hospital from August 2012 to May 2015. To identify respiratory pathogens in inpatients and outpatients suffering from asthma attacks, RT-PCR/sequencing/phylogenetic analysis methods were applied alongside conventional microbiological methods. Phylogenetic and pairwise distance analyses of 10 viruses were performed.A total of 106 asthma attack patients enrolled in this study in both inpatient (n = 49) and outpatient (n = 57) settings. The total 106 respiratory samples were obtained from nasopharyngeal swab (n = 68) or sputum (n = 38). Among these, patients with virus alone (n = 39), virus and bacterial (n = 5), and bacterial alone (n = 5) were identified. The ratio of virus-positive patients in inpatient or outpatient to the total cases were 31.1% (n = 33) and 10.4% (n = 11), respectively. The frequency of virus-positive patients was significantly higher in inpatients (75.3%, n = 33) than in outpatients (19.3%, n = 11). Major VRIs included human rhinovirus (HRV) (n = 24), human metapneumovirus (hMPV) (n = 9), influenza virus (Inf-V) (n = 8), and respiratory syncytial virus (RSV) (n = 3) infections with seasonal variations. HRV-A and HRV-C were the most commonly detected viruses, with wide genetic divergence on phylogenetic analysis.Asthmatic exacerbations in adults are highly associated with VRIs such as HRV-A or HRV-C, hMPV, RSV, and Inf-V infections with seasonal variations and genetic divergence, but similar frequencies of VRIs occurred in asthma attack patients throughout the seasons.


Use of professional home care in persons with spinal cord injury in Switzerland: a cross-sectional study.
Persons with spinal cord injury (SCI) living in the community often require care. The boundaries between professional home care and informal care are blurred, and it is unclear who the typical user of home care is. The objective of this study was to describe the characteristics of persons with SCI using professional home care in Switzerland, determine the frequency of home care visits, and investigate the association of sociodemographic factors, SCI-specific characteristics, secondary health conditions, and functional independence with the use of home care. We used cross-sectional data from the 2017 community survey of the Swiss Spinal Cord Injury Cohort Study (SwiSCI). Out of 3,959 eligible individuals 1294 completed the questionnaire and were included in the analysis (response rate 33%). Using descriptive statistics, differences between home care users and non-users as well as the frequency of home care visits were investigated. The association between sociodemographic factors, SCI-specific characteristics, secondary health conditions, functional independence and the use of home care was analyzed using multivariable logistic regression. Multiple imputation was used to account for missing data. Of 1,294 participants, 280 (22%) used professional home care. The median weekly professional home care duration was 6 h (Q1 = 2, Q3 = 12). More home care was used in persons with lower functional independence (Odds ratio (OR) 0.30 per 10 unit decrease in the Spinal Cord Independence Measure, 95%-Confidence interval (CI) 0.24-0.37), fewer secondary health conditions (OR 0.96 per unit Spinal Cord Injury Secondary Conditions Scale, 95%-CI 0.94-0.99), tetraplegia (OR 2.77, 95%-CI 1.92-4.00), women (OR 2.42, 95%-CI 1.70-3.43), higher age (OR 1.22 per 10 years increase, 95%-CI 1.06-1.39), living alone (OR 2.48, 95%-CI 1.53-4.03), and those receiving support from an informal caregiver (OR 1.88, 95%-CI 1.27-2.77). This is the first study to examine the use of professional home care from the perspective of persons with SCI in Switzerland. Lower functional independence strongly predicts increased home care use. The findings showed that professional home care complements informal care and is more likely to be used by individuals with SCI who live alone, have tetraplegia, and are female.


Microwave-assisted synthesis of HKUST-1 and functionalized HKUST-1-@H3PW12O40: selective adsorption of heavy metal ions in water analyzed with synchrotron radiation.
A simple, rapid and efficient synthesis of the metal-organic framework (MOF) HKUST-1 [Cu3(1,3,5-benzene-tri-carboxilic-acid)2] by microwave irradiation is described, which afforded a homogeneous and highly selective material. The unusually short time to complete the synthesis by microwave irradiation is mainly attributable to rapid nucleation rather than to crystal growth rate. Using this method, HKUST-1-MW (MW=microwave) could be prepared within 20 min, whereas by hydrothermal synthesis, involving conventional heating, the preparation time is 8 h. Work efficiency was improved by the good performance of the obtained HKUST-1-MW which exhibited good selective adsorption of heavy metal ions, as well as a remarkably high adsorption affinity and adsorption capacity, but no adsorption of Hg(2+) under the same experimental conditions. Of particular importance is the preservation of the structure after metal-ion adsorption, which remained virtually intact, with only a few changes in X-ray diffraction intensity and a moderate decline in surface area. Synthesis of the polyoxometalate-containing HKUST-1-MW@H3PW12O40 afforded a MOF with enhanced stability in water, due to the introduced Keggin-type phosphotungstate, which systematically occluded in the cavities constituting the walls between the mesopores. Different Cu/W ratios were investigated according to the extrusion rate of cooper ions concentration, without significant structural changes after adsorption. The MOFs obtained feature particle sizes between 10-20 μm and their structures were determined using synchrotron-based X-ray diffraction. The results of this study can be considered important for potentially wider future applications of MOFs, especially to attend environmental issues.


Progenitor egress from the bone marrow after allergen challenge: role of stromal cell-derived factor 1alpha and eotaxin.
CCR3 expression on CD34+ cells mediates migration to eotaxin in vitro. CXCR4 and stromal cell-derived factor (SDF)-1alpha are important for stem cell homing to hemopoietic compartments. To study chemokine-mediated progenitor cell traffic in allergic inflammation. Bone marrow (BM) aspirates were obtained at baseline from normal subjects; atopic subjects without asthma; and subjects with asthma before, 5 hours after, and 24 hours after allergen inhalation (dual and early responders). Changes in chemokine receptor expression and migration were assessed. Expression of CXCR4, but not CCR3, on BM CD34+ cells was greater in normal subjects compared with atopic subjects with asthma. Likewise, SDF-1alpha, but not eotaxin, stimulated a greater migrational response by BM CD34+ cells from normal subjects compared with subjects with asthma. For all subjects, a positive correlation was found between intensity of CXCR4 expression and magnitude of CD34+ cell response to SDF-1alpha. Allergen inhalation attenuated both intensity of CXCR4 expression and SDF-1alpha levels in marrow from dual compared with early responders 24 hours postallergen. In contrast, the intensity of CCR3 expression on BM CD34+ cells increased in dual compared with early responders at 24 hours postallergen. In addition, an increase in migrational responsiveness of BM CD34+ cells to eotaxin and a decrease to SDF-1alpha 24 hours postallergen was found in dual responder subjects with asthma. After allergen inhalation in subjects with asthma, a downregulation in CXCR4 intensity on BM CD34+ cells and a reduction in BM SDF-1alpha levels may reduce progenitor retention to marrow stroma promoting peripheral egress, possibly mediated by the CCR3/eotaxin axis.


An interactive resource of molecular signalling in the developing human haematopoietic stem cell niche.
The emergence of definitive human haematopoietic stem cells (HSCs) from Carnegie Stage (CS) 14 to CS17 in the aorta-gonad-mesonephros (AGM) region is a tightly regulated process. Previously, we conducted spatial transcriptomic analysis of the human AGM region at the end of this period (CS16/CS17) and identified secreted factors involved in HSC development. Here, we extend our analysis to investigate the progression of dorso-ventral polarised signalling around the dorsal aorta over the entire period of HSC emergence. Our results reveal a dramatic increase in ventral signalling complexity from the CS13-CS14 transition, coinciding with the first appearance of definitive HSCs. We further observe stage-specific changes in signalling up to CS17, which may underpin the step-wise maturation of HSCs described in the mouse model. The data-rich resource is also presented in an online interface enabling in silico analysis of molecular interactions between spatially defined domains of the AGM region. This resource will be of particular interest for researchers studying mechanisms underlying human HSC development as well as those developing in vitro methods for the generation of clinically relevant HSCs from pluripotent stem cells.


Blood flow to the uterine tube (oviduct) of the early pregnant and pseudopregnant rabbit.
Blood flow to the uterus and uterine tube was measured in 46 rabbits in estrus and early pregnancy or pseudopregnancy. Uterine blood flow in estrus averaged 0.910 +/- 0.253 (SD) ml/g/minute and remained unchanged through postcoital day (PCD) 15. Blood flow to the uterine tube in estrus was 0.810 +/- 0.287 ml/g/minute. A peak blood flow of 1.323 +/- 0.424 ml/g/minute, was measured in the uterine tube on PCD 4, followed by a decrease of blood flow to estrous levels on PCD 8 to 15. The gross blood vasculature of the uterus uterine tube, and ovary was studied by intravascular silicone rubber injection in 17 rabbits. The architecture of the blood vascular system remained unchanged from estrus through early pregnancy or pseudopregnancy. The differences were vascularization of the corpus luteum, vascular accommodation of uterine distension, and enlargement of the lateral arcuate vein which spans the uterotubal junction.


The Role of Basal Forebrain Neurons in Adrenomyeloneuropathy in Mouse and Human.
X-linked adrenoleukodystrophy is caused by mutations in the peroxisomal half-transporter ABCD1. The most common manifestation is adrenomyeloneuropathy, a hereditary spastic paraplegia of adulthood. The study set out to understand the role of neuronal ABCD1 in mice and humans with adrenomyeloneuropathy. Neuronal expression of ABCD1 during development was assessed in mice and humans. ABCD1 deficient mice and human brain tissues were examined for corresponding pathology. Next, we silenced ABCD1 in cholinergic Sh-sy5y neurons to investigate its impact upon neuronal function. Finally, we tested adeno-associated virus vector mediated ABCD1 delivery to brain in mice with adrenomyeloneuropathy. ABCD1 is highly expressed in neurons located in the periaqueductal gray matter, basal forebrain and hypothalamus. In ABCD1-deficient mice (Abcd1-/y), these structures exhibited mild accumulations of α-synuclein. Similarly, healthy human controls had high expression of ABCD1 in deep gray nuclei, while X-ALD patients displayed increased levels of phosphorylated tau, gliosis and complement activation in those same regions, albeit not to the degree seen in neurodegenerative tauopathies. Silencing ABCD1 in Sh-sy5y neurons impaired expression of functional proteins and decreased acetylcholine levels, similar to observations in plasma of Abcd1-/y mice. Notably, hind limb clasping in Abcd1-/y mice was corrected through transduction of ABCD1 in basal forebrain neurons following intracerebroventricular gene delivery. Our study suggests that the basal forebrain-cortical cholinergic pathway may contribute to dysfunction in adrenomyeloneuropathy. Rescuing peroxisomal transport activity in basal forebrain neurons and supporting glial cells might represent a viable therapeutic strategy. This article is protected by copyright. All rights reserved.


White pupae phenotype of tephritids is caused by parallel mutations of a MFS transporter.
Mass releases of sterilized male insects, in the frame of sterile insect technique programs, have helped suppress insect pest populations since the 1950s. In the major horticultural pests Bactrocera dorsalis, Ceratitis capitata, and Zeugodacus cucurbitae, a key phenotype white pupae (wp) has been used for decades to selectively remove females before releases, yet the gene responsible remained unknown. Here, we use classical and modern genetic approaches to identify and functionally characterize causal wp- mutations in these distantly related fruit fly species. We find that the wp phenotype is produced by parallel mutations in a single, conserved gene. CRISPR/Cas9-mediated knockout of the wp gene leads to the rapid generation of white pupae strains in C. capitata and B. tryoni. The conserved phenotype and independent nature of wp- mutations suggest this technique can provide a generic approach to produce sexing strains in other major medical and agricultural insect pests.


Perceiving the target's state or state provoked by the target? An analysis of the descriptive and evaluative knowledge in person perception.
In line with the theory of traits as generalized affordances, the present article argues that target's states (TSs) and states provoked by a target (other's states (OSs) towards target) are two components of the meaning of traits referring, respectively, to a descriptive and to an evaluative knowledge of people. A preliminary study confirmed that TS and OS were equally representative of a trait. Two studies were designed to study the effects of practising the use of traits as either TS or OS categories (an induction procedure) on a subsequent person perception task, requiring participants to rate photographed targets on a series of traits. Results show that both the differentiation between targets and evaluative consistency of ratings were enhanced under the OS condition compared to TS and control (with no practice of traits) conditions. Importantly, Study 2 tends to show that the effects of the induction procedure are not limited to the practised traits but also generalize to unpractised traits. Implications of these findings for social perception research are discussed.


The Escherichia coli SOS mutagenesis proteins UmuD and UmuD' interact physically with the replicative DNA polymerase.
The Escherichia coli umuDC operon is induced in response to replication-blocking DNA lesions as part of the SOS response. UmuD protein then undergoes an RecA-facilitated self-cleavage reaction that removes its N-terminal 24 residues to yield UmuD'. UmuD', UmuC, RecA, and some form of the E. coli replicative DNA polymerase, DNA polymerase III holoenzyme, function in translesion synthesis, the potentially mutagenic process of replication over otherwise blocking lesions. Furthermore, it has been proposed that, before cleavage, UmuD together with UmuC acts as a DNA damage checkpoint system that regulates the rate of DNA synthesis in response to DNA damage, thereby allowing time for accurate repair to take place. Here we provide direct evidence that both uncleaved UmuD and UmuD' interact physically with the catalytic, proofreading, and processivity subunits of the E. coli replicative polymerase. Consistent with our model proposing that uncleaved UmuD and UmuD' promote different events, UmuD and UmuD' interact differently with DNA polymerase III: whereas uncleaved UmuD interacts more strongly with beta than it does with alpha, UmuD' interacts more strongly with alpha than it does with beta. We propose that the protein-protein interactions we have characterized are part of a higher-order regulatory system of replication fork management that controls when the umuDC gene products can gain access to the replication fork.


Physical Activity Patterns in Infants With and Without Down Syndrome.
Individuals with Down syndrome (DS) are at greater risk for obesity than their peers who are developing typically. One factor contributing to an early onset of obesity is low levels of physical activity (PA). However, there is little known regarding PA patterns during infancy. The purpose of this study was to examine the daily PA patterns in 22 infants developing typically and 11 infants with Down syndrome (aged 1-12 months) using Actigraph GT3X+ (wrist and ankle). No significant differences between groups were identified in PA counts at the ankle. Both groups produced significantly more PA at the wrist than at the ankle and PA counts increased across months in age. This study represents an important first step in establishing baseline PA patterns during infancy.


[Specific features of humoral immunity in cryptogenic fibrosing alveolitis patients].
Cryptogenic fibrosing alveolitis (CFA) is a severe autoimmune disease of unclear etiology and prognostically unfavorable. The complexity of the diagnostics of this disease makes it necessary to search for new methods; for this reason immunity in CFA patients must be studied. The study of humoral organ-specific, organ-unspecific and antibacterial immunity of CFA patients revealed that the latter differed from the members of the groups used for comparison by a higher frequency of positive reactions in EIA determinations of IgG antibodies to cytokeratin-8 and Moraxella catarrhalis antigens. In addition, only in CFA patients a high degree of correlation (r=0.88) between these results was established. This made it possible to propose to use these reactions for confirming the diagnosis of CFA and suggested the probable role of M. catarrhalis in triggering autoimmune reactions characteristic of this disease.


Molecular isomerization triggered by H2S to an NIR accessible first direct visualization of Ca2+-dependent production in living HeLa cells.
Few studies determined the role of intracellular labile Ca2+ in H2S homeostasis. Undoubtedly, fluorescent probes are powerful tools for exploring the question because of their unique advantages: non-destruction, visualization, and multi-levels imaging. Herein, a near-infrared (λem = 687 nm) and methylene blue chromophore-based fluorescent probe (MB1) for H2S was rationally developed. Based on its high sensitivity and selectivity, MB1 was employed to image the concentration change of H2S, upon stimulating it with ionomycin (a specific calcium ionophore). We found that the intracellular labile Ca2+ acted as a promotor for H2S production in living cells. Furthermore, cystathionine γ-lyase (CSE) might have functioned as a positive mediator of Ca2+-dependent H2S production. These direct and visible links for H2S/Ca2+ will help us to understand the complex signaling in a better way.


Assessment of consumption of marine food in Greenland by a food frequency questionnaire and biomarkers.
We studied the association and agreement between questionnaire data and biomarkers of marine food among Greenland Inuit. Cross sectional study. The study population comprised 2,224 Inuit, age 18+ (43% men); data collected 2005-2008 in Greenland. Using a food frequency questionnaire (FFQ), we calculated consumption of seal, whale, and fish (g/day) and as meals/month, intake of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), total N3, and mercury. We measured erythrocyte membrane fatty acids (FA) and whole blood mercury (Hg). Associations were assessed by Pearson correlation and agreement between the 2 methods was assessed by Bland-Altman plots depicting mean difference between the methods. Using multiple linear regressions, the associations were studied between whole blood mercury, erythrocyte FA and frequency or gram per day of seal, whale, and fish. Partial correlations ranged from r=0.16, p<0.0001 (DHA) to r=0.56, p<0.0001 (mercury). The best fitted lines were found for mercury and DHA. Mean difference was negative for mercury but positive for all the FA biomarkers. In a multiple logistic regression analysis, the best association was found between whole blood mercury and seal consumption, both as frequency in meals and actual intake gram per day: β=1.07 µg (95% CI: 1.06; 1.08) and β=1.04 µg (95% CI: 1.03; 1.04), respectively. Mercury showed the best correlation and agreement between calculated and measured values. Calculated actual intake in gram per day and frequency of meals showed similar associations with whole blood mercury and erythrocyte membrane FAs.


Randomized control trials using a tablet formulation of hyperimmune bovine colostrum to prevent diarrhea caused by enterotoxigenic Escherichia coli in volunteers.
Enterotoxigenic Escherichia coli (ETEC) is the leading cause of travelers' diarrhea. The aim of this study was to investigate the ability of a powdered extract of hyperimmune bovine colostrum to protect against diarrhea in volunteers challenged with ETEC. Tablets were manufactured from a colostrum extract from cattle immunized with 14 ETEC strains, including serogroup O78. Two separate randomized, double-blind, placebo-controlled trials involving 90 healthy adult volunteers were performed to investigate the ability of different tablet formulations to protect against diarrhea following an oral challenge with an O78 ETEC strain. The first study with 30 participants evaluated the efficacy of tablets, containing 400 mg of colostrum protein, taken thrice daily with bicarbonate buffer. This regimen conferred 90.9% protection against diarrhea in the group receiving the active preparation compared with the placebo group (p = 0.0005). The second study examined the efficacy of tablets containing 400 mg colostrum protein given with buffer (83.3% protection; p = 0.0004) or without buffer (76.7% protection; p = 0.007), and tablets containing 200 mg colostrum protein given without buffer (58.3% protection; p = 0.02), compared with placebo. The difference between buffered and unbuffered treatments was not significant (p > 0.1). Active tablet formulations were significantly more effective than placebo in protecting volunteers against the development of diarrhea caused by ETEC. These results suggest that administration of a tablet formulation of hyperimmune bovine colostrum containing antibodies against ETEC strains may reduce the risk of travelers' diarrhea.


Long-term naturalistic follow-up of patients with bipolar depression and mixed state treated with electroconvulsive therapy.
The aim of the present study was to evaluate the long-term outcome in a sample of patients with bipolar disorder with severe depression or mixed-state resistant to pharmacological treatment who have responded to electroconvulsive therapy (ECT). The study involved 36 patients with major depression (5 patients with bipolar I depression, and 14 patients with bipolar II depression) or mixed state (17 patients) treated with bilateral ECT delivered using a brief pulse stimulator Mecta 5000 Q on a twice-a-week schedule. The patients were evaluated before ECT (baseline) and 1 week after the ECT course (final score) using the Hamilton Depression Rating Scale, Mania Rating Scale, Brief Psychiatric Rating Scale, and Clinical Global Improvement. The Longitudinal Interval Follow-up Evaluation was administered every 16 weeks to assess time to relapse (defined as LIFE scores ≥5 for at least 2 consecutive weeks or as the need for hospitalization) and periods of response and remission. The mean duration of follow-up was 55.3 ± 30.4 weeks (range, 24-160 weeks). Thirteen patients (36.1%) showed a depressive relapse during the follow-up; the mean time (length) of depressive relapse was 20.4 ± 21.8 weeks (range, 2-60 weeks). Twenty-nine patients (80.5%) fulfilled the criteria for a full remission from depressive symptoms after 6.7 ± 7.9 weeks from the last ECT. Seventeen patients (47.2%) were in remission for more than 70% of the time. No manic episodes occurred during the follow-up, only 1 patient had a mixed episode, and 11 patients had a hypomanic episode. Electroconvulsive therapy showed a positive impact on the clinical course of severe and treatment-resistant patients with bipolar disorders, as suggested by the high number of weeks spent in remission during the follow-up period. In our study, the duration of depressive episode was related to early relapse during follow-up period.


TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells.
Non-small cell lung cancer (NSCLC) is one the types of cancer with higher prevalence and mortality. Apo2-Ligand/TRAIL is a TNF family member able to induce apoptosis in tumor cells but not in normal cells. It has been tested in clinical trials against different types of human cancer including NSCLC. However, results of clinical trials have shown a limited efficacy of TRAIL-based therapies. Recently we have demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) greatly improved TRAIL cytotoxic ability being capable of killing chemoresistant hematological cancer cells. In the present work we have extended the study to NSCLC. LUV-TRAIL-induced cytotoxicity was assessed on different NSCLC cell lines with different sensitivity to soluble TRAIL and on primary human tumor cells from three patients suffering from NSCLC cancer. We also tested LUV-TRAIL-cytotoxic ability in combination with several anti-tumor agents. LUV-TRAIL exhibited a greater cytotoxic effect compared to soluble TRAIL both in A549 cells and primary human NSCLC cells. LUV-TRAIL-induced cell death was dependent on caspase-8 and caspase-3 activation. Moreover, combination of LUV-TRAIL with other anti-tumor agents such as flavopiridol, and SNS-032 clearly enhanced LUV-TRAIL-induced cytotoxicity against NSCLC cancer cells. The novel formulation of TRAIL based on displaying it on the surface of lipid nanoparticles greatly increases its anti-tumor activity and has clinical potential in cancer treatment.


New insights in the pathogenesis of atopic disease.
A causal link between the increasing environmental pollution and the fast spreading of allergic diseases is currently discussed. The exogenic and endogenic noxious agents contributing to the total environmental load are primarily acting through immunotoxic, sensitizing and neurotoxic mechanisms in animal experiments and in humans. Beside classic allergic-triggering factors (allergen potency, intermittent exposure to different allergen concentrations, presence of microbial bodies and sensitizing phenols), the adjuvant role of environmental pollutants gains increasing importance in allergy induction. Our therapy experience with more than 18.000 atopic eczema patients shows that beside allergic reactions pseudoallergic mechanisms through toxic environmental agents (formaldehyde, industrial and traffic smog, wood preservatives, microbial toxins, additive-rich food, nicotine, alcohol, pesticides, solvents, amalgam-heavy metals) are increasingly incriminated as causal factors for the complex symptomatology. The avoidance and elimination of such triggering factors before and during pregnancy and in early childhood may result in a significant decrease of the incidence of atopic diseases.


Identification of sigma S-dependent genes associated with the stationary-phase acid-resistance phenotype of Shigella flexneri.
Shigella flexneri grown to stationary phase has the ability to survive for several hours at pH 2.5. This acid resistance, which may contribute to the low infective dose associated with shigellosis, is dependent upon the expression of the stationary-phase-specific sigma factor sigma S. Using random TnphoA and TnlacZ mutagenesis we isolated five acid-sensitive mutants of S. flexneri, which had lost their ability to survive at pH 2.5 for 2 h in vitro. Each transposon insertion with flanking S. flexneri DNA was cloned and sequenced. Database searches indicated that two TnlacZ mutants had an insertion within the hdeA gene, which is the first gene in the hdeAB operon. Acid resistance was restored in one of these mutants by a plasmid carrying the entire hdeAB operon. Further sequence analysis from the remaining TnlacZ and two TnphoA mutants demonstrated that they all had insertions within a previously unidentified open reading frame (ORF), which is directly downstream from the gadB gene. This putative ORF encodes a protein that has homology to a number of inner membrane amino acid antiporters. A 1.8 kb polymerase chain reaction (PCR) product containing this gene was cloned, which was able to restore acid resistance in each mutant. These fusions were induced during entry into late exponential phase and were positively regulated by RpoS. We confirmed that the expression of the acid-resistance phenotype in acidified minimal media was dependent upon the supplementation of glutamic acid and that this glutamate-dependent system was RpoS regulated. Southern hybridization revealed that both the gadC and hdeAB loci are absent in Salmonella. An rpoS deletion mutant of S. flexneri was also constructed to confirm the important role played by this gene in acid resistance. This rpoS- derivative was extremely acid sensitive. Two-dimensional gel electrophoresis of this mutant revealed that it no longer expressed 27 proteins in late log phase that were present in its isogenic parent. These data indicate that the expression of acid resistance in S. flexneri may be multifactorial and involve proteins located at different subcellular locations.


Measuring GLUT4 translocation in mature muscle fibers.
Skeletal muscle is the major tissue for postprandial glucose disposal. Facilitated glucose uptake into muscle fibers is mediated by increases in surface membrane levels of the glucose transporter GLUT4 via insulin- and/or muscle contraction-mediated GLUT4 translocation. However, the regulatory mechanisms controlling GLUT4 translocation in skeletal muscle have been difficult to characterize at the cell biology level due to muscle tissue complexity. Muscle cell culture models have improved our understanding of GLUT4 translocation and glucose transport regulation, but in vitro muscle models lack many of the characteristics of mature muscle fibers. Thus, the molecular and cellular details of GLUT4 translocation in mature skeletal muscle are deficient. The objective of this review is to highlight how advances in recent experimental approaches translate into an enhanced understanding of the regulation of GLUT4 translocation and glucose transport in mature skeletal muscle.


[Treatment of patients with fistulas on eventrated intestinal loops].
Treatment of 119 patients with unformed intestinal fistulas on eventrated loops is analyzed. Traditional method of treatment was used at 67 (56.3%) patients, 31 (46.3%) of them died. Original method of treatment was performed at 52 (43.7%) patients, 3 (5.8%) of them died. Fistulas on eventrated loops were diagnosed at 12 (10.1%) of 119 patients. Original method of treatment permits to reduce the rate of complications, lethality and hospital stay.


[Swelling properties and structural stability of spun protein fibers].
With spun protein fibers of casein and a mixture of casein and vegetable proteins results in a solution of sodium hydrogencarbonate an increased diameter of the protein fibers. The determination of this change makes possible an examination of the swellability and stability of the structure of protein fibers.


[Girolamo Fracastoro and the invention of syphilis].
Girolamo Fracastoro wrote two works on syphilis: his famous poem, in which he gave a name to the disease, and a prose treatise. From the comparison of these works, in this paper we have identified the combination of several approaches as main characteristic of his description. On the one hand Fracastoro followed the classical medical explanation that emphasized the corruption of the air in order to explain the origins of the disease. On the other hand, when referring to the forms of contagion, he stated clearly that the disease is contracted by direct contact with an infected person. It is possible then to talk of the "invention" of syphilis by Fracastoro since he combined the information empirically collected, with the renaissance medical traditional perspective.


The relation of conjunctival and corneal findings in severe ocular allergies.
Corneal lesions such as ulcers and erosions are major complications observed in patients with severe ocular allergic diseases. We aimed to look into the relationship between specific clinical conjunctival findings and the severity of corneal complications. Thirty eyes of 6 patients with vernal keratoconjunctivitis (VKC) and 13 patients with atopic keratoconjunctivitis (AKC) were evaluated in this study. Slit-lamp photographs of upper tarsal conjunctiva and cornea were used to evaluate the clinical findings objectively. The corneal findings and clinical findings of upper tarsal conjunctiva such as conjunctival injection, edema, the height of papillae, and mucous discharge were evaluated and graded. Statistical correlations between conjunctival findings and the severity of corneal damage were analyzed. Conjunctival injection and edema significantly correlated with the severity of corneal complications. The height of the papillae and the amount of mucous discharge did not correlate with the severity of corneal complications. Direct signs of inflammation such as injection and edema correlated with corneal damage. The height of papillae did not show a significant correlation with the corneal findings. Our results suggest that inflammation of the conjunctiva rather than mechanical factors may play a greater role in the formation of corneal damage in severe ocular allergies.


[Histologic changes in the lungs and heart in children with extrahepatic blockade of the portal circulation].
The lungs and heart of 16 children with extrahepatic block of portal circulation who had died of esophageal-gastric bleeding and postoperative complications were studied histologically. The signs of restructuring of the lung microcirculation bed showing development of secondary pulmonary hypertension were observed in all the patients regardless of the duration and degree of portal hypertension. This was manifested in hypertrophy of the artery walls of the 2nd and 3rd order, hyperelastosis and sclerosis of their intima. "Arterialization" of the wall of the lobular and interlobular veins, arterio-venous, veno-venular and glomus anastomoses, focal alveolar proteinosis, hyperplasia and metaplasia of bronchial epithelium were observed. Irregular hypertrophy and degeneration of cardiomyocytes up to necrosis of some units were found in the heart. Pericellular and perivascular sclerosis developed in the subendocardial areas.


SRPK1 and Akt Protein Kinases Phosphorylate the RS Domain of Lamin B Receptor with Distinct Specificity: A Combined Biochemical and In Silico Approach.
Activated Akt has been previously implicated in acting on RS domain-containing proteins. However, it has been questioned whether its action is direct or it is mediated by co-existing SR kinase activity. To address this issue we studied in detail the phosphorylation of Lamin B Receptor (LBR) by Akt. Using synthetic peptides and a set of recombinant proteins expressing mutants of the LBR RS domain we now demonstrate that while all serines of the RS domain represent more or less equal phosphoacceptor sites for SRPK1, Ser80 and Ser82 are mainly targeted by Akt. 3D-modeling combined with molecular dynamics (MD) simulations show that amongst short, overlapping LBR RS-containing peptides complying with the minimum Akt recognition consensus sequence, only those bearing phosphosites either at Ser80 or Ser82 are able to fit into the active site of Akt, at least as effectively as its known substrate, GSK3-β. Combined our results provide evidence that Akt kinases directly phosphorylate an RS domain-containing protein and that both the residues N-terminal the phosphosite and at position +1 are essential for Akt specificity, with the latter substrate position being compatible with the arginine residue of RS-repeats.


One View of the Current State of Understanding in Basal Ganglia Pathophysiology and What is Needed for the Future.
Deep Brain Stimulation (DBS), arguably, is the most dramatic development in movement disorders since the levodopa for Parkinson's disease. Yet, its mechanisms of action of DBS are unknown. However, DBS related research already has demonstrated that current concepts of basal ganglia pathophysiology are wrong. Specifically, the notion that over-activity of the globus pallidus interna causes parkinsonism, the basis for the most current theories, is no longer tenable. The development of any new theory will be aided by an understanding of how current theories are wrong and why have these flawed theories persist. Many of the problems of current theories are more matters of inference, assumptions, presumptions, and the accepted level of ambiguity than they are of fact. Consequently, it is imperative that these issues be addressed. Just as the inappropriate use of a tool or method is grounds for criticism, methods of reasoning are tools that can be used inappropriately and should be subject to discussion just as misuse of any other tool. Thorough criticism can provide very important lesions though the process could be mistaken as harsh or personal; neither is the case here. At the least, such analyzes can point to potential pitfalls that could be avoided in the development of new theories. As will be discussed, theories are important for the development of therapies but perhaps most important, for the acceptance of new therapies, as was the case for the recent resurgence of interest in surgical therapies.


Modified Gouy phase in optical resonators with mixed boundary conditions, via the Born-Oppenheimer method.
We investigate near-paraxial modes of high-finesse, plano-concave microresonators without using the paraxial approximation. The goal is to develop an analytical approach which is able to incorporate not only the spatial shape of the resonator boundaries, but also the dependence of reflectivities on angle of incidence. It is shown that this can be achieved using the Born-Oppenheimer method, augmented by a local Bessel wave approximation. We discuss how this approach extends standard paraxial theory. It is found that the Gouy phase of paraxial theory, which is determined purely by ray-optics, is no longer the sole parameter governing transverse mode splittings. The additional determining factor is the sensitivity with which boundary reflection phases depend on incident angle.


Inhibition of auxin transport from the ovary or from the apical shoot induces parthenocarpic fruit-set in tomato mediated by gibberellins.
Fruit-set in tomato (Solanum lycopersicum) depends on gibberellins and auxins (GAs). Here, we show, using the cv MicroTom, that application of N-1-naphthylphthalamic acid (NPA; an inhibitor of auxin transport) to unpollinated ovaries induced parthenocarpic fruit-set, associated with an increase of indole-3-acetic acid (IAA) content, and that this effect was negated by paclobutrazol (an inhibitor of GA biosynthesis). NPA-induced ovaries contained higher content of GA(1) (an active GA) and transcripts of GA biosynthetic genes (SlCPS, SlGA20ox1, and -2). Interestingly, application of NPA to pollinated ovaries prevented their growth, potentially due to supraoptimal IAA accumulation. Plant decapitation and inhibition of auxin transport by NPA from the apical shoot also induced parthenocarpic fruit growth of unpollinated ovaries. Application of IAA to the severed stump negated the plant decapitation effect, indicating that the apical shoot prevents unpollinated ovary growth through IAA transport. Parthenocarpic fruit growth induced by plant decapitation was associated with high levels of GA(1) and was counteracted by paclobutrazol treatment. Plant decapitation also produced changes in transcript levels of genes encoding enzymes of GA biosynthesis (SlCPS and SlGA20ox1) in the ovary, quite similar to those found in NPA-induced fruits. All these results suggest that auxin can have opposing effects on fruit-set, either inducing (when accumulated in the ovary) or repressing (when transported from the apical shoot) that process, and that GAs act as mediators in both cases. The effect of NPA application and decapitation on fruit-set induction was also observed in MicroTom lines bearing introgressed DWARF and SELF-PRUNING wild-type alleles.


Melatonin decreases estrogen receptor binding to estrogen response elements sites on the OCT4 gene in human breast cancer stem cells.
Cancer stem cells (CSCs) pose a challenge in cancer treatment, as these cells can drive tumor growth and are resistant to chemotherapy. Melatonin exerts its oncostatic effects through the estrogen receptor (ER) pathway in cancer cells, however its action in CSCs is unclear. Here, we evaluated the effect of melatonin on the regulation of the transcription factor OCT4 (Octamer Binding 4) by estrogen receptor alpha (ERα) in breast cancer stem cells (BCSCs). The cells were grown as a cell suspension or as anchorage independent growth, for the mammospheres growth, representing the CSCs population and treated with 10 nM estrogen (E2) or 10 μM of the environmental estrogen Bisphenol A (BPA) and 1 mM of melatonin. At the end, the cell growth as well as OCT4 and ERα expression and the binding activity of ERα to the OCT4 was assessed. The increase in number and size of mammospheres induced by E2 or BPA was reduced by melatonin treatment. Furthermore, binding of the ERα to OCT4 was reduced, accompanied by a reduction of OCT4 and ERα expression. Thus, melatonin treatment is effective against proliferation of BCSCs in vitro and impacts the ER pathway, demonstrating its potential therapeutic use in breast cancer.


Cardioprotection of ischaemic preconditioning is associated with inhibition of translocation of MLKL within the plasma membrane.
Necroptosis, a form of cell loss involving the RIP1-RIP3-MLKL axis, has been identified in cardiac pathologies while its inhibition is cardioprotective. We investigated whether the improvement of heart function because of ischaemic preconditioning is associated with mitigation of necroptotic signaling, and these effects were compared with a pharmacological antinecroptotic approach targeting RIP1. Langendorff-perfused rat hearts were subjected to ischaemic preconditioning with or without a RIP1 inhibitor (Nec-1s). Necroptotic signaling and the assessment of oxidative damage and a putative involvement of CaMKII in this process were analysed in whole tissue and subcellular fractions. Ischaemic preconditioning, Nec-1s and their combination improved postischaemic heart function recovery and reduced infarct size to a similar degree what was in line with the prevention of MLKL oligomerization and translocation to the membrane. On the other hand, membrane peroxidation and apoptosis were unchanged by either approach. Ischaemic preconditioning failed to ameliorate ischaemia-reperfusion-induced increase in RIP1 and RIP3 while pSer229-RIP3 levels were reduced only by Nec-1s. In spite of the additive phosphorylation of CaMKII and PLN because of ditherapy, the postischaemic contractile force and relaxation was comparably improved in all the intervention groups while antiarrhythmic effects were observed in the ischaemic preconditioning group only. Necroptosis inhibition seems to be involved in cardioprotection of ischaemic preconditioning and is comparable but not intensified by an anti-RIP1 agent. Changes in oxidative stress nor CaMKII signaling are unlikely to explain the beneficial effects.


Enhanced NIR radiation-triggered hyperthermia by mitochondrial targeting.
Mitochondria are organelles that are readily susceptible to temperature elevation. We selectively delivered a coumarin-based fluorescent iron oxide nanoparticle, Mito-CIO, to the mitochondria. Upon 740 nm laser irradiation, the intracellular temperature of HeLa cells was elevated by 2.1 °C within 5 min when using Mito-CIO, and the treatment resulted in better hyperthermia and a more elevated cytotoxicity than HeLa cells treated with coumarin iron oxide (CIO), which was missing the mitochondrial targeting unit. We further confirmed these results in a tumor xenograft mouse model. To our knowledge, this is the first report of a near-infrared laser irradiation-induced hyperthermic particle targeted to mitochondria, enhancing the cytotoxicity in cancer cells. Our present work therefore may open a new direction in the development of photothermal therapeutics.


Indole-3-acetic acid (IAA) synthesis in the biocontrol strain CHA0 of Pseudomonas fluorescens: role of tryptophan side chain oxidase.
Pseudomonas fluorescens strain CHA0 is an effective biocontrol agent against soil-borne fungal plant pathogens. In this study, indole-3-acetic acid (IAA) biosynthesis in strain CHA0 was investigated. Two key enzyme activities were found to be involved: tryptophan side chain oxidase (TSO) and tryptophan transaminase. TSO was induced in the stationary growth phase. By fractionation of a cell extract of strain CHA0 on DEAE-Sepharose, two distinct peaks of constitutive tryptophan transaminase activity were detected. A pathway leading from tryptophan to IAA via indole-3-acetamide, which occurs in Pseudomonas syringae subsp. savastanoi, was not present in strain CHA0. IAA synthesis accounted for less than or equal to 1.5% of exogenous tryptophan consumed by resting cells of strain CHA0, indicating that the bulk of tryptophan was catabolized via yet another pathway involving anthranilic acid as an intermediate. Strain CHA750, a mutant lacking TSO activity, was obtained after Tn5 mutagenesis of strain CHA0. In liquid cultures (pH 6.8) supplemented with 10 mM-L-tryptophan, growing cells of strains CHA0 and CHA750 synthesized the same amount of IAA, presumably using the tryptophan transaminase pathway. In contrast, resting cells of strain CHA750 produced five times less IAA in a buffer (pH 6.0) containing 1 mM-L-tryptophan than did resting cells of the wild-type, illustrating the major contribution of TSO to IAA synthesis under these conditions. In artificial soils at pH approximately 7 or pH approximately 6, both strains had similar abilities to suppress take-all disease of wheat or black root rot of tobacco. This suggests that TSO-dependent IAA synthesis is not essential for disease suppression.


[Research progression of extralevator abdominoperineal excision].
The application of extralevator abdomino-perineal excision (ELAPE) and total mesorectal excision has improved the prognosis of rectal cancer. However, compared with anterior resection for rectal cancer, the circumferential resection margin (CRM) positive rate and intraoperative perforation (IOP) rate are still high. The ELAPE can reduce the CRM positive rate and IOP rate, therefore reduce postoperative local recurrence rate and increase the survival rate of patients. The disadvantage of its trauma, longer operative time, and higher perineum complication in ELAPE is controversial. This review mainly discusses the key points of operative procedure, advantages and disadvantages, research status and development prospects of ELAPE.


Transcriptome and Metabolome Analyses Reveal Sugar and Acid Accumulation during Apricot Fruit Development.
The apricot (Prunus armeniaca L.) is a fruit that belongs to the Rosaceae family; it has a unique flavor and is of important economic and nutritional value. The composition and content of soluble sugars and organic acids in fruit are key factors in determining the flavor quality. However, the molecular mechanism of sugar and acid accumulation in apricots remains unclear. We measured sucrose, fructose, glucose, sorbitol, starch, malate, citric acid, titratable acid, and pH, and investigated the transcriptome profiles of three apricots (the high-sugar cultivar 'Shushanggan', common-sugar cultivar 'Sungold', and low-sugar cultivar 'F43') at three distinct developmental phases. The findings indicated that 'Shushanggan' accumulates a greater amount of sucrose, glucose, fructose, and sorbitol, and less citric acid and titratable acid, resulting in a better flavor; 'Sungold' mainly accumulates more sucrose and less citric acid and starch for the second flavor; and 'F43' mainly accumulates more titratable acid, citric acid, and starch for a lesser degree of sweetness. We investigated the DEGs associated with the starch and sucrose metabolism pathways, citrate cycle pathway, glycolysis pathway, and a handful of sugar transporter proteins, which were considered to be important regulators of sugar and acid accumulation. Additionally, an analysis of the co-expression network of weighted genes unveiled a robust correlation between the brown module and sucrose, glucose, and fructose, with VIP being identified as a hub gene that interacted with four sugar transporter proteins (SLC35B3, SLC32A, SLC2A8, and SLC2A13), as well as three structural genes for sugar and acid metabolism (MUR3, E188.8.131.52, and CSLD). Furthermore, we found some lncRNAs and miRNAs that regulate these genes. Our findings provide clues to the functional genes related to sugar metabolism, and lay the foundation for the selection and cultivation of high-sugar apricots in the future.


[Active radical surgical tactics in acute varicothrombophlebitis of the lower extremities].
The experience of surgical treatment of 170 patients for an acute varicothrombophlebitis of the lower extremities subcutaneous veins was summarized. There was proved the efficacy and safety of application of an acute radical surgical tactics for prophylaxis of the pulmonary artery thromboembolism and for radical treatment of varicose disease as well.


Long Noncoding RNA Nuclear Enriched Abundant Transcript 1 (NEAT1) Regulates Proliferation, Apoptosis, and Inflammation of Chondrocytes via the miR-181a/Glycerol-3-Phosphate Dehydrogenase 1-Like (GPD1L) Axis.
BACKGROUND Osteoarthritis (OA) is one of the most common chronic musculoskeletal diseases, yet to date it lacks effective therapeutic strategies. Increasing evidence suggests that long noncoding RNAs (lncRNAs) serve pivotal roles in the occurrence and development of OA. However, the possible molecular mechanism involving lncRNAs, such as nuclear enriched abundant transcript 1 (NEAT1), in OA progression is still unclear. MATERIAL AND METHODS First, NEAT1 and miR-181a expression in OA synovium tissues and normal synovium tissues were detected. Then, the effect of NEAT1 on modulating growth ability, apoptosis, and inflammation in OA chondrocytes was investigated by a series of loss-function experiments. Next, the correlation between NEAT1, miR-181a, and glycerol-3-phosphate dehydrogenase 1-like (GPD1L) was fully investigated. Finally, the downregulation of miR-181a was employed as a recovery experiment to explore the functional mechanism of NEAT1 in OA. RESULTS In the present study, we found that NEAT1 expression was downregulated in OA tissues, while miR-181a expression was prominently upregulated. Moreover, reduced expression of NEAT1 suppressed cell growth while elevating the apoptotic rate and increasing the abundance of inflammatory cytokines released in OA chondrocytes. Furthermore, we clarified that miR-181a was a direct sponge of NEAT1, and GPD1L was able to bind to miR-181a. Additionally, we found that downregulation of miR-181a was able to attenuate the effect of NEAT1 on apoptosis, inflammatory response, and proliferation in OA chondrocytes. CONCLUSIONS Our findings indicate that downregulation of NEAT1 aggravated progression of OA via modulating the miR-181a/GPD1L axis, providing a novel insight into the mechanism of OA pathogenesis.


Borderline Personality Disorder Symptom Severity and Sexually Transmitted Infection and HIV Risk in African American Incarcerated Men.
Sexually transmitted infections (STI)/HIV rates are disproportionately high among men involved in the criminal justice system. Mental health disorders, including personality disorders, are also elevated among inmates. Borderline personality disorder (BPD) may be an important risk factor for STI/HIV, yet remains relatively understudied, particularly among inmates. We used baseline data from Project DISRUPT, a cohort study of African American men being released from prison in North Carolina who were in heterosexual relationships at prison entry (n=189), to assess their STI/HIV risk in the 6 months before incarceration and BPD symptoms focused on emotional lability and relationship dysfunction. We created a continuous BPD symptom severity score and a dichotomous BPD indicator split at the top quartile of the score (BPD-TQ) to examine associations between BPD and STI/HIV outcomes using logistic regression. We also examined associations between individual symptoms and outcomes. After adjustment for sociodemographics and antisocial personality disorder, BPD-TQ was associated with sexual risk behaviors including multiple partnerships (adjusted odds ratio, 2.58; 95% confidence interval, 1.24-5.36) and sex with nonmonogamous partners (adjusted odds ratio, 2.54; 95% confidence interval, 1.17-5.51). Prevalence of previous STI (47.5% vs. 29.6%) and prevalent chlamydial infection (6.9% vs. 3.1%) seemed higher in those in BPD-TQ, although the associations were not statistically significant. Associations were similar to those with the continuous score. Borderline personality disorder symptoms most associated with STI/HIV risk were abandonment worry, mood swings, and shifts in opinions. Borderline personality disorder is strongly associated with STI/HIV risk in this sample. Researchers should further evaluate the relationship between STI/HIV and BPD, in addition to mood disorders.


123I-ioflupane brain SPECT and 123I-MIBG cardiac planar scintigraphy combined use in uncertain parkinsonian disorders.
We evaluated the clinical usefulness of the combined use of I-ioflupane brain single photon emission computed tomography (SPECT) and I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy in discriminating uncertain parkinsonism with vascular lesions in striatal nuclei at magnetic resonance imaging (MRI). Forty-three consecutive patients with uncertain parkinsonism and vascular lesions at MRI in striatal nuclei were retrospectively evaluated; the uncertain differential diagnosis was between Parkinson's disease and vascular parkinsonism (PD/VP) in 22 patients, between PD and other neurodegenerative parkinsonism (PD/PS) in 11 patients and between Lewy body dementia and Alzheimer disease (LBD/AD) in the remaining 10 cases. All patients underwent I-ioflupane SPECT with striatal dopaminergic activity determination as binding potentials (BP; cut-off: 3.3). I-MIBG cardiac planar scintigraphy was performed 2 weeks later, in early (15 minutes) and delayed (240 minutes) phases also calculating heart to mediastinum (H/M) ratio (cut-off: 1.56). I-Ioflupane uptake was normal in 9 patients with BP values >3.3, while it was reduced in 34/43 cases with BP values <3.3 at least in one of the striatal nuclei. I-MIBG uptake was normal in 21/43 patients (5 of whom with normal and 16 with I-ioflupane striatal defects) showing the H/M ratio >1.56 in all cases; the uptake was reduced in 22/43 cases, (4 of whom were normal and 18 were with I-ioflupane striatal defects) with the H/M ratio <1.56 in all cases. No statistical differences were found when early and delayed H/M ratios were mutually compared. Combining the 2 radioisotopic procedures, a more reliable diagnosis was achieved in 39/43 cases properly classifying 13 PD, 10 VP, 7 PS, 5 LBD, and 4 AD. However, the diagnosis remained uncertain in four patients with normal I-ioflupane and reduced I-MIBG uptake. The results of the present study confirmed that in uncertain parkinsonian syndromes associated with vascular lesions in striatal nuclei, brain I-ioflupane SPECT alone did not prove able to discriminate between the different forms of disease. Only the association with I-MIBG cardiac scintigraphy, also with the early acquisition alone, allowed the most appropriate diagnosis in 90.7% of our cases. However, patients with normal I-ioflupane and reduced I-I-MIBG uptakes need a close clinical and instrumental follow-up as sympathetic damage could precede striatal disorders in the early stage of PD and LBD.


Estimation of human herpesvirus 8 prevalence in high-risk patients by analysis of humoral and cellular immunity.
Immunocompromized individuals, such as patients with end-stage renal disease, transplant recipients, and HIV-infected patients, are at increased risk of acquiring human herpesvirus (HHV)-8 associated infectious complications. The prevalence of HHV-8 infection generally is determined by detection of immunoglobulin G. However, because serological assays differ greatly, estimations on the actual HHV-8 prevalence vary considerably. HHV-8-specific cellular and humoral immunity were analyzed in 128 controls, 73 patients on dialysis, 67 transplant recipients, and 69 HIV-infected patients with the use of flow cytometry and indirect immunofluorescence microscopy. A higher seroprevalence (from 13.7% to 44.9%) was confirmed for all groups of immunocompromised individuals as compared with healthy controls (3.9%). Among immunocompetent individuals, as little as 12.5% had HHV-8 reactive T-cell frequencies greater than the detection limit. In line with a higher seroprevalence in immunosuppressed patients, HHV-8-specific T cells were detectable in 30.1% of dialysis patients, 20.9% of transplant recipients, and 24.6% of HIV-infected individuals. When combining the individual presence of either HHV-8-specific antibodies or T cells or both, the prevalence of HHV-8 infection approached 15.6% in healthy individuals and 41.1%, 40.3%, and 55.1% in dialysis patients, transplant recipients, and HIV-infected individuals, respectively. The exclusive serological analysis considerably underestimates the prevalence of HHV-8 infection in all study groups. Thus, the combined quantitation of both humoral and cellular immunity may instead be a superior method to assign the individual HHV-8 status. Moreover, this study suggests that the relative contributions of humoral and cellular immunity in control of HHV-8 may be different depending on the type of immunodeficiency.


Molecular evolution of proadrenomedullin N-terminal 20 peptide (PAMP): evidence for gene co-option.
Posttranslational processing of proadrenomedullin generates two biologically active peptides, adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP). Sequence comparison of homologous proadrenomedullin genes in vertebrate evolution shows a high degree of stability in the reading frame for AM, whereas PAMP sequence changes rapidly. Here we investigate the functional significance of PAMP phylogenetic variation studying two of PAMP's better characterized physiological activities, angiogenic potential and antimicrobial capability, with synthetic peptides carrying the predicted sequence for human, mouse, chicken, and fish PAMP. All tested peptides induced angiogenesis when compared with untreated controls, but chicken and fish PAMP, which lack terminal amidation, were apparently less angiogenic than their human and mouse homologs. Confirming the role of amidation in angiogenesis, Gly-extended and free acid variants of human PAMP produced responses similar to the natural nonamidated peptides. In contrast, antimicrobial activity was restricted to human PAMP, indicating that this function may have been acquired at a late time during the evolution of PAMP. Interestingly, free acid human PAMP retained antimicrobial activity whereas the Gly-extended form did not. This fact may reflect the need for maintaining a tightly defined structural conformation in the pore-forming mechanism proposed for these antimicrobial agents. The evolution of PAMP provides an example of an angiogenic peptide that developed antimicrobial capabilities without losing its original function.


MLVA-16 Genotyping of Brucella abortus and Brucella melitensis Isolates from Different Animal Species in Egypt: Geographical Relatedness and the Mediterranean Lineage.
Brucellosis is a common zoonotic disease in Egypt. However, there are limited data available on the genetic diversity of brucellae circulating in Egypt and other Mediterranean areas. One hundred and nine Brucella (B.) strains were isolated from different animal species in thirteen Egyptian governorates. Multi-locus variable number tandem repeats (VNTRs) analysis (MLVA-16) was employed to determine the geographical relatedness and the genetic diversity of a panel of selected Egyptian strains (n = 69), with strains originating from Italy (n = 49), Portugal (n = 52), Greece (n = 63), and Tunisia (n = 4). Egyptian B. melitensis strains clustered into two main clusters containing 21 genotypes. Egyptian B. abortus strains clustered into three main clusters containing nine genotypes. The genotypes were irregularly distributed over time and space in the study area. Egyptian strains of B. melitensis showed MLVA-16 patterns closer to that of Italian strains. Egyptian B. abortus strains isolated from cattle share the same genotype with strains from Portugal and similar to strains from Italy with low genetic diversity. Strains with similar MLVA patterns isolated from different governorates highlight the movement of the pathogen among governorates. Hence, it may also reflect the long endemicity of brucellosis in Egypt with earlier dispersal of types and great local genetic diversity. Open markets may contribute to cross-species transmission and dissemination of the new types nationwide. The presence of West Mediterranean lineages of B. melitensis and relatedness of B. abortus strains from the studied countries is a result of the socio-historical connections among the Mediterranean countries. Transnational eradication of brucellosis in the Mediterranean basin is highly demanded.


Development of a web-based patient decision aid for initiating disease modifying anti-rheumatic drugs using user-centred design methods.
A main element of patient-centred care, Patient Decision Aids (PtDAs) facilitate shared decision-making (SDM). A recent update of the International Patient Decision Aids Standards (IPDAS) emphasised patient involvement during PtDA development, but omitted a methodology for doing so. This article reports on the value of user-centred design (UCD) methods for the development of a PtDA that aims to support inflammatory arthritis patients in their choice between disease modifying anti-rheumatic drugs (DMARDs). The IPDAS development process model in combination with UCD methods were applied. The process was overseen by an eight-member multidisciplinary steering group. Patients and health professionals were iteratively consulted. Qualitative in-depth interviews combined with rapid prototyping were conducted with patients to assess their needs for specific functionality, content and design of the PtDA. Group meetings with health professionals were organized to assess patients' needs and to determine how the PtDA should be integrated into patient pathways. The current literature was reviewed to determine the clinical evidence to include in the PtDA. To evaluate usability among patients, they were observed using the PtDA while thinking aloud and then interviewed. The combination of patient interviews with rapid prototyping revealed that patients wanted to compare multiple DMARDs both for their clinical aspects and implications for daily life. Health professionals mainly wanted to refer patients to a reliable, easily adjustable source of information about DMARDs. A web-based PtDA was constructed consisting of four parts: 1) general information about SDM, inflammatory arthritis and DMARDs; 2) an application to compare particular DMARDs; 3) value clarification exercises; and 4) a printed summary of patients' notes, preferences, worries and questions that they could bring to discuss with their rheumatologist. The study demonstrated that UCD methods can be of great value for the development of PtDAs. The early, iterative involvement of patients and health professionals was helpful in developing a novel user-friendly PtDA that allowed patients to choose between DMARDs. The PtDA fits the values of all stakeholders and easily integrates with the patient pathway and daily workflow of health professionals. This collaborative designed PtDA may improve SDM and patient participation in arthritis care.


Effect of soy-based meal replacement on weight loss: A systematic review and meta-analyses protocol.
Background: Obesity is a complex and multifactorial disease that is strongly associated with multiple comorbidities and mortality. Weight reduction in overweight and obese patients was highly desired to minimize future complications. Meal replacement is emerging as one of the effective tools to promote weight loss. Isoflavones and soy protein present in soybean are able to promote weight loss and alleviate obesity. Aim: Our systematic review aims to investigate the weight loss effect of soy-based meal replacement among the overweight and obese population. Methods: We will conduct a systematic review of RCTs that evaluated the effect of a soy-based meal replacement on weight loss in overweight and obese patients. The primary outcome of this review is weight loss. Besides that, we will assess BMI, body fat, waist circumference and hip circumference as the secondary outcome. We will search PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library. Two reviewers will independently screen titles and abstracts, review full texts, extract information and assess the risk of bias of individual studies. We will conduct meta-analyses using a random-effect model if sufficient data are available. If meta-analysis is not performed, we will present a systematic qualitative synthesis. Summary: This systematic review will identify the weight loss effect of soy-based meal replacement among the overweight and obese adult population. We expect the result may strengthen the evidence on the role of soy-based meal replacement in optimal body weight management.


Targeting the spindle assembly checkpoint for breast cancer treatment.
Breast cancer is the most common malignancy in women worldwide and the second leading cause of cancer deaths after lung cancer. As in other malignancies, aneuploidy is a common feature of breast cancer and influences its behavior. Aneuploidy has been linked to inappropriate activity of the spindle assembly checkpoint (SAC), a surveillance mechanism that, in normal cells, prevents anaphase onset until correct alignment of all chromosomes at the metaphase is achieved. Interestingly, the widely used anti-microtubule drugs, vinca alkaloids and taxanes, kill cancer cells through chronic arrest in mitosis as a consequence of chronic SAC activation. Deregulated SAC has been reported in breast cancer in many reports and presents an attractive therapeutic strategy. We present here a review of the current knowledge on the SAC defects and the underlying molecular mechanisms in breast cancer, and discuss the potential of SAC components as targets for breast cancer therapies.


ECTRIMS/EAN consensus on vaccination in people with multiple sclerosis: Improving immunization strategies in the era of highly active immunotherapeutic drugs.
With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy. To develop a European evidence-based consensus for the vaccination strategy of pwMS who are candidates for disease-modifying therapies (DMTs). This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions, and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk-benefit balance. Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in sub-populations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines, and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus. This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.


Developmentally regulated alternative splicing of densin modulates protein-protein interaction and subcellular localization.
Densin is a member of the leucine-rich repeat (LRR) and PDZ domain (LAP) protein family that binds several signaling molecules via its C-terminal domains, including calcium/calmodulin-dependent protein kinase II (CaMKII). In this study, we identify several novel mRNA splice variants of densin that are differentially expressed during development. The novel variants share the LRR domain but are either prematurely truncated or contain internal deletions relative to mature variants of the protein (180 kDa), thus removing key protein-protein interaction domains. For example, CaMKIIalpha coimmunoprecipitates with densin splice variants containing an intact C-terminal domain from lysates of transfected HEK293 cells, but not with variants that only contain N-terminal domains. Immunoblot analyses using antibodies to peptide epitopes in the N- and C- terminal domains of densin are consistent with developmental regulation of splice variant expression in brain. Moreover, putative splice variants display different subcellular fractionation patterns in brain extracts. Expression of green fluorescent protein (GFP)-fused densin splice variants in HEK293 cells shows that the LRR domain can target densin to a plasma membrane-associated compartment, but that the splice variants are differentially localized and have potentially distinct effects on cell morphology. In combination, these data show that densin splice variants have distinct functional characteristics suggesting multiple roles during neuronal development.


A fluorogenic C4N4 probe for azide-based labelling.
The design, synthesis and photophysical properties of a new fluorogenic probe are described. The structure is based on the recently identified 2,5-diaminopyrimidine (C4N4) fluorophore. The strain-promoted [3 + 2] cycloaddition of the azido-C4N4 probe furnished a triazole that exhibited more than 30-fold enhancement in fluorescence intensity as compared to the azide.


Investigational drugs in HIV: Pros and cons of entry and fusion inhibitors (Review).
Despite the profound changes and improvements reached in the field of HIV treatment, tolerability and adherence to highly active antiretroviral therapy remains a challenge. Furthermore, multi-experienced patients could take advantage of drugs with different mechanisms of action to combat the spread of resistance to actual therapy. For these reasons identification of new HIV drugs is crucial. Among all the molecules that at present are under investigation, entry and fusion inhibitors pose an interesting class owing to their peculiar characteristics, including prevention of entry of the virus into the human cells. In this study, we reviewed articles, clinical trials, and conference communications about all the drugs under investigation belonging to the class of entry and fusion inhibitors that are at least in phase I clinical trials.


Enantioselective complexation of chiral propylene oxide by an enantiopure water-soluble cryptophane.
ECD and NMR experiments show that the complexation of propylene oxide (PrO) within the cavity of an enantiopure water-soluble cryptophane 1 in NaOH solution is enantioselective and that the (R)-PrO@PP-1 diastereomer is more stable than the (S)-PrO@PP-1 diastereomer with a free energy difference of 1.7 kJ/mol. This result has been confirmed by molecular dynamics (MD) and ab initio calculations. The enantioselectivity is preserved in LiOH and KOH solutions even though the binding constants decrease, whereas PrO is not complexed in CsOH solution.


Synthesis of a Macroporous Conjugated Polymer Framework: Iron Doping for Highly Stable, Highly Efficient Lithium-Sulfur Batteries.
Porous conjugated polymers offer enormous potential for energy storage because of the combined features of pores and extended π-conjugated structures. However, the drawbacks such as low pore volumes and insolubilities of micro- and mesoporous conjugated polymers restrict the loading of electroactive materials and thus energy storage performance. Herein, we report the synthesis of iron-doped macroporous conjugated polymers for hosting sulfur as the cathode of high-performance lithium-sulfur (Li-S) batteries. The macroporous conjugated polymers are synthesized via in situ growth of poly(3-hexylthiophene) (P3HT) from reduced graphene oxide (RGO) sheets, followed by gelation of the composite (RGO- g-P3HT) in p-xylene and freeze-drying. The network structures of the macroporous materials can be readily tuned by controlling the chain length of P3HT grafted to RGO sheets. The large pore volumes of the macroporous RGO- g-P3HT materials (ca. 34 cm3 g-1) make them excellent frameworks for hosting sulfur as cathodes of Li-S batteries. Furthermore, incorporation of Fe into the macroporous RGO- g-P3HT cathode results in reduced polarization, enhanced specific capacity (1,288, 1,103, and 907 mA h g-1 at 0.05, 0.1, and 0.2 C, respectively), and improved cycling stability (765 mA h g-1 after 100 cycles at 0.2 C). Density functional theory calculations and in situ characterizations suggest that incorporation of Fe enhances the interactions between lithium polysulfides and the P3HT framework.


Identification of specific inhibin A-binding proteins on mouse Leydig (TM3) and sertoli (TM4) cell lines.
The binding of human inhibin A to cell surface binding proteins of mouse Leydig (TM3) and Sertoli (TM4) cell lines was investigated. Scatchard analysis identified two classes of inhibin A-binding sites on TM3 (K(d(1)) = 85 pM and 4,160 sites/cell; K(d(2)) = 520 pM and 12,500 sites/cell) and TM4 (K(d(1)) = 61 pM and 2,620 sites/cell; K(d(2)) = 520 pM and 10,400 sites/cell) cells. Compared with inhibin A, inhibin B only partially competed [(125)I]inhibin A binding (6-8%), whereas activin A competed weakly (<0.01%). Chemical cross-linking of [(125)I]inhibin A to both cell lines identified five [(125)I]inhibin A binding complexes with apparent molecular masses of 70, 95, 145, 155, and more than 200 kDa. Inhibin A displacement of [(125)I]inhibin A from each of these cross-linked species (ED(50) = 60-110 pM) closely resembled displacement from intact TM3 (ED(50) = 97 +/- 32 pM) and TM4 (ED(50) = 75 +/- 28 pM) cells, suggesting that all of these proteins are involved in the high affinity inhibin A binding complex. Immunoprecipitation of iodinated inhibin A complexed to TM3 and TM4 cells with an antibody against human betaglycan identified protein complexes of more than 200, 145, and 95 kDa. It is concluded that the high affinity binding complex for inhibin A found in these cell lines consists of betaglycan and several proteins of unknown identity and may represent the putative inhibin receptor complex.