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One hypothesis for thyroid cancer development is its derivation from thyroid cancer stem cells (CSCs). Such cells could arise via different paths including from mutated resident stem cells within the thyroid gland or via epithelial to mesenchymal transition (EMT) from malignant cells since EMT is known to confer stem-like characteristics. Furthermore, EMT is a critical process for epithelial tumor progression, local invasion, and metastasis formation. In addition, stemness provides cells with therapeutic resistance and is the likely cause of tumor recurrence. However, the relevance of EMT and stemness in thyroid cancer progression has not been extensively studied. To examine the status of stemness in thyroid papillary cancer, we employed a murine model of thyroid papillary carcinoma and examined the expression of stemness and EMT using qPCR and histochemistry in mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf((V600E))/TPO-Cre). This construct is only activated at the time of thyroid peroxidase (TPO) expression in differentiating thyroid cells and cannot be activated by undifferentiated stem cells, which do not express TPO. There was decreased expression of thyroid-specific genes such as Tg and NIS and increased expression of stemness markers, such as Oct4, Rex1, CD15, and Sox2 in the thyroid carcinoma tissue from 6-week-old BRAF(V600E) mice indicating the dedifferentiated status of the cells and the fact that stemness was derived in this model from differentiated thyroid cells. The decreased expression of the epithelial marker E-cadherin and increased EMT regulators including Snail, Slug, and TGF-β1 and TGF-β3, and the mesenchymal marker vimentin demonstrated the simultaneous progression of EMT and the CSC-like phenotype. Stemness was also found in a cancer thyroid cell line (named Marca cells) derived from one of the murine tumors. In this cell line, we also found that overexpression of Snail caused up-regulation of vimentin expression and up-regulation of stemness markers Oct4, Rex1, and CD15, with enhanced migration ability of the cells. We also showed that TGF-β1 was able to induce Snail and vimentin expression in the Marca cell thyroid cancer line, indicating the induction of EMT in these cells, and this induction of EMT and stemness was significantly inhibited by celastro a natural inhibitor of neoplastic cells.

Is stemness Derived from Thyroid Cancer Cells?

Hydrodynamic gene delivery has proved an efficient strategy for nonviral gene therapy in the murine liver but it has been less efficient in pigs. The reason for such inefficiency remains unclear. The present study used a surgical strategy to seal the whole pig liver in vivo. A solution of enhanced green fluorescent protein (eGFP) DNA was injected under two different venous injection conditions (anterograde and retrograde), employing flow rates of 10 and 20 ml/s in each case, with the aim of identifying the best gene transfer conditions. The gene delivery and information decoding steps were evaluated by measuring the eGFP DNA, mRNA and protein copy number 24 h after transfection. In addition, gold nanoparticles (diameters of 4 and 15 nm) were retrogradely injected (10 ml/s) to observe, by electron microscopy, the ability of the particle to access the hepatocyte. The gene delivery level was higher with anterograde injection, whereas the efficacy of gene expression was better with retrograde injection, suggesting differences in the decoding processes. Thus, retrograde injection mediates gene transcription (mRNA copy/cell) equivalent to that of intermediate expression proteins but the mRNA translation was lower than that of rare proteins. Electron microscopy showed that nanoparticles within the hepatocyte were almost exclusively 4 nm in diameter.

Does low RNA translation activit limit the efficacy of hydrodynamic gene transfer to pig liver in vivo?

To explore the signal transducer and activator of transcription 3 (STAT3) signaling pathway, especially STAT3 acetylation, in angiotensin II (Ang II)-induced pro-fibrotic responses in renal tubular epithelial cells. Rat renal tubular epithelial cell line (NRK-52E) was used. STAT3 acetylation and phosphorylation, as well as the expression of fibronectin, collagen IV and transforming growth factor-β1 (TGF-β1) were examined using Western blotting. The level and localization of STAT3 phosphorylation on Tyr705 were detected with fluorescence immunocytochemistry. The cells were transfected with a plasmid vector carrying p300 gene or siRNA targeting p300 to regulate p300 expression. Overexpression of p300 significantly increased STAT3 acetylation on Lys685, STAT3 phosphorylation on Tyr705, and the expression of TGF-β1, collagen IV and fibronectin in the cells. Treatment of the cells with Ang II (1 μmol/L) significantly increased STAT3 phosphorylation on Tyr705 through JAK2 activation, and dose-dependently increased the expression of fibronectin, collagen IV and TGF-β1. Pretreatment with curcumin, an inhibitor of JAK2 and p300, blocked Ang II-induced effects. Knockdown of p300 significantly decreased STAT3 acetylation on Lys685, and abolished Ang II-stimulated STAT3 phosphorylation on Tyr705, whereas pretreatment of the cells with C646, a selective inhibitor of p300, inhibited Ang II-induced STAT3 nuclear translocation and the expression of TGF-β1, collagen IV and fibronectin. Pretreatment of the cells with AG490, a JAK2 inhibitor, markedly inhibited Ang II-induced STAT3 phosphorylation on Tyr705 and fibronectin expression.

Is p300-dependent STAT3 acetylation necessary for angiotensin II-induced pro-fibrotic responses in renal tubular epithelial cells?

To retrospectively review the safety and clinical efficacy of bevacizumab concomitant with chemotherapy in Chinese patients with advanced non-squamous non-small cell lung cancer (NSNSCLC). Clinical data for 79 patients with NSNSCLC who received bevacizumab concomitant with chemotherapy in Chinese PLA General Hospital from April 28th 2009 to May 5th 2013 were retrospectively reviewed to analyze the clinical efficacy including disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), the Eastern Cooperative Oncology Group (ECOG) score and the safety. The Eastern Cooperative Oncology Group (ECOG) score was 0-2. By the final cutoff date (June 9, 2013), 54 (68.4%) patients had disease progression and 37 (46.8%) died. The ORR was 32.9% and the DCR was 83.5%. The ORR of the first-, second-, and third- or later-line treatments were 51.4%, 25.0% and 12.5%, while the DCR were 94.3%, 80.0% and 70.8%, respectively. The median OS (mOS) and PFS (mPFS) were 13.5 and 5.83 months, respectively. The mOS of patients with the first-, second-, and third- or later-line treatments were 16.2, 10.9 and 8.30 months, while the mPFS were 7.27, 5.90 and 5.17 months, respectively. Chemotherapy-related adverse events included myelosuppression, vomiting, hepatic dysfunction and renal dysfunction, while the common serious bevacizumab-related adverse events were thromboembolic problems, gastrointestinal perforation and reversible posterior leukoencephalopathy syndrome, which could be well managed.

Is bevacizumab concomitant with chemotherapy effective in treating Chinese patients with advanced non-squamous non-small cell lung cancer?

Despite the potential benefits of total quality management (TQM), many healthcare organisations encountered difficulties in its implementation. The purpose of this paper is to explore the barriers to successful implementation of TQM in healthcare organisations of Iran. This study involved a mixed research design. In-depth interviews were conducted with TQM practitioners to explore TQM implementation obstacles in Iranian healthcare organisations. In addition, this study involved survey-based research on the obstacles associated with successful TQM transformation. TQM implementation and its impact depend on the ability of managers to adopt and adapt its values and concepts in professional healthcare organisations. Unsuccessful TQM efforts in Iranian healthcare organisations can be attributed to the non-holistic approach adopted in its implementation, inadequate knowledge of managers' about TQM implementation, frequent top management turnover, poor planning, vague and short-termed improvement goals, lack of consistent managers' and employees' commitment to and involvement in TQM implementation, lack of a corporate quality culture, lack of team orientation, lack of continuous education and training and lack of customer focus. Human resource problems, cultural and strategic problems were the most important obstacles to TQM successful implementation, respectively.

Does why TQM work in Iranian healthcare organisations?

As elegant structures designed for neural communication, synapses are the building bricks of our mental functions. Recently, many studies have pointed out that synaptic protein-associated mutations may lead to dysfunctions of social cognition. Dlgap2, which encodes one of the main components of scaffold proteins in postsynaptic density (PSD), has been addressed as a candidate gene in autism spectrum disorders. To elucidate the disturbance of synaptic balance arising from Dlgap2 loss-of-function in vivo, we thus generated Dlgap2 (-/-) mice to investigate their phenotypes of synaptic function and social behaviors. The creation of Dlgap2 (-/-) mice was facilitated by the recombineering-based method, Cre-loxP system and serial backcross. Reversal learning in a water T-maze was used to determine repetitive behaviors. The three-chamber approach task, resident-intruder test and tube task were performed to characterize the social behaviors of mutant mice. Cortical synaptosomal fraction, Golgi-Cox staining, whole-cell patch electrophysiology and transmission electron microscopy were all applied to investigate the function and structure of synapses in the orbitofrontal cortex (OFC) of Dlgap2 (-/-) mice. Dlgap2 (-/-) mice displayed exacerbated aggressive behaviors in the resident-intruder task, and elevated social dominance in the tube test. In addition, Dlgap2 (-/-) mice exhibited a clear reduction of receptors and scaffold proteins in cortical synapses. Dlgap2 (-/-) mice also demonstrated lower spine density, decreased peak amplitude of miniature excitatory postsynaptic current and ultra-structural deficits of PSD in the OFC.

Do autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits?

Next-generation sequencing (NGS) allows for sampling numerous viral variants from infected patients. This provides a novel opportunity to represent and study the mutational landscape of Hepatitis C Virus (HCV) within a single host. Intra-host variants of the HCV E1/E2 region were extensively sampled from 58 chronically infected patients. After NGS error correction, the average number of reads and variants obtained from each sample were 3202 and 464, respectively. The distance between each pair of variants was calculated and networks were created for each patient, where each node is a variant and two nodes are connected by a link if the nucleotide distance between them is 1. The work focused on large components having > 5% of all reads, which in average account for 93.7% of all reads found in a patient.

Does next-generation sequencing reveal large connected networks of intra-host HCV variants?

The role of signal transducer and activator of transcription 3 (Stat3) in liver fibrosis is still controversial. Since hepatic stellate cells (HSCs) and transforming growth factor-β1 (TGF-β1) are central to the fibrogenesis, our goal was to clarify the mechanism of Stat3 crosslinking of TGF-β1 signaling. Stat3, TGF-β1 mRNA and protein expressions were examined in liver tissues of chronic hepatitis B (CHB) patients and diethylinitrosamine (DEN)-induced rat fibrosis model. The effect of Stat3 activation or suppression on TGF-β1 signaling in HSCs was tested in vitro and in vivo. Stat3 expression as well as TGF-β1 was increased in CHB patients and DEN-induced fibrosis rat model. This was strongly correlated with increase in fibrosis staging. TGF-β1, a mediator of fibrosis, was enhanced by Stat3, but suppressed by siRNA-mediated RNA knockdown of Stat3 (siStat3) or Janus kinase 2 inhibitor (AG490) both in vivo and in vitro. Stat3 crosslinking TGF-β1 signaling plays an important role in HSC activation and increasing fibrosis related products. TGF-β1 could not achieve profibrogenic cytokine and anti-apoptosis characteristics without Stat3 activation in HSCs.

Does stat3 signaling activation crosslinking of TGF-β1 in hepatic stellate cell exacerbate liver injury and fibrosis?

Eotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. Since inflammation is often associated with an increased generation of reactive oxygen species (ROS), oxidative stress is a mechanistically imperative factor in asthma. Astragalin (kaempferol-3-O-glucoside) is a flavonoid with anti-inflammatory activity and newly found in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways. Airway epithelial BEAS-2B cells were exposed to lipopolysaccharide (LPS) in the absence and presence of 1-20 μM astragalin. Western blot and immunocytochemical analyses were conducted to determine induction of target proteins. Cell and nuclear staining was also performed for ROS production and epithelial apoptosis. When airway epithelial cells were exposed to 2 μg/ml LPS, astragalin nontoxic at ≤ 20 μM suppressed cellular induction of Toll-like receptor 4 (TLR4) and ROS production enhanced by LPS. Both LPS and H2O2 induced epithelial eotaxin-1 expression, which was blocked by astragalin. LPS activated and induced PLCγ1, PKCβ2, and NADPH oxidase subunits of p22phox and p47phox in epithelial cells and such activation and induction were demoted by astragalin or TLR4 inhibition antagonizing eotaxin-1 induction. H2O2-upregulated phosphorylation of JNK and p38 MAPK was dampened by adding astragalin to epithelial cells, while this compound enhanced epithelial activation of Akt and ERK. H2O2 and LPS promoted epithelial apoptosis concomitant with nuclear condensation or caspase-3 activation, which was blunted by astragalin.

Does astragalin inhibit airway eotaxin-1 induction and epithelial apoptosis through modulating oxidative stress-responsive MAPK signaling?

A cross-sectional study in a general health examination. To investigate the relationship between brachial-ankle pulse wave velocity (baPWV) and lumbar disk herniation (LDH). Lumbar disk herniation (LDH) is a major cause of low back pain and sciatica. Various vascular risk factors such as obesity, diabetes mellitus, and smoking have been reported to be associated with LDH. BaPWV is an early indicator of subclinical atherosclerosis. A total of 490 participants with LDH and 490 participants without LDH were selected for the evaluation of baPWV. BaPWV was measured using an automatic device. The prevalence of LDH was calculated by the quartiles of baPWV levels. Multiple linear regression analysis was performed to evaluate the risk factors for baPWV. LDH patients had significantly higher readings of baPWV compared with non-LDH subjects (P<0.001). The prevalence rate of LDH gradually increased according to baPWV quartiles. In addition, the levels of baPWV tended to increase as the frequency of physical activity reduced. Multiple linear regression analysis showed that body mass index, low-density lipoprotein cholesterol, physical activity, and systolic blood pressure contributed to increased baPWV.

Is physical activity associated with elevated arterial stiffness in patients with lumbar disk herniation?

To investigate changes in autoreactive T-cell responses against PMP-22 and P2 antigen as well as a T-cell memory repertoire in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) induced by repeated intravenous immunoglobulin (IVIg) treatment. In an observational trial, we prepared cryopreserved human peripheral blood monocytes from blood from 34 patients with CIDP (18 treatment naïve and 16 maintenance IVIg treatment) and from 14 healthy controls (non-immune neuropathy and healthy control). Treatment response was defined by clinical evaluation. The autoantigen-specific T-cell response was analysed by enzyme linked immunosorbent spot (ELISPOT) assay before IVIg start (baseline) and at follow-up. The T-cell memory subsets were analysed by using flow cytometric analysis. Myelin-derived P2-specific and PMP-22-specific IFN-γ producers were increased in IVIg responders compared with non-responders before treatment, which decreased by repeated IVIg infusion cycles. Treatment responders but not non-responders showed higher frequencies of CD4 T effector memory (TEM) and T central memory frequencies at baseline compared with maintenance IVIg treatment patients and controls. In addition, IVIg treatment was associated with a significant reduction in CD8 TEM at follow-up.

Does effective treatment with intravenous immunoglobulins reduce autoreactive T-cell response in patients with CIDP?

The purpose of the present study was to investigate the effects of self-controlled feedback on the learning of a sequential-timing motor task in introverts and extroverts. Fifty-six university students were selected by the Eysenck Personality Questionnaire. They practiced a motor task consisting of pressing computer keyboard keys in a specific spatial and temporal pattern. The experiment consisted of practice, retention, and transfer phases. The participants were distributed into 4 groups, formed by the combination of personality trait (extraversion/introversion) and type of feedback frequency (self-controlled/yoked). The results showed superior learning for the groups that practiced in a self-controlled schedule, in relation to groups who practiced in an externally controlled schedule, F(1, 52) = 4.13, p < .05, eta2 = .07, regardless of personality trait.

Does self-controlled practice enhance motor learning in introverts and extroverts?

Left atrial pressure and its surrogate, pulmonary capillary wedge pressure (PCWP), are important for determining diastolic function. The role of transthoracic echocardiography (TTE) in assessing diastolic function is well established in awake subjects. The objective was to assess the accuracy of predicting PCWP by TTE and transesophageal echocardiography (TEE) during coronary artery surgery. In 27 adult patients undergoing on-pump coronary artery surgery, simultaneous echocardiographic and hemodynamic measurements were obtained immediately before anesthesia (TTE), after anesthesia and mechanical ventilation (TTE and TEE), during conduit harvest (TEE), and after separation from cardiopulmonary bypass (TEE). Twenty patients had an ejection fraction (EF) of 0.5 or greater. With the exception of E/e' and S/D ratios, echocardiographic values changed over the echocardiographic studies. In patients with low EF, E velocity, deceleration time, pulmonary vein D, S/D, and E/e' ratios correlated well with PCWP before anesthesia. After induction of anesthesia using TTE or TEE, correlations were poor. In normal EF patients, correlations were poor for both TEE and TTE at all five stages. The sensitivity and specificity of echocardiographic values were not high enough to predict raised PCWP except for a fixed curve pattern of interatrial septum (area under the curve 0.89 for PCWP ≥ 17, and 0.98 for ≥ 18 mmHg) and S/D less than 1 (area under the curve 0.74 for PCWP ≥ 17, and 0.78 for ≥ 18 mmHg).

Does interatrial septum motion but not Doppler assessment predict elevated pulmonary capillary wedge pressure in patients undergoing cardiac surgery?

The precise pathogenesis of chronic spontaneous urticaria (CSU) remains unknown. However, an important association between CSU and autoimmune disorders such as Hashimoto's disease (HD) has been reported. We investigated the frequency of HD as a comorbidity of CSU and the prevalence rate of autoreactivity among CSU patients with HD. The presence of thyroid autoantibodies and the levels of thyroid hormones were examined in 40 CSU patients who showed urticaria symptoms for >4 weeks. Patients who were diagnosed with HD, including subclinical ones, and were in need of treatment received thyroid therapy, and the changes in their urticarial symptoms were observed. An autologous serum skin test (ASST) was also performed to examine the relation of CSU with autoreactivity. Eleven of the 40 CSU patients were diagnosed with HD, and 4 of the 5 patients who received and completed thyroid therapy showed considerable remission of urticarial symptoms during and after treatment. In addition, the rate of positive ASST results tended to be higher in CSU patients with HD (5 of 7) than in those without HD (2 of 6).

Is hashimoto 's disease a frequent comorbidity and an exacerbating factor of chronic spontaneous urticaria?

Various types of periacetabular osteotomies have been proposed to treat acetabular dysplasia for young and active patients. Acetabular dysplasia is prevalent in women and rare in men, therefore few reports exist concerning periacetabular osteotomy of male patients. The purpose of this study is to clarify the gender differences in surgical techniques, radiographic and clinical outcomes. Between 1989 and 2007, we performed 530 eccentric rotational acetabular osteotomies and followed them annually for more than five years. Thirty-six male patients were investigated. As a control group, 72 female patients were matched for age and preoperative stage of osteoarthritis at the time of surgery. We evaluated operative time and blood loss, radiographic parameters, Harris Hip Score (HHS) and survival rate. We investigated the clinical and radiographic differences between men and women. The mean operative time was 148 min in males and 135 min in females. The bleeding during surgery was 445 g in males and 351 g in females. HHS improved 94.1 points in males and 93.5 points in women postoperatively. The mean CE angle improved 31.7° in males and 35.1° in females. The mean AHI was 90.8% in males and 94.1% in females postoperatively. The survival rate of male patients were 92.8% and that of female patients were 98.1%.

Does gender difference affect the outcomes of eccentric rotational acetabular osteotomy used in hip dysplasia?

Known factors affecting the management of vesicoureteral reflux (VUR) include reflux grade, infection frequency, age and gender. We hypothesized that provider preference is highly associated with management. Utilizing the national billing database, Faculty Practice Solutions Center, a multivariable logistic regression model, was applied to analyze the association of pediatric urologist treatment patterns, patient age, gender, uni- or bilateral disease, insurance type, presence of nephropathy and race with the type of VUR treatment a patient would receive. We identified 59 pediatric urologists who managed 7,882 new reflux patients from 2009 to 2011. Over this 3-year period there was wide variation in surgical utilization between surgeons (mean 50 %) but minimal change for each surgeon (5 %). For every 100 new reflux patients, median utilization of reimplantation surgery and injection of dextranomer/hyaluronic acid copolymer (Deflux) was 26 and 20 %, respectively. Age ranked highest in predicting surgical versus non-surgical management, while a surgeon's historic Deflux utilization rate ranked highest in predicting surgery type. Older age, female gender and white race also increased the odds of Deflux utilization over reimplantation.

Is physician preference a major factor in management of vesicoureteral reflux?

Filaggrin (FLG) is a major protein component of the stratum corneum (SC) layer, and FLG loss-of-function mutations are a predisposing factor for atopic dermatitis (AD). Previous cohort studies of children from northern and western Europe have reported FLG loss-of-function mutation frequencies of 15.1-20.9% and 5.8-13.0% in AD and non-AD groups, respectively. To elucidate the association between AD prevalence of FLG loss-of-function mutation carriers and climate conditions, we determined the AD prevalence and FLG loss-of-function mutation frequencies in a cohort of children from Ishigaki Island. Ishigaki Island has a subtropical climate with high humidity (monthly average, 60.8-78.7%) and high temperature (monthly average, 18.5-29.4°C) throughout the year. We diagnosed AD prevalence and analyzed eight FLG loss-of-function mutations in the Japanese population against a cohort of 721 children from the Kyushu University Ishigaki Atopic Dermatitis Study (KIDS) cohort. Parents gave consent for the mutation analysis during their medical examinations from 2001 to 2006. Average AD prevalence was 7.3% per year, and a total of 127 children (17.6%) were diagnosed with AD at least once between 2001 and 2006. The average total serum IgE level differed significantly between the AD and non-AD groups (199.0 and 69.0IU/ml, respectively). Although five kinds of FLG loss-of-function mutations isolated in previous Japanese FLG mutation studies were identified, the FLG loss-of-function mutation frequency in children of the KIDS cohort was not significantly different between the AD and non-AD groups (7.9% and 6.1%, respectively; P=0.174).

Are filaggrin loss-of-function mutations a predisposing factor for atopic dermatitis in an Ishigaki Island under subtropical climate?

Our study reexamines the prevalence of interval colorectal cancer (I-CRC) by manually reviewing CRC cases at a single institution. In 2% to 8% of patients with CRC, diagnosis occurs during the interval 6 to 36 months after a cancer-free colonoscopy. Rates are often determined by linking the date of colonoscopy with cancer registry information. We examined all colonoscopies from 1993 to 2011. These examinations were linked with Pennsylvania Cancer Registry data. Matched charts were manually reviewed. We determined whether the CRC was "prevalent" or, for patients with a previous colonoscopy, whether they were interval or noninterval based on time from last colonoscopy. For interval cases, we identified "administrative errors" that could falsely increase the number of reported I-CRC. Over the study period, 43,661 colonoscopies were performed, with 1147 (2.6%) positive for CRC after excluding cases (n=52) in which patients had IBD, previous surgery, or nonadenocarcinoma malignancy. Prevalent CRCs totaled 1062 (92.6%). Noninterval CRCs (diagnosed over 36 mo from index colonoscopy) were present in 40 (3.5%). There remained 45 (3.9%) potential I-CRC cases. However, after manual review, 21 cases were found to be administrative errors. Therefore, the accurate proportion of colonoscopies that found an I-CRC was 2.1% (95% confidence interval, 1.5%-3.2%).

Does administrative Database Research overestimate the Rate of Interval Colon Cancer?

Innate immune protein C1q plays a dual role in the chronic inflammatory disease of atherosclerosis. Complement activation via C1q exacerbates pathology in the atherosclerotic lesion in later stages of the disease. However, in early stages of disease C1q is protective. We hypothesize that complement-independent activities of C1q are involved in reprogramming macrophage inflammatory polarization. The influence of C1q on macrophage inflammatory responses during clearance of oxLDL was examined. Changes in cytokines at the gene and protein level were measured by quantitative PCR and ELISA assay. C1q modulated cytokine expression in Raw264.7 macrophages during ingestion of oxLDL. Levels of pro-inflammatory cytokines IL-1β and IL-6 were downregulated by C1q, whereas levels of the anti-inflammatory cytokine IL-10 were increased. In addition, data from an NFκB-luciferase gene reporter assay suggest that C1q suppresses activation of NFκB during lipoprotein clearance in macrophages, providing one mechanism by which C1q downregulates pro-inflammatory cytokine production.

Does complement protein C1q promote macrophage anti-inflammatory M2-like polarization during the clearance of atherogenic lipoproteins?

The reconstruction of large facial bony defects using microvascular transplants requires extensive surgery to achieve full rehabilitation of form and function. The purpose of this study is to measure the agreement between virtual plans and the actual results of maxillofacial reconstruction. This retrospective cohort study included 30 subjects receiving maxillofacial reconstruction with a preoperative virtual planning. Parameters including defect size, position, angle and volume of the transplanted segments were compared between the virtual plan and the real outcome using paired t test. A total of 63 bone segments were transplanted. The mean differences between the virtual planning and the postoperative situation were for the defect sizes 1.17 mm (95 % confidence interval (CI) (-.21 to 2.56 mm); p = 0.094), for the resection planes 1.69 mm (95 % CI (1.26-2.11); p = 0.033) and 10.16° (95 % CI (8.36°-11.96°); p < 0.001) and for the planes of the donor segments 10.81° (95 % CI (9.44°-12.17°); p < 0.001) The orientation of the segments differed by 6.68° (95 % CI (5.7°-7.66°); p < 0.001) from the virtual plan; the length of the segments differed by -0.12 mm (95 % CI (0.89-0.65 mm); not significant (n.s.)), respectively, while the volume differed by 73.3 % (95 % CI (69.4-77.6 %); p < 0.001). The distance between the transplanted segments and the remaining bone was 1.49 mm (95 % CI (1.24-1.74); p < 0.001) and between the segments 1.49 mm (95 % CI (1.16-1.81); p < 0.001).

Does virtual planning of complex head and neck reconstruction result in satisfactory match between real outcomes and virtual models?

Administration of infliximab to patients with acute severe ulcerative colitis (ASUC) (rescue therapy) can reduce the rate of early colectomy (within 12 months), but long-term rates of colectomy are the same as those of the pre-biologic era for these patients. The half-life of infliximab is shorter in patients with ASUC than in patients with non-severe UC, so more frequent dosing might be required to produce a therapeutic effect. We performed a retrospective analysis of 50 hospitalized patients who received infliximab for steroid-refractory ASUC at a single academic center from September 2005 through 2013. In 2011 an accelerated dosing strategy for infliximab was introduced; we compared outcomes of standard and accelerated dosing regimens. One group of patients (n = 35) were placed on a standard dosing regimen for infliximab and then given the drug at 0, 2, and 6 weeks and then every 8 weeks thereafter. A second group (n = 15) were placed on an accelerated regimen and received 3 induction doses of infliximab within a median period of 24 days. Rates of colectomy were compared between the groups during induction and follow-up periods. There were no differences between groups in median baseline levels of C-reactive protein, albumin, or hemoglobin. The rate of colectomy during induction therapy was significantly lower with the accelerated regimen (6.7%, 1 of 15) than with the standard regimen (40%, 14 of 35) (Fisher exact test, P = .039). The standard regimen was associated with shorter time to colectomy (log-rank test, P = .042). Among patients who completed induction therapy, subsequent need for colectomy was similar between the groups during the follow-up period. Multivariate analysis showed that factors independently associated with successful induction therapy were level of albumin (g/L) when the treatment began (P = .003) and the accelerated dosing regimen (P = .03).

Does an accelerated infliximab induction regimen reduce the need for early colectomy in patients with acute severe ulcerative colitis?

Dehydroepiandrosterone (DHEA) was shown to improve the immune function and survival in experimental sepsis. This study examined the effect of DHEA on intestinal leukocyte recruitment during experimental sepsis, considering factors of gender (male, female and ovariectomized female animals) and combined treatment using orthovanadate (OV) in two models of sepsis. Male rats underwent colon ascendens stent peritonitis (CASP) or endotoxemia. DHEA was administered after induction of experimental sepsis. Changes in leukocyte adherence and capillary perfusion (measured as intestinal functional capillary density - FCD) were assessed using intravital microscopy. While DHEA increased baseline leukocyte adherence in control animals, DHEA reduced leukocyte adherence and increased FCD in male animals with CASP. These effects were also observed in DHEA-treated ovariectomized female rats with CASP. Similarly, the administration of DHEA reduced the number of adherent leukocytes to intestinal venules by 30% in the endotoxemia model. The combined treatment of DHEA and OV significantly reduced adherence of leukocytes to intestinal venules and improved FCD.

Does combination of dehydroepiandrosterone and orthovanadate administration reduce intestinal leukocyte recruitment in models of experimental sepsis?

In many areas of orthopaedics, patients with greater levels of psychological distress report inferior self-assessments of pain and function. This effect can lead to lower-than-expected baseline scores on common patient-reported outcome scales, even those not traditionally considered to have a psychological component. This study attempts to answer the following questions: (1) Are higher levels of psychological distress associated with clinically important differences in baseline scores on the VAS for pain, the Simple Shoulder Test, and the American Shoulder and Elbow Surgeons score in patients undergoing arthroscopic rotator cuff repair? (2) Does psychological distress remain a negative predictor of baseline shoulder scores when other clinical variables are controlled? Eighty-five patients with full-thickness rotator cuff tears were prospectively enrolled. Psychological distress was quantified using the Distress Risk Assessment Method questionnaire. Patients completed baseline self-assessments including the VAS for pain, the Simple Shoulder Test, and the American Shoulder and Elbow Surgeons score. Age, sex, BMI, smoking status, American Society of Anesthesiologists classification, tear size, and tear retraction were recorded for each patient. Bivariate correlations and multivariate regression models were used to assess the effect of psychological distress on patient self-assessment of shoulder pain and function. Distressed patients reported higher baseline VAS scores (6.7 [95% CI, 4.4-9.0] versus 2.9 [95% CI, 2.3-3.6], p = 0.001) and lower baseline Simple Shoulder Test (3.7 [95% CI, 2.9-4.5] versus 5.7 [95% CI 5.0-6.4], p = 0.001) and American Shoulder and Elbow Surgeons scores (39 [95% CI, 34-45] versus 58 [95% CI, 53-63], p < 0.001). Distress remained associated with higher VAS scores (p = 0.001) and lower Simple Shoulder Test (p < 0.001) and American Shoulder and Elbow Surgeons scores (p < 0.001) when age, sex, BMI, American Society of Anesthesiologists classification, smoking status, tear size, and tear retraction were controlled.

Does psychological distress negatively affect self-assessment of shoulder function in patients with rotator cuff tears?

Plants, fungal endophytes (FEs) and the changing environment interact with each other forming an interlaced network. This study evaluates nonadditive and interactive effects of the FE Acremonium strictum and drought treatment on Atractylodes lancea plantlets. By applying FEs (meristem cultures of At. lancea, fungal inoculation of Ac. strictum and plantlet acclimatization) and drought treatment (regular watering, mild drought, severe drought), a research system of At. lancea ramets under different treatments was established. During 12 days of drought treatment, the plantlets' physiological responses and basic growth traits were measured and analysed. Although drought and FE presence affected plantlet traits to differing degrees, the interactive effects of the two were more pronounced. In particular under mild drought treatment, the FE conferred drought tolerance to plantlets by enhancing leaf soluble sugars, proteins, proline and antioxidant enzyme activity; decreasing the degree of plasmalemma oxidation; and increasing the host's abscisic acid level and root:shoot ratio. When exposed to regular watering or severe drought, these effects were not significant.

Does drought degree constrain the beneficial effects of a fungal endophyte on Atractylodes lancea?

H3K9 methylation is one of the essential histone post-translational modifications for heterochromatin formation and transcriptional repression. Recently, several studies have demonstrated that H3K9 methylation negatively regulates the type I interferon response. We report the application of EHMT1 and EHMT2 specific chemical inhibitors to sensitize CML cell lines to interferon and imatinib treatments. Inhibition of EHMT1 and EHMT2 with BIX01294 enhances the cytotoxicity of IFNα2a in four CML cell lines, K562, KCL22, BV173 and KT1 cells. Chromatin immunoprecipitation assay shows that BIX01294 treatment enhances type I interferon response by reducing H3K9me2 at the promoters of interferon-stimulated genes. Additionally, BIX01294 treatment augments IFNα2a- and imatinib-mediated apoptosis in CML cell lines. Moreover, our data suggest that the expression level of EHMT1 and EHMT2 inversely correlates with the type I interferon responsiveness in CML cell lines.

Does inhibition of euchromatic histone methyltransferase 1 and 2 sensitize chronic myeloid leukemia cells to interferon treatment?

Computed tomography (CT) substitute images can be generated from ultrashort echo time (UTE) MRI sequences with radial k-space sampling. These CT substitutes can be used as ordinary CT images for PET attenuation correction and radiotherapy dose calculations. Parallel imaging allows faster acquisition of magnetic resonance (MR) images by exploiting differences in receiver coil element sensitivities. This study investigates whether non-Cartesian parallel imaging reconstruction can be used to improve CT substitutes generated from shorter examination times. The authors used gridding as well as two non-Cartesian parallel imaging reconstruction methods, SPIRiT and CG-SENSE, to reconstruct radial UTE and gradient echo (GE) data into images of the head for 23 patients. For each patient, images were reconstructed from the full dataset and from a number of subsampled datasets. The subsampled datasets simulated shorter acquisition times by containing fewer radial k-space spokes (1000, 2000, 3000, 5000, and 10,000 spokes) than the full dataset (30,000 spokes). For each combination of patient, reconstruction method, and number of spokes, the reconstructed UTE and GE images were used to generate a CT substitute. Each CT substitute image was compared to a real CT image of the same patient. The mean absolute deviation between the CT number in CT substitute and CT decreased when using SPIRiT as compared to gridding reconstruction. However, the reduction was small and the CT substitute algorithm was insensitive to moderate subsampling (≥ 5000 spokes) regardless of reconstruction method. For more severe subsampling (≤ 3000 spokes), corresponding to acquisition times less than a minute long, the CT substitute quality was deteriorated for all reconstruction methods but SPIRiT gave a reduction in the mean absolute deviation of down to 25 Hounsfield units compared to gridding.

Does cT substitute derived from MR images reconstructed with parallel imaging?

The aim of this study is to examine the hypothesis that prolonged rupture of membranes (PROM) is associated with increased cord blood erythropoietin (EPO) concentrations, proportional to the duration of ruptured membranes. This study is a prospective, cross-sectional, observational (noninterventional) cohort study of mother-infant pairs. Criteria for inclusion were as follows: active labor with or without ruptured membranes and vaginally delivered neonates. Excluded were infants with major factors known to be associated with a potential increase in fetal erythropoiesis. A total of 40 mother-infant pairs were recruited. EPO was not influenced by duration of ruptured membranes and significantly correlated only with maternal body mass index.

Does increased nucleated red blood cells count in prolonged rupture of membranes is not erythropoietin driven?

To confirm that the severity of inflammation can promote the colitis-associated colorectal cancer(CAC) and explore the function of STAT3 signal pathway in CAC. Mutagenic agent azoxymethane(AOM) and pro-inflammatory agent dextran sodium sulfate salt (DSS) were used to develop a mouse model of CAC. By changing the concentration of DSS (0, 1% and 2% respectively), the mouse model with different extent of severity of inflammation was developed and the risk of carcinogenesis among these groups was compared. The expression of STAT3 signal pathway was detected by immunohistochemistry staining. In the evaluation of inflammatory severity, disease activity index, histopathological inflammation scores and the expression of pro-inflammation chemokines such as TNF-α, IL-6 and IL-12 in the higher inflammatory response group were higher than that in the lower inflammatory response group. The incidence of colorectal tumor was 100%(12/12) in the higher inflammatory response group and the incidence of colorectal tumor was 58.3%(7/12) in the lower inflammatory response group, and the difference between these two group was statistically significant (P<0.05). The multiplicity(number of tumors/colon) was 12.5±0.5 in the higher inflammatory response group and the multiplicity was 6.6±1.0 in the lower inflammatory response group, and the difference between these two groups was statistically significant (P<0.001). The tumor load(sum of tumor diameters per mouse) in the higher inflammatory response group was 44.2±2.4 mm and that in the lower inflammatory response group was only 18.7±2.7 mm, and the difference between these two groups was statistically significant (P<0.0001). Moreover, the expression of p-STAT3 (Tyr705) was higher in colitis tissue of the higher inflammatory response group than that of the lower inflammatory response group.

Does [ Inflammation promote the development of colitis-associated colorectal cancer ]?

High fructose intake has been suggested to be a key factor that induces nonalcoholic fatty liver disease (NAFLD), but the evidence from large epidemiologic studies is lacking. We examined the cross-sectional association between fructose intake and NAFLD by using the Fatty Liver Index (FLI) and the NAFLD liver fat score. The Helsinki Birth Cohort Study investigated 2003 Finnish men and women born in 1943-1944 in Helsinki who participated in a clinical health examination in the years 2001-2004. Trained study nurses measured weight, height, and waist circumference, and body mass index was calculated. Laboratory staff drew fasting blood for measurements of triglycerides and γ-glutamyl-transferase. The FLI and the NAFLD liver fat score were calculated on the basis of these measurements. Habitual fructose and other dietary intake over the past year were assessed by using validated and standardized 131-item food-frequency questionnaires. Data were analyzed in a cross-sectional manner by using logistic regression modeling with statistical software. In a model adjusted for age, sex, and energy intake, participants in the highest fructose intake quartile (range: 29.2-88.0 g/d) had lower risk of NAFLD assessed by using the FLI (OR: 0.56; 95% CI: 0.42, 0.75; P-trend < 0.001) and NAFLD liver fat score (OR: 0.72; 95% CI: 0.53, 0.99; P-trend < 0.001) than that of the lowest intake quartile (range: 2.2-15.2 g/d). This association remained after adjustment for educational attainment, smoking, physical activity, and other dietary variables only for the FLI (OR: 0.68; 95% CI: 0.47, 0.84; P-trend < 0.05).

Is higher fructose intake inversely associated with risk of nonalcoholic fatty liver disease in older Finnish adults?

Diabetic retinopathy is a common diabetic eye disease caused by changes in retinal ganglion cells (RGCs). Several studies suggest that the oxidative stress plays a role in the pathogenesis of diabetic retinopathy in adults. Formononetin is a flavone with powerful antioxidant properties that exists naturally in various plants and Chinese medicine. In the present study, an attempt has been made to investigate the antioxidative effects of formononetin on H2O2-induced apoptosis of RGC-5 cells. Exposure of retinal ganglion cells (RGCs) to the indicated concentrations of formononetin and H2O2 for 24 h, analyzed by MTT assay. Cells were stained with Annexin V-FITC and PI, analyzed by flow cytometry. And the level of superoxide anions, malondialdehyde (MDA, a marker of lipid peroxidation), 8-hydroxy-2-deoxyguanosine (8-OHdG, indicator of oxidative DNA damage) and MnSOD (manganese superoxide dismutase) activity were measured by kits. Formononetin reduced hydrogen peroxide (H2O2)-induced apoptosis and improved the levels or activity of indicators of oxidative stress. Formononetin also inhibited the activation of nuclear factor-kappaB (NF-κB), which is a significant transcription factor for RGC-5 apoptosis.

Does formononetin attenuate hydrogen peroxide ( H2O2 ) -induced apoptosis and NF-κB activation in RGC-5 cells?

Zuo-Jin-Wan (ZJW), a traditional Chinese medicine formula, has been identified to be effective against drug resistance in cancer. In the present study, we investigated the effect of ZJW on acquired oxaliplatin-resistant and the PI3K/Akt/NF-κB pathway in vitro. We tested the dose-response relationship of ZJW on reversing drug-resistance by CCK-8 assay and flow cytometry analysis in vitro. The protein expression of P-gp, MRP-2, LRP, and ABCB1 mRNA expression level were evaluated by Western blot and quantitative RT-PCR. The activities of PI3K/Akt/NF-κB pathway were also examined with or without ZJW, including Akt, IκB, p65 and their phosphorylation expression. We found that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs and increased oxaliplatin (L-OHP)-induced cell apoptosis in a time- and dose-dependent manner. Moreover, both ZJW and a PI3K specific inhibitor (LY294002) suppressed phosphorylation of Akt (Ser473) and NF-κB, which is necessary in the activation of the PI3K/Akt/NF-κB pathway. The effect of ZJW in reversing drug-resistance and suppressing phosphorylation of Akt (Ser473) and NF-κB were weakened after treatment with a PI3K/Akt activator in HCT116/L-OHP cells.

Does zuo Jin Wan reverse P-gp-mediated drug-resistance by inhibiting activation of the PI3K/Akt/NF-κB pathway?

To determine if patients with pathological, medical renal disease, defined as evidence of pathological abnormalities indicative of renal damage in the non-neoplastic partial nephrectomy specimens, have worsened functional outcomes following robot-assisted partial nephrectomy. Sixty patients with and 101 without pathologically proven renal disease on non-neoplastic renal specimens were evaluated for differences in postoperative outcomes following robot-assisted partial nephrectomy. Multiple linear regression modeling assessed for factors influencing early and late declines in renal function. The two groups were similar in all preoperative parameters. Both patients with and without pathological renal disease had similar lengths of hospitalization, transfusions, and complication rates. The percent change in glomerular filtration rate was similar for patients with and without pathological renal disease (-8.8% vs. -12.2%, p=0.194). Patients with pathological renal disease had less chronic kidney disease upstaging than patients without renal disease (18.3% vs. 39.6%, p=0.006). Increasing age (p=0.030) and higher preoperative glomerular filtration rates (p=0.044) predicted worse late percentage declines in renal function, while increased warm ischemia time predicted late chronic kidney disease upstaging (p=0.043).

Do patients with Pathologically Proven Renal Disease Have Similar Declines in Renal Function Following Robot-Assisted Partial Nephrectomy?

We performed diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) studies in a group of patients with subacute sclerosing panencephalitis (SSPE) in order to estimate the pathologic process underlying the phenotypic variability. Patients with SSPE who had MRI including DTI and MRS examinations were evaluated according to their clinical status as determined by the SSPE Scoring System and their mental age as determined by tests appropriate for age and developmental level. Comparisons of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values and metabolite ratios of frontal periventricular white matter, parieto-occipital periventricular white matter, and globus pallidus in both hemispheres were made between control and SSPE groups, and between SSPE subgroups. Control (n = 18) and SSPE (n = 39) groups differed in all DTI and MRS parameters except FA, choline (Cho), and Cho/creatine (Cr). SSPE cases had higher ADC and lower N-acetylaspartate (NAA), NAA/Cho, and NAA/Cr in all regions of interest, suggesting cell loss. Disease progression rate and neurologic deficit appeared to be associated with the degree of ADC elevation and NAA reduction: the group with severe global deterioration had the lowest NAA (230.75 ± 197.97 in forceps minor), and rapid progression was associated with acute reduction in NAA.

Is neuronal loss an early component of subacute sclerosing panencephalitis?

Coronary artery calcification (CAC) is a prominent feature of atherosclerosis and is associated with cardiovascular events. In vitro studies have suggested that osteoprotegerin (OPG) and osteocalcin (OC) exert anticalcification potential in the vessel wall. The objective of this study was to investigate the association of CAC and serum bone biomarkers in persons with type 2 diabetes. We examined 50 individuals with type 2 diabetes. CAC imaging was performed by multidetector computed tomography. CAC scores ≥10, expressed in Agatston units, were considered abnormal. OC, undercarboxylated OC (ucOC), and OPG levels were determined by enzyme-linked immunosorbent assay. Abnormal CAC scores were found for 64% of the study cohort. OPG levels were significantly elevated (5.5 ± 2.0 pmol/L vs. 4.2 ± 1.7 pmol/L; P = .026) for those with abnormal CAC scores. No univariate differences were found for OC or ucOC. Logistic regression analyses revealed that an increase in serum OPG level was significantly associated with an increase in CAC score (odds ratio, 3.324; 95% confidence interval, 1.321 to 8.359; P = .011). Longer duration of diabetes was a significant covariate (P = .026), whereas nonsignificant covariates in the final model were age, gender, systolic blood pressure, body mass index, insulin resistance determined by the homeostasis model assessment for insulin resistance, leptin, adiponectin, and glycemic control. The Nagelkerke R2 for the model was 0.66. Neither OC nor ucOC were significantly associated with elevated CAC scores.

Is osteoprotegerin a Better Serum Biomarker of Coronary Artery Calcification than Osteocalcin in Type 2 Diabetes?

We hypothesized that variability from year to year in how much of the bone map was filled in at the bottom of the spine region of interest (ROI) contributes substantially to variability in measurement of spine bone mineral density (BMD). A total of 110 spine BMDs with defects in the bone mapping at the bottom were reanalyzed, with the only change being manually drawing a straight line across the bottom of the ROI and filling in the bone map. The mean (SD) change in area, bone mineral content, and BMD for total spine when the bottom of the bone map was filled in was 0.919 (0.411) cm2, 0.201 (0.121) g, and -0.0098 (0.0043) g/cm2, respectively, and all changes were significant (P<.0001). The largest individual change in total spine BMD with reanalysis was 0.0238 g/cm2, close to the least significant change (LSC) of 0.026 g/cm2 in our center. To quantify variability due to this change in analysis, we calculated an LSC(fill), in which the pairs of scans consisted of the same scan before and after filling in the bottom of the spine bone map, without any other change. The LSC(fill) attributable just to the reanalysis of missing bone map at the bottom of the spine was 0.021 g/cm2, suggesting substantial variance due to variability in mapping the bottom of the spine.

Does inconsistency in filling in the bottom of the spine bone map affect reported spine bone mineral density?

Chronic intermittent hypobaric hypoxia (CIHH) protects the heart against ischemia/reperfusion (I/R) injury. This study investigated the calcium homeostasis mechanism and the role of Na(+)/Ca(2+) exchanger (NCX) in the cardiac protective effect of CIHH in developing rats. Neonatal male rats received CIHH treatment or no treatment (control) in a hypobaric chamber simulating 3000-meter altitude for 42 days. The left ventricular function of isolated hearts was evaluated after 30 minutes of ischemia and 60 minutes of reperfusion. Myocardial infarct size, intracellular Ca(2+) concentration ([Ca(2+)]i), Na(+)-Ca(2+) exchanger currents (I(Na/Ca)) in ventricular myocytes, and NCX1 protein level in the sarcolemmal membrane were determined. The recovery of cardiac function after I/R was improved, with the myocardial infarct size reduced, in CIHH rats compared with control rats (p<0.05). These effects were attenuated by Bay K8644, an L-type Ca(2+) channel agonist, or ryanodine, a sarcoplasmic reticulum Ca(2+) channel receptor activator. Furthermore, the increases in [Ca(2+)]i during I/R were blunted in CIHH rats, but this effect was abolished by Bay K8644 or chelerythrine, a protein kinase C (PKC) inhibitor. The I(Na/Ca) was decreased and the reversal potential of INa/Ca was shifted toward negative potential during simulated ischemia in the control cardiomyocytes (p<0.05). The inhibition of NCX1 protein expression during I/R was smaller in the CIHH rats than in the control rats (p<0.05).

Does chronic intermittent hypobaric hypoxia ameliorate ischemia/reperfusion-induced calcium overload in heart via Na/Ca2+ exchanger in developing rats?

Diffusion-weighted MRI (DWI) has been used in neurosurgical practice mainly to distinguish cerebral metastases from abscess and glioma. There is evidence from other solid organ cancers and metastases that DWI may be used as a biomarker of prognosis and treatment response. We therefore investigated DWI characteristics of cerebral metastases and their peritumoral region recorded pre-operatively and related these to patient outcomes. Retrospective analysis of 76 cases operated upon at a single institution with DWI performed pre-operatively at 1.5T. Maps of apparent diffusion coefficient (ADC) were generated using standard protocols. Readings were taken from the tumor, peritumoral region and across the brain-tumor interface. Patient outcomes were overall survival and time to local recurrence. A minimum ADC greater than 919.4 × 10(-6) mm(2)/s within a metastasis predicted longer overall survival regardless of adjuvant therapies. This was not simply due to differences between the types of primary cancer because the effect was observed even in a subgroup of 36 patients with the same primary, non-small cell lung cancer. The change in diffusion across the tumor border and into peritumoral brain was measured by the "ADC transition coefficient" or ATC and this was more strongly predictive than ADC readings alone. Metastases with a sharp change in diffusion across their border (ATC >0.279) showed shorter overall survival compared to those with a more diffuse edge. The ATC was the only imaging measurement which independently predicted overall survival in multivariate analysis (hazard ratio 0.54, 95% CI 0.3 - 0.97, p = 0.04).

Does diffusion-weighted MRI characteristics of the cerebral metastasis to brain boundary predict patient outcomes?

Impairment of proteasomal function is pathogenic in several cardiac proteinopathies and can eventually lead to heart failure. Loss of proteasomal activity often results in the accumulation of large protein aggregates. The ubiquitin proteasome system (UPS) is primarily responsible for cellular protein degradation, and although the role of ubiquitination in this process is well studied, the function of an ancillary post-translational modification, SUMOylation, in protein quality control is not fully understood. To determine the role of ubiquitin-conjugating enzyme 9 (UBC9), a small ubiquitin-like modifier-conjugating enzyme, in cardiomyocyte protein quality control. Gain- and loss-of-function approaches were used to determine the importance of UBC9. Overexpression of UBC9 enhanced UPS function in cardiomyocytes, whereas knockdown of UBC9 by small interfering RNA caused significant accumulations of aggregated protein. UPS function and relative activity was analyzed using a UPS reporter protein consisting of a short degron, CL1, fused to the COOH-terminus of green fluorescent protein (GFPu). Subsequently, the effects of UBC9 on UPS function were tested in a proteotoxic model of desmin-related cardiomyopathy, caused by cardiomyocyte-specific expression of a mutated αB crystallin, CryAB(R120G). CryAB(R120G) expression leads to aggregate formation and decreased proteasomal function. Coinfection of UBC9-adenovirus with CryAB(R120G) virus reduced the proteotoxic sequelae, decreasing overall aggregate concentrations. Conversely, knockdown of UBC9 significantly decreased UPS function in the model and resulted in increased aggregate levels.

Is sumo E2 enzyme UBC9 required for efficient protein quality control in cardiomyocytes?

In multiple sclerosis (MS), pathological studies have identified substantial demyelination and neuronal loss in the spinal cord grey matter (GM). However, there has been limited in vivo investigation of cord GM abnormalities and their possible functional effects using MRI combined with clinical evaluation. We recruited healthy controls (HC) and people with a clinically isolated syndrome (CIS), relapsing remitting (RR) and secondary progressive (SP) MS. All subjects had 3 T spinal cord MRI with measurement of cord cross-sectional area and diffusion tensor imaging metrics in the GM and posterior and lateral column white matter tracts using region of interest analysis. Physical disability was assessed using the expanded disability status scale (EDSS) and motor components of the MS functional composite scale. We calculated differences between MS and HC using a ANOVA and associations with disability using linear regression. 113 people were included in this study: 30 controls, 21 CIS, 33 RR and 29 SPMS. Spinal cord radial diffusivity (RD), fractional anisotropy and mean diffusivity in the GM and posterior columns were significantly more abnormal in SPMS than in RRMS. Spinal cord GM RD (β=0.33, p<0.01) and cord area (β=-0.45, p<0.01) were independently associated with EDSS (R(2)=0.77); spinal cord GM RD was also independently associated with a 9-hole peg test (β=-0.33, p<0.01) and timed walk (β=-0.20, p=0.04).

Are spinal cord grey matter abnormalities associated with secondary progression and physical disability in multiple sclerosis?

One third of non-small cell lung cancer (NSCLC) affects elderly patients in a locally advanced (LA) stage. Induction therapy followed by a curative approach is becoming the standard-of-care for LA-NSCLC. We compared the efficacy and tolerance to induction chemotherapy or chemo-radiation followed by surgery or definitive radiotherapy in patients younger (N=64) and older (N=44) than 70 years with LA-NSCLC. Elderly patients trended towards having a worse baseline performance status, and presented a higher percentage of IIIB, and squamous tumors. Nevertheless, no significant differences in response rate, operability, or disease-free and overall survival were found between age groups in the whole series, nor in the sub-group of resected patients. Grade 3-4 toxicity tended to be lower in elderly patients.

Does age worsen the efficacy nor tolerance to combined induction therapies in locally advanced non-small cell lung cancer?

Successful cancer treatments still require more compounds to be isolated from natural sources. Thus, we have investigated anti-proliferative/apoptotic effects of methanolic extracts of lichen species Parmelia sulcata Taylor and Usnea filipendula Stirt on human lung cancer (A549, PC3), liver cancer (Hep3B) and rat glioma (C6) cells. Anti-proliferative effects were monitored by MTT and adenosine triphosphate viability assays, while genotoxic activity was studied using the comet assay. Additionally, cell death mode and apoptosis assays (fluorescence staining, caspase-cleaved cytokeratin 18, caspase-3 activity and PARP cleavage) were performed. Extracts produced anti-population growth effects in a dose-dependent manner (1.56-100 μg/ml) by inducing apoptosis-like cell death. This resulted in the lines having the presence of pyknotic cell nuclei. In addition, significant increase in genetic damage in the cell lines was seen, indicating that DNA damage may have been responsible for apoptotic cell death.

Do parmelia sulcata Taylor and Usnea filipendula Stirt induce apoptosis-like cell death and DNA damage in cancer cells?

LV hypertrophy (LVH) is frequent after aortic valve replacement (AVR) and is often associated with comorbidities, including hypertension, obesity, renal failure and prosthesis-patient mismatch (PPM). However, whether other biological mechanism(s) may participate to LVH after AVR is still unknown. Parathyroid hormone (PTH) may play a role in LVH. However, it is presently unknown whether PTH is associated with LVH in patients that have undergone an AVR. In this cross-sectional study, 195 patients have been investigated at a mean of 8 ± 3.5 years following AVR. LV function and mass were evaluated by Doppler echocardiography. The plasma levels of PTH, 25-hydroxyvitamin D (25-OHD), calcium and phosphate were measured. There were 102 (52%) patients with LVH after AVR. In univariate analyses, PTH blood level was associated with LV mass (LVMi) and LVH. After adjustment for other risk factors, elevated PTH remained associated with LVMi (p=0.003) and LVH (p=0.02). In turn, the blood levels of 25-OHD and the renal function (GFR) were independently and inversely related to the blood level of PTH.

Is parathyroid hormone associated with the LV mass after aortic valve replacement?

Asymmetric cell division (ACD) is a key process that allows different cell types to be generated at precisely defined times and positions. In Drosophila, neural precursor cells rely heavily on ACD to generate the different cell types in the nervous system. A conserved protein machinery that regulates ACD has been identified in Drosophila, but how this machinery acts to allow the establishment of differential cell fates is not entirely understood. To identify additional proteins required for ACD, we have carried out an in vivo live imaging RNAi screen for genes affecting the asymmetric segregation of Numb in Drosophila sensory organ precursor cells. We identify Banderuola (Bnd), an essential regulator of cell polarization, spindle orientation, and asymmetric protein localization in Drosophila neural precursor cells. Genetic and biochemical experiments show that Bnd acts together with the membrane-associated tumor suppressor Discs-large (Dlg) to establish antagonistic cortical domains during ACD. Inhibiting Bnd strongly enhances the dlg phenotype, causing massive brain tumors upon knockdown of both genes. Because the mammalian homologs of Bnd and Dlg are interacting as well, Bnd function might be conserved in vertebrates, and it might also regulate cell polarity in higher organisms.

Does the conserved discs-large binding partner Banderuola regulate asymmetric cell division in Drosophila?

The PINK1-Parkin pathway is known to play important roles in regulating mitochondria dynamics, motility, and quality control. Activation of this pathway can be triggered by a variety of cellular stress signals that cause mitochondrial damage. How this pathway senses different levels of mitochondrial damage and mediates cell fate decisions accordingly is incompletely understood. Here, we present evidence that PINK1-Parkin has both cytoprotective and proapoptotic functions. PINK1-Parkin operates as a molecular switch to dictate cell fate decisions in response to different cellular stressors. Cells exposed to severe and irreparable mitochondrial damage agents such as valinomycin can undergo PINK1-Parkin-dependent apoptosis. The proapoptotic response elicited by valinomycin is associated with the degradation of Mcl-1. PINK1 directly phosphorylates Parkin at Ser65 of its Ubl domain and triggers activation of its E3 ligase activity through an autocatalytic mechanism that amplifies its E3 ligase activity toward Mcl-1.

Does pINK1 trigger autocatalytic activation of Parkin to specify cell fate decisions?

A complex network of putative molecular interactions underlies the architecture and function of cell-matrix adhesions. Most of these interactions are implicated from coimmunoprecipitation studies using expressed components, but few have been demonstrated or characterized functionally in living cells. We introduce fluorescence fluctuation methods to determine, at high spatial and temporal resolution, "when" and "where" molecular complexes form and their stoichiometry in nascent adhesions (NAs). We focus on integrin-associated molecules implicated in integrin activation and in the integrin-actin linkage in NAs and show that these molecules form integrin-containing complexes hierarchically within the adhesion itself. Integrin and kindlin reside in a molecular complex as soon as adhesions are visible; talin, although also present early, associates with the integrin-kindlin complex only after NAs have formed and in response to myosin II activity. Furthermore, talin and vinculin association precedes the formation of the integrin-talin complex. Finally, α-actinin enters NAs periodically and in clusters that transiently associate with integrins. The absolute number and stoichiometry of these molecules varies among the molecules studied and changes as adhesions mature.

Do integrin-associated complexes form hierarchically with variable stoichiometry in nascent adhesions?

In humans, glucocorticoid-induced osteoporosis is the most common cause of medication-induced osteoporosis. Recent clinical data suggest that glucocorticoid therapy increases the risk of vertebral fractures within a short treatment period. Therefore, this study aimed at investigating vertebral bone in a rat model of glucocorticoid-induced postmenopausal osteoporosis. Fifty Sprague-Dawley rats were randomly assigned into three groups: 1) untreated controls, 2) Sham-operated group, and 3) ovariectomized rats treated with glucocorticoid (dexamethasone) for 3 months (3M) after recovery from bilateral ovariectomy. Osteoporotic bone status was determined by means of the gold standard dual energy X-ray absorptiometry (DEXA) scan. Vertebral bodies were examined using µCT, histological analysis, mRNA expression analysis, and biomechanical compression testing. Further systemic effects were studied biochemically using serum marker analysis. Dexamethasone treatment showed at 3M a significantly lower bone mineral density in ovariectomized rats compared to Sham-operated control (p < 0.0001) as analyzed in vivo by DEXA. Furthermore, Z scores reached levels of -5.7 in the spine indicating sever osteoporotic bone status. Biomechanical testing of compression stability indicated a lower functional competence (p < 0.0001) in the spine of treated rats. µCT analysis showed significant reduction of bone volume density (BV/TV%; p < 0.0001), significantly enhanced trabecular spacing (Tb.Sp; p < 0.0001) with less trabecular number (Tb.N; p < 0.001) and complete loss of trabecular structures in glucocorticoid-treated ovariectomized rats. Histological analysis by osteoblast and osteoclast activities reflected a higher bone catabolism reflected by osteoclast counts by TRAP (p < 0.019) and lower bone catabolism indicated by ALP-stained area (p < 0.035).Serum analysis showed a significant increase in osteocalcin (p < 0.0001), osteopontin (p < 0.01) and insulin (p < 0.001) at 3M. Expression analysis of molecular markers in the vertebral body revealed lower expression in tenascin C in the OVX-steroid animals at 3M.

Does short-term glucocorticoid treatment cause spinal osteoporosis in ovariectomized rats?

Adult acquired flatfoot deformity is characterized by midfoot abduction and collapse of the medial longitudinal arch. Lateral column lengthening osteotomies primarily correct the abduction deformity, but the effects of graft shape on deformity correction and forefoot loading are unclear. Therefore, the purpose of this study was to demonstrate the effect of graft shape and taper on deformity correction and forefoot loading mechanics in a cadaveric flatfoot model. Flatfoot deformity was simulated in 18 cadaveric specimens. A lateral column lengthening osteotomy was performed using a triangular, trapezoidal, and rectangular graft for each specimen. During each testing condition, talonavicular joint angles and forefoot plantar pressures were measured. Each graft shape corrected abduction and dorsiflexion deformity at the talonavicular joint. Coronal plane correction was affected by graft shape, and the less tapered trapezoidal and rectangular grafts overloaded the lateral forefoot compared to the intact condition. The more tapered triangular graft did not cause a lateral shift in forefoot pressures. Forefoot plantar pressures were strongly correlated with talonavicular abduction correction (R (2) = .473, P < .001).

Does graft shape affect midfoot correction and forefoot loading mechanics in lateral column lengthening osteotomies?

Frozen Shoulder Syndrome is a fibrosis of the shoulder joint capsule that is clinically associated with Dupuytren's disease, a fibrosis of the palmar fascia. Little is known about any commonalities in the pathophysiology of these connective tissue fibroses. β-catenin, a protein that transactivates gene expression, and levels of IGF2 mRNA, encoding insulin-like growth factor-II, are elevated in Dupuytren's disease. The aim of this study was to determine if correlating changes in β-catenin levels and IGF2 expression are evident in Frozen Shoulder Syndrome. Tissue from patients with Frozen Shoulder Syndrome and rotator cuff tear were obtained during shoulder arthroscopies. Total protein extracts were prepared from tissue aliquots and β-catenin immunoreactivity was assessed by Western immunoblotting. In parallel, primary fibroblasts were derived from these tissues and assessed for IGF2 expression by quantitative PCR. β-catenin levels were significantly increased in Frozen Shoulder Syndrome relative to rotator cuff tear when assessed by Western immunoblotting analyses. IGF2 mRNA levels were significantly increased in primary fibroblasts derived from frozen shoulder syndrome tissues relative to fibroblasts derived from rotator cuff tissues.

Are iGF2 expression and β-catenin levels increased in Frozen Shoulder Syndrome?

Vibrio cholerae is a globally dispersed pathogen that has evolved with humans for centuries, but also includes non-pathogenic environmental strains. Here, we identify the genomic variability underlying this remarkable persistence across the three major niche dimensions space, time, and habitat. Taking an innovative approach of genome-wide association applicable to microbial genomes (GWAS-M), we classify 274 complete V. cholerae genomes by niche, including 39 newly sequenced for this study with the Ion Torrent DNA-sequencing platform. Niche metadata were collected for each strain and analyzed together with comprehensive annotations of genetic and genomic attributes, including point mutations (single-nucleotide polymorphisms, SNPs), protein families, functions and prophages.

Does comparative genomics of 274 Vibrio cholerae genomes reveal mobile functions structuring three niche dimensions?

The study investigated the effect of supplementation with maltodextrin (CHO) alone or associated to caffeine during exercise in T2DM subjects. Pilot study, using eight subjects with T2DM, aged 55±10 years, received CHO (1 g/kg) or caffeine (1.5 mg/kg) alone or associated before exercise protocol. The exercise was executed at 40% heart rate (HR) reserve for 40 min, with 10-min recovery. Blood pressure (BP) and perceived exertion scale (Borg) were checked every 2 min. Blood glucose (BG) was checked every 10 min. For statistical analysis, ANOVA test was used and the value was considered statistically significant at p <0.05. The results showed that BP and HR did not change significantly among all treatments. Caffeine promoted a significant reduction in BG of 75 mg/dL (65%, p <0.05) during 40 min of exercise protocol compared to all groups.

Does caffeine modify blood glucose availability during prolonged low-intensity exercise in individuals with type-2 diabetes?

To examine the relationship between changes in objectively assessed sleep and global cognitive functioning from inpatient postacute rehabilitation to 6-month follow-up. Secondary analysis of two prospective, longitudinal studies. Inpatient rehabilitation units at a Veterans Affairs Medical Center. Older adults (mean age 73.8 ± 9.4) undergoing inpatient rehabilitation (n = 192). All participants completed 7 nights and days of ambulatory sleep monitoring using wrist actigraphy (yielding an estimate of nighttime wakefulness and daytime sleep) and the Mini-Mental State Examination (MMSE) during a postacute inpatient rehabilitation stay and 6 months after discharge. The 5-item Geriatric Depression Scale, Geriatric Pain Measure, and Cumulative Illness Rating Scale for Geriatrics were completed during inpatient rehabilitation. Growth curve modeling (controlling for baseline age, education, sex, body mass index, depression, pain, and comorbidity burden) revealed that individuals whose amount of daytime sleep decreased from inpatient postacute rehabilitation to 6-month follow-up also experienced improvements in MMSE score (β = -0.01, t(80 = -3.22, P = .002)). Change in nighttime wakefulness was not a significant predictor of change in MMSE score.

Is decrease in daytime sleeping associated with improvement in cognition after hospital discharge in older adults?

Studies have demonstrated the efficacy of metformin (MTF ) in reducing insulin resistance and N-acetyl cysteine (NAC) in inhibiting oxidative stress which are involved in the pathogenesis of polycystic ovarian syndrome (PCOS). We aimed to compare the effects of MTF and NAC combination on serum metabolite and hormonal levels during the course of ovulation induction in PCOS individual candidates of intracytoplasmic sperm injection (ICSI). In this prospective randomized clinical trial, placebo con- trolled pilot study, 80 patients of polycystic ovarian syndrome at the age of 25-35 years were divided into 4 groups (n=20): i. NAC=treated with N-acetyl cysteine (600 mg three times daily), ii. MTF=treated with metformin (500 mg three times daily), iii. MTF+NAC=treated with N-acetyl cysteine plus metformin (the offered doses) and iv. placebo (PLA). A total number of 20 patients (6 from MTF group, 4 from NAC group, 6 from MTF+NAC group and 4 from PLA group) were dropped of the study. The drugs were administrated from day 3 of menses of previous cycle until ovum pick-up. Serum levels of luteinizing hormone (LH), total testosterone, cholester- ol and triglyceride, insulin and leptin significantly reduced in the MTF and NAC groups compared to the placebo (p<0.01). But levels of LH, total testosterone, cholesterol and triglyceride had no significant reduction in the MTF+NAC groups compared to the placebo. The serum levels of malonyldialdehyde (MDA), insulin and leptin reduced significantly after treatment in the MTF+NAC group compared to the placebo (p<0.05).

Does co-Administration of Metformin and N-Acetyl Cysteine fail to Improve Clinical Manifestations in PCOS Individual Undergoing ICSI?

Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. PATIENTS with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement. To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism. An open-label nonrandomized study at the National Institutes of Health. Thirty-one patients with CGL (ages 4.3 to 46.7 y). Metreleptin (0.06 to 0.24 mg/kg/d) for 6 months to 11 years. BMC was assessed by dual-energy x-ray absorptiometry. SD scores (SDS) for BMC were calculated based on height, race, sex, and age using population normative data. Calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at baseline and follow-up. At baseline, patients demonstrated significantly increased total body less head BMC (mean SDS, 1.8 ± 0.7), height (mean SDS, 1.3 ± 1.3), and lean mass index, defined as lean body mass per height squared (mean SDS, 1.5 ± 0.83), vs population normative data. No change in total body less head BMC was observed after metreleptin. Lean mass index decreased with metreleptin. Serum calcium decreased with metreleptin, but remained within normal limits. No changes were seen in phosphorus, PTH, or vitamin D.

Is bone mineral content in patients with congenital generalized lipodystrophy unaffected by metreleptin replacement therapy?

p16(INK4a) Is overexpressed in almost all precancerous and carcinomatous lesions of the uterine cervix, secondary to interference between high-risk human papillomaviruses (hr-HPVs) and the retinoblastoma gene product. Overexpression of p16(INK4a) has also been identified in patients with high-grade urothelial lesions, both cytologically and histologically. However, the etiological role of HPV has not been documented except in inverted papillomas, low-grade bladder tumors, and younger patients. We therefore attempted to verify if HPV DNA was detectable in p16(INK4a) -positive urothelial tumors. A total of 90 urinary cytology samples (33 negative/low-grade cases and 57 high-grade proliferations) were analyzed for p16(INK4a) and HPV DNA. HPV genotyping was performed by polymerase chain reaction using a low-density DNA microarray enabling the detection of 35 HPVs. A reasoned approach combining tissue genotyping and in situ hybridization (ISH) for hr-HPVs was used in patients with urinary HPV. Low-risk HPV (HPV-84) and hr-HPVs (HPV-16, -31, and -70) were detected. The prevalence of hr-HPVs in the urine was low: 5 of 82 patients (6.1%) and only 4 of 50 patients (8.0%) with high-grade urothelial malignancy. p16(INK4a) overexpression was noted in 49 high-grade samples (85.9%). In patients with p16(INK4a) -positive tumor cells and hr-HPV in the urine, HPV genotyping and ISH for hr-HPVs were negative in matched tissue sections.

Is p16 ( INK4a ) overexpression linked to oncogenic human papillomaviruses in patients with high-grade urothelial cancer cells?

To assess disability more efficiently with less burden on the patient, the National Institutes of Health has developed the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function-an instrument based on item response theory and using computer adaptive testing (CAT). Initially, upper and lower extremity disabilities were not separated and we were curious if the PROMIS Physical Function CAT could measure upper extremity disability and the Quick Disability of Arm, Shoulder and Hand (QuickDASH). We aimed to find correlation between the PROMIS Physical Function and the QuickDASH questionnaires in patients with upper extremity illness. Secondarily, we addressed whether the PROMIS Physical Function and QuickDASH correlate with the PROMIS Depression CAT and PROMIS Pain Interference CAT instruments. Finally, we assessed factors associated with QuickDASH and PROMIS Physical Function in multivariable analysis. A cohort of 93 outpatients with upper extremity illnesses completed the QuickDASH and three PROMIS CAT questionnaires: Physical Function, Pain Interference, and Depression. Pain intensity was measured with an 11-point ordinal measure (0-10 numeric rating scale). Correlation between PROMIS Physical Function and the QuickDASH was assessed. Factors that correlated with the PROMIS Physical Function and QuickDASH were assessed in multivariable regression analysis after initial bivariate analysis. There was a moderate correlation between the PROMIS Physical Function and the QuickDASH questionnaire (r=-0.55, p<0.001). Greater disability as measured with the PROMIS and QuickDASH correlated most strongly with PROMIS Depression (r=-0.35, p<0.001 and r=0.34, p<0.001 respectively) and Pain Interference (r=-0.51, p<0.001 and r=0.74, p<0.001 respectively). The factors accounting for the variability in PROMIS scores are comparable to those for the QuickDASH except that the PROMIS Physical Function is influenced by other pain conditions while the QuickDASH is not.

Does the PROMIS physical function correlate with the QuickDASH in patients with upper extremity illness?

This study was conducted to quantify the effect of multidisciplinary care (MDC) on amputation-free survival (AFS) and wound healing within a chronic critical limb ischemia (CLI) population. We performed a retrospective, single-center cohort study of consecutive CLI patients presenting to the Vascular Surgery Service. Patients who received initial and follow-up wound care from the MDC were compared with patients who received standard wound care (SWC). The MDC team consisted of vascular, plastic, and podiatric surgeons who jointly managed wound care and directed any other consults or services as deemed necessary. SWC consisted of an inconsistent mix of providers without a defined manager, including nurses, wound care midlevel providers, general surgeons, internists, or the patients themselves. The referring physician determined the allocation of patients. The primary outcome variable was AFS, with a secondary evaluation of wound healing. The effects of baseline demographics, comorbid medical conditions, laboratory values, ischemic lesion severity and location, Rutherford classification, and participation in MDC were assessed. Significant univariate predictors (P < .10) of AFS were entered into a multivariate Cox regression model and assessed at an α = .05. Between August 2010 and June 2012, 146 CLI patients (91 male [63%]) were evaluated by the Vascular Surgery Service and were followed up for a median of 539 days (interquartile range 314-679 days). Ischemic tissue loss was present in 85 patients (38 at Rutherford category 5, and 47 at Rutherford category 6). Within this cohort, 51 (60%) had MDC, and 34 (40%) had SWC. Fifty-eight patients (68%) underwent revascularization (open in 17, endovascular in 35, and hybrid in 6), 14 (8%) were managed with primary major amputation, and 13 (15%) declined revascularization. AFS was superior for patients in the MDC arm vs the SWC arm (593.3 ± 53.5 days vs 281.0 ± 38.2 days; log-rank, P = .02). Wound-healing times favored the MDC arm over the SWC arm (444.5 ± 33.2 days vs 625.2 ± 126.5 days), although this was not statistically significant (log-rank, P = .74). Multivariate modelling revealed that independent predictors of major amputation or death, or both, were nonrevascularized patients (hazard ratio [HR], 3.76; 95% confidence interval [CI], 1.78-8.02; χ(2), P < .01), treatment by SWC (HR, 2.664; 95% CI, 1.23-5.77; χ(2), P = .012), and baseline nonambulatory status (HR, 1.89; 95% CI, 1.17-2.85; χ(2), P < .01).

Does multidisciplinary care improve amputation-free survival in patients with chronic critical limb ischemia?

To determine if adolescents with unilateral hearing loss (UHL) demonstrate worse language skills than their siblings with normal hearing (NH). Case-control study of 12-17-year-old adolescents with UHL (20 cases) compared with sibling controls with NH (13 controls). Scores on the oral portion of the Oral and Written Language Scales (OWLS) and the Clinical Evaluation of Language Fundamentals (CELF) were the primary outcome measure. Wechsler's Abbreviated Scales of Intelligence (WASI) scores were also used as an outcome measure. Adolescents with UHL demonstrated worse overall and expressive language scores than controls, (98 vs. 114, P=0.001; 100 vs. 114, P=0.006) and had significantly lower full scale (98 vs. 112, P=0.017), verbal (101 vs. 113, P=0.032), and performance IQ (95 vs. 107, P=0.037).

Is unilateral hearing loss associated with a negative effect on language scores in adolescents?

A high catabolic rate characterizes the acute phase of critical illness. Guidelines recommend an early nutritional support, regardless of the previous nutritional status. We aimed to assess whether the nutritional status of patients, which was defined by the body mass index (BMI) at admission in an intensive care unit (ICU), affected the time of nutritional support initiation. We conducted a cohort study that reported a retrospective analysis of a multicenter ICU database (OUTCOMEREA) by using data prospectively entered from January 1997 to October 2012. Patients who needed orotracheal intubation within the first 72 h and >3 d were included. Data from 3257 ICU stays were analyzed. The delay before feeding was different according to BMI groups (P = 0.035). The delay was longer in obese patients [BMI (in kg/m²) ≥30; n = 663] than in other patients with either low weight (BMI <20; n = 501), normal weight (BMI ≥20 and <25; n = 1135), or overweight (BMI ≥25 and <30; n = 958). The association between nutritional status and a delay in nutrition initiation was independent of potential confounding factors such as age, sex, and diabetes or other chronic diseases. In comparison with normal weight, the adjusted RR (95% CI) associated with a delayed nutrition initiation was 0.92 (0.86, 0.98) for patients with low weight, 1.00 (0.94, 1.05) for overweight patients, and 1.06 (1.00, 1.12) for obese patients (P = 0.004).

Is initiation of nutritional support delayed in critically ill obese patients : a multicenter cohort study?

To study the effects of Gambogenic acid (GNA) on the growth of human gastric carcinoma cell line MGC-803 and its underlying mechanisms. MTT assay was used to measure the cell viability. Apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) were detected using flow cytometry method. Among them, Annexin V-FITC/PI double staining was employed in the analysis of apoptosis, Rh123 in analyzing MMP and H2DCFDA in analyzing ROS formation. P53 expression was confirmed by Western blot. 4.0 micromol/L GNA inhibited MGC-803 cells growth in a time dependent manner from 24 to 48 h. At the concentration range from 1.0 to 12.0 micromol/L, the inhibitory effect was in a concentration dependent manner. After treatment with 4.0 micromol/L GNA for 48 h, apoptosis was obviously observed as assayed by Annexin V-FITC/PI staining. Importantly, MMP was decreased and ROS formation was increased following GNA treatment. Additionally, P53 expression was up-regulated following 4.0 micromol/ L GNA treatment in a time dependent manner.

Does [ Gambogenic acid induce mitochondria-dependent apoptosis in human gastric carcinoma cell line ]?

Cigarette smoking is correlated with other risk factors for gout such as adiposity and alcohol intake. The goal of this study was to study the direction and magnitude of association between cigarette smoking and risk for gout. We analysed 54-year follow-up data (1948-2002) for 2279 men and 2785 women who were gout-free at their first assessment as a part of the Framingham Heart Study. Using Cox proportional hazards models we estimated the association between cigarette smoking and incident gout among men and women separately after adjusting for age, BMI, alcohol intake, hypertension, kidney disease and diabetes. There were 399 incident cases (249 men and 150 women) of gout over 151 058 person-years of observation. Incidence rates of gout per 1000 person-years for smokers and non-smokers were 2.13 (95% CI 1.79, 2.53) and 3.04 (95% CI 2.70, 3.42), respectively. In multivariable Cox models, cigarette smoking was associated with gout with a hazard ratio of 0.76 (95% CI 0.59, 0.98) overall, 0.68 (95% CI 0.49, 0.93) among men and 0.92 (95% CI 0.60, 1.41) among women. Lower risk for smokers was evident among all obesity categories, but not among women. Sensitivity analysis suggested that the magnitude of the true odds ratio might be lower than our calculations.

Is cigarette smoking associated with a reduction in the risk of incident gout : results from the Framingham Heart Study original cohort?

Comorbidity among childhood mental health symptoms is common in clinical and community samples and should be accounted for when investigating etiology. We therefore aimed to uncover latent classes of mental health symptoms in middle childhood in a community sample, and to determine the latent genetic and environmental influences on those classes. The sample comprised representative cohorts of twins. A questionnaire-based assessment of mental health symptoms was used in latent class analyses. Data on 3223 twins (1578 boys and 1645 girls) with a mean age of 7.5 years were analyzed. The sample was predominantly non-Hispanic Caucasian (92.1%). Latent class models delineated groups of children according to symptom profiles--not necessarily clinical groups but groups representing the general population, most with scores in the normative range. The best-fitting models suggested 9 classes for both girls and boys. Eight of the classes were very similar across sexes; these classes ranged from a "Low Symptom" class to a "Moderately Internalizing & Severely Externalizing" class. In addition, a "Moderately Anxious" class was identified for girls but not boys, and a "Severely Impulsive & Inattentive" class was identified for boys but not girls. Sex-combined analyses implicated moderate genetic influences for all classes. Shared environmental influences were moderate for the "Low Symptom" and "Moderately Internalizing & Severely Externalizing" classes, and small to zero for other classes.

Does relative influence of genetics and shared environment on child mental health symptoms depend on comorbidity?

Gestational diabetes mellitus (GDM) may be an expression of early metabolic syndrome. It is unknown whether weight and/or glucose parameters assessed at GDM pregnancies predict the risk of metabolic syndrome at the early postpartum period. A group of women with GDM (N=1512) was evaluated at 3-11 months postpartum. Incident cases of diabetes were excluded. Antenatal measurements of GDM severity, third-trimester average glycated hemoglobin levels, prepregnancy body mass index (BMI), and increased gestational weight gain were considered. The predictive capability of these factors for postpartum metabolic syndrome was estimated. The prevalence of postpartum metabolic syndrome was 10.9%. The three most common features of metabolic syndrome were low levels of high-density lipoprotein cholesterol (31.2%), high fasting glucose values (23.5%), and a high waist circumference (22.8%). The main predictors of metabolic syndrome were overweight or obesity prepregnancy and high antenatal fasting glycemia. This analysis was adjusted for family history of diabetes, prior GDM, dyslipidemia before pregnancy, chronic arterial hypertension, age, and smoking. The model area 95% confidence interval under the receiver operating characteristic curve was 0.87 (0.84-0.90) for metabolic syndrome presence. The risk for metabolic syndrome was progressively increased as risk factors were added (P<0.001 for trend). When obesity and high fasting glycemia were combined, a multiplied effect ensued.

Are prepregnancy body mass index and prenatal fasting glucose effective predictors of early postpartum metabolic syndrome in Spanish mothers with gestational diabetes?

A subset of human hepatocellular carcinomas (HCC) exhibit mutations of β-catenin gene CTNNB1 and overexpress Glutamine synthetase (GS). The CTNNB1-mutated HCC cell line HepG2 is sensitive to glutamine starvation induced in vitro with the antileukemic drug Crisantaspase and the GS inhibitor methionine-L-sulfoximine (MSO). Immunodeficient mice with subcutaneous xenografts of the CTNNB1-mutated HCC cell lines HepG2 and HC-AFW1 were treated with Crisantaspase and/or MSO, and tumour growth was monitored. At the end of treatment, tumour weight and histology were assessed. Serum and tissue amino acids were determined by HPLC. Gene and protein expression were estimated with RT-PCR and western blot and GS activity with a colorimetric method. mTOR activity was evaluated from the phosphorylation of p70S6K1. Crisantaspase and MSO depleted serum glutamine, lowered glutamine in liver and tumour tissue, and inhibited liver GS activity. HepG2 tumour growth was significantly reduced by either Crisantaspase or MSO, and completely suppressed by the combined treatment. The combined treatment was also effective against xenografts of the HC-AFW1 cell line, which is Crisantaspase resistant in vitro.

Does glutamine depletion by crisantaspase hinder the growth of human hepatocellular carcinoma xenografts?

GRAF is a recognized tumor suppressor gene that was found inactivated in AML. However, the prognostic role of a GRAF transcript has not been studied in patients with AML. In this study, we investigated the expression of the GRAF transcript by real time quantitative PCR in 60 AML patients and 30 healthy age and sex matched controls. GRAF expression was significantly lower in patients with AML when compared to controls (P=0.008). There were no significant differences in clinical features, FAB subtypes and cytogenetic risk subgroups between patients with high and low GRAF expression levels. Kaplan-Meier analysis showed that patients with high GRAF expression had longer overall survival (OS). Multivariate analysis revealed that, besides WBC count, GRAF expression was also an independent prognostic factor for AML.

Is high expression of GTPase regulator associated with the focal adhesion kinase ( GRAF ) a favorable prognostic factor in acute myeloid leukemia?

The clinical trial design for primary progressive multiple sclerosis (PPMS) requires understanding of disability progression in modern patient cohorts. The objective of this paper is to characterize demographic and clinical characteristics of PPMS and assess rate of disability progression. We studied PPMS (n = 73) and relapsing-onset MS (ROMS) patients (n = 1541) enrolled in CLIMB, a longitudinal study of MS patients at the Brigham and Women's Hospital (Boston, MA). Disability progression for each group was compared using interval-censored survival analysis and time to six-month sustained progression. The PP group had a 1.09:1 male:female ratio compared to 1:2.89 for the RO group and greater mean age of onset (PP: 44.4±9.6; RO: 32.7±9.9; p < 0.0001). Motor symptoms at onset and first symptoms localized to spinal cord were each strongly associated with PPMS (p < 0.001). Median time from onset to EDSS 6.0 was faster in PPMS (p < 0.001). PPMS patients progressed faster to EDSS 3 (p < 0.001) and from EDSS 3 to 6 (p < 0.001). Median time to sustained progression in the PP group was 4.85 years (95% CI 2.83-8.35), significantly faster than the RO group (p < 0.001).

Does progression rates and sample size estimate for PPMS based on the CLIMB study population?

The aim of this study was to investigate whether microelectronic wear-time documentation can contribute to individualized orthodontic management. The wear times and behaviors of 281 patients undergoing orthodontic treatment with removable appliances were quantified and analyzed using the TheraMon microelectronic system (Sales Agency Gschladt, Hargelsberg, Austria) over a 6-month treatment period. The 281 study participants wore their removable appliances for a median of 9.0 hours per day, compared with the 12 to 15 hours per day prescribed. Wear behavior was variable and heterogeneous in patients with almost identical median wear times, with fluctuating and numerous zero wear-time periods observed.

Does microelectronic wear-time documentation of removable orthodontic devices detect heterogeneous wear behavior and individualizes treatment planning?

Urokinase (uPA) modulates cellular and extracellular matrix responses within the microenvironment of the vessel wall and has been shown to activate the epidermal growth factor receptor (EGFR). This study examines the role of the protease domain of uPA during EGFR activation in human vascular smooth muscle cells (VSMC). Human coronary VSMC were cultured in vitro. Assays of cell proliferation and EGFR phosphorylation were examined in response to the carboxyterminal fragment of uPA (CTF) in the presence and absence of the plasmin, metalloprotease and a disintegrin and metalloproteinase (ADAM) inhibitors, heparin-bound epidermal growth factor (HB-EGF), and EGFR inhibitors, and small interfering RNA to EGFR and ADAMs. CTF produced a dose-dependent increase in DNA synthesis and cell proliferation in human VSMC, which was blocked in a dose-dependent manner by both plasmin inhibitors and the EGFR inhibitor, AG1478. CTF induced time-dependent EGFR phosphorylation, which was blocked by inhibitors of plasmin and metalloproteinases activity. The presence of urokinase plasminogen activator receptor was not required. Inhibition of ADAM-10 and -12, and of HB-EGF blocked EGFR activation in response to CTF. CTF-mediated activation of EGFR was mediated through Gβγ, src, and NAD(P)H oxidase.

Does protease-mediated human smooth muscle cell proliferation by urokinase require epidermal growth factor receptor transactivation by triple membrane signaling?

The aim of this study was to evaluate and compare microwave disinfection with chemical disinfection of dental gypsum casts. A total of 120 casts were prepared from a silicone mold using Type III dental stone. Of the 120 casts, 60 casts were contaminated with 1 ml suspension of Staphylococcus aureus and 60 casts were contaminated with 1 ml suspension of Pseudomonas aeruginosa. Then, the casts were disinfected with microwave irradiation and chemical disinfection using the microwave oven and 0.5% sodium hypochlorite. Bacteriologic procedures were performed; the cfu/ml for each cast was calculated as a weighted mean. The results were analyzed using Kruskal-Wallis test and Mann-Whitney test. The untreated casts showed Brain heart infusion broth counts of 106 log cfu/ml compared to irradiated and chemically disinfected casts, in which 105 log reduction of cfu/ml was seen. These results satisfied the requirements of current infection control guidelines for the dental laboratory. The results obtained for chemical disinfection were in equivalence with microwave disinfection.

Does evaluation and comparison of high-level microwave oven disinfection with chemical disinfection of dental gypsum cast?

Neural crest stem cells derived from the boundary cap (bNCSCs), markedly promote survival, proliferation and function of insulin producing β-cells in vitro and in vivo after coculture/transplantation with pancreatic islets [ 1, 2 ]. Recently, we have shown that beneficial effects on β-cells require cadherin contacts between bNCSCs and β-cells [ 3, 4 ]. Here we investigated whether hair follicle (HF) NCSCs, a potential source for human allogeneic transplantation, exert similar positive effects on β-cells. We established cocultures of HF-NCSCs or bNCSCs from mice expressing enhanced green fluorescent protein together with pancreatic islets from DxRed expressing mice or NMRI mice and compared their migration towards islet cells and effect on proliferation of β-cells as well as intracellular relations between NCSCs and islets using qRT-PCR analysis and immunohistochemistry. Whereas both types of NCSCs migrated extensively in the presence of islets, only bNCSCs demonstrated directed migration toward islets, induced β-cell proliferation and increased the presence of cadherin at the junctions between bNCSCs and β-cells. Even in direct contact between β-cells and HF-NCSCs, no cadherin expression was detected.

Do neural crest stem cells from hair follicles and boundary cap have different effects on pancreatic islets in vitro?

To examine the association between breastfeeding pattern and growth in the first year of life. A cross-sectional survey was carried out on 349 mothers with infants <12 months in a rural and a semi-urban community in Mangochi district, Malawi. Data on socio-demographic characteristics, infant weight, length and feeding patterns since birth were collected. Multivariate linear regression was performed to test the association between feeding pattern and infant anthropometric status. Exclusive breastfeeding (EBF) until 6 months was practised by 13.1% semi-urban and 1.3% rural mothers. No infant was exclusively breastfed beyond 6 months. Breastfeeding was continued among all infants who had stopped EBF. Among infants 6-12 months of age, duration of EBF during the first 6 months was positively associated with length-for-age Z-score (LAZ) (regression coefficient=0.19, 95% confidence interval: 0.06, 0.31) in a model adjusted for socio-demographic factors. Urban residence and female gender yielded positive associations in the same model. The model explained 27% of the variation in LAZ. Among infants <6 months, duration of EBF was not significantly associated with LAZ, but being female and urban residence yielded positive associations. Breastfeeding patterns were not associated with weight-for-age Z-score (WAZ) or weight-for-height Z-score (WLZ) either in the 0-6-month or in the 6-12-month group. Birth outside a health facility was negatively associated with WAZ and WLZ in the older group.

Is exclusive breastfeeding duration during the first 6 months of life positively associated with length-for-age among infants 6-12 months old , in Mangochi district , Malawi?

Monkey 20α-hydroxysteroid dehydrogenase (20α-HSD) is a catabolic enzyme responsible for converting progesterone into biologically inactive 20α-hydroxyprogesterone, thereby playing a key role in the estrous cycle or pregnancy and allowing ovulation and parturition to occur in most mammalian animals. Monkey 20α-HSD was highly abundant in ovarian and placental tissues during the pre-ovulation and pre-parturition phase and was primarily localized in the syncytiotrophoblast of the placenta. In this study, we focused on the molecular characterization of the monkey 20α-HSD promoter region by conducting reporter assays in Chinese hamster ovary (CHO) K1 cells. A reporter assay using constructs of various lengths of the 5'-flanking region (-890-Luc, -513-Luc, -306-Luc, -273-Luc, and -70-Luc) revealed that a region corresponding to the activator protein 1 (Ap-1) located between -281 and -274 bp was essential for the transcriptional activity. Absence of the Ap-1 site in -273-Luc dramatically decreased the transcription levels to the control levels. When the reporter constructs were co-transfected with Ap-1 (Jun) and specificity protein (Sp-1) genes, the transcription activities of the constructs increased with the exception of -273 and -70, while that of the double construct was reduced compared to that of Ap-1 alone. Furthermore, mutational analysis demonstrated that a putative Ap-1 site played an important role in the expression of the reporter gene. These findings were confirmed by EMSA examining the interactions of the protein Ap-1 in a nuclear extract from CHO-K1 cells and the expression levels of the Ap-1 transcription factor in pre-parturition placenta and CHO-K1 cells. Although mut-1 and mut-2 of Ap-1 bound with nuclear extracts from CHO-K1 cells, the transcriptional activity of mut-3 was almost completely suppressed.

Does the transcription factor Ap-1 regulate monkey 20α-hydroxysteroid dehydrogenase promoter activity in CHO cells?

Anxiety disorders increase risk of future cardiovascular disease (CVD) and mortality, even after controlling for confounds including smoking, lifestyle, and socioeconomic status, and irrespective of a history of medical disorders. While impaired vagal function, indicated by reductions in heart rate variability (HRV), may be one mechanism linking anxiety disorders to CVD, prior studies have reported inconsistent findings highlighting the need for meta-analysis. Studies comparing resting-state HRV recordings in patients with an anxiety disorder as a primary diagnosis and healthy controls were considered for meta-analysis. Meta-analyses were based on 36 articles, including 2086 patients with an anxiety disorder and 2294 controls. Overall, anxiety disorders were characterized by lower HRV [high frequency (HF): Hedges' g = -0.29. 95% CI: -0.41 to -0.17, p < 0.001; time domain: Hedges' g = -0.45, 95% CI: -0.57 to -0.33, p < 0.001] than controls. Panic disorder (n = 447), post-traumatic stress disorder (n = 192), generalized anxiety disorder (n = 68), and social anxiety disorder (n = 90), but not obsessive-compulsive disorder (n = 40), displayed reductions in HF HRV relative to controls (all ps < 0.001).

Are anxiety Disorders Associated with Reduced Heart Rate Variability : A Meta-Analysis?

Indication for rotating hinge (RH) total knee arthroplasty (TKA) includes primary and revision cases, with contradictory results. The aim of this study was to report prospective early results of a new modular rotating hinge TKA (EnduRo). For this implant several new design features and a new bearing material (carbon-fiber reinforced poly-ether-ether-ketone) have been developed. Furthermore, we tried to establish a new classification of failure modes for revision TKA. 152 EnduRo rotating-hinge prostheses were implanted in two centers. In 90 patients a primary implantation has been performed and 62 patients were revision cases. Knee Society Score (KSS), Western Ontario and McMaster Osteoarthritis Index (WOMAC), Oxford Knee Score (OKS), and Range of motion (ROM) were assessed before surgery, 3 months postoperatively, 12 months postoperatively, and annually thereafter. We defined 3 types of complications: Type 1, infection; type 2, periprosthetic complications; type 3, implant failures. KSS, WOMAC, OKS, and ROM revealed significant improvements between the preoperative and the follow-up investigations. There were 14 complications (9.2%) leading to revision surgery, predominantly type 2.

Do early results of a new rotating hinge knee implant?

To investigate the effects of Artemisia lavandulaefolia essential oil on apoptosis and necrosis of HeLa cells. Cell viability was assayed using MTT method. The morphological and structure alterations in HeLa cells were observed by microscopy. Furthermore, cell apoptosis was measured by DNA Ladder and flow cytometry. DNA damage was measured by comet assay, and the protein expression was examined by Western blot analysis. MTT assay displayed essential oil from Artemisia lavandulaefolia could inhibit the proliferation of HeLa cells in a dose-dependent manner. After treated with essential oil of Artemisia lavadulaefolia for 24 h, HeLa cells in 100 and 200 microg/mL experiment groups exhibited the typical morphology changes of undergoing apoptosis, such as cell shrinkage and nucleus chromatin condensed. However, the cells in the 400 microg/mL group showed the necrotic morphology changes including cytomembrane rupture and cytoplasm spillover. In addition, DNA Ladder could be demonstrated by DNA electrophoresis in each experiment group. Apoptosis peak was also evident in flow cytometry in each experiment group. After treating the HeLa cells with essential oil of Artemisia lavadulaefolia for 6 h, comet tail was detected by comet assay. Moreover, western blotting analysis showed that caspase-3 was activated and the cleavage of PARP was inactivated.

Does [ Essential oil from Artemisia lavandulaefolia induce apoptosis and necrosis of HeLa cells ]?

To investigate the effect of targeted antiosteosarcoma methotrexate-bisphosphonate conjugate on growth inhibition and apoptosis in human osteosarcoma MG-63 cells. MG-63 cells were treated with various concentrations of methotrexate-bisphosphonate conjugate and apoptosis was monitored via an MTT assay, cell morphology, TUNEL assay and flow cytometry analysis. The survival rate of MG-63 cells treated for 24 to 96 hours with 2000 mg/ml or more of methotrexate-bisphosphonate conjugate decreased significantly. Cells treated with conjugate showed typical apoptotic features using inverted phase contrast microscopy and fluorescence staining, and the majority of cells demonstrated a positive result in the TUNEL assay. Karyopyknosis and crescent aggregation of chromatin were observed in conjugate-treated cells by electron microscopy. Flow cytometry of MG-63 cells treated with methotrexate-bisphosphonate conjugate showed a time and dose-dependent increase in apoptosis (p < 0.05).

Does targeted antiosteosarcoma methotrexate-bisphosphonate conjugate induce apoptosis of osteosarcoma cells in vitro?

To prove that DNA damage, intracellular reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential (MMP) are contributing factors for the inhibition of cell proliferation induced by doxorubicin (DOX) administration combined with microbubble-assisted low-level therapeutic ultrasound (US) in K562 cells. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay was adopted to examine cytotoxicity of different treatments. Changes on apoptosis and necrosis rates, DNA fragmentation, intracellular reactive oxygen species production, mitochondrial membrane potential, cellular membrane permeability and DOX-uptake were analysed by flow cytometry. Nuclear morphology changes were observed under a fluorescence microscope. Ultrasonic cavitation was measured by spectrofluorimetry. Under optimal conditions, MB-US significantly aggravated DOX-induced K562 cell death, especially necrosis, when compared with either monotherapy. Synergistic potentiation on DNA damage, ROS generation and MMP loss were observed. Ultrasonic cavitation effects, plasma membrane permeabilization and DOX-uptake were notably improved after MB-US exposure.

Does activation of microbubbles by low-level therapeutic ultrasound enhance the antitumor effects of doxorubicin?

Intact surface active agent (surfactant) composed of surfactant-associated proteins (SPs) and lipids is necessary for respiration and prevents alveoli from collapsing. CD26, a transmembrane glycoprotein exerting dipeptidyl peptidase activity (DPP4), highly expressed in lung parenchyma, is involved in inflammatory processes. A pharmacological inhibition of DPP4 influenced not only the inflammation but also elevated the SPs. Thus, DPP4 inhibitors may be a novel drug for treatment of diseases with surfactant deficiency. Therefore, we tested firstly the hypothesis that DPP4 inhibitors increase the expression of SPs in healthy rats. SP mRNA and protein expression were determined different times after nebulization of aerosolized DPP4 inhibitors [L-isoleucine-thiazolidide (L-Ile-Thia), L-valine-pyrrolidide (L-Val-Pyrr)], budesonide, saline or stereoisomers. Compared with negative controls (1) L-Ile-Thia as well as budesonide led to a significant higher and L-Val-Pyrr had the tendency to a significant higher expression of SP-A mRNA 6 h after nebulization, (2) the expression of SP-D mRNA increased significantly 6 h after nebulization with L-Ile-Thia and 3 and 6 h after nebulization with Val-pyrr, (3) SP-B mRNA levels showed significantly higher values 3 and 6 h after nebulization with L-Val-Pyrr, (4) protein levels of SP-A, SP-B and SP-C were elevated significantly 6 h after nebulization with L-Val-Pyrr as well as with budesonide, and (5) phospholipids were also increased in response to DPP4 inhibition; the minimal surface tension was comparable.

Do dPP4 inhibitors increase differentially the expression of surfactant proteins in Fischer 344 rats?

Recently, there has been increasing concern about adverse health effects of exposure to desert dust events. However, the association between dust and the incidence of ischemic heart diseases is unknown. The aim of the present study was to elucidate whether Asian dust (AD), a windblown sand dust originating from mineral soil in China and Mongolia, is associated with the incidence of acute myocardial infarction (AMI). We investigated the data regarding hospitalization because of AMI among 3068 consecutive patients from 4 AMI centers in Fukuoka, Japan, and data for AD from April 2003 to December 2010. We applied a time-stratified case-crossover design to examine the association between AD and the incidence of AMI. Using a conditional logistic regression analysis, we estimated the odds ratios of AMI associated with AD after controlling for ambient temperature and relative humidity. The occurrence of AD events 0 to 4 days before the day of admission was significantly associated with the incidence of AMI. In particular, the occurrence of AD 4 days before admission was significantly associated with the onset of AMI.

Is desert dust a risk factor for the incidence of acute myocardial infarction in Western Japan?

Photodynamic therapy with aminolevulinic acid (ALA-PDT) is effective therapy for acne vulgaris; however, relatively strong side effects limit its wide usage. We have previously demonstrated that ALA-induced protoporphyrin IX distribution with lower concentrations and shorter contact time of ALA resulted in focused damage in sebaceous glands in vivo. We have formulated a protocol for ALA-PDT using 5% ALA with 2 hours contact time. The objective of this study was to establish the effectiveness and side effect profile of the new protocol in humans. Eleven Japanese patients (Fitzpatrick's skin type III - IV, mean age 23.7±7.2) with facial acne received topical application of 5% ALA for 2 hours with subsequent illumination by a broadband light (600 - 1100 nm, 15J/cm(2), 60 mW/cm(2)). Subjects were evaluated prior to the procedure, 1 month, and 3 months after the treatment by a blinded dermatologist using the global acne grading system (GAGS). Side effects were monitored through the treatment period. The mean GAGS score decreased from 22.1±3.8 at baseline to 19.4 at 1 month, and to 16.3 at 3 months after PDT (P<0.05). Ten of eleven patients experienced local side effects, such as erythema, which were of minimal to mild severity. However, most side effects were of minimal to mild severity, and all of them resolved within several days without post inflammatory hyper pigmentation.

Is photodynamic Therapy with 5 % δ-Aminolevulinic Acid Safe and Effective Treatment of Acne Vulgaris in Japanese Patients?

To investigate the risk of adhesions after laparoscopic myomectomy (LM). To establish the percentage of adhesions, their kind, situation and magnitude. For the period form June 2011 to November 2013 totally 81 patients were operated by LM. In the study only patients with intramural leymyomas bigger than 5 sm were included. For this period 14 patients had second-look because of the need of another operation--LS or Ceasarean section. 22 myoma incisions were checked. We established 35.7% adhesions per patient. After LM adnexas were engaged in 14.2%.

Is [ `` Second look '' after laparoscopic myomectomy -- that a prevention of postoperative adhesions ]?

Regenerative endodontics aims to re-establish a functional pulp-dentin complex. First, the root canal system is disinfected primarily by irrigants and medicaments. Triple antibiotic paste (TAP), a commonly used intracanal medicament, has been shown to be directly toxic to stem cells at concentrations greater than 0.1 g/mL. Thus, its complete removal is a crucial step in regenerative endodontic procedures. We hypothesized that currently used irrigation techniques do not completely remove TAP from root canal system. TAP was radiolabeled by the incorporation of I(125), and calcium hydroxide (Ultracal; Ultradent, South Jordan, UT) was radiolabeled with Ca(45). The intracanal medicaments were placed into standardized human root segments and incubated for 28 days at 37°C. Then, canals were irrigated with EndoActivator (Dentsply, Tulsa, OK), passive ultrasonic irrigation, EndoVac (SybronEndo, Coppell, TX), or a syringe/Max-i-Probe needle (Dentsply Rinn, Elgin, IL) using a standardized irrigation protocol in a closed system. Radioactivity levels (counts per minute values) were measured for each tooth before and after the irrigation protocols. Furthermore, the canals were sequentially enlarged and dentin samples collected and evaluated for radioactivity. Data were analyzed with analysis of variance and Bonferroni post hoc testing (P < .05). Approximately 88% of the TAP was retained in the root canal system regardless of the irrigation technique used (no difference among groups). Furthermore, approximately 50% of the radiolabeled TAP was present circumferentially up to 350 μm within the dentin. Conversely, up to 98% of the radiolabeled intracanal calcium hydroxide was removed, and most residual medicament was found present in the initial 50 μm of dentin.

Do evaluation of triple antibiotic paste removal by different irrigation procedures?

In Europe, extracts of Equisetum arvense (common horsetail) have a long tradition in the treatment of inflammatory disorders. To understand the molecular basis for its use, we investigated the immunomodulatory capacity of a standardized commercially available common horsetail extract on human primary lymphocyte function in vitro. The standardized extract of Equisetum arvense was phytochemically characterized. Effects on proliferation, viability and activity of mitogen-activated human lymphocytes were assessed in comparison to cyclosporine A using annexin V/propidium iodide staining assays and flow cytometry-based surface receptor characterization, respectively. Intracellular levels of effector molecules (IL-2, IFN-γ and TNF-α) were analyzed with cytokine assays. T cell proliferation was inhibited dose dependently by the Equisetum extract without induction of apoptosis or necrosis. This effect was mediated through inhibition of lymphocyte activation, specifically by diminishing CD69 and IL-2 surface receptor expression and intracellular IL-2 production. Furthermore, treatment with Equisetum arvense inhibited effector functions, as indicated by reduced production of IFN-γ and TNF-α.

Does equisetum arvense ( common horsetail ) modulate the function of inflammatory immunocompetent cells?

To investigate the protective effects of remote ischemic postconditioning (RIP) against limb ischemia-reperfusion (IR)-induced gastric mucosal injury. Gastric IR was established in male Wistar rats by placing an elastic rubber band under a pressure of 290-310 mmHg on the proximal part of both lower limbs for 3 h followed by reperfusion for 0, 1, 3, 6, 12 or 24 h. RIP was performed using three cycles of 30 s of reperfusion and 30 s of reocclusion of the femoral aortic immediately after IR and before reperfusion for up to 24 h. Rats were randomly assigned to receive IR (n = 36), IR followed by RIP (n = 36), or sham treatment (n = 36). Gastric tissue samples were collected from six animals in each group at each timepoint and processed to determine levels of malondialdehyde (MDA), superoxide dismutase (SOD), xanthine oxidase (XOD) and myeloperoxidase (MPO). Additional samples were processed for histologic analysis by hematoxylin and eosin staining. Blood samples were similarly collected to determine serum levels of lactate dehydrogenase (LDH), creatine kinase (CK), tumor necrosis factor (TNF)-α and interleukin (IL)-10. The pathologic changes in gastric tissue induced by IR were observed by light microscopy. Administration of RIP dramatically reduced the gastric damage score after 6 h of reperfusion (5.85 ± 0.22 vs 7.72 ± 0.43; P < 0.01). In addition, RIP treatment decreased the serum activities of LDH (3.31 ± 0.32 vs 6.46 ± 0.03; P < 0.01), CK (1.94 ± 0.20 vs 4.54 ± 0.19; P < 0.01) and the concentration of TNF-α (53.82 ± 0.85 vs 88.50 ± 3.08; P < 0.01), and elevated the concentration of IL-10 (101.46 ± 5.08 vs 99.77 ± 4.32; P < 0.01) induced by IR at 6 h. Furthermore, RIP treatment prevented the marked elevation in MDA (3.79 ± 0.29 vs 6.39 ± 0.81) content, XOD (7.81 ± 0.75 vs 10.37 ± 2.47) and MPO (0.47 ± 0.05 vs 0.82 ± 0.03) activities, and decrease in SOD (4.95 ± 0.32 vs 3.41 ± 0.38; P < 0.01) activity in the gastric tissue as measured at 6 h.

Does remote ischemic postconditioning protect against gastric mucosal lesions in rats?

The association between HIV and emphysema remains incompletely understood. We sought to determine whether HIV is an independent risk factor for emphysema severity and whether markers of HIV severity and systemic biomarkers of inflammation (IL-6), altered coagulation (D-dimer), and immune activation (soluble CD14) are associated with emphysema. We performed a cross-sectional analysis of 114 participants with HIV infection and 89 participants without HIV infection in the Examinations of HIV-Associated Lung Emphysema (EXHALE) study. Participants underwent chest CT imaging with blinded semiquantitative interpretation of emphysema severity, distribution, and type. We generated multivariable logistic regression models to determine the risk of HIV for radiographic emphysema, defined as > 10% lung involvement. Similar analyses examined associations of plasma biomarkers, HIV RNA, and recent and nadir CD4 cell counts with emphysema among participants with HIV infection. Participants with HIV infection had greater radiographic emphysema severity with increased lower lung zone and diffuse involvement. HIV was associated with significantly increased risk for > 10% emphysema in analyses adjusted for cigarette smoking pack-years (OR, 2.24; 95% CI, 1.12-4.48). In multivariable analyses restricted to participants with HIV infection, nadir CD4 < 200 cells/μL (OR, 2.98; 95% CI, 1.14-7.81), and high soluble CD14 level (upper 25th percentile) (OR, 2.55; 95% CI, 1.04-6.22) were associated with increased risk of > 10% emphysema. IL-6 and D-dimer were not associated with emphysema in HIV.

Is increased risk of radiographic emphysema in HIV associated with elevated soluble CD14 and nadir CD4?

Knowledge about supportive care needs in patients with cutaneous invasive melanoma is scarce. We examined the unmet needs of melanoma patients treated with surgery and factors associated with these needs to assist health professionals identify areas needing clinical attention. Cross-sectional multisite survey of UK patients ascertained 3 months to 5 years after complete resection of stage I-III cutaneous melanoma. Participants completed the following validated questionnaires: Supportive Care Needs Survey (SCNS-SF34 with melanoma module), Hospital Anxiety and Depression Scale and 51-item Functional Assessment of Cancer Therapy-Melanoma quality-of-life scale. A total of 472 participants were recruited [319 (67%) clinical stage I-II). Mean age was 60 years (standard deviation = 14) and 255 (54%) were female. One hundred and twenty-three (27%) participants reported at least one unmet need (mostly 'low' level). The most frequently reported unmet needs were fears of cancer returning (n = 138, 29%), uncertainty about the future (n = 119, 25%), lack of information about risk of recurrence (n = 112, 24%) and about possible outcomes if melanoma were to spread (n = 91, 20%). One hundred and thirty-eight (29%) participants reported anxiety and 51 (11%) depression at clinical or subclinical levels. Patients with nodal disease had a significantly higher level of unmet supportive care needs (P < 0.001) as did patients with anxiety or depression (P < 0.001). Key correlates of the total SCNS-SF34 score for unmet supportive care needs were younger age (odds ratio, OR = 2.23, P < 0.001) and leaving school early (OR = 4.85, P < 0.001), while better emotional (OR = 0.89, P < 0.001) and social well-being (OR = 0.91, P < 0.001) were linked with fewer unmet needs. Neither patients' sex nor tumour thickness was associated with unmet needs.

Does prevalence and correlate of unmet supportive care needs in patients with resected invasive cutaneous melanoma?

The objective of this cross-sectional study was to characterize long-term breast pain in patients undergoing breast-conserving surgery and radiation (BCT) and to identify predictors of this pain. We identified 355 eligible patients with Tis-T2N0M0 breast cancer who underwent BCT in 2007 to 2011, without recurrent disease. A questionnaire derived from the Late Effects Normal Tissue Task Force (LENT) Subjective, Objective, Management, Analytic (SOMA) scale was mailed with 7 items detailing the severity, frequency, duration, and impact of ipsilateral breast pain over the previous 2 weeks. A logistic regression model identified predictors of long-term breast pain based on questionnaire responses and patient, disease, and treatment characteristics. The questionnaire response rate was 80% (n=285). One hundred thirty-five patients (47%) reported pain in the treated breast, with 19 (14%) having pain constantly or at least daily; 15 (11%) had intense pain. The pain interfered with daily activities in 11 patients (8%). Six patients (4%) took analgesics for breast pain. Fourteen (10%) thought that the pain affected their quality of life. On univariable analysis, volume of breast tissue treated to ≥105% of the prescribed dose (odds ratio [OR] 1.001 per cc, 95% confidence interval [CI] 1.000-1.002; P=.045), volume treated to ≥110% (OR 1.009 per cc, 95% CI 1.002-1.016; P=.012), hormone therapy use (OR 1.95, 95% CI 1.12-3.39; P=.02), and other sites of pain (OR 1.79, 95% CI 1.05-3.07; P=.03) predicted for long-term breast pain. On multivariable analysis, volume ≥110% (OR 1.01 per cc, 95% CI 1.003-1.017; P=.007), shorter time since treatment (OR 0.98 per month, 95% CI 0.96-0.998; P=.03), and hormone therapy (OR 1.84, 95% CI 1.05-3.25; P=.03) were independent predictors of pain.

Does dosimetric Inhomogeneity predict for Long-Term Breast Pain After Breast-Conserving Therapy?

Venous stasis is a well-known risk factor for the development of venous thromboembolism. It is likely that stasis increases the risk of thrombosis by inducing hypercoagulability via the hypoxic procoagulant activation of endothelial and mononuclear cells and the accumulation of activated clotting factors. However, increased rates of thrombin formation have not been demonstrated in response to venous stasis in vivo. In this study, we used the venous occlusion (VO) test to determine, if stasis triggers thrombin formation in healthy individuals (n=25) and patients with additional thrombotic risk factors, such as inherited thrombophilia (n=19) and symptomatic atherosclerosis (n=15). Thrombin formation was monitored by measuring plasma levels of free thrombin using a highly sensitive oligonucleotide enzyme capture assay (OECA) in addition to the plasma levels of prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin-complexes (TAT). The plasma levels of activated protein C (APC) were additionally measured using an APC-OECA. VO induced a significant (p<0.05) increase in the levels of tissue-type plasminogen activator and plasmin-α2-antiplasmin-complexes. In all three cohorts, the majority of samples obtained during VO showed no quantifiable thrombin or APC levels. Consistent with these findings F1+2 and TAT did not change.

Does short-term venous stasis induce fibrinolytic activation but not thrombin formation?

Population studies have shown obesity and diabetes to be risk factors for atherosclerosis. We assessed changes in the common carotid arteries in rat models of obesity and diabetes without hypertension. Twenty 30-week-old male spontaneously diabetic and obese model Otsuka Long-Evans Tokushima Fatty (OLETF) and 20 control Long-Evans Tokushima Otsuka (LETO) rats were used in the experiments. The animals were considered diabetic if the plasma glucose level peaked at >300 mg/dL and remained at >200 mg/dL for 120 minutes. Blood gas physiological parameters were continuously monitored under anesthesia, and the flow of the carotid artery was assessed with ultrasonography. All animals were sacrificed with an overdose of anesthesia at the end of the experiment. Sections of the middle portion of the internal carotid artery were cut and stained with hematoxylin and eosin to assess the overall morphology. All OLETF rats were diabetic, and all LETO rats were non-diabetic. The physiological parameters did not differ significantly between the control and model rats, whereas the carotid artery wall thickness (19.3 ± 3.2 vs. 6.1 ± 4.5 μm) was significantly different between the two groups. The blood flow velocity in the common carotid artery determined using ultrasonography and color Doppler sonography was significantly increased during systole in the model rats compared with that observed in the control rats (203 ± 20.3 vs. 55.3 ± 21.4 cm/sec).

Is carotid artery stenosis exacerbated in spontaneously obese model rats with diabetes?

Central core disease is a congenital myopathy, characterized by presence of central core-like areas in muscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is caused by mutations in the human ryanodine receptor gene (RYR1), which encodes a calcium-release channel. Since the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three 'hot spots', with particular attention to the C-terminal region. Recent next-generation sequencing methods are now identifying multiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult. In a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a new case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1 gene identified two different missense mutations: c.14256 A > C polymorphism in exon 98 and c.14693 T > C in exon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed because patient's daughter, mother and sister carried only the exon 98's mutation, a synonymous variant that was subsequently found in the frequency of 013-0,05 of alleles. Further next generation sequencing study of the whole RYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and 8 polymorphisms in heterozygosis.

Do silent polymorphisms in the RYR1 gene modify the phenotype of the p.4898 I > T pathogenic mutation in central core disease : a case report?

Flavonoids, which have been identified in a variety of plants, have been demonstrated to elicit beneficial effects on memory. Some studies have reported that flavonoids derived from Erythrina plants can provide such beneficial effects on memory. The aim of this study was to identify the flavonoids present in the stem bark crude extract of Erythrina falcata (CE) and to perform a bioactivity-guided study on conditioned fear memory. The secondary metabolites of CE were identified by high performance liquid chromatography combined with a diode array detector, electrospray ionization tandem mass spectrometry (HPLC-DAD-ESI/MSn) and nuclear magnetic resonance (NMR). The buthanolic fraction (BuF) was obtained by partitioning. Subfractions from BuF (BuF1 - BuF6) and fraction flavonoidic (FfA and FfB) were obtained by flash chromatography. The BuF3 and BuF4 fractions were used for the isolation of flavonoids, which was performed using HPLC-PAD. The isolated substances were quantified by HPLC-DAD and their structures were confirmed by nuclear magnetic resonance (NMR). The activities of CE and the subfractions were monitored using a one-trial, step-down inhibitory avoidance (IA) task to identify the effects of these substances on the acquisition and extinction of conditioned fear in rats. Six subclasses of flavonoids were identified for the first time in CE. According to our behavioral data, CE, BuF, BuF3 and BuF4, the flavonoidic fractions, vitexin, isovitexin and 6-C-glycoside-diosmetin improved the acquisition of fear memory. Rats treated with BuF, BuF3 and BuF4 were particularly resistant to extinction. Nevertheless, rats treated with FfA and FfB, vitexin, isovitexin and 6-C-glycoside-diosmetin exhibited gradual reduction in conditioned fear response during the extinction retest session, which was measured at 48 to 480 h after conditioning.

Are flavones from Erythrina falcata modulators of fear memory?

Wee1-like kinase (Wee1) is a tyrosine kinase which negatively regulates entry into mitosis at the G2 to M-phase transition and has a role in inhibition of unscheduled DNA replication in S-phase. The present study investigated the clinical role of Wee1 in advanced-stage (FIGO III-IV) ovarian serous carcinoma. Wee1 protein expression was analyzed in 287 effusions using immunohistochemistry. Expression was analyzed for association with clinicopathologic parameters, including survival. Forty-five effusions were additionally studied using Western blotting. Wee1 was further silenced in SKOV3 and OVCAR8 cells by siRNA knockdown and proliferation was assessed. Nuclear expression of Wee1 in tumor cells was observed in 265/287 (92%) and 45/45 (100%) effusions by immunohistochemistry and Western blotting, respectively. Wee1 expression by immunohistochemistry was significantly higher in post-chemotherapy disease recurrence compared to pre-chemotherapy effusions obtained at diagnosis (p=0.002). Wee1 silencing in SKOV3 and OVCAR8 cells reduced proliferation. In univariate survival analysis of the entire cohort, a trend was observed between high (>25% of cells) Wee1 expression and poor overall survival (p=0.083). Survival analysis for 109 patients with post-chemotherapy effusions showed significant association between Wee1 expression and poor overall survival (p=0.004), a finding which retained its independent prognostic role in Cox multivariate analysis (p=0.003).

Is wee1 a novel independent prognostic marker of poor survival in post-chemotherapy ovarian carcinoma effusions?

Liver ischemia reperfusion (I/R) injury is a common pathophysiological process in many clinical settings. Carvacrol, a food additive commonly used in essential oils, has displayed antimicrobials, antitumor and antidepressant-like activities. In the present study, we investigated the protective effects of carvacrol on I/R injury in the Wistar rat livers and an in vitro hypoxia/restoration (H/R) model. The hepatoportal vein, hepatic arterial and hepatic duct of Wistar rats were isolated and clamped for 30 min, followed by a 2 h reperfusion. Buffalo rat liver (BRL) cells were incubated under hypoxia for 4 h, followed normoxic conditions for 10 h to establish the H/R model in vitro. Liver injury was evaluated by measuring serum levels of alanine aminotransferase (ALT) and aspatate aminotransferase (AST), and hepatic levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondiadehyde (MDA), and hepatic histology and TUNEL staining. MTT assay, flow cytometric analysis and Hoechst 33258 staining were used to evaluate the proliferation and apoptosis of BRL cells in vitro. Protein expression was examined by Western Blot analysis. Carvacrol protected against I/R-induced liver damage, evidenced by significantly reducing the serum levels of ALT and AST, histological alterations and apoptosis of liver cells in I/R rats. Carvacrol exhibited anti-oxidative activity in the I/R rats, reflected by significantly reducing the activity of SOD and the content of MDA, and restoring the activity of CAT and the content of GSH, in I/R rats. In the in vitro assays, carvacrol restored the viability and inhibited the apoptosis of BRL cells, which were subjected to a mimic I/R injury induced by hypoxia. In the investigation on molecular mechanisms, carvacrol downregulated the expression of Bax and upregulated the expression of Bcl-2, thus inhibited the activation of caspase-3. Carvacrol was also shown to enhance the phosphorylation of Akt.

Does carvacrol alleviate ischemia reperfusion injury by regulating the PI3K-Akt pathway in rats?

Chikungunya virus causes chronic infection with manifestations of joint pain. Human synovial fibroblasts get infected with CHIKV and could lead to pro-inflammatory responses. MicroRNAs have potentials to regulate the gene expression of various anti-viral and pro-inflammatory genes. The study aims to investigate the role of miR-146a in modulation of inflammatory responses of human synovial fibroblasts by Chikungunya virus. To study the role of miR-146a in CHIKV pathogenesis in human synovial cells and underlying inflammatory manifestations, we performed CHIKV infection in primary human synovial fibroblasts. Western blotting, real-time PCR, luciferase reporter assay, overexpression and knockdown of cellular miR-146a strategies have been employed to validate the role of miR-146a in regulation of pro-inflammatory NF-κB pathway. CHIKV infection induced the expression of cellular miR-146a, which resulted into down-regulation of TRAF6, IRAK1, IRAK2 and increased replication of CHIKV in human synovial fibroblasts. Exogenous expression of miR-146a in human synovial fibroblasts led to decreased expression of TRAF6, IRAK1, IRAK2 and decreased replication of CHIKV. Inhibition of cellular miR-146a by anti-miR-146a restored the expression levels of TRAF6, IRAK1 and IRAK2. Downregulation of TRAF6, IRAK1 and IRAK2 led to downstream decreased NF-κB activation through negative feedback loop.

Does chikungunya virus exploit miR-146a to regulate NF-κB pathway in human synovial fibroblasts?

Mitochondrial permeability transition pore (mPTP) opening is a terminal event leading to mitochondrial dysfunction and cell death under conditions of oxidative stress (OS). However, mPTP blockade with cyclosporine A (CsA) has shown variable efficacy in limiting post-ischemic dysfunction and arrhythmias. We hypothesized that strong feedback between energy dissipating (mPTP) and cardioprotective (mKATP) channels determine vulnerability to OS. Guinea pig hearts (N = 61) were challenged with H2O2 (200 μM) to elicit mitochondrial membrane potential (ΔΨm) depolarization. High-resolution optical mapping was used to measure ΔΨm or action potentials (AP) across the intact heart. Hearts were treated with CsA (0.1 μM) under conditions that altered the activity of mKATP channels either directly or indirectly via its regulation by protein kinase C. mPTP blockade with CsA markedly blunted (P < 0.01) OS-induced ΔΨm depolarization and delayed loss of LV pressure (LVP), but did not affect arrhythmia propensity. Surprisingly, prevention of mKATP activation with the chemical phosphatase BDM reversed the protective effect of CsA, paradoxically exacerbating OS-induced ΔΨm depolarization and accelerating arrhythmia onset in CsA treated compared to untreated hearts (P < 0.05). To elucidate the putative molecular mechanisms, mPTP inhibition by CsA was tested during conditions of selective PKC inhibition or direct mKATP channel activation or blockade. Similar to BDM, the specific PKC inhibitor, CHE (10 μM) did not alter OS-induced ΔΨm depolarization directly. However, it completely abrogated CsA-mediated protection against OS. Direct pharmacological blockade of mKATP, a mitochondrial target of PKC signaling, equally abolished the protective effect of CsA on ΔΨm depolarization, whereas channel activation with 30 μM Diazoxide protected against ΔΨm depolarization (P < 0.0001). Conditions that prevented mKATP activation either directly or indirectly via PKC inhibition led to accelerated ΔΨm depolarization and early onset of VF in response to OS. Investigation of the electrophysiological substrate revealed accelerated APD shortening in response to OS in arrhythmia-prone hearts.

Do functional crosstalk between the mitochondrial PTP and KATP channels determine arrhythmic vulnerability to oxidative stress?

The effect of in vitro expansion of human adipose-derived stem cells (ASCs) on stem cell properties is controversial. We examined serial subcultivation with expansion on the ability of ASCs to grow and differentiate into osteoblastic lineages. Flow cytometric analysis, growth kinetics, cell population doubling time, light microscopy and confocal analysis, and osteogenesis induction were performed to assess growth and osteogenic potential of subcultivated ASCs at passages 2 (P2), P4 and P6. Flow cytometric analysis revealed that ASCs at P2 express classical mesenchymal stem cell markers including CD44, CD73, and CD105, but not CD14, CD19, CD34, CD45, or HLA-DR. Calcium deposition and alkaline phosphatase activity were the highest at P2 but completely abrogated at P4. Increased passage number impaired cell growth; P2 cultures exhibited exponential growth, while cells at P4 and P6 showed near linear growth with cell population doubling times increased from 3.2 at P2 to 4.8 d at P6. Morphologically, cells in various subcultivation stages showed flattened shape at low density but spindle-like structures at confluency as judged by phalloidin staining.

Are proliferation and differentiation of human adipose-derived mesenchymal stem cells ( ASCs ) into osteoblastic lineage passage dependent?

Intestinal inflammation is often associated with an increased level of serotonin (5-HT), an important gastrointestinal signaling molecule involved in gut homeostasis through stimulation of specific receptors. In this study, we investigated the role of 5-HT7 receptor (5-HT7R) in the induction and development of intestinal inflammation using a mouse model of acute and chronic colitis and human patients with Crohn's disease (CD). Acute colitis was induced through administration of dextran sodium sulfate to wild-type, 5-HT7R-deficient mice and hematopoietic bone marrow chimera. Chronic colitis was induced in interleukin 10-deficient mice. The role of 5-HT7R in gut inflammation was assessed using agonist/antagonist treatment. We investigated expression and distribution of 5-HT7R, extent of gut inflammation with magnetic resonance imaging and histological analysis, survival rate, and disease activity index. Finally, biopsies from the large intestine of patients with CD were analyzed. Under basal conditions, 5-HT7R is expressed both in enteric neurons and CD11c cells of the large intestine. Expression of 5-HT7R significantly increased after induction of colitis in mice and in inflamed intestinal regions of patients with CD in CD11c/CD86 double-positive cells. Pharmacological blockade or genetic ablation of 5-HT7R resulted in increased severity of both acute and chronic dextran sodium sulfate-induced colitis, whereas receptor stimulation showed an anti-inflammatory effect. Analysis of bone marrow chimera indicated importance of 5-HT7R expressed by hematopoietic cells in intestinal inflammation.

Is serotonin 5-HT7 receptor critically involved in acute and chronic inflammation of the gastrointestinal tract?

Platelet-derived growth factor-BB (PDGF-BB) has been implicated in the proliferation, migration and synthetic activities of smooth muscle cells that characterize physiologic and pathologic tissue remodeling in hollow organs. However, neither the molecular basis of PDGFR-regulated signaling webs, nor the extent to which specific components within these networks could be exploited for therapeutic benefit has been fully elucidated. Expression profiling and quantitative proteomics analysis of PDGF-treated primary human bladder smooth muscle cells identified 1,695 genes and 241 proteins as differentially expressed versus non-treated cells. Analysis of gene expression data revealed MYC, JUN, EGR1, MYB, RUNX1, as the transcription factors most significantly networked with up-regulated genes. Forty targets were significantly altered at both the mRNA and protein levels. Proliferation, migration and angiogenesis were the biological processes most significantly associated with this signature, and MYC was the most highly networked master regulator. Alterations in master regulators and gene targets were validated in PDGF-stimulated smooth muscle cells in vitro and in a model of bladder injury in vivo. Pharmacologic inhibition of MYC and JUN confirmed their role in SMC proliferation and migration. Network analysis identified the diaphanous-related formin 3 as a novel PDGF target regulated by MYC and JUN, which was necessary for PDGF-stimulated lamellipodium formation.

Does integration of proteomic and transcriptomic profiles identify a novel PDGF-MYC network in human smooth muscle cells?

Dairy foods help achieve essential nutrient adequacy. This role may be conflicted where so-called chronic diseases prevail. We have examined associations between dairy intake and mortality where dairy foods have not been traditional. A representative Taiwanese cohort of 3810 subjects, aged 19-64 years, derived from the Nutrition and Health Survey in Taiwan (NAHSIT, 1993-1996) was linked to death registration (1993-2008). Participants were categorized by 4 dairy weekly intake frequencies from 0 to >7 times. Mortality hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional-hazards models. Nonconsumers of dairy products included 30.7% of the men and 22.1% of the women. Adverse sociodemographic and personal behaviors were generally significantly associated with lower dairy consumption. After adjustment for covariates, together with body mass index (BMI) and supplement use, those with 3-7 times/week intakes had an HR (95% CI) for all-cause mortality of 0.61 (0.39-0.96) with a significant dose-response trend (p = 0.043). Similarly, the HR for cardiovascular disease (CVD) mortality with dairy weekly intake frequency >7 was 0.14 (0.02-0.97) with a significant linear trend (p = 0.007). For stroke, the corresponding HR (95% CI) was 0.03 (0.00-0.28) with a linear trend. By age and with adjustment for dietary quality, food, and calcium or vitamin D intake, significance and dose-response relationships remained. Dairy intake and cancer mortality were not associated.

Is optimal dairy intake predicated on total , cardiovascular , and stroke mortalities in a Taiwanese cohort?

The aim of this study was to prospectively evaluate the feasibility and potential advantages of freehand single-photon emission computed tomography (fhSPECT) compared with conventional intraoperative localization techniques for sentinel lymph node biopsy (SLNB) in oral cancer. Between November 2012 and February 2014, 23 consecutive patients with clinical T1/T2 oral squamous cell carcinoma and a cN0 neck were recruited. All patients underwent SLNB followed by elective neck dissection (END). All patients received preoperative lymphoscintigraphy. To detect the SLNs intraoperatively, fhSPECT with a combination of conventional acoustic SLN localization and 3-D visual navigation was used. All but one of the SLNs detected by preoperative imaging were successfully mapped intraoperatively by fhSPECT (detection rate 98%), including those in six patients with a tumour in the floor of the mouth. A histopathology analysis revealed positive SLNs in 22% of patients. No further metastases were found in LNs resected during END. SLNB correctly predicted the final LN stage in all patients (accuracy 100%). Additional radioactive LNs, which were not present on preoperative lymphoscintigraphy, were observed in three patients.

Does intraoperative 3-D imaging improve sentinel lymph node biopsy in oral cancer?

The main aim was to compare robotic gait training vs. balance training for reducing postural instability in patients with Parkinson's disease. The secondary aim was to compare their effects on the level of confidence during activities of daily living requiring balance, functional mobility and severity of disease. Randomized controlled trial. University hospital. A total of 66 patients with Parkinson's disease at Hoehn and Yahr Stage 3. After balanced randomization, all patients received 12, 45-minute treatment sessions, three days a week, for four consecutive weeks. A group underwent robot-assisted gait training with progressive gait speed increasing and body-weight support decreasing. The other group underwent balance training aimed at improving postural reactions (self and externally induced destabilization, coordination, locomotor dexterity exercises). Patients were evaluated before, after and one month posttreatment. Berg Balance Scale. Activities-Specific Balance Confidence Scale; Timed Up and Go Test; Unified Parkinson's Disease Rating Scale. No significant differences were found between the groups for the Berg Balance Scale either immediately after intervention (mean score in the robotic training group 51.58 ±3.94; mean score in the balance training group 51.15 ±3.46), or one-month follow-up (mean score in the robotic training group 51.03 ±4.63; mean score in the balance training group 50.97 ±4.28). Similar results were found for all the secondary outcome measures.

Is robot-assisted gait training superior to balance training for improving postural instability in patients with mild to moderate Parkinson 's disease : a single-blind randomized controlled trial?