Hatha Yoga practice decreases menopause symptoms and improves quality of life: A randomized controlled trial.
Yoga practice includes a group of specific psychophysical techniques. Although previous studies showed beneficial effects of yoga for health and rehabilitation, improving quality of life, there are few studies on the possible therapeutic application of yoga during the climacteric period. The purpose of this study was to investigate the psychophysiological effects of Hatha Yoga regular practice in post-menopausal women. Eighty-eight post-menopausal women volunteered for this 12-week trial. They were randomly assigned to one of three groups: control (no intervention), exercise, and yoga. Questionnaires were applied in order to evaluate climacteric syndrome (Menopause Rating Scale), stress (Lipp Stress Symptom Inventory), quality of life (Brief World Health Organization Quality of Life), depression (Beck Depression Inventory) and anxiety (State/Trait Anxiety Inventories). Physiological changes were evaluated through hormone levels (cortisol, FSH, LH, progesterone and estradiol). At 12 weeks, yoga practitioners showed statistically lower scores for menopausal symptoms, stress levels and depression symptoms, as well as significantly higher scores in quality of life when compared to control and exercise groups. Only control group presented a significant increase in cortisol levels. The yoga and exercise groups showed decreased levels of FSH and LH when compared to control group. These results suggest that yoga promotes positive psychophysiological changes in post-menopausal women and may be applied as a complementary therapy towards this population.


Inflammatory markers: linking unstable plaques to coronary event, an interventional perspective.
Abundant data links inflammatory mechanisms to atheromatous plaque destabilization leading to plaque rupture and coronary events. The discovery of inflammatory cells and inflammatory mediators within atherosclerotic plaques prone to rupture led to a series of studies demonstrating an association between various markers of inflammation and future coronary events. Inflammatory markers have also been used in patients undergoing coronary angioplasty in an attempt to predict restenosis and risk for post-procedural coronary events. This review article provides an overview on the potential use of inflammatory markers in the context of coronary interventions.


Probing a Device's Active Atoms.
Materials science and device studies have, when implemented jointly as "operando" studies, better revealed the causal link between the properties of the device's materials and its operation, with applications ranging from gas sensing to information and energy technologies. Here, as a further step that maximizes this causal link, the paper focuses on the electronic properties of those atoms that drive a device's operation by using it to read out the materials property. It is demonstrated how this method can reveal insight into the operation of a macroscale, industrial-grade microelectronic device on the atomic level. A magnetic tunnel junction's (MTJ's) current, which involves charge transport across different atomic species and interfaces, is measured while these atoms absorb soft X-rays with synchrotron-grade brilliance. X-ray absorption is found to affect magnetotransport when the photon energy and linear polarization are tuned to excite FeO bonds parallel to the MTJ's interfaces. This explicit link between the device's spintronic performance and these FeO bonds, although predicted, challenges conventional wisdom on their detrimental spintronic impact. The technique opens interdisciplinary possibilities to directly probe the role of different atomic species on device operation, and shall considerably simplify the materials science iterations within device research.


CD36 regulates fatty acid composition and sensitivity to insulin in 3T3-L1 adipocytes.
In the current study, we tested a hypothesis that CD36 fatty acid (FA) transporter might affect insulin sensitivity by indirect effects on FA composition of adipose tissue. We examined the effects of CD36 downregulation by RNA interference in 3T3-L1 adipocytes on FA transport and composition and on sensitivity to insulin action. Transfected 3T3-L1 adipocytes, without detectable CD36 protein, showed reduced neutral lipid levels and significant differences in FA composition when levels of essential FA and their metabolites were lower or could not be detected including gamma linolenic (C18:3 n6), eicosadienic (C20:2 n6), dihomo-gamma linolenic (C20:3 n6), eicosapentaenoic (EPA) (C20:5 n3), docosapentaenoic (DPA) (C22:5 n3), and docosahexaenoic (DHA) (C22:6 n3) FA. Transfected 3T3-L1 adipocytes exhibited a significantly higher n6/n3 FA ratio, reduced 5-desaturase and higher 9-desaturase activities. These lipid profiles were associated with a significantly reduced insulin-stimulated glucose uptake (4.02+/-0.1 vs. 8.42+/-0.26 pmol.10(-3) cells, P=0.001). These findings provide evidence that CD36 regulates FA composition thereby affecting sensitivity to insulin action in 3T3-L1 adipocytes.


Molecular characterization of the plasmid-encoded eps gene cluster essential for exopolysaccharide biosynthesis in Lactococcus lactis.
Lactococcus lactis strain NIZO B40 produces an extracellular phosphopolysaccharide containing galactose, glucose, and rhamnose. A 40 kb plasmid encoding exopolysaccharide production was isolated through conjugal transfer of total plasmid DNA from strain NIZO B40 to the plasmid-free L. lactis model strain MG1614 and subsequent plasmid curing. A 12 kb region containing 14 genes with the order epsRXABCDEFGHIJKL was identified downstream of an iso-IS982 element. The predicted gene products of epsABCDEFGHIJK show sequence homologies with gene products involved in exopolysaccharide, capsular polysaccharide, lipopolysaccharide, or teichoic acid biosynthesis of other bacteria. Transcriptional analysis of the eps gene cluster revealed that the gene cluster is transcribed as a single 12 kb mRNA. The transcription start site of the promoter was mapped upstream of the first gene epsR. The involvement of epsD in exopolysaccharide (EPS) biosynthesis was demonstrated through a single gene disruption rendering an exopolysaccharide-deficient phenotype. Heterologous expression of epsD in Escherichia coli showed that its gene product is a glucosyltransferase linking the first sugar of the repeating unit to the lipid carrier.


Asymptomatic Huge Cardiac Hydatid Cyst Located in the Interventricular Septum.
The cardiac involvement of hydatid cyst, which is rarely seen, with the location of asymptomatic huge cyst in the interventricular septum (IVS) is an extraordinary condition. We report an isolated cardiac hydatid cyst located in the IVS in an 18-year-old man diagnosed incidentally by transthoracic echocardiography. Cardiac magnetic resonance imaging confirmed a mass lesion of 47×74 mm in diameter located at the base of IVS. The cystic content and its germinative membrane were resected and the cavity was applicated under cardiopulmonary bypass. Postoperative course was uneventful and the patient was discharged on the 6th postoperative day, with oral albendazole therapy.


Treatment of mandibular class II furcation defects by the use of amelogenins and autologous bone. Two case reports.
The aim of this preliminary study was to evaluate the clinical effectiveness of the association of amelogenins and autologous bone graft in the management of mandibular class II furcation defects. This randomized case-controlled study was conducted on 2 patients who presented 2 contralateral mandibular buccal class II furcation lesions. One defect was treated by amelogenins and autologous bone graft (test site) and the other one by open flap debridement (control site). At baseline and at 12 months postoperatively, the full-mouth plaque score (FMPS) and the full-mouth bleeding score (FMBS), the probing depth (PD), the clinical attachment level (CAL) and the recession (REC) were recorded and a periapical radiograph of the selected area was taken. In addition, at 12 months a surgical re-entry was performed. Test sites had a greater horizontal PD reduction and radiographic bone filling compared to control sites. None of the treated sites achieved complete furcation closure. At the time of re-entry, furcations treated by amelogenins were partially filled by newly formed not soundable hard tissue, while furcations treated by conventional flap surgery were filled by epithelial and connective tissue. These findings suggest that the treatment of mandibular class II furcations by amelogenins and autologous bone graft may result in a significant clinical improvement. Further long-term studies conducted on a larger sample size are therefore needed to confirm our results.


Cryopreservation of cell/scaffold tissue-engineered constructs.
The aim of this work was to study the effect of cryopreservation over the functionality of tissue-engineered constructs, analyzing the survival and viability of cells seeded, cultured, and cryopreserved onto 3D scaffolds. Further, it also evaluated the effect of cryopreservation over the properties of the scaffold material itself since these are critical for the engineering of most tissues and in particular, tissues such as bone. For this purpose, porous scaffolds, namely fiber meshes based on a starch and poly(caprolactone) blend were seeded with goat bone marrow stem cells (GBMSCs) and cryopreserved for 7 days. Discs of the same material seeded with GBMSCs were also used as controls. After this period, these samples were analyzed and compared to samples collected before the cryopreservation process. The obtained results demonstrate that it is possible to maintain cell viability and scaffolds properties upon cryopreservation of tissue-engineered constructs based on starch scaffolds and goat bone marrow mesenchymal cells using standard cryopreservation methods. In addition, the outcomes of this study suggest that the greater porosity and interconnectivity of scaffolds favor the retention of cellular content and cellular viability during cryopreservation processes, when compared with nonporous discs. These findings indicate that it might be possible to prepare off-the-shelf engineered tissue substitutes and preserve them to be immediately available upon request for patients' needs.


Extending the source-sink potential method to include electron-nucleus coupling.
The source-sink potential (SSP) method provides a simple tool for the qualitative analysis of the conductance of molecular electronic devices, and often analytical expressions for the conductance can be obtained. Here, we extend the SSP approach to account for decoherent, inelastic electron transport by including the non-adiabatic coupling between the electrons and the nuclei in the molecule. This coupling results in contributions to electron transport that can modify the qualitative structure-conductance relationships that we unraveled previously with SSP. In the approach proposed, electron-nucleus interactions are treated starting from the harmonic approximation for the nuclei, using a non-perturbative approach to account for the non-adiabatic coupling. Our method qualitatively describes experimentally observed phenomena and allows for a simple analysis that often provides analytical formulas in terms of the physical parameters of the junction, e.g., vibrational energies, non-adiabatic coupling, and molecule-contact coupling.


Trypanocidal drugs for late stage, symptomatic Chagas disease (Trypanosoma cruzi infection).
People with Chagas disease (American Trypanosomiasis) may develop progressive and potentially lethal heart conditions. Drugs to eliminate the causative parasite, Trypanosoma cruzi, currently in use have limited therapeutic value and are used in early stages of the disease. Extending the use of these drugs to treat symptomatic chronic parasitism with chronic Chagasic cardiopathy (CCC) and progressive dilated cardiomyopathy has been proposed. To assess the effects (harms and benefits) of nitrofurans and imidazolic trypanocidal drugs for treating late stage chronic Chagas disease and CCC. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 3, 2004), MEDLINE (1985-2004), EMBASE (1985-2004), BIREME (1985-2004), LILACS (1985-2004), ARTEMISA (1985-2004), SCIELO (1985-2004). Indexing terms in English and Spanish were used. References obtained were assessed for relevance by two reviewers independently. We included randomized controlled clinical trials (RCTs), single or double blind using trypanocidal drugs versus placebo or no treatment in CCC. All articles retrieved were assessed using a predefined check list to determine if they met the inclusion criteria. Two independent reviewers collected data using a pre-designed form piloted on three articles before the review process started. Disagreements were resolved by a third reviewer. If the information was unavailable the articles were excluded. We planned a quantitative analysis of reduction of parasite load whether recorded as a categorical variable or the reduction of specific antibody titers. However insufficient data were available for quantitative analysis. We prepared a qualitative description of data identified. We found only one randomized double blind placebo controlled trial. We also found six uncontrolled or non-randomized studies which were of some relevance and were therefore described. We found insufficient evidence to define the effects of drug treatment for people with CCC. There is insufficient evidence to support the efficacy of nitrofurans or imidazolic drugs as recommended treatment in CCC and chronic T.cruzi infections, specifically if overt heart disease is present. A well designed randomized controlled trial is necessary to establish if new drugs are suitable for treatment of cardiac patients with CCC.


Characteristics of Labial Gland Mesenchymal Stem Cells of Healthy Individuals and Patients with Sjögren's Syndrome: A Preliminary Study.
Sjögren's syndrome (SS) is a systemic autoimmune disease that is characterized by focal lymphocytic infiltration into exocrine organs such as salivary and lacrimal glands, resulting in dry mouth and eyes, and other systemic injuries. There is no curative clinical therapy for SS, and stem cell therapy has shown great potential in this area. The mesenchymal stem cells (MSCs) in the salivary glands of healthy individuals and in patients with SS have not been extensively studied. The aim of this study was to elucidate the characteristics of MSCs from the labial glands of healthy controls and of those from patients with SS to elucidate the related pathogenesis and to uncover potential avenues for novel clinical interventions. Labial glands from patients with SS and healthy subjects were obtained, and MSCs were isolated and cultured by using the tissue adherent method. The MSC characteristics of the cultured cells were confirmed by using morphology, proliferation, colony forming-unit (CFU) efficiency, and multipotentiality, including osteogenic, adipogenic, and salivary gland differentiation. The MSCs from the healthy controls and SS patients expressed characteristic MSC markers, including CD29, CD44, CD73, CD90, and CD105; they were negative for CD34, CD45, and CD106, and also negative for the salivary gland epithelium markers (CD49f and CD117). Labial gland MSCs from both groups were capable of osteogenic and adipogenic differentiation. The CFU efficiency and adipogenic differentiation potential of MSCs were significantly lower in the SS group compared with the healthy controls. Cells from both groups could also be induced into salivary gland-like cells. Real-time polymerase chain reaction and immunofluorescence staining showed that the gene and protein expression of AMY1, AQP5, and ZO-1 in cells from the SS group was lower than that in cells from the healthy group. Thus, MSCs from the labial glands in patients with SS could lack certain characteristics and functions, especially related to salivary secretion. These preliminary data provided insights that could lead to the development of novel therapeutic strategies for the treatment of SS.


Overview of IgG4 - Related Disease.
Rationale (hypothesis): IgG4-related disease (IgG4-RD) is a pathological entity recently recognized by the medical world that can affect any organ or system. However, there is insufficient data about this disease in medical literature. Aim (objective): A more extensive clarification of the IgG4 molecule, the diversified aspects of IgG4-related disease, and the response of this disease to treatment, will provide a crucial understanding of the immune system and other diseases now known to be associated with IgG4. The MEDLINE online medical database was used, and, after a comprehensive review of medical articles regarding IgG4-RD, published after 2003, using the search words "IgG4- related disease" and "IgG4 molecule", we have described the clinical, pathological and therapeutic features of IgG4-RD, as well as the presence of the IgG4 molecule in the evolution, diagnosis and management of this syndrome. We characterized the potential disease mechanisms and discussed early observations related to treatment. Given the response to immunosuppressive therapy, it is hypothesized that IgG4-related disease is most likely an autoimmune disease. Therefore, IgG4-related disease is a fibro-inflammatory condition that can affect any organ and can lead to the formation of pseudotumoral lesions requiring differential diagnosis with various malignancies. Positive diagnostic criteria are histopathological and require at least two features out of the following three: dense limphoplasmocitary infiltrate, storiform fibrosis, obliterative phlebitis.


[Secondary fluorescence of intraocular vessels of the anterior segment of the rat eye after local drug application (author's transl)].
After local application of gentamycine, dexamethasone and tropicamide to rat eyes, no effect was observed on the permeability of the vascular wall of the iris and ciliary body compared with fluorescein-Na. Nor were there any changes in vessel caliber. The constriction of the dye column observed in corneal neovascularizations was not seen in the (normal) iris vessels and the vessels of the ciliary body. With regard to the iris region, however, this might be due to mechanical causes and/or the possibility that vessels of different origins react differently.


Review article: Maxillofacial emergencies: Maxillofacial trauma.
Fractures of the facial skeleton are a common reason for patients to present to EDs and general medical practice in Australia. Trauma to the maxillofacial region can lead to airway obstruction, intracranial injuries, loss of vision or long term cosmetic and functional deficits. This article focuses on the emergency assessment, triage and non-specialist management of traumatic injuries of the orbit and facial skeleton.


Cytisine versus nicotine for smoking cessation.
Placebo-controlled trials indicate that cytisine, a partial agonist that binds the nicotinic acetylcholine receptor and is used for smoking cessation, almost doubles the chances of quitting at 6 months. We investigated whether cytisine was at least as effective as nicotine-replacement therapy in helping smokers to quit. We conducted a pragmatic, open-label, noninferiority trial in New Zealand in which 1310 adult daily smokers who were motivated to quit and called the national quitline were randomly assigned in a 1:1 ratio to receive cytisine for 25 days or nicotine-replacement therapy for 8 weeks. Cytisine was provided by mail, free of charge, and nicotine-replacement therapy was provided through vouchers for low-cost patches along with gum or lozenges. Low-intensity, telephone-delivered behavioral support was provided to both groups through the quitline. The primary outcome was self-reported continuous abstinence at 1 month. At 1 month, continuous abstinence from smoking was reported for 40% of participants receiving cytisine (264 of 655) and 31% of participants receiving nicotine-replacement therapy (203 of 655), for a difference of 9.3 percentage points (95% confidence interval, 4.2 to 14.5). The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, cytisine was superior to nicotine-replacement therapy among women and noninferior among men. Self-reported adverse events over 6 months occurred more frequently in the cytisine group (288 events among 204 participants) than in the group receiving nicotine-replacement therapy (174 events among 134 participants); adverse events were primarily nausea and vomiting and sleep disorders. When combined with brief behavioral support, cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12610000590066.).


Epithelial and stromal circadian clocks are inversely regulated by their mechano-matrix environment.
The circadian clock is an autonomous molecular feedback loop inside almost every cell in the body. We have shown that the mammary epithelial circadian clock is regulated by the cellular microenvironment. Moreover, a stiff extracellular matrix dampens the oscillations of the epithelial molecular clock. Here, we extend this analysis to other tissues and cell types, and identify an inverse relationship between circadian clocks in epithelia and fibroblasts. Epithelial cells from mammary gland, lung and skin have significantly stronger oscillations of clock genes in soft 3D microenvironments, compared to stiff 2D environments. Fibroblasts isolated from the same tissues show the opposite response, exhibiting stronger oscillations and more prolonged rhythmicity in stiff microenvironments. RNA analysis identified that a subset of mammary epithelial clock genes, and their regulators, are upregulated in 3D microenvironments in soft compared to stiff gels. Furthermore, the same genes are inversely regulated in fibroblasts isolated from the same tissues. Thus, our data reveal for the first time an intrinsic difference in the regulation of circadian genes in epithelia and fibroblasts.


Pleurospermum kamtschaticum extract induces apoptosis via mitochondrial pathway and NAG-1 expression in colon cancer cells.
To evaluate the anticarcinogenic activity of methanol extract of Pleurospermum kamtschaticum (PKE), we assessed its apoptosis-inducing capability in HT-29 colon carcinoma cells. PKE treatment for 2 h reduced cell viability in a dose-related manner, and induced apoptotic morphological changes. Flow cytometric analysis indicated that PKE treatment at 0.05 mg/ml induced early apoptosis in 66.2% of HT-29 cells. Additionally, Bcl-2 expression was substantially reduced in PKE-treated HT-29 cells, increasing the Bax/Bcl-2 ratio. The protein levels of procaspase-9 and procaspase-3 were decreased markedly, reflecting caspase-9 and caspase-3 activation, and resulting PARP cleavage was noted in the PKE-treated HT-29 cells. Furthermore, we detected increased NAG-1 expression in the PKE-treated HT-29 cells. In an in vivo study, intraperitoneal PKE administration suppressed the formation of tumor nodules in the lungs of mice. These results indicate that PKE can serve as a beneficial supplement in the treatment and the prevention of colon cancer.


Spectrin and related molecules.
This review begins with a complete discussion of the erythrocyte spectrin membrane skeleton. Particular attention is given to our current knowledge of the structure of the RBC spectrin molecule, its synthesis, assembly, and turnover, and its interactions with spectrin-binding proteins (ankyrin, protein 4.1, and actin). We then give a historical account of the discovery of nonerythroid spectrin. Since the chicken intestinal form of spectrin (TW260/240) and the brain form of spectrin (fodrin) are the best characterized of the nonerythroid spectrins, we compare these molecules to RBC spectrin. Studies establishing the existence of two brain spectrin isoforms are discussed, including a description of the location of these spectrin isoforms at the light- and electron-microscope level of resolution; a comparison of their structure and interactions with spectrin-binding proteins (ankyrin, actin, synapsin I, amelin, and calmodulin); a description of their expression during brain development; and hypotheses concerning their potential roles in axonal transport and synaptic transmission.


An experimental model of cachexia induced by a xenografted human tumor.
A hypernephroma removed from a male patient who had lost 30 kg in weight in the 2 months preceding surgery was established in immunosuppressed CBA/Lac mice as a nonmetastasizing transplantable xenograft. The xenografted tumors, although comprising less than 5% of the total body weight of the mice, produced considerable weight loss (greater than 25%). A slight reduction in food intake of tumor-bearing mice was noted, but some animals bearing mouse or human tumors not inducing cachexia had equally low food intake without accompanying weight losses. No obvious defects in gastrointestinal histology or absorption were observed. The precise mechanism(s) producing the severe cachexia remains to be established.


Specificity of antibodies in amphibian larvae possessing a small number of lymphocytes.
Tadpoles of Rana catesbiana, possessing about two million lymphocytes, were immunized with 2,4-dinitrophenyl- and 2,4,6-trinitrophenyl-conjugated bacteria and proteins, and the antibodies produced were studied by inactivation of dinitrophenyl- and trinitrophenyl-conjugated bacteriophages. Crossreactions were determined by inhibition of inactivation of modified phages with the lysine derivatives of 2,4-dinitrophenyl-,2,4,6-trinitrophenyl-, and 4-mononitrophenyl-groups. Antibodies to the two hapten-conjugates differed as significantly from each other in tadpoles as in larger animals. The ability of the small number of lymphocytes in tadpoles to discriminate between structurally similar determinants, and the estimated large number of antibodies required to cover the whole spectrum of antigenic specificities, suggests that an antigen-reactive cell changes specificity during its life time.


Emerging Role of Carotid MRI for Personalized Ischemic Stroke Risk Prediction in Patients With Carotid Artery Stenosis.
Rupture of a vulnerable carotid plaque is an important cause of ischemic stroke. Prediction models can support medical decision-making by estimating individual probabilities of future events, while magnetic resonance imaging (MRI) can provide detailed information on plaque vulnerability. In this review, prediction models for medium to long-term (>90 days) prediction of recurrent ischemic stroke among patients on best medical treatment for carotid stenosis are evaluated, and the emerging role of MRI of the carotid plaque for personalized ischemic stroke prediction is discussed. A systematic search identified two models; the European Carotid Surgery Trial (ECST) medical model, and the Symptomatic Carotid Atheroma Inflammation Lumen stenosis (SCAIL) score. We critically appraised these models by means of criteria derived from the CHARMS (CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modeling Studies) and PROBAST (Prediction model Risk Of Bias ASsessment Tool). We found both models to be at high risk of bias. The ECST model, the most widely used model, was derived from data of large but relatively old trials (1980s and 1990s), not reflecting lower risks of ischemic stroke resulting from improvements in drug treatment (e.g., statins and anti-platelet therapy). The SCAIL model, based on the degree of stenosis and positron emission tomography/computed tomography (PET/CT)-based plaque inflammation, was derived and externally validated in limited samples. Clinical implementation of the SCAIL model can be challenging due to high costs and low accessibility of PET/CT. MRI is a more readily available, lower-cost modality that has been extensively validated to visualize all the hallmarks of plaque vulnerability. The MRI methods to identify the different plaque features are described. Intraplaque hemorrhage (IPH), a lipid-rich necrotic core (LRNC), and a thin or ruptured fibrous cap (TRFC) on MRI have shown to strongly predict stroke in meta-analyses. To improve personalized risk prediction, carotid plaque features should be included in prediction models. Prediction of stroke in patients with carotid stenosis needs modernization, and carotid MRI has potential in providing strong predictors for that goal.


Evaluation of goserelin effectiveness based on assessment of inflammatory cytokines and symptoms in uterine leiomyoma.
Background Uterine leiomyoma is a benign tumour of the uterine smooth muscles associated with an elevated level of inflammatory cytokines. Goserelin, a synthetic gonadotropin-releasing hormone analogue, suppresses the production of sex hormones and release of inflammatory cytokines in uterine leiomyoma cells. Objective The primary objective of this study was to find out the effectiveness of subcutaneous goserelin therapy on lowering serum levels of inflammatory cytokines and improving uterine leiomyoma-related symptoms in female patients diagnosed with uterine leiomyoma. The secondary objective was to assess the tolerability to goserelin therapy used in the management of this tumour. Setting Outpatient gynaecological clinic of the medical consultation department of Baghdad Teaching Hospital, Baghdad province, Iraq. Methods A single centre, prospective, longitudinal, cohort study was carried out on female patients diagnosed with uterine leiomyoma. Goserelin 3.6 mg subcutaneous injection was given in a consecutive monthly dose for the total time duration of three months. Serum levels of inflammatory cytokines, tumour necrosis factor-α and monocyte chemotactic protein-1 were detected before and after goserelin therapy in a consecutive monthly assessment. The study also assessed the improvement in uterine leiomyoma-related symptoms, including pelvic pain alongside the incidence of goserelin-related side effects during therapy schedules. Main Outcome Measures Assessment of serum levels of tumour necrosis factor-α and monocyte chemotactic protein-1 alongside uterine leiomyoma-related symptoms, including pelvic pain and goserelin-related side effects. Results There was a significant decrease in serum levels of tumour necrosis factor-α and monocyte chemotactic protein-1 compared to the baseline level over the 3-month duration of goserelin therapy (0.11 ± 0.02 vs. 0.74 ± 0.19) pg/mL; (0.07 ± 0.00 vs. 0.44 ± 0.18) pg/mL respectively. Patients showed a clinical improvement regarding uterine leiomyoma-related symptoms following each of the consecutive monthly doses of goserelin therapy (n = 11, 55%, P < 0.0001; n = 15, 75%, P < 0.0001; n = 18, 90%, P < 0.0001) respectively. This also includes a significant decrease in the intensity of leiomyoma-related pelvic pain before and after goserelin therapy (7.2 ± 1.43 vs. 3.05 ± 1.14, P < 0.0001). The majority of patients reported vaginal dryness (60%) as the main goserelin-related side effect. Conclusion Goserelin therapy reduces serum levels of inflammatory cytokines, tumour necrosis factor- α and monocyte chemotactic protein-1, improving leiomyoma-related symptoms with good tolerability in patients with uterine leiomyoma.


Ruta graveolens water extract inhibits cell-cell network formation in human umbilical endothelial cells via MEK-ERK1/2 pathway.
Angiogenesis is a process encompassing several steps such as endothelial cells proliferation, differentiation and migration to form a vascular network, involving different signal transduction pathways. Among these, ERK1/2 signaling mediates VEGF-dependent signaling pathway. Here we report that the water extract of Ruta graveolens (RGWE), widely known as a medicinal plant, is able to impair in a dose-dependent manner, cell network formation without affecting cell viability. Biochemical analysis showed that the major component of RGWE is rutin, unable to reproduce RGWE effect. We found that RGWE inhibits ERK1/2 phosphorylation and that this event is crucial in cell network formation since the transfection of HUVEC with a constitutively active MEK (caMEK), the ERK1/2 activator, induces a robust cell network formation as compared to untransfected and/or mock transfected cells and, more importantly, caMEK transfected cells became unresponsive to RGWE. Moreover, RGWE inhibits VEGF and nestin gene expression, necessary for vessel formation, and the caMEK transfection induces their higher expression. In conclusion, we report that RGWE is able to significantly impair vessels network formation without affecting cell viability, preventing ERK1/2 activation and, in turn, down-regulating VEGF and nestin expression. These findings point to RGWE as a potential therapeutic tool capable to interfere with pathologic angiogenesis.


[The 2013-2014 epidemic season. Hospital monitoring and antiviral therapy for influenza ].
To characterize the 2013-2014 epidemic season from the results of detection of influenza infection in patients; to provide the molecular genetic characteristics of the strains isolated from deceased patients. The investigators examined 1203 patients (387 children, 509 people older than 16 years of age, 307 pregnant women) admitted to Moscow Clinical Infectious Diseases Hospital One with the clinical signs of acute respiratory viral diseases. Nasal lavage and autopsy specimens were used to isolate viral strains, then to sequence genomic fragments, and to determine receptor specificity. Out of the 1203 examinees, 284 (23.6%) were influenza-positive: 221 (77.8%), 24 (8.5%), and 39 (13.7%) patients had influenza A(H3N2), influenza A(H1N1)pdm09, and influenza B, respectively. Influenza was notified in 42,7% of the pregnant women. There was a preponderance of its moderate form; its severe form developed in single cases having comorbidities. One fatal outcome was registered. The intake of antiviral medications in the first 48 hours of the disease could prevent complications. The investigators revealed mutations in the strain isolated from the bronchoalveolar lavage fluid of a patient with severe pneumonia complicated by acute respiratory distress syndrome. There is evidence that there are mutant A(H1N1)pdm09 viruses that have high pneumotropicity. The high risk of their circulation in the population and the risk of severe influenza forms involving the lower respiratory tract remain. Early antiviral therapy in the first 36-48 hours diminishes the clinical manifestations of influenza and reduces the risk of developing complications.


Gapex-5, a Rab31 guanine nucleotide exchange factor that regulates Glut4 trafficking in adipocytes.
Insulin stimulates glucose uptake by promoting translocation of the Glut4 glucose transporter from intracellular storage compartments to the plasma membrane. In the absence of insulin, Glut4 is retained intracellularly; the mechanism underlying this process remains uncertain. Using the TC10-interacting protein CIP4 as bait in a yeast two-hybrid screen, we cloned a RasGAP and VPS9 domain-containing protein, Gapex-5/RME-6. The VPS9 domain is a guanine nucleotide exchange factor for Rab31, a Rab5 subfamily GTPase implicated in trans-Golgi network (TGN)-to-endosome trafficking. Overexpression of Rab31 blocks insulin-stimulated Glut4 translocation, whereas knockdown of Rab31 potentiates insulin-stimulated Glut4 translocation and glucose uptake. Gapex-5 is predominantly cytosolic in untreated cells; its overexpression promotes intracellular retention of Glut4 in adipocytes. Insulin recruits the CIP4/Gapex-5 complex to the plasma membrane, thus reducing Rab31 activity and permitting Glut4 vesicles to translocate to the cell surface, where Glut4 docks and fuses to transport glucose into the cell.


Elastography and Doppler May Bring a New Perspective to TIRADS, Altering Conventional Ultrasonography Dominance.
The main aim of ultrasonography (US) examining thyroid nodules is to differentiate malignant nodules from benign nodules. Several professional societies and groups of investigators have defined guidelines such as Thyroid Imaging Reporting and Data System (TIRADS) to provide the standardized language and approach to thyroid nodules. This study is aimed to investigate the compatibility of such classification systems with the pathological diagnosis of nodules and evaluate the contribution of the Shear-wave elastography (SWE) and Doppler ultrasonography (DUS) findings. This is a prospective study. Patients with thyroid US exams between December 2017 and April 2019 were included. In the study, eligible 210 nodules from 210 patients were enrolled. For stratification, the conventional B-mode US, SWE and DUS were performed. According to Kwak, American College of Radiology (ACR), and European (EU)-TIRADS, Nodules were classified separately, and a new scoring system whose the criteria was put defined in the study has developed. For SWE; Emean cut-off value was 33 kPa with a sensitivity and specificity of 95,6% (95% CI: 0,85-0,98) and 95% (95% CI:0,90-0,97) respectively (p <0.001). For spectral DUS; resistivity index (RI) cut-off value was 0.64 with a sensitivity and specificity of 73,3% (95% CI:0,59-0,83) and 80% (95% CI:0,73-0,85) respectively (p <0.001). Kwak TIRADS, American College of Radiology TIRADS, EU-TIRADS, and new system were compared by ROC curve analysis. The new system has the highest sensitivity, specificity, PPV, NPV, accuracy, and AUC compared to others. The new scoring system has shown that SWE and DUS findings may alter the categorization in TIRADS and increase sensitivity and specificity.


Intravitreal ranibizumab for choroidal neovascularization secondary to gyrate atrophy in a young patient: a multimodal imaging analysis.
To present a case of choroidal neovascularization (CNV) due to gyrate atrophy (GA) treated with intravitreal ranibizumab. A 35-year-old man presented with sudden loss of vision and central scotoma in the right eye, as well as progressive night vision deterioration over the past several years in both eyes. His best-corrected visual acuity (BCVA) was 6/60 in the right eye and 6/5 in the left eye. Funduscopy revealed bilateral confluent areas of chorioretinal atrophy and optical coherence tomography showed subretinal fluid consistent with CNV development in the right eye, which was confirmed by fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA). The left eye was normal. The patient had a family history of GA. Elevated levels of plasma ornithine were detected, establishing the diagnosis. The patient received a regimen of 3 monthly off-label intravitreal ranibizumab injections in the right eye. At the 6-month follow-up, no subretinal fluid was noticed and BCVA was 6/48. No other injections were performed, but the patient was advised to start an arginine-restricted diet and take vitamin B6 (pyridoxine) 300 mg daily. The BCVA was preserved and chorioretinal atrophy had not progressed on funduscopy, FFA, or ICGA 1 year later. Intravitreal ranibizumab can offer promising anatomical and functional results, maintaining visual acuity in patients with CNV secondary to GA, especially if used in combination with arginine-restricted diet and vitamin B6 supplementation.


Time-dependent effect of acute hypoxia on corticospinal excitability in healthy humans.
Contradictory results regarding the effect of hypoxia on cortex excitability have been reported in healthy subjects, possibly depending on hypoxia exposure duration. We evaluated the effects of 1- and 3-h hypoxia on motor corticospinal excitability, intracortical inhibition, and cortical voluntary activation (VA) using transcranial magnetic stimulation (TMS). TMS to the quadriceps cortex area and femoral nerve electrical stimulations were performed in 14 healthy subjects. Motor-evoked potentials (MEPs at 50-100% maximal voluntary contraction; MVC), recruitment curves (MEPs at 30-100% maximal stimulator power output at 50% MVC), cortical silent periods (CSP), and VA were measured in normoxia and after 1 (n = 12) or 3 (n = 10) h of hypoxia (Fi(O(2)) = 0.12). One-hour hypoxia did not modify any parameters of corticospinal excitability but reduced slightly VA, probably due to the repetition of contractions 1 h apart (96 ± 4% vs. 94 ± 4%; P = 0.03). Conversely, 3-h hypoxia significantly increased 1) MEPs of the quadriceps muscles at all force levels (+26 ± 14%, +24 ± 12%, and +27 ± 17% at 50, 75, and 100% MVC, respectively; P = 0.01) and stimulator power outputs (e.g., +21 ± 14% at 70% maximal power), and 2) CSP at all force levels (+20 ± 18%, +18 ± 19%, and +14 ± 22% at 50, 75, and 100% MVC, respectively; P = 0.02) and stimulator power outputs (e.g., +9 ± 8% at 70% maximal power), but did not modify VA (98 ± 1% vs. 97 ± 3%; P = 0.42). These data demonstrate a time-dependent hypoxia-induced increase in motor corticospinal excitability and intracortical inhibition, without changes in VA. The impact of these cortical changes on physical or psychomotor performances needs to be elucidated to better understand the cerebral effects of hypoxemia.


Real-world Outcomes of Sequential Androgen-receptor Targeting Therapies with or Without Interposed Life-prolonging Drugs in Metastatic Castration-resistant Prostate Cancer: Results from the Dutch Castration-resistant Prostate Cancer Registry.
Cross resistance between androgen-receptor targeting therapies (ARTs) (abiraterone acetate plus prednisone [ABI+P] or enzalutamide [ENZ]) for treatment of metastatic castration-resistant prostate cancer (mCRPC) may affect responses to second ART (ART2). To establish treatment duration and prostate-specific antigen (PSA) response of ART2 in real-world mCRPC patients treated with or without other life-prolonging drugs (LPDs; ie, docetaxel, cabazitaxel, or radium-223) between ART1 and ART2. Castration-resistant prostate cancer patients, diagnosed between 2010 and 2016 were retrospectively registered in Castration-resistant Prostate Cancer Registry (CAPRI). Patients treated with both ARTs were clustered into two subgroups: ART1>ART2 or ART1>LPD>ART2. Outcomes were ≥50% PSA response and treatment duration of ART2. Descriptive statistics and binary logistic regression after multiple imputations were performed. A total of 273 patients were included with a median follow-up of 8.4 mo from ART2. Patients with ART1>ART2 were older and had favourable prognostic characteristics at ART2 baseline compared with patients with ART1>LPD>ART2. No differences between ART1>ART2 and ART1>LPD>ART2 were found in PSA response and treatment duration. Multivariate analysis suggested that PSA response of ART2 was less likely in patients with visceral metastases (odds ratio [OR] 0.143, p=0.04) and more likely in patients with a relatively longer duration of androgen-deprivation treatment (OR 1.028, p=0.01) and with ABI + P before ENZ (OR 3.192, p=0.02). A major limitation of this study was missing data, a common problem in retrospective observational research. The effect of ART2 seems to be low, with a low PSA response rate and a short treatment duration irrespective of interposed chemotherapy or radium-223, especially in patients with short time on castration, visceral disease, and ENZ before ABI+P. We observed no differences in outcomes of patients treated with sequential abiraterone acetate plus prednisone (ABI+P) and enzalutamide (ENZ) with or without interposed chemotherapy or radium-223. In general, outcomes were lower than those in randomised trials, questioning the additional effect of second treatment with ABI+P or ENZ in daily practice.


Primary care in England: between a rock and a hard place.
A well-established primary care sector has allowed England's National Health Service (NHS) to make efficient use of resources through the gatekeeping role that general practitioners have in controlling access to specialist services. Because of the poor economic situation in the United Kingdom, there is now considerable pressure on the NHS to use its resources more efficiently. These financial challenges are putting enormous pressure on general practices at a time when the NHS is also going through other major structural changes. Consequently, general practitioners in England increasingly find themselves having to make difficult decisions about the future of their practices.


Genome scans with gene-covariate interaction.
Genetic models for gene-covariate interactions are described. Methods of linkage analysis that utilize special features of these models and the corresponding score statistics are derived. Their power is compared with that of simple genome scans that ignore these special features, and substantial gains in power are observed when the gene-covariate interaction is strong. Quantitative trait mapping in randomly ascertained sibships and affected sibpair mapping are discussed. For the latter case, a simpler statistic is proposed that has similar performance to the score statistic, but does not require the estimation of nuisance parameters. Since the nuisance parameters are not estimable solely from affected sib-pair data, this statistic would be much easier to apply in practice. Similarities with linkage analysis of models for longitudinal data and multivariate phenotypes are also briefly discussed. Approximations for the P-value and power are derived under the framework of local alternatives.


Bioactive Pentacyclic Triterpene Ester Derivatives from Alnus viridis ssp. viridis Bark.
Seven derivatives of pentacyclic triterpene acids (1-7) were isolated from the bark of Alnus viridis ssp. viridis using a combination of column chromatography and semipreparative HPLC. Compounds 1-3, 6, and 7 were determined to be new after spectroscopic data interpretation and were assigned as 27-hydroxyalphitolic acid derivatives (1-3), a 27-hydroxybetulinic acid derivative (6), and a 3-epi-maslinic acid derivative (7), respectively. Pentacyclic triterpenoids with a C-27 hydroxymethyl group have been found in species of the genus Alnus for the first time. These compounds were subjected to cytotoxicity testing against a number of cancer cell lines. Also, selected pentacyclic triterpenoids were selected as potential inhibitors of topoisomerases I and IIα for an in silico investigation.


Ki-67 expression in mature B-cell neoplasms: a flow cytometry study.
Ki-67 is a nuclear protein associated with cellular proliferation in normal or leukemic conditions that can help identify more aggressive diseases and is usually evaluated with immunohistochemistry. The aim of this was to assess Ki-67 expression on mature B-cell neoplasms samples with flow cytometry immunophenotyping. After surface staining with CD19 and CD45, intracellular staining for Ki-67 was performed in leukemic mature B-cells. Ki-67 expression was evaluated with flow cytometry. Ki-67 expression was higher in mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cases. It was also associated with CD38 mean fluorescence intensity. Ki-67 expression evaluated by flow cytometry can be a useful tool in the diagnosis of mature B-cell neoplasms. More studies are needed to validate Ki-67 assessment with flow cytometry immunophenotyping.


In Situ Activation of Superhydrophobic Surfaces with Triple Icephobicity at Low Temperatures.
Superhydrophobic surfaces have been widely studied due to their potential applications in aerospace fields. However, superhydrophobic surfaces with excellent water-repellent, anti-icing, and icephobic performances at low temperatures have rarely been reported. Herein, superhydrophobic surfaces with heating capability were prepared by etching square micropillar arrays on the surface of multiwalled carbon nanotube (MWCNT)/poly(dimethylsiloxane) (PDMS) films. The fabricated superhydrophobic surface has triple icephobicity, which can be activated even at low temperatures. The triple icephobicity is triggered by an applied voltage to achieve excellent water-repellent and icephobic capabilities, even at -40 °C. Additionally, theoretical calculations reveal that a droplet on a superhydrophobic surface loses heat at a rate of 8.91 × 10-5 J/s, which is 2 orders of magnitude slower than a flat surface (2.15 × 10-3 J/s). Also, at -40 °C, the mechanical interlocking force formed between the superhydrophobic surface and ice can be released by the heating property of the superhydrophobic surface. This low-energy, multifunctional superhydrophobic surface opens up new possibilities for bionic smart multifunctional materials in icephobic applications.


Assays of fibrin network properties altered by VKAs in atrial fibrillation - importance of using an appropriate coagulation trigger.
Atrial fibrillation (AF) is a prothrombotic condition, involving increased thrombin generation and fibrinogen concentrations. Vitamin K antagonists (VKAs) prevent arterial thromboembolism if optimal anticoagulation is achieved by individualised drug doses, assessed by determining the Prothrombin time-related International Normalized Ratio (Pt-INR). There is evidence that formation of tight-laced fibrin networks is pathogenic in prothrombotic diseases. This study was performed among AF patients, to test whether long-term treatment with VKAs affects the structure of fibrin networks, and whether the effect is altered by employing different coagulation triggers: exogenous thrombin (1 IU/ml), 10 pM tissue factor (TF) or a commercial Pt-INR reagent (containing 400-fold more TF). In the thrombin-based method, fibrin network porosity (scanning electron microscopy) and liquid permeability (flow measurements) correlated inversely to fibrinogen concentrations, while positive correlations to the degree of anticoagulation were shown with the Pt-INR reagent. In the method with 10 pM TF, the two above relationships were detected, though the influence of Pt-INR was more profound than that of fibrinogen concentrations. Moreover, greater shortening of clot lysis time (CLT) arose from more permeable clots. As a coagulation trigger, 10 pM TF vs exogenous thrombin or the Pt-INR reagent is more informative in reflecting the in vivo process from thrombin generation to fibrin formation. Since fibrin network permeability rose in parallel to elevations of INR and shortening of CLT in AF patients, antithrombotic effects on prevention of thrombotic complications may be achieved from impairment of thrombin generation, resulting in formation of permeable clots susceptible to fibrinolysis.


MicroRNA and mRNA expression associated with ectopic germinal centers in thymus of myasthenia gravis.
A characteristic pathology of early onset myasthenia gravis is thymic hyperplasia with ectopic germinal centers (GC). However, the mechanisms that trigger and maintain thymic hyperplasia are poorly characterized. Dysregulation of small, non-coding microRNAs (miRNAs) and their target genes has been identified in the pathology of several autoimmune diseases. We assessed the miRNA and mRNA profiles of the MG thymus and have investigated their role in GC formation and maintenance. MG thymus samples were assessed by histology and grouped based upon the appearance of GC; GC positive and GC negative. A systems biology approach was used to study the differences between the groups. Our study included miRNA and mRNA profiling, quantitative real-time PCR validation, miRNA target identification, pathway analysis, miRNA-mRNA reciprocal expression pairing and interaction. Thirty-eight mature miRNAs and forty-six annotated mRNA transcripts were differentially expressed between the two groups (>1.5 fold change, ANOVA p<0.05). The miRNAs were found to be involved in immune response pathways and identified in other autoimmune diseases. The cellular and molecular functions of the mRNAs showed involvement in cell death and cell survival, cellular proliferation, cytokine signaling and extra-cellular matrix reorganization. Eleven miRNA and mRNA pairs were reciprocally regulated. The Regulator of G protein Signalling 13 (RGS13), known to be involved in GC regulation, was identified in specimens with GC and was paired with downregulation of miR-452-5p and miR-139-5p. MiRNA target sites were validated by dual luciferase assay. Transfection of miRNA mimics led to down regulation of RGS13 expression in Raji cells. Our study indicates a distinct miRNA and mRNA expression pattern in ectopic GC in MG thymus. These miRNAs and mRNAs are involved in regulatory pathways common to inflammation and immune response, cell cycle regulation and anti-apoptotic pathways suggesting their involvement in support of GC formation in the thymus. We demonstrate for the first time that miR-139-5p and miR-452-5p negatively regulate RGS13 expression.


Light-Driven Metabolic Pathways in Non-Photosynthetic Biohybrid Bacteria.
Biomanufacturing via microorganisms relies on carbon substrates for molecular feedstocks and a source of energy to carry out enzymatic reactions. This creates metabolic bottlenecks and lowers the efficiency for substrate conversion. Nanoparticle biohybridization with proteins and whole cell surfaces can bypass the need for redox cofactor regeneration for improved secondary metabolite production in a non-specific manner. Here we propose using nanobiohybrid organisms (Nanorgs), intracellular protein-nanoparticle hybrids formed through the spontaneous coupling of core-shell quantum dots (QDs) with histidine-tagged enzymes in non-photosynthetic bacteria, for light-mediated control of bacterial metabolism. This proved to eliminate metabolic constrictions and replace glucose with light as the source of energy in Escherichia coli, with an increase in growth by 1.7-fold in 75 % reduced nutrient media. Metabolomic tracking through carbon isotope labeling confirmed flux shunting through targeted pathways, with accumulation of metabolites downstream of respective targets. Finally, application of Nanorgs with the Ehrlich pathway improved isobutanol titers/yield by 3.9-fold in 75 % less sugar from E. coli strains with no genetic alterations. These results demonstrate the promise of Nanorgs for metabolic engineering and low-cost biomanufacturing.


Chronic cerebral hypoperfusion independently exacerbates cognitive impairment within the pathopoiesis of Parkinson's disease via microvascular pathologys.
To date, the role of microvascular pathology and chronic cerebral hypoperfusion (CHH) in the development of mild cognitive impairment in Parkinson's disease (PD-MCI) is unclear. Here, we investigated how the combined injury through interaction of CHH and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity act as an exacerbating element to damagae cognitive fuction in a mouse model. In the present study, C57BL/6 mice underwent MPTP injection. Subjects were classified into a PD with normal cognitive performance (PDCN) group or a PD-MCI group using the Morris Water Maze test. Further, CHH was induced by stenosis of the bilateral common carotid arteries (BCCAs). Consequently, the animals were divided into 7 groups: they are control, sham, BCCAs, PDCN, PD-MCI, PDCN+BCCAs and PD-MCI+BCCAs. The Morris Water Maze test, open field test, histological investigation and western blotting were performed to analyze cerebral microvascular impairment in each group. The results showed that CHH and MPTP injection caused spatial memory and behavioral impairment, accompanied by microvascular impairment and down-regulation of ZO-1 and Occludin at the protein level compared to the control group. The above injuries were synergistically exacerbated in the PDCN+BCCAs group and the PD-MCI+BCCAs group, which paralleled the elevated expression of p-MAPK and p-Akt. In short, our data demonstrate that CHH and MPTP caused cognitive and microvascular impairment separately. Moreover, CHH may exacerbate cognitive impairment in a mouse model of PD. The study provides a new opportunity for understanding the pathogenesis of PD-MCI.


The impact of violence on health in low- to middle-income countries.
More than 90% of violence-related deaths occur in low- to middle-income countries (LMICs), where the mortality rate due to violence is almost 2.5 times greater than in high-income countries. Over and above the substantial contribution of violence as a cause of death and physical injuries, victims of violence are also more vulnerable to a range of mental and physical health problems. Several studies describe the deleterious impact of different types of violence on a range of health outcomes, but no review has yet been undertaken that presents a composite overview of the current state of knowledge in LMICs. This paper reviews the scientific literature describing the nature, magnitude and impact of violence on health, describing the current state of violence-prevention policy developments within the global health agenda and highlighting the health consequences, disease burden and economic costs of violence. Although data are limited, the review indicates that costs relating to violence deplete health care budgets considerably and that scarce resources could be better used to address other health threats that hamper development.


Synergic Renoprotective Effects of Combined ASC Therapy with RAAS Blockade in Experimental Advanced CKD.
Global prevalence of chronic kidney disease (CKD) has increased considerably in the recent decades. Overactivity of the renin-angiotensin-aldosterone system (RAAS), associated to renal inflammation and fibrosis, contributes to its evolution. The treatments currently employed to control CKD progression are limited and mainly based on the pharmacological inhibition of RAAS, associated with diuretics and immunosuppressive drugs. However, this conservative management promotes only partial deceleration of CKD evolution and does not completely avoid the progression of the disease and the loss of renal function, which motivates the medical and scientific community to investigate new therapeutic approaches to detain renal inflammation/fibrosis and CKD progression. Recent studies have shown the application of mesenchymal stem cells (mSC) to exert beneficial effects on the renal tissue of animals submitted to experimental models of CKD. In this context, the aim of the present study was to evaluate the effects of subcapsular application of adipose tissue-derived mSC (ASC) in rats submitted to the 5/6 renal ablation model, 15 days after the establishment of CKD, when the nephropathy was already severe. We also verify whether ASC associated to Losartan would promote greater renoprotection when compared to the respective monotherapies. Animals were followed until 30 days of CKD, when body weight, systolic blood pressure, biochemical, histological, immunohistochemical, and gene expression analysis were performed. The combination of ASC and Losartan was more effective than Losartan monotherapy in reducing systolic blood pressure and glomerulosclerosis and also promoted the complete normalization of proteinuria and albuminuria, a significant reduction in renal interstitial macrophage infiltration and downregulation of renal IL-6 gene expression. The beneficial effects of ACS are possibly due to the immunomodulatory and anti-inflammatory role of factors secreted by these cells, modulating the local immune response. Although studies are still required, our results demonstrated that a subcapsular inoculation of ASC, associated with the administration of Losartan, exerted additional renoprotective effect in rats submitted to a severe model of established CKD, when compared to Losartan monotherapy, thus suggesting ASC may be a potential adjuvant to RAAS-blockade therapy currently employed in the conservative management of CKD.


D-optimal Design for Preparation and Optimization of Fast Dissolving Bosentan Nanosuspension.
Bosentan is a drug currently taken orally for the treatment of pulmonary arterial hypertension. However, the water solubility of bosentan is very low, resulting in low bioavailability. The aim of this study was preparation and optimization of bosentan nanosuspension to improve solubility and dissolution rate. The different formulations designed by Design Expert® software. Nanosuspensions were prepared using precipitation method and the effects of stabilizer type and content and drug content on the particle size, polydispersity (PDI) and yield of nanosuspensions were investigated. Particle size, PDI and yield of the optimal nanosuspension formulation were 200.9 nm, 0.24 and 99.6%, respectively. Scanning electron microscopy (SEM) results showed spherical morphology for bosentan nanoparticles. Thermal analysis indicated that there was a partial crystalline structure and change in the pholymorphism of bosentan in the nanoparticles. In addition, reduction of particle size, significantly increased in vitro dissolution rate of the drug. Optimization by design expert software was shown to be a successful method for optimization and prediction of responses by less than 10% error and formulation with 15.8 mg span 85 as an internal stabilizer and 45 mg drug content were introduced as the optimum formulation. The solubility of bosentan in the optimal formulation was 6.9 times higher than coarse bosentan and could be suggested as promising drug delivery systems for improving the dissolution rate and possibly the pharmacokinetic of bosentan.


Hair growth promoting effect of white wax and policosanol from white wax on the mouse model of testosterone-induced hair loss.
White wax (WW) has been traditionally used to treat hair loss in China. However there has been no reporter WW and its extract responsible for hair growth-promoting effect on androgenetic alopecia. In this paper, we examined the hair growth-promoting effects of WW and policosanol of white wax (WWP) on model animal of androgenetic alopecia and the potential target cell of WW and WWP. WW (1, 10 and 20%) and WWP (0.5, 1 and 2%) were applied topically to the backs of mice. Finasteride (2%) was applied topically as a positive control. MTS assays were performed to evaluate cell proliferation in culture human follicle dermal papilla cells (HFDPCs). The inhibition of WW and WWP for 5α- reductase were tested in Vitro. Results showed more lost hairs were clearly seen in mice treated with TP only and TP plus vehicle. Mice which received TP plus WW and WWP showed less hair loss. WW and WWP showed an outstanding hair growth-promoting activity as reflected by the follicular length, follicular density, A/T ratio, and hair bulb diameter. The optimal treatment effect was observed at 10% WW and 1% WWP, which were better than 2% finasteride treatment. MTS assay results suggested that WW and WWP remarkably increased the proliferation of HFDPCs. Inhibitor assay of 5α- reductase showed that WW and WWP inhibited significantly the conversion of testosterone to dihydrotesterone, and the IC50 values of WW and WWP were higher than that of finasteride. In Conclusion, WW and WWP could act against testosterone-induced alopecia in mice, and they promoted hair growth by inhibiting 5α-reductase activity and HFDPCs proliferation. DPCs is the target cell of WW and WWP.


A Website System for Communicating Psychological Science.
The peer review and journal system have shortcomings, and both computers and the Internet have made complementary or alternative systems attractive. In this article, I recommend that we implement a new platform for open communication of psychological science on a dedicated website to complement the current review and journal system, with reader reviews of the articles and with all behavioral scientists being eligible to publish and review articles. The judged merit of articles would be based on the citations and the ratings of the work by the whole scientific community. This online journal will be quicker, more democratic, and more informative than the current system. Although the details of the system should be debated and formulated by a committee of scientists, adding this online journal to the existing publications of a society such as the Association for Psychological Science has few risks and many possible gains. An online journal deserves to be tried and assessed.


A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Québec.
An increase in the incidence and severity of Clostridium difficile-associated disease in Québec and the United States has been associated with a hypervirulent strain referred to as North American pulsed-field type 1 (NAP1)/027. In 2005, a prospective study was conducted in 88 Québec hospitals, and 478 consecutive nosocomial isolates of C. difficile were obtained. The isolates were subjected to pulsed-field gel electrophoresis (PFGE) typing, antimicrobial susceptibility testing, and detection of binary toxin genes and tcdC gene deletion. Data on patient age and occurrence of complications were collected. PFGE typing of 478 isolates of C. difficile yielded 61 PFGE profiles. Pulsovars A (57%), B (10%), and B1 (8%) were predominant. The PFGE profile of pulsovar A was identical to that of strain NAP1. It showed 67% relatedness with 15 other PFGE patterns, among which 11 had both binary toxin genes and a partial tcdC deletion but different antibiotic susceptibility profiles. Pulsovars B and B1 were identical to strain NAP2/ribotype 001. In hospitals showing a predominant clonal A or B-B1 PFGE pattern, incidence of C. difficile-associated disease was 2 and 1.3 times higher, respectively, than in hospitals without any predominant clonal PFGE pattern. Severe disease was twice as frequent among patients with strains possessing binary toxin genes and tcdC deletion than among patients with strains lacking these virulence factors. This study helped to quantify the impact of strain NAP1 on the incidence and severity of C. difficile-associated disease in Québec in 2005. The identification of the geographic dissemination of this predominant strain may help to focus regional infection-control efforts.


Targeting the vicious inflammation-oxidative stress cycle for the management of heart failure.
Oxidative stress and inflammation are each implicated independently in the development and progression of heart failure. Their interaction, however, is also evident throughout the process from initial injury to cardiac remodeling and failure. In the failing heart, the linkage between excessive reactive oxygen species (ROS) and the cytokine elaboration is manifested in shared elements and cross-promotion within downstream signaling pathways. In spite of this, the failure of anticytokine immunotherapy and antioxidant therapy, which had previously shown promise, suggests that a more complete perspective of ROS-cytokine interaction is required. The present review focuses on two of the major cytokines that are demonstrably connected to oxidative stress--the pro-inflammatory tumor necrosis factor-alpha (TNF-alpha) and the anti-inflammatory interleukin-10 (IL-10)--and their interactions in cardiac remodeling and failure. It is proposed that an optimal balance between TNF-alpha and IL-10 may be of crucial importance in mitigating both inflammation and oxidative stress processes leading to heart failure.


The startle reflex in alcohol-dependent patients: changes after cognitive-behavioral therapy and predictive validity for drinking behavior. A pilot study.
Previous studies demonstrated an attenuation of the affect-modulated startle reflex when alcohol-dependent patients were viewing alcohol-associated pictures. This indicates an appetitive valence of these stimuli. We used the affect-modulated startle reflex to assess the effects of behavioral treatment on the emotional processing of alcohol-associated stimuli. Further, we examined whether the affect-modulated startle reflex is a predictor of treatment success. Forty-three alcohol-dependent patients (21 females, mean age 45.67 years, SD 9.45) were recruited consecutively from an inpatient alcohol detoxification facility where patients attended a 3-week detoxification program including cognitive-behavioral treatment to successfully handle high-risk situations. The eye blink component of the affect-modulated startle response, self-reported cue-induced craving and skin conductance responses to alcohol-associated and control slides were assessed before and after treatment. Changes were analyzed using repeated measures analysis of variance. Drinking behavior was assessed in the 6 months following treatment, and a regression analysis was performed to evaluate the predictive validity of the affect-modulated startle response for drinking behavior. Drinking behavior as well as craving and skin conductance responses decreased significantly over time. The pattern of the affective modulation of the startle reflex was not altered over time. However, startle modulation and relapse were related, and within the group of relapsers, startle modulation was a significant predictor of drinking behavior. Our results suggest that the modulation of the startle reflex may reflect more enduring and permanent processes of emotional responding to alcohol-related cues than autonomic arousal and self-reported craving, and that startle modulation by alcohol-associated cues may be a better predictor of drinking behavior for relapsers than other measures. Further studies including a control condition are necessary to validate these findings.


Rational Design of Three-Layered TiO2 @Carbon@MoS2 Hierarchical Nanotubes for Enhanced Lithium Storage.
Here we demonstrate the rational design and synthesis of three-layered TiO2 @carbon@MoS2 hierarchical nanotubes for anode applications in lithium-ion batteries (LIBs). Through an efficient step-by-step strategy, ultrathin MoS2 nanosheets are grown on nitrogen-doped carbon (NC) coated TiO2 nanotubes to achieve the TiO2 @NC@MoS2 tubular nanostructures. This smart design can effectively shorten the diffusion length of Li+ ions, increase electric conductivity of the electrode, relax volume variation of electrode materials upon cycling, and provide more active sites for electrochemical reactions. Owing to these structural and compositional features, the hierarchical TiO2 @NC@MoS2 nanotubes manifest remarkable lithium storage performance with good rate capability and long cycle life.


Note on rare snake eels (Anguilliformes: Ophichthidae) and additional data on three Neenchelys recently described from Taiwan.
Three rare snake eel species, Allips concolor McCosker, 1972, Neenchelys daedalus McCosker, 1982, and Apterichtus moseri (Jordan Snyder, 1901), were newly collected from Taiwan. The distribution ranges of the first two species are now extended to the South China Sea off southern Taiwan and that of the third is extended southward to off northwestern Taiwan. Supplemental data for three recently described species, Neenchelys diaphora, N. gracilis and N. similis, from Taiwan are provided.


Calcium sparks in human ventricular cardiomyocytes from patients with terminal heart failure.
Cardiomyocytes from terminally failing hearts display significant abnormalities in e-c-coupling, contractility and intracellular Ca(2+) handling. This study is the first to demonstrate the influence of end-stage heart failure on specific properties of Ca(2+) sparks in human ventricular cardiomyocytes. We investigated the frequency and characteristics of spontaneously arising Ca(2+) sparks in single isolated human myocytes from terminally failing (HF) and non-failing (NF) control myocardium by using the Ca(2+) indicator Fluo-3. The Ca(2+) sparks were recorded by line-scan images along the longitudinal axis of the myocytes at a frequency of 250Hz. After loading the sarcoplasmic reticulum (SR) with Ca(2+) by repetitive field stimulation (10 pulses at 1Hz) the frequency of the Ca(2+) sparks immediately after stimulation (t = 0s) was reduced significantly in HF compared to NF (4.15 +/- 0.42 for NF vs. 2.81 +/- 0.20 for HF sparks s(-1), P = 0.05). This difference was present constantly in line-scan recordings up to 15s duration (t = 15s: 2.75 +/- 0.65 for NF vs. 1.36 +/- 0.34 for HF sparks s(-1), P = 0.05). The relative amplitude (F/F(0)) of Ca(2+) sparks was also significantly lower in HF cardiomyocytes (1.33 +/- 0.015 NF vs. 1.19 +/- 0.003 HF, t = 0s) and during subsequent recordings of 15s. Significant differences between HF and NF were also present in calculations of specific spark properties. The time to peak was estimated at 25.75 +/-0.88ms in HF and 18.68 +/- 0.45ms in NF cardiomyocytes (P = 0.05). Half-time of decay was 66.48 +/- 1.89ms (HF) vs. 44.15 +/- 1.65ms (NF, P < 0.05), and the full width at half-maximum (FWHM) was 3.99 +/- 0.06 microm (HF) vs. 3.5 +/- 0.07 microm (NF, P < 0.05). These data support the hypothesis that even in the absence of cardiac disease, Ca(2+) sparks from human cardiomyocytes differ from previous results of animal studies with respect to the time-to-peak, half-time of decay and FWHM. The role of elevated external Ca(2+) in HF was studied by recording Ca(2+) sparks in HF cardiomyocytes with 10mmol external Ca(2+) concentration. Under these conditions, the average spark amplitude was increased from 1.19 +/- 0.003 (F/F(0), 2mmol Ca(2+)) to 1.26 +/- 0.01 (F/F(0), 10mmol Ca(2+)). We conclude that human heart failure causes distinct changes in Ca(2+) spark frequency and characteristics comparable to results established in animal models of heart failure. A reduced Ca(2+) load of the SR alone is unlikely to account for the observed differences between HF and NF and additional alterations in intracellular Ca(2+) release mechanisms must be postulated.


[Interstitial temperature measurement during balloon lasertherapy (Prostalase) of the canine prostate].
We examined the distribution of interstitial temperatures during balloon lasertherapy, using 4 mongrel canines. The laser equipment (CL50FS, SLT Japan Co. Ltd. Tokyo, Japan) consisted of Nd:YAG laser that produced 360 spindle-shaped radiation from a laser balloon (2 cm long) with a water-cooled circulation system. By measuring the temperature 3-5 minutes after the beginning of the treatment, we obtained following results. The temperature of the bladder neck and urethral sphincter remained below 42 degrees C except under extreme conditions. The temperature at a 6 mm depth from the prostatic urethra rose as laser energy increased, but was not affected by increased circulation of cooling water. The temperature at a 10 mm depth from the prostatic urethra was not affected by either increased laser energy or increased circulation of cooling water. We concluded that the limit of tissue cooling is within 6 mm and direct transmission of laser energy is within 10 mm. Distribution of the tissue temperature peaked at a 6 mm depth in the prostatic urethra. When cooling water was circulated at a 200 ml/min and laser-energy was generated at 30 W, the temperature distribution demonstrated that at a 4-10 mm depth from the prostatic urethra reached over 45 degrees C and at a 6 mm depth from the prostatic urethra, a peak of 52 degrees C was obtained. The possibility of thermotherapy of the prostate was suggested.


[Chromatin fractionation according to the strength of its matrix bond].
Extraction in low salt concentration followed by centrifugation allows rat liver nuclear chromatin to be divided into two fractions: the supernatant chromatin and matrix chromatin. The former fraction contains about 60-70% of initial DNA and about 15% of initial protein along with all five histones, and an insignificant amount of non-histone proteins. RNA synthesis in the matrix chromatin fraction is 2-3 times more intense than that in the original nuclei. The data on gradient centrifugation do not suggest the elongation of RNA molecules synthesized in the matrix fraction. The results obtained as compared with the literature data suggest that the matrix chromatin fraction is enriched with active genes.


AP2α controls the dynamic balance between miR-126&126* and miR-221&222 during melanoma progression.
Accumulating evidences have shown the association between aberrantly expressed microRNAs (miRs) and cancer, where these small regulatory RNAs appear to dictate the cell fate by regulating all the main biological processes. We demonstrated the responsibility of the circuitry connecting the oncomiR-221&222 with the tumor suppressors miR-126&126* in melanoma development and progression. According to the inverse correlation between endogenous miR-221&222 and miR-126&126*, respectively increasing or decreasing with malignancy, their enforced expression or silencing was sufficient for a reciprocal regulation. In line with the opposite roles of these miRs, protein analyses confirmed the reverse expression pattern of miR-126&126*-targeted genes that were induced by miR-221&222. Looking for a central player in this complex network, we revealed the dual regulation of AP2α, on one side directly targeted by miR-221&222 and on the other a transcriptional activator of miR-126&126*. We showed the chance of restoring miR-126&126* expression in metastatic melanoma to reduce the amount of mature intracellular heparin-binding EGF like growth factor, thus preventing promyelocytic leukemia zinc finger delocalization and maintaining its repression on miR-221&222 promoter. Thus, the low-residual quantity of these two miRs assures the release of AP2α expression, which in turn binds to and induces miR-126&126* transcription. All together these results point to an unbalanced ratio functional to melanoma malignancy between these two couples of miRs. During progression this balance gradually moves from miR-126&126* toward miR-221&222. This circuitry, besides confirming the central role of AP2α in orchestrating melanoma development and/or progression, further displays the significance of these miRs in cancer and the option of utilizing them for novel therapeutics.


Soft tissue radiography of the hands in the rheumatoid arthritis.
25 cases of rheumatoid arthritis were investigated radiologically and clinically over a period of 3 months, using soft tissue radiograms of the hands and Lansbury's Activity Index. The soft tissue radiography technique was a new combination using molybdenum target mammographic equipment and immersion of the hands in a 2.5 cm layer of 1:1 ethanol-water solution, in order to reduce the uneven darkening of films. Periarticular oedema and progression of erosive and soft tissue changes were observed in clinically active cases. High scores for joint swelling and erosions were also registered in some clinically inactive cases. Determination of the rapid progression of erosive and soft tissue changes and the determination of periarticular hyperaemic oedema using special radiographic methods appear to be of some value in assessing the activity of rheumatoid arthritis.


Study of gramicidin A--phospholipid interactions in Langmuir monolayers: analysis of their mechanical, thermodynamical, and electrical properties.
The mechanisms of interactions between gramicidin A (gA) and dimyristoylphosphatidylcholine (DMPC) in monolayers formed at the air-water interface were studied by analyzing their mechanical, thermodynamical, and electrical properties evaluated from measurements of pressure-area isotherms and of Maxwell displacement currents (MDC). A contactless method of recording MDC enabled us to monitor changes in the charge state of the monolayer-constituting molecules and to find the relation between a phase state of the monolayer and structural transitions of gA. The peptide-lipid interactions were quantified in terms of the excess of Gibbs free energy, excess entropy, as well as the molecular dipole moments at various gA/DMPC molar ratios, at various temperatures (in the gel phase and also in the liquid-crystalline phase of DMPC molecule), and at various surface pressures. It was found that the strongest interactions between gA and DMPC took place at the gA/DMPC molar ratio at around 0.25. At this monolayer composition, the phospholipids, via their carbonyl moieties, dominantly interact with the single helical gA, which mostly stands upright on the surface and is anchored by its C-terminus to the water surface, and prevent the formation of the intertwined helical gA dimers. The optimum ratio was confirmed also by anomalous electrical behavior of electrical dipole moments derived from MDC measurements.


[Transient periventricular echodensities (TPE) in preterm infants under 1500 gramms: an analysis of the outcome of the last 10 years].
The aim of our study was to analyze neurodevelopmental outcome in preterm infants with TPE. 46 preterm infants with a birthweight (BW) < or = 1500 g were included in the study. They all had TPE in parieto-occipital location (some combined with frontal flares). Exclusion criteria were PVL II-IV, intraventricular hemorrhage, asphyxia and isolated frontal TPE. We analyzed ultrasound scans (1992 - 2001) of patients with TPE (diameter > 1 cm, visible in both sagittal and coronal planes, duration > 7 days), and neurological follow-up visits (date of demission, corrected age of 4, 8, 12 months, and after that every 2 years until 6 years of age) regarding the neurodevelopmental outcome. We devided the patients in group 1 (duration of TPE 8 - 14 days) and group 2 (duration of TPE > 14 days) and then analyzed the groups regarding neurodevelopmental disorders and factors increasing the risk of occurrence of TPE. From 1992 - 2001 578 children < or = 1500 g were admitted at our department. 48 patients (8,3 %) fulfilled the entry criteria, 2 of them died, so 46 were included in the study. In group 1 (10 patients) the median gestational age (GA) was 28 weeks (range 25 - 31), median BW 1075 g (range 685 - 1430), 6 children were neurologically unimpaired, one developed a motor handicap, and 3 a psychomotor retardation. In group 2 (36 patients) the median GA was 28 weeks (range 25 - 35), median BW 1034,5 g (range 540 - 1470), 24 patients were neurologically unimpaired, 7 developed a motor handicap, and 5 a psychomotor retardation. No statistical difference was found between the groups neither in neurodevelopmental outcome nor factors increasing the risk of the occurrence of TPE. Obviously, the finding of TPE is of clinical relevance already at a duration of only 7 days regarding later neurological development.


Intestinal Microbial Community Dynamics of White-Tailed Deer (Odocoileus virginianus) in an Agroecosystem.
The intestinal microbiota has important functions that contribute to host health. The compositional dynamics of microbial communities are affected by many factors, including diet and presence of pathogens. In contrast to humans and domestic mammals, the composition and seasonal dynamics of intestinal microbiota of wildlife species remain comparatively understudied. White-tailed deer (Odocoileus virginianus) is an ecologically and economically important wildlife species that inhabits agricultural ecosystems and is known to be a reservoir of enteric pathogens. Nevertheless, there is a lack of knowledge of white-tailed deer intestinal microbiota diversity and taxonomic composition. This study's first objective was to characterize and compare the intestinal microbiota of 66 fecal samples from white-tailed deer collected during two sampling periods (March and June) using 16S rDNA pyrosequencing. Associations between community diversity and composition and factors including season, sex, host genetic relatedness, and spatial location were quantified. Results revealed that white-tailed deer intestinal microbiota was predominantly comprised of phyla Firmicutes and Proteobacteria, whose relative frequencies varied significantly between sampling periods. The second objective was to examine the associations between the presence of Escherichia coli and Salmonella, and microbiota composition and diversity. Results indicated that relative abundance of some microbial taxa varied when a pathogen was present. This study provides insights into microbial compositional dynamics of a wildlife species inhabiting coupled natural and agricultural landscapes. Data focus attention on the high prevalence of Proteobacteria particularly during the summer and highlight the need for future research regarding the role of white-tailed deer as a natural pathogen reservoir in agroecosystems.


Correlation between genotype and phenotype in three families with Peutz-Jeghers Syndrome.
Peutz-Jeghers syndrome (PJS) is a hereditary disorder characterized by mucocutaneous pigmentations, gastrointestinal (GI) polyposis and an increased risk of certain malignancies. Little is known about the causative genes of PJS, or their association with the clinical phenotypes of PJS. The present study reports the results of clinical and genetic analysis of three Chinese families with PJS. In addition, the medical histories and clinical manifestations of these families were compared. DNA was collected from the blood samples of patients with PJS and controls. Serine/threonine kinase 11 (STK11), olfactory receptor family 4 subfamily C member 45 (OR4C45) and zonadhesin (ZAN) were amplified by polymerase chain reaction, and analyzed by sequencing and cloning. Two PJS-affected members of one family had a de novo single base deletion (NM_000455.4:c.842delC) in the STK11 gene, and their clinical presentations reflected the quantity of mutant STK11 copies in a dose-dependent manner. No pathogenic variants of OR4C45 or ZAN were found in the patients with PJS, although a new single nucleotide polymorphism (NM_003386.2:c.5768delG) of ZAN was identified. The results of the current study identified that a STK11 mutation dose-dependent genotype-phenotype relationship exists in patients with PJS. In addition, an early onset and high severity of oral pigmentations in PJS was indicative of serious GI phenotypes. These findings may aid the diagnosis and treatment of PJS.


Mechanisms of action of DNA intercalating acridine-based drugs: how important are contributions from electron transfer and oxidative stress?
Reactive oxygen species (ROS) are produced continuously in living cells as a by-product of respiration and other metabolic activity. Some ROS may react with DNA, and in some cases may abstract an electron from the double helix, leading to long range electron transfer (ET) reactions. Thus, the DNA of living cells may be in a continuous state of ET. We consider here whether acridine-based anticancer or antimicrobial drugs, which bind to DNA by intercalation, might either donate electrons to, or accept electrons from, the double helix, thus actively participating in ET reactions. We focus in particular on two acridine-based drugs that have been tested against human cancer in the clinic. Amsacrine is a 9-anilinoacridine derivative that appears to act as an electron donor in ET reactions on DNA, while N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) may act as an electron acceptor. Such reactions may make important contributions to the antitumor activity of these drugs.


Sequential dosing in chemosensitization: targeting the PI3K/Akt/mTOR pathway in neuroblastoma.
Breaking resistance to chemotherapy is a major goal of combination therapy in many tumors, including advanced neuroblastoma. We recently demonstrated that increased activity of the PI3K/Akt network is associated with poor prognosis, thus providing an ideal target for chemosensitization. Here we show that targeted therapy using the PI3K/mTOR inhibitor NVP-BEZ235 significantly enhances doxorubicin-induced apoptosis in neuroblastoma cells. Importantly, this increase in apoptosis was dependent on scheduling: while pretreatment with the inhibitor reduced doxorubicin-induced apoptosis, the sensitizing effect in co-treatment could further be increased by delayed addition of the inhibitor post chemotherapy. Desensitization for doxorubicin-induced apoptosis seemed to be mediated by a combination of cell cycle-arrest and autophagy induction, whereas sensitization was found to occur at the level of mitochondria within one hour of NVP-BEZ235 posttreatment, leading to a rapid loss of mitochondrial membrane potential with subsequent cytochrome c release and caspase-3 activation. Within the relevant time span we observed marked alterations in a ∼30 kDa protein associated with mitochondrial proteins and identified it as VDAC1/Porin protein, an integral part of the mitochondrial permeability transition pore complex. VDAC1 is negatively regulated by the PI3K/Akt pathway via GSK3β and inhibition of GSK3β, which is activated when Akt is blocked, ablated the sensitizing effect of NVP-BEZ235 posttreatment. Our findings show that cancer cells can be sensitized for chemotherapy induced cell death - at least in part - by NVP-BEZ235-mediated modulation of VDAC1. More generally, we show data that suggest that sequential dosing, in particular when multiple inhibitors of a single pathway are used in the optimal sequence, has important implications for the general design of combination therapies involving molecular targeted approaches towards the PI3K/Akt/mTOR signaling network.


African, Amerindian and European hepatitis B virus strains circulate on the Caribbean Island of Martinique.
Ten Hepatitis B virus (HBV) genotypes, as well as numerous subgenotypes, have been described in well-characterized ethnogeographical populations. Martinique has been at a crossroads between Africa, Europe, India and the Americas because of the slave trade (17th-19th centuries), followed by an important immigration of Indian and West African workers. In this work, we aimed to study the molecular epidemiology of HBV infection in Martinique according to this unique settlement pattern. To that end, blood samples from 86 consecutive HBV-infected patients from the main hospitals of the island, were retrospectively analysed. Direct sequencing of the pre-S1 or pre-C-C region or complete genome sequencing, followed by phylogenetic analyses were performed. HBV genotypes were: HBV/A1 (68.6 %), HBV/A2 (10.5 %), HBV/D, mainly HBV/D3 and HBV/D4 (8.1 %), HBV/F (3.5 %), and also HBV/E (2.3 %), two strains isolated from two West-African patients. Moreover, 74 % of the HBeAg-negative strains harboured classical pre-C-C mutations, and most HBV/A1 strains also containing specific mutations. Finally, various patterns of deletion mutants in pre-S and pre-C-C regions were found. In conclusion, our findings point to historical and migration-related issues in HBV-genotype distribution suggesting that HBV/A1, but not HBV/E, was imported from Africa during the slave trade, and further supporting the hypothesis that HBV/E has emerged recently in West Africa (<150 years). Potential origins of 'European' HBV/A2 and HBV/D3, 'Amerindian' HBV/F, and HBV/D4 strains are also discussed. Such HBV genetic diversity, beyond its epidemiological interest, may have a clinical impact on the natural history of HBV infection in Martinique.


Prevalence and genotype distribution of human papillomavirus among females in the suburb of Shanghai, China.
To describe the prevalence of human papillomavirus (HPV) and its genotype distribution among females in the suburb of Shanghai. A total of 33 562 participants were enrolled in this study from January to December 2016. HPV GenoArray test kit was used to perform HPV genotyping and was also used in DNA amplification and HybriBio's proprietary flow-through hybridization technique. The overall prevalence of HPV was 18.98% and the top ten genotypes of HPV infection were HPV 16 (3.36%), HPV 58 (2.65%), HPV 52 (2.48%), HPV 51 (1.58%), HPV 54 (1.40%), HPV 68 (1.32%), HPV 18 (1.23%), HPV 6 (1.15%), HPV 56 (1.10%), and HPV 33 (1.07%). Single infection (4749, 14.15%) was the most common types among all the infected cases. Significant differences were found among age groups and month groups in terms of simple and multiple infection (P < 0.05), pure HR, LR and mixed HPV infection (P < 0.05). The prevalence of HR and LR HPV infection among females in the suburb of Shanghai is high, prevalence of single and multiple infection, pure HR, LR and mixed infection is correlated with the age and month.


Unilateral tubal twin pregnancy. A report of two cases.
Unilateral tubal twin pregnancy is exceedingly rare: only 91 cases have been reported in the English literature to date. Two additional such cases are described.


Phase transitions induced by competition of two driven parts in a periodic system.
This paper studies a periodic driven diffusive system, which separates into two equal-sized parts with different values of hopping rates. Competition of the two different driven parts leads to various bulk-driven phase transitions, including shock and antishock. More interestingly, for the symmetric scenario, one can observe shock and antishock simultaneously in the system. We have explained the coexistence of shock and antishock via the effective boundary reservoir density. Theoretical analysis has been carried out to characterize the emerging nonequilibrium steady states, which is in good agreement with Monte Carlo simulations.


Molecular and catalytic properties of ribulose 1,5-bisphosphate carboxylase from the photosynthetic extreme halophile Ectothiorhodospira halophila.
D-Ribulose 1,5-bisphosphate (RuBP) carboxylase has been purified from the photosynthetic extreme halophile Ectothiorhodospira halophila. Despite a growth requirement for almost saturating sodium chloride in the medium, both crude and homogeneous preparations of RuBP carboxylase obtained from this organism were inhibited by salts. Sedimentation equilibrium analyses showed the enzyme to be large (molecular weight: 601,000). The protein was composed of two types of polypeptide chains of 56,000 and of 18,000 daltons. The small subunit appeared to be considerably larger than the small subunit obtained from the RuBP carboxylase isolated from Chromatium, an organism related to E. halophila. Amino acid analyses of hydrolysates of both E. halophilia and Chromatium RuBP carboxylases were very similar. Initial velocity experiments showed that the E. halophila RuBP carboxylase had a Km for ribulose diphosphate of 0.07 mM and a Km for HCO3- of 10 mM. Moreover, 6-phospho-D-gluconate was found to markedly inhibit the E. halophila carboxylase; a Ki for phosphogluconate of 0.14 mM was determined.


[Correlation between androgen receptor expression and surrogate molecular subtypes in invasive breast carcinoma].
Objective: To investigate androgen receptor(AR)expression in invasive breast carcinoma and the correlation with surrogate molecular breast carcinoma subtypes. Methods: Immunohistochemical staining of AR and other biomarkers was performed in a cohort of 870 cases of primary invasive breast carcinomas collected from August to December, 2016. The association of AR expression with different histological and surrogate molecular subtypes was analyzed. Results: The positive expression rate of AR in the immunohistochemistry-based surrogate subtypes was 96.3%(207/215) for Luminal A, 89.8%(378/421) for Luminal B, 82.4%(75/91) for HER2 overexpression and 37.1%(53/143) for triple negative breast carcinoma, with significant differences among the four groups (P<0.01). AR correlated positively with the expression of ER(P<0.01), PR(P<0.01), HER2(P=0.007), GATA3(P<0.01), GCDFP15(P<0.01)and mammaglobin(P<0.01), while negatively with the expression of Ki-67(P<0.01), CK5/6(P<0.01)and CK14(P<0.01). Conclusions: AR exhibits a high expression in invasive breast carcinoma, which is mainly correlated with ER-positive breast carcinoma. Regardless of the relatively low expression rate, AR is a potential therapeutic target in triple negative breast carcinoma.


Investigation on CO(2) laser irradiation inducing glass strip peeling for microchannel formation.
The study investigates the use of CO(2) laser to induce glass strip peeling off to form microchannels on soda lime gass substrate. The strip peeling exhibits a strong dependence on the energy deposition rate on the glass surface. In spite of the vast difference in the combination of laser power and scanning speed, when the ratio of the two makes the energy deposition rate in the range 3.0-6.0 J/(cm(2) s), the temperature rising inside glass will be above the strain point and reach the softening region of the glass. As a result, glass strip peeling is able to occur and form microchannels with dimensions of 20-40 μm in depth and 200-280 μm in width on the glass surface. Beyond this range, higher energy depsotion rate would lead to surface melting associated with solidification cracks and lower energy deposition rate causes the generation of fragment cracks.


Cross-specialty PROMIS-global health differential item functioning.
To investigate the functioning of the PROMIS-Global Health (PROMIS-GH) across clinical setting, patient age, and medical complexity by evaluating differential item functioning (DIF) within the Global Physical Health (GPH) and Global Mental Health (GMH) domains. To our knowledge, no study demonstrates lack of differential item functioning (DIF) for PROMIS-GH across these populations. We hypothesize that the PROMIS-GH domains of GMH and GPH will perform similarly when compared across these populations. Seven thousand nine hundred and seventy four complete PROMIS Global Health measures were retrospectively analyzed using the 'Lordif' package on the R platform. DIF was investigated for both GMH and GPH across clinical environment (Orthopedic Surgery, Family Medicine, & Internal Medicine), age group (≤ 53, > 53-66, > 66), and Charlson Comorbidity Index (CCI:0, CCI:1, CCI:2 +) using quasi Monte Carlo estimation. To assess the significance of DIF, Wald tests were used with the Benjamini & Hochberg procedure. No items contained in the GMH or GPH demonstrated DIF across age groups, medical complexity, or clinical environment. Items assessing the domains of GMH and GPH within the PROMIS-GH function comparably across treatment setting, age category, and medical comorbidities. The PROMIS-Global Health holds potential to facilitate interdisciplinary patient care and patient optimization prior to surgical intervention.


[In vitro maturation of reticulocytes. Behavior of RNA and inorganic pyrophosphatase].
A simple system of incubation of reticulocytes with a small degree of haemolysis has been developed. It was possible to test the influence of inorganic phosphate, pH-values in the range of 7.0--9.0 and anaerobic conditions on the in vitro maturation of reticulocytes. As main criteria of the maturation the RNA-content and the activity of PPase has been tested. The decrease of the RNA-content and the activity of the PPase is highly significant during maturation. The decrease of RNA and the reduction of reticulocytes are stimulated by inorganic phosphate.