A new class of peroxisome proliferator-activated receptor agonists with a novel binding epitope shows antidiabetic effects.
The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to improve insulin sensitivity and to lower serum triglyceride levels. All of the previously reported PPAR agonists form the same characteristic interactions with the receptor, which have been postulated to be important for the induction of agonistic activity. Here we describe a new class of PPARalpha/gamma modulators, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs). As shown by x-ray crystallography, the representative compounds BVT.13, BVT.762, and BVT.763, utilize a novel binding epitope and lack the agonist-characteristic interactions. Despite this, some compounds within the 2-BABA family are potent agonists in a cell-based reporter gene assay. Furthermore, BVT.13 displays antidiabetic effects in ob/ob mice. We concluded that the 2-BABA binding mode can be used to design isoform-specific PPAR modulators with biological activity in vivo.


Dynamic interferometry techniques for optical path length measurements.
Two dynamic interferometric techniques based on electrically tunable lasers are described and experimentally demonstrated. The first technique allows for measurements of small phase modulations in interferometers independently of dc drifts and low frequency noise in the interferometer. The second scheme is a true FM technique suited for continuous real-time noncontact measurements of the optical thickness of transparent materials.


Consensus-based recommendations for standardizing terminology and reporting adverse events for emergency department procedural sedation and analgesia in children.
Children commonly require sedation and analgesia for procedures in the emergency department. Establishing accurate adverse event and complications rates from the available literature has been difficult because of the difficulty in aggregating results from previous studies that have used varied terminology to describe the same adverse events and outcomes. Further, serious adverse events occur infrequently, necessitating the study of large numbers of children to assess safety. These limitations prevent the establishment of a sufficiently large database on which evidence-based practice guidelines may be based. We assembled a panel of pediatric sedation researchers and experts to develop consensus-based recommendations for standardizing procedural sedation and analgesia terminology and reporting of adverse events. Our goal was to create a uniform reporting mechanism for future studies to facilitate the aggregation and comparison of results.


Reconciling Imbalanced and Nonadiabatic Reactivity in Transition Metal-Oxo-Mediated Concerted Proton Electron Transfer (CPET).
Recently, there have been several experimental demonstrations of how the rates of concerted proton electron transfer (CPET) are affected by stepwise thermodynamic parameters of only proton (ΔG°PT) or electron (ΔG°ET) transfer. Semiclassical structure-activity relationships have been invoked to rationalize these linear free energy relationships, but it is not clear how they would manifest in a nonadiabatic reaction. Using density functional theory calculations, we demonstrate how a decrease in ΔG°PT can lead to transition state imbalance in a nonadiabatic framework. We then use these calculations to anchor a theoretical model that reproduces experimental trends with ΔG°PT and ΔG°ET. Our results reconcile predictions from semiclassical transition state theory with models that treat proton transfer quantum mechanically in CPET reactivity, make new predictions about the importance of basicity for uphill CPET reactions, and suggest similar treatments may be possible for other nonadiabatic reactions.


Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease.
Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3)+ Treg cells. Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4+ T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4+ T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4+ T cells were FOXP3+CD39+ Treg cells, which reside within the pool of memory CD4+CD25+CD127lowCD45RO+ Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3+CD39+ Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. This study provides the first estimation of FOXP3+CD39+ Treg cell frequency within circulating gluten-specific CD4+ T cells after oral gluten challenge of patients with celiac disease. FOXP3+CD39+ Treg cells comprised a major proportion of all circulating gluten-specific CD4+ T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis.


Autologous bone marrow derived mononuclear cells combined with β-tricalcium phosphate and absorbable atelocollagen for a treatment of aneurysmal bone cyst of the humerus in child.
Aneurysmal bone cyst is a benign, locally destructive lesion of bone. Based on progressive cortical thinning pathological fractures are common, and are often the presenting feature. Despite the long experience of orthopaedists, radiologists and pathologists with aneurysmal bone cyst there is limited knowledge regarding the cause of the lesion and optimal treatment. Common methods of treatment vary considerably in the literature, particularly in children. A large variety of bone substitutes have been used to fill the cystic lesions. To date there has been no graft material which can be regarded as completely satisfactory. Our experience with freshly isolated autologous bone marrow derived mononuclear cells combined with β-tricalcium phosphate and absorbable atelocollagen for bone formation is presented. The concept of this treatment is based on stimulation of natural events continuously present in living bone appear to be a reasonable and beneficial alternative to promote healing of bone cysts and offering both osteoinduction and osteoconductive features.


Cancer glycan epitopes: biosynthesis, structure and function.
Aberrant glycan epitopes are a classic hallmark of malignant transformation, yet their full clinical potential in cancer diagnostics and therapeutics is yet to be realized. This is partly because our understanding of how these epitopes are regulated remains poorly understood. In this review cancer glycan epitopes for the major glycan classes are summarized with a focus on their biosynthesis, structure and role in cancer progression. Their application as cancer biomarkers, in particular the more recent work on cancer glycoforms, and the advantages these offer over the glycan or protein alone are discussed. Finally, emerging concepts which expand on the current view of the cancer glycan epitope beyond the single structure, to patterns and the whole glycocalyx, are described. These new approaches that consider the cancer glycan epitope as a glycoform, or as a pattern of many epitope structures, are providing new targets both for cancer biomarkers and therapeutics currently in development at the bench and the clinic.


Sexually dimorphic morphology of hatchling snapping turtles (Chelydra serpentina) from contaminated and reference sites in the Great Lakes and St. Lawrence River basin, North America.
Some organochlorine pesticides and industrial chemicals may alter sexually dimorphic traits through endocrine disruption. Therefore, we examined a sexually dimorphic trait, precloacal length, of hatchling snapping turtles (Chelydra serpentina) incubated from 31 clutches from a heavily contaminated site (Hamilton Harbour, ON, Canada; n = 14), a moderately contaminated site (Akwesasne Mohawk Territory; n = 3), and from a reference site (Algonquin Provincial Park, ON, Canada; n = 14). The mean sum polychlorinated biphenyls from Algonquin were low (20.33 ng/g wet wt), but were high from both Hamilton and Akwesasne (2,956.28 and 3,377.0 ng/g wet wt, respectively). Organochlorine pesticides, such as dichlorodiphenyldichloroethylene, were low from Algonquin (1.67 ng/g wet wt), moderate from Akwesasne (10.00 ng/g wet wt), and relatively high from Hamilton (135.14 ng/g wet wt). At all sites, the precloacal length of male hatchlings was larger than that of females by an equal amount at any given body size. However, the precloacal length of both males and females from Hamilton increased with body size at a slower rate than of males and females from the other two sites. Our results support an earlier study that found differences in sexually dimorphic morphology of adult snapping turtles among contaminated and uncontaminated sites. Furthermore, these alterations in secondary sexual characteristics previously observed in adults likely are initiated early in development, and may result in permanent organizational changes in morphology.


Selective ratiometric red-emission detection of In3+ in aqueous solutions and in live cells using a fluorescent peptidyl probe and metal chelating agent.
Indium has been regarded as one of the most rarely used metal ions; however, the consumption of indium has increased intensively due to its increasing use in electrodes of liquid crystal displays (LCDs). In recent years, warnings have been issued about the toxicity of indium to aquatic ecosystems and humans. Thus, the development of efficient and selective detection methods for In3+ in aquatic environments as well as in live cells is highly required. However, the selective and sensitive detection of In3+ in the presence of trivalent metal ions and other metal ions is highly challenging. In the present study, we synthesized a fluorescent probe (1) for In3+ and Al3+ based on an unnatural peptide receptor and an aggregation-induced emission fluorophore and developed a selective fluorescent detection method for In3+ in aqueous solutions and live cells using the probe and a metal chelating agent. 1 recognized In3+ and Al3+ selectively among 19 metal ions in aqueous solutions depending on pH by the enhancement of the red emission at 600 nm and decrease in the green emission at 530 nm. 1 sensitively detected In3+ and Al3+ by ratiometric response in a wide pH range (3.5-7.4), and the ratiometric response was complete within 20 seconds in an aqueous buffered solution at pH 5.0. Interestingly, the addition of EDTA to the complex of 1 with In3+ or Al3+ did not induce the Al3+-free spectrum but instead induced the In3+-free spectrum; thus, In3+ and Al3+ could be easily differentiated. The detection limit of 1 for In3+ ions was 211 nM (R2 = 0.981) in purely aqueous solutions. The fluorescence ratiometric detection method using 1 could quantify low concentrations of In3+ in ground water and tap water. Fluorescence cell image studies revealed that the probe was cell-permeable, and low concentrations of In3+ inside the cells could be recognized by the enhancement of the red emission at 600 nm. The binding mode study via NMR, IR, and CD spectroscopy revealed how the peptide receptor of 1 interacted with In3+ and resulted in the enhancement of the red emission in an aqueous solution.


Transitional cell carcinoma of the endometrium: a case report and review of the literature.
We report a case of primary transitional cell carcinoma of the endometrium and review the literature which reveals only 12 cases described to date. The patient presented with postmenopausal bleeding, and there were no distinctive clinical features. An endometrial sample taken at hysteroscopy was reported as a poorly differentiated, papillary, nonserous carcinoma with probable squamous metaplasia. The tumor removed at hysterectomy and bilateral salpingo-oophorectomy was almost all transitional cell with small areas of endometrioid, glandular differentiation. Immunohistochemistry demonstrated a similar immunoprofile to endometrioid carcinoma of the endometrium and different from reported cases of transitional cell carcinoma of the ovary and of the urinary tract.


The evolutionary origin of the need to sleep: an inevitable consequence of synaptic neurotransmission?
It is proposed that the evolutionary origin of the need to sleep is the removal of neurotransmitters (NTs) that escape reuptake and accumulate in brain interstitial fluid (ISF). Recent work suggests that the activity of ionotropic postsynaptic receptors, rapidly initiated by binding of NTs to extracellular sites, is modulated over longer times by adsorption of these NTs to the lipid bilayers in which the receptors are embedded. This bilayer-mediated mechanism is far less molecularly specific than binding, so bilayer adsorption of NTs that have diffused into synapses for other receptors would modulate their activity as well. Although NTs are recycled by membrane protein reuptake, the process is less than 100% efficient; a fraction escapes the region in which these specific reuptake proteins are localized and eventually diffuses throughout the ISF. It is estimated that even if only 0.1% of NTs escape reuptake, they would accumulate and adsorb to bilayers in synapses of other receptors sufficiently to affect receptor activity, the harmful consequences of which are avoided by sleep: a period of efficient convective clearance of solutes together with greatly reduced synaptic activity.


An investigation of emotion dynamics in major depressive disorder patients and healthy persons using sparse longitudinal networks.
Differences in within-person emotion dynamics may be an important source of heterogeneity in depression. To investigate these dynamics, researchers have previously combined multilevel regression analyses with network representations. However, sparse network methods, specifically developed for longitudinal network analyses, have not been applied. Therefore, this study used this approach to investigate population-level and individual-level emotion dynamics in healthy and depressed persons and compared this method with the multilevel approach. Time-series data were collected in pair-matched healthy persons and major depressive disorder (MDD) patients (n = 54). Seven positive affect (PA) and seven negative affect (NA) items were administered electronically at 90 times (30 days; thrice per day). The population-level (healthy vs. MDD) and individual-level time series were analyzed using a sparse longitudinal network model based on vector autoregression. The population-level model was also estimated with a multilevel approach. Effects of different preprocessing steps were evaluated as well. The characteristics of the longitudinal networks were investigated to gain insight into the emotion dynamics. In the population-level networks, longitudinal network connectivity was strongest in the healthy group, with nodes showing more and stronger longitudinal associations with each other. Individually estimated networks varied strongly across individuals. Individual variations in network connectivity were unrelated to baseline characteristics (depression status, neuroticism, severity). A multilevel approach applied to the same data showed higher connectivity in the MDD group, which seemed partly related to the preprocessing approach. The sparse network approach can be useful for the estimation of networks with multiple nodes, where overparameterization is an issue, and for individual-level networks. However, its current inability to model random effects makes it less useful as a population-level approach in case of large heterogeneity. Different preprocessing strategies appeared to strongly influence the results, complicating inferences about network density.


Parental influences of sexual risk among urban African American adolescent males.
This study examined the influence of parental marital status, parent-child sexual communication, parent-child closeness on the HIV-related knowledge, safer-sex intentions, and behaviors of late adolescent urban African American males. The study employed a cross-sectional design with retrospective recall of salient parental influences and behaviors. Data were collected via paper-and-pencil questionnaire from 134 late adolescent African American males, 18 to 22 years of age, recruited from urban communities in and around Boston, Massachusetts. Data were analyzed using bivariate correlations, paired t tests, and regression modeling. Young men reported greater amounts of sexual communication with mothers than fathers (p < .001). Parent-child closeness was positively correlated with amount of parent-child sexual communication with both mothers and fathers (p < .001 for both). Parent-child closeness was, in turn, associated with greater condom use self-efficacy (p < .01), less permissive sexual attitudes (p < .001), fewer sexual partners (p < .01), and less unprotected sex (p < .01). Greater amounts of parent-child sexual communication were associated with fewer sexual risk behaviors, more consistent condom use, and greater intentions to use condoms in the future. There was evidence that parental influences on sexual risk behaviors and condom use intentions were mediated through young men's condom use self-efficacy, attitudes, and beliefs. These findings highlight the importance of the parent-child relationship and the role of parent-child communication between parents and sons. Further studies are needed to better understand the nature of father-son communication and develop strategies to help parents communicate effectively with sons. Evidence has shown that African American adolescent males are more likely to engage in high-risk sexual behaviors. Understanding the sexual risk communication between African American adolescent males and their parents is important to developing strategies in reducing sexual risk behavior.


A word of caution-when uniportal VATS should not be done.
Uniportal VATS (U-VATS) is gaining more and more popularity. Herein, we discuss the current status of adoption of the technique and-from a "laggard's" point of view-some situations when the use of U-VATS should be reconsidered. As we all do lack scientific evidence for the superiority of one minimally invasive approach over the other, these situations reflect a gut feeling rather than solid arguments. The article should raise awareness of currently discussed issues with minimally invasive approaches. Finally, it highlights the need for randomized controlled trials, if we really want to rank minimally invasive accesses.


Antioxidants are not useful in reducing both pain and inflammation in chronic pancreatitis.
Pain is the main clinical symptom of chronic pancreatitis at its early stages; then the pain tends to disappear during the progression of the disease. Several options have been proposed to treat pain and inflammation in chronic pancreatitis; medical, endoscopic or surgical treatments have been considered, and the controversy surrounding their efficacy is ongoing. One medical option is to use antioxidants for both preventing and curing the flare-ups of chronic pancreatitis. The data regarding this treatment are highly debated; some authors have reported their efficacy in reducing pain and inflammation whereas others have not. We have reviewed the current knowledge and recent patents on this topic and, at present, we do not recommend this therapeutic approach and additional studies are required for reconsidering this interesting therapeutic option.


An 8-week, randomized, controlled, clinical study of the use of a 0.1% chlorhexidine mouthwash by chronic periodontitis patients.
To evaluate the efficacy of a 2-week administration of a 0.1% chlorhexidine mouthwash in the short-term treatment of chronic periodontitis patients and the impact of this product when administered twice by pocket irrigation. Sixty patients were enrolled in a single-centre, placebo-controlled, randomized study with the blind allocation of product to two parallel groups. Clinical assessments were performed, and samples from six selected subgingival sites were collected for microbial analysis by culture at baseline, D15 and D56. Three of the six sites were randomly selected and were treated by subgingival irrigation with the same 0.1% chlorhexidine product at D0 and D7. A subsequent statistical analysis was performed using the paired Student's t-test and Wilcoxon rank sum test for within-group analyses; analysis of variance and the Kruskall-Wallis test were used for between-group analyses. Two-week treatment with a 0.1% chlorhexidine mouthwash slightly reduced the gingival inflammation associated with periodontitis. We observed a significant decrease in Gram-negative, facultative anaerobes and micro-aerophiles, and a significant increase in Gram-positive cocci. No increase in the treatment effect was demonstrated by irrigation of the periodontal pockets. The 0.1% chlorhexidine mouthwash showed limited beneficial effects in the treatment of periodontitis patients.


Prevalence and clinical significance of mammalian target of rapamycin phosphorylation (p-mTOR) and vascular endothelial growth factor (VEGF) in clear cell carcinoma of the ovary.
To determine the prevalence of mammalian target of rapamycin phosphorylation (p-mTOR) and vascular endothelial growth factor (VEGF) and any correlation with clinical characteristics and prognosis in ovarian clear cell carcinoma patients. Seventy four paraffin-embedded specimens of such carcinomas frompatients who underwent surgery, received adjuvant chemotherapy and were followed up at King Chulalongkorn Memorial Hospital during January 2002 to December 2008 were stained with rabbit monoclonal IgG p-mTOR and rabbit polyclonal IgG VEGF using immunohistochemical methods. Medical records were reviewed and clinical variables were analysed. The prevalence of positive p-mTOR in ovarian clear cell carcinoma was 87.9% and significantly higher in advance-stage than early-stage patients (100% versus 83.6%, P<0.05). Two-year disease free survival and 2-year overall survival in patients with positive p-mTOR expression were 60% and 69.2% with no differences from patients with negative p-mTOR expression (p>0.05). The prevalence of VEGF expression was 63.5% and significantly higher in chemo-sensitive than chemo-resistant patients (70.7% versus 37.5%, P<0.05). Two-year disease free survival and 2-year overall survival in patients with VEGF expression were 72.3% and 83% respectively which were significantly different from patients with negative VEGF expression (p<0.05 ). p-mTOR expression in ovarian clear cell carcinoma was significantly correlated with the stage of disease. VEGF expression was significantly correlated with chemosensitivity, and survival. Further studies of related targeted therapy might be promising.


Osteoinduction by bone morphogenetic protein 2-expressing adenoviral vector: application of biomaterial to mask the host immune response.
We constructed a human bone morphogenetic protein 2 (BMP-2)-expressing adenoviral vector, AxCABMP-2, which showed osteoinduction in immunosuppressed rats. In immunocompetent rats, new bone was not induced, because of the rapid elimination of transduced cells. Biomaterials such as collagen can be used as carriers for the delivery of DNA vectors, allowing prolonged expression of plasmid DNA in normal animals. We evaluated osteoinduction with AxCABMP-2 and atelopeptide type I collagen in immunocompetent rats. Collagen plus AxCABMP-2 (BMP group), collagen plus AxCALacZ (LacZ group), or collagen alone (CL group) was implanted into calf muscle pouches in immunocompetent rats, or AxCABMP-2 alone (injection group) was injected into the calf muscle. On days 3, 7, 14, and 21 after treatment, osteoinduction was evaluated. In the BMP group, bone formation was not observed on days 3 and 7. On day 14, radiographic formation was seen, but little bone formation was detected histologically. On day 21, new bone formation was observed both radiologically and histologically. In the other groups, osteoinduction was not found at any time. Immunohistochemical analysis on days 3 and 7 revealed decreased immunogenicity in the BMP group compared with the injection group. These findings suggested that collagen was an effective masking material for our vector.


Relationship of the angiotensin-converting enzyme gene polymorphism to glucose intolerance, insulin resistance, and hypertension in NIDDM.
The deletion (D) allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been shown to be associated with cardiovascular and renal diseases in diabetes mellitus, but the mechanism underlying this association is not known. In addition, recent studies of the effect of the ACE gene on blood pressure have yielded conflicting results. Therefore, we studied the association of the ACE gene I/D polymorphism with glucose intolerance and insulin resistance, and the contribution of this locus to genetic susceptibility to hypertension in non-insulin-dependent diabetic mellitus (NIDDM). We analysed the ACE genotype in 84 unrelated NIDDM patients with a known disease duration of less than 1 year and in 115 age- and sex-matched controls. The I/D polymorphism was determined by the polymerase chain reaction. There were no differences in ACE genotype distribution and allele frequencies between patients with NIDDM and nondiabetic controls. The frequencies of the D and I alleles in both groups were identical, viz., 0.65 and 0.35, respectively. The NIDDM patients with the DD genotype had significantly higher blood glucose levels in the oral glucose tolerance test than those with the other genotypes; the incremental glucose area under the curve in the order of II, ID, and DD was 7.2+/-2.4, 9.2+/-4.0, and 10.7+/-2.7 mmol/l x h (II vs ID vs DD, P=0.0066 by ANOVA). No significant difference was found between the ACE genotype and serum insulin values. Similarly, there were no differences in body mass index, blood pressure, or serum lipids between the three genotypes. Among the non-diabetic controls, there was no statistically significant association of the I/D polymorphism with serum lipids, blood glucose levels, serum insulin concentrations, or blood pressure values. In conclusion, NIDDM patients with the DD genotype have higher blood glucose levels and are more glucose intolerant; this may help to explain the reported association between the D allele and vascular complications in NIDDM.


[A result of surgical treatment for ductal adenocarcinoma of the head of the pancreas].
Ductal adenocarcinoma of the head of the pancreas can only be cured with pancreaticoduodenectomy. However, the prognosis after resection has been poor. This study analyzed the possible prognostic factors of resected ductal adenocarcinoma through pancreaticoduodenectomy in a single institution. Between Oct. 1994 and May. 2002, 81 patients underwent pancreatoduodenectomy for ductal adenocarcinoma of the head of the pancreas. Perioperative and pathologic factors were analyzed with univariate and multivariate analysis. The overall 5-year survival rate of the 81 patients was 10.8% with median survival of 11.8 months. Ninety-six percent of the patients were in stage IIa, IIb or III. In univariate analysis, factors favoring survival were as follows: CA19-9 antigen<or=200 U/mL (p=0.0055), no preoperative biliary drainage (p=0.018), operation time<or=6.5 hr (p=0.009), R0 (curative) resection (p=0.0001), negative gross vascular invasion (p=0.0012), tumor size<or=3 cm (p=0.002), T lesion<or=T3 (p=0.0014), no tumor necrosis (p=0.0041), no duodenal invasion (p=0.0004) and postoperative chemoradiation therapy (p=0.0365). In multivariate analysis, R0 resection (p<0.001), T lesion<or=T3 (p=0.03) and no duodenal invasion (p=0.001) were independent predictors of prognosis. In 20 patients, who had T lesion<or=T3 without duodenal invasion and R0 resection, the 5-year survival rate was 67.8%. After pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas, a favorable 5-year survival rate can be achieved in the group of patients who have T lesion<or=T3 without duodenal invasion and R0 resection.


Simple formulas for gauging the potential impacts of population stratification bias.
The case-control study design is popular for genetic association studies of complex human diseases. However, case-control studies may suffer from bias due to population stratification. In this paper, the authors present simple formulas that can set a limit to the havoc population stratification bias can wreak (the lower and upper bounds of the confounding rate ratio and the upper bound of the type I error rate). The authors demonstrate applications of these formulas using two examples. The formulas can help researchers make more prudent interpretations of their (potentially biased) results.


Improving the safety of cell therapy products by suicide gene transfer.
Adoptive T-cell therapy can involve donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation, the administration of tumor infiltrating lymphocyte expanded ex-vivo, or more recently the use of T cell receptor or chimeric antigen receptor redirected T cells. However, cellular therapies can pose significant risks, including graft-vs.-host-disease and other on and off-target effects, and therefore strategies need to be implemented to permanently reverse any sign of toxicity. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene-modified cells, preventing collateral damage to contiguous cells and/or tissues. The "ideal" suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of "all" and "only" the cells responsible for the unwanted toxicity. This review presents the suicide gene safety systems reported to date, with a focus on the state-of-the-art and potential applications regarding two of the most extensively validated suicide genes, including the clinical setting: herpes-simplex-thymidine-kinase and inducible-caspase-9.


The Impact of Financial Incentives on Service Engagement Among Adults Experiencing Homelessness and Mental Illness: A Pragmatic Trial Protocol.
Background: People experiencing homelessness and mental illness have poorer service engagement and health-related outcomes compared to the general population. Financial incentives have been associated with increased service engagement, but evidence of effectiveness is limited. This protocol evaluates the acceptability and impact of financial incentives on service engagement among adults experiencing homelessness and mental illness in Toronto, Canada. Methods: This study protocol uses a pragmatic field trial design and mixed methods (ClinicalTrials.gov Identifier: NCT03770221). Study participants were recruited from a brief multidisciplinary case management program for adults experiencing homelessness and mental illness following hospital discharge, and were randomly assigned to usual care or a financial incentives arm offering $20 for each week they attended meetings with a program provider. The primary outcome of effectiveness is service engagement, measured by the count of participant-provider health-care contacts over the 6-month period post-randomization. Secondary health, health service use, quality of life, and housing outcomes were measured at baseline and at 6-month follow-up. Quantitative data will be analyzed using descriptive statistics and inferential modeling including Poisson regression and generalized estimating equations. A subset of study participants and other key informants participated in interviews, and program staff in focus groups, to explore experiences with and perspectives regarding financial incentives. Qualitative data will be rigorously coded and thematically analyzed. Conclusions: Findings from this study will contribute high quality evidence to an underdeveloped literature base on the effectiveness and acceptability of financial incentives to improve service engagement and health-related outcomes among adults experiencing homelessness and mental illness.


Diagnosis of pulmonary embolism with helical C.T. scan.
To determine the role of helical C.T. scan in the diagnosis of pulmonary embolism. Radiology department, Aga Khan University Hospital. One year prospective study May 2001 to May 2002. Sixty patients suspected of having pulmonary embolism were included in this study. Helical C.T. scan chest was performed from aortic arch to lung bases with intravenous contrast medium. Images were acquired in mediastinal and lung windows. Image interpretation was performed on the console and hard copies for main branch and segmental thrombus. Fifteen patients were diagnosed of having pulmonary embolism on C.T. scan. Clinical correlation and follow up with pulmonary angiography and Doppler ultrasound of leg was carried out. Pulmonary angiography was performed in one patient with embolectomy done after confirmation of diagnosis. 8 patients had associated DVT confirmed on Doppler sonography. Sensitivity of helical C.T. is 93.75%, specificity 100% and positive predictive value 95.65%. Helical CT scan is a quick, easy and accurate imaging modality for diagnosing pulmonary embolism.


Liraglutide overdose: A case report and an updated review.
Little is known about liraglutide overdose and in particular its association with hypoglycemia. The aim of this study was to report on an accidental case of liraglutide overdose and to review similar cases in the literature. Here, we report a case of a young female presented with an accidental injection of 18 mg of liraglutide subcutaneously. She presented with relative hypoglycemia with gastrointestinal symptoms that resembled pancreatitis. We concluded with several implications and policies targeting accidental injections from the use of such medication and similar subcutaneous medications in clinical practice.


Role of Primary Care Clinicians in the Diagnosis and Treatment of LUTS and BPH.
Primary care clinicians are often responsible for the treatment of lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH). The combination of the compelling epidemiologic presence of BPH, compromised quality of life due to LUTS, and the availability of highly effective oral therapeutic agents, offers an opportunity for substantial clinical impact in the primary care setting. Evolving management pathways include utilization of both symptom-modifying treatment and disease-modifying treatment. Alpha blockers are excellent to provide symptomatic treatment, but do not alter long-term disease progression. Alpha reductase inhibitors provide therapy by reducing the need for surgical intervention and the incidence of acute urinary retention. The combination of alpha blockers and alpha reductase inhibitors will be best for some patients, typically those with large prostate glands in whom disease progression is most likely. Primary care clinicians will want to become more familiar with recent clinical trails that are shaping emerging therapeutic practice.


Physicochemical analysis of slip flow phenomena in liquids under nanoscale confinement.
Eyring theory employs the statistical mechanical theory of absolute reaction rates to analyse the transport mechanisms in fluids. A physicochemical methodology combining molecular dynamics (MD) and Eyring theory of reaction rates is proposed for investigating the liquid slip on a solid wall in the nanoscale domain. The method involves the determination of activation energy required for the flow process directly from the MD trajectory information and then calculate the important transport properties of the confined fluid from the activation energy. In order to demonstrate the universal applicability of the proposed methodology in nanofluidics, the slip flow behavior of argon, water and ionic liquid confined in various nanostructures has been investigated. The slip length is found to be size dependent in all the cases. The novelty of this method is that the variations in slip length are explained on the basis of molecular interactions and the subsequent changes in the activation energy.


How gambling harms others: The influence of relationship-type and closeness on harm, health, and wellbeing.
Concerned significant others (CSOs) can experience gambling-related harm, impacting their health and wellbeing. However, this harm varies depending on the type and closeness of the relationship with the person who gambles. We sought to determine the type and closeness of relationships that are more likely to experience harm from another person's gambling, and examine which aspects of health and wellbeing are related to this harm. We examined survey data from 1,131 Australian adults who identified as being close to someone experiencing a gambling problem. The survey included information on relationship closeness, gambling-related harm (GHS-20-AO), and a broad range of health and wellbeing measures; including the Personal Wellbeing Index (PWI), the 12-item Short Form Survey (SF-12), and the Positive and Negative Affect Schedule Short Form (PANAS-SF). CSOs in relationships where finances and responsibilities are shared were more likely to be harmed by another person's gambling problem, particularly partners (current and ex) and family members. This harm was most strongly associated with high levels of distress and negative emotions, impacting the CSO's ability to function properly at work or perform other responsibilities. Support and treatment services for CSOs should consider addressing the psychological distress and negative emotions commonly experienced by CSOs.


Metal-promoted intermolecular electron transfer in tetrathiafulvalene-thiacalix[4]arene conjugates and tetrachlorobenzoquinone.
In this work, two series of tetrathiafulvalene (TTF) and thiacalix[4]arene (TCA) conjugates (TTF-TCA) were designed by CuAAC click reactions. The results obtained from NMR and (1)H NMR NOE indicated that their conformations of thiacalix[4]arene framework may prefer to 1,3-alternate. The cyclic voltammograms of four TTF-TCA compounds containing electroactive TTF units were provided. Meanwhile, their intermolecular electron-transfer (ET) behaviors with tetrachlorobenzoquinone (Q) mediated by different metal ions, Sc(3+), Pb(2+), Ag(+), Cd(2+), and Zn(2+), in CH3CN-CH2Cl2 (V/V = 1:1) solution were studied and analyzed via UV-vis spectroscopy. It was determined that intermolecular ET between each TTF-TCA and Q ensemble was not observed without introduction of the metal ions mentioned above. The added specified metal ions most likely induced the intermolecular ET between TTF-TCA and Q ensemble, and the effects of Sc(3+) functions were the most imperative. The intermolecular ET also proved to be reliant on the structure of TTF-TCA, where TTF-TCA 7a and 7b were more effective than TTF-TCA 6a and 6b. The difference may be credited to TTF-TCA 7a or 7b possessing two independent TTF pendants and providing a more synergic coordination among the TTF radical cation and Q radical anion with a metal ion.


Massive head trauma as a cause of intravascular air.
Three examples of intravascular air caused by massive head trauma are presented. The basic types of air embolism are discussed and the pathophysiology in the three cases is offered. The association should be recognized to avoid misinterpretation of the radiographs.


Clinical Awareness and Acceptance of Sonographically Diagnosed Epiploic Appendagitis (EA): A Retrospective Analysis of EA in a Single Tertiary Academic Referral Center.
Purpose To describe the clinical awareness and acceptance of ultrasound-diagnosed acute epiploic appendagitis (EA) and their importance to avoid unnecessary therapeutic and imaging measures. Patients and Methods The data were obtained of n=54 patients with acute, localized, peritonitic pain and EA diagnosed by B-mode ultrasound and contrast-enhanced ultrasound examination from November 2003 to September 2020. All examinations were performed by a German Society for Ultrasound in Medicine (DEGUM) Level III qualified examiner. Based on documentation by the treating physicians, the clinical awareness and acceptance of EA diagnosis was determined in all patients and compared between subgroups diagnosed before 2013 and from 2013 onwards. In 2013, a local educational training program regarding the diagnosis of and therapy for EA was initiated for physicians. Results In all patients, EA was sonographically diagnosed by a DEGUM level III qualified examiner. At enrollment, EA was mentioned as a suspected clinical diagnosis in n=1/54 (1.9%) patient. Furthermore, in n=39/54 (72.2%) cases, the EA was documented and accepted by the treating physicians at the time of patient discharge as the final clinical diagnosis. The clinical acceptance was significantly higher from 2013 onwards compared with before 2013 (p<0.05). Moreover, in n=26/54 (48.1%) patients, unnecessary therapeutic measures were initiated, with no significant difference between pre-2013 and post-2013 numbers (p>0.05). Conclusion In our retrospective study, we showed that awareness and acceptance of the disease EA are low. Low diagnostic acceptance of EA by the clinician leads to unnecessary therapeutic and imaging measures and is a general problem related to rare diseases in the healthcare system.


TGFβ signalling pathway regulates angiogenesis by endothelial cells, in an adipose-derived stromal cell/endothelial cell co-culture 3D gel model.
This study aimed to investigate the role of the TGFβ signalling pathway in angiogenesis in a three-dimensional (3D) collagen gel model, with co-culture between adipose-derived stromal cells (ASCs) and endothelial cells (ECs). A 3D collagen gel, implanted with green fluorescent protein-labelled mouse ASCs and red fluorescent protein-labelled mouse ECs, was established in vitro. Phenomena of angiogenesis with or without type I TGFβ receptor inhibitor (LY2157299) treatment, were observed 7 days post-implantation, using confocal laser scanning microscopy. To detect expression of angiogenesis-related genes, semi-quantitative PCR and quantitative real-time PCR were conducted. Zymography was performed to explore secretion of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) after treatment with LY2157299 of 5, 10, 20 to 50 μm concentrations, for 24 h. Angiogenesis was found to be attenuated in co-culture gels after ASC and EC treatment with LY2157299. Genes VEGF-A, VEGF-B, VE-ca, FGF-1, FGF-2, PDGF, HGF, BMP-4 were significantly reduced in the presence of LY2157299 in both mono-cultured and co-cultured ECs. Furthermore, reduction in co-cultured ECs was prominent relative to mono-cultured ECs, while the same results did not occur to ASCs. We further confirmed that gelatinases secreted by ECs were reduced in a dose-dependent manner, after treatment with LY2157299. These results indicate that in ASC/EC co-culture, the TGFβ signalling pathway regulated angiogenesis via EC activity. Co-cultured ECs were regulated more significantly than mono-cultured ECs suggesting that inhibition of TGFβRI may regulate paracrine secretion of ASCs to further modulate EC angiogenesis.


Transplacental permeability of 125I-sfericase in mice.
125I-sfericase was administered intravenously into the tail vein of mice on day 20 of gestation at a dose of 1 mg/kg as sfericase. The penetrability of sfericase into the placenta, radioactivity levels, and precipitable high molecular 125I treated with TCA were measured in maternal blood and plasma and fetal homogenates collected at 20 and 90 min after i.v. injection. The radioactivity level in fetuses was considerably lower than that in dams at 20 min but almost comparable to that of dams at 90 min, indicating considerably good penetrability of the radioactivity into the placenta. However, after treatment with TCA, the content of high molecular 125I in fetuses was considerably lower than that in maternal blood. These results suggested that high molecular 125I degraded into a low molecular fraction while passing the placenta to reach the fetus.


Effect of Balance Training in Sitting Position Using Visual Feedback on Balance and Gait Ability in Chronic Stroke Patients.
Chronic stroke often results in balance and gait impairments, significantly impacting patients' quality of life. The purpose of this study was to investigate whether the combined effect of unstable surface balance training and visual feedback, based on proprioceptive neuromuscular stimulation in patients with chronic stroke, is effective in restoring balance and gait ability. A total of 39 chronic stroke patients were randomly assigned to a visual feedback combined with unstable surface balance training group (VUSBG), an unstable surface balance training group (USBG), or a conventional physical therapy group (CG). This study was conducted with the Trunk Impairment Scale, the Bug Balance Scale, the Timed Get Up and Go Test, and Gait Analysis. VUSBG and USBG improved function and gait (stride length and hip/knee flexion angle), but there was no significant difference in the CG group. Specific results showed that the stride length in the VUSBG improved by 25% (p < 0.05), and the hip/knee flexion angle improved by 18% (p < 0.05). The post-hoc analysis revealed that VUSBG had a greater impact on the hip/knee flexion angle relative to the other two groups, as well as gait velocity and stride length relative to CG. Visual feedback complex exercise based on the principle of proprioceptive neuromuscular facilitation could be an intervention strategy to improve gait speed, trunk stability, and mobility in chronic stroke patients.


Clinical utility of office-based cognitive predictors of fitness to drive in persons with dementia: A systematic review.
To perform a systematic review of evidence available regarding in-office cognitive tests that differentiate safe from unsafe drivers with dementia. A comprehensive literature search of multiple databases including Medline, CINAHL, PsychInfo, AARP Ageline, and Sociofile from 1984 to 2005 was performed. This was supplemented by a search of Current Contents and a review of the bibliographies of all relevant articles. English prospective cohort, retrospective cohort, and case-control studies that used accepted diagnostic criteria for dementia or Alzheimer's disease and that employed one of the primary outcomes of crash, simulator assessment, or on-road assessment were included. Two reviewers. The reviewers independently assessed study design, main outcome of interest, cognitive tests, and population details and assigned a Newcastle-Ottawa quality assessment rating. Sixteen articles met the inclusion criteria. Tests recommended by guidelines (e.g., the American Medical Association (AMA) and Canadian Medical Association guidelines) for the assessment of fitness to drive did not demonstrate robustly positive findings (e.g., Mini-Mental State Examination, Trails B) or were not evaluated in any of the included studies (e.g., Clock Drawing). Fifteen studies did not report any cutoff scores. Without validated cutoff scores, it is impossible to employ tests in a standardized fashion in front-line clinical settings. This study identified a research gap that will prevent the development of evidence-based guidelines. Recommendations to address this gap are that driving researchers routinely perform cutoff score analyses and that stakeholder organizations (e.g., AMA, American Geriatrics Society) sponsor consensus fora to review driving research methodologies.


[Overproduction of agouti-protein did not affect cAMP level but increased steroidogenesis in adrenal glands under forskolin stimulation].
Mutation Agouti yellow (Ay) in mice Ay/a results in overproduction of agouti protein (AP), adult onset of obesity, increased corticosterone responses to restrain stress as compared with a/a mice (absence of AP). The enhanced corticosterone response in restrained Ay/a-mice compared with restrained a/a-mice occurred in result of increased adrenal reactivity to ACTH. The purpose of this work was to investigate the influence of AP overproduction on adenylate cyclase (AC) activity and steroidogenesis in forskolin stimulated adrenal cells. To estimate obesity influence, these parameters were measured in young (3 weeks) and adult (15 weeks) animals. The data obtained demonstrated that AP overproduction and the obesity did not affect the AC activity. However, forskolin stimulated corticosterone production in Ay/a-mice was higher than in a/a-mice (in young--during 0.5 h, in adult--during 3 hrs of incubation). So AP overproduction and obesity affect the corticosterone production. We hypothesize that AP overproduction affects steroidogenesis gene expression: accelerates gene activation in ontogenesis and increases enzyme de novo synthesis during long-term stimulation in adults.


Role of G-proteins in odor-sensing and CO2-sensing neurons in Drosophila.
A central question in insect chemoreception is whether signaling occurs via G-proteins. Two families of seven-transmembrane-domain chemoreceptors, the odor (Or) and gustatory receptor (Gr) families, have been identified in Drosophila (Clyne et al., 1999, 2000; Vosshall et al., 1999). Ors mediate odor responses, whereas two Grs, Gr21a and Gr63a, mediate CO2 response (Hallem et al., 2004; Jones et al., 2007; Kwon et al., 2007). Using single-sensillum recordings, we systematically investigate the role of Galpha proteins in vivo, initially with RNA interference constructs, competitive peptides, and constitutively active Galpha proteins. The results do not support a role for Galpha proteins in odor sensitivity. In parallel experiments, manipulations of Galpha(q), but not other Galpha proteins, affected CO2 response. Transient, conditional, and ectopic expression analyses consistently supported a role for Galpha(q) in the response of CO2-sensing neurons, but not odor-sensing neurons. Genetic mosaic analysis confirmed that odor responses are normal in the absence of Galpha(q). Ggamma30A is also required for normal CO2 response. The simplest interpretation of these results is that Galpha(q) and Ggamma30A play a role in the response of CO2-sensing neurons, but are not required for Or-mediated odor signaling.


Children's beliefs about smoking.
Children's beliefs about smoking were examined in a multi-ethnic urban sample of 4th through 7th grade children. Results showed that, relative to those in earlier grades, children in higher grades held more positive beliefs about the positive outcomes of smoking and the long-term negative consequences of smoking, but there was no association between grade level and beliefs about the immediate negative consequences of smoking. Children in higher grades also perceived more favorable norms toward smoking. There were few gender or race/ethnicity differences at these ages in children's beliefs about smoking. These outcome and normative beliefs were related to smoking behavior. Of the nine beliefs about the effects of smoking, all but two were significantly related to smoking behavior.


Pooling, meta-analysis, and the evaluation of drug safety.
BACKGROUND: The "integrated safety report" of the drug registration files submitted to health authorities usually summarizes the rates of adverse events observed for a new drug, placebo or active control drugs by pooling the safety data across the trials. Pooling consists of adding the numbers of events observed in a given treatment group across the trials and dividing the results by the total number of patients included in this group. Because it considers treatment groups rather than studies, pooling ignores validity of the comparisons and is subject to a particular kind of bias, termed "Simpson's paradox." In contrast, meta-analysis and other stratified analyses are less susceptible to bias. METHODS: We use a hypothetical, but not atypical, application to demonstrate that the results of a meta-analysis can differ greatly from those obtained by pooling the same data. In our hypothetical model, a new drug is compared to 1) a placebo in 4 relatively small trials in patients at high risk for a certain adverse event and 2) an active reference drug in 2 larger trials of patients at low risk for this event. RESULTS: Using meta-analysis, the relative risk of experiencing the adverse event with the new drug was 1.78 (95% confidence interval [1.02; 3.12]) compared to placebo and 2.20 [0.76; 6.32] compared to active control. By pooling the data, the results were, respectively, 1.00 [0.59; 1.70] and 5.20 [2.07; 13.08]. CONCLUSIONS: Because these findings could mislead health authorities and doctors, regulatory agencies should require meta-analyses or stratified analyses of safety data in drug registration files.


The structural determination and skeletal ring modes of tetrahydropyran.
A high-resolution molecular spectroscopy study was carried out on the cyclic ether tetrahydropyran (THP), one of the smallest molecules composed of a pyranose ring. As this ring structure is closely related to carbohydrates, THP can offer relevant insight into structural variations of this unit. Thus, an extensive probe of THP using three broadband instruments ranging from the microwave to the far-infrared (2-8 GHz, 75-110 GHz and 100-650 cm-1 frequency ranges) was performed to accrue both accurate sets of rotational constants and structural information. This array of experimental setups provided an accurate set of data to improve the description of the ground state of THP and revise the principal parameters of its backbone structure. The structural information was deduced from the assignment of the 13C and 18O isotopologues present in natural abundance. In addition, the complementary dataset obtained from these experiments led to a better characterization of the vibrational motions involving the skeletal ring of the molecule. In particular, the vibrational frequencies of four of these modes (ν23 (∼250 cm-1), ν22 (∼403 cm-1), ν21 (∼430 cm-1), and ν20 (∼562 cm-1)) have been determined from the analysis of the first rotationally resolved vibrational spectrum reported for THP. Quantum-chemical calculations aided in the analysis of the experimental results.


External longitudinal splitting of the biceps brachii muscle for coverage of repaired brachial vessels: an anatomical study and clinical application.
The external longitudinal splitting of the biceps brachii muscle offers a convenient and safe method for covering exposed vessels in the medial aspect of the arm in cases with loss of soft tissue. This anatomical study reveals rather variable and inconsistent patterns of blood supply to the biceps brachii muscle. The common denominator among the patterns is the fact that the nutrient vessels to the muscle originate in its posterior deep surface and course thereafter in a fan shape upward to the surface of the anterior aspect of the muscle. This microcirculatory pattern permits the external longitudinal splitting of the biceps brachii muscle along the whole anteromedial aspect of the short-headed belly without compromising its blood supply and function. An illustrative case is described.


Accuracy of Pulmonary Nodule Sampling Using Robotic Assisted Bronchoscopy with Shape Sensing, Fluoroscopy, and Radial Endobronchial Ultrasound (The ACCURACY Study).
Despite recent advances in guided bronchoscopy, the yield of bronchoscopic biopsy of a peripheral pulmonary nodule (PPN) remains highly variable. The aim of the study was to evaluate which features of robotic assisted bronchoscopy (RAB) contribute to a successful biopsy in a cadaver model. A preclinical, prospective, single-blinded trial using a ventilated human cadaveric model assessed the successful puncture of implanted pulmonary nodules using various localization techniques with RAB. The different approaches included positioning the robotic catheter at predefined distances from the target nodule (<10 mm, 10-20 mm, 20-30 mm), bronchoscopist correction of divergence between the software virtual map and bronchoscopic view if observed, and impact of fluoroscopy and radial endobronchial ultrasound (rEBUS). The primary endpoint was a central target hit (defined as an inner 2/3 target puncture) verified by cone-beam computed tomography. Thirty-eight RAB procedures were performed to target 16 PPNs. Median nodule size was 16.2 mm. All targets were located in the outer 1/3 of the lung with a bronchus sign in 31.3%. Central target hit rates were improved when the robotic catheter tip was closer to the nodule (<10 mm 68%, 10-20 mm 66%, 20-30 mm 11%, p < 0.001). Multivariable analysis confirmed the strongest predictor of a central target hit was robotic catheter distance to nodule (OR 0.89 per increase in 1 mm, p < 0.001), independent of the presence of a bronchus sign, divergence or concentric rEBUS view. Utilizing a RAB platform, closer proximity of the robotic catheter to the target nodule results in an increase in peripheral nodule biopsy success.


Enteric parasites can disturb leptin and adiponectin levels in children.
Infection by intestinal parasites in childhood may be the main cause of many health-related problems in developed countries such as anemia, anorexia, loss of appetite, retarded growth and development. The aim of the present study was to assess the effect of different intestinal parasites on white adipose tissue hormones. Eighty-one children infected by different parasites and 35 apparently healthy children were enrolled in this study. All patients and controls were subjected to clinical examination, measurement of body mass index (BMI) and laboratory examination. For BMI percentiles, there was a significant increase in serum leptin level (p = 0.042) and a significant decrease in serum adiponectin level (p = 0.039) in uninfected children, whereas there were no significant changes in the infected group (p = 0.068 and 0.082 respectively). A significant increase in leptin and decrease in adiponectin levels were observed for E. histolytica, Strongyloides and E. histolytica and Giardia infections compared to the control group (p = 0.047, 0.035 and 0.019 for leptin, and p = 0.025, 0.038 and 0.041 for adiponectin, respectively). The infection by some intestinal parasites may deregulate the secretion of leptin and adiponectin and also affect the absorption of some nutrients which can disturb the BMI and cause anorexia.


A new panenteric capsule endoscopy-based strategy in patients with melena and a negative upper gastrointestinal endoscopy: a prospective feasibility study.
patients presenting with melena and nondiagnostic esophagogastroduodenoscopy are usually investigated with colonoscopy and if negative, with small bowel capsule endoscopy. In this pilot study, we tested feasibility and performance of panenteric capsule endoscopy (PCE) in patients presenting with melena and negative esophagogastroduodenoscopy. Between January and December 2018, consecutive patients presenting with melena, clinically significant bleeding and negative esophagogastroduodenoscopy were invited to undergo PCE by swallowing PillCam Colon 2 (Medtronic Inc., Dublin, Ireland). PCE results, further diagnostic or therapeutic examinations, rebleeding rates at 30 days and 12 months were recorded. Out of 128 patients with melena, 23 had negative esophagogastroduodenoscopy. Of them, 12 (8 female, mean age 76 years) underwent PCE, which allowed complete small bowel and colonic evaluation in 12 (100%) and 11 (91.7%) patients, respectively. The small bowel and colon cleansing were adequate in 100 and 83.3%, respectively. No PCE-related complications were observed. The PCE diagnostic yield was 83.3%: significant findings were located in the small bowel, colon or both in 5 (41.7%), 4 (33.3%) and 1 (8.3%) patients, respectively. Device-assisted enteroscopy was performed in 6 (50%) patients. Thirty days and 1 year rebleeding rates were 0 and 18.1%, respectively. In this proof-of-concept study, PCE was feasible and safe in patients with melena and negative esophagogastroduodenoscopy, identifying the bleeding site in 83% of patients. PCE lead to small bowel therapeutic interventions in 50% of patients, thus avoiding unnecessary standard colonoscopy. Further large prospective randomized studies investigating this strategy are warranted.


Mechano- and Thermoresponsive Photoluminescent Supramolecular Polymer.
Mechanoresponsive luminescent (MRL) materials change their emission color upon application of external forces. Many dyes with MRL behavior are known, but they normally do not display useful mechanical properties. Here, we introduce a new approach to overcome this problem, which relies on combining MRL compounds with the concept of supramolecular polymerization. As a first embodiment, a cyano-substituted oligo(p-phenylenevinylene), whose MRL behavior is associated with different solid-state assemblies, was derivatized with two ureido-4-pyrimidinone groups, which support the formation of a dynamic supramolecular polymer. The new material displays the thermomechanical characteristics of a supramolecular polymer glass, offers three different emission colors in the solid state, and exhibits both MRL and thermoresponsive luminescent behavior.


Screening and Identification of Survival-Associated Splicing Factors in Lung Squamous Cell Carcinoma.
Lung squamous cell carcinoma (LUSC) is a disease with high morbidity and mortality. Many studies have shown that aberrant alternative splicing (AS) can lead to tumorigenesis, and splicing factors (SFs) serve as an important function during AS. In this research, we propose an analysis method based on synergy to screen key factors that regulate the initiation and progression of LUSC. We first screened alternative splicing events (ASEs) associated with survival in LUSC patients by bivariate Cox regression analysis. Then an association network consisting of OS-ASEs, SFs, and their targeting relationship was constructed to identify key SFs. Finally, 10 key SFs were selected in terms of degree centrality. The validation on TCGA and cross-platform GEO datasets showed that some SFs were significantly differentially expressed in cancer and paracancer tissues, and some of them were associated with prognosis, indicating that our method is valid and accurate. It is expected that our method would be applied to a wide range of research fields and provide new insights in the future.


What do community health workers want? Findings of a discrete choice experiment among Accredited Social Health Activists (ASHAs) in India.
A number of factors contribute to the performance and motivation of India's Accredited Social Health Activists (ASHAs). This study aims to identify the key motivational factors (and their relative importance) that may help retain ASHAs in service. A discrete choice experiment (DCE) survey presented ASHAs with eight unlabelled choice sets, each describing two hypothetical jobs that varied based on five attributes, specifically salary, workload, travel allowance, supervision and other job benefits. Multinomial logit and latent class (LC) models were used to estimate stated preferences for the attributes. We invited 318 ASHAs from 53 primary health centres of Guntur, a district in south India. The DCE was completed by 299 ASHAs using Android tablets. ASHAs were found to exhibit a strong preference for jobs that incorporated training leading to promotion, a fixed salary and free family healthcare. ASHAs were willing to sacrifice 2530 Indian rupee (INR) from their monthly salary, for a job offering training leading to promotion opportunity and 879 INR for a free family health-check. However, there was significant heterogeneity in preferences across the respondents. The LC model identified three distinct groups (comprising 51%, 35% and 13% of our cohort, respectively). Group 1 and 2 preferences were dominated by the training and salary attributes with group 2 having higher preference for free family health-check while group 3 preferences were dominated by workload. Relative to group 3, ASHAs in groups 1 and 2 were more likely to have a higher level of education and less likely to be the main income earners for their families. ASHAs are motivated by both non-financial and financial factors and there is significant heterogeneity between workers. Policy decisions aimed at overcoming workforce attrition should target those areas that are most valued by ASHAs to maximise the value of investments into these workers. CTRI/2018/03/012425.


Effects of crank length on maximal cycling power and optimal pedaling rate of boys aged 8-11 years.
It is generally reported that cycle crank length affects maximal cycling power of adults and that optimal crank length is related to leg length. This suggests that the use of standard length cycle cranks may provide nonoptimal test conditions for children. The purpose of this study was to determine the effects of cycle-crank length on maximal cycling power and optimal pedaling rate of 17 boys aged 8-11 years. The boys performed maximal cycle ergometry with standard (170 mm) cycle cranks and with a crank length that was 20% of estimated leg length (LL20). Power produced when using the 170 mm cranks [mean (SEM)] [364 (18) W] did not differ from that produced with the LL20 cranks [366 (19)]. Optimal pedaling rate was significantly greater for the LL20 cranks [129 (4) rpm] than for the 170 mm cranks [114 (4) rpm]. These data suggest that standard 170 mm cranks do not compromise maximal power measurements in boys aged 8-11 years so that the test apparatus does not bias physiological or developmental inferences made from tests of maximal cycling power.


Coexistence of Eckhaus instability in forced zigzag Turing patterns.
Wavelength selection is an important feature in pattern forming systems. There are two distinct instabilities that arise when a mismatching wavelength is imposed on a pattern forming system, the Eckhaus instability (when the imposed wavelength is smaller than the preferred wavelength) and the zigzag instability (when the imposed wavelength is larger than the preferred wavelength). These two perhaps contradicting instabilities coexist in an experiment in which Turing patterns are forced with slowly moving stripes with a wavelength that is about 1.5 the wavelength of the Turing patterns. We also show that these two instabilities coupled together can lead to the reorientation of patterns under traveling stripe forcing.


A multi-university assessment of patient safety competence during clinical training among baccalaureate nursing students: A cross-sectional study.
To assess the perceived patient safety competence during clinical training of Saudi nursing students. Ensuring safety in healthcare settings requires improvements in the educational and clinical practice of professionals. Experts stressed that shared patient safety culture must be of primary importance; they also emphasised the resolute need for theoretically driven research approaches for patient safety competence in healthcare organisations and educational institutions. Descriptive, cross-sectional design. This study was conducted in six government universities in Saudi Arabia. A sample of 829 nursing students was surveyed using the health professional education in patient safety survey. Descriptive and inferential statistics were used to analyse the data. The study adhered to the STROBE guideline for cross-sectional studies (See Supporting Information Appendix S1). The percentage of agreement on the items of the health professional education in patient safety survey ranged from 61.5%-76.5%. The dimension "understanding human and environmental factors" received the highest perceived competence, whereas the dimension "working in teams" received the lowest competence. Significant differences in students' patient safety competence from different universities were reported. Male students perceived their competence in "working in teams" higher than the female students. Students in their internship year had significantly higher levels of competence in all the six dimensions of the health professional education in patient safety survey than students in the third- and fourth-year levels. Saudi nursing students have positive perceptions towards their patient safety competencies. Significant differences were found in the patient safety competence of nursing students between universities, gender and year of study. The results provide valuable insights and guidance for improving the patient safety competence of nursing students. The findings can be used to guide the creation of policies and interventions that may ensure the continuous development of patient safety competence of nursing students as they navigate the clinical area.


Beta-catenin up-regulates the expression of cyclinD1, c-myc and MMP-7 in human pancreatic cancer: relationships with carcinogenesis and metastasis.
To investigate whether abnormal expression of beta-catenin in conjunction with overexpression of cyclinD1, c-myc and matrix metalloproteinase-7 (MMP-7) correlated with the carcinogenesis, metastasis and prognosis of pancreatic cancer, and to analyze the relationship of beta-catenin expression with cyclinD1, c-myc and MMP-7 expression. Using immunohistochemistry, we examined the expression of beta-catenin, cyclinD1, c-myc and MMP-7 in 47 pancreatic adenocarcinoma tissues, 12 pancreatic intraepithelial neoplasia (PanIN) and 10 normal pancreases, respectively. Proliferation cell nuclear antigen was also tested as the index of proliferative activity of pancreatic cancer cells. In 10 cases of normal pancreatic tissues, epithelial cells showed equally strong membranous expression of beta-catenin protein at the cell-cell boundaries, but the expression of cyclinD1, c-myc and MMP-7 was negative. The expression of beta-catenin, cyclinD1, c-myc and MMP-7 in PanIN and pancreatic adenocarcinoma tissues had no significant difference [6/12 and 32/47 (68.1%), 6/12 and 35/47 (74.5%), 5/12 and 33/47 (70.2%), 7/12 and 30/47 (63.8%), respectively]. The abnormal expression of beta-catenin was significantly correlated to metastasis and one-year survival rate of pancreatic cancer, but had no relation with size, differentiation and cell proliferation. The expression of cyclinD1 was correlated with cell proliferation and extent of differentiation, but not with size, metastasis and one-year survival rate of the pancreatic cancer. The expression of c-myc was not correlated with size, extent of differentiation, metastasis and 1-year survival rate, but closely with cell proliferation of pancreatic cancer. The overexpression of MMP-7 was significantly associated with metastasis and 1-year survival rate of pancreatic cancer, but not with size, extent of differentiation and cell proliferation. There was a highly significant positive association between abnormal expression of beta-catenin and overexpression of cyclinD1, c-myc and MMP-7 not only in PanIN (r = 1.000, 0.845, 0.845), but also in pancreatic cancer (r = 0.437, 0.452, 0.435). The abnormal expression of beta-catenin plays a key role in the carcinogenesis and progression of human pancreatic carcinoma by up-regulating the expression of cyclinD1, c-myc and MMP-7, resulting in the degradation of extracellular matrix and uncontrolled cell proliferation and differentiation. beta-catenin abnormal expression and MMP-7 overexpression may be considered as two useful markers for determining metastasis and prognosis of human pancreatic cancer.


Injury Trends for School Rugby Union in Ireland: The Need for Position-specific Injury-prevention Programs.
Concern has been raised over the injury risk to school Rugby union (Rugby) players and the potential long-term health consequences. Despite the increase in studies for this cohort, the influence of playing position on injury incidence and presentation is unclear. To describe the incidence, nature and severity of match injuries for school Rugby in Ireland overall, and as a function of playing position. Prospective cohort study. Data were collected from 15 male (aged 16-19 years) school Senior Cup teams across 2 seasons. In total, 339 players participated in season 1, whereas 326 players participated in season 2. Injury data were recorded onto a bespoke online platform. Match exposure was also recorded. The incidence rate of match injuries (24-hour time loss) was 53.6 per 1000 hours. Across both seasons, 6810 days were lost from play due to injury. Forwards (65.4 per 1000 hours) sustained significantly more (P < 0.05) injuries than backs (40.5 per 1000 hours). The head, shoulder, knee, and ankle were the most common injured body regions; however, forwards sustained significantly more (P < 0.05) head and shoulder injuries than backs. The tackle was responsible for the majority of injuries in both groups. The highest proportion of injuries occurred during the third quarter. Clear differences in injury presentation and incidence were evident when comparing forwards versus backs. The high rate of head and shoulder injuries in the forwards suggest the need for more targeted injury-prevention strategies and further research on education and laws around the tackle event. The spike of injuries in the third quarter suggests that fatigue or inadequate half-time warm-up may be a contributing factor warranting further exploration. This study demonstrates clear differences in injury presentation according to playing position in school Rugby and highlights the need for a more tailored approach to the design and implementation of injury-prevention strategies. Level 3.


Roles of growth hormone and growth factors in the pathogenesis and treatment of kidney disease.
Growth hormone and a number of polypeptide growth factors exert actions on renal development, growth, and metabolism and on repair processes following renal injury. There is increasing evidence that under selected circumstances, these agents play roles in the pathogenesis of kidney disease and that under others, they may be useful in its treatment. Growth hormone, platelet-derived growth factor, or transforming growth factor-beta may be causative of glomerulosclerosis. The reduction in epidermal growth factor expression within the kidney in the setting of acute ischemic injury could delay regeneration, and replacement may be therapeutic. Insulin-like growth factor I may play a role in the regenerative response to acute renal injury. Pharmacologic properties of growth hormone or insulin-like growth factor I to enhance glomerular filtration rate and renal plasma flow and to increase skeletal growth may be harnessable for treating chronic renal failure and its complications. It is likely that strategies designed to employ growth hormone or growth factors as pharmacologic agents or to block their activities will assume increasingly important roles in therapy for renal disease.


In vitro flowering of orchids.
Flowering is the most elusive and fascinating of all plant developmental processes. The ability to induce flowering in vitro in orchids would reduce the relatively long juvenile phase and provide deeper insight into the physiological, genetic and molecular aspects of flowering. This review synthesizes all available studies that have been conducted on in vitro flowering of orchids with the objective of providing valuable clues as to the mechanism(s) that is possibly taking place.


Efficient Polymer Solar Cells with High Open-Circuit Voltage Containing Diketopyrrolopyrrole-Based Non-Fullerene Acceptor Core End-Capped with Rhodanine Units.
Herein we report the synthesis of a novel A-D-A-D-A non-fullerene small-molecule acceptor (NFSMA) bearing a diketopyrrolopyrrole (DPP) acceptor central core coupled to terminal rhodanine acceptors via a thiophene donor linker (denoted as MPU1) for use in non-fullerene polymer solar cells (PSCs). This NFSMA exhibits a narrow optical band gap (1.48 eV), strong absorption in the 600-800 nm wavelength region of the solar spectrum, and a lowest unoccupied energy level of -3.99 eV. When the mixture of a medium band gap D-A copolymer P (1.75 eV) was used as donor and MPU1 as acceptor, the blend film showed a broad absorption profile from 400 to 850 nm, beneficial for light harvesting efficiency of the resulted polymer solar cell. After optimization of the donor-to-acceptor weight ratios and concentration of solvent additive, the P-MPU1-based PSC exhibited a power conversion efficiency of 7.52% (Jsc= 12.37 mA/cm2, Voc = 0.98 V, and fill factor = 0.62), which is much higher than that for a P3HT-MPU1-based device (2.16%) prepared under identical conditions. The higher value for the P-MPU1-based device relative to the P3HT-MPU1-based one is related to the low energy loss and more balanced charge transport in the device based on the P donor. These results indicate that alteration of the absorption spectra and electrochemical energy levels of non-fullerene acceptors, and appropriate selection of the polymer donor with complementary absorption profile, is a promising means to further boost the performance of PSCs.


CRISPR/Cas9-mediated genome editing in vancomycin-producing strain Amycolatopsis keratiniphila.
Amycolatopsis is an important source of diverse valuable bioactive natural products. The CRISPR/Cas-mediated gene editing tool has been established in some Amycolatopsis species and has accomplished the deletion of single gene or two genes. The goal of this study was to develop a high-efficient CRISPR/Cas9-mediated genome editing system in vancomycin-producing strain A. keratiniphila HCCB10007 and enhance the production of vancomycin by deleting the large fragments of ECO-0501 BGC. By adopting the promoters of gapdhp and ermE*p which drove the expressions of scocas9 and sgRNA, respectively, the all-in-one editing plasmid by homology-directed repair (HDR) precisely deleted the single gene gtfD and inserted the gene eGFP with the efficiency of 100%. Furthermore, The CRISPR/Cas9-mediated editing system successfully deleted the large fragments of cds13-17 (7.7 kb), cds23 (12.7 kb) and cds22-23 (21.2 kb) in ECO-0501 biosynthetic gene cluster (BGC) with high efficiencies of 81%-97% by selecting the sgRNAs with a suitable PAM sequence. Finally, a larger fragment of cds4-27 (87.5 kb) in ECO-0501 BGC was deleted by a dual-sgRNA strategy. The deletion of the ECO-0501 BGCs revealed a noticeable improvement of vancomycin production, and the mutants, which were deleted the ECO-0501 BGCs of cds13-17, cds22-23 and cds4-27, all achieved a 30%-40% increase in vancomycin yield. Therefore, the successful construction of the CRISPR/Cas9-mediated genome editing system and its application in large fragment deletion in A. keratiniphila HCCB10007 might provide a powerful tool for other Amycolatopsis species.


Stress and steroid interaction modulates expression of estrogen receptor alpha in the brain, pituitary, and testes of immature Gallus gallus domesticus.
In nature, food availability stimulates hypothalamo-pituitary-gonadal (HPG) axis while its scarcity induces stress, which further stimulates hypothalamo-pituitary-adrenal (HPA) axis producing a detrimental effect on the avian reproductive physiology. The present experiment was designed to examine the interaction of stress like food restriction and estradiol on male reproductive physiology with special emphasis on estrogen receptor alpha (ERα) as these play crucial role in reproduction. To achieve this, 60 day old White Leghorn immature cockrels were taken and divided into four groups (n = 8 per group). One group was provided with food and water ad libitum. Second group was food restricted (FR) for 9 h/day after 5 days, third and fourth were administered with estradiol benzoate (EB 0.5 mg/100g/day) for 12 days. Fourth group was FR for 9 h/day after 5 days of EB treatment till last day of experiment (EB + FR). Immunofluorescent localization of ERα was principally in the pre-optic area and paraventricular nuclei of hypothalamus and in anterior pituitary gland. ERα expression was highly reduced (from 40 AU to 20 AU) after FR in testis but it increased (50 AU) after EB administration, EB + FR reflects a diminishing pattern in the increment after EB. FR decreased plasma estradiol while EB increased it. Increased plasma corticosterone, hydrogen peroxide, malondialdehyde, and decreased anti-oxidant enzymes in brain and testis of all groups indicate oxidative stress in the HPG axis. The increased ERα after EB and a decrease with FR and EB + FR support their reproductive function. Estrogen and its receptor alpha are responsible for maintaining epithelial morphology but FR along with EB administration modulates the testicular development by significantly decreasing its size (p<.0001) and seminiferous tubules (p<.0001) and no sperm formation via highly reduced expression of ir-ERα in HPG axis. Our findings led us to conclude that stress like FR and estradiol induces testicular regression immature male chickens by modulating ir-ERα expression in the HPG axis thereby resulting in reduction in reproductive physiology.


Progress of untreated massive cardiac echinococcosis--echocardiographic follow-up.
A 56-year-old man was admitted with chest pain and dyspnea. Echocardiographic evaluation revealed a giant cystic cardiac mass with multiple loculations at interventricular septum extended to inferoposterior region protruding inside the cavity. The patient refused surgical therapy. His complaints persisted without significant changes after 5 months. Second echocardiographic evaluation revealed conjugation of previous multiple cyst to gigantic intramyocardial cyst and minimal pericardial effusion. We intend to illustrate herein an unusual echocardiographic appearance and progress of an untreated massive "cardiac echinococcosis." If cardiac hydatid cyst is left untreated it may transform to large cavity with a high risk of rupture.


Key to Prevention of Bradycardia: Be Relax Postoperatively: A Case Report.
Hypotension and bradycardia are commonly observed after the spinal anesthesia and various mechanisms have been postulated for these hemodynamic changes.A middle-aged otherwise healthy male Caucasian patient developed several episodes of bradycardia postoperatively after the umbilical hernia repair under subarachnoid block (SAB) while trying to lean forward and move his legs. Episodes were aborted when patient was advised to relax in supine position.The common mechanism of bradycardia and hypotension under SAB is postulated as sympathetic blockade, decrease venous return, and parasympathetic over-dominance leading to a decrease in right arterial pressure and pressure in the great veins as they enter the right atrium. But over time, the parasympathetic inhibition is usually withdrawn first, leading to the risk of severe bradycardia that is probably favored by the reverse Trendelenburg position as described in our case.Postoperative severe hemodynamic changes can occur even under stable spinal anesthesia; however, can be prevented by vigilant monitoring and simple maneuver which includes maintenance of relax posture on the bed.


Micrografting in the treatment of severely burned patients.
The micrografting technique, employed to treat patients with extensive TBSA burns and reduced areas of healthy donor skin, was assessed simultaneously with traditional mesh grafts (STSG) or Tiersch grafts in the treatment five severely burned subjects (average TBSA burned 35.6 per cent; average per cent of full thickness wounds 32.6 per cent). At the first clinical control on day 6 post-surgery, 93 per cent of the micrografted area was in situ and health; epithelialization of the wound sites was complete at day 21. Meshed STSG yielded 90 per cent attachment at day 6 post-surgery, with epithelialization complete at 12 +/- 2 days post-surgery. Functional results were equivalent no matter what technique was used, while aesthetic results were better in the areas where micrografting was carried out. Although the micrograft technique is labour-intensive, if the expansion needed is at least 1:6, the aesthetic and functional results obtained are comparable to, or better than, those with meshed grafts. Also, large segments of micrograft are not compromised if a small area of mesh becomes detached, and epithelialization is faster and more uniform, enabling a reduction in both infection and length of hospital stay.


Changing trend in nutrition and food consumption predisposes school children to overweight and obesity in Ile-Ife, Osun State, Nigeria.
The consumption of instant foods like pasta and sweetened soft drinks have virtually replaced the traditional diets among children. This changing trend in food consumption could negatively affect the health status of school-aged children. The aim of this study is to investigate the effect of consumption of instant foods (pasta) on anthropometric parameters and nutrient intake among children in Ile-Ife, Nigeria. Participants (126 healthy children, 66 boys and 60 girls, aged 4-12 years) were recruited from nursery and primary schools in Ife Central Local Government, Ile-Ife. The anthropometric measurements were taken and participants were classified based on body mass index (BMI) percentiles. A food frequency questionnaire was administered to evaluate participants' pasta consumption patterns, while food intakes were obtained through 24-h dietary recall. The samples of food consumed by the children were analyzed for their nutrient contents. Nutrient intake was calculated using the data obtained from 24-h dietary recall and the results were compared with the recommended dietary allowances. The average estimated energy intakes were 6167 kJ and 6095 kJ for male and female participants, respectively. The energy intake per kg body weight increased with increasing frequency of the consumption of pasta. There was a positive correlation ( r = 0.873 and 0.998 at P ≤ 0.05 for male and female participants, respectively) between energy intake and weight. The BMI classification showed that 12% of males and 17% of females were overweight or obese. It can be concluded that the consumption of pasta could predispose children to overweight/obesity.


Brachial plexus paresis associated with fetal neck compression from forceps.
Instrumental vaginal deliveries have been associated with higher risks of brachial plexus injuries. The proposed mechanisms involve the indirect association of instrumental deliveries with shoulder dystocia and nerve stretch injuries secondary to rotations of 90 degrees or more. We present a brachial plexus paresis resulting from direct compression of the forceps blade in the fetal neck. A term infant was delivered by a low Kielland forceps rotation. No shoulder dystocia was noted. The immediate neonatal exam revealed an Erb's palsy and an ipsilateral bruise in the lateral aspect of the neck. The paresis resolved during the first day of life. Direct cervical compression of the fetal neck by forceps in procedures involving rotations of the presentation may result in brachial plexus injuries.


WHICH FACTORS ARE ASSOCIATED WITH MALIGNANCY IN THYROID NODULES CLASSIFIED AS BETHESDA CATEGORY 3 (AUS/FLUS) AND HOW DO THEY INFLUENCE THE PATIENT'S MANAGEMENT?
Thyroid nodules are a common pathology worldwide. Fine needle aspiration biopsy (FNAB) is an important diagnostic method for the investigation of malignancy in thyroid nodules. However, according to the Bethesda System used to classify the results, patients with atypia of undetermined significance/follicular lesion of undetermined significance (AUS / FLUS) may not be classified as benign or malignant. Therefore, it may be necessary to determine some clinical risk factors to apply the best treatment in these patients. To determine the factors that increase the risk of malignancy in this patient group. A retrospective study including 138 patients with an FNAB categorized as AUS/FLUS and operated between June 2015-September 2018. Demographical, Laboratory (TSH) and Ultrasound variables (number, size and characteristics of nodules) of the patients were compared among postoperative histopathological results. Hypo-echoic structure, microcalcification and irregular margin of the nodules were detected to be associated with malignancy in patients with FNAB results of AUS/FLUS (p <0.001). We suggest that surgical treatment should be considered if the patients have nodules with the hypo-echoic structure, microcalcification and irregular margin with an FNAB histopathological result of AUS / FLUS.


Studies on the activation of isocitrate dehydrogenase kinase/phosphatase (AceK) by Mn2+ and Mg2.
Isocitrate dehydrogenase kinase/phosphatase (AceK) is a bifunctional enzyme with both kinase and phosphatase activities that are activated by Mg2+. We have studied the interactions of Mn2+and Mg2+ with AceK using isothermal titration calorimetry (ITC) combined with molecular docking simulations and show for the first time that Mn2+ also activates the enzyme activities. However, Mn2+ and Mg2+ exert their effects by different mechanisms. Although they have similar binding constants (of 1.11 × 105 and 0.98 × 105 M-1, respectively) for AceK and induce conformational changes of the enzyme, they do not compete for the same binding site. Instead Mn2+ appears to bind to the regulatory domain of AceK, and its effect is transmitted to the active site of the enzyme by the conformational change that it induces. The information in this study should be very useful for understanding the molecular mechanism underlying the interaction between AceK and metal ions, especially Mn2+ and Mg2+.


Accurate monitoring and fault detection in wind measuring devices through wireless sensor networks.
Many wind energy projects report poor performance as low as 60% of the predicted performance. The reason for this is poor resource assessment and the use of new untested technologies and systems in remote locations. Predictions about the potential of an area for wind energy projects (through simulated models) may vary from the actual potential of the area. Hence, introducing accurate site assessment techniques will lead to accurate predictions of energy production from a particular area. We solve this problem by installing a Wireless Sensor Network (WSN) to periodically analyze the data from anemometers installed in that area. After comparative analysis of the acquired data, the anemometers transmit their readings through a WSN to the sink node for analysis. The sink node uses an iterative algorithm which sequentially detects any faulty anemometer and passes the details of the fault to the central system or main station. We apply the proposed technique in simulation as well as in practical implementation and study its accuracy by comparing the simulation results with experimental results to analyze the variation in the results obtained from both simulation model and implemented model. Simulation results show that the algorithm indicates faulty anemometers with high accuracy and low false alarm rate when as many as 25% of the anemometers become faulty. Experimental analysis shows that anemometers incorporating this solution are better assessed and performance level of implemented projects is increased above 86% of the simulated models.


Tick-borne encephalitis in dogs: neuropathological findings and distribution of antigen.
Eight dogs originating from different regions of Austria [all of them known as tick-borne encephalitis (TBE) areas] with severe neurological signs were either euthanatized or died spontaneously. Tick-borne encephalitis virus (TBEV) antigen was detected in the brains of five of these dogs by immunohistology, but not in the others. All of the dogs, however, had identical neuropathological changes. There were moderate lymphohistiocytic meningitis, widespread neuronal necroses, karyorrhexis of glial cells, numerous neuronophagic nodules, and extensive microgliosis. In the cerebellum, loss of Purkinje cells and proliferation of microglial cells in the molecular layer were found. All brain regions showed numerous perivascular cuffs consisting of lymphocytes, macrophages, plasma cells and, occasionally, red blood cells. The blood-derived cells were not restricted to the perivascular spaces but diffusely infiltrated the neuropil. The most severe changes were localized in the neuroparenchyma surrounding the fourth ventricle. Lesions were less severe in basal ganglia, thalamus, mesencephalon, nuclei of pons and medulla oblongata. Moderate lesions were found in the gray matter of neocortex and allocortex, hippocampus and molecular and Purkinje cell layers of the cerebellum. White matter was slightly to moderately affected. The choroid plexus was free of inflammation. Due to rapid virus clearance mechanisms in this disease, antigen was not detectable in all cases. Neuropathological changes identical with those of immunohistologically proven cases justified the diagnosis TBE in these cases. In addition, the neuropathological diagnosis was supported by the origin of the affected dogs from endemic areas, the seasonal occurrence of the disease and a clinical history of a highly febrile neurological disease with short duration.


Epidemiological investigation of the relationship between common lower genital tract infections and high-risk human papillomavirus infections among women in Beijing, China.
The incidence of lower genital tract infections in China has been increasing in recent years. The link between high-risk human papillomavirus (HR-HPV) and other sexually transmitted diseases (STDs) remains unclear. From March to October 2014, gynecological examinations and questionnaires were conducted on 1218 married women. Cervical secretions and vaginal swab specimens were tested for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Ureaplasma urealyticum (UU), yeast, clue cells and HR-HPV. Laboratory results were available for 1195 of 1218 married women. HR-HPV was detected in 7.0% of participants. Forty-seven percent of women had lower genital tract infections (LGTIs). UU was the most common infection (35.5%), followed by bacterial vaginosis (BV) (10.5%), yeast infection (3.7%), CT (2.2%), and Trichomonas vaginalis (1.7%). BV was associated with an increased risk of HR- HPV (P < 0.0001; odds ratio, 3.0 [95% CI, 1.7-5.4]). There was a strong correlation between abnormal cervical cytology and HR-HPV infection (P < 0.0001). The prevalence of LGTIs in Beijing is at a high level. It is clinically important to screen for the simultaneous presence of pathogens that cause co-infections with HR-HPV.


Antigenic conservation of primary structural regions of S-adenosylmethionine synthetase.
Although the physical and kinetic properties of S-adenosylmethionine (AdoMet) synthetases from different sources are quite different, it appears that these enzymes have structurally or antigenically conserved regions as demonstrated by studies with AdoMet synthetase specific antibodies. Polyclonal anti-human lymphocyte AdoMet synthetase crossreacted with enzyme from rat liver (beta isozyme), Escherichia coli and yeast. In addition, polyclonal anti-E. coli enzyme and antibodies to synthetic peptides copying several regions of the yeast enzyme reacted with the human gamma and rat beta isozymes. Antibodies to yeast SAM1 encoded protein residues 6-21, 87-113 and 87-124 inhibited the activity of human lymphocyte AdoMet synthetase, while antibodies to residues 272-287 had no effect on the enzyme activity. Our results suggest that these conserved regions may be important in enzyme activity.


Exosomes as a delivery tool of exercise-induced beneficial factors for the prevention and treatment of cardiovascular disease: a systematic review and meta-analysis.
Exercise-derived exosomes have been identified as novel players in mediating cell-to-cell communication in the beneficial effects of improving cardiovascular disease (CVD). This review aimed to systematically investigate exosomes as delivery tools for the benefits of exercise in the prevention and treatment of CVD and summarize these outcomes with an overview of their therapeutic implications. Among the 1417 articles obtained in nine database searches (PubMed, EBSCO, Embase, Web of Science, CENTRAL, Ovid, Science Direct, Scopus, and Wiley), 12 articles were included based on eligibility criteria. The results indicate that exercise increases the release of exosomes, increasing exosomal markers (TSG101, CD63, and CD81) and exosome-carried miRNAs (miR-125b-5p, miR-122-5p, miR-342-5p, miR-126, miR-130a, miR-138-5p, and miR-455). These miRNAs mainly regulate the expression of MAPK, NF-kB, VEGF, and Caspase to protect the cardiovascular system. Moreover, the outcome indicators of myocardial apoptosis and myocardial infarction volume are significantly reduced following exercise-induced exosome release, and angiogenesis, microvessel density and left ventricular ejection fraction are significantly increased, as well as alleviating myocardial fibrosis following exercise-induced exosome release. Collectively, these results further confirm that exercise-derived exosomes have a beneficial role in potentially preventing and treating CVD and support the use of exercise-derived exosomes in clinical settings.