Prospective investigation of pituitary functions in patients with acute infectious meningitis: is acute meningitis induced pituitary dysfunction associated with autoimmunity?
Previous case reports and retrospective studies suggest that pituitary dysfunction may occur after acute bacterial or viral meningitis. In this prospective study we assessed the pituitary functions, lipid profile and anthropometric measures in adults with acute bacterial or viral meningitis. Moreover, in order to investigate whether autoimmune mechanisms could play a role in the pathogenesis of acute meningitis-induced hypopituitarism we also investigated the anti-pituitary antibodies (APA) and anti-hypothalamus antibodies (AHA) prospectively. Sixteen patients (10 males, 6 females; mean ± SD age 40.9 ± 15.9) with acute infectious meningitis were included and the patients were evaluated in the acute phase, and at 6 and 12 months after the acute meningitis. In the acute phase 18.7% of the patients had GH deficiency, 12.5% had ACTH and FSH/LH deficiencies. At 12 months after acute meningitis 6 of 14 patients (42.8%) had GH deficiency, 1 of 14 patients (7.1%) had ACTH and FSH/LH deficiencies. Two of 14 patients (14.3%) had combined hormone deficiencies and four patients (28.6%) had isolated hormone deficiencies at 12 months. Four of 9 (44.4%) hormone deficiencies at 6 months were recovered at 12 months, and 3 of 8 (37.5%) hormone deficiencies at 12 months were new-onset hormone deficiencies. At 12 months there were significant negative correlations between IGF-I level vs. LDL-C, and IGF-I level vs. total cholesterol. The frequency of AHA and APA positivity was substantially high, ranging from 35 to 50% of the patients throughout the 12 months period. However there were no significant correlations between AHA or APA positivity and hypopituitarism. The risk of hypopituitarism, GH deficiency in particular, is substantially high in the acute phase, after 6 and 12 months of the acute infectious meningitis. Moreover we found that 6th month after meningitis is too early to make a decision for pituitary dysfunction and these patients should be screened for at least 12 months. In addition, the occurrence of AHA and APA positivity due to acute infectious meningitis was demonstrated for the first time. Further longer-term prospective investigations need to be carried out on a larger cohort of patients to understand the role of autoimmunity in the pathogenesis of late hypopituitarism after acute infectious meningitis.


Effect of alpha-lipoic acid on relieving ammonia stress and hepatic proteomic analyses of broilers.
Ammonia in poultry houses not only affects worker health but also induces a variety of poultry diseases. Alpha-lipoic acid (LA) is an effective antioxidant that protects cells against oxidative injury during various toxic and pathological processes. This study was designed to evaluate the mitigating effects of LA supplementation on ammonia stress and hepatic proteome changes in broilers. Male broilers (22 d old) were allocated to 3 groups: (1) a control group without ammonia stress (CTRL); (2) exposure to 70 ppm ammonia (AM); and (3) exposure to 70 ppm ammonia and dietary administration of 300 mg/kg LA (AM+LA). Ammonia exposure significantly decreased broiler growth performance and plasma glutathione peroxidase activity (P < 0.05), and increased plasma malondialdehyde content and glutamic-pyruvic transaminase activity (P < 0.05). These negative effects were eliminated by LA supplementation. Comparative proteomic analyses revealed 291 differentially expressed proteins in the AM group compared to the CTRL and AM+LA groups. A total of 30 proteins were differentially expressed between the AM/CTRL and (AM+LA)/AM groups. The addition of LA restored 24 of these proteins to control levels; these proteins were mainly related to transcription regulation, detoxification, protein translation and degradation, and immune and stress responses. The differentially expressed proteins included the high mobility group box (HMGB) and glutathione S-transferase (GST), which is closely related to immune response and oxidative stress, and collagens, which are implicated in liver injury. The addition of LA to broiler diet may reduce ammonia toxicity by maintaining the antioxidant system, xenobiotic metabolism, and metabolic pathways.


[Regression of biochemical changes in heart muscle hypertrophy].
Reduction in arterial blood pressure caused by ACE inhibitors, calcium antagonists and beta-blockers leads to regression of heart muscle hypertrophy. However, this regression may also occur in the absence of a significant reduction in blood pressure (alpha-Methyldopa), whereas no decrease in heart muscle mass may be observed in the presence of pronounced decreases in blood pressure (hydralazine, minoxidil, diuretics). In the present review, biochemical factors are analyzed that might be important in the regression of heart muscle hypertrophy. It will be seen that angiotensin II and cardiac catecholamines play important roles in modifying the influence of various drugs on regression of heart muscle hypertrophy. Reductions in angiotensin II and cardiac catecholamines lead to decreases in cardiac mRNA contents and thus to a decrease in the myocardial protein synthesis. Changes in myocardial protein degradation do not contribute to the regression of heart muscle hypertrophy.


Phosphorus-Alloying as a Powerful Method for Designing Highly Active and Durable Metal Nanoparticle Catalysts for the Deoxygenation of Sulfoxides: Ligand and Ensemble Effects of Phosphorus.
The modification of metal nanoparticles (NPs) by incorporating additional metals is a key technique for developing novel catalysts. However, the effects of incorporating nonmetals into metal NPs have not been widely explored, particularly in the field of organic synthesis. In this study, we demonstrate that phosphorus (P)-alloying significantly increases the activity of precious metal NPs for the deoxygenation of sulfoxides into sulfides. In particular, ruthenium phosphide NPs exhibit an excellent catalytic activity and high durability against sulfur-poisoning, outperforming conventional catalysts. Various sulfoxides, including drug intermediates, were deoxygenated to sulfides with excellent yields. Detailed investigations into the structure-activity relationship revealed that P-alloying plays a dual role: it establishes a ligand effect on the electron transfer from Ru to P, facilitating the production of active hydrogen species, and has an ensemble effect on the formation of the Ru-P bond, preventing strong coordination with sulfide products. These effects combine to increase the catalytic performance of ruthenium phosphide NPs. These results demonstrate that P-alloying is an efficient method to improve the metal NP catalysis for diverse organic synthesis.


A series of enterococcal brain abscesses.
Neurosurgeons in developing countries come across brain abscess frequently, but Enterococcus as a cause of abscess is rare. To describe clinical profile and treatment of a series of patients with enterococcal brain abscess. We retrospectively reviewed microbiological records of patients with brain abscess to identify Enterococcus as a causative organism. 12 patients (nine males) were diagnosed to have enterococcal brain abscess. All were due to E. species. The clinical feature and management are not different from other etiological agents. The prognosis of enterococcal brain abscess is more favourable than bacteremia.


Use of the Sport Concussion Assessment Tool 5 (SCAT5) in professional hockey, part 1: cross-cultural normative data.
This paper provides comprehensive normative data stratified by language preference and age on the components of the National Hockey League (NHL) Sport Concussion Assessment Tool 5 (SCAT5) in a multilingual sample of professional ice hockey players and compares the findings from a paper form of the NHL SCAT5 with an electronic (App) version of the tool. A total of 1924 male NHL and American Hockey League (AHL) players (ages 17-41) were assessed during preseason medical evaluations (baseline); 1881 were assessed with the NHL SCAT5 App via tablet and 43 received the paper version of the NHL Modified SCAT5. No significant differences between the App and paper modes of administration emerged in a subsample of English preference players. Significant SCAT5 differences among language preference groups emerged on measures of cognitive functioning (Immediate Memory,Concentration). No language preference differences emerged on the Delayed Recall component. Using age as a continuous variable, older participants outperformed younger players on Immediate Memory, Delayed Recall and Concentration. Players wearing skates demonstrated significantly more modified Balance Error Scoring System (mBESS) total errors than barefoot players. Normative data tables for language preference groups are presented. Significant differences were found between English and non-English language preference groups on the components of SCAT5, which suggest that language-specific normative data, rather than aggregated normative data, are preferable when interpreting test scores. Similarly, age-specific normative data tables may provide greater precision in data interpretation. Due to clear ceiling effects on the mBESS single leg and tandem stances, players should not be tested while wearing skates.


Nutrition Literacy and Healthy Diet: Findings from the Validation of a Short Seniors-Oriented Screening Tool, the Spanish Myths-NL.
A good level of nutrition literacy (NL) is proposed as a determinant factor for following a healthy diet. Improving seniors' NL might be particularly pertinent to enhance the quality of their diets. This study aimed to systematically design and validate a short seniors-oriented questionnaire as a screening tool to evaluate NL. We developed the Myths-NL questionnaire, composed of 10 widespread nutrition myths, and checked for its content and face validity. An observational cross-sectional study was conducted to explore the validity and the test-retest reliability, involving a community-dwelling group of 316 individuals aged 65 years and over. Construct validity was proved by establishing both discriminant and convergent validity. Cronbach α = 0.61 and Spearman r = 0.79 (p = 0.02) demonstrated internal consistency and test-retest reliability. Participants who had secondary/university studies scored significantly higher compared with those with primary (p < 0.001), and a significant linear relationship (R2 = 0.044, p = 0.001) with a positive slope (β = 0.209) between Mediterranean Diet Adherence Screener (MEDAS) and Myths-NL scores was observed, proving construct validity. In conclusion, the Myths-NL questionnaire is a valid and reliable tool to screen NL in Spanish seniors and it might be useful as an assessment NL tool for designing and implementing lifestyle interventions to promote healthy eating.


Immunoregulatory role of CD8alpha in the veto effect.
Allogeneic bone marrow cell (allo-BMC) infusion induces tolerance to incompatible renal allografts in rhesus macaques after depletion of peripheral T lymphocytes with cytolytic anti-T cell antibodies. The tolerogenic effect of allo-BMC, ascribed to a veto mechanism, associates with specific functional deletion of antidonor cytotoxic T lymphocyte precursor (CTLp), and is dependent on a CD8+ donor BMC subset. In previous studies, the CD8 molecule was implicated by loss of suppression after blocking interaction between CD8 on allo-BMC and major histocompatibility complex class Ialpha3 domain on CTLp. CD8 cross-linking on BMC induced secretion of active transforming growth factor-beta1 (TGF-beta1), suggesting a regulatory mechanism(s) operating via a CD8-mediated signaling pathway. CD8 on rhesus cells was cross-linked using IgG-conjugated beads, and TGF-beta1 mRNA and protein were quantified. CD8+ cells were tested for veto activity by mixed lymphocyte reaction (MLR)-induced cell-mediated lymphocytotoxicity (CML) assay. Activated rhesus T cells exposed to TGF-beta1 were examined for apoptosis by TdT-mediated end-labeling and annexin staining. CD8 cross-linking induces accumulation of TGF-beta1 mRNA and protein. Both CD3- CD8+CD16+ and CD3+ CD8+CD16- subsets of allo-BMC up-regulate TGF-beta1 mRNA after CD8 cross-linking, and exhibit veto activity. The CD3-CD8+CD16+ subset expresses more TGF-beta1 mRNA and increased veto activity at low BMC/CTLp ratios. Exposure of activated T cells to TGF-beta1 induces apoptosis. CD8+ allo-BMC are enriched for veto activity and activation via CD8 induces TGF-beta1 mRNA and protein accumulation. These results agree with the hypothesis that paracrine TGF-beta1 may be involved in peripheral deletion of alloreactive CTLp by CD8+ allo-BMC. We suggest that TGF-beta1 overexpression by donor lymphohematopoietic cells may enhance tolerance induction.


RNA Editing Enzymes Modulate the Expression of Hepatic CYP2B6, CYP2C8, and Other Cytochrome P450 Isoforms.
A-to-I RNA editing, the most frequent type of RNA editing in mammals, is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes. Recently, we found that there is a large interindividual variation in the expression of ADAR1 protein in the human livers. In this study, we investigated the possibility that A-to-I RNA editing may modulate the expression of cytochrome P450 (P450), causing interindividual variations in drug metabolism potencies. We found that knockdown of ADAR1 or ADAR2 in HepaRG cells resulted in the decreased expression of CYP2B6 and CYP2C8 mRNA and protein. Knockdown of ADARs significantly decreased the stability of CYP2B6 mRNA but not CYP2C8 mRNA. Luciferase assays revealed that the 3'-untranslated region of CYP2B6 and the promoter region of CYP2C8 would be involved in the decrease in their expression by the knockdown of ADARs. We found that the decreased expression of the hepatocyte nuclear factor 4α (HNF4α) protein by the knockdown of ADARs was one of the reasons for the decreased transactivity of CYP2C8. The mRNA levels of other P450 isoforms, such as CYP2A6, 2C9, 2C19, 2D6, and 2E1, which are known to be regulated by HNF4α, were also decreased by ADAR1 or ADAR2 knockdown. Exceptionally, the CYP3A4 mRNA level was significantly increased by ADAR1 knockdown, suggesting the possibility that the change could be due to the change in the expression or function of other regulatory factors. In conclusion, this study revealed that the RNA editing enzymes ADAR1 and ADAR2 are novel regulatory factors of P450-mediated drug metabolism in the human liver.


Chrysotile asbestos-induced membrane damage in human erythrocytes.
Chrysotile asbestos causes the release of K+ and hemoglobin from erythrocytes. At short incubation times K+ release is slightly higher than hemoglobin release but for incubation times of 10 min or longer the percentage K+ release, and the percentage hemolysis are the same. The results suggest that asbestos causes a sudden and complete disruption of the membrane permeability for K+, which is probably followed by colloid osmotic hemolysis. Polyanions inhibit asbestos-induced hemolysis completely. Leaching of asbestos diminishes its hemolytic potency, as does a decrease in pH. The results support the view that positive charges, probably of magnesium, play a predominant role in asbestos-induced hemolysis.


Characterization of Biomarkers in Colorectal Cancer Liver Metastases as a Prognostic Tool.
Unfortunately, the majority of patients with colorectal cancer liver metastases (CRCLM) experience disease recurrence following hepatic surgery. The key challenge is therefore optimal patient selection, which currently relies on anatomical and clinical parameters. Exploring a potential molecular signature may be predictive for seeing a clinical benefit from CRCLM resection. Consecutive patients who underwent CRCLM resection at our medical center between 2006 and 2016 were divided into cohorts of "good prognosis" (GP) or "poor prognosis" (PP) based on the time interval between their resection and disease recurrence. Proteomic analysis was performed on the surgical specimen and correlation analysis was carried out with demographics and clinical outcomes. Proteomic analysis revealed 99 differentially expressed proteins of which a third were associated with extracellular matrix (ECM) pathways as the matrix metalloproteinases (MMPs). Multivariate analysis yielded a statistically differential proteomic pattern between the cohort regardless of perioperative treatment. Our results indicate a different proteomic landscape in the cohort of patients who had a clinical benefit from CRCLM resection which appears to be correlated with ECM pathways. Further prospective studies are needed to define the role of ECM pathways in prognostics and patient selection for surgical procedures for CRCLM.


Neonatal 6-hydroxydopamine lesioning of rats and dopaminergic neurotoxicity: proposed animal model of Parkinson's disease.
The neurotoxin 6-hydroxydopamine (6-OHDA), following pretreatment with the norepinephrine transport inhibitor desipramine, selectively destroys dopaminergic neurons. When given to rats, neonatal 6-OHDA (n6-OHDA) crosses the blood-brain barrier to destroy 90-99% of dopaminergic nerves in pars compacta substantia nigra (SNpc). The n6-OHDA-lesioned rat is posed as a reasonable animal model for PD: (a) the magnitude of dopaminergic neuronal destruction is expansive, (b) mapping of dopaminergic denervation has been defined, (c) effects on dopamine (DA) receptor alterations have been elucidated (d) as well as changes in receptor sensitivity status, (e) reactive sprouting of serotoninergic innervation (i.e. hyperinnervation) has been mapped, and (f) interplay between serotoninergic and dopaminergic systems is characterized. (g) A broad range of locomotor and stereotyped behaviors has been assessed and (h) large numbers of neurochemical assessments have been attained. (i) n6-OHDA-lesioned rats survive 6-OHDA lesioning and (j) the rat is behaviorally indistinguishable from controls. Dopaminergic destruction in early ontogeny rather in adulthood is a 'treatment liability' of this model, yet other animal models have liability issues of a serious nature-the initial one being use of a neurotoxin to produce the animal model of PD. The n6-OHDA-lesioned rat is proposed as a PD model for its value in associating the SNpc dopaminergic lesion with behavioral outcomes, also for replicability of dopaminergic destruction, and the accompanying neuronal adaptations and interplay between neuronal phenotypes in brain-which provide a means to better define and understand the range of deficits and neuronal adaptations that are likely to occur in human PD.


Automatic diagnosis of mammographic abnormalities based on hybrid features with learning classifier.
Breast cancer screening is currently performed by mammography, which is limited by overlying anatomy and dense breast tissue. Computer-aided detection (CAD) systems can serve as a double reader to improve radiologist performance. In this paper, we have applied a novel approach to segmentation of suspicious region by mammogram and classification based on hybrid features with learning classifier. We formulated differentiation of lesion from normal tissue as a supervised learning problem, and applied this learning method to develop the classification algorithm. The algorithm has been verified with 164 mammograms in the mini Mammographic Image Analysis Society database. The experimental results show that the detection method has a sensitivity of 94.5% at 0.26 false positives per image. The efficiency of algorithm is measured using free receiver operating characteristics curve and the results are highlighted. We conclude that CAD technology with learning classifier has the potential to help radiologists with the task of discriminating between lesion and normal tissues.


Development of head and neck squamous cell carcinoma is associated with altered cytokine responsiveness.
Growth of head and neck squamous cell carcinoma (HNSCC) is generally associated with an inflammatory component. It is hypothesized that these tumor cells develop mechanisms to evade the growth inhibitory effects of cytokines that are present in the tumor microenvironment. This study determined the changes in responsiveness to inflammatory cytokines that accompany the transition of normal to transformed epithelial cells. Paired primary cultures of normal epithelial cells (NEC) and SCC cells were established from 16 patients. Receptor-mediated activation of signal transducer and activator of transcription and extracellular signal-regulated kinase pathways in response to cytokine treatments was identified by immunoblot analysis. Thymidine incorporation determined the impact of the cytokines on DNA synthesis. HNNEC and HNSCC displayed a prominent signaling in response to oncostatin M, interleukin-6, IFN-gamma, and epidermal growth factor. Untreated HNSCC showed an elevated level of phosphorylated signal transducer and activator of transcription 3 and extracellular signal-regulated kinase (P < 0.001) compared with HNNEC, suggesting constitutively activated pathways. Moreover, HNSCC cells phosphorylated significantly more signal transducer and activator of transcription 1 in response to oncostatin M (P = 0.002) and IFN-gamma (P = 0.018) treatments. DNA synthesis of SCC cells was less inhibited by cytokines produced by endotoxin-stimulated macrophages (P = 0.016) than that of NEC. Low-dose oncostatin M slightly enhanced proliferation of SCC, whereas that of NEC was suppressed (P = 0.016). This study identified significant alterations in signal transduction pathways engaged by cytokines and which are associated with loss of growth inhibition of HNSCC. Increased signal transducer and activator of transcription phosphorylation, along with constitutively phosphorylated extracellular signal-regulated kinase in HNSCC, suggest that these pathways as molecular markers are important in the malignant transformation process and are potential targets for treatment.


Regulation of cyclin T1 and HIV-1 Replication by microRNAs in resting CD4+ T lymphocytes.
The replication of integrated human immunodeficiency virus type 1 (HIV-1) is dependent on the cellular cofactor cyclin T1, which binds the viral Tat protein and activates the RNA polymerase II transcription of the integrated provirus. The activation of resting CD4(+) T cells upregulates cyclin T1 protein levels independently of an increase in cyclin T1 mRNA levels, suggesting a translational repression of cyclin T1 in resting CD4(+) T cells. Hypothesizing that microRNAs (miRNAs) repress cyclin T1 translation in resting CD4(+) T cells and that this inhibition is lifted upon cell activation, we used microarray expression analysis to identify miRNAs miR-27b, miR-29b, miR-150, and miR-223 as being significantly downregulated upon CD4(+) T cell activation. The overexpression of these miRNAs decreased endogenous cyclin T1 protein levels, while treatment with the corresponding antagomiRs increased cyclin T1 protein levels. An miR-27b binding site within the cyclin T1 3' untranslated region (3'UTR) was identified and confirmed to be functional after the mutation of key resides abrogated the ability of miR-27b to decrease the expression of a luciferase reporter upstream of the cyclin T1 3'UTR. Ago2 immunoprecipitation revealed an association with cyclin T1 mRNA that was decreased following treatment with miR-27b and miR-29b antagomiRs. Cells overexpressing miR-27b showed decreased viral gene expression levels of the HIV-1 reporter virus and a decreased replication of strain NL4.3; a partial rescue of viral transcription could be seen following the transfection of cyclin T1. These results implicate miR-27b as a novel regulator of cyclin T1 protein levels and HIV-1 replication, while miR-29b, miR-223, and miR-150 may regulate cyclin T1 indirectly.


Task-Induced Pyramid and Attention GAN for Multimodal Brain Image Imputation and Classification in Alzheimer's Disease.
With the advance of medical imaging technologies, multimodal images such as magnetic resonance images (MRI) and positron emission tomography (PET) can capture subtle structural and functional changes of brain, facilitating the diagnosis of brain diseases such as Alzheimer's disease (AD). In practice, multimodal images may be incomplete since PET is often missing due to high financial costs or availability. Most of the existing methods simply excluded subjects with missing data, which unfortunately reduced the sample size. In addition, how to extract and combine multimodal features is still challenging. To address these problems, we propose a deep learning framework to integrate a task-induced pyramid and attention generative adversarial network (TPA-GAN) with a pathwise transfer dense convolution network (PT-DCN) for imputation and classification of multimodal brain images. First, we propose a TPA-GAN to integrate pyramid convolution and attention module as well as disease classification task into GAN for generating the missing PET data with their MRI. Then, with the imputed multimodal images, we build a dense convolution network with pathwise transfer blocks to gradually learn and combine multimodal features for final disease classification. Experiments are performed on ADNI-1/2 datasets to evaluate our method, achieving superior performance in image imputation and brain disease diagnosis compared to state-of-the-art methods.


From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world.
Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma.


Particle Swarm Optimization and Salp Swarm Algorithm for the Segmentation of Diabetic Retinal Blood Vessel Images.
In recent years, the incidence of diabetes has been increasing year by year. Since most of the fundus lesions are located near blood vessels, the image information is complex, and the end vessels are difficult to identify. So, a new segmentation method of diabetic retinal vessel images based on particle swarm optimization and salp swarm algorithm is proposed. This paper uses a Gaussian filter to enhance the main blood vessels, and a top-bot hat transform is used to strengthen the end vessels. The preprocessing process is completed by combining and reconstructing the two images through a normalization operation. The improved particle swarm optimization and salp swarm algorithms perform multi-threshold segmentation on the preprocessed vessel images. The best fit value, Structural Similarity Index Measure, Peak Signal to Noise Rati, feature similarity index measure, sensitivity, accuracy, regional consistency, Dice coefficient, Jaccard similarity, and Shannon entropy are selected for comprehensive evaluation and analysis. The results showed that this paper's improved particle swarm-salp swarm algorithm for segmenting diabetic retinal blood vessel images is more efficient, and the threshold is better. The vascular segmentation method in this paper is applied in medical image processing, which improves the accuracy of medical image processing and reduces the computational effort.


Alpha,beta-D-CNA induced rigidity within oligonucleotides.
Introduction of alpha,beta-D-CNA featuring canonical values of the torsional angles alpha and beta within oligonucleotides leads to an overall stabilization and improved rigidity of the duplex DNA as demonstrated by UV experiments, circular dichroism and corroborated by molecular dynamics simulations.


Risk Assessment of the Skin Sensitization Induction Potential of Kathon CG in Rinse-off and Leave-on Personal Care and Cosmetic Products.
Kathon CG is a commonly used cosmetic-grade preservative that contains active ingredients methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI). The aim of the study was to perform a skin sensitization induction risk assessment of daily exposure to Kathon CG after use of various personal care and cosmetic products. We calculated an estimated daily consumer exposure level for rinse-off and leave-on products using the amount of product applied per application, number of applications per day, a retention factor, the MCI/MI concentration, and body surface area values. We assumed that the products contained the maximum recommended safe concentration of MCI/MI: 15 ppm in rinse-off products and 7.5 ppm in leave-on products. We compared estimated consumer exposure levels with the no expected sensitization induction level for MCI/MI and applied sensitization assessment factors to calculate product-specific margins of safety (MOSs). The MOSs for rinse-off products ranged from 5 to 63, whereas the MOSs for leave-on products ranged from 0.03 to 1.49. Overall, our results provide evidence that some leave-on products containing the maximum recommended safe concentration of Kathon CG may increase the risk of sensitization induction due to exposure to MCI/MI. In contrast, rinse-off products were not associated with a potential increased risk of skin sensitization induction.


Reaching the unreached: Mobile surgical camps in a remote village of Himachal Pradesh.
The aim was to study the epidemiological factors responsible for pelvic organ prolapse (POP) in poor women of the remote village Shillai, do their POP quantification staging, to study the variety of surgeries conducted in mobile surgical camps in this area. Retrospective analysis of surgeries conducted in five mobile surgical camps in Shillai, Himachal Pradesh from 2009 to 2013, under "Project Prolapse". A total number of surgeries conducted in five camps from 2009 to 2013 were 490 including 192 gynecological surgeries. Eighty-two percent of gynecological surgery was conducted for POP. Poor nutritional status (mean weight 41.1 kg), multiparty (mean 3.5), early marriage (mean age 18.2 years), unassisted home deliveries (100%), premature bearing down (23.8%), early postpartum resumption of strenuous activity (54.7%) and smoking (33%) contribute to the high incidence of POP. Anterior compartment prolapse was seen in 99% of patients undergoing surgery while posterior compartment prolapse was seen in 4% of patients. Vaginal hysterectomy with anterior repair with culdoplasty was the most common procedure performed (73.4%), and vault suspension was done in 3.6% subjects. The complication rate was negligible. Uterovaginal prolapse is not only socially embarrassing and disabling; its surgical treatment is complex and costly too. The free mobile surgical camps under Project Prolapse in Shillai, Himachal Pradesh has provided relief to old neglected, disabled women suffering from prolapse in this remote village. Parallel counseling of women and dais for safe hospital delivery and training subordinates in prolapse surgery may help in addressing the problem of POP in this area in the long run.


Fuchs Heterochromic Iridocylitis: Clinical Characteristics and Outcome of Cataract Extraction with Intra Ocular Lens Implantation in a Kashmiri Population- A Hospital Based Study.
Fuchs Heterochromic Iridocylitis (FHI) is a rare form of uveitis which is frequently complicated by cataract and glaucoma, but it does not show typical features of uveitis like pain, redness and posterior synechia. To study the clinical characteristics and outcome of cataract extraction with Intra Ocular Lens (IOL) implantation in patients with FHI. The present prospective study was carried out in the Postgraduate Department of Ophthalmology, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Bemina from March 2012 to January 2015. The study included 33 eyes of 32 patients of FHI who underwent thorough clinical examination and cataract surgery with IOL implantation and were evaluated based on their visual outcome and intra and post-operative complications. Post-operative follow-up was done on 1st day, one week, one month, two month, six month and at twelve months. Mean age of our study group was 33.9 years (Range 18 to 65 years). No male or female preponderance was seen. There was bilateral involvement of eyes in only one case. Cataract and stellate keratic precipitates were present in all cases whereas, heterochromia was present in only six eyes (18.75%). Best Corrected Visual Acuity (BCVA) showed a significant improvement following cataract surgery (p<0.001). Post-operatively, 26 eyes (78.78%) showed an improvement of four lines or more (BCVA of > 6/12). Most common causes of decreased vision post-operatively were vitreous opacities in nine eyes (27.27%) followed by glaucoma in eight eyes (24.24%) and posterior capsular opacification in six eyes (18.18%). Cataract extraction with IOL lens implantation in FHI is a safe procedure associated with good visual prognosis and few complications. However, glaucoma is one of the main concerns and should be closely monitored both pre and post-operatively.


Security of attachment and quality of mother-toddler social interaction in a high-risk sample.
The quality of children's social interactions and their attachment security with a primary caregiver are two widely studied indices of socioemotional functioning in early childhood. Although both Bowlby and Ainsworth suggested that the parent-child interactions underlying the development of attachment security could be distinguished from other aspects of parent-child interaction (e.g., play), relatively little empirical research has examined this proposition. The aim of the current study was to explore this issue by examining concurrent relations between toddler's attachment security in the Strange Situation Procedure and quality of mother-child social interaction in a high-risk sample of toddlers characterized by prenatal cocaine exposure and low levels of maternal education. Analyses of variance suggested limited relations between attachment security and quality of social interaction. Further research examining the interrelations among various components of the parent-child relationship is needed.


Management of pregnancy in women with thrombophilia.
Hereditary thrombophilia increases the risk of thrombosis during pregnancy and postpartum. The recommendations resulting from the Fifth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy were published in Chest in late 1998. However, levels of evidence on this subject were low (C2). Furthermore, since publication of this ACCP consensus, new studies have demonstrated the safety of low-molecular-weight heparins (LMWHs) in pregnant women. In addition, it is now clear that all thrombophilias are not associated with the same level of thrombotic risk: factor V Leiden mutation and factor II 20210A variant are associated with a lower risk than antithrombin deficiency. Consequently, the ACCP recommendations have been reconsidered in the light of a more widespread use of LMWH and taking into account the differences in the level of risk of the different thrombophilias. A prophylaxis of thrombosis in pregnant women with thrombophilia is proposed based on published data and our personal experience. Although laboratory monitoring is usually not required during treatments with LMWH, it seems to be needed in pregnant women who receive long-term treatments.


Brief Report: High Peak Level of Plasma Raltegravir Concentration in Patients With ABCB1 and ABCG2 Genetic Variants.
Raltegravir was recently identified to be a substrate of ATP-binding cassette transporter B1 (ABCB1) and G2 (ABCG2), which are efflux transporters and expressed in the intestines. We analyzed the relations between plasma raltegravir concentrations and single nucleotide polymorphism of ABCB1 and ABCG2 genes. The peak plasma concentration of raltegravir was significantly higher in the patients with ABCB1 4036 AG/GG and ABCG2 421 CA/AA than in other genotype holders (P = 0.0052), though no difference was identified in trough raltegravir concentrations, which may be explained by reduced expression of efflux transporters in intestine by these genetic variants.


The role of carboxylate ligands in two novel cyanido-bridged 2D coordination networks Cu(II)-W(V) and Mn(II)-Nb(IV).
We report on the synthesis, molecular structure and magnetic properties of two novel coordination polymers: [{Cu(II)(4)(pic)(2)(H(2)O)(2)(MeOH)}{W(V)(CN)(8)}(2)]·MeOH·4H(2)O (1) and [{Mn(II)(3)(HCOO)(2)(H(2)O)(4)}{Mn(II)(H(2)O)(3)(HCONH(2))}(2){Nb(IV)(CN)(8)}(2)]·4HCONH(2)·2H(2)O (2). The single-crystal X-ray diffraction analysis of 1 shows that its molecular structure can be interpreted as a cyanido bridged (3,4,7)-connected 2D bilayer built of two different subnets sharing the tungsten centers. The magnetic measurements suggest that the system reveals long-range ferromagnetic ordering between Cu(II) and W(V) centers below 13.4 K. The molecular structure of (2) reveals a 2D topology of layers built of cyanido and formato bridging ligands. The system reveals ferrimagnetic behavior with a critical temperature at 17.8 K.


[Comparison of development condition of different Liriope spicata seedlings].
The study identified the main morphological index of the seedlings classification including seedling age,the root width and number of newborn buds and coarse roots, according to the local agricultural production techniques and assessment of Liriope spicata's growth and development condition. After carrying on K cluster analysis of the morphological, we separated the seedlings into two levels. The first level (Ⅰ): the new talent with the root width exceeding two point five millimeters, the new born buds exceeding three, and with the coarse root exceeding one. The second level (Ⅱ): the old talent with the root width below one millimeters, the newborn buds below two and without coarse root. The study surveyed the plants' growth index dynamics, as well as the yield and quality of the tuberous root. The experimental results suggested that the growth condition of seedling Ⅰwas better, the yield of earthnut higher, the quality of earthnut more excellent. The study lied the foundation of L. spicata's grading standards and standardized production.


[The physician as teacher. Ways to measure the quality of medical training].
Ninety percent of medical students' training is comprised of working and learning in the clinical setting. Good training is the responsibility of the physicians who also work in that setting. It is important that these physicians are aware of what is expected of them in this role. We defined 7 domains for clinical teachers: being a role model, task allocation, planning, providing feedback, teaching methodology, assessment, and personality. There are several feedback instruments for measuring the quality of a clinical teacher, each addressing these seven domains differently. When providing clinical teachers with feedback, written evaluation alone is not sufficient to induce change. Dialogue between residents and their clinical teacher leads to mutual understanding and enhances the effect of feedback. This is beneficial to the individual trainer, training team and the residents.


In vitro formation and aggregation of heterotypic collagen I and III fibrils.
In vitro fibrillogenesis of solutions containing pepsin digested and acid soluble collagens I and III from human and bovine skin were investigated by turbidity-time measurements, dark-field and electron microscopy. The maximum turbidity of these solutions exhibited inversely proportional dependence on the collagen III content. Self-assembly was accelerated by collagen III. As a measure of mass per unit length, the maximum turbidity shows a mean decrease of 88% when comparing the absorbance at 313 nm for 0% and 50% collagen III in a composite solution of acid extracted collagen. In contrast to these findings, the diameter of fibrils from acid extracted fetal calf skin with 50% collagen III, determined from electron micrographs, was only 23% smaller than for pure collagen I. Correspondence with investigations on in vitro fibrillogenesis with dark-field microscopy and electron microscopy, this phenomenon apparently derives from the bundling of fibrils. This may be interpreted to mean that bundling of fibrils is already suppressed at low collagen III concentrations. A comparison of acid and pepsin extracted fetal calf skin yielded similar behaviour of collagen I and III mixtures, even though the pepsin extract displayed a turbidity reduction that was about 25% less than the acid extract. For pepsin digested collagen from human and bovine skin, differences were found for maximum turbidity and the ability to form bundles decreasing with the biological age of the donor.


Do selective serotonin reuptake inhibitors increase the risk of bleeding or mortality following coronary artery bypass graft surgery? A meta-analysis of observational studies.
Depressive illness has a high prevalence in patients undergoing coronary artery bypass graft surgery (CABG). The first line treatment for depression are selective serotonin reuptake inhibitors (SSRIs) which inhibit serotonin reuptake in the presynaptic neuronal membrane and uptake by platelets, inhibiting subsequent serotonin-mediated platelet activation. This presents a theoretically increased risk of bleeding and subsequent postoperative mortality. This review aims to investigate the effects of SSRIs on postoperative bleeding, defined as the need for transfusions and re-operation for bleeding, as well as 30-day mortality in patients undergoing CABG. Four hundred and thirty-seven papers were screened with seven meeting the full inclusion criteria. Meta-analysis demonstrated that SSRI use increased the risk of red blood cell transfusion (odds ratio (OR) = 1.15; 95% confidence interval (CI): 1.06-1.26), but resulted in no difference in the rate of re-operation for bleeding (OR = 1.07; 95% CI: 0.66-1.74). SSRI use had no effect on the rates of platelet (OR = 0.93; 95% CI: 0.79-1.09) or fresh frozen plasma (OR = 0.96; 95% CI: 0.74-1.24) transfusion nor on the mortality rate (OR =1.03; 95 CI: 0.90-1.17). This review demonstrates that SSRIs are largely safe in cardiac surgery as no increase in mortality was observed. However, there is a significantly raised chance of red blood cell transfusion. The heterogeneous nature of the current evidence base highlights the need for further research into SSRIs and whether any effect on patient outcomes in cardiac surgery occurs.


South American snake venom proteins antigenically related to Bothrops asper myotoxins.
1. The presence of proteins antigenically related to Bothrops asper myotoxins in various snake venoms, mainly from South America, was investigated by using polyclonal and monoclonal antibodies. 2. Myotoxin-like components were detected in ten Bothrops venoms from South America, and in the venoms of Crotalus atrox (North America), Trimeresurus flavoviridis (Japan), and Micrurus alleni (Costa Rica). 3. Cross-reactive components detected in several Bothrops venoms show a common subunit of 15-16 kDa by sodium dodecyl sulphate-polyacrylamide gel electrophoresis, although significant charge variations are evident by immunoelectrophoresis. 4. It is concluded that proteins antigenically related to B. asper myotoxins are relatively common in the genus Bothrops and, in the light of findings discussed, are likely to possess myotoxic activity.


Metabolic syndrome and cognition in patients with manifest atherosclerotic disease: the SMART study.
It is unclear whether the metabolic syndrome (MetS) increases risk of cognitive dysfunction beyond the level expected from its individual components. We examined the association of MetS with cognitive dysfunction and assessed whether MetS increased risk of cognitive dysfunction more than that of the sum of its individual components. Data on 823 participants were used from the SMART-study, a cohort study among patients with atherosclerotic disease. MetS was defined according to the NCEP-ATPIII-criteria. Neuropsychological tests assessing memory, executive, and visuospatial functioning were performed. Regression analyses were performed to assess the association of MetS and its individual components with cognitive dysfunction. To examine whether MetS increased risk of cognitive dysfunction beyond its individual components we tested whether there was interaction on an additive scale by calculating the relative excess risk due to interaction (RERI). MetS was associated with increased risk of memory (OR 2.0, 95% CI 1.1-3.3) and visuospatial dysfunction (OR 2.3, 95% CI 1.4-2.7) but not with executive dysfunction. However, risk of memory and visuospatial dysfunction for having all MetS components was not greater than that of the sum of the individual components (RERI 0.2 and -0.9). In this population, MetS is related to increased risk of cognitive dysfunction but not more than that of the sum of its individual components.


TLR8 is highly conserved among the Saudi population and its mutations have no effect on the severity of COVID-19 symptoms.
Coronavirus 2019 (COVID-19) is an infection caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The innate system is the first line of defense against pathogens and diverse infectious agents. It has been suggested to play a key role in the development of the cytokine storm and promoting other severe forms of chronic inflammation. Toll-like receptors (TLRs) are crucial for the innate immune response to pathogens. TLR8 is expressed on myeloid cells and phagocytes, where it acts as an endosomal sensor of RNA degradation. The present study aimed to investigate whether the severity of COVID-19 symptoms could be associated with certain genetic variations of TLR8. We collected blood samples from 45 participants who had moderate to severe respiratory symptoms and a positive COVID-19 PCR test result within 3-5 days of sample collection. Genomic DNA was extracted from the blood samples, then exon 2 of the TLR8 gene was amplified with polymerase chain reaction (PCR), and PCR products were utilized for sequencing. DNA sequencing showed an average of 99.63% sequence homology in TLR8 across all samples. Base-pair homology analysis revealed variations in TLR8 at two positions: X:12937804 (rs5744080) and X:12937513 (rs2159377). The results revealed that these two mutations had no detrimental effect on symptoms in the target population. Our results show that specific SNPs did not affect the final receptor function of TLR8. This finding also indicates that the innate immune response, once activated, does not depend on the innate immune receptor's level of affinity for identifying their respective glycoprotein structures on the SARS-CoV-2 virus.


Aberrant Expression of miR-1301 in Human Cancer.
miR-1301 is a newly discovered miRNA, which is abnormally expressed in 14 types of tumors. miR-1301 inhibits 23 target genes, forms a ceRNA network with 2 circRNAs and 8 lncRNAs, and participates in 6 signaling pathways, thereby affecting tumor cell proliferation, invasion, metastasis, apoptosis, angiogenesis, etc. Abnormal expression of miR-1301 is often associated with poor prognosis of cancer patients. In addition, miR-1301 is related to the anti-tumor effect of epirubicin on osteosarcoma and imatinib on chronic myeloid leukemia(CML) and can enhance the cisplatin sensitivity of ovarian cancer. This work systematically summarizes the abnormal expression and prognostic value of miR-1301 in a variety of cancers, depicts the miR-1301-related signaling pathways and ceRNA network, and provides potential clues for future miR-1301 research.


Robot-assisted Laparoscopic Augmentation Ileocystoplasty and Mitrofanoff Appendicovesicostomy in Children: Updated Interim Results.
Robot-assisted laparoscopic augmentation ileocystoplasty with Mitrofanoff appendicovesicostomy (RALIMA) may protect the upper urinary tract and reestablish continence in patients with refractory neurogenic bladder. Robotic assistance can provide the benefits of minimally invasive surgery without the steep learning curve of pure laparoscopy. To highlight the interim outcomes of RALIMA with salient tips and technical modifications through comparison with patients undergoing open augmentation ileocystoplasty (OAI). A retrospective chart review of 17 patients undergoing robot-assisted laparoscopic augmentation ileocystoplasty (RALI) and 13 patients undergoing OAI by a single surgeon at an academic center from 2008 to 2012 (OAI) or 2014 (RALI). RALI and all concomitant procedures were performed completely intracorporeally using the da Vinci surgical system (Intuitive Surgical, Inc., Sunnyvale, CA, USA). Outcomes of interest included change in bladder capacity, operative time, pain medication use, hospitalization time, and perioperative complication rates. Of 17 patients selected, 15 successfully underwent RALI. Overall, 11, 6, and 4 patients had a concomitant Mitrofanoff appendicovesicostomy, antegrade colonic enema channel, and bladder neck closure, respectively. The median operative time was significantly longer in RALI (623 vs 287 min; p<0.01). Median length of stay (LOS) was shorter in RALI (6 vs 8 d; p=0.01). The postoperative percentage increase in bladder capacity, narcotic use, and complication rates did not differ between RALI and OAI. Limitations include the retrospective study design and the small cohort of patients. RALI appears to offer functional outcomes similar to OAI. Although it is a significantly longer procedure, it may decrease LOS and avoid epidural use. Further refinements may reduce operative time. In this report, we examined outcomes after robotic bladder augmentation surgery in children. We found that the robotic approach may eliminate epidural analgesia use and decrease hospitalization time after surgery.


Ablation of Perk in Schwann Cells Improves Myelination in the S63del Charcot-Marie-Tooth 1B Mouse.
In factory cells, the accumulation of misfolded protein provokes the unfolded protein response (UPR). For example, deletion of serine 63 (S63del) in myelin protein zero (P0) induces P0 accumulation in the endoplasmic reticulum (ER) of Schwann cells and a persistent UPR associated with Charcot-Marie-Tooth 1B (CMT1B) demyelinating peripheral neuropathy in human and mouse. PERK (protein kinase RNA-like ER kinase) is the ER stress sensor that attenuates global translation by phosphorylating eIF2α. Inhibition of the eIF2α holophosphatase GADD34:PP1, increases the phosphorylation of eIF2α in Schwann cells and largely rescues S63del neuropathy. Nonetheless, reducing phosphorylation of eIF2α, by Perk haploinsufficiency, also ameliorates the myelin defects of S63del nerves. This contradictory finding prompted us to investigate whether the beneficial effect of Perk deficiency on myelination could derive from neurons. To test this hypothesis, we generated and compared Schwann cell- and neuron-specific ablation of Perk in S63del nerves. Our data suggest that the detrimental effect of Perk in CMT1B derives primarily from Schwann cells. Furthermore, we show that Perk loss of function in Schwann cells restores myelination without diminishing accumulation of P0 or markers of ER stress, suggesting that Perk may modulate myelination through a pathway independent of the UPR. In many endoplasmic reticulum (ER) stress-related disorders, activation of the unfolded protein sensor protein kinase RNA-like ER kinase (PERK) kinase is beneficial. Nonetheless, in Charcot-Marie-Tooth 1B neuropathy mice, we show that activation of PERK in Schwann cells, but not in neurons, is detrimental for myelination. PERK may interfere with myelination, independent of its role in ER stress.


Surveying drug consumption: Assessing reliability and validity of the European Web Survey on Drugs questionnaire.
The European Web Survey on Drugs aimed to obtain in-depth data on consumption of cannabis, ecstasy/MDMA, cocaine, and amphetamines in different populations of drug users in 16 European countries. This paper examines test-retest reliability, the consistency and the comprehensibility of the prevalence and frequency of use questions in the Czech part of the survey. A baseline web survey was performed (N = 610) with follow-up data collection in a sub-sample of volunteers providing email addresses (N = 158). The baseline sample was self-selecting, responding to advertisements made available through multiple channels designed to attract diverse samples of drug users. Test-retest analysis was conducted for core questionnaire items. Respondents to the follow-up were predominantly socially integrated; 91% reported last year cannabis use, 42% used Ecstasy/MDMA, 23% amphetamines, and 27% reported cocaine use. Test-retest reliability was rated moderate to good (reliability coefficients between 0.55-0.87) for most prevalence items with sufficient sample sizes. Items assessing frequency of use were more reliable for most substances when asking about the exact number of days used, compared to categorical items that implicitly assume a regular pattern of use and were interpreted differently by different respondents. Simplicity and unambiguity of questions increase the reliability of results. Tools measuring drug consumption need to take into consideration the irregularity of drug using patterns. Question testing is important to increase validity and support a correct interpretation of the data.


The effect of statin on the aortic gene expression profiling.
Beyond lipid lowering, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) has been found to have anti-inflammatory and anti-thrombotic effects. However, the genetic expression pattern changes in atherosclerotic lesions produced by statin are rarely studied. Cholesterol-fed apolipoprotein (Apo) E-deficient mice were examined for the treatment effect of statin on aortic gene expression. ApoE-deficient mice were fed with a hypercholesterolemic diet started at 8 weeks of age for a total of 22 weeks. In the statin treatment group (n=25), the ApoE-deficient mice were treated with pravastatin (80 mg/kg/day) dissolved in water by daily oral inoculation from 25 to 30 weeks of age. For the control group (n=25), the ApoE-deficient mice were orally inoculated with water only for the same period of time. The aortic gene expression affected by pravastatin was identified using oligonucleotide microarray technology with Agilent gene chips. The total cholesterol and atherosclerotic lesion/total aortic area were significantly lower in the pravastatin treatment group. Microarray analysis of the expression of 20,281 murine genes in the aortas between the two groups indicated that 94 genes were significantly regulated. Thirty genes were up-regulated and 64 genes were down-regulated. The most up-regulated genes were troponin T3, actin alpha1, tubulin alpha1, regulator of G-protein signaling 5 (Rgs5), stathmin-like 2 and myosin light chain kinase. Most of them are related with cytoskeleton organization, while Rgs5 is a G-protein signal transduction molecule. The most down-regulated genes were adenosine deaminase, atrial natriuretic peptide, troponin T2, FXYD domain-containing ion transport regulator 3, and glutathione S-transferase alpha4. The beneficial effect of the 6-week statin treatment in ApoE-deficient mice is largely dependent on its influence on the cytoskeleton organization. Our study results might provide insight into the clinical benefits of chronic statin treatment.


Zinc protects against apoptosis of endothelial cells induced by linoleic acid and tumor necrosis factor alpha.
Zinc requirements of the vascular endothelium may be increased in inflammatory conditions, ie, atherosclerosis, in which apoptotic cell death is prevalent. We hypothesized that zinc deficiency may potentiate disruption of endothelial cell integrity mediated by fatty acids and inflammatory cytokines by enhancing pathways that lead to apoptosis and up-regulation of caspase genes. Endothelial cells were maintained in low-serum medium or grown in culture media containing selected chelators, ie, diethylenetriaminepentaacetate or N,N,N', N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), with or without zinc supplementation. Subsequently, cells were treated with linoleic acid, tumor necrosis factor alpha (TNF-alpha), or both. We studied the effect of zinc deficiency and supplementation on the induction of apoptosis by measuring caspase-3 activity, cell binding of annexin V, and DNA fragmentation. Our results indicated that linoleic acid and TNF-alpha independently, but more markedly in concert, up-regulated caspase-3 activity and induced annexin V binding and DNA fragmentation. Zinc deficiency, especially when induced by TPEN, dramatically increased apoptotic cell death induced by cytokines and lipids compared with control cultures. Supplementation of low-serum- or chelator-treated endothelial cells with physiologic amounts of zinc caused a marked attenuation of apoptosis induced by linoleic acid and TNF-alpha. Morphologic changes of cells observed during zinc deficiency were prevented by zinc supplementation. Media supplementation with other divalent cations (eg, calcium and magnesium) did not mimic the protective role of zinc against apoptosis. Our data indicate that zinc is vital to vascular endothelial cell integrity, possibly by regulating signaling events to inhibit apoptotic cell death.


A new plan quality objective function for determining optimal collimator combinations in prostate cancer treatment with stereotactic body radiation therapy using CyberKnife.
Stereotactic body radiation therapy with CyberKnife for prostate cancer has long treatment times compared with conventional radiotherapy. This arises the need for designing treatment plans with short execution times. We propose an objective function for plan quality evaluation, which was used to determine an optimal combination between small and large collimators based on short treatment times and clinically acceptable dose distributions. Data from 11 prostate cancer patients were used. For each patient, 20 plans were created based on all combinations between one small (⌀ 10-25 mm) and one large (⌀ 35-60 mm) Iris collimator size. The objective function was assigned to each combination as a penalty, such that plans with low penalties were considered superior. This function considered the achievement of dosimetric planning goals, tumor control probability, normal tissue complication probability, relative seriality parameter, and treatment time. Two methods were used to determine the optimal combination. First, we constructed heat maps representing the mean penalty values and standard deviations of the plans created for each collimator combination. The combination giving a plan with the smallest mean penalty and standard deviation was considered optimal. Second, we created two groups of superior plans: group A plans were selected by histogram analysis and group B plans were selected by choosing the plan with the lowest penalty from each patient. In both groups, the most used small and large collimators were assumed to represent the optimal combination. The optimal combinations obtained from the heat maps included the 25 mm as a small collimator, giving small/large collimator sizes of 25/35, 25/40, 25/50, and 25/60 mm. The superior-group analysis indicated that 25/50 mm was the optimal combination. The optimal Iris combination for prostate cancer treatment using CyberKnife was determined to be a collimator size between 25 mm (small) and 50 mm (large).


Three common GJB2 mutations causing nonsyndromic hearing loss in Chinese populations are retained in the endoplasmic reticulum.
The three most common GJB2 mutations found in the Chinese populations, c.235delC, c.299-300delAT, and c.176-191de1 (16) bp, cannot form gap junctons (GJs) in the plasma membrane. These mutant proteins were retained in the endoplasmic reticulum (ER), suggesting that ER stress (ERS) and subsequent ERS-induced cell death may be responsible for hearing loss caused by these GJB2 truncation mutations. The objective of this study was to investigate the subcellular location of the protein products of three GJB2 mutants (c.235de1C, c.299-300delAT, and c.176-191de1 (16) bp) and to explore the deafness mechanism caused by these GJB2 truncation mutations. Mutant-eGFP fusion protein vectors were constructed by PCR and TA cloning. HEK293 cells were transfected by a liposome-mediated method. Transfected cells were incubated with ER-Tracker and observed under a confocal microscope. Cells transfected with wild type gave characteristic punctuate patterns of GJs in the cell membrane. In contrast, c.235de1C, c.299-300delAT, and c.176-191de1 (16) bp mutant proteins were found to be trapped in the ER, and were therefore unable to form GJs in the plasma membrane.


Prenatal detection of cerebral lesions in a fetus with tuberous sclerosis.
We report a newborn, diagnosed prenatally with both cardiac rhabdomyomas and a brain tumor. To the best of our knowledge, this is the first report of central nervous system (CNS) lesions detected prenatally in a child with tuberous sclerosis with term follow-up. At 36 months, the child has normal growth and is developing appropriately. Thus the finding of CNS tumors on fetal ultrasound examination can help in the prenatal diagnosis of tuberous sclerosis but does not necessarily indicate a poor prognosis.


Are tennis players at increased risk for low back pain and sciatica?
Tennis practiced intensively is generally held to be a risk factor for low back pain. The objective of our study was to evaluate the prevalence of low back pain with or without sciatica during the last week in tennis players versus controls. During an international tennis competition held in Brest, France, ten physicians or medical students interviewed 633 spectators older than 18 years and divided them into tennis players and controls. The sample size was selected to allow detection of a twofold increase in the risk of low back pain in tennis players (with alpha = 5% and 1-beta = 80%). Of the 633 subjects, 388 were and 245 were not tennis players. There were 421 men with a mean age of 37 +/- 13.7 years and 212 women with a mean age of 34.3 +/- 12.7. Among the men, 49 of the 281 tennis players (17.4%) reported low back pain during the last week versus 26 of the 140 controls (18.6%). Corresponding figures in women were 20 of 107 tennis players (18.7%) and 29 of 105 controls (27.6%). Sciatica was not more common in tennis players (men, 20 of 281 tennis players [7.1%] versus 6 of 140 controls [4.3%]; women, 8 of 107 tennis players [7.5%] versus 10 of 105 controls [9.5%]). None of the differences between tennis players and controls were significant. The number of hours spent playing tennis per week was similar in tennis players with and without low back pain. Our interview-based cross-sectional study found no evidence that playing tennis involves a higher risk of low back pain with or without sciatica.


Body fluid volume status and the renal response to atrial natriuretic peptide in rats.
The effect of altering the volumes of different body fluid compartments on the renal response to atrial natriuretic peptide (ANP) was studied in anesthetized rats before and during administration of the peptide at 170 ng/min. Four different groups were used. In the first (De), reduction of total body water content was induced by 48 h water deprivation. In the second (De+NaCl), an acute intravenous infusion after the same 48 h dehydration was used to restore the extracellular, but not the intracellular, fluid compartment. In the third (Eu+NaCl), euvolemic rats were infused with isotonic saline at the same rate as in group De+NaCl to expand both intravascular and interstitial components of extracellular fluid. In the fourth group (Eu+BSA) an infusion of hyperoncotic (6%) bovine serum albumin in isotonic saline was used to expand the intravascular volume while contracting the interstitial volume. Excretion of water and salt was predictably reduced in the De group compared with the others. This reduction was associated with increased tubular reabsorption, both upstream from the medullary collecting duct and in the duct itself. Administration of ANP did not significantly affect diuresis and saluresis, or tubular transport. By contrast, there were marked and similar diuretic and natriuretic responses to ANP in groups De+NaCl and Eu+NaCl, associated with transport inhibition primarily in the medullary collecting duct. Surprisingly, the rats infused with hyperoncotic solution (Eu+NaCl) also failed to show marked excretory or duct transport responses to ANP. According to the study design, the two nonresponding groups had, respectively, a decreased or a normal intracellular compartment, and a decreased or increased plasma volume. The common feature of both nonresponding groups was a decreased interstitial fluid compartment, whereas the two responding groups had normal or increased interstitial volume. We suggest, therefore, that a replete interstitial fluid compartment is essential for the renal response to ANP.


Novel mutations of the cathepsin K gene in patients with pycnodysostosis and their characterization.
Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acroosteolysis, bone fragility, and skull deformities. Recently, mutations in the gene encoding cathepsin K (CK), a lysosomal cysteine protease localized exclusively in osteoclasts, were found to be responsible for this disease. We analyzed genomic DNA from four unrelated Japanese patients with this disorder and identified three different mutations of their CK genes: a previously reported missense mutation (A277 V), a novel single base deletion mutation (531 del T) causing a frame shift from codon 142 that results in a premature termination codon, and a novel missense mutation (L9P) in the signal peptide region. To investigate whether the L9P mutation disrupts signal peptide function and decreases protein synthesis, mutant and wild-type CK complementary DNAs driven by the cytomegalovirus promoter were transfected into COS-7 cells, and their gene products were detected by immunohistochemistry and Western blotting. Expression of the mutant protein was markedly reduced, suggesting decreased mature CK production in this patient, which may have been due to dysfunction of the signal peptide. These results provide evidence that a structural change in the signal peptide of the CK protein was involved in the pathogenesis of pycnodysostosis.


In situ observations of fullerene fusion and ejection in carbon nanotubes.
We present in situ experimental observations of fullerenes seamlessly fusing to single-walled carbon nanotubes. The morphing-entry of a fullerene to the interior of a nanotube is also captured. The confined (1D) motion of the newly-encapsulated fullerene within its host attests to the actual change from the exterior to interior.


Isolated buccofacial apraxia subsequent to a left ventral premotor cortex infarction.
Buccofacial apraxia (BFA, or oral apraxia) is a nonspeech skilled movement disorder that involves orofacial structures in the absence of paresis. BFA usually co-occurs with aphasia or apraxia of speech (AOS) and isolated BFA is an extremely rare phenomenon. The brain regions correlated with BFA have been studied in patients with concomitant aphasia or limb apraxia. Therefore, the exact brain regions responsible for BFA remain unclear. We report a patient with pure BFA and discuss the localization of the brain lesion.


Compositional variations in DNA sequences.
Biologically occurring nucleotide sequences differ from randomly generated ones. Here we describe general patterns found in prokaryotic and in eukaryotic DNA. In the accompanying paper (Nussinov, 1991) we also describe DNA signals recognized by their corresponding protein factors. In particular, we focus on modes of searches for such patterns and signals and on the potential properties such sequences may possess.


Understanding BACE1: essential protease for amyloid-beta production in Alzheimer's disease.
The identification of the aspartic protease BACE1 (beta-secretase) was a defining event in research aimed at understanding the molecular mechanisms that underlie Alzheimer's disease (AD) pathogenesis. This is because BACE1 catalyses the rate limiting step in the production of amyloid-beta (Abeta) the principal component of plaque pathology in AD, the excessive production of which is believed to be a primary cause of neurodegeneration, and cognitive dysfunction in AD. Subsequent discoveries showed that genetic deletion of BACE1 completely abolishes Abeta production and deposition in vivo, and that BACE1 activity is significantly increased in AD brain. In this review we present current knowledge on BACE1, discussing its structure, function and complex regulation with a view to understanding BACE1 function in the brain, and BACE1 as a target in blocking aberrant Abeta production in AD.


Who learns from whom? Supporting users and developers of a major biodiversity e-infrastructure.
Support systems play an important role for the communication between users and developers of software. We studied two support systems, an issues tracker and an email service available for Scratchpads, a Web 2.0 social networking tool that enables communities to build, share, manage and publish biodiversity information on the Web. Our aim was to identify co-learning opportunities between users and developers of the Scratchpad system by asking which support system was used by whom and for what type of questions. Our results show that issues tracker and emails cater to different user mentalities as well as different kind of questions and suggest ways to improve the support system as part of the development under the EU funded ViBRANT programme.


The effect of circulation lifetime and drug-to-lipid ratio of intravenously administered lipid nanoparticles on the biodistribution and immunostimulatory activity of encapsulated CpG-ODN.
The encapsulation of conventional drugs in lipid nanoparticles (LNs) has been extensively utilized to enhance therapeutic activity by altering their pharmacokinetic (PK) and biodistribution (BD) properties. We have previously shown that the immunostimulatory activity of unmethylated cytidine-guanosine (CpG)-containing immunostimulatory oligodeoxynucleotides (ODN) is greatly enhanced when encapsulated in an LN (LN CpG-ODN). Here, we investigate the effect of circulation lifetime (determined by lipid composition) and drug-to-lipid (D/L) ratio of intravenously (i.v.) administered LN CpG-ODN on PK, BD, and cellular uptake and correlate these parameters with the immunostimulatory activity. Results from these studies show that despite significant differences in the circulation lifetime and the D/L ratio, the immune response is similar with respect to immune cell activation and cytolytic activity in the spleen and the blood compartments. Our findings indicate that the benefits of liposomal nanoparticles for the delivery of immunomodulatory drugs such as CpG-ODN are defined by a different paradigm than that for conventional drugs.


The effect of induced COVID-19-related fear on psychological distance and time perception.
Emotional experience can influence cognitive estimates such as perceived psychological distance and time judgements. These estimators are crucial in threatening situations like the COVID-19 pandemic because the subjective perception of the closeness of a potential infection might influence behaviour. However, to date it remains unclear how fear affects these estimates. We report on data from N = 183 participants collected in Germany during the summer of 2020, when a "second wave" of COVID-19 infections was still only on the horizon of public awareness. We induced COVID-19-related fear in members of one group and compared their estimates of psychological distance and time judgements to those of a neutral group. Fear induction influenced these conjoint estimates in the way that an increase in infection rates appeared farther away and of shorter duration. Mediation analysis revealed inverse effects of changes in valence and ratings of Fear of COVID-19 on psychological distance. Possible explanations for these effects are discussed.


Geospatial Analysis of Neighborhood Deprivation Index (NDI) for the United States by County.
Little is known about the spatial clustering of neighborhood deprivation across the United States (U.S.). Using data from the 2010 U.S. Census Bureau, we created a neighborhood deprivation index (NDI: higher NDI indicates higher deprivation/ lower neighborhood socioeconomic status) for each county within the U.S. County level scores were loaded into ArcGIS 10.5.1 where they were mapped and analyzed using Moran's I and Anselin Local Moran's I. Ultimately, NDI varies spatially across the US. The highest NDI scores were found in the Southeastern and Southwestern U.S. states, and inland regions of Southern California. This information is critical for public health initiative development as planners may need to tailor the scale of their efforts based on the higher NDI neighborhoods of the county or geographic region with potentially greater chronic disease burden.


Structural dynamics govern substrate recruitment and catalytic turnover in H/ACA RNP pseudouridylation.
H/ACA ribonucleoproteins catalyse the sequence-dependent pseudouridylation of ribosomal and spliceosomal RNAs. Here, we reconstitute site-specifically fluorophore labelled H/ACA complexes and analyse their structural dynamics using single-molecule FRET spectroscopy. Our results show that the guide RNA is distorted into a substrate-binding competent conformation by specific protein interactions. Analysis of the reaction pathway using atomic mutagenesis establishes a new model how individual protein domains contribute to catalysis. Taken together, these results identify and characterize individual roles for all accessory proteins on the assembly and function of H/ACA RNPs.


The effect of angiotensin II on the number of macula densa cells through the AT1 receptor.
The present study was performed to obtain information about a possible correlation between the activity of the renin-angiotensin system and the stereological features of the macula densa (MD). In normal kidneys, the numbers of angiotensin II AT1 receptors were estimated in MD cells and in the neighboring tubular cells. The total volumes of MD, MD cells, neighboring tubular cells, and the total number of MD cells, were measured in normal and candesartan-treated rats (15 mg/kg/day over 21 days). In the normal kidneys, the relative number of AT1 receptors in MD cells [mean = 0.17 (CV = 0.23)] was significantly (p = 0.03) lower than that in normal tubular cells [0.25 (0.21)]. A significant difference (p < 0.01) was observed in the total volume between MD cells [515 microm(3) (0.14)] and normal tubular cells [984 microm(3) (0.19)]. Candesartan treatment significantly elevated (p < 0.01) the total volume of the MD, whereas the total number of MD cells was increased [from 14.2 (0.11) to 19.5 (0.11)]. The results demonstrated that the transdifferentiation from normal tubular cells to MD cells can be controlled by pharmacological means. The structural features of MD controlled by the renin-angiotensin system may be one of the important factors governing the sensitivity of tubuloglomerular feedback.


Measuring participation in a prevention trial with parents of young children.
This paper describes parent participation in a clinical trial of preventive parent training (PT) targeting low-income parents of young children. Participation encompassed enrollment, attendance, and engagement. Average enrollment rate was 34.9%, although enrollment rates were significantly higher in the control (39.1%) than in the intervention (30.6%) centers. Parents attended an average of 39% of the PT sessions. Higher attendance was associated with lower parenting self-efficacy, more parent-reported child behavior problems, and attending the first PT session. Level of engagement in the PT sessions was related to improvements in parent and child outcomes. Findings suggest that attendance is linked to parent perceived need for help and that resources should be focused on ensuring parent attendance at the first intervention session.


[Ecological control effects of Litchi chinensis-Desmodium intortum complex plant ecosystem on litchi pests].
An investigation on the community structure and dynamics of litchi pests and their natural enemies in constructed Litchi chinensis-Desmodium intortum complex plant ecosystem and single L. chinensis ecosystem showed that the total amount of litchi pests in the complex plant ecosystem was 61.27% of that in the single ecosystem in whole year, and only 50.45% in May, the key time for fruit development, which suggested that there was an interaction between D. intortum and L. chinensis. D. intortum and L. chinensis had a few common pests, but many common natural enemies. D. intortum florescence in winter provided shelter and substitutive food for the natural enemies of pests to survive in the extreme environmental conditions in winter. L. chinensis florescence was on the heel of D. intortum florescence, which provided better conditions for the natural enemies to survive and multiply. During florescence and fruit development stages of L. chinensis (from March to June), the predator/prey ratio in complex plant system was 4.22, 2.34, 2.2 and 20.63 times of that in single plant system in March, April, May and June, respectively, indicating the good control effect on pests of L. chinensis.


A New Cage-Like Particle Adjuvant Enhances Protection of Foot-and-Mouth Disease Vaccine.
Foot-and-Mouth Disease (FMD) is an acute viral disease that causes important economy losses. Vaccines with new low-cost adjuvants that stimulate protective immune responses are needed and can be assayed in a mouse model to predict their effectiveness in cattle. Immunostimulant Particle Adjuvant (ISPA), also known as cage-like particle adjuvant, consisting of lipid boxes of dipalmitoyl-phosphatidylcholine, cholesterol, sterylamine, alpha-tocopherol, and QuilA saponin, was shown to enhance protection of a recombinant vaccine against Trypanosoma cruzi in a mouse model. Thus, in the present work, we studied the effects on the magnitude and type of immunity elicited in mice and cattle in response to a vaccine based on inactivated FMD virus (iFMDV) formulated with ISPA. It was demonstrated that iFMDV-ISPA induced protection in mice against challenge and elicited a specific antibody response in sera, characterized by a balanced Th1/Th2 profile. In cattle, the antibody titers reached corresponded to an expected percentage of protection (EPP) higher than 80%. EPP calculates the probability that livestock would be protected against a 10,000 bovine infectious doses challenge after vaccination. Moreover, in comparison with the non-adjuvanted iFMDV vaccine, iFMDV-ISPA elicited an increased specific T-cell response against the virus, including higher interferon gamma (IFNγ)+/CD8+ lymphocyte production in cattle. In this work, we report for first time that an inactivated FMDV serotype A vaccine adjuvanted with ISPA is capable of inducing protection against challenge in a murine model and of improving the specific immune responses against the virus in cattle.


MYC in Brain Development and Cancer.
The MYC family of transcriptional regulators play significant roles in animal development, including the renewal and maintenance of stem cells. Not surprisingly, given MYC's capacity to promote programs of proliferative cell growth, MYC is frequently upregulated in cancer. Although members of the MYC family are upregulated in nervous system tumours, the mechanisms of how elevated MYC promotes stem cell-driven brain cancers is unknown. If we are to determine how increased MYC might contribute to brain cancer progression, we will require a more complete understanding of MYC's roles during normal brain development. Here, we evaluate evidence for MYC family functions in neural stem cell fate and brain development, with a view to better understand mechanisms of MYC-driven neural malignancies.


Varioilluminator (subtractive double monochromator with variable bandpass).
A varioilluminator is a double monochromator in which the dispersion in the second half of the instrument is subtractive rather than additive and in which the central slit can be opened very wide. The wavelength bandpass depends almost entirely upon the width of the central slit. The jaws of the central slit in the instrument described here were made independently variable, so that the long and short wavelength cutoffs could be independently selected. Quartz or glass prisms could be used, and bandpasses from about 15A to several hundred Acould be chosen.


Use of immobilized PCR primers to generate covalently immobilized DNAs for in vitro transcription/translation reactions.
We have developed a novel biochemical method to simultaneously amplify and immobilize a target gene onto insoluble particles using PCR. This method employs the covalent attachment of one of two PCR primers to a particle surface either directly during DNA synthesis of the primer or post-DNA synthesis, through the use of chemical crosslinkers. Immobilization of the target gene can be achieved directly during PCR amplification, with one bead-bound primer and one soluble primer. Alternatively, this can be achieved post-PCR, through covalent attachment of a chemically modified primer incorporated into the amplicon to an activated particle. All of the immobilized DNA templates containing appropriate regulatory regions were fully competent for transcription and translation reactions and several could be re-used in serial reactions. The most successful strategy utilized amino-silanized controlled pore glass beads, which were coupled to phosphorylated primers using carbodiimide chemistry. These bead-bound primers were used during PCR to generate attached DNA templates that could be collected and re-used for at least seven sequential transcription reactions without significant loss in efficiency. This method has also been successfully applied to the amplification, transcription and translation of multiple DNA templates using a single, immobilized primer. The combined PCR-based amplification/immobilization method was shown to be more durable than post-PCR chemical immobilization and affords the convenience of performing sequential PCR amplification, transcription and translation reactions in a single tube.


Analysis of Spatially Distributed Data in Internet of Things in the Environmental Context.
The Internet of Things consists of "things" made up of small sensors and actuators capable of interacting with the environment. The combination of devices with sensor networks and Internet access enables the communication between the physical world and cyberspace, enabling the development of solutions to many real-world problems. However, most existing applications are dedicated to solving a specific problem using only private sensor networks, which limits the actual capacity of the Internet of Things. In addition, these applications are concerned with the quality of service offered by the sensor network or the correct analysis method that can lead to inaccurate or irrelevant conclusions, which can cause significant harm for decision makers. In this context, we propose two systematic methods to analyze spatially distributed data Internet of Things. We show with the results that geostatistics and spatial statistics are more appropriate than classical statistics to do this analysis.


Intelligent Mining of Urban Ventilation Corridors Based on High-Precision Oblique Photographic Images.
With the advancement of urbanization and the impact of industrial pollution, the issue of urban ventilation has attracted increasing attention. Research on urban ventilation corridors is a hotspot in the field of urban planning. Traditional studies on ventilation corridors mostly focus on qualitative or simulated research on urban climate issues such as the intensified urban heat island effect, serious environmental pollution, and insufficient climate adaptability. Based on the high-precision urban remote sensing image data obtained by aeromagnetic oblique photography, this paper calculates the frontal area density of the city with reference to the urban wind statistics. Based on the existing urban patterns, template matching technology was used to automatically excavate urban ventilation corridors, which provides scientific and reasonable algorithmic support for the rapid construction of potential urban ventilation corridor paths. It also provides technical methods and decision basis for low-carbon urban planning, ecological planning and microclimate optimization design. This method was proved to be effective through experiments in Deqing city, Zhejiang Province, China.


A distant 10-bp sequence specifies the boundaries of a programmed DNA deletion in Tetrahymena.
Programmed DNA deletion occurs at thousands of specific sites in most ciliates studied. To understand the mechanism of this prominent DNA rearranging process, we analyzed one of the deletion elements (the M-element) in Tetrahymena by making specific mutations in cloned DNAs and testing their effects on rearrangement in vivo. We found that a 10-bp polypurine sequence (5'-AAAAAGGGGG) plays a crucial role. This sequence is located at a short distance (approximately 45 bp) outside of the element on either side. Removal of it abolishes the deletion process. Moving it short distances away causes the deletion boundary to move with it. Insertion of this sequence into a site within the element induces new boundaries to form near the insertion site. Sequence analysis reveals that all new boundaries created are 41-54 bp away from the sequence. Thus, this sequence is necessary and sufficient to determine the boundaries of DNA deletion, and it does so from a short distance outside of the element. These results offer a possible explanation for the control of DNA deletion in ciliates and suggest that a new type of mechanism for site-specific DNA rearrangements is involved.


Lentivirus-mediated gene transfer to human epidermis.
For long-term cutaneous gene therapy, the therapeutic gene must be targeted to stem cells and be stably transmitted to and expressed in descendant cells. Retroviral vectors are highly efficient in gene transfer to human keratinocyte stem cells in culture; however, they cannot transduce quiescent stem cells in vivo. As lentiviral vectors (LVV) transduce non-proliferating cells, their ability to target human epidermal stem cells was evaluated. LVV were highly efficient in gene transfer to clonogenic keratinocytes in vitro. Despite higher transgene DNA content and comparable levels of transgene mRNA, levels of transgene product directed by lentivectors were 3-folds lower than that of retrovectors. When transduced keratinocytes were grafted onto mice, transgene expression persisted for at least 20 wk; however, transgene product was detected primarily in the uppermost layers of epidermis. Inclusion of an element that is known to facilitate nuclear export of intron-less transcripts, resulted in enhanced transgene expression in keratinocytes. In vivo transduction of xenografted human skin with these vectors resulted in efficient gene transfer to epidermal progenitor cells. These results demonstrate stem cell transduction by LVV and point out the utility of using these vectors for direct gene transfer to and sustained expression in human epidermis.


[Better cure for anxiety, sleep disorders, epilepsy?].
Gamma-aminobutyric acid (GABA), the most important inhibitory neurotransmitter, is characterised by rapid effects that are mediated via GABAA, receptors. These receptors are also targets for many drugs including benzodiazepines, barbiturates and general anaesthetics. Recognition of the heterogeneity of GABAA receptors has opened up new possibilities for the development of more selective therapeutic agents. In particular, subtype-specific receptor ligands varying in intrinsic activity are likely to give rise to fewer side effects than do currently available drugs.


Considerations in assessing effectiveness and costs of diabetes care: lessons from DARTS.
Use of a population-based diabetes clinical information system is crucial to understanding the nature and magnitude of disease burden, effects of treatment, and personal and economic costs of diabetes. Information from the DARTS (Diabetes Audit and Research in Tayside Scotland) project has shown that patients with diabetes account for a disproportionate amount of cardiovascular disease, have a poorer associated prognosis, and do not receive effective secondary preventive therapies as frequently as do patients without diabetes. In addition, the prevalence of type 2 diabetes is associated with lower socioeconomic status - as, in turn, is significantly increased body mass index (BMI). The DARTS findings also revealed that much of the cost of diabetes treatment is accounted for by costs associated with treatment of coronary vascular disease and hospitalization. The vast majority of type 2 patients have inadequately controlled blood pressure, and many of these patients do not adhere to prescribed oral therapy. It is clear that much work remains to be done to implement and maintain standards of care that will improve outcome in diabetes. Efforts in this regard can best be monitored by effective population-based programs.


Predictors of early discontinuation of dapagliflozin versus other glucose-lowering medications: a retrospective multicenter real-world study.
In routine clinical practice, early discontinuation of newly initiated glucose-lowering medications (GLM) is relatively common. We herein evaluated if the clinical characteristics associated with early discontinuation of dapagliflozin were different from those associated with early discontinuation of other GLM. The DARWIN-T2D was a multicenter retrospective study conducted at diabetes specialist outpatient clinics in Italy. We included 2484 patients who were initiated on dapagliflozin in 2015-2016 and 14,801 patients who were initiated on other GLM (DPP-4 inhibitors, GLP-1 receptor agonists, or gliclazide) in the same period. After excluding patients who had not (yet) returned to follow-up, we compared the characteristics of patients who persisted on drug versus those who were no longer on drug at the first available follow-up after at least 3 months. As compared to those who persisted on drug, patients who discontinued dapagliflozin (51.7%) were more often female, had higher baseline fasting plasma glucose (FPG), HbA1c, and eGFR, and less common use of metformin. Upon multiple regression, higher HbA1c, higher eGFR, and lower metformin use remained independently associated with early discontinuation. Among patients who had been initiated on other GLM, 41.7% discontinued. Variables independently associated with discontinuation were older age, longer diabetes duration, higher HbA1c, eGFR, and albumin excretion, more common use of insulin and less metformin. In routine clinical practice, all variables associated with dapagliflozin discontinuation were also associated with discontinuation of other GLM. Thus, despite a distinctive mechanism of action and a peculiar tolerability profile, no specific predictor of dapagliflozin discontinuation was detected.


Eliminating air bubble in microfluidic systems utilizing integrated in-line sloped microstructures.
In most microfluidic systems, formation and accumulation of air and other gas bubbles can be detrimental to their operation. Air bubbles in a microfluidic channel induce a pressure profile fluctuation and therefore disturb the stability of the system. Once an air bubble is generated, it is also extremely difficult to remove such bubbles from the microfluidic systems. In tissue and cell culture microfluidic systems, a single air bubble can completely shear off cells that are being cultured. Air bubbles can be especially problematic in microfluidic systems that have to operate for long periods of time, since completely eliminating the generation of air bubbles for prolonged periods of time, where a single air bubble can ruin an entire multi-day/multi-week experiment, is extremely challenging. Several in-line and off-chip bubble traps have been developed so far, but cannot completely eliminate air bubbles from the system or are relatively difficult to integrate into microfluidic systems. Recent advancements in two-photon polymerization (2PP)-based microfabrication method eliminates the restriction in Z-axis control in conventional two-dimensional microfabrication methods, and thus enables complex 3D structures to be fabricated at sub-micrometer resolution. In this work, by utilizing this 2PP technique, we developed a sloped microfluidic structure that is capable of both trapping and real-time removal of air bubbles from the system in a consistent and reliable manner. The novel structures and designs developed in this work present a unique opportunity to overcome many limitations of current methods, bring state-of-the-art solutions in air bubble removal, and enable a multifunctional microfluidic device to operate seamlessly free from air bubble disruption. The microfabricated system was tested in both droplet microfluidics and continuous-flow microfluidics applications, and demonstrated to be effective in preventing air bubble aggregation over time. This simple sloped microstructure can be easily integrated into broad ranges of microfluidic devices to minimize bubble introduction, which will contribute to creating a stable and bubble-free microfluidic platform amenable for long-term operation.


A method for preparing skeletal muscle fiber basal laminae.
Previous attempts to prepare skeletal muscle basal laminae (BL) for ultrastructural analyses have been hampered by difficulties in successfully removing skeletal muscle proteins and cellular debris from BL tubes. In the present study we describe a two phase method which results in an acellular muscle preparation, the BL of which are examined by light, transmission electron, and scanning electron microscopy. In the first phase, excised rat extensor digitorum longus muscles are subjected to x-radiation and then soaked in Marcaine to inhibit muscle regeneration and to destroy peripheral muscle fibers. The muscles are then grafted back into their original sites and allowed to remain in place 7-14 days to allow for maximal removal of degenerating muscle tissue with minimal scar tissue formation. In the second phase, the muscle grafts are subjected sequentially to EDTA, triton X-100, DNAase, and sodium deoxycholate to remove phagocytizing cells and associated degenerating muscle tissue. These procedures result in translucent, acellular muscle grafts which show numerous empty tubes of BL backed by endomysial collagenous fibers. These preparations should be useful for morphological analyses of isolated muscle BL and for possible in vitro studies by which the biological activity of muscle BL can be examined.


mHealth in emergency medicine [special report]
With the proliferation of smartphones over the past several years, apps now play a prominent role in many social and work contexts, including medicine. This is enough of a phenomenon to have inspired the abbreviation "mHealth," short for mobile health. The number of app-driven clinical calculators, checklists, and risk scores in common use in the emergency department (ED) has significantly increased and shows no sign of slowing. Thanks to this digital development and innovation, clinical decision support is now just a finger-tap away. As of 2016, there were approximately 20,000 apps in the "Medical" category of Apple's app store. There are at least 300 apps specifically targeted to emergency clinicians, and given the variety of patient presentations, general-purpose apps and apps from other specialties likely merit usage in the ED. Despite the abundance of apps and their potential to improve patient care, the decision of which apps to choose and use is left largely to each clinician, with little guidance on best practices or potential risks. The purpose of this report is to educate emergency clinicians about medical apps that can be utilized to improve patient care during a shift.


Reciprocal Influence of Couple Dynamics and Eating Disorders.
Little research has focused on the ways that eating disorder processes and adult couple dynamics influence one another. The purpose of this study was to investigate the reciprocal influence of couple dynamics and eating disorder illness and recovery processes. We conducted 51 interviews with 17 couples where one member identified as currently suffering or having recovered from an eating disorder. Using grounded theory analytical methods, findings include the systemic interplay of the eating disorder and relationship, both partners' perspectives on the eating disorder and its role in the relationship, the noneating disorder partner's impact on the eating disorder, and coping strategies for recovery as a couple. Clinical implications for supporting couples experiencing eating disorder illness and recovery are discussed.


Metal complexes of ruthenium: a potential class of selective anticancer drugs.
Metal complexes of ruthenium were subjected to a number of studies concerning their chemical behaviour and their potential role in medical applications. Particular emphasis was given to the examination of the antineoplastic properties of ruthenium complexes with a number of ligands of biological interest. The possibility of obtaining compounds of potential value in the chemotherapeutic approach to neoplastic disease is supported by observations that ruthenium compounds could interact with tumor cells better than with normal tissues. This interaction can be considered the result of the chemical characteristics of ruthenium ions which can confer much more selectivity than do the actually available and clinically used organic compounds or cis-dichlorodiammine-platinum (II). Thus, ruthenium-based compounds represent the way for introducing a new class of antitumor drugs endowed with a great potential for the management of human tumors.