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Does the Boston keratoprosthesis provide a wide depth of focus? | To measure the through-focus curve for eyes implanted with a type 1 Boston keratoprosthesis (KPro) and compare it to that of pseudophakic controls with fixed pupil sizes. The results should assist in evaluating postoperative visual quality after surgery. They should also help to determine the necessary KPro inventories in terms of refractive power steps. Autorefraction and manifest refraction were performed on all eyes. The monocular through-focus acuity curve was plotted in reference to the best-corrected visual acuity by spectacle plane defocus ranging from +5.00 to -5.00 dioptres in 0.50 dioptre increments. These measurements were obtained on KPro-implanted eyes, pseudophakic eyes as controls, and on the same control eyes after fixing the pupil diameter to 3 and 2 mm using black painted iris contact lenses. Ten KPro eyes and five control eyes were included. Good agreement was noted between the subjective refractions and autorefraction in KPro eyes. The average through-focus curve for the control eyes was significantly steeper than that of the KPro curve, but became comparable after fixing the control pupil to 2 and 3 mm. | To study whether Termitomyces albuminosus can degrade lignocelluloses and to understand the symbiotic relationship between termite mushroom and fungus-growing termite. cDNA library of T. albuminosus was sequenced by the Roche 454 GS FLX Titanium platform, and the diverse enzymes relevant to degradation of cellulose and lignin of symbiotic fungus T. albuminosus were analyzed. Eighth sequencing run resulted in a total of 82386 reads (express sequence tags, EST). After removing the vector and primer sequences, the remained 54410 reads were assembled into 3301 contigs and 3193 singletons. Comparing sequence similarity with known proteins, these sequences, representing approximately 2681 unique genes, were successfully annotated using BLAST searches (E-value < or = 1e(-10)) against the Nr, SwissProt and CDD databases. The T. albuminosus transcripts included 33 enzymes putatively involved in cellulose and hemicelluloses biodegradation. 5 enzymes could hydrolyze cellulose and others had catalytic activities for degradation of hemicelluloses, starch and glycogen and chitin. Moreover, four genes encoding laccases and a single aryl-alcohol oxidase which could degrade lignin were also identified. These results revealed symbiosis fungus T. albuminosus had many laccases and possibly decomposed phenolic compounds from plant litter. |
Are aggregate National Early Warning Score ( NEWS ) values more important than high scores for a single vital signs parameter for discriminating the risk of adverse outcomes? | The Royal College of Physicians (RCPL) National Early Warning Score (NEWS) escalates care to a doctor at NEWS values of ≥5 and when the score for any single vital sign is 3. We calculated the 24-h risk of serious clinical outcomes for vital signs observation sets with NEWS values of 3, 4 and 5, separately determining risks when the score did/did not include a single score of 3. We compared workloads generated by the RCPL's escalation protocol and for aggregate NEWS value alone. Aggregate NEWS values of 3 or 4 (n=142,282) formed 15.1% of all vital signs sets measured; those containing a single vital sign scoring 3 (n=36,207) constituted 3.8% of all sets. Aggregate NEWS values of either 3 or 4 with a component score of 3 have significantly lower risks (OR: 0.26 and 0.53) than an aggregate value of 5 (OR: 1.0). Escalating care to a doctor when any single component of NEWS scores 3 compared to when aggregate NEWS values ≥5, would have increased doctors' workload by 40% with only a small increase in detected adverse outcomes from 2.99 to 3.08 per day (a 3% improvement in detection). | Acid hydrolysis is a popular pretreatment for removing hemicellulose from lignocelluloses in order to produce a digestible substrate for enzymatic saccharification. In this work, a novel model for the dilute acid hydrolysis of hemicellulose within sugarcane bagasse is presented and calibrated against experimental oligomer profiles. The efficacy of mathematical models as hydrolysis yield predictors and as vehicles for investigating the mechanisms of acid hydrolysis is also examined. Experimental xylose, oligomer (degree of polymerisation 2 to 6) and furfural yield profiles were obtained for bagasse under dilute acid hydrolysis conditions at temperatures ranging from 110°C to 170°C. Population balance kinetics, diffusion and porosity evolution were incorporated into a mathematical model of the acid hydrolysis of sugarcane bagasse. This model was able to produce a good fit to experimental xylose yield data with only three unknown kinetic parameters k a ,k b and k d . However, fitting this same model to an expanded data set of oligomeric and furfural yield profiles did not successfully reproduce the experimental results. It was found that a "hard-to-hydrolyse" parameter, α, was required in the model to ensure reproducibility of the experimental oligomer profiles at 110°C, 125°C and 140°C. The parameters obtained through the fitting exercises at lower temperatures were able to be used to predict the oligomer profiles at 155°C and 170°C with promising results. |
Are perioperative complications after hemiarthroplasty and total shoulder arthroplasty equivalent? | Total shoulder arthroplasty (TSA) results in superior clinical outcomes to hemiarthroplasty (HA); however, TSA is a more technical and invasive procedure. This study retrospectively compares perioperative complications after HA and TSA using the National Surgical Quality Improvement Program (NSQIP) database. The NSQIP user file was queried for HA and TSA cases from the years 2005 through 2010. Major complications were defined as life-threatening or debilitating. All complications occurred within 30 days of the initial procedure. We performed multivariate analysis to compare complication rates between the two procedures, controlling for patient comorbidities. The database returned 1,718 patients (HA in 30.4% [n = 523] and TSA in 69.6% [n = 1,195]). The major complication rates in the HA group (5.2%, n = 29) and TSA group (5.1%, n = 61) were similar (P = .706). Rates of blood transfusions for postoperative bleeding in patients undergoing HA (2.3%, n = 12) and TSA (2.9%, n = 35) were indistinguishable (P = .458). Venous thromboembolism was a rare complication, occurring in 0.4% of patients in each group (2 HA patients and 5 TSA patients, P > .999). On multivariate analysis, the operative procedure was not associated with major complications (P = .349); however, emergency case, pulmonary comorbidity, anemia with a hematocrit level lower than 36%, and wound class of III or IV increased the risk of a major complication (P < .05 for all). | Gestational diabetes mellitus (GDM) is a disease often manifests in mid to late pregnancy with symptoms including hyperglycemia, insulin resistance and fetal mal-development. The C57BL/KsJ-Lep (db/+) (db/+) mouse is a genetic GDM model that closely mimicked human GDM symptoms. Resveratrol (RV) is a naturally existing compound that has been reported to exhibit beneficial effects in treating type-2 diabetes. In this study, we investigated the effect of RV on the pregnant db/+ GDM mouse model, and the underlying molecular mechanism. RV greatly improved glucose metabolism, insulin tolerance and reproductive outcome of the pregnant db/+ females. Moreover, we found that RV relieved GDM symptoms through enhancing AMPK activation, which in turn reduced production and activity of glucose-6-phosphatase in both pregnant db/+ females and their offspring. |
Is interleukin-6 associated with obesity , central fat distribution , and disease severity in patients with acute pancreatitis? | Acute pancreatitis (AP) is a systemic inflammatory disease, and cytokines are suggested to be related to the course of AP. Obesity and central fat distribution are considered to have been associated with severe AP. This study investigated the profile of inflammatory cytokines in AP to determine how they are related to obesity, central fat distribution, and AP severity. Fifty-nine patients with AP were prospectively enrolled in the study. Body mass index and waist circumference were obtained at admission. Serum levels of inflammatory cytokines, IL-Iβ, IL-1ra, IL-6, TNF-α, sTNFR-I, and sTNFR-II, were measured on day 1 and 2 of AP. Of the patients included in the study, 19 (32%) were overweight, 23 (39%) had central fat distribution, and 23 (39%) had moderate AP. IL-1ra and IL-6 were significantly higher in overweight patients compared with non-overweight patients. IL-1ra, IL-6, TNF-α, and sTNFR-I were significantly higher in patients with central fat distribution compared with patients with non-central fat distribution. IL-6, sTNFR-I, and sTNFR-II were significantly higher in patients with moderate pancreatitis compared to those with mild pancreatitis. Among the six cytokines, IL-6 was commonly elevated in patients with central fat distribution, overweight, and moderate AP. The areas under the receiver operating characteristic curves of IL-6 for predicting the association with overweight, central fat distribution, and AP severity were 0.678, 0.716, and 0.801, respectively (P < 0.05). | Subcortical band heterotopia (SBH) is a cortical malformation formed when neocortical neurons prematurely stop their migration in the white matter, forming a heterotopic band below the normotopic cortex, and is generally associated with intractable epilepsy. Although it is clear that the band heterotopia and the overlying cortex both contribute to creating an abnormal circuit prone to generate epileptic discharges, it is less understood which part of this circuitry is the most critical. Here, we sought to identify the origin of epileptiform activity in a targeted genetic model of SBH in rats. Rats with SBH (Dcx-KD rats) were generated by knocking down the Dcx gene using shRNA vectors transfected into neocortical progenitors of rat embryos. Origin, spatial extent, and laminar profile of bicuculline-induced interictal-like activity on neocortical slices were analyzed by using extracellular recordings from 60-channel microelectrode arrays. Susceptibility to pentylenetetrazole-induced seizures was assessed by electrocorticography in head-restrained nonanesthetized rats. We show that the band heterotopia does not constitute a primary origin for interictal-like epileptiform activity in vitro and is dispensable for generating induced seizures in vivo. Furthermore, we report that most interictal-like discharges originating in the overlying cortex secondarily propagate to the band heterotopia. Importantly, we found that in vivo suppression of neuronal excitability in SBH does not alter the higher propensity of Dcx-KD rats to display seizures. |
Is gOLP3 a predictor of survival in patients with hepatocellular carcinoma? | Hepatocellular carcinoma (HCC) is one of the most common solid tumors and ranks the third leading cause of cancer mortality worldwide. The purpose of this study was to examine the expression dynamics of GOLPH3 in HCC tissue samples, and explore the correlation between GOLPH3 expression and prognosis in patients with HCC. The levels of Golgi phosphoprotein 3 (GOLPH3) mRNA and protein in liver cancer cell lines and fresh tissues were determined by qRT-PCR and Western blotting. Additionally, the protein expression of GOLPH3 was detected by immunohistochemistry. High GOLPH3 expression was positively correlated with serum AFP level (P=0.015) and tumor recurrence or metastasis (P=0.010). In addition, liver cancer patients with high GOLPH3 expression had significantly poorer overall survival (HR, 1.87; 95% CI, 1.19-2.94; P=0.006) and poorer disease-free survival (HR, 1.90; 95% CI, 1.21-2.98; P=0.005) than those with low GOLPH3 expression. The cumulative 5-year survival rate was only 35.19% (95% CI, 26.18%-44.20%) in the high GOLPH3 expression group, whereas it was 55.93% (95% CI, 43.26%-68.60%) in the low GOLPH3 expression group. Furthermore, multivariate Cox regression analysis demonstrated that the expression of GOLPH3, tumor size and tumor multiplicity were independent prognostic predictors for HCC patients. | The modulation of intracortical inhibition is thought to be impaired in older adults, which may contribute to their reduced fine motor control, particularly during lengthening muscle contractions. To quantify the magnitude of intracortical inhibition and movement performance during postural, shortening and lengthening contractions of a hand muscle in young and old adults. In 18 young (23.2 ± 4.2) and 16 old (70.6 ± 6.5) subjects, paired-pulse transcranial magnetic stimulation (TMS) was used to assess short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) during a movement task involving the first dorsal interosseous muscle. The task required a constant load (50 g) to be slowly lifted and lowered using the index finger while single- or paired-pulse TMS was delivered during the shortening or lengthening contraction. Relative to postural contractions, SICI during shortening contractions was reduced by 29% in young subjects (P < 0.0001) and 43% in old subjects (P < 0.0001), whereas SICI during lengthening contractions was reduced by 11% in young subjects (P = 0.0004) and 33% in old subjects (P < 0.0001). Furthermore, SICI was significantly less in older adults during lengthening contractions (P-values < 0.01). For LICI, inhibition was not influenced by contraction type in old subjects, but was increased by 11% during shortening contractions (P < 0.0001) and by 9% during lengthening contractions in young subjects (P = 0.0008). In addition, old subjects showed significantly less LICI than young subjects in each movement phase (both P-values < 0.05). |
Is fibulin-5 protein reduced in the lung of patients with spontaneous pneumothorax who are under 25 years old? | To clarify whether fibulins-5 is associated with primary spontaneous pneumothorax (PSP) in young PSP patients. Forty-six surgically resected, fresh lung specimens were used. Patients were divided into 3 groups: younger than 25 years with pneumothorax (group Y), 25 years or older with pneumothorax (group O), and without pneumothorax (group C). Chest X-ray, computed tomography data, height/width ratio (H/W) and anteroposterior/transverse diameter ratio (a/b) were measured. Elastica van Gieson staining and immunofluorescence staining for fibulin-5 were performed. Fibulin-5 mRNA expression and protein levels were measured by real-time PCR and western blotting. Direct sequences of the fibulin-5 gene in PSP patients were performed. The mean H/W ratio in group Y was significantly larger than that in the other groups (p <0.01). The mean a/b ratio in group Y was significantly smaller than that in the other groups (p = 0.02). Fibulin-5 mRNA expression was not significantly different among the groups (p = 0.64). The relative intensity of fibulin-5 protein in group Y was significantly lower than that in group O (p = 0.006), with no significant differences between groups O and C (p = 0.14). | Hypertension is one of the most important risk factors for coronary heart disease. Recent studies have pointed out the possibility that virgin olive oil (VOO) may lower blood pressure in hypertensive (HT) subjects. However, until the date there is scarce information regarding elderly people. The present study was designed to assess the effect of dietary VOO on blood pressure in medically treated hypertensive elderly patients. 31 medically treated HT elderly patients and 31 normotensive (NT) elderly volunteers participated in a randomized sequential dietary intervention. Subjects consumed diets enriched in sunflower oil (SO) or VOO for 4 weeks each with a 4-week washout period between them. VOO reduced total and LDL-cholesterol in NT but not in HT (P < 0.01) and the concentrations were lower than in the group consuming SO. In contrast, no significant differences were found in the levels of tocopherols among the groups studied. Iron-induced oxidation of LDL resulted in a complete loss of monoacylglycerols (MG) and diacylglycerols (DG) and a reduction in triacylglycerols (TG) (60-80%), which was found to be greater in HT (P < 0.01) with no effect of diet. VOO consumption normalized systolic pressure in the HT group (136 +/- 10 mmHg) compared to SO (150 +/- 8 mmHg). |
Does pressure immobilization delays mortality and increase intracompartmental pressure after artificial intramuscular rattlesnake envenomation in a porcine model? | We determine the effect of pressure immobilization on mortality and intracompartmental pressure after artificial intramuscular Crotalus atrox envenomation in a porcine model. We prospectively studied 20 pigs using a randomized, controlled design. After anesthesia, C atrox venom (20 mg/kg) was injected with a 22-gauge needle 10 mm deep into the tibialis anterior muscle of the hind leg. Pigs were randomized to receive either pressure immobilization (applied 1 minute after envenomation and maintained throughout the duration of the experiment) or no pressure immobilization. We measured time to death, intracompartmental pressure before venom injection and at 2 hours after injection, and leg circumference at a standardized location before injection and immediately postmortem. Duration of survival was compared using Kaplan-Meier survival analysis. The dose of venom resulted in 100% mortality. The median survival was longer in the pressure immobilization group (191 minutes, range 140 to 240 minutes) than in the control group (median 155 minutes, range 119 to 187 minutes). The difference between the groups was 36 minutes (95% confidence interval [CI] 2 to 64 minutes; P =.0122). The mean intracompartmental pressures were 67+/-13 mm Hg+/-SD with pressure immobilization and 24+/-5 mm Hg without pressure immobilization. The difference between groups was 43 mm Hg (95% CI 32 to 53 mm Hg). The mean circumferences were 14.3 cm in the pressure immobilization group and 19.1 cm in the control group. The difference between groups was -4.8 cm (95% CI -5.7 to -3.9 cm). | The EML4-ALK fusion gene is more frequently found in younger, never smoking patients with lung cancer. Meanwhile, never smokers exposed to secondhand tobacco smoke (SHS) during childhood are diagnosed at a younger age compared with never smoking patients with lung cancer who are not exposed. We, therefore, hypothesized that SHS, which can induce DNA damage, is associated with the EML4-ALK fusion gene. We compared the frequency of the EML4-ALK fusion gene among 197 never smoker patients with lung cancer with and without a history of exposure to SHS during childhood at Mayo Clinic. The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, whereas 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene. |
Does steroid therapy improve endothelial function in patients with biopsy-proven giant cell arteritis? | Endothelial dysfunction has been found to be present in subjects with both small and medium-size blood vessel vasculitides. We assess whether endothelial dysfunction was also present in patients with biopsy-proven giant cell arteritis (GCA) and whether it might be improved following steroid treatment. Endothelial function was determined in cross-sectional and longitudinal studies of 6 patients with biopsy-proven GCA diagnosed between January and May 2002 by measuring flow-mediated endothelial-dependent and independent vasodilatation (EDV and EIV) by brachial ultrasonography. Patients were assessed for endothelial function within 48 hours after the onset of steroid therapy, 4 weeks after the onset of steroid therapy, and 2 years after the disease diagnosis. EDV was significantly impaired in patients with GCA compared with 12 matched controls [mean 2.9%, median 2.45% (range 2.1% to 4.7%) vs mean 6.5%, median 6.6% (range 3.9% to 9.3%) in matched controls; p = 0.002]. However, no significant difference existed between patients and controls in EIV. Significant improvement of EDV after the suppression of inflammation was achieved. At Week 4 after the onset of steroid therapy all 6 patients showed enhanced responses (p = 0.028). This improvement of EDV was still present when steroid treatment was ended, 2 years after diagnosis. | Traumatic intestinal injuries are less common with blunt compared to penetrating mechanisms of trauma and blunt injuries are often associated with diagnostic delays. The purpose of this study is to evaluate differences in the characteristics and outcomes between blunt and penetrating intestinal injuries to facilitate insight into optimal recognition and management. A retrospective analysis of trauma admissions from January 2009 to June 2011 was performed. Patient demographics, ISS, early shock, injury type, timing to OR, blood loss and transfusions, surgical management, infections, EC fistulas, enteric leaks, LOS and mortality were compared. Demographics - There was 3866 blunt admissions and 966 penetrating admissions to our level II trauma centre (Total n=4832) during this interval. The final study group comprised n=131 patients treated for intestinal injuries. Blunt n=54 (BI) vs. penetrating (PI) n=77. Age was similar between the groups: (BI 34 SD 12 vs. PI 30 SD 12). Comorbid conditions were similar as were ED hypotension and blood transfusions. Blunt mechanisms had higher ISS; BI (20 SD 14) vs. PI (16 SD 12), p=0.08 and organ specific injury scales were higher in blunt injuries. Operative Management - Time to operation was higher in BI: (500 SD 676min vs. PI 110 SD 153min, p=0.01). The use of an open abdomen technique was higher for BI: n=19 (35%) vs. PI: n=5 (6%), p=<0.001, as well as delayed intestinal repair in damage control cases. Outcomes - Anastomotic leaks were more prevalent in BI: n=4 (7%) vs. PI: n=2 (3%), p=0.38. Enteric fistulas were: (BI n=8 (15%), vs. PI n=2 (3%), p=0.02). Surgical site infections and other nosocomial infections were: (BI n=11 (20%) vs. PI n=4 (5%), p=0.02), (BI n=11 (20%) vs. PI n=2 (3%), p=0.002), respectively. Hospital and ICU LOS was: (BI=20 SD 14 vs. PI=11 SD 11, p=0.001), (BI=10 SD 10 vs. PI=5 SD 5, p=0.01) respectively. These differences were reflected in higher hospital charges in BI. |
Do chemokines indicate allergic bronchopulmonary aspergillosis in patients with cystic fibrosis? | Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a Th2 immune response. Mouse models suggest a critical role for the Th2 chemokines thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in ABPA. To determine whether serum levels of TARC and MDC characterize ABPA in patients with cystic fibrosis (CF) and to examine longitudinally if levels of TARC and MDC indicate ABPA exacerbations in patients with CF. Levels of TARC and MDC and levels of Th1 (IL-12 and IFN-gamma) and Th2 (IL-4, IL-5, and IL-13) cytokines were analyzed in serum of 16 patients with CF with ABPA, six non-CF patients with asthma with ABPA, 13 patients with CF colonized with Aspergillus fumigatus, six patients with CF sensitized to A. fumigatus, 12 atopic patients with CF, and 13 non-CF atopic control subjects by ELISA. The longitudinal course of TARC, MDC, and IgE levels was assessed during ABPA episodes. Patients with ABPA had significantly higher serum levels of TARC compared with the other patient groups. Cytokine levels did not differ among the patient groups. Longitudinally, levels of TARC indicated ABPA exacerbations in patients with CF more clearly than IgE levels. In patients with CF and ABPA, levels of TARC correlated positively with specific IgE to A. fumigatus and rAsp f4. | Fractional flow may identify hemodynamic effects and ischemic risk beyond percent stenosis of an artery. We hypothesized that diminished TOF-MRA signal intensity distal to an intracranial stenosis predicts stroke risk. TOF-MRA was acquired prospectively in the SONIA-WASID trials. The distal/proximal signal intensity ratio (SIR) was calculated from 3 mm regions of interest, blinded to outcome. Univariate and multivariate analyses included clinical variables, SIR, and invasive angiography measures to identify predictors for risk of stroke in the territory. 189 patients with 50-99% symptomatic intracranial stenosis in SONIA-WASID had TOF-MRA available. In univariate analysis, the hazard ratio (HR) for stroke in the territory of the symptomatic artery with SIR < .9 was 5.2 (1.8, 15.3; P < .001) as compared to SIR ≥ .9. Multivariate analysis correcting for baseline systolic blood pressure, LDL, centrally measured percent stenosis, recency of symptoms, TICI and downstream collaterals, the HR for SIR < .9 was 10.9 (2.0, 58.9; P < .001). In those with <70% stenosis, a SIR < .9 maintained a significant association with recurrent stroke in the territory (P = .006), with a 2-year event rate of 17.3%. |
Do chronic celecoxib users more often show regression of gastric intestinal metaplasia after Helicobacter pylori eradication? | To test whether the chronic users of celecoxib, a selective cyclo-oxygenase-2 inhibitor, had less Helicobacter pylori-related intestinal metaplasia or if such users' intestinal metaplasia could be prone to disappear after H. pylori eradication. The study enrolled 150 chronic celecoxib users and 216 non-users who underwent pan-endoscopy to detect H. pylori infection and its related intestinal metaplasia. One hundred and three H. pylori-infected patients with intestinal metaplasia (43 chronic celecoxib users and 60 non-users) received anti-H. pylori therapy and completed the 12-month follow-up to survey the regression of intestinal metaplasia by mean intestinal metaplasia score. There were no differences in the prevalence of H. pylori-related intestinal metaplasia between the chronic celecoxib users and controls (P > 0.05). On the 12th month of follow-up, chronic celecoxib users had a lower mean intestinal metaplasia score (1.2 vs. 1.8, P < 0.005) and a higher regression rate of intestinal metaplasia (42% vs. 20%, P = 0.027) than non-users. | To investigate the effect of therapeutic hypothermia in the prognostic value of the pituitary-adrenal axis in comatose patients after cardiac arrest. Prospective observational study in intensive care units (ICU) of a university and an affiliated regional hospital. Twenty-nine consecutive patients, in coma after cardiac arrest, admitted to the ICU and treated by hypothermia. On ICU-admission (T=1), at reaching the target of 32-33 degrees C during therapeutic hypothermia (T=2), at the end of hypothermia (T=3) and 48h later (T=4), plasma adrenocorticotrophic hormone (ACTH), serum cortisol, albumin and corticosteroid-binding globulin (CBG) were measured. A short 250 microg ACTH test was performed at each time-point, except at T=1. The free cortisol index (FCI) and free cortisol calculated by Coolens method were also evaluated. The ICU mortality was 59%, including withdrawal of life-sustaining treatment in 45% because of negative somatosensory evoked potentials. ACTH and (free) cortisol levels (mean 13.1 pmol/L vs. 6.0 pmol/L and 1250 nmol/L vs. 596 nmol/L, respectively) were higher in non-survivors than in survivors. Levels decreased in time, but the relative difference between outcome groups was maintained until T=4. The cortisol response to ACTH was lower in non-survivors at T=3 (P=0.047) only. |
Are the rate and anisotropy of impulse propagation in the postnatal terminal crest correlated with remodeling of Cx43 gap junction pattern? | Disruptions to intermyocyte coupling have been implicated in arrhythmogenesis and development of conduction disturbances. At present, understanding of the relationship between the microscopic organization of intercellular coupling and the macroscopic spread of impulse in the normal and diseased heart is largely confined to theoretical analyses. The abundance and arrangement of gap junctions, as well as conduction properties, were assessed in terminal crest preparations isolated from the atria of neonate, weanling, and adult rabbits. We report that the connexin composition of terminal crest was uncomplicated, with Cx43 being the most prominent isoform detectable by Western blotting and immunostaining. Terminal crest myocytes showed little change in total Cx43-gap junction per cell during postnatal growth as assessed by stereology. However, marked non-uniformities emerged in the sarcolemmal distribution of Cx43-gap junctions. Cx43-gap junction area at myocyte termini increased 3.5-fold from birth to adulthood. Correlated with this change in Cx43, impulse propagation velocity parallel to the myofiber axis, as assessed by multi-site optical mapping using voltage-sensitive dye (di-4-ANEPPS), increased 2.4-fold. Conversely, the amount of Cx43-gap junctions on myocyte sides, and the conduction velocity transverse to the myofiber axis, remained relatively invariant during maturation. Hence, the increasing electrical anisotropy of maturing terminal crest was wholly accounted for by increases in conductance velocity along the bundle. This increase in longitudinal conduction velocity was correlated with changes in the sarcolemmal pattern, but not the overall density, of Cx43-gap junctions. | Multiple population-based studies have suggested increasing omission of radiation therapy in favor of alternative treatment strategies in lymphomas, with an associated negative impact on survival. Radiation therapy has long been considered the standard management for many mucosa-associated lymphoid tissue lymphomas. Thus, we aimed to evaluate patterns of treatment utilization and survival. A retrospective analysis based on the National Cancer Database was performed on 22,378 patients with splenic, nodal, or extranodal stage I-II marginal zone lymphoma diagnosed between 1998 and 2012. A logistic regression model was used to assess the association between sociodemographic, tumor, and treatment characteristics and the utilization of radiation therapy. Multivariate propensity score-adjusted Cox proportional hazards models were performed to identify factors independently associated with overall survival (OS). Of 22,378 patients, 82% had stage I disease, 77% had extranodal mucosa-associated lymphoid tissue lymphoma, 5% had splenic marginal zone lymphoma, and 64% were older than 60 years. Radiation therapy utilization decreased from a peak of 39% in 2007 to 33% in 2011 (P < .001), with a corresponding significant increase in systemic therapy utilization. Radiation therapy was associated with a 5- and 10-year OS of 86.7% and 68.8% compared with 78.3% and 54.3% for no radiation therapy (P < .001). On multivariate propensity score-adjusted survival analysis, radiation therapy remained independently associated with improved OS (hazard of death, 0.75; 95% confidence interval, 0.65-0.85; P < .001). |
Does biliopancreatic diversion with duodenal switch improve insulin sensitivity and secretion through caloric restriction? | To assess the rapid improvement of insulin sensitivity and β-cell function following biliopancreatic diversion with duodenal switch (BPD-DS) and determine the role played by caloric restriction in these changes. Standard meals were administrated before and on day 3, 4, and 5 after BPD-DS to measure total caloric intake, glucose excursion, insulin sensitivity, and secretion in matched type 2 diabetes and normoglycemic (NG) subjects. In a second set of study, other subjects with type 2 diabetes had the same meal tests prior to and after a 3-day caloric restriction identical to that observed after BPD-DS and then 3 days after actually undergoing BPD-DS. Improvement of HOMA-IR occurred at day 3 after BPD-DS in diabetes and after 3 days of caloric restriction. The disposition index (DI) improved rapidly in diabetes after BPD-DS and to a similar extent after caloric restriction. DI was higher and did not change after BPD-DS in NG. Changes in glucagon-like peptide-1, gastric inhibitory peptide, peptide tyrosine tyrosine, ghrelin, and pancreatic polypeptide levels were not associated with modulation of DI in the participants. | Cenicriviroc is a potent antagonist of the chemokine coreceptors 5 and 2 (CCR5/CCR2) and blocks HIV-1 entry. The CCR5 inhibitor maraviroc has been shown in tissue culture to be able to repel cell-free virions from the cell surface into extracellular space. We hypothesized that cenicriviroc might exhibit a similar effect, and tested this using clinical samples from the Phase IIb study 652-2-202, by measuring rates of intracellular DNA decline. We also monitored viral RNA levels in culture fluids. We infected PM-1 cells with CCR5-tropic HIV-1 BaL in the presence or absence of inhibitory concentrations of cenicriviroc (20 nM) or maraviroc (50 nM) or controls. Viral load levels and p24 were measured by ELISA, quantitative PCR and quantitative real-time reverse transcription PCR at 4 h post-infection. Frozen PBMC DNA samples from 30 patients with virological success in the Phase IIb study were studied, as were early and late reverse transcript levels. Docking studies compared binding between cenicriviroc/CCR5 and maraviroc/CCR5. Unlike maraviroc, cenicriviroc did not cause an increase in the amount of virus present in culture fluids at 4 h compared with baseline. The use of cenicriviroc did, however, result in lower levels of intracellular viral DNA after 4 h. Structural modelling indicates that cenicriviroc binds more deeply than maraviroc to the hydrophobic pocket of CCR5, providing an explanation for the absence of viral rebound with cenicriviroc. |
Does computer-assisted analysis of biopsy specimen microvessels predict the outcome of esophageal cancers treated with chemoradiotherapy? | A computer-assisted microvessel analysis system was developed to evaluate correlations between the architecture of biopsy specimen microvessels and the outcome for patients with esophageal cancer treated with chemoradiotherapy. Biopsy specimens from 51 patients with esophageal cancer (T(2-3), any N, M0) treated with chemoradiotherapy were immunostained with an anti-CD31 antibody and quantified using computerized image analysis. We evaluated the association of several microvessel factors with overall survival, including the ratio of total microvessel perimeter to total tumor area (TP/TA), the tumor hypoxic ratio, and the ratio of total microvessel number to total tumor area (TN/TA). Results from traditional manual microvessel density (MVD) hotspot count and computerized hotspot count were compared and the relation between hotspot MVD count and survival rate was evaluated. The median follow-up time was 32 months. Both univariate and multivariate analyses revealed that computer-counted hotspot MVD and TN/TA and TP/TA ratios correlated significantly with the outcome of chemoradiotherapy. Kaplan-Meier survival curves showed that patients with high computer-counted hotspot MVDs and high TN/TA and TP/TA ratios had better overall survival rate than patients with low MVDs or ratios (P = 0.025, 0.008, and 0.031, respectively). Combining computer-counted MVD or TN/TA ratio with TP/TA ratio proved more predictive than any single factor. Two researcher-counted hotspot MVDs had no significant relation with outcome. | Are low vitamin D levels linked with semen quality and sex steroids in infertile men? |
Does cREB transcription factor modulate Bcl2 transcription in response to C5a in HL-60-derived neutrophils? | Complement fragment C5a and neutrophils have been implicated in the pathogenesis of renal disease and C5a has also been shown to delay apoptosis of human neutrophils via a transcription-independent pathway. However, transcription-dependent pathways have not been well described. The present study examined whether activation of HL-60-derived neutrophils by C5a modulates the transcription of two members of the Bcl2 family, Bax (pro-apoptotic) and Bcl2 (anti-apoptotic) molecules, and whether the cAMP-response element-binding protein (CREB) transcription factor mediates these effects through the phosphatidylinositol 3-kinase (PI3K)/Akt and extra-cellular signal-regulated kinase (ERK) signalling pathways. The human promyelocytic leukaemia HL-60 cell line was differentiated into neutrophils using 1.25% DMSO. Differentiated cells were incubated with recombinant human C5a for 30-120 min with, or without, pretreatment with wortmannin or PD98059. The cells were lysed and quantified for gene-specific Bax and Bcl2 mRNA. In separate experiments, cells were incubated with C5a for 5-30 min with, or without, pretreatment with wortmannin, PD98059, or alkaline phosphatase. Cells were then lysed and immunoblotted using antihuman phospho-CREB (Ser133) antibody. Apoptosis was assessed by measuring active caspase-3 in differentiated HL-60 cells. C5a inhibited caspase-3 activation in HL-60-derived neutrophils (P=0.003). C5a significantly increased the expression of Bcl2 mRNA (P=0.028), which was time-dependent, peaking at 30 min, and was abrogated in the presence of either wortmannin or PD98059 (both P=0.028). The C5a had no impact on Bax mRNA expression. The Bax : Bcl2 mRNA ratio markedly decreased at 30 min (P=0.028). Time-dependent effect of C5a on CREB phosphorylation was demonstrable and rapid, peaking at 5 min, and was abrogated by either wortmannin or PD98059 (both P=0.028). Phosphorylation of CREB, but not of Akt and ERK, was inhibited by alkaline phosphatase (P=0.028). The effect of C5a on Bcl2 mRNA expression was abrogated by alkaline phosphatase (P=0.028). The Bax : Bcl2 mRNA ratio markedly increased in the presence of alkaline phosphatase (P=0.046). | Understanding what causes changes in the flux of free fatty acids (FFA) is important to elucidate the etiology of metabolic syndrome. The first aim of this study was to test whether or not hormones and the autonomic nervous system influence blood FFA levels. A secondary aim was to test by means of a multiple group path analysis whether the consumption of fermented red ginseng (FRG; Panax ginseng) would influence those causal relationships. Ninety-three postmenopausal women (age 50-73 yr) were randomly divided into two groups. One group (44 women; age, 58.4 ± 5.9 yr; body mass index, 23.6 ± 2.5 kg/m(2)) was supplied placebo capsules and the other group (49 women, age 58.4 ± 5.5 yr; body mass index, 22.9 ± 2.4 kg/m(2)) was supplied FRG capsules. Both prior to and after the study (2 wk), blood samples were collected from the participants and several blood variables were measured and analyzed. Squared multiple correlations of FFA were 0.699 in the placebo group and 0.707 in the FRG group. The unstandardized estimate of estradiol (E2) for FFA was 0.824 in both groups. |
Is functional recovery considered the most important target : a survey of dedicated professionals? | The aim of this study was to survey the relative importance of postoperative recovery targets and perioperative care items, as perceived by a large group of international dedicated professionals. A questionnaire with eight postoperative recovery targets and 13 perioperative care items was mailed to participants of the first international Enhanced Recovery After Surgery (ERAS) congress and to authors of papers with a clear relevance to ERAS in abdominal surgery. The responders were divided into categories according to profession and region. The recovery targets 'To be completely free of nausea', 'To be independently mobile' and 'To be able to eat and drink as soon as possible' received the highest score irrespective of the responder's profession or region of origin. Equally, the care items 'Optimizing fluid balance', 'Preoperative counselling' and 'Promoting early and scheduled mobilisation' received the highest score across all groups. | A 34-year-old man presented with herpes simplex encephalitis (HSE), with magnetic resonance imaging (MRI) showing dense foci of restricted diffusion in the temporal lobe. With treatment and clinical improvement, follow-up MRI done 8 days later showed complete resolution of the restricted diffusion abnormalities, whereas other MRI sequences suggested interval progression. |
Do work status and burn specific health after work-related burn injury? | Work status is a valid indicator of post burn health. There is limited information on this issue after work-related burn injury. To investigate long-term health- and work status after work-related burns. Eighty-six former patients treated for severe work-related burn injuries an average of 9.0 years previous to follow-up were questioned about their present work status. They were also assessed with the Burn Specific Health Scale-Brief (BSHS-B) and a pain scale adopted from the abbreviated Burn Specific Health Scale. At follow-up 71 (83%) of the former patients were working, nine (10%) were on sick leave or had a disability pension, and six (7%) were unemployed. Those who were not working reported a poorer outcome in three of the BSHS-B psychosocial domains (Body Image, Affect and Interpersonal Relationships) and in two of the BSHS-B physical domains (Treatment Regimens and Work). They also reported significantly more pain. | The APOE genotype has a uniquely strong influence on the outcome of viral infection. The mechanism is unknown, although one possibility is direct inhibition of viral entry into cells. We have examined the direct anti-infective activity of a peptide analogue of the receptor-binding region of apolipoprotein E (apoE) that is known as "apoE dimer tandem repeat peptide" (apoEdp) and has previously been shown to mimic some of the biological effects of apoE and that recently was shown to bind low-density lipoprotein receptor-related protein. apoEdp has activity against herpes simplex virus types 1 and 2, human immunodeficiency virus, Pseudomonas aeruginosa, and Staphylococcus aureus; concentrations in the range of 1-20 micromol/L inhibit infection by 50%. These biological actions depend on adoption of an alpha -helical structure, as has been found for other biological effects of apoE peptides. The peptide interferes with the earliest stages of viral infection, preventing viral attachment and exerting a mild virucidal action. In addition, an N-terminal fragment of apoE that also contains this binding domain has antiviral activity. |
Is interleukin 6 associated with cachexia in patients with prostate cancer? | To evaluate the relationship between serum interleukin (IL)-6 and cachexia in patients with prostate cancer. Serum levels of IL-6, total protein, albumin, total cholesterol, and hemoglobin concentration were determined in 164 blood samples from patients with prostate cancer. The body mass index and performance status were also determined. The serum total protein, albumin, and cholesterol levels, hemoglobin levels, and body mass index of the patients whose serum IL-6 level was 7 pg/mL or greater were significantly lower (P <0.05) than the corresponding values in patients with a serum IL-6 level of less than 7 pg/mL. The serum IL-6 level of patients with a serum albumin level of less than 3.5 g/dL, serum total protein level of less than 7.0 g/dL, serum total cholesterol level of less than 180 mg/dL, hemoglobin level of less than 11.0 g/dL, and body mass index of less than 21 kg/m2 were significantly greater (P <0.05) than the values in their respective counterparts. A significant correlation was found between the elevation of serum IL-6 and performance status (P <0.05). The mortality rate of patients with greater serum IL-6 levels was significantly greater than that of those with lower serum IL-6 levels in patients with untreated disease, patients in remission, and patients with relapse (all P <0.05). | Accurate and reproducible assessment of extrinsic staining is pivotal to determining efficacy of some tooth whitening oral hygiene products. The aim of this study was: (1) to produce a stain shade guide to aid the in vitro and in vivo stain assessment (2) to assess intra- and inter-examiner reproducibility of stain assessment using the stain shade guide. Using chlorhexidine and tea, perspex and acrylic teeth specimens were stained. The amount of staining on the perspex was measured with a spectrophotometer and the values obtained were assigned to the stained acrylic teeth, which were made into a stain guide. Using clinical photographs and a group of 10 volunteers, stain area and intensity were assessed using the stain guide and the recognized Lobene stain index by two examiners. The degree of intra- and inter-examiner reproducibility for these measurements were assessed using Cohen's kappa statistics. For both the clinical examination and use of photographs, intra-examiner reproducibility for stain intensity was improved when using the stain guide compared with the Lobene Index. Similarly, when assessing inter-examiner reproducibility, stain intensity kappa values were greater using the stain guide (kappa = 0.82) compared with the Lobene Index (kappa = 0.57). |
Does high or low calcium intake increase cardiovascular disease risks in older patients with type 2 diabetes? | We investigated the effects of dietary calcium (Ca) and magnesium (Mg) intakes on cardiovascular disease risks in older patients with diabetes. In this cross-sectional study, 197 patients with type 2 diabetes aged 65 years and above were recruited. The 24-h dietary recalls and 1-week self-reported typical dietary intake patterns were collected. The Ca and Mg intakes of <67% of the recommended dietary allowance (RDA), 67%-100% of RDA, and >100% of RDA were defined as low, moderate, and high Ca and Mg intakes, respectively. Anthropometric measurements were determined and biochemical analysis of blood and urine was performed. Our data indicated that 60.9% and 87.3% of our patients were Ca and Mg intakes below RDA, respectively. Patients whose Ca intake was high or low (81.2%) had significantly higher C-reactive protein (CRP) than those whose Ca intake was moderate (p = 0.043). Furthermore, patients whose Mg intake was low (87.3%) had significantly higher CRP than that of those who took adequate Mg (p = 0.025). The dietary Ca:Mg intake ratios were highly correlated with CRP, platelet counts, and red blood cell distribution (p < 0.05). A dietary Ca:Mg intake ratio of 2.0-2.5 was significantly correlated to lower CRP levels (p = 0.013). | Hox transcription factors modulate signaling pathways controlling organ morphogenesis and maintain cell fate and differentiation in adults. Retinoid signaling, key in regulating Hox expression, is altered in pulmonary hypoplasia. Information on pattern-specific expression of Hox proteins in normal lung development and in pulmonary hypoplasia is minimal. Our objective was to determine how pulmonary hypoplasia alters temporal, spatial, and cellular expression of Hoxa5, Hoxb4, and Hoxb6 proteins compared to normal lung development. Temporal, spatial, and cellular Hoxa5, Hoxb4, and Hoxb6 expression was studied in normal (untreated) and nitrofen-induced hypoplastic (NT-PH) lungs from gestational day 13.5, 16, and 19 fetuses and neonates using Western blot and immunohistochemistry. Modification of protein levels and spatial and cellular Hox expression patterns in NT-PH lungs was consistent with delayed lung development. Distinct protein isoforms were detected for each Hox protein. Expression levels of the Hoxa5 and Hoxb6 protein isoforms changed with development and were altered further in NT-PH lungs. Compared to normal lungs, GD19 and neonatal NT-PH lungs had decreased Hoxb6 and increased Hoxa5 and Hoxb4. Hoxa5 cellular localization changed from mesenchyme to epithelia earlier in normal lungs. Hoxb4 was expressed in mesenchyme and epithelial cells throughout development. Hoxb6 remained mainly in mesenchymal cells around distal airways. |
Does early sac shrinkage predict a low risk of late complications after endovascular aortic aneurysm repair? | Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm repair (EVAR). Patients with early postoperative shrinkage may experience fewer subsequent complications, and consequently require less intensive surveillance. Patients undergoing EVAR from 2000 to 2011 at three vascular centres (in 2 countries), who had two imaging examinations (postoperative and after 6-18 months), were included. Maximum diameter, complications and secondary interventions during follow-up were registered. Patients were categorized according to early sac dynamics. The primary endpoint was freedom from late complications. Secondary endpoints were freedom from secondary intervention, postimplant rupture and direct (type I/III) endoleaks. Some 597 EVARs (71.1 per cent of all EVARs) were included. No shrinkage was observed in 284 patients (47.6 per cent), moderate shrinkage (5-9 mm) in 142 (23.8 per cent) and major shrinkage (at least 10 mm) in 171 patients (28.6 per cent). Four years after the index imaging, the rate of freedom from complications was 84.3 (95 per cent confidence interval 78.7 to 89.8), 88.1 (80.6 to 95.5) and 94.4 (90.1 to 98.7) per cent respectively. No shrinkage was an independent risk factor for late complications compared with major shrinkage (hazard ratio (HR) 3.11; P < 0.001). Moderate compared with major shrinkage (HR 2.10; P = 0.022), early postoperative complications (HR 3.34; P < 0.001) and increasing abdominal aortic aneurysm baseline diameter (HR 1.02; P = 0.001) were also risk factors for late complications. Freedom from secondary interventions and direct endoleaks was greater for patients with major sac shrinkage. | Widespread transcription activities in the human genome were recently observed in high-resolution tiling array experiments, which revealed many novel transcripts that are outside of the boundaries of known protein or RNA genes. Termed as "TARs" (Transcriptionally Active Regions), these novel transcribed regions represent "dark matter" in the genome, and their origin and functionality need to be explained. Many of these transcripts are thought to code for novel proteins or non-protein-coding RNAs. We have applied an integrated bioinformatics approach to investigate the properties of these TARs, including cross-species conservation, and the ability to form stable secondary structures. The goal of this study is to identify a list of potential candidate sequences that are likely to code for functional non-protein-coding RNAs. We are particularly interested in the discovery of those functional RNA candidates that are primate-specific, i.e. those that do not have homologs in the mouse or dog genomes but in rhesus. Using sequence conservation and the probability of forming stable secondary structures, we have identified approximately 300 possible candidates for primate-specific noncoding RNAs. We are currently in the process of sequencing the orthologous regions of these candidate sequences in several other primate species. We will then be able to apply a "phylogenetic shadowing" approach to analyze the functionality of these ncRNA candidates. |
Is downregulation of MicroRNA-1 Associated with Poor Prognosis in Hepatocellular Carcinoma? | The relationship between microRNA-1 (miR-1) expression and prognosis has not been reported in hepatocellular carcinoma (HCC). The present study aimed to explore the clinicopathological significance and the prognostic role of miR-1 in HCC. The expression levels of miR-1 were quantified using real-time quantitative PCR (q-PCR) in 40 surgically resected HCC samples and matched adjacent non-cancerous tissues. MiR-1 expression was significantly downregulated in HCC compared with matched non-cancerous tissues. Aberrant miR-1 expression was significantly correlated with gender, expression of hepatitis B virus surface antigen (HBsAg), tumor differentiation, vein invasion, and TNM stage. Patients with low expression of miR-1 had significantly reduced overall survival compared with patients with high expression of miR-1 (p = 0.04).The multivariate Cox regression analysis indicated that miR-1 expression (HR = 2.79; p = 0.005), gender (HR = 0.087; p = 0.005), vein invasion (HR = 0.172; p = 0.007), and TNM stage (HR = 3.421; p = 0.001) were independent prognostic factors for overall survival. | Diffusion tensor imaging (DTI) was used to evaluate white matter architecture after preterm birth. The goals were (1) to compare white matter microstructure in two cohorts of preterm- and term-born children; and (2) within preterm groups, to determine if sex, gestational age, birthweight, white matter injury score from conventional magnetic resonance imaging (MRI), or IQ was associated with DTI measures. Participants (n=121; 66 females, 55 males) were aged 9 to 16 years. They comprised 58 preterm children (site 1, n=25; and site 2, n=33) born at less than 36 weeks' gestation (mean 29.4 wks; birthweight 1289g) and 63 term children (site 1, n=40; site 2, n=23) born at more than 37 weeks' gestation. DTI was analyzed using tract-based spatial statistics. Diffusion measures were fractional anisotropy, axial, radial, and mean diffusivity. In no region of the white matter skeleton was fractional anisotropy lower in the preterm group at either site. Within the preterm groups, fractional anisotropy was significantly associated with white matter injury score, but not sex, gestational age, or birthweight. At site 1, fractional anisotropy was associated with IQ. |
Does short-term exercise training stimulate skeletal muscle ATP synthesis in relatives of humans with type 2 diabetes? | We tested the hypothesis that short-term exercise training improves hereditary insulin resistance by stimulating ATP synthesis and investigated associations with gene polymorphisms. We studied 24 nonobese first-degree relatives of type 2 diabetic patients and 12 control subjects at rest and 48 h after three bouts of exercise. In addition to measurements of oxygen uptake and insulin sensitivity (oral glucose tolerance test), ectopic lipids and mitochondrial ATP synthesis were assessed using(1)H and(31)P magnetic resonance spectroscopy, respectively. They were genotyped for polymorphisms in genes regulating mitochondrial function, PPARGC1A (rs8192678) and NDUFB6 (rs540467). Relatives had slightly lower (P = 0.012) insulin sensitivity than control subjects. In control subjects, ATP synthase flux rose by 18% (P = 0.0001), being 23% higher (P = 0.002) than that in relatives after exercise training. Relatives responding to exercise training with increased ATP synthesis (+19%, P = 0.009) showed improved insulin sensitivity (P = 0.009) compared with those whose insulin sensitivity did not improve. A polymorphism in the NDUFB6 gene from respiratory chain complex I related to ATP synthesis (P = 0.02) and insulin sensitivity response to exercise training (P = 0.05). ATP synthase flux correlated with O(2)uptake and insulin sensitivity. | MicroRNA-222 (miR-222) has been shown to play a potential oncogenic role in bladder cancer. The aim of this study was to evaluate the expression of miR-222 in bladder cancer and its potential relevance to clinicopathological characteristics and patient survival. Surgical specimens of cancer tissue and adjacent normal tissue were obtained from 97 patients with bladder cancer. The relative expression levels of miR-222 in the cancer and the normal adjacent tissue were measured by quantitative reverse-transcriptase PCR. We analyzed their correlation with clinicopathological parameters and prognostic value. The expression level of miR-222 was significantly higher in tumor tissues than in corresponding non-cancerous tissues (5.46 ± 1.45 versus 1.92 ± 0.65, P < 0.0001), and a high expression of miR-222 was found to be significantly associated with tumor grade (P = 0.003) and tumor stage (P = 0.005). The miR-222 expression level was classified as high or low in relation to the median value (cutoff value = 5.15). Kaplan-Meier analysis showed that patients with higher levels of miR-222 had significantly poorer survival than those with lower expression of this miRNA in patients, with a 5-year overall survival of 29.53% and 52.75%, respectively (P = 0.0034). In the multivariate Cox proportional hazards analysis, which included miR-222 level, tumor grade, tumor stage, and tumor number, high miR-222 expression was independently associated with poor survival (P < 0.001; hazard ratio 6.17; 95% CI 2.33 to 10.39). |
Do aged mice exhibit greater mortality concomitant to increased brain and plasma TNF-alpha levels following intracerebroventricular injection of lipopolysaccharide? | Age-related defects in the development of peripheral inflammatory responses have been observed in rodents and humans. We examined the effects of age on a centrally injected endotoxin-induced cytokine production and cellular activation in mice. Male C57BL/6J (B6) mice, C3H/HeN mice, and C3H/HeJ mice received an intracerebroventricular injection of lipopolysaccharide (LPS) and were sacrificed at various times (2, 4, 8 h) thereafter. ELISA for IL-1beta, IL-6, IL-12, and TNF-alpha were conducted on forebrain tissue homogenates as well as plasma samples, and lectin staining to detect activated microglia was prepared for selected brain slices. Intracerebroventricular injection of LPS in B6 mice produced an age-associated increase in mortality which was paralleled with a significant increase in brain and plasma levels of TNF-alpha. AntiTNF-alpha- and IL-6-immunoreactive cells possessed macrophagelike morphologies and were observed along the LPS injection tract and scattered throughout the hilus of the dorsal hippocampus and cerebral cortices. This LPS-mediated response was found to be specific in that the LPS-hyporesponsive mouse strain (C3H/HeJ) failed to demonstrate significant brain or plasma levels of TNF-alpha after LPS administration compared to C3H/HeN mice. | RNA editing is the process whereby an RNA sequence is modified from the sequence of the corresponding DNA template. In the mitochondria of land plants, some cytidines are converted to uridines before translation. Despite substantial study, the molecular biological mechanism by which C-to-U RNA editing proceeds remains relatively obscure, although several experimental studies have implicated a role for cis-recognition. A highly non-random distribution of nucleotides is observed in the immediate vicinity of edited sites (within 20 nucleotides 5' and 3'), but no precise consensus motif has been identified. Data for analysis were derived from the the complete mitochondrial genomes of Arabidopsis thaliana, Brassica napus, and Oryza sativa; additionally, a combined data set of observations across all three genomes was generated. We selected datasets based on the 20 nucleotides 5' and the 20 nucleotides 3' of edited sites and an equivalently sized and appropriately constructed null-set of non-edited sites. We used tree-based statistical methods and random forests to generate models of C-to-U RNA editing based on the nucleotides surrounding the edited/non-edited sites and on the estimated folding energies of those regions. Tree-based statistical methods based on primary sequence data surrounding edited/non-edited sites and estimates of free energy of folding yield models with optimistic re-substitution-based estimates of approximately 0.71 accuracy, approximately 0.64 sensitivity, and approximately 0.88 specificity. Random forest analysis yielded better models and more exact performance estimates with approximately 0.74 accuracy, approximately 0.72 sensitivity, and approximately 0.81 specificity for the combined observations. |
Does standardized EEG interpretation accurately predict prognosis after cardiac arrest? | To identify reliable predictors of outcome in comatose patients after cardiac arrest using a single routine EEG and standardized interpretation according to the terminology proposed by the American Clinical Neurophysiology Society. In this cohort study, 4 EEG specialists, blinded to outcome, evaluated prospectively recorded EEGs in the Target Temperature Management trial (TTM trial) that randomized patients to 33°C vs 36°C. Routine EEG was performed in patients still comatose after rewarming. EEGs were classified into highly malignant (suppression, suppression with periodic discharges, burst-suppression), malignant (periodic or rhythmic patterns, pathological or nonreactive background), and benign EEG (absence of malignant features). Poor outcome was defined as best Cerebral Performance Category score 3-5 until 180 days. Eight TTM sites randomized 202 patients. EEGs were recorded in 103 patients at a median 77 hours after cardiac arrest; 37% had a highly malignant EEG and all had a poor outcome (specificity 100%, sensitivity 50%). Any malignant EEG feature had a low specificity to predict poor prognosis (48%) but if 2 malignant EEG features were present specificity increased to 96% (p < 0.001). Specificity and sensitivity were not significantly affected by targeted temperature or sedation. A benign EEG was found in 1% of the patients with a poor outcome. | TNFα and IL-17 have been shown to be the major inflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA). Here, we examined the effect of these cytokines on spontaneously occurring RA in our newly established arthritis-prone FcγRIIB- deficient C57BL/6 (B6) mice, designated KO1, by introducing genetic deficiency of TNFα and IL-17 into KO1 mice. KO1.TNFα(-/-) and KO1.IL-17(-/-) mice were established by crossing KO1 with TNFα-deficient and IL-17-deficient B6 mice, respectively. The incidence and severity of RA, cartilage and bone destruction, immunological abnormalities, and transcription levels of receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) and inflammatory cytokines/chemokines in ankle joints were compared among KO1, KO1.TNFα(-/-), and KO1.IL-17(-/-) mice. The development of RA was completely inhibited in KO1.TNFα(-/-) mice. In contrast, KO1.IL-17(-/-) mice unexpectedly developed severe RA comparable to KO1. Compared with those in KO1 and KO1.IL-17(-/-) mice, frequencies of peripheral monocytes, known to be containing osteoclast precursors, were significantly decreased in KO1.TNFα(-/-) mice. Intriguingly, while RANKL expression levels in ankle joints did not differ among the three strains, OPG expression levels were drastically decreased in arthritis-prone, but not arthritis-free, mice. The expression levels of inflammatory cytokines/chemokines, such as MCP-1, IL-6, and TNFα, were up-regulated in arthritis-prone mice. |
Do depression symptoms predict heart rate recovery after treadmill stress testing? | Altered autonomic nervous system (ANS) functioning may help to explain the relationship between depression and cardiac mortality. Heart rate (HR) recovery after the cessation of a treadmill stress test assesses ANS functioning and predicts mortality. This study examined the relationship between depression symptoms and HR recovery among patients entering phase II cardiac rehabilitation. Two hundred sixty patients were assessed at the time of their enrollment in cardiac rehabilitation. Patients completed a ramped-protocol treadmill stress test, providing an assessment of exercise capacity and HR recovery at 2 minutes post exercise. Depression symptoms were measured using the Beck Depression Inventory. Other medical information was obtained by chart review. Patients with higher Beck Depression Inventory scores exhibited slower HR recovery after exercise. This remained true after controlling for age, sex, and beta-blocker usage. Controlling for exercise capacity rendered the relationship between depression score and HR recovery non significant, suggesting that exercise capacity may partly account for this relationship. | Celecoxib, an inhibitor of cyclooxygenase-2 (COX2), was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs), as well as elucidate the underlying mechanisms. The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway. MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 μmol/L) plus 5-fluorouracil (8.1 × 10(-3) g/L) or sorafenib (4.4 μmol/L) increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR) and phosphorylated (p)-AKT expression. Gefitinib (5 μmol/L), which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 μmol/L) plus celecoxib (21.8 μmol/L) increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited. |
Does lysophosphatidylcholine increase 3-Hydroxy-3-methylglutaryl-coenzyme A reductase gene expression in CaCo-2 cells? | The small intestine plays an important role in cholesterol homeostasis. The aim of this study was to examine the regulation of cholesterol synthesis by lysophosphatidylcholine in intestinal cells. CaCo-2 cells cultured on semipermeable supports were incubated with taurocholate and lysophosphatidylcholine, and cholesterol synthesis rate, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity, mass, and messenger RNA abundance were estimated. Lysophosphatidylcholine increased the rate of cholesterol synthesis as estimated by HMG-CoA reductase activity and acetate or water incorporation into sterols. Reductase was also increased by lysophosphatidylinositol or lysophosphatidylethanolamine but not by lysophosphatidylserine. Lysophosphatidylcholine increased HMG-CoA reductase messenger RNA and mass, suggesting that lysophosphatidylcholine regulated reductase at the level of gene expression. The various lysophospholipids caused the efflux of cellular cholesterol into the apical medium, and the amount effluxed correlated with the observed increase in reductase activity. Adding cholesterol to micelles containing lysophosphatidylcholine prevented the increase in HMG-CoA reductase activity and mass. | Prognosis and treatment of patients with breast carcinoma of no special type (NST) is dependent on a few established parameters, such as tumor size, histological grade, lymph node stage, expression of estrogen receptor, progesterone receptor, and HER-2/neu, and proliferation index. The original Nottingham Prognostic Index (NPI) employs a three-tiered classification system that stratifies patients with breast cancer into good, moderate, and poor prognostic groups. The aim of our study was to use robust immunohistochemical methodology for determination of ER, PR, HER-2/neu, Ki-67, p53, and Bcl-2, and to observe differences in the expression of these markers when patients are stratified according to the original, three-tiered Nottingham Prognostic Index. Paraffin blocks from 120 patients diagnosed with breast carcinoma, NST, were retrieved from our archive. Cases included in the study were female patients previously treated with modified radical mastectomy and axillary dissection. Our study demonstrates that expression of markers of good prognosis, such as ER, PR, and Bcl-2, is seen with higher frequency in good and moderate NPI groups. In contrast, overexpression of HER-2/neu, a marker of adverse prognosis, is more frequent in moderate and poor NPI groups. High proliferation index, as measured by Ki-67, is seen in moderate and poor NPI groups, whereas low proliferation index is seen in good NPI groups. |
Is gain of human telomerase RNA gene associated with progression of cervical intraepithelial neoplasia grade I or II? | The 3q26 chromosome region, where the human telomerase RNA gene (hTERC) is located, is a biomarker for cervical cancer and precancerous lesions. The aim of this study was to confirm the value of measuring hTERC gene gain in predicting the progression of cervical intraepithelial neoplasia grade I or II (CIN-I and -II, respectively) to CIN-III and cervical cancer. Liquid-based cytological samples from 54 patients with CIN-I or CIN-II lesions were enrolled in this study. Follow-up was performed with colposcopy and biopsy within 24 months after the diagnosis of CIN-I or CIN-II. Copy numbers of the hTERC gene were measured by fluorescence in situ hybridization with a dual-color probe mix containing the hTERC gene probe (labeled red) and the control, the chromosome 3 centromere-specific probe (labeled green). All patients whose lesions progressed from CIN-I or CIN-II to CIN-III displayed a gain of the hTERC gene, whereas patients where the hTERC gene was not amplified did not subsequently progress to CIN-III or cervical cancer. The signal ratio pattern per cell was recorded as N:N (green:red). The numbers of cells with the signal ratio pattern of 4:4 or N:≥5 in patients whose lesions progressed to CIN-III were significantly higher than those whose lesions did not progress. Significantly, none of the patients with a 4:4 signal ratio pattern regressed spontaneously. | Obesity is a growing health problem and associated with immune dysfunction. Sepsis is defined as systemic inflammatory response syndrome that occurs during infection. Excessive inflammation combined with immune dysfunction can lead to multiorgan damage and death. The authors investigated the influence of a class 1 obesity (body mass index between 30 and 34.9) on immune function and outcome in sepsis and the role of leptin on the immune response. The authors used a long-term high-fat-diet feeding model (12 weeks) on C57Bl/6 mice (n = 100) and controls on standard diet (n = 140) followed by a polymicrobial sepsis induced by cecal ligation and puncture. The authors show that class 1 obesity is connected to significant higher serum leptin levels (data are mean ± SEM) (5.7 ± 1.2 vs. 2.7 ± 0.2 ng/ml; n = 5; P = 0.033) and improved innate immune response followed by significant better survival rate in sepsis (71.4%, n = 10 vs. 10%, n = 14; P < 0.0001). Additional sepsis-induced increases in leptin levels stabilize body temperature and are associated with a controlled immune response in a time-dependent and protective manner. Furthermore, leptin treatment of normal-weight septic mice with relative hypoleptinemia (n = 35) also significantly stabilizes body temperature, improves cellular immune response, and reduces proinflammatory cytokine response resulting in improved survival (30%; n = 10). |
Does lung density associate with survival in alpha 1 antitrypsin deficient patients? | CT density correlates with quality of life (QOL) scores and impaired upper zone lung density associates with higher mortality in alpha one antitrypsin deficiency (A1ATD). We hypothesised that decline in CT densitometry would relate to survival or deterioration in QOL in A1ATD. All augmentation naïve PiZZ patients in the UK A1ATD registry with ≥ two successive quantitative CT scans were selected. Patients were divided into groups based on CT density decline and the relationship to survival and change in QOL compared by univariate analyses and multivariate Cox regression. Analyses were performed for whole lung, upper zone and lower zone density separately. Exploratory analyses of FEV1 subgroups were conducted. 110 patients were identified; 77 had whole lung and lung zone density recorded on two CT scans, 33 patients had upper zone data only on four scans. Decline in lower zone density associated with survival, even after adjustment for baseline lung density (p = 0.048), however upper zone density and whole lung density decline did not. This difference appeared to be driven by those with FEV1 >30% predicted. | Emerging evidence has indicated the bad effect of periodontal inflammation on diabetes control. However, the exact regulatory mechanisms within the association between periodontitis and diabetic development remain unclear. This study aims to investigate the function of microRNAs in regulating periodontitis-induced inflammation in an obese rat model. Experimental periodontitis was introduced into OLETF and LETO rat. Intraperitoneal glucose tolerance test was performed to detect diabetic development. Serum cytokines levels and microRNAs expression were detected by ELISA and RT-PCR analysis respectively. And, macrophages were isolated for gain- and loss-of-function studies, to investigate the regulatory mechanism of miR-147 in periodontitis-induced inflammation. Periodontitis induced proinflammatory response with classical activated macrophages in both rats, but distinctively aggravated the impaired glucose tolerance of OLETF rat with spontaneous type 2 diabetes. Analysis for serum microRNAs expression showed the distinctive and synergistic upregulation of miR-147 with periodontitis-induced effects in rats, while further experiments demonstrated the positive regulatory mechanism of miR-147 on classical activated macrophages with overexpressed proinflammatory markers, showing M1 phenotype. |
Do catheter closure of atrial septal defects with deficient inferior vena cava rim under transesophageal echo guidance? | To describe the case selection, imaging considerations, technique, and results of catheter closure of atrial septal defects (ASD) with deficient inferior vena cava (IVC) rim. Transcatheter closure with Amplatzer septal occluder (ASO) has become standard treatment for most secundum ASDs. Defects with deficient IVC rim continue to be challenging to image and close in the catheterization laboratory. Records of 12 patients with deficient IVC rim (<5 mm), who underwent catheter closure (April 2007 to June 2008) were reviewed. General anesthesia and transesophageal echo (TEE) guidance was used in all. The IVC rim was imaged at 70 degrees-90 degrees with retroflexion of the TEE probe, in addition to the conventional views. Devices 1-4 mm > maximal ASD size were selected. Deployment was accomplished either from the left atrium, left upper or from the right pulmonary veins. The median age was 5.5 (2.5-27) years and median weight was 19.5 (9-65) kg. The defects measured 16-32 mm and 18-36 mm septal occluders were used. The median fluoroscopic time was 13.1 (4.2-32.7) min. Initial device selection was revised in four patients. Two patients had residual flows at IVC margin. The device embolized to right ventricular outflow tract in one patient. This was retrieved, and a larger device was deployed. No other complications were observed immediately or on follow-up (median 6; range 1-14 months). | To investigate the expression of cyclooxygenase (COX)-1, -2, and -3 RNA and protein in retinal pigment epithelial (ARPE-19) cells and in human neural (HN) cells exposed to the stress-inducing cytokines IL-1beta and TNF-a, the oxidizing peroxide H(2)O(2), the combination of TNF-alpha + H(2)O(2), and the lipofuscin fluorophore A2E. Three-week-old ARPE-19 and HN cells were incubated with IL-1beta (10 ng/ml), TNF-alpha (10 ng/ml), H(2)O(2) (0.6 microM), TNF-alpha + H(2)O(2) (10 ng/ml and 0.6 microM), or A2E (10 microM) for 8 hr, after which total RNA and whole cellular proteins were isolated. Cyclooxygenase-1, -2, and -3 RNA and protein levels were quantified using Northern and Western immunoassay. IL-1beta-, H(2)O(2)-, TNF-alpha-, TNF-alpha + H(2)O(2)-, or A2E-stressed ARPE-19 or HN cells displayed no significant upregulation in COX-1 or COX-3 RNA message abundance; however, significant upregulation was observed in COX-2 RNA message and protein abundance. A2E treatment of HN cells resulted in modest increases in COX-3 protein, an effect that was not observed in ARPE-19 cells. |
Are mutations in the aryl hydrocarbon receptor interacting protein gene highly prevalent among subjects with sporadic pituitary adenomas? | Limited screening suggests that three germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are not involved in sporadic pituitary tumorigenesis. Multiple novel mutations of this gene have since been identified in familial isolated pituitary adenoma cohorts. The objective of the study was to undertake full AIP coding sequence screening to assess for the presence of germline and somatic mutations in European Union subjects with sporadic pituitary tumors. The study design was the analysis of DNA from peripheral blood lymphocytes and analysis of exons 1-6 and paraexonic intron sequences of AIP. Multiplex ligation-dependent probe amplification was used to screen separate sporadic pituitary tumor tissue samples for discrete and extensive deletions or mutations of the AIP gene. The study was conducted in university tertiary referral Clinical Genetics, Molecular Biology, and Endocrinology Departments. In 107 patients [prolactinomas (n =49), nonfunctioning tumors (n = 29), somatotropinomas (n = 26), ACTH-secreting tumors (n = 2), TSH-secreting tumors (n = 1)], no germline mutations of AIP were demonstrated. Among a group of 41 tumor samples from other subjects, a novel AIP mutation (R22X) was found in one sample in which the corresponding allele was deleted; follow-up screening of the patient demonstrated a germline R22X AIP mutation. | We investigated whether direct hemoperfusion with an immobilized polymyxin B column (DHP with PMX) could reduce the blood level of neutrophil elastase. 20 sepsis patients were enrolled in the study. DHP with PMX was performed twice within a 24-hour period. Neutrophil elastase was measured 7 times. Neutrophil elastase was 468 +/- 75.1 microg/l, while it was 1,531 +/- 201.7 microg/l immediately after the first session, declined to 351 +/- 73.9 microg/l before the second session of DHP with PMX, and increased again to 599.3 +/- 112.7 microg/l immediately after the second session, 328 +/- 73.7 microg/l at 24 h, 264 +/- 39.3 microg/l at 48 h, and 230 +/- 36.1 microg/l at 72 h after DHP with PMX. The levels from 48 h onwards were significantly lower compared with that before treatment. |
Does strong Notch activation hinder bevacizumab efficacy in advanced colorectal cancer? | To assess the role of Notch activation in predicting bevacizumab efficacy in colorectal cancer (CRC). Notch activation was evaluated by immunohistochemistry (IHC) on 65 CRC enrolled within randomized clinical trials assessing first-line bevacizumab-based chemotherapy and on 21 CRC treated with chemotherapy alone. Strong Notch (IHC 3+) activation was negatively associated with response (18 vs 62% in low Notch cases [IHC 0, 1, 2+]; p = 0.016), progression-free survival (4.9 vs 12.1 months; p = 0.002) and overall survival (19.3 vs 30.4 months; p = 0.039). No correlation was found between Notch activation and clinical outcome in CRC treated with chemotherapy alone. | To assess the utility of standard equations for calculating caloric requirements in patients with amyotrophic lateral sclerosis (ALS). Malnutrition substantially increases the risk of death in ALS. Weight loss can be stabilized and survival prolonged with early gastrostomy feeding. However the use of standard nutrition equations has not been validated in this population. We therefore compared measured caloric expenditure to 2 predictive equations in patients with varying stages of ALS. Thirty-four patients were studied. Caloric expenditure and respiratory quotient (R) were measured using indirect calorimetry. Results were compared with the Harris-Benedict equation. The prediction error for the Harris-Benedict equation was 18.6 + 14.9%. Limits of agreement showed this equation could overestimate caloric expenditure by 591 kcal/d and underestimate requirements by 677 kcal/d. R was >0.86 in 11 patients, suggesting overfeeding, and <0.8 in 15 patients, suggesting underfeeding. The difference between predicted and measured caloric expenditure did not correlate with disease severity, disease duration, or body mass index. Mechanically ventilated patients had higher than predicted energy expenditure. |
Is abdominal aortic diameter increased in males with a family history of abdominal aortic aneurysms : results from the Danish VIVA-trial? | To investigate, at a population level, whether a family history of abdominal aortic aneurysm (AAA) is independently related to increased aortic diameter and prevalence of AAA in men, and to elucidate whether the mean aortic diameter and the prevalence of AAA are different between participants with male and female relatives with AAA. Observational population-based cross-sectional study. 18,614 male participants screened for AAA in the VIVA-trial 2008-2011 with information on both family history of AAA and maximal aortic diameter. Standardized ultrasound scan measurement of maximum antero-posterior aortic diameter. Family history obtained by questionnaire. Multivariate regression analysis was used to test for confounders: age, sex, smoking, comorbidity and medication. From the screened cohort, 569 participants had at least one first degree relative diagnosed with AAA, and 38 had AAA. Participants with a family history of AAA (+FH) had a significantly larger mean maximum aortic diameter (20.50 mm) compared with participants without family history of AAA (-FH) (19.07 mm, p < .0001), and +FH with female relatives with AAA had significantly larger mean maximum aortic diameter (21.8 mm) than +FH with male relatives (19.9 mm, p = .007). Furthermore the prevalence of AAA was significantly higher among +FH (6.7%) compared with -FH (3.0%) with an odds ratio (OR) of 2.2 (95% CI: 1.6 to 3.2, p < .001) and +FH with female relatives with AAA had a more than two and a half times increased prevalence of AAA compared with +FH with male relatives with AAA with an OR of 2.65. | Efficient enzymatic saccharification of plant cell wall material is key to industrial processing of agricultural and forestry waste such as straw and wood chips into fuels and chemicals. Saccharification assays were performed on steam-pretreated wheat straw under ambient and O2-deprived environments and in the absence and presence of a lytic polysaccharide monooxygenase (LPMO) and catalase. A kinetic model was used to calculate catalytic rate and first-order inactivation rate constants of the cellulases from reaction progress curves. The addition of a LPMO significantly (P < 0.01, Student's T test) enhanced the rate of glucose release from 2.8 to 6.9 h(-1) under ambient O2 conditions. However, this also significantly (P < 0.01, Student's T test) increased the rate of inactivation of the enzyme mixture, thereby reducing the performance half-life from 65 to 35 h. Decreasing O2 levels or, strikingly, the addition of catalase significantly reduced (P < 0.01, Student's T test) enzyme inactivation and, as a consequence, higher efficiency of the cellulolytic enzyme cocktail was achieved. |
Is aging associated with a diminished axon reflex response to local heating on the gaiter skin area? | Elderly patients are susceptible to skin ulcerations on the supramedial malleolar area of the leg. Our aim was, using local thermal hyperemia, to study microvascular function on the gaiter skin area of elderly, but otherwise healthy volunteers, because abnormal microvascular reactivity could contribute to ulcerations in this region. Two groups of healthy volunteers were enrolled according to age, including 20 subjects aged from 18 to 30 years (young group) and 42 subjects aged from 60 to 86 years (older group). Local thermal hyperemia to 43°C was performed for 1 h using heating circular probes and skin blood flow was recorded using Laser Doppler Imaging, with or without 2 h lidocaine/prilocaine cream application. Sodium nitroprusside iontophoresis was also performed. The initial local thermal hyperemia peak was lower in the older group (14.7 mV/mmHg±6.9) compared to the young group (19.9±7.2, P=0.009). Lidocaine/prilocaine cream decreased the initial local thermal hyperemia peak and the late plateau for all groups. The local thermal hyperemia plateau and sodium nitroprusside iontophoresis corrected for skin resistance did not differ between older and younger subjects. | It is well established that environmental toxins, such as exposure to arsenic, are risk factors in the development of urinary bladder cancer, yet recent genome-wide association studies (GWAS) provide compelling evidence that there is a strong genetic component associated with disease predisposition. A single-nucleotide polymorphism (SNP), rs8102137, was identified on chromosome 19q12, residing 6 kb upstream of the important cell-cycle regulator and proto-oncogene, Cyclin E1 (CCNE1). However, the functional role of this variant in bladder cancer predisposition has been unclear because it lies within a non-coding region of the genome. Here, it is demonstrated that bladder cancer cells heterozygous for this SNP exhibit biased allelic expression of CCNE1 with 1.5-fold more transcription occurring from the risk allele. Furthermore, using chromatin immunoprecipitation assays, a novel enhancer element was identified within the first intron of CCNE1 that binds Kruppel-like Factor 5 (KLF5), a known transcriptional activator in bladder cancer. Moreover, the data reveal that the presence of rs200996365, a SNP in high-linkage disequilibrium with rs8102137 residing in the center of a KLF5 motif, alters KLF5 binding to this genomic region. Through luciferase assays and CRISPR-Cas9 genome editing, a novel polymorphic intronic regulatory element controlling CCNE1 transcription is characterized. These studies uncover how a cancer-associated polymorphism mechanistically contributes to an increased predisposition for bladder cancer development. |
Does histological examination confirm clinical clearance of actinic keratoses following treatment with ingenol mebutate 0·05 % gel? | To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint. This phase I, multicentre, single-arm, open-label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis. Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25-cm The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8-week complete clearance rate was 41% (95% confidence interval 32-50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application-site pain (four patients, 3·7%) was the most common treatment-related AE inside the treatment area. | Changes in gene regulation are suspected to comprise one of the driving forces for evolution. To address the extent of cis-regulatory changes and how they impact on gene regulatory networks across eukaryotes, we systematically analyzed the evolutionary dynamics of target gene batteries controlled by 16 different transcription factors. We found that gene batteries show variable conservation within vertebrates, with slow and fast evolving modules. Hence, while a key gene battery associated with the cell cycle is conserved throughout metazoans, the POU5F1 (Oct4) and SOX2 batteries in embryonic stem cells show strong conservation within mammals, with the striking exception of rodents. Within the genes composing a given gene battery, we could identify a conserved core that likely reflects the ancestral function of the corresponding transcription factor. Interestingly, we show that the association between a transcription factor and its target genes is conserved even when we exclude conserved sequence similarities of their promoter regions from our analysis. This supports the idea that turnover, either of the transcription factor binding site or its direct neighboring sequence, is a pervasive feature of proximal regulatory sequences. |
Does treatment with TNF-alpha or bacterial lipopolysaccharide attenuate endocardial endothelial cell-mediated stimulation of cardiac fibroblasts? | The endocardial endothelium that lines the inner cavity of the heart is distinct from the microvascular endothelial cells and modulates cardiac muscle performance in a manner similar to the vascular endothelial modulation of vascular structure and vasomotor tone. Although the modulatory effects of endocardial endothelium (EE) on cardiomyocytes are firmly established, the regulatory effects of endocardial endothelium on the cardiac interstitium and its cellular components remain ill defined. We investigated whether the stimulatory effect of EE on cardiac fibroblasts would be altered when EECs are activated by the cytokine tumor necrosis factor-alpha (TNF-alpha) or the endotoxin bacterial lipopolysaccharide (LPS). Both TNF-alpha and LPS were found to independently attenuate the stimulatory effect of EE on cardiac fibroblasts. These agents lowered the synthesis or release of ET-1 and increased the secretion of TGF-beta and NO. | The Finnish Diabetes Risk Score (FINDRISC) questionnaire is a practical screening tool to estimate the diabetes risk and the probability of asymptomatic type 2 diabetes. In this study we evaluated the usefulness of the FINDRISC to predict insulin resistance in a population at increased diabetes risk. Data of 771 and 526 participants in a cross-sectional survey (1996) and a cohort study (1997-2000), respectively, were used for the analysis. Data on the FINDRISC and oral glucose tolerance test parameters were available from each participant. The predictive value of the FINDRISC was cross-sectionally evaluated using the area under the curve-receiver operating characteristics method and by correlation analyses. A validation of the cross-sectional results was performed on the prospective data from the cohort study. The FINDRISC was significantly correlated with markers of insulin resistance. The receiver operating characteristics-area under the curve for the prediction of a homeostasis model assessment insulin resistance index of more than five was 0.78 in the cross-sectional survey and 0.74 at baseline of the cohort study. Moreover, the FINDRISC at baseline was significantly associated with disease evolution (P < 0.01), which was defined as the change of glucose tolerance during the 3 yr follow-up. |
Does a long-form alpha-neurotoxin from cobra venom produce potent opioid-independent analgesia? | In light of the antinociceptive activity of the short-chain neurotoxin, cobrotoxin, and other acetylcholine antagonists, the antinociceptive activity and mechanisms of cobratoxin (CTX), a long-chain postsynaptic alpha-neurotoxin, was investigated in rodent pain models. CTX was administered intraperitoneally (30, 45, 68 microg/kg), intra-cerebral ventricularly (4.5 microg/kg) or microinjected into periaqueductal gray (PAG; 4.5 microg/kg). The antinociceptive action was tested using the hot-plate and acetic acid writhing tests in mice and rats. The involvement of the cholinergic system and opioid system in CTX-induced analgesia was examined by pretreatment of animals with atropine (0.5 mg/kg, im; or 10 mg/kg, ip) or naloxone (1 and 5 mg/kg, ip). The effect of CTX on motor activity was tested using the Animex test. CTX exhibited a dose-dependent analgesic action in mice as determined by both the hot-plate and acetic acid writhing tests. The peak effect of analgesia was seen 3 h after administration. In the mouse acetic acid writhing test, the intra-cerebral ventricular administration of CTX at 4.5 microg/kg (1/12th of a systemic dose) produced marked analgesic effects. Microinjection of CTX (4.5 microg/kg) into the PAG region did not elicit an analgesic action in rats in the hot-plate test. Atropine at 0.5 mg/kg (im) and naloxone at 1 and 5 mg/kg (ip) both failed to block the analgesic effects of CTX, but atropine at 10 mg/kg (ip) did antagonize the analgesia mediated by CTX in the mouse acetic acid writhing test. Acetylsalicylic acid (300 mg/kg) did not enhance the analgesic effects of CTX. At the highest effective dose of 68 microg/kg the neurotoxin did not change the spontaneous mobility of mice. | Obese patients with idiopathic pulmonary fibrosis (IPF) have higher 90-day mortality after lung transplantation. We sought to determine whether body mass index (BMI) differentially modified the effect of transplant procedure type on 90-day mortality in IPF patients. We analyzed data from the Organ Procurement and Transplantation Network (OPTN) for all patients with IPF who were transplanted between 2000 and 2010. Post-transplant survival was examined using Kaplan-Meier estimates. Multivariable logistic regression modeling was used to determine the difference in 90-day survival. The primary variable of interest was the interaction term between body mass index (BMI) and transplant type. A total of 3,389 (58% single-lung transplant [SLT] and 42% bilateral lung transplant [BLT]) subjects were included. Multivariable logistic regression modeling demonstrated a statistically significant interaction between BMI and transplant type (p = 0.047). Patients with a BMI > 30 kg/m(2) who received a BLT are 1.71 times (95% CI [1.03 to 2.85], p = 0.038) more likely to die within 90 days than BLT recipients with a BMI of 18.5 to 30 kg/m(2). |
Does comparative DNA methylation and gene expression analysis identify novel genes for structural congenital heart diseases? | For the majority of congenital heart diseases (CHDs), the full complexity of the causative molecular network, which is driven by genetic, epigenetic, and environmental factors, is yet to be elucidated. Epigenetic alterations are suggested to play a pivotal role in modulating the phenotypic expression of CHDs and their clinical course during life. Candidate approaches implied that DNA methylation might have a developmental role in CHD and contributes to the long-term progress of non-structural cardiac diseases. The aim of the present study is to define the postnatal epigenome of two common cardiac malformations, representing epigenetic memory, and adaption to hemodynamic alterations, which are jointly relevant for the disease course. We present the first analysis of genome-wide DNA methylation data obtained from myocardial biopsies of Tetralogy of Fallot (TOF) and ventricular septal defect patients. We defined stringent sets of differentially methylated regions between patients and controls, which are significantly enriched for genomic features like promoters, exons, and cardiac enhancers. For TOF, we linked DNA methylation with genome-wide expression data and found a significant overlap for hypermethylated promoters and down-regulated genes, and vice versa. We validated and replicated the methylation of selected CpGs and performed functional assays. We identified a hypermethylated novel developmental CpG island in the promoter of SCO2 and demonstrate its functional impact. Moreover, we discovered methylation changes co-localized with novel, differential splicing events among sarcomeric genes as well as transcription factor binding sites. Finally, we demonstrated the interaction of differentially methylated and expressed genes in TOF with mutated CHD genes in a molecular network. | Pluronic F-127 (PF127) has previously shown to prolong the sustained release of various proteinous drugs and their serum half-lives. Subsequently, we have extended this approach to look at in vitro release, in vivo efficacy and pharmacokinetics of interleukin-1 receptor antagonist (IL-1Ra). Various concentrations of PF127 gels were prepared using cold method. In vitro drug release kinetic studies were performed using membraneless dissolution method. Stability of IL-1Ra was assessed by SDS-PAGE. In vivo studies and in vivo bioactivity of IL-1Ra were also performed on wistar rats. IL-1Ra loaded PF127 gels showed in vitro sustained release of IL-1Ra, depending on the concentration of gel used. SDS-PAGE confirmed the stability of protein during its in vitro release. PF127 gel also exhibited prolonged release of IL-1Ra in rats as compared to that of IL-1Ra aq. solution. In vivo bioactivity of IL-1Ra loaded in gel was confirmed by its ability to inhibit IL-1β-stimulated induction of IL-6. |
Does interleukin-1 reversibly inhibit the synthesis of biglycan and decorin in intact articular cartilage in culture? | To study the effect of interleukin-1 (IL-1) on the synthesis of proteoglycans biglycan (DSPG-I) and decorin (DSPG-II) in intact bovine articular cartilage. Cartilage bearing sesamoid bones from the metacarpophalangeal joint were cultured with 10 ng/ml IL-1 for 2 days and labelled with [35S] sulfate. One sesamoid bone from each animal had been labelled ex vivo. The remaining 2 were cultured with IL-1 and allowed to recover in control medium before labelling. Control cultures were maintained in medium without IL-1 and labelled concurrently with the experimental series. The dermatan sulfate proteoglycans were purified from 4 M guanidinium chloride extracts of the cartilage by gel filtration on Sepharose CL-2B and CL-4B, on which they appeared as a single peak. Biglycan and decorin were separated by sodium dodecyl sulfide polyacrylamide gel electrophoresis in high salt. Individual lanes from the gel were cut in slices, which were dissolved and counted for radioactivity. Ex vivo, biglycan accounted for 4% and decorin for 2% of total incorporated sulfate. IL-1 reduced the synthesis of biglycan to 77% of the level of cultured controls and that of decorin to 73%. The synthesis of both proteoglycans returned to the control levels when the IL-1 was removed. IL-1 (10 ng/ml, 2 days) had no significant effect on total proteoglycan synthesis. | Our aim was to analyze the effects of 3-month antihypertensive therapy by nebivolol, a beta-blocking agent with nitric oxide-mediated vasodilatory properties, on coronary flow reserve (CFR) and left ventricular filling pressure (LVFP) in uncomplicated arterial hypertension. Twenty newly diagnosed, never treated, uncomplicated hypertensive patients (14 male and six female patients, mean age = 49 years), I-II WHO grade, underwent single-blind nebivolol treatment. At baseline and at 3-month follow-up, patients underwent Doppler echocardiography including pulsed Tissue Doppler of septal mitral annulus: the ratio between transmitral E velocity and myocardial early diastolic velocity (E/Em ratio) was calculated as an index of LVFP degree. Transthoracic Doppler-derived CFR (high-dose dipyridamole coronary diastolic peak flow velocity to resting coronary peak flow velocity ratio) of distal left anterior descending artery was also determined. After 3-month nebivolol therapy, rate-pressure product decreased (P < 0.0001). No significant change of left ventricular mass index, relative wall thickness and midwall shortening was detected. Left ventricular end-diastolic diameter and stroke volume were both marginally increased. Nebivolol increased Em (P < 0.0001), reduced E/Em ratio (from 9.0 +/- 1.6 to 8.2 +/- 1.1, P < 0.0001) and enhanced CFR (from 2.07 +/- 0.2 to 2.20 +/- 0.2, P = 0.003), because of increased hyperemic coronary flow velocity (P < 0.001). CFR increase remained significant (P < 0.001) after normalizing resting and dipyridamole coronary velocities for the respective rate-pressure product. The increase of normalized CFR induced by nebivolol was related with E/Em ratio decrease (r = -0.65, P < 0.002). |
Does [ be THERE A PLACE FOR VIA AND VILI IN OUR PRACTICE ]? | The aim of this review is to discuss the possibilities and disadvantages of the techniques for visual inspection of the uterine cervix with acetic acid (VIA) and with Lugol's iodine (VILI) for early detection of cervical neoplasia. Efficient cervical screening method, approved in practice, is cytology--PAP smear. The lack of organized screening program in Bulgaria is the reason why a lot of cases of cervical cancer are missed or diagnosed late. This raises the question for searching alternative tests to assess the uterine cervix that do not use special techniques and have a reasonable cost. Published results show that VIA and VILI represent an appropriate alternative for cervical screening. The results of VIA and VILI are immediately available and do not require any laboratory processing. | Several strategies have been used to improve running economy (RE). Defined as the oxygen uptake required at a given submaximal running velocity, it has been considered a key aerobic parameter related to endurance running performance. In this context, concurrent strength and endurance training has been considered an effective method, although conclusions on the optimal concurrent training cannot yet be drawn. To evaluate the effect of concurrent training on RE in endurance running athletes and identify the effects of subject characteristics and concurrent training variables on the magnitude of RE improvement. We conducted a computerized search of the PubMed and Web of Science databases, and references of original studies were searched for further relevant studies. The analysis comprised 20 effects in 16 relevant studies published up to August 2015. The outcomes were calculated as the difference in percentage change between control and experimental groups (% change) and data were presented as mean ± 95 % confidence limit. Meta-analyses were performed using a random-effects model and, in addition, simple and multiple meta-regression analyses were used to identify effects of age, training status, number of sessions per week, training duration, type of strength training, and neuromuscular performance on % change in RE. The concurrent training program had a small beneficial effect on RE (% change = -3.93 ± 1.19 %; p < 0.001). In addition, explosive (% change = -4.83 ± 1.53; p < 0.001) and heavy weight (% change = -3.65 ± 2.74; p = 0.009) training programs produced similar improvements in RE, while isometric training (% change = -2.20 ± 4.37; p = 0.324) in selected studies did not induce a significant effect. The multiple linear meta-regression analysis showed that all the differences between % changes could be explained by including the above-mentioned characteristics of subjects and weight training program elements. This model showed that the magnitude of the % change in RE was larger for longer training duration (β = -0.83 ± 0.72, p = 0.02). |
Does walking-induced muscle fatigue impair postural control in adolescents with unilateral spastic cerebral palsy? | Fatigue is likely to be an important limiting factor in adolescents with spastic cerebral palsy (CP). To determine the effects of walking-induced fatigue on postural control adjustments in adolescents with unilateral CP and their typically developing (TD) peers. Ten adolescents with CP (14.2 ± 1.7 yr) and 10 age-, weight- and height-matched TD adolescents (14.1 ± 1.9 yr) walked for 15 min on a treadmill at their preferred walking speed. Before and after this task, voluntary strength capacity of knee extensors (MVC) and postural control were evaluated in 3 conditions: eyes open (EO), eyes closed (EC) and with dual cognitive task (EODT). After walking, MVC decreased significantly in CP (-11%, P<0.05) but not in TD. The CoP area was only significantly increased in CP (90%, 34% and 60% for EO, EC and EODT conditions, respectively). The CoP length was significantly increased in the EO condition in CP and TD (20% and 21%) and was significantly increased in the EODT condition by 18% in CP only. | The earliest response of esophageal mucosa to gastric reflux is the development of oxidative damage and inflammation. These processes contribute to the development of metaplasia known as Barrett's esophagus, as well as the progression to malignancy. Secretory phospholipase A(2) is a mediator of inflammation with levels that are increased in Barrett's metaplasia and carcinoma when compared with levels in normal samples. Our goal is to determine the role of secretory phospholipase A(2) in the development of reflux-associated changes in the esophageal mucosa. Secretory phospholipase A(2)-deficient mice (C57BL/6, n = 5) and mice known to express high levels of secretory phospholipase A(2) (BALB/c, n = 5) underwent side-to-side surgical anastomosis of the first portion of the duodenum and gastroesophageal junction, allowing exposure of esophageal mucosa to duodenal and gastric contents duodeno-gastroesophageal anastomosis. Control animals (n = 5) of each strain underwent laparotomy with esophagotomy and repair. Tissue was frozen in embedding medium. Hematoxylin and eosin staining and Ki67 and secretory phospholipase A(2) immunohistochemistry were used to evaluate esophageal tissue and its response to duodeno-gastroesophageal anastomosis. Immunofluorescent staining confirmed the absence of secretory phospholipase A(2) in C57BL/6 mice and its presence in BALB/c mice. Hematoxylin and eosin staining demonstrated significant thickening of the esophageal mucosa in response to gastroesophageal reflux in the presence of secretory phospholipase A(2). Mice known to express high levels of secretory phospholipase A(2) also demonstrated increased numbers of proliferating cells. Secretory phospholipase A(2)-deficient mice were immune to the early changes induced by mixed reflux. |
Does acute intravenous injection of serelaxin ( recombinant human relaxin-2 ) cause rapid and sustained bradykinin-mediated vasorelaxation? | A recent clinical trial (RELAXin in Acute Heart Failure [RELAX-AHF]) demonstrated that 48 hours of continuous intravenous infusion of the vasorelaxant peptide serelaxin (recombinant human relaxin-2) to patients with acute heart failure reduced cardiovascular mortality at 180 days. The persistence of a vasorelaxant response as a potential mechanism for this long-term benefit and the vascular effects of a bolus intravenous injection of serelaxin have not been examined. This study investigates changes in resistance artery reactivity and passive mechanical wall properties following an intravenous serelaxin injection and whether these vascular effects persist in the absence of detectable circulating serelaxin. Male rats were injected with 13.3 μg/kg serelaxin into the tail vein; mesenteric arteries were assessed 3 and 24 hours after treatment by using wire-myography. Serelaxin increased basal nitric oxide synthase activity and reduced maximal contraction to endothelin-1 at 3 hours after administration. Serelaxin treatment also selectively enhanced bradykinin-mediated endothelium-dependent relaxation. This effect was sustained for 24 hours in the absence of circulating serelaxin. Serelaxin-mediated augmentation of bradykinin-evoked relaxation involved endothelium-derived hyperpolarization after 3 hours and prostacyclin-mediated relaxation after 24 hours. Furthermore, upregulation of inducible nitric oxide synthase, phosphorylation of protein kinase B at Ser473 and endothelial nitric oxide synthase at Ser1177 was observed at 24 hours after serelaxin injection. There were no effects of serelaxin on passive arterial wall stiffness. | The frequency of chromosomal aberrations (CA) in peripheral blood lymphocytes of healthy individuals has been associated with cancer risk. It is presently unclear whether this association is influenced by individual susceptibility factors such as genetic polymorphisms of xenobiotic-metabolizing enzymes. To evaluate the role of polymorphisms in glutathione S-transferase (GST) M1 (GSTM1) and theta 1 (GSTT1) as effect modifiers of the association between CA and cancer risk. A case-control study was performed pooling data from cytogenetic studies carried out in 1974-1995 in three laboratories in Italy, Norway, and Denmark. A total of 107 cancer cases were retrieved from national registries and matched to 291 controls. The subjects were classified as low, medium, and high by tertile of CA frequency. The data were analyzed by setting up a Bayesian model that included prior information about cancer risk by CA frequency. The association between CA frequency and cancer risk was confirmed [OR(medium) (odds ratio)(medium) = 1.5, 95% credibility interval (CrI), 0.9-2.5; OR(high) = 2.8, 95% CrI, 1.6-4.6], whereas no effect of the genetic polymorphism was observed. A much stronger association was seen in the Italian subset (OR(high)= 9.4, 95% CrI, 2.6-28.0), which was characterized by a lower technical variability of the cytogenetic analysis. CA level was particularly associated with cancer of the respiratory tract (OR(high)= 6.2, 95% CrI, 1.5-20.0), the genitourinary tract (OR(high) = 4.0, 95% CrI, 1.4-10.0), and the digestive tract (OR(high) = 2.8, 95% CrI, 1.2-5.8). |
Does rSPO3 expand intestinal stem cell and niche compartments and drives tumorigenesis? | The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models. The current study determines the extent into which solely a gain in RSPO3 actually functions as a driver of intestinal cancer in a direct, causal fashion, and addresses the in vivo activities of RSPO3 in parallel. We generated a conditional Rspo3 transgenic mouse model in which the Rspo3 transgene is expressed upon Cre activity. Cre is provided by cross-breeding with Lgr5-GFP-Cre Upon in vivo Rspo3 expression, mice rapidly developed extensive hyperplastic, adenomatous and adenocarcinomatous lesions throughout the intestine. RSPO3 induced the expansion of Lgr5 | Cerebral embolism from cardiac source is an important cause of stroke, specially in patients younger than 45 years old. To describe the transesophageal echocardiography (TEE) findings in young and non-young stroke patients without any prior evidence of cardiac source for cerebral embolism. Transversal study: 523 patients (267 men and 256 women) with ischemic stroke, without any evidence of cardiac abnormality, underwent to TEE. Ten percent were aged 45 years; or less. Left ventricle hypertrophy, left atrial enlargement, spontaneous contrast in aorta, interatrial septum aneurysm, mitral and aortic valve calcification, aortic valve regurgitation, and atherosclerotic plaques in aorta were significantly more frequent in patients aged more than 45 years; 2.8% of non-young patients had thrombus in left heart. |
Are deletions and de novo mutations of SOX11 associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome? | SOX11 is a transcription factor proposed to play a role in brain development. The relevance of SOX11 to human developmental disorders was suggested by a recent report of SOX11 mutations in two patients with Coffin-Siris syndrome. Here we further investigate the role of SOX11 variants in neurodevelopmental disorders. We used array based comparative genomic hybridisation and trio exome sequencing to identify children with intellectual disability who have deletions or de novo point mutations disrupting SOX11. The pathogenicity of the SOX11 mutations was assessed using an in vitro gene expression reporter system. Loss-of-function experiments were performed in xenopus by knockdown of Sox11 expression. We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*). The biological consequences of the missense mutations were assessed using an in vitro gene expression system. These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin-Siris syndrome. To further investigate the function of SOX11, we knocked down the orthologous gene in xenopus. Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly. | This study was designed to evaluate the hemostatic effect of tranexamic acid in off-pump coronary artery bypass surgery. A prospective, randomized, double-blind, placebo-controlled study. The Department of Anesthesiology and Cardiac Surgery, Medical Sciences University. One hundred eight patients undergoing off-pump coronary artery bypass surgery were enrolled into the study. Eight patients were withdrawn, and 100 patients were divided into 2 groups. Fifty patients received tranexamic acid (bolus 1 g before skin incision and followed by maintenance dose of 400 mg/h during surgery), and 50 patients received saline. Hematologic parameters, volume of blood loss, blood transfusion, and other clinical data were recorded throughout the perioperative period. Twenty-four-hour postoperative blood loss was significantly less in the tranexamic acid group compared with the control group (471 +/- 182 v 844 +/- 303). Patients in the tranexamic acid group received significantly less allogeneic blood (8 v 31 units). |
Does proteomic analysis reveal novel proteins associated with progression and differentiation of colorectal carcinoma? | The objective of this study is to characterize differential proteomic expression among well-differentiation and poor-differentiation colorectal carcinoma tissues and normal mucous epithelium. The study is based on quantitative 2-dimensional gel electrophoresis and analyzed by PDquest. Excluding redundancies due to proteolysis and posttranslational modified isoforms of over 600 protein spots, 11 proteins were revealed as regulated with statistical variance being within the 95th confidence level and were identified by peptide mass fingerprinting in matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Progression-associated proteins belong to the functional complexes of tumorigenesis, proliferation, differentiation, metabolism, and the regulation of major histocompatibility complex processing and other functions. Partial but significant overlap was revealed with previous proteomics and transcriptomics studies in CRC. Among various differentiation stage of CRC tissues, we identified calreticulin precursor, MHC class I antigen (human leukocyte antigen A ), glutathione S-transferase pi1, keratin 8, heat shock protein 27, tubulin beta chain, triosephosphate, fatty acid-binding protein, hemoglobin (deoxy) mutant with val b 1 replaced by met (HBB), and zinc finger protein 312 (FEZF2). | Respiratory failure is a major complication after cardiac surgery. The purpose was to evaluate the impact of minimally invasive aortic valve replacement (mini AVR) on the occurrence of left lower lobe atelectasis (LLLA) in the cardiac intensive care unit (ICU). 98 patients were scheduled to undergo mini AVR. 14 of these patients were converted to a full sternotomy due to technical problems. These patients were compared to a group of 50 patients having planned AVR through a full sternotomy. The incidence of LLLA was evaluated on the first postoperative chest X-ray in the cardiac ICU. In the group having completed mini AVR 20/84 (24%) had a partial LLLA while in the group having extension to a full sternotomy 9/14 (64%) had LLLA lobe (P<0.005). In the group of 50 patients who had AVR through a full sternotomy, 27 patients (54%) had LLLA in the ICU which is also significantly higher (P<0.008) than the percentage of atelectasis in the mini AVR group. |
Does survey of microsatellite clustering in eight fully sequenced species shed light on the origin of compound microsatellites? | Compound microsatellites are a special variation of microsatellites in which two or more individual microsatellites are found directly adjacent to each other. Until now, such composite microsatellites have not been investigated in a comprehensive manner. Our in silico survey of microsatellite clustering in genomes of Homo sapiens, Maccaca mulatta, Mus musculus, Rattus norvegicus, Ornithorhynchus anatinus, Gallus gallus, Danio rerio and Drosophila melanogaster revealed an unexpected high abundance of compound microsatellites. About 4 - 25% of all microsatellites could be categorized as compound microsatellites. Compound microsatellites are approximately 15 times more frequent than expected under the assumption of a random distribution of microsatellites. Interestingly, microsatellites do not only tend to cluster but the adjacent repeat types of compound microsatellites have very similar motifs: in most cases (>90%) these motifs differ only by a single mutation (base substitution or indel). We propose that the majority of the compound microsatellites originates by duplication of imperfections in a microsatellite tract. This process occurs mostly at the end of a microsatellite, leading to a new repeat type and a potential microsatellite repeat track. | In uraemia there is a reduction in the total number of T lymphocytes and an imbalance in the ratio of Th1/Th2 T-helper (Th) lymphocytes. A higher rate of apoptosis in T lymphocytes has been reported in haemodialysis patients. The aims of the present study were to assess the Th1/Th2 pattern in uraemia and to evaluate whether a relative increase in Th1 apoptosis may explain the Th1/Th2 imbalance observed in uraemic patients. Seventeen non-dialysed uraemic patients were evaluated; eight healthy volunteers served as controls. Intracellular interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) were measured by direct intracellular immunofluorescence and flow cytometry. Apoptosis was determined by flow cytometry using annexin V or TUNEL. Mechanisms of apoptosis were assessed by determination of Fas and Bcl-2 expression. Cell production of cytokines is significantly higher in uraemic patients than in controls. In addition, in uraemic patients only 5.1+/-2.1% of the T lymphocytes contained IFN-gamma (Th1 cells) while 61.9 +/- 14.8% contained IL-4 (Th2 cells) (P < 0.0001). The percentage of apoptosis was 29.6 +/- 6.3% and 4.7 +/- 1.6% in Th1 and Th2 lymphocytes, respectively (P < 0.001). Fas expression was higher in Th1 than in Th2 cells and the expression of Bcl-2 was lower in Th1 than in Th2 cells. The apoptosis induced by anti-Fas antibodies was similar in both types of lymphocytes. |
Is breathlessness at rest the dominant presentation of patients admitted with heart failure? | Many assume that most patients hospitalized with heart failure (HF) are short of breath at rest (SOBAR). The National HF Audit for England and Wales suggests that this assumption is false, which has profound implications for management A retrospective case-note review was carried out of patients hospitalized with HF to determine how many present with shortness of breath at rest or are comfortable at rest but breathless on slight exertion (CARBOSE). Vital signs were tracked for 24 h and mortality for 180 days. Of 311 patients, those who were SOBAR (42%) had higher median heart rate (HR) (100 vs. 85 b.p.m.; P < 0.001), systolic blood pressure (SBP) (141 vs. 122 mmHg; P < 0.001), and respiratory rate (RR) (24 vs. 18 breaths/min; P < 0.001) compared with those who were CARBOSE (56%). Vital signs changed little in those who were CARBOSE over the first 4-6 h, but SBP (141-128 mmHg; P < 0.001), HR (100-90 b.p.m.; P = 0.002), and RR (24-20 breaths/min; P < 0.001) fell in those who were SOBAR. At presentation, SBP was >125 mmHg in 73% of patients who were SOBAR and in 46% who were CARBOSE, dropping to 52% and 37%, respectively, by 4-6 h. Mortality amongst those who were SOBAR and those who were CARBOSE was, respectively, 19% and 34% (odds ratio 2.29; P = 0.005, 95% confidence interval 1.29-4.06). | Ovarian germ cell tumours (OGCTs) typically arise in young females and their pathogenesis remains poorly understood. We investigated the origin of malignant OGCTs and underlying molecular events in the development of the various histological subtypes of this neoplasia. We examined in situ expression of stem cell-related (NANOG, OCT-3/4, KIT, AP-2gamma) and germ cell-specific proteins (MAGE-A4, NY-ESO-1, TSPY) using a tissue microarray consisting of 60 OGCT tissue samples and eight ovarian small cell carcinoma samples. Developmental pattern of expression of NANOG, TSPY, NY-ESO-1 and MAGE-A4 was determined in foetal ovaries (gestational weeks 13-40). The molecular genetic part of our study included search for the presence of Y-chromosome material by fluorescence in situ hybridisation (FISH), and mutational analysis of the KIT oncogene (exon 17, codon 816), which is often mutated in testicular GCTs, in a subset of tumour DNA samples. We detected a high expression of transcription factors related to the embryonic stem cell-like pluripotency and undifferentiated state in OGCTs, but not in small cell carcinomas, supporting the view that the latter do not arise from a germ cell progenitor. Bilateral OGCTs expressed more stem cell markers than unilateral cases. However, KIT was mutated in 5/13 unilateral dysgerminomas, whereas all bilateral dysgerminomas (n = 4) and all other histological types (n = 22) showed a wild type sequence. Furthermore, tissue from five phenotypic female patients harbouring combined dysgerminoma/gonadoblastoma expressed TSPY and contained Y-chromosome material as confirmed by FISH. |
Do perceptions of outcomes of implant therapy in patients with ectodermal dysplasia syndromes? | The purpose of this study was to evaluate patient-specific outcomes and satisfaction using dental implants in a population affected with ectodermal dysplasia. Patient-based data were collected using a self-reported survey instrument sent to patients belonging to a private patient foundation and/or treated previously at a government clinic. A standardized survey instrument was developed to evaluate patient satisfaction, outcomes, and potential complications using dental implants. The survey instrument was mailed to 253 affected individuals self-reported to have various forms of ectodermal dysplasia and who were voluntarily participants in the National Foundation for Ectodermal Dysplasias and/or were participants in the US National Institute for Dental Craniofacial Research Intramural Ectodermal Dysplasia clinical research program. A total of 109 responses were obtained (43% response rate). The duration following completion of implant therapy ranged from to 1 to 23 years. Of the 109 participants, 50% reported either an implant or prosthetic complication with implant treatment, and 24% reported some form of failure with implant therapy. However, 91% of participants reported being either satisfied or very satisfied with dental implants, and 95% reported that the treatment was worth the time and cost. | Inflammation within paraventricular nucleus of the hypothalamus (PVN), a key circulatory control center in the hypothalamus, is an important pathology of sympathetic hyperactivity. Brain inflammation is mainly mediated by microglia, innate immune cells in the brain. Activated microglia produce inflammatory cytokines with alteration of their morphology. Increase in inflammatory cytokines synthesis coincides with activation of microglia within PVN of angiotensin II-induced hypertensive model and myocardial infarction-induced heart failure model. Although the increase in inflammatory cytokines and the microglial activation within PVN were also seen in spontaneously hypertensive rats (SHR), the model of essential hypertension, their involvement in blood pressure regulation has still be fully clarified. In the present study, we examined whether activated microglia within PVN were involved in maintenance of established severe hypertension with sympathoexcitation. Minocycline (25mg/kg/day), an inhibitor of microglial activation, or vehicle were orally administered to stroke-prone SHR (SHRSP) and normotensive Wistar-Kyoto (WKY) rats for 2 weeks from 15-weeks-old, the age of established hypertension. Systolic blood pressure was comparable between minocycline treated-SHRSP and vehicle treated-SHRSP, whereas morphological analysis of microglia revealed smaller cell size in minocycline treated-SHRSP than vehicle treated-SHRSP, implying that minocycline deactivated microglia within PVN. |
Does fracture clinic redesign reduce the cost of outpatient orthopaedic trauma care? | "Virtual fracture clinics" have been reported as a safe and effective alternative to the traditional fracture clinic. Robust protocols are used to identify cases that do not require further review, with the remainder triaged to the most appropriate subspecialist at the optimum time for review. The objective of this study was to perform a "top-down" analysis of the cost effectiveness of this virtual fracture clinic pathway. National Health Service financial returns relating to our institution were examined for the time period 2009 to 2014 which spanned the service redesign. The total staffing costs rose by 4% over the time period (from £1 744 933 to £1 811 301) compared with a national increase of 16%. The total outpatient department rate of attendance fell by 15% compared with a national fall of 5%. Had our local costs increased in line with the national average, an excess expenditure of £212 705 would have been required for staffing costs. | The tumor suppressor gene TSLC1/IGSF4 on chromosomal region 11q23 is frequently inactivated by promoter methylation in various cancers, including nonsmall cell lung carcinoma (NSCLC). Several studies have demonstrated that the hypermethylation of the CpG islands of genes, including tumor suppressors, is associated with exposure to tobacco smoke. The purpose of this study was to investigate the possible association of TSLC1/IGSF4 methylation with tobacco smoking as well as with the clinical characteristics of tumors using a large number of primary NSCLC. The promoter methylation of TSLC1/IGSF4 was analyzed in 103 primary NSCLC. TSLC1/IGSF4 expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry, whereas its methylation status was determined by bisulfite single-strand conformation polymorphism (SSCP) coupled with bisulfite sequencing. The TSLC1/IGSF4 promoter was methylated in 45 (44%) of 103 primary NSCLC. Methylation was observed in all histologic subtypes of NSCLC, including adenocarcinoma (29 of 68, 43%), squamous cell carcinoma (14 of 26, 54%), adenosquamous carcinoma (1 of 2, 50%), and large cell carcinoma (1 of 7, 14%). The incidence of methylation in tumors was significantly higher in male patients than in female patients (P = .027). The TSLC1/IGSF4 methylation was preferentially observed in heavy smokers (smoking index > or = 800) (P = .0054). Furthermore, in smokers the methylation was significantly associated with pack-years smoked (P = .034) and cigarettes per day (P = .021). The TSLC1/IGSF4 methylation was also significantly associated with a shorter disease-free survival (P = .049), providing an independent prognostic factor (P = .038) in adenocarcinoma patients. |
Is glomerular dysfunction in the aging Fischer 344 rat associated with excessive growth and normal mesangial cell function? | Fischer 344 (F344) rats display focal and diffuse glomerulosclerosis with aging postulated to result from loss of normal mesangial cell intrinsic function, e.g., vasoactive hormone signaling, or preservation of normal responsiveness to extrinsic growth factors. In 3-, 17-, and 24-month-old F344 male rats, glomerular structure, measured by PC-based morphometry, and function were compared. Immunoperoxidase staining of glomerular proliferating cell nuclear antigen (PCNA) detected cellular proliferation. Primary cultured mesangial cells from the 3 age groups were studied in parallel. Calcium (Ca2+) signaling, measured by Fura-2 fluorescence, contraction to vasopressin (AVP) 1 microM, measured by videomicroscopy, and proliferative response to platelet-derived growth factor-beta beta (PDGF) were compared. Proteinuria was 13 +/- 4, 38 +/- 17, and 110 +/- 35 mg/24 hours at 3, 17, and 24 months, respectively (n = 5, mean +/- SE, p < .01, 3 vs 24 months), with no change in 24-hour creatinine clearances. Glomerular volumes (n = 200/group) for 3, 17, and 24 months, respectively, were .30 +/- .01, .60 +/- .02, .74 +/- 0.2 x 10(6) micron3 (p < .001, 3 months vs 17 months, and 17 vs 24 months). Glomerular basement membrane (GBM) widths and fractional mesangial volumes increased significantly with aging. Glomerular cell PCNA staining remained positive at 24 months. Cultured mesangial cell Ca2+ signaling and contraction to AVP were unchanged with aging. Proliferation to PDGF, which was partially inhibited with verapamil, was similar at 3 and 24 months. | The objective of the ICF Core Sets project is the development of internationally agreed Brief ICF Core Sets and Comprehensive ICF Core Sets. The methods to develop both ICF Core Sets, the Comprehensive ICF Core Set and the Brief ICF Core Set, involved a formal decision-making and consensus process integrating evidence gathered from preliminary studies and expert opinion. The results regarding the development of the ICF Core Sets for 12 health conditions (chronic widespread pain, low back pain, osteoarthritis, osteoporosis, rheumatoid arthritis, chronic ischemic heart disease, diabetes mellitus, obesity, obstructive pulmonary diseases, breast cancer, depression, and stroke) are presented in this supplement. |
Is rescue therapy with tacrolimus effective in patients with severe and refractory inflammatory bowel disease? | Oral tacrolimus, approved for the prophylaxis of organ rejection in liver or kidney transplants, has been reported to be effective in anecdotal cases of refractory inflammatory bowel disease. To evaluate the usefulness of low-dose oral tacrolimus in refractory inflammatory bowel disease. Thirty-one adult Caucasian patients with steroid-dependent (n = 15) or steroid-refractory (n = 16) inflammatory bowel disease (Crohn's disease, n = 6; ulcerative colitis, n = 23; pouchitis, n = 2) were enrolled. Tacrolimus (0.1 mg/kg body weight per day) was administered orally in 30 patients and initially intravenously in one patient (0.01 mg/kg body weight per day), aiming for serum trough levels of 4-6 ng/mL. The median treatment duration was 12 months (range, 1-137 months). Twenty-eight patients (90.3%) experienced a clinical and laboratory response and 20 (64.5%) went into remission. One ulcerative colitis patient and two Crohn's disease patients did not improve. Three ulcerative colitis patients (9.7%) were colectomized at 1, 12 and 24 months after tacrolimus initiation. In 19 of 23 patients (82.6%) taking steroids, steroids were reduced or discontinued. Side-effects included a temporary rise of creatinine (n = 3, 9.7%), tremor or paraesthesias (n = 3, 9.7%), hyperkalaemia (n = 1, 3.2%), hypertension (n = 1, 3.2%) and an opportunistic infection (n = 1, 3.2%). | We recently demonstrated a significant correlation between enamel delamination and tooth-level radiation dose in oral cancer patients. Since radiation can induce the synthesis and activation of matrix metalloproteinases, we hypothesized that irradiated teeth may contain active matrix metalloproteinases. Extracted teeth from oral cancer patients treated with radiotherapy and from healthy subjects were compared. Extracted mature third molars from healthy subjects were irradiated in vitro and/or incubated for 0-6 months at 37°C. All teeth were then pulverized, extracted, and extracts subjected to proteomic and enzymatic analyses. Screening of irradiated crown extracts using mass spectrometry identified MMP-20 (enamelysin) which is expressed developmentally in dentine and enamel but believed to be removed prior to tooth eruption. MMP-20 was composed of catalytically active forms at Mr=43, 41, 24 and 22kDa and was immunolocalized predominantly to the morphological dentine enamel junction. The proportion of different sized MMP-20 forms changed with incubation and irradiation. While the pattern was not altered directly by irradiation of healthy teeth with 70Gy, subsequent incubation at 37°C for 3-6 months with or without prior irradiation caused the proportion of Mr=24-22kDa MMP-20 bands to increase dramatically. Extracts of teeth from oral cancer patients who received >70Gy radiation also contained relatively more 24 and 22kDa MMP-20 than those of healthy age-related teeth. |
Does alteration of neuropeptides in the lung tissue correlate brain death-induced neurogenic edema? | Increased intracranial pressure induces neurogenic pulmonary edema (NPE), potentially explaining why only lungs from less than 20% of brain dead organ donors can be used for transplantation. This study investigated the underlying mechanisms of NPE, focusing on neuropeptides, which potently induce vasoconstriction, vasodilatation, and neurogenic inflammation. Brain death was induced in 10 pigs by increasing the intracranial pressure. Eight additional pigs served as controls. Neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), and substance P were analyzed in plasma, bronchoalveolar lavage (BAL) fluid, and homogenized lung tissue 6 hours after brain death. Pulmonary oxygen exchange was estimated using partial pressure of arterial oxygen (Pao2)/fraction of inspired oxygen (Fio2), and pulmonary edema by wet/dry weight ratio. Brain death induced a decrease in Pao(2)/Fio2 (p < 0.001) and increased the wet/dry weight of both apical (p = 0.01) and basal lobes (p = 0.03). NPY and CGRP concentrations were higher in the BAL fluid of brain-dead animals compared with controls (p = 0.02 and p = 0.02) and were positively correlated with the wet/dry weight ratio. NPY content in lung tissue was lower in brain-dead animals compared with controls (p = 0.04) and was negatively correlated with the wet/dry weight ratio. There were no differences in substance P concentrations between the groups. | 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%). |
Is serum CA-125 level after 6 cycles of primary adjuvant chemotherapy a useful prognostic factor for complete responders ' survival in patients with advanced epithelial ovarian cancer? | The aim of this study was to evaluate the prognostic value of the serum CA-125 level for complete responders after 6 cycles of primary adjuvant paclitaxel/carboplatin chemotherapy in advanced epithelial ovarian cancer. The clinical data of 123 complete responders after 6 cycles of primary adjuvant paclitaxel/carboplatin chemotherapy for epithelial ovarian cancer FIGO stages III and IV were collected between January 1997 and March 2007. All patients were divided into 3 groups according to the serum CA-125 level after 6 cycles of the chemotherapy: group I (< 10 U/ml), group II (10-21 U/ml), and group III (> 21 U/ml). The effect of the serum CA-125 level on survival was evaluated using the Kaplan-Meier method and Cox proportional hazard analysis. The median progression-free survival was 26, 14, and 10 months, and the median overall survival was 105, 42, and 37 months in groups I, II, and III, respectively (p < 0.05). The lower serum CA-125 level and optimal debulking surgery were prognostic factors for improving survival (p < 0.05). | Although home renovation exposure during childhood has been identified as a risk factor for the development of allergy, there is limited information on the association between prenatal exposure to home renovation and cord blood (CB) IgE response. The aims of this study were to identify the effect of prenatal exposure to home renovation on CB IgE levels, and to investigate whether this exposure interacts with neonatal genes and whether the effect can be modified by maternal atopy. This study included 1,002 mother-neonate pairs from the COhort for Childhood Origin of Asthma and allergic diseases (COCOA). Prenatal environmental factors were collected using a questionnaire. The levels of CB IgE were measured by the ImmunoCAP system, and DNA was extracted from CB. Exposure to home renovation during the prenatal period was associated with significantly higher levels of CB IgE only in neonates from atopic mothers, and the effect of renovation exposure on CB IgE levels persisted from 31 months before birth. Furthermore, prenatal exposure to home renovation increased the risk of CB IgE response interacting with polymorphisms of NRF2 and GSTP1 genes only in neonates from atopic mothers. |
Does the yeast histone chaperone hif1p function with RNA in nucleosome assembly? | Hif1p is an H3/H4-specific histone chaperone that associates with the nuclear form of the Hat1p/Hat2p complex (NuB4 complex) in the yeast Saccharomyces cerevisiae. While not capable of depositing histones onto DNA on its own, Hif1p can act in conjunction with a yeast cytosolic extract to assemble nucleosomes onto a relaxed circular plasmid. To identify the factor(s) that function with Hif1p to carry out chromatin assembly, multiple steps of column chromatography were carried out to fractionate the yeast cytosolic extract. Analysis of partially purified fractions indicated that Hif1p-dependent chromatin assembly activity resided in RNA rather than protein. Fractionation of isolated RNA indicated that the chromatin assembly activity did not simply purify with bulk RNA. In addition, the RNA-mediated chromatin assembly activity was blocked by mutations in the human homolog of Hif1p, sNASP, that prevent the association of this histone chaperone with histone H3 and H4 without altering its electrostatic properties. | Although general agreement exists on internal mammary graft as the first conduit, the second choice is still questioned. Despite radial artery (RA) grafting has been suggested, saphenous veins (SV) continue to be extensively used. A prospective series of isolated RA-CABG (150 patients) or SV-CABG (180 patients), performed either off-pump (OP-CABG) and on-pump (CPB-CABG), in diabetics and non-diabetics, in elderly and young patients, during the last 5-years at a single institution were evaluated. RA was harvested with harmonic scalpel, flowmetry was performed with a transit-time flowmeter (TTF). Graft flow reserve (GFR) was calculated with intra-aortic balloon-pump. Follow-up was collected by outpatient clinic database or by telephone interview with general practitioners. The 2 groups showed comparable preoperative and intraoperative variables. Mortality, morbidity, myocardial infarction, troponin I leakage, and echocardiographic parameters were comparable (p=NS). RA-CABG demonstrated significantly higher TTF maximum, mean and minimum flow (p<.001) with lower Pulsatility Index (p<.001), either in the circumflex and the right coronaries. Compared to SVG-grafting, significantly higher GFR was found in RA-CABG on the circumflex (p=.001) and right (p=.028) coronaries. 38.1+/-0.9 SE months follow-up resulted in higher survival and freedom from cardiac events in RA-CABG. Better TTF and GFR were demonstrated in OP-CABG, CPB-CABG, diabetics, non-diabetics, either on the circumflex and right coronary systems (p<.05). Better mean flow was detected in RA-CABG on the circumflex in the elderly (p=.04) and the young (p=.05). |
Do pollen tube cell walls of wild and domesticated tomatoes contain arabinosylated and fucosylated xyloglucan? | In flowering plants, fertilization relies on the delivery of the sperm cells carried by the pollen tube to the ovule. During the tip growth of the pollen tube, proper assembly of the cell wall polymers is required to maintain the mechanical properties of the cell wall. Xyloglucan (XyG) is a cell wall polymer known for maintaining the wall integrity and thus allowing cell expansion. In most angiosperms, the XyG of somatic cells is fucosylated, except in the Asterid clade (including the Solanaceae), where the fucosyl residues are replaced by arabinose, presumably due to an adaptive and/or selective diversification. However, it has been shown recently that XyG of Nicotiana alata pollen tubes is mostly fucosylated. The objective of the present work was to determine whether such structural differences between somatic and gametophytic cells are a common feature of Nicotiana and Solanum (more precisely tomato) genera. XyGs of pollen tubes of domesticated (Solanum lycopersicum var. cerasiforme and var. Saint-Pierre) and wild (S. pimpinellifolium and S. peruvianum) tomatoes and tobacco (Nicotiana tabacum) were analysed by immunolabelling, oligosaccharide mass profiling and GC-MS analyses. Pollen tubes from all the species were labelled with the mAb CCRC-M1, a monoclonal antibody that recognizes epitopes associated with fucosylated XyG motifs. Analyses of the cell wall did not highlight major structural differences between previously studied N. alata and N. tabacum XyG. In contrast, XyG of tomato pollen tubes contained fucosylated and arabinosylated motifs. The highest levels of fucosylated XyG were found in pollen tubes from the wild species. | Hospital readmissions after surgical operations are considered serious complications and have an impact on health care-associated costs. The Centers for Medicare and Medicaid Services strongly encourage identification and ramification of factors associated with hospital readmissions after operations. Despite advances in endovascular surgery, lower extremity arterial bypass remains the "gold standard" treatment for severe, symptomatic peripheral arterial disease. The purpose of this study was to retrospectively review the factors associated with hospital readmission after lower extremity bypass surgery. The 2013 lower extremity revascularization-targeted American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database and generalized 2013 general and vascular surgery NSQIP Participant Use Data File were used for this study. Patient, diagnosis, and procedure characteristics of patients undergoing lower extremity bypass surgery were assessed. Multivariate logistic regression analysis was used to determine independent risk factors for hospital readmission within 30 days after surgery. A total of 2646 patients (65% male, 35% female) were identified in the NSQIP database who underwent lower extremity open revascularization during the year 2013. Indications for operations included tissue loss (39%), rest pain (32%), and severe claudication (25%). Preoperative ankle-brachial indices were 0.4 to 0.9 (32%) and <0.4 (16.5%). A total of 425 patients (16%) were readmitted within 30 days of index operation. Risk factors associated with readmission included wound complication (odds ratio [OR], 8.54; 95% confidence interval [CI], 6.68-10.92; P < .001), need for reoperation (OR, 5.95; 95% CI, 4.45-7.97; P < .001), postoperative myocardial infarction (OR, 2.19; 95% CI, 1.25-3.83; P = .006), wound dehiscence (OR, 8.45; 95% CI, 4.54-15.71; P < .001), organ or space surgical site infection (OR, 7.62; 95% CI, 2.89-20.14; P < .001), postoperative pneumonia (OR, 2.66; 95% CI, 1.28-5.52; P = .009), progressive renal insufficiency (OR, 4.12; 95% CI, 1.52-11.11; P = .005), superficial surgical site infection (OR, 7.37; 95% CI, 5.31-10.23; P < .001), urinary tract infection (OR, 2.67; 95% CI, 1.42-5.01; P = .002), and deep wound infection (OR, 14.0; 95% CI, 7.62-24.80; P < .001). |
Does a default normal chest CT structured reporting field for coronary calcifications cause excessive false-negative reporting? | The aim of this study was to compare the accuracy of coronary atherosclerosis reporting before and after the implementation of a structured reporting chest CT template. A noncardiac, noncontrast chest CT structured reporting template was developed and mandated for department-wide use at a large academic center. The template included the statement "There are no coronary artery calcifications." All noncardiac, noncontrast chest CT examinations reported over 3 days, 1 month after template implementation (structured template group), and from a 3-day period 1 year prior (control group) were retrospectively collected. Final radiology reports were reviewed and designated positive or negative for coronary calcifications. CT images were reviewed in consensus by 2 radiologists, who scored each case for the presence or absence of coronary calcifications, blinded to the original report. Statistical analysis was performed using Pearson χ(2) and Fisher exact tests. Sixty-five percent (69 of 106) of structured template group and 58% (62 of 106) of control group cases had coronary calcifications. Reports from the structured template group were more likely to correctly state the presence or absence of coronary atherosclerosis compared with those from the control group (96.2% vs 85.8%; odds ratio, 4.2; 95% confidence interval, 1.3-13.1; P = .008). Structured template group reports were less likely to be falsely negative compared with control group reports (3.8% vs 11.7%; odds ratio, 3.4; 95% confidence interval, 1.0-10.8; P = .03). | A defect in retinal pigment epithelial (RPE) cells may cause dysfunction of the neural retina, so rapid recovery of differentiated RPE cells is required after RPE injury. We investigated the effect of hepatocyte growth factor (HGF) on wound healing in RPE cells. Confluent monolayers of bovine RPE cells were denuded, and the cells were allowed to recover in the presence or absence of HGF. The effect of HGF on RPE cell proliferation was evaluated by a 3-(4;5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetraz olium assay. In a migration assay, mitomycin C was used to inhibit proliferation, and the number of migrated cells was counted. The signaling pathways involved were examined using inhibitors of mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 (PI3) kinase and protein kinase C pathways. At 80 ng/mL, HGF stimulated the wound closure of RPE monolayers and rendered the restituted cells more epithelioid in shape. HGF at 10 ng/mL stimulated RPE cell migration the most, whereas 80 ng/mL of HGF inhibited migration, but stimulated proliferation the most. In particular, PI3 kinase and MAPK inhibitor inhibited PRE cell migration and proliferation, respectively. |
Is prothrombin G20210A mutation , but not factor V Leiden , a risk factor in patients with persistent foramen ovale and otherwise unexplained cerebral ischemia? | Paradoxical embolism via persistent foramen ovale (PFO) is suspected to be a frequent cause of stroke in younger patients. We investigated whether the prevalence of the risk factors for venous thrombosis factor V Leiden (FVL) and prothrombin G20210A mutation (PT G20210A) is increased in this group of patients. We examined FVL and PT G20210A mutation in 220 patients (group 1) with cerebral ischemia associated with a PFO and without other etiology, in 196 patients with cerebral ischemia of an etiology other than PFO (group 2), and in 362 healthy subjects (group 3) from the same region in Germany. Heterozygosity for the PT G20210A mutation was more common in group 1 (5.0%) than in group 3 (1.4%; sex- and age-adjusted odds ratio 3.66; 95% CI 1.25-10.75; p = 0.01). By contrast, the mutation was not more common in group 2 (2.6%; odds ratio 1.50; 95% CI 0.42-5.41; p = 0.5). Prevalences of FVL were not different between groups. | Lysozyme is an innate immune peptide with bactericidal and fungicidal activity (FA). Despite increased expression of lysozyme protein in chronic rhinosinusitis (CRS) sinus mucosa, CRS patients experience repeated bacterial and/or fungal infections. Commercial sinus irrigation solutions are often used to provide symptomatic relief. However, one of the mechanisms of action of lysozyme involves ionic interactions with the microbial cell wall, which may be inhibited by ionic solutions such as commercial sinus irrigation solutions. Determine if the FA of lysozyme is reduced in the presence of solutions with increasing ionic strength and inhibited in the presence of commercial sinus irrigation solutions. Using an in vitro colony-forming unit (CFU) assay, the FA of lysozyme (5 μM) was tested against a fungi commonly isolated from CRS patients, Aspergillus fumigatus, in solutions of increasing ionic strength or commercial sinus irrigation solutions. FA was presented as percent of control. FA of lysozyme against A. fumigatus was 95% in a 21-mM ionic strength solution. However, with increasing ionic strength, FA decreased and was abolished in a 46-mM ionic strength solution. Commercial sinus irrigation solutions abolished the FA of lysozyme against A. fumigatus. |
Do gene-expression patterns in peripheral blood classify familial breast cancer susceptibility? | Women with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery. Accurate and individualized risk-estimation approaches may help these women make more informed decisions. Although highly penetrant genetic variants have been associated with familial breast cancer (FBC) risk, many individuals do not carry these variants, and many carriers never develop breast cancer. Common risk variants have a relatively modest effect on risk and show limited potential for predicting FBC development. As an alternative, we hypothesized that additional genomic data types, such as gene-expression levels, which can reflect genetic and epigenetic variation, could contribute to classifying a person's risk status. Specifically, we aimed to identify common patterns in gene-expression levels across individuals who develop FBC. We profiled peripheral blood mononuclear cells from women with a family history of breast cancer (with or without a germline BRCA1/2 variant) and from controls. We used the support vector machines algorithm to differentiate between patients who developed FBC and those who did not. Our study used two independent datasets, a training set of 124 women from Utah (USA) and an external validation (test) set from Ontario (Canada) of 73 women (197 total). We controlled for expression variation associated with clinical, demographic, and treatment variables as well as lymphocyte markers. Our multigene biomarker provided accurate, individual-level estimates of FBC occurrence for the Utah cohort (AUC = 0.76 [0.67-84]) . Even at their lower confidence bounds, these accuracy estimates meet or exceed estimates from alternative approaches. Our Ontario cohort resulted in similarly high levels of accuracy (AUC = 0.73 [0.59-0.86]), thus providing external validation of our findings. Individuals deemed to have "high" risk by our model would have an estimated 2.4 times greater odds of developing familial breast cancer than individuals deemed to have "low" risk. | To determine the role of glycine (Gly) in the generation and modulation of basic respiratory rhythm. Neonatal (0-3 days) SD rats of either sex were used in this study. The medulla oblongata brain slice containing the medial region of the nucleus retrofacialis (mNRF) and the hypoglossal nerve rootlets was prepared, and the surgical procedure was performed in the modified Kreb's solution (MKS) with continuous carbogen (95% O(2) and 5% CO(2)) within 3 min. The rhythmical respiratory discharge activity (RRDA) of the hypoglossal nerve rootlets was recorded using suction electrode. Eighteen medulla oblongata slice preparations were divided into 3 groups and treated for 20 min with Gly receptor specific agonist Gly (10 micromol/L), Gly receptor antagonist strychnine (STR, 1 micromol/L), or Gly+STR after a 20 min Gly application. The changes in RRDA of the hypoglossal nerve rootlets were observed. Gly significantly decreased the inspiratory time and integral amplitude (IA), but the changes of respiratory cycle (RC) and expiratory time (TE) were not statistically significant. STR induced a decrease in expiratory time and respiratory cycle without significantly affecting the inspiratory time or integral amplitud. The effect of Gly on the respiratory rhythm was partially reversed by additional application of STR. |
Does the PTEN tumor suppressor inhibit telomerase activity in endometrial cancer cells by decreasing hTERT mRNA levels? | Loss of PTEN expression is one of the most prevalent and earliest molecular abnormalities associated with endometrial carcinogenesis. Given that PTEN is often absent and telomerase is overexpressed by endometrial cancers, we hypothesize that PTEN signaling is important in telomerase regulation. PTEN expression was reconstituted in the PTEN-null Ishikawa endometrial cancer cells by adenovirus-mediated gene transduction. Cell proliferation was evaluated 12-96 h after infection. Western blot analysis was performed to assess PTEN status and phosphorylated Akt expression. Telomerase activity was determined by the telomeric repeat amplification protocol (TRAP) assay. hTERT mRNA levels were assessed by real-time RT-PCR. Ishikawa cells were also treated with LY294002, a PI3-kinase inhibitor. Infection of Ishikawa cells by replication-defective recombinant adenovirus expressing wild-type PTEN, but not control adenovirus or adenovirus expressing lipid phosphatase defective PTEN GE mutant, inhibited constitutive Akt activation and suppressed proliferation of Ishikawa cells. Infection by wild-type PTEN adenovirus, but not control adenovirus, inhibited telomerase activity 24 h after infection. This inhibition of telomerase activity was parallel to decreased hTERT mRNA levels. LY294002 treatment resulted in dose-dependent inhibition of Akt activation and cellular proliferation. LY294002 suppressed telomerase activity and decreased hTERT transcript levels in a dose-dependent manner. | The cutaneous microcirculation vasodilates during acute 6 degrees head-down tilt (HDT, simulated microgravity) relative to upright conditions, more in the lower body than in the upper body. We expected that relative magnitudes of and differences between upper and lower body cutaneous blood flow elevation would be sustained during initial acclimation to simulated microgravity. We measured cutaneous microvascular blood flow with laser-Doppler flowmetry at the leg (over the distal tibia) and cheek (over the zygomatic arch) of eight healthy men before, during, and after 24 h of HDT. Results were calculated as a percentage of baseline value (100% measured during pre-tilt upright sitting). Cutaneous blood flow in the cheek increased significantly to 165 +/- 37% (mean +/- SE, p < 0.05) at 9-12 h HDT, then returned to near baseline values by 24 h HDT (114 +/- 29%, NSD), despite increased local arterial pressure. Microvascular flow in the leg remained significantly elevated above baseline throughout 24 h HDT (427 +/- 85% at 3 h HDT and 215 +/- 142% at 24 h HDT, p < 0.05). During the 6-h upright sitting recovery period, cheek and leg blood flow levels returned to near pre-tilt baseline values. |
Are beta-Catenin mutation and its nuclear localization confirmed to be frequent causes of Wnt signaling pathway activation in pilomatricomas? | beta-Catenin has been shown to play an important role in the formation of hair follicle-related tumors, including pilomatricomas. Several investigators have shown that beta-catenin gene mutation is observed in pilomatricomas. However, the relationship between the pattern of beta-catenin localization in the cell and beta-catenin gene mutation is still controversial. This work was performed to determine the frequency of beta-catenin nuclear localization in pilomatricoma, the relationship between the pattern of beta-catenin localization and beta-catenin mutation, and the involvement of APC mutation. Typical 32 pilomatricomas were examined for beta-catenin expression by immunostaining. Genomic DNA was extracted, amplified and sequenced from 23 pilomaticomas with nuclear beta-catenin staining and 4 pilomaticomas without nuclear beta-catenin staining. Mutations of beta-catenin gene were confirmed by subcloning assay and restriction endonuclease assay. Using immunostaining, we found that 81% (26/32) of pilomatricomas displayed nuclear beta-catenin staining in basophilic cells. Sequence analysis revealed that 61% (14/23) contained mutations in exon 3 of beta-catenin. However, no mutations were detected in 4 pilomaticomas without beta-catenin nuclear staining. Detected mutations were adjacent to or abolished well-known regulatory phosphorylation sites of beta-catenin. APC gene mutations were not detected in 27 pilomatricomas with/without beta-catenin nuclear staining. | We aimed to test the outcome-predictive power of routine fasting glucose (FG) obtained at second day after onset in intravenous thrombolysis (IVT) acute ischemic stroke (AIS) patients. We identified AIS patients presenting to our institution between December 2011 and July 2013 within 4.5 hours of onset, who received admission glucose (AG) before IVT, FG, and glycated hemoglobin (HbA1c) the second day after admission, from our prospectively recorded stroke database. Multivariate logistic regression was used to assess the association of FG and 90-day modified Rankin Scale (mRS). Between December 2011 and July 2013, a total of 166 AIS patients received intravenous plasminogen activator. Of those, 119 patients who have AG before IVT, FG, and HbA1c the second day were included in the study. FG independently predicted 90-day clinical unfavorable outcome (mRS, 3-6 with an odds ratio of 1.576; 95% confidence interval [CI], 1.053-2.358; P = .027). This association was not significant in AG (P = .714), HbA1c (P = .655), and history of diabetes (P = .547). In receiver operating characteristic analysis, increased FG was associated with 90-day mRS (3-6) with an area under curve of .72, (95% CI, .65-.9; P = .001). |
Does interaction with monocytes enhance IL-5 gene transcription in peripheral T cells of asthmatic patients? | The regulatory mechanisms of IL-5 gene transcription in human peripheral T cells are unclear because the transfection efficiency of plasmid constructs into nontransformed T cells is very low. Concanavalin A (ConA)-stimulated blastocytes derived from peripheral blood lymphocytes of asthmatic subjects were transiently transfected with the human IL-5 gene promoter/enhancer-luciferase gene construct, pIL-5 (-511)Luc, and cultured with THP-1 cells (human monocytoid cells) and anti-CD3 monoclonal antibody (mAb). IL-5 level in the culture medium was determined by an enzyme-linked immunosorbent assay. Transcriptional activity of the IL-5 gene was measured by luciferase reporter analysis. ConA-blast lymphocytes of asthmatic patients produced a significant amount of IL-5 upon combined stimulation with anti-CD3 mAb and THP-1 cells, but not with anti-CD3 mAb alone. Costimulation with anti-CD28 mAb also enhanced the anti-CD3 mAb- induced IL-5 production. Accordingly, luciferase activity induced by anti-CD3 mAb stimulation in pIL-5(-511)Luc-transfected ConA-blast lymphocytes was increased 1.9- and 3.4-fold by the addition of anti-CD28 mAb and THP-1 cells, respectively. Serial 5' deletion analysis of the reporter gene demonstrated that the cis-regulatory element located at -119 to -80 is critical for anti-CD3 mAb-induced IL-5 gene transcription. | Cerebral white matter lesions (WMLs) predict long-term survival of conservatively treated acute stroke patients with etiology other than carotid stenosis. In carotid endarterectomy patients, WMLs are associated with severe carotid stenosis and unstable plaques, with the risk of perioperative complications and with increased 30-day perioperative risk of death. However, no data exist on their effect on postoperative long-term survival, a factor important when considering the net benefit from carotid endarterectomy. Whether this effect is independent of classical risk factors and indications for surgery is not known either. We hypothesized that WMLs could be evaluated from preoperative routine computed tomography (CT) scans and are predictors of postoperative survival, independent of classical cardiovascular risk factors, indication category and degree of carotid stenosis. A total of 353 of 481 (73.4%) consecutive patients subjected to carotid endarterectomy due to different indications, i.e. asymptomatic stenosis (n = 28, 7.9%), amaurosis fugax (n = 52, 14.7%), transient ischemic attack (n = 135, 38.2%) or ischemic stroke (n = 138, 39.1%), from prospective vascular registries during the years 2001-2010 with digital preoperative CT scans, were included in the study. WMLs were rated by a radiologist (Wahlund criteria) in a blinded fashion. Internal carotid artery (ICA) stenoses were angiographically graded (<50, 50-69, 70-99 and 100%). Odds ratios (ORs) and hazard ratios (HRs) are reported (ORs and HRs ≤1 indicate a beneficial effect). The median follow-up time was 67 months (interquartile range 45.5, range 0-129 months). Spearman's rho was used to estimate intraobserver agreement. Binary logistic regression was performed to analyze the association of risk factors with WMLs. Cox regression proportional hazards analysis was used to study the effect of different factors on survival. WML severity could be assessed with a substantial intraobserver agreement (Spearman's rho 0.843, p < 0.0001). Only age (OR 1.10, 95% CI 1.06-1.15; p < 0.0001 per year), degree of ipsilateral ICA stenosis (OR 2.22, 95% CI 1.08-4.55; p < 0.05 per stenosis grade) and indication category (OR 1.63, 95% CI 1.19-2.24; p < 0.01 per category) remained independently associated with WMLs. Age (HR 1.04, 95% CI 1.01-1.08; p < 0.05 per year), diabetes (HR 1.59, 95% CI 1.01-2.49; p < 0.05), peripheral arterial disease (HR 2.47, 95% CI 1.46-4.15; p < 0.01), degree of ipsilateral ICA stenosis (HR 2.56, 95% CI 1.12-5.87; p < 0.05 per stenosis grade) and WMLs (HR 3.83, 95% CI 1.17-12.5; p < 0.05) remained independently associated with increased long-term mortality. |
Does tumor transcriptome reveal the predictive and prognostic impact of lysosomal protease inhibitors in non-small-cell lung cancer? | Insight into clinical response to platinum-based chemotherapy (PBC) in non-small-cell lung cancer (NSCLC). Matched tumor and nontumor lung tissues from PBC-treated NSCLC patients (four nonresponders and four responders) and tumor tissue from an independent test set (four nonresponders and four responders), were profiled using microarrays. Lysosomal protease inhibitors SerpinB3 and cystatin C were highly correlated with clinical response and were further evaluated by immunohistochemistry in PBC-treated patients (36 prechemotherapy and 13 postchemotherapy). Investigation of the pathogenic and prognostic significance of SerpinB3 was performed in 251 primary tumors, with 64 regional lymph node pairs, from chemotherapy-naïve NSCLC patients using immunohistochemistry. Bioinformatic analyses of gene expression in the training set identified a gene set (n = 17) that separated all patients in the training and test sets (n = 16) according to response in hierarchical clustering. Transcriptome profiling revealed that SerpinB3 mRNA was highly correlated with degree of response (r = -0.978; P < .0001) and was a clear outlier (nonresponders:responders > 50-fold). SerpinB3 protein expression was correlated with clinical response in PBC-treated NSCLC patients (P = .045). Expression of SerpinB3 and cystatin C, relative to the target, protease cathepsin B, was independently predictive of response (odds ratio, 17.8; 95% CI, 2.0 to 162.4; P = .01), with an accuracy of 72%. High SerpinB3 expression levels, invariably associated with chemoresistance, had contrasting prognostic impact in untreated squamous cell carcinomas (hazard ratio [HR], 0.43; 95% CI, 0.18 to 0.93) or adenocarcinomas (HR, 2.09; 95% CI, 1.03 to 4.72). | To study the prevalence of hand abnormalities in diabetic patients and to evaluate associations between the hand abnormalities and diabetic variables, ergonomic factors and smoking habits. Cross-sectional study of 100 patients selected at random. Setting. Out-patient clinic, Department of Internal Medicine, Orebro Medical Centre Hospital in Sweden. Presence and extent of carpal tunnel syndrome (CTS), Dupuytren's contracture (DC), flexor tenosynovitis (FTS), and limited joint mobility (LJM). Duration of diabetes, metabolic control, chronic diabetic complications, blood pressure, ergonomic factors and smoking habits. Carpal tunnel syndrome, DC, FTS and LJM were each present in about 20% of the patients. Hand abnormalities were observed in 50 patients and more than one abnormality was found in 26 of the patients. The hand abnormalities were associated with the duration of diabetes but not with the metabolic control or with other diabetic complications. However, the diabetic complications were associated with bad metabolic control and with the duration of diabetes. Hand abnormalities correlated with heavy manual work but not with smoking habits. Twenty-five of the 50 patients with hand syndromes were disabled to such an extent that surgery was recommended. |
Is level of consciousness on admission to a Heart Attack Centre a predictor of survival from out-of-hospital cardiac arrest? | The relationship between the neurological status at the time of handover from the ambulance crew to a Heart Attack Centre (HAC) in patients who have achieved return of spontaneous circulation (ROSC) and subsequent outcome, in the context of current treatment standards, is unknown. A retrospective review of all patients treated by London Ambulance Service (LAS) from 1(st) April 2011 to 31(st) March 2013 admitted to a HAC in Greater London was undertaken. Neurological status (A - alert; V - responding to voice; P - responding to pain; U - unresponsive) recorded by the ambulance crew on handover was compared with length of hospital stay and survival to hospital discharge. A total of 475 sequential adult cardiac arrests of presumed cardiac origin, achieving ROSC on admission to a HAC were identified. Outcome data was available for 452 patients, of whom 253 (56.0%) survived to discharge. Level of consciousness on admission to the HAC was a predictor of duration of hospital stay (P<0.0001) and survival to hospital discharge (P<0.0001). Of those presenting with a shockable rhythm, 32.3% (120/371) were 'A' or 'V', compared with 9.1% (9/99) of those with non-shockable rhythms (P<0.001). | To quantify functional age-related changes in the cartilage antioxidant network in order to discover novel mediators of cartilage oxidative stress and osteoarthritis (OA) pathophysiology. We evaluated histopathologic changes of knee OA in 10-, 20-, and 30-month-old male F344BN rats and analyzed cartilage oxidation according to the ratio of reduced to oxidized glutathione. Antioxidant gene expression and protein abundance were analyzed by quantitative reverse transcription-polymerase chain reaction and selected reaction-monitoring mass spectrometry, respectively. Superoxide dismutase 2 (SOD2) activity and acetylation were analyzed by colorimetric enzyme assays and Western blotting, respectively. We examined human OA cartilage to evaluate the clinical relevance of SOD2 acetylation, and we tested age-related changes in the mitochondrial deacetylase sirtuin 3 (SIRT-3) in rats and mice. Cartilage oxidation and OA severity in F344BN rats increased with age and were associated with an increase in SOD2 expression and protein abundance. However, SOD2-specific activity decreased with age due to elevated posttranslational lysine acetylation. Consistent with these findings, SIRT-3 levels decreased substantially with age, and treatment with SIRT-3 increased SOD2 activity in an age-dependent manner. SOD2 was also acetylated in human OA cartilage, and activity was increased with SIRT-3 treatment. Moreover, in C57BL/6J mice, cartilage SIRT-3 expression decreased with age, and whole-body deletion of SIRT-3 accelerated the development of knee OA. |
Is p21 deficiency susceptible to osteoarthritis through STAT3 phosphorylation? | Osteoarthritis (OA) is a multifactorial disease, and recent studies have suggested that cell cycle-related proteins play a role in OA pathology. p21 was initially identified as a potent inhibitor of cell cycle progression. However, it has been proposed that p21 is a regulator of transcription factor activity. In this study, we evaluated the role of p21 in response to biomechanical stress. Human chondrocytes were treated with p21-specific small interfering RNA (siRNA), and cyclic tensile strain was introduced in the presence or absence of a signal transducer and activator of transcription 3 (STAT3)-specific inhibitor. Further, we developed an in vivo OA model in a p21-knockout background for in vivo experiments. The expression of matrix metalloproteinase (MMP13) mRNA increased in response to cyclic tensile strain following transfection with p21 siRNA, whereas the expression of aggrecan was decreased. Phospho-STAT3 and MMP-13 protein levels increased following downregulation of p21, and this was reversed by treatment with a STAT3 inhibitor. p21-deficient mice were susceptible to OA, and this was associated with increased STAT3 phosphorylation, elevated MMP-13 expression, and elevation of synovial inflammation. The expression of p21 mRNA was decreased and phosphorylation of STAT3 was elevated in human OA chondrocytes. | Reagent strip testing for microhaematuria has long been used for community diagnosis of Schistosoma haematobium. Sensitivities and specificities are reasonable, and hence, microhaematuria can serve as a proxy for S. haematobium infection. However, assessment of test performance in the context of the underlying S. haematobium prevalence is rare and test parameters other than sensitivity and specificity have been neglected. Data about the association between microhaematuria and urine filtration results from three studies were compared and put into context with findings from a recent Cochrane review. Data were stratified by S. haematobium prevalence to identify prevalence-related differences in test performance. Kappa agreement and regression models were employed to compare data for different S. haematobium prevalence categories. We found a "background" prevalence of microhaematuria (13 %, on average) which does not seem to be associated with schistosomiasis in most settings, irrespective of the prevalence of S. haematobium. This background level of microhaematuria might be due to cases missed with urine filtration, or alternative causes apart from S. haematobium. Especially in very-low prevalence settings, positive results for microhaematuria likely give an inaccurate picture of the extent of S. haematobium, whereas negative results are a sound indicator for the absence of infection. |
Does tetrodotoxin reduce cue-induced drug craving and anxiety in abstinent heroin addicts? | Tetrodotoxin (TTX) is a neurotoxin found in puffer fish and other marine animals. New clinical studies suggest that low-dose TTX can safely relieve severe, treatment-resistant cancer pain. The therapeutic potential of TTX in addiction is supported by studies in laboratory animals. The purpose of this double-blind, placebo-controlled study was to assess the effect of a single intramuscular dose of TTX on cue-induced craving and anxiety in abstinent heroin addicts. Forty-five abstinent heroin addicts were randomly assigned to three treatment groups: placebo, 5 microg TTX, or 10 microg TTX. Participants were exposed to a neutral video or a heroin-related video. Craving, anxiety, blood pressure, and heart rate were measured pre- and post-exposure. Heroin-related cues increased both craving and anxiety and had no effect on blood pressure and heart rate. A single dose of TTX dose-dependently attenuated the increases in craving and anxiety while having no effect on blood pressure or heart rate. | It is widely accepted that chronic renal failure is associated with severe alterations of immune system. However, few studies looked into the immune alteration in earlier stage of chronic kidney disease (CKD) patients. To characterize immune defect in CKD patients, we performed lymphocyte subset analysis and explored its relationship to renal function in this population. 472 CKD patients were enrolled in this study. Lymphocyte subsets (CD19(+), CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD56(+)CD16(+)) were determined by flow cytometry. Clinical and laboratory data were collected. Patterns of immune cells in different stages of CKD were compared. Multivariate linear regression was used to evaluate the relationship between lymphocyte subset group and renal function. Correlation analysis was used to assess the relationship between lymphocyte subset and other clinical and laboratory data. Decreased lymphocyte counts occurred long before the end stage of renal disease. Increased NK cell percentage was negatively related to estimated glomerular filtration rate (eGFR) (r = -0.259, p < 0.001) while B cell percentage was positively related to eGFR (r = 0.249, p < 0.001). Further multivariate linear regression showed increased B cell percentage (β = 16.470, 95%CI [1.018-31.922], p = 0.037) and decreased NK cell percentage (β = -10.659, 95%CI [-20.063 to -1.254], p = 0.026) were independently correlated with higher eGFR, respectively. Patients with lower NK cell percentage and higher B cell percentage tended to have the best renal function. |
Is a gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity associated with familial Inappropriate Sinus Tachycardia? | Inappropriate Sinus Tachycardia (IST), a syndrome characterized by abnormally fast sinus rates and multisystem symptoms, is still poorly understood. Because of the relevance of HCN4 channels to pacemaker activity, we used a candidate-gene approach and screened IST patients for the presence of disease-causing HCN4 mutations. Forty-eight IST patients, four of whom of known familial history, were enrolled in the study. We initially identified in one of the patients with familial history the R524Q mutation in HCN4. Investigation extended to the family members showed that the mutation co-segregated with IST-related symptoms. The R524Q mutation is located in the C-linker, a region known to couple cAMP binding to channel activation. The functional relevance of the mutation was investigated in heterologous expression systems by patch-clamp experiments. We found that mutant HCN4 channels were more sensitive to cAMP than wild-type channels, in agreement with increased sensitivity to basal and stimulated adrenergic input and with a faster than normal pacemaker rate. The properties of variant channels indicate therefore that R524Q is a gain-of-function mutation. Increased channel contribution to activity was confirmed by evidence that when spontaneously beating rat newborn myocytes were transfected with R524Q mutant HCN4 channels, they exhibited a faster rate than when transfected with wild-type HCN4 channels. | To retrospectively assess changes in disease activity and skeletal damage in children with chronic nonbacterial osteomyelitis (CNO) after infliximab and methotrexate, with or without zoledronic acid or nonsteroidal antiinflammatory drug (NSAID) monotherapy, using a standardized magnetic resonance imaging (MRI) approach. Treatment-related changes in clinical and MRI measures from aggressive therapy and NSAID monotherapy groups (n = 9 per group) were evaluated using nonparametric methods. Pain, physical function, physician global assessment, inflammatory markers, nonvertebral inflammatory lesion number, and maximum bone edema score all improved significantly with aggressive therapy (p < 0.03), whereas only the maximum soft tissue inflammation severity decreased (p = 0.02) with NSAID monotherapy. Vertebral deformities and physeal damage did not worsen in the aggressive therapy group but 1 in the NSAID group had worsening of growth plate damage. |
Does carotid intima-media thickness measurement promise to improve cardiovascular risk evaluation in head and neck cancer patients? | Radiation-treated head and neck cancer (HNC) patients are at high risk for developing radiation vasculopathy, as evidenced by an increased stroke risk. The benefits of screening and assessing the cardiovascular (CV) risk of HNC patients using carotid intima-media thickness (CIMT) ultrasound are not known. Our objective was to determine the prevalence of high CV risk in patients without known CV diseases who received radiation for HNC, determine the percentage of screened patients who had a change in clinical management as a result of an increased CIMT, and to compare this risk-assessment tool to patients' risk classification using the Framingham Risk Score (FRS) and Pooled Cohort Atherosclerotic Cardiovascular Disease (ASCVD) Risk Equation (recommended by American College of Cardiology/American Heart Association Guidelines on the Assessment of Cardiovascular Risk). Risk calculators may not accurately predict risk in this population with a unique risk factor. Carotid IMT may be used to detect radiation vasculopathy in HNC patients. Retrospective medical chart review was conducted on 134 radiation-treated HNC patients. The main outcome measures were CV risk (as determined by CIMT) and clinical management. Also, the FRS and the Pooled Cohort ASCVD Risk Equation were used to compare classification with CIMT. Approximately 74% of the cases were at high CV risk using CIMT technique. Approximately half of the HNC patients screened had a change in clinical management characterized by recorded initiation of aspirin and recorded initiation or increase of statin therapies. The FRS and the Pooled Cohort ASCVD Risk Equation failed to detect 40% to 50% of cases found to be at high risk using the CIMT technique. | To detect the resistin expression of white adipose tissue in diet-induced obese (DIO) versus diet-resistant (DR) rats, and to investigate the relationship of mutated resistin and 3T3-L1 preadipocytes differentiation. RT-PCR and Western Blot were used to detect gene /protein expression. 3T3-L1 cells were cultured, transfected, and induced to differentiation using 0.5 mmol/L 3-isobutyl-1-methylxanthine (MIX), 1 mg/L insulin, and 1 micromol/L dexamethasone. Oil red O staining was applied to detect the degree of preadipocytes differentiation. Expression of resistin mRNA was upregulated in DIO rats and downregulated in DR rats. However, the expression levels varied greatly within the groups. Sequencing of the resistin genes from DIO and DR rats revealed a Leu9Val (C25G) missense mutation within the signal peptide in one DR rat. The mutant resistin inhibited preadipocyte differentiation. Local experiments and Western blotting with tagged resistin fusion proteins identified both mutant and wild type proteins in the cytoplasm and secreted into the culture medium. Computer predictions using the Proscan and Subloc programs revealed four putative phosphorylation sites and a possible leucine zipper motif within the rat resistin protein. |
Is fatigue in primary Sjögren 's syndrome associated with lower levels of proinflammatory cytokines? | This article reports relationships between serum cytokine levels and patient-reported levels of fatigue, in the chronic immunological condition primary Sjögren's syndrome (pSS). Blood levels of 24 cytokines were measured in 159 patients with pSS from the United Kingdom Primary Sjögren's Syndrome Registry and 28 healthy non-fatigued controls. Differences between cytokines in cases and controls were evaluated using Wilcoxon test. Patient-reported scores for fatigue were evaluated, classified according to severity and compared with cytokine levels using analysis of variance. Logistic regression was used to determine the most important predictors of fatigue levels. 14 cytokines were significantly higher in patients with pSS (n=159) compared to non-fatigued healthy controls (n=28). While serum levels were elevated in patients with pSS compared to healthy controls, unexpectedly, the levels of 4 proinflammatory cytokines-interferon-γ-induced protein-10 (IP-10) (p=0.019), tumour necrosis factor-α (p=0.046), lymphotoxin-α (p=0.034) and interferon-γ (IFN-γ) (p=0.022)-were inversely related to patient-reported levels of fatigue. A regression model predicting fatigue levels in pSS based on cytokine levels, disease-specific and clinical parameters, as well as anxiety, pain and depression, revealed IP-10, IFN-γ (both inversely), pain and depression (both positively) as the most important predictors of fatigue. This model correctly predicts fatigue levels with reasonable (67%) accuracy. | How adaptive phenotypes are shaped by the action of key developmental genes during ontogeny remains poorly understood. Water striders, a group of hemipteran insects, present a unique example of adaptation to life on the fluid water surface substrate. The group has undergone a set of leg modifications allowing them to efficiently move on the water surface and hence invade a variety of niches from ponds to open oceans. The elongated legs of water striders play a key role in generating efficient movement on the fluid by acting as propelling oars. To determine the developmental mechanisms underlying leg elongation, we examined the function of the key developmental genes decapentaplegic (dpp), wingless (wg), epidermal growth factor receptor (egfr), and hedgehog (hh) during embryonic development in the water strider Limnoporus dissortis. By analyzing expression patterns and RNAi knockdown phenotypes, we uncover the role of these genes in leg growth and patterning during embryogenesis. Our results indicate that wg and egfr contribute to the elongation of all the three segments of all thoracic legs, whereas hh specifies distal leg segments. |
Is silica gel as effective as acyclovir cream in patients with recurrent herpes labialis : results of a randomized , open-label trial? | To compare silica gel with acyclovir cream in the treatment of recurrent herpes labialis. In this randomized, open-label, comparator-controlled trial, 74 patients with recurrent herpes labialis applied silica gel or acyclovir cream respectively over a period of 10 days. The treatment started within 24 hours of the first symptoms of a new recurrence. Patients rated five symptoms (tautness, tingling, itching, burning sensation, pain), lesion stage, efficacy, tolerability, and duration until the onset of improvement. Their willingness-to-pay was assessed. Physicians rated the severity of the herpes recurrence and efficacy. There was no significant difference between silica gel and acyclovir cream in the overall patients' assessment. There is evidence that silica gel relieved all investigated symptoms earlier than acyclovir cream. The efficacy and tolerability of both medications were rated as good to very good. | The failing heart displays increased glycolytic flux that is not matched by a commensurate increase in glucose oxidation. This mismatch induces increased anaplerotic flux and inefficient glucose metabolism. We previously found adult transgenic mouse hearts expressing the fetal troponin I isoform, (ssTnI) to be protected from ischemia by increased glycolysis. In this study, we investigated the metabolic response of adult mouse hearts expressing ssTnI to chronic pressure overload. At 2 to 3 months of age, ssTnI mice or their nontransgenic littermates underwent aortic constriction (TAC). TAC induced a 25% increase in nontransgenic heart size but only a 7% increase in ssTnI hearts (P<0.05). Nontransgenic TAC developed diastolic dysfunction (65% increase in E/A ratio), whereas the E/A ratio actually decreased in ssTnI TAC. Isolated perfused hearts from nontransgenic TAC mice showed reduced cardiac function and reduced creatine phosphate:ATP (16% reduction), but ssTnI TAC hearts maintained cardiac function and energy charge. Contrasting nontransgenic TAC, ssTnI TAC significantly increased glucose oxidation at the expense of palmitate oxidation, preventing the increase in anaplerosis observed in nontransgenic TAC hearts. Elevated glucose oxidation was mediated by a reduction in pyruvate dehydrogenase kinase 4 expression, enabling pyruvate dehydrogenase to compete against anaplerotic enzymes for pyruvate carboxylation. |
Do anthracycline-Associated T1 Mapping Characteristics Are Elevated Independent of the Presence of Cardiovascular Comorbidities in Cancer Survivors? | Cardiovascular magnetic resonance T1 mapping characteristics are elevated in adult cancer survivors; however, it remains unknown whether these elevations are related to age or presence of coincident cardiovascular comorbidities. We performed blinded cardiovascular magnetic resonance analyses of left ventricular T1 and extracellular volume (ECV) fraction in 327 individuals (65% women, aged 64±12 years). Thirty-seven individuals had breast cancer or a hematologic malignancy but had not yet initiated their treatment, and 54 cancer survivors who received either anthracycline-based (n=37) or nonanthracycline-based (n=17) chemotherapy 2.8±1.3 years earlier were compared with 236 cancer-free participants. Multivariable analyses were performed to determine the association between T1/ECV measures and variables associated with myocardial fibrosis. Age-adjusted native T1 was elevated pre- (1058±7 ms) and post- (1040±7 ms) receipt of anthracycline chemotherapy versus comparators (965±3 ms; P<0.0001 for both). Age-adjusted ECV, a marker of myocardial fibrosis, was elevated in anthracycline-treated cancer participants (30.4±0.7%) compared with either pretreatment cancer (27.8±0.7%; P<0.01) or cancer-free comparators (26.9±0.2%; P<0.0001). T1 and ECV of nonanthracycline survivors were no different than pretreatment survivors (P=0.17 and P=0.16, respectively). Native T1 and ECV remained elevated in cancer survivors after accounting for demographics (including age), myocardial fibrosis risk factors, and left ventricular ejection fraction or myocardial mass index (P<0.0001 for all). | The systemic injection of neural stem/precursor cells (NPCs) provides remarkable amelioration of the clinico-pathological features of experimental autoimmune encephalomyelitis (EAE). This is dependent on the capacity of transplanted NPCs to engage concurrent mechanisms of action within specific microenvironments in vivo. Among a wide range of therapeutic actions alternative to cell replacement, neuroprotective and immune modulatory capacities of transplanted NPCs have been described. However, lacking is a detailed understanding of the mechanisms by which NPCs exert their therapeutic plasticity. This study was designed to identify the first candidate that exemplifies and sustains the immune modulatory capacity of transplanted NPCs. To achieve the exclusive targeting of the peripheral immune system, SJL mice with PLP-induced EAE were injected subcutaneously with NPCs and the treatment commenced prior to disease onset. NPC-injected EAE mice showed significant clinical improvement, as compared to controls. Exogenous NPCs lacking the expression of major neural antigens were reliably (and for long-term) found at the level of draining lymph nodes, while establishing sophisticated anatomical interactions with lymph node cells. Importantly, injected NPCs were never found in organs other than lymph nodes, including the brain and the spinal cord. Draining lymph nodes from transplanted mice showed focal up-regulation of major developmental stem cell regulators, such as BMP-4, Noggin and Sonic hedgehog. In lymph nodes, injected NPCs hampered the activation of myeloid dendritic cells (DCs) and steadily restrained the expansion of antigen-specific encephalitogenic T cells. Both ex vivo and in vitro experiments identified a novel highly NPC-specific-BMP-4-dependent-mechanism hindering the DC maturation. |
Does [ Mucosal administration of altered CII263-272 peptide inhibit collagen-induced arthritis ]? | To evaluate the effect of mucosal administration of altered collagen II(CII)263-272 peptide (267Q-->A, 270K-->A and 271G-->A) on collagen induced arthritis (CIA), and to explore the mechanism of the inhibitory effect of the altered CII263-272 peptide on CIA. CIA was induced in Lewis rats by immunization with bovine CII. Altered CII263-272 peptide was given intranasally beginning from the onset of arthritis (100 microg/dose, daily for 5 doses and continuing every other day for other 7 doses). Wild CII263-272 peptide (100 microg/dose) or PBS was administered as controls with the same procedure. Therapeutic effects were evaluated by arthritis scores, body weight change, and joint pathologic scores. The anti-CII antibody and its subtypes were measured with ELISA. The cytokines of IFN-gamma and IL-10 were measured with ELISA. The induction of regulatory T cells was assessed by FACS analysis of percentage of peripheral CD4(+)CD25(+) T cells, and by real-time PCR analysis of the expression of Foxp3 and TGF-beta mRNA. (1) Following treatment with the altered CII263-272 peptide, arthritis scores were reduced and body weight was increased. The mean arthritis scores of rats treated with altered peptide, wild peptide and PBS were 2.50 +/- 2.43, 4.50 +/- 2.23 and 6.33 +/- 2.73, respectively. The altered peptide could retard the histologic lesion of the joints. (2) The titers of anti-CII antibodies IgG and IgG1 in the three groups were similar, but the IgG2a in altered peptide-treated rats decreased markedly as compared with PBS-treated rats (0.56 +/- 0.19 vs 0.95 +/- 0.29, P<0.05). The serum IFN-gamma in rats treated with altered peptide, wild peptide and PBS were (185.33 +/- 29.77), (231.62 +/- 41.82) and (220.64 +/- 83.61) ng/L, respectively (P<0.05). No difference was found in the levels of serum IL-10 among the three groups. (3) There was no significant difference in the percentage of peripheral CD4(+)CD25(+) T cells and the expression level of Foxp3 and TGF-beta mRNA. | We explored the role of endoplasmic reticulum (ER)-mitochondria Ca(2+) cross talk involving voltage-dependent anion channel-1 (VDAC1)/glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex and mitofusin 2 in endothelial cells during hypoxia/reoxygenation (H/R), and investigated the protective effects of acetylcholine. Acetylcholine treatment during reoxygenation prevented intracellular and mitochondrial Ca(2+) increases and alleviated ER Ca(2+) depletion during H/R in human umbilical vein endothelial cells. Consequently, acetylcholine enhanced mitochondrial membrane potential and inhibited proapoptotic cascades, thereby reducing cell death and preserving endothelial ultrastructure. This effect was likely mediated by the type-3 muscarinic acetylcholine receptor and the phosphatidylinositol 3-kinase/Akt pathway. In addition, interactions among members of the VDAC1/glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex were increased after H/R and were associated with mitochondrial Ca(2+) overload and cell death. Inhibition of the partner of the Ca(2+) channeling complex (VDAC1 siRNA) or a reduction in ER-mitochondria tethering (mitofusin 2 siRNA) prevented the increased protein interaction within the complex and reduced mitochondrial Ca(2+) accumulation and subsequent endothelial cell death after H/R. Intriguingly, acetylcholine could modulate ER-mitochondria Ca(2+) cross talk by inhibiting the VDAC1/glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex and mitofusin 2 expression. Phosphatidylinositol 3-kinase siRNA diminished acetylcholine-mediated inhibition of mitochondrial Ca(2+) overload and VDAC1/glucose-regulated protein 75/inositol 1,4,5-trisphosphate receptor 1 complex formation induced by H/R. |
Does cement augmentation of vertebral screws enhance the interface strength between interbody device and vertebral body? | An in vitro cadaveric study comparing cage-vertebra interface strengths for 3 different screw-cement configurations. To determine the effects of cement augmentation of pedicle screws on cage-vertebra interface failure properties for 2 interbody device shapes (elliptical or cloverleaf); and to compare between pedicle and anterior vertebral body screws with cement augmentation. Pedicle or anterior screw fixation is commonly used with interbody device fixation. Cement has recently been shown to augment screw fixation in the osteoporotic spine by improving the screw-bone interface strength. The effect of cement augmentation of pedicle or anterior screws on cage-vertebra interface properties has not been previously studied or compared. An elliptical or a cloverleaf-shaped indentor covering 40% of the endplate was axially compressed against the superior endplate of 48 thoracolumbar vertebrae. Each vertebra had polymethylmethacrylate cement augmentation of 1) anterior screws, 2) pedicle screws, or 3) pedicle screws without cement. Compressive load was applied through a mechanism that allowed unconstrained rotation of the indentors. Cement augmentation of pedicle screws resulted in significantly higher failure loads (54%) and failure strength (69%) for both shaped indentors when compared with uncemented pedicle screws. There was no significant difference in failure load and failure strength between pedicle and anterior screws with cement augmentation. Indentor shape was not a significant factor on failure load or failure strength. | Psoriasis is a chronic, immune-mediated inflammatory skin disease with many extracutaneous manifestations. Several recent studies have indicated an increased prevalence of nonalcoholic fatty liver disease (NAFLD) among patients with psoriasis. In the present study, we investigated the prevalence of NAFLD in a population of Iranian patients with psoriasis. NAFLD was assessed and graded using ultrasonography in 123 patients with psoriasis and 123 healthy controls (HCs) matched by age, sex and body mass index (BMI). The prevalence of NAFLD was significantly higher in the psoriatic group compared with the HC group (65.6% vs. 35%, P < 0.01, OR = 3.53). Median NAFLD grade was significantly greater in patients with psoriasis compared with HCs (grade 2 vs. grade 1, P < 0.01). In patients with psoriasis, NAFLD was associated with a higher frequency of hypertension (16.5%), abnormal liver function test (LFT) results (16.4%) and metabolic syndrome (46.6%). Moreover, patients with psoriasis and NAFLD tended to have significantly higher values for BMI, waist circumference (WC), Psoriasis Activity and Severity Index (PASI), and levels of serum triglyceride, cholesterol, low-density lipoprotein and fasting blood sugar (FBS). Multivariate logistic regression revealed that WC, PASI, LFT abnormalities, hypertension and cigarette smoking were independent predictors of NAFLD grade. |
Is mechanical dyssynchrony additive to ECG criteria and independently associated with reverse remodelling and clinical response to cardiac resynchronisation therapy in patients with advanced heart failure? | QRS duration and morphology are known established predictors of cardiac resynchronisation therapy (CRT) response, whereas mechanical dyssynchrony is not. Our aim was to determine if mechanical dyssynchrony provides independent prognostic information on CRT response. We studied 369 consecutive patients with heart failure (HF) with low ejection fraction (EF) and widened QRS receiving CRT. Radial dyssynchrony (septal-posterior radial peak strain delay ≥130 ms by speckle tracking) assessment was possible in 318 patients (86%). Associations with left ventricular end-systolic volume (LVESV) changes were examined using linear regression, and clinical outcomes analysed using Cox regression adjusted for multiple established outcome correlates. Patients with radial dyssynchrony before CRT (64%) had greater improvements in EF (8.8±9.4 vs 6.1±9.7 units, p=0.04) and LVESV (-30±41 vs -10±30 mL, p<0.01). Radial dyssynchrony was independently associated with reduction in LVESV (regression coefficient -10.5 mL, 95% CI -20.5 to -0.5, p=0.040) as was left bundle-branch block (-17.7 mL, -27.6 to -7.7, p=0.001). Patients with radial dyssynchrony had a 46% lower incidence of death, transplant or implantation of a left ventricular assist device (adjusted HR 0.54, 95% CI 0.31 to 0.92, p=0.02) and a 39% lower incidence of death or HF hospitalisation (0.61, 0.40 to 0.93, p=0.02) over 2 years. | Morus alba, a medicinal plant in Asia, has been used traditionally to treat diabetes mellitus and hypoglycemia. However, the effects of M. alba extract (MAE) on atopic dermatitis have not been verified scientifically. We investigated the effects of MAE on atopic dermatitis through in vitro and in vivo experiments. We evaluated the effects of MAE on the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7, as well as thymus and activation-regulated chemokine (TARC/CCL17) in HaCaT cells. In an in vivo experiment, atopic dermatitis was induced by topical application of house dust mites for four weeks, and the protective effects of MAE were investigated by measuring the severity of the skin reaction on the back and ears, the plasma levels of immunoglobulin E (IgE) and histamine, and histopathological changes in the skin on the back and ears. MAE suppressed the production of NO and PGE2 in RAW 264.7 cells, as well as TARC in HaCaT cells, in a dose-dependent manner. MAE treatment of NC/Nga mice reduced the severity of dermatitis and the plasma levels of IgE and histamine. MAE also reduced the histological manifestations of atopic dermatitis-like skin lesions such as erosion, hyperplasia of the epidermis and dermis, and inflammatory cell infiltration in the skin on the back and ears. |
Do antigen-presenting cells represent targets for R5 HIV-1 infection in the first trimester pregnancy uterine mucosa? | During the first trimester of pregnancy, HIV-1 mother-to-child transmission is relatively rare despite the permissivity of placental cells to cell-to-cell HIV-1 infection. The placenta interacts directly with maternal uterine cells (decidual cells) but the physiological role of the decidua in the control of HIV-1 transmission and whether decidua could be a source of infected cells is unknown. To answer to this question, decidual mononuclear cells were exposed to HIV-1 in vitro. Decidual cells were shown to be more susceptible to infection by an R5 HIV-1, as compared to an X4 HIV-1. Infected cells were identified by flow cytometry analysis. The results showed that CD14(+) cells were the main targets of HIV-1 infection in the decidua. These infected CD14(+) cells expressed DC-SIGN, CD11b, CD11c, the Fc gamma receptor CD16, CD32 and CD64, classical MHC class-I and class-II and maturation and activation molecules CD83, CD80 and CD86. The permissivity of decidual tissue was also evaluated by histoculture. Decidual tissue was not infected by X4 HIV-1 but was permissive to R5 HIV-1. Different profiles of infection were observed depending on tissue localization. | Exercise tests are increasingly used during preoperative evaluation before lung resection. This study assessed the association between performance at the symptom-limited stair-climbing test and postoperative cardiopulmonary morbidity, mortality, and costs after major lung resections. As part of their routine preoperative evaluation, 640 patients who had lobectomy (n = 533) or pneumonectomy (n = 107) for lung cancer from January 2000 through April 2007 performed a preoperative symptom-limited stair-climbing test. Sensitivity/specificity analysis was used to identify the best cutoff values of altitude climbed (number of steps x height of the step in m) associated with outcome. Univariate and multivariate regression analyses (validated by bootstrap) were used to test associations between preoperative and operative factors and postoperative cardiopulmonary complications, mortality, and postoperative costs. The altitude reached at the stair-climbing test was reliably associated with increased cardiopulmonary complications (p = 0.04), mortality (p = 0.02), and costs (p < 0.0001). In patients who climbed less than 12 m, cardiopulmonary complications, mortality, and costs were 2-fold (p < 0.0001), 13-fold (p < 0.0001), and 2.5-fold higher, respectively, than in patients who climbed more than 22 m. |
Does foxo3 circular RNA promote cardiac senescence by modulating multiple factors associated with stress and senescence responses? | Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches. Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence. Doxorubicin-induced cardiomyopathy was aggravated by ectopic expression of circ-Foxo3 but was relieved by silencing endogenous circ-Foxo3. We also found that silencing circ-Foxo3 inhibited senescence of mouse embryonic fibroblasts and that ectopic expression of circ-Foxo3 induced senescence. We found that circ-Foxo3 was mainly distributed in the cytoplasm, where it interacted with the anti-senescent protein ID-1 and the transcription factor E2F1, as well as the anti-stress proteins FAK and HIF1α. | Fingertip injuries are common and bear significant costs associated with treatment, lost work, and functional impairment. This study compared these factors in occupationally related fingertip injuries treated with becaplermin, a recombinant human platelet-derived growth factor, and those treated with surgical reconstruction. This was a prospective controlled trial involving occupationally related fingertip injuries. Fifty men (ages 23-51) with full thickness, single fingertip injuries > or =1.5 cm(2) with or without phalangeal exposure and distal to the distal interphalangeal (DIP) joint were evaluated. Group I (n = 25) underwent treatment with daily topical becaplermin. Group II (n = 25) underwent surgical reconstruction with a skin graft or local soft tissue flap. Time to wound healing, time to return to work, associated treatment costs, and calculated functional impairment were recorded. Patients in Group I returned to work in significantly less time than those in Group II-10 days versus 38 days respectively). The average calculated functional impairment in Group I was 10% versus 22% in Group II. Associated treatment costs in group A were 1580 +/- 145 US Dollars compared with 6750 +/- 785 US Dollars in Group II. All differences were statistically significant at p < 0.05 |
Does butyrate impair atherogenesis by reducing plaque inflammation and vulnerability and decreasing NFκB activation? | Butyrate is a four-carbon fatty acid that presents anti-inflammatory, anti-oxidative and apoptotic properties in colon and several cell lines. Because atherosclerosis has important oxidative and inflammatory components, butyrate could reduce oxidation and inflammation, impairing atherogenesis. We evaluated the effects of butyrate supplementation of butyrate on atherosclerosis and its mechanisms of action. ApoE knockout mice were fed on chow diet or 1% butyrate-supplemented chow diet (Butyrate) for 10 weeks to assess atherosclerosis lesions area and inflammatory status. Macrophage and endothelial cells were also pretreated with butyrate (0.5 mM) for 2 h before oxLDL stimulation to study oxLDL uptake and pro and anti-inflammatory cytokine production. Butyrate reduced atherosclerosis in the aorta by 50%. In the aortic valve, butyrate reduced CCL2, VCAM1 and MMP2 productions in the lesion site, resulting in a lower migration of macrophage and increased collagen depositions in the lesion and plaque stability. When EA.hy926 cells were pretreated with butyrate, oxLDL uptake, CD36, VCAM1, CCL2 TNF, IL1β and IL6 productions were reduced, whereas IL10 production was increased. These effects were accompanied by a lower activation of NFκB due to a lower nuclear translocation of the p65 subunit. | To report outcome of pars plana vitrectomy in patients with chronic hypotony due to uveitis. Assessment of ciliary body was done preoperatively by ultrasound biomicroscopy and intraoperatively by direct visualization. Surgical procedure included pars plana or limbal lensectomy and vitrectomy with removal of ciliary membranes and traction. Silicone oil tamponade was used in selected eyes. Postoperatively subtenon triamcinolone acetonide was given if intraocular pressure (IOP) remained low. Fifteen eyes of nine patients, all woman at mean age of 15.66 +/- 12.57 (4-40) years, were included. In 7 eyes with intact ciliary processes, mean pre- and postoperative IOP was 4.00 +/- 1.6 mmHg and 9.1 +/- 4.1 mmHg, respectively. In 4 eyes with ciliary atrophy that did not receive silicone oil tamponade, mean pre- and postoperative IOP was 4.25 +/- 1.7 and 3.75 +/- 0.9 mmHg, respectively. In 4 eyes with ciliary atrophy that received silicone oil tamponade mean pre- and postoperative IOP was 3.75 +/- 1.7 and 11.5 +/- 2.3 mmHg, respectively. Mean follow-up was 19.9 +/- 14.9 (8-56) months. Postoperative mean logMAR visual acuity improved significantly (P < 0.001) from 2.29 +/- 0.67 to 1.01 +/- 0.89. |
Does retinal function in rabbits improve 4-5 months after terminating treatment with vigabatrin? | We have previously reported changes in retinal function and histopathology in rabbits treated with vigabatrin. The purpose of the present study was to evaluate retinal function and histopathology of retina in rabbits 4-5 months after terminating vigabatrin medication. Five rabbits were treated with a daily per oral dose of vigabatrin during 12-13 months. After terminating treatment an observation period of 4-5 months followed. Six rabbits receiving water served as controls. Standardized full-field electroretinograms were performed every 6-8 weeks, using a Burian-Allen bipolar contact lens. After 18 months the rabbits were sacrificed and the morphology of the sectioned retina was studied. The antibodies used for staining were GABA, GFAP, GAD, and vimentin. After 12-13 months of treatment the full-field ERG was reduced in all rabbits treated with vigabatrin. There was a statistically significant difference in the dark adapted cone b-wave amplitude between treated animals and controls (Wilcoxon signed-rank test, p = 0.043). This difference was consistent also 4-5 months after terminating treatment. Immunohistology of the sectioned retina demonstrated no significant difference in immunoreactivity between treated animals and controls. All treated rabbits demonstrated elevated serum concentration of the drug during medication. | Adiponectin, an adipose tissue derived hormone, is known to have insulin-sensitizing, anti-inflammatory, and anti-atherogenic properties in the general population. Adiponectin secretion is suppressed by systemic inflammation, a highly prevalent condition in maintenance hemodialysis (MHD) patients. We evaluated whether short-term administration of interleukin 1 receptor antagonist (IL-1ra) improves adiponectin levels and insulin sensitivity in MHD patients. Ad hoc analysis was performed on a pilot randomized placebo-controlled trial of the administration of IL-1ra in chronically inflamed MHD patients. Twenty-two patients were randomly assigned to receive 100 mg of IL-1ra or placebo (1:1) for 4 weeks, and 14 completed the trial. ANCOVA was used to compare percent change from baseline to 4 weeks. The primary outcome was percent change in adiponectin and the secondary outcomes were changes in leptin, homeostatic model assessment of insulin resistance (HOMA-IR) and the leptin-to-adiponectin ratio (LAR). Patients' mean age was 49 ± 13 years, and 71 % were males. At baseline, the median values for adiponectin, leptin, LAR and HOMA-IR were 11.5 μg/ml [interquartile range (IQR) 9, 28.5], 17.8 ng/ml (3.9, 50.0), 2.20 (0.13, 3.98), and 2.8 (2.0, 3.6), respectively. IL-1ra administration resulted in a mean percent increase in serum adiponectin of 22 % vs. 14 % decrease in the placebo arm (p = 0.003). Leptin, LAR or HOMA-IR levels did not change in either arm. |
Is multimodal endovascular management of acute ischemic stroke in patients over 75 years old safe and effective? | Greater attention has been directed to endovascular recanalization of acute ischemic stroke in septuagenarians and above. A retrospective chart review was conducted to include patients treated for acute ischemic stroke from 2006 to 2012. All patients underwent initial neurological assessment and non-contrast head CT. Patients treated from 2009 to 2012 additionally received emergent CT angiogram and CT perfusion. 51 patients met the clinical and radiographic criteria and underwent multimodal endovascular revascularization for acute ischemic events. All patients underwent cerebral angiography and met angiographic criteria for endovascular thrombolysis. 34 patients (67%) were older than 80 years of age. 23 patients (45%) received intravenous tissue plasminogen activator prior to admission. Eight (16%) patients underwent stent placement after intra-arterial thrombolysis, 10 (20%) underwent balloon angioplasty and seven (14%) underwent both angioplasty and stent placement. 21 (41%) required only intra-arterial thrombolytics. An improvement in Thrombolysis in Myocardial Infarction score was noted in 34 patients (67%). The average modified Rankin Scale score on discharge was 3.9. Symptomatic intracranial hemorrhage occurred in three patients (6%); none required surgery. One patient (1.9%) had a postoperative retroperitoneal hematoma, which was managed conservatively. Two fatalities resulted from intraoperative vessel rupture (3.9%), with a combined morbidity and mortality of 27.5%. | To investigate whether palatable sweet foods have a beneficial effect on chronic stress-induced colonic motility and inflammatory cytokines. Adult male rats were divided into 3 groups: control (CON, n = 5), chronic variable stress with chow (CVS-A, n = 6), and chronic variable stress with chow and sweet food (CVS-B, n = 6). The rats were fed standard rodent chow as the chow food and/or AIN-76A as the sweet food. A food preference test for AIN-76A was performed in another group of normal rats (n = 10) for twelve days. Fecal pellet output (FPO) was measured for 6 wk during water bedding stress in the CVS groups. The weight of the adrenal glands, adrenocorticotropic hormone (ACTH) and corticosterone levels in plasma were measured. The expression levels of transforming growth factor-β, interleukin (IL)-2, and interferon-gamma (IFN-γ) were measured in the distal part of colonic tissues and plasma using Western blot analysis. In sweet preference test, all rats initially preferred sweet food to chow food. However, the consumption rate of sweet food gradually decreased and reduced to below 50% of total intake eight days after sweet food feeding. Accumulated FPO was higher in the CVS-A group compared with the CVS-B group over time. All stress groups showed significant increases in the adrenal to body weight ratio (CVS-A, 0.14 ± 0.01; CVS-B, 0.14 ± 0.01) compared with the control group (0.12 ± 0.01, P < 0.05). The plasma corticosterone and ACTH levels were significantly higher in the CVS-A (537.42 ± 32.95, 44.44 ± 6.54 pg/mL) and CVS-B (655.07 ± 30.82, 65.46 ± 4.44 pg/mL) groups than in the control group (46.96 ± 13.29, 8.51 ± 1.35 pg/mL, P < 0.05). Notably, the ratio of corticosterone to ACTH was significantly increased in the CVS-A group only. Rats exposed to CVS displayed significantly increased expression of IL-2 and IFN-γ in the plasma and distal colon compared to the control group, whereas this effect was significantly attenuated in the CVS-B group. |
Does basics of flow cytometry-based sterility testing of platelet concentrate? | Flow cytometry (FACS) is a common technique in blood banking. It is used, for example, for the enumeration of residual white blood cells in plasma and in cellular blood products. It was investigated whether it can also be applied for sterility testing of buffy coat-derived platelet concentrates (PCs). Plasma-reduced PCs were spiked with bacteria and stored at 20 to 24 or 37 degrees C for various times. The following 10 species were used: Bacillus cereus, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Propionibacterium acnes, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Serratia marcescens, and Yersinia enterocolitica. Bacterial DNA was stained with thiazole orange. After the platelets were lysed, bacteria were enumerated by FACS. All bacteria species used were detectable by FACS. The lower detection limit was approximately 100 bacteria per microL, that is, 10(5) per mL. In general, the titers measured were 1.2- to 3-fold higher than those determined by colony forming assay. In one case (K. pneumoniae) in which the dot plot of the bacteria cloud overlapped with that of bacteria debris, they were consistently lower. When PC samples were inoculated with approximately 1 colony-forming unit per mL of bacteria and kept at 37 degrees C, most species were detected within 21 hours or less. Exceptions were E. cloacae and P. acnes, which were detected after 24 to 40 and 64 hours, respectively. At 20 to 24 degrees C, the detection times were strongly prolonged. | This study used dopamine D2 receptor (D2R) knockout (KO) mice to investigate the role of D2R activity in the development of form-deprivation myopia (FDM). Sulpiride, a D2R antagonist, was administered systemically into wild-type (WT) mice to validate the involvement of D2R in FDM development. The D2R KO and WT C57BL/6 mice were subjected to FDM. Wild-type mice received daily intraperitoneal injections of sulpiride, 8 μg/g body weight, for a period of 4 weeks. The body weight, refraction, corneal radius of curvature, and ocular axial components were measured at week 4 of the experiment. Differences in all ocular parameters between the experimental and control groups were compared statistically. Form-deprivation myopia in D2R KO mice (FD-KO) was significantly reduced compared with their WT littermates (interocular difference, -2.12 ± 0.91 diopter [D] in FD-KO versus -5.35 ± 0.83 D in FD-WT, P = 0.014), with a smaller vitreous chamber depth (0.008 ± 0.006 vs. 0.026 ± 0.006 mm, P = 0.044) and axial length (-0.001 ± 0.007 vs. 0.027 ± 0.008 mm, P = 0.007). Furthermore, FDM was attenuated in animals treated with sulpiride (-2.01 ± 0.31 D in FD-sulpiride versus -4.06 ± 0.30 D in FD-DMSO, P < 0.001) compared with those treated with vehicle, with a retardation in growth of vitreous chamber depth (-0.001 ± 0.006 vs. 0.022 ± 0.004 mm, P = 0.003) and axial length (-0.004 ± 0.007 vs. 0.027 ± 0.005 mm, P = 0.001). |
Is vegetable intake associated with lower Frammingham risk scores in Korean men : Korea National Health and Nutrition Survey 2007-2009? | Observational studies suggest that an association between vegetable consumption and coronary heart disease (CHD). However, the results are inconsistent. This study aimed to investigate the daily intake of vegetables on a national level and its effect on the risk of CHD risk, as determined by the Framingham Risk Score (FRS). This study was conducted a cross-sectional design of 2,510 male adults 40-64y of age who participated in the 2007-2009 Korean National Health and Nutrition Examination Survey. Daily intake of vegetable was assessed by 24-h recall, and the consumption frequency of vegetables was determined using a food frequency questionnaire. The odd ratio of CHD risk according to daily intake and frequency of vegetables was analyzed. Total vegetable intake was inversely and significantly associated with the risk of CHD (Model 1: 4th vs. 1st quartile, OR = 0.74, 95% CI = 0.58-0.96, P for trend = 0.0015), and the significant relationship with CHD risk remained even after adjusting for potential confounders (Model 3: 4th vs. 1st quartile, adjusted OR [aOR] = 0.69, 95% CI = 0.49-0.95, P for trend = 0.0492). Subjects in the higher quartiles of non-salted vegetable intake had 31% lower odds of the risk of CHD compared to those in the lowest quartile after adjusting for various potential confounders in model 3 (aOR = 0.69; 95% CI = 0.49-0.97, P for trend = 0.0478). No significant associations between the frequency of vegetable intake (total, green, white and red vegetable) and the risk of CHD were found. | Androgen ablation is the standard initial treatment for advanced prostate cancer; however, tumors eventually develop androgen independence and become incurable. Chemotherapy is commonly used after hormone treatment fails but has not shown significant survival benefit. Studies suggest that androgen ablation can select for a population of hormone-independent cells that are also relatively chemotherapy resistant. Thus, it may be therapeutically advantageous to target prostate cancer with chemotherapy before hormone ablation. This study was undertaken to determine the relative efficacy of such an approach in a preclinical model of prostate cancer. Severe combined immunodeficient mice bearing human LNCaP prostate tumors were treated with docetaxel and/or surgical castration applied singly, concurrently, or in different sequences. Treatment efficacy was determined by tumor volume and growth delay measurements. The extent of apoptosis in tumors in response to treatments was assessed via terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assays. In addition, Western blots were done to study the relative expression of Bcl-2 and Bax in the tumors. Docetaxel followed by castration showed the most potent antitumor effects. In contrast, with the exception of castration alone, castration followed by docetaxel produced the least antitumor activity. TUNEL assays confirmed that the density of apoptotic tumor cells was significantly greater for docetaxel followed by castration than for any other treatment. In tumors of mice treated with single modality therapies, Bax to Bcl-2 ratios decreased significantly after castration, whereas this ratio remained high after docetaxel treatment. |
Does hormone replacement therapy cause a decrease in hepatocyte growth factor in hypertensive women? | Serum hepatocyte growth factor (HGF) is associated with blood pressure. We investigated whether the serum HGF level differs between hypertensive and normotensive postmenopausal women (PMW) and whether hormone replacement therapy (HRT) alters the serum HGF level and blood pressure in hypertensive and normotensive PMW. Prospective observational study. A total of 33 PMW with mild to moderate essential hypertension controlled by antihypertensive treatment (mean age, 57 +/- 6 years) and 23 normotensive PMW (mean age, 57 +/- 7 years) received continuous HRT (0.625 mg of conjugated equine estrogen combined with 2.5 mg of medroxyprogesterone acetate) once a day orally for 12 months, and we measured serum HGF levels and blood pressure before and 12 months after the start of HRT. The baseline serum HGF level was significantly higher in hypertensive PMW than in normotensive PMW. HRT significantly decreased the serum HGF level in hypertensive subjects, from 2.85 +/- 0.64 pmol/l to 2.49 +/- 0.65 pmol/l (P < 0.001), but not in normotensive subjects. HRT did not change blood pressure in either group. | Multiple sclerosis (MS) lesions demonstrate immunopathological heterogeneity in patterns of demyelination. Previous cross-sectional studies reported immunopatterns of demyelination were identical among multiple active demyelinating lesions from the same individual, but differed between individuals, leading to the hypothesis of intraindividual pathological homogeneity and interindividual heterogeneity. Other groups suggested a time-dependent heterogeneity of lesions. The objective of our present study was to analyze tissue samples collected longitudinally to determine whether patterns of demyelination persist over time within a given patient. Archival tissue samples derived from patients with pathologically confirmed central nervous system inflammatory demyelinating disease who had undergone either diagnostic serial biopsy or biopsy followed by autopsy were analyzed immunohistochemically. The inclusion criteria consisted of the presence of early active demyelinating lesions--required for immunopattern classification--obtained from the same patient at 2 or more time points. Among 1,321 surgical biopsies consistent with MS, 22 cases met the study inclusion criteria. Twenty-one patients (95%) showed a persistence of immunopathological patterns in tissue sampled from different time points. This persistence was demonstrated for all major patterns of demyelination. A single patient showed features suggestive of both pattern II and pattern III on biopsy, but only pattern II among all active lesions examined at autopsy. |
Do foxP3+ regulatory T cells suppress effector T-cell function at pathologic site in miliary tuberculosis? | The inadequacy of effector T-cell response in containment of tubercle bacilli is believed to result in the development of disseminated forms of tuberculosis (TB), such as miliary tuberculosis (MTB). Regulatory T cells (Treg) plausibly play a critical role in the immunopathogenesis of disseminated TB by suppression of effector immune response against Mycobacterium tuberculosis at the pathologic site(s). To understand the role of Treg cells in disseminated tuberculosis, we studied the frequency and function of Treg cells derived from the local disease site specimens (LDSS) of patients with TB pleural effusion and MTB as clinical models of contained and disseminated forms of disease, respectively. To (1) enumerate the frequency of Treg cells in bronchoalveolar lavage (BAL) fluid of patients with MTB and compare with that of peripheral blood, (2) study the role of Treg cells in suppression of local T-cell response, and (3) study the selective recruitment of Treg cells at the local disease site(s). Flow cytometry, reverse transcriptase polymerase chain reaction, and 3-(4,5-dimethylthythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)-based cell proliferation assay. Frequency of Treg cells (CD4(+)CD25(+)FoxP3(+)) was significantly higher in LDSS in MTB along with higher levels of FoxP3 mRNA. Importantly, FoxP3(+) Treg cells obtained from the BAL of patients with MTB predominantly produced IL-10 and could suppress the autologous T-cell proliferation in response to M. tuberculosis antigen. | Vasopeptidase inhibitors are drugs that inhibit angiotensin-converting enzyme and neutral endopeptidase (NEP). The latter is a protease that degrades vasoactive peptides and is increased in diabetes. We have previously shown that treating streptozotocin-induced diabetic rats, an animal model of type 1 diabetes, with AVE7688, a vasopeptidase inhibitor, improves neurovascular and neural function. In this study, we determined the effect of treating Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes, with AVE7688 on vascular and neural function. ZDF rats at 12 weeks of age were treated for 12 weeks with AVE7688 (500 mg/kg diet). Afterwards, vascular reactivity of epineurial arterioles of the sciatic nerve and nerve conduction velocity and blood flow was determined. Vascular and neural function was significantly impaired in ZDF rats compared with age-matched lean (control) rats. Treating ZDF rats with AVE7688 improved vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles. Motor and sensory nerve conduction velocity, endoneurial blood flow and thermal nociception end-points were also improved by treatment compared with untreated ZDF rats. Superoxide and expression of NEP were increased in epineurial arterioles from ZDF rats and attenuated by treatment with AVE7688. |
Are higher plasma myeloperoxidase levels associated with an increased risk for cardiovascular events in HIV-infected adults? | Elevated myeloperoxidase (MPO) levels are predictive of high cardiovascular (CV) risk in the general population. The value of MPO as a CV marker in the HIV population has not been investigated. Medical records were reviewed to identify HIV+ patients with a documented CV event (myocardial ischemia/infarction) and stored plasma samples within 12 months prior to the event. HIV+ adults with no CV history and with similarly available stored plasma samples were site-, age-, and gender-matched 1:1 to cases. We identified 124 participants (62 case-control pairs): 94% male, median age 46 years. Median (IQR) MPO levels (pmoles/L) were lower in cases vs. controls: 292 (235-376) vs. 320 (249-467); p= .004. Cases were more likely to have other CV risk factors, including smoking, hypertension, and higher cholesterol and triglycerides. The observed MPO directional difference persisted after controlling for CV risk factors. In the reduced model, observed differences in MPO remained independently and negatively associated with CV event (p= .03) after adjusting for two positively associated risk factors, differences in cholesterol levels (p= .01), and differences in smoking history (ever smoked vs. never smoked; p= .04). Differences in triglyceride levels and hypertension were not statistically significant independent risk factors in this sample (p> .05). Within cases, MPO was negatively correlated with CD4 count (rs= -0. 40, p= .0023) and age (rs= -0. 34, p= .01). In contrast, age at blood draw was positively correlated with MPO in controls (rs= 0.28, p= .031) and CD4 was uncorrelated (rs= -0. 01, p> .9). No other factors were significantly correlated with MPO within groups. | Loading otoprotective drug into cochlear implant might change its mechanical properties, thus compromising atraumatic insertion. This study evaluated the effect of incorporation of dexamethasone (DXM) in the silicone of cochlear implant arrays on insertion forces. Local administration of DXM with embedded array can potentially reduce inflammation and fibrosis after cochlear implantation procedure to improve hearing preservation and reduce long-term impedances. Four models of arrays have been tested: 0.5-mm distal diameter array (n = 5) used as a control, drug-free 0.4-mm distal diameter array (n = 5), 0.4-mm distal diameter array with 1% eluded DXM silicone (n = 5), and 0.4-mm distal diameter array with 10% eluded DXM silicone (n = 5). Via a motorized insertion bench, each array has been inserted into an artificial scala tympani model. The forces were recorded by a 6-axis force sensor. Each array was tested seven times for a total number of 140 insertions. During the first 10-mm insertion, no difference between the four models was observed. From 10- to 24-mm insertion, the 0.5-mm distal diameter array presented higher insertion forces than the drug-free 0.4-mm distal diameter arrays, with or without DXM. Friction forces for drug-free 0.4-mm distal diameter array and 0.4-mm distal diameter DXM eluded arrays were similar on all insertion lengths. |
Is l-NMMA ( a nitric oxide synthase inhibitor ) effective in the treatment of cardiogenic shock? | The objective was to assess the safety and efficacy of L-NMMA in the treatment of cardiogenic shock. We enrolled 11 consecutive patients with cardiogenic shock that persisted after >24 hours from admission, despite coronary catheterization and primary percutaneous transluminal coronary revascularization, when feasible, and treatment with mechanical ventilation, intraaortic balloon pump (IABP), and high doses of catecholamines. L-NMMA was administered as an IV bolus of 1 mg/kg and continuous drip of 1 mg. kg(-1). h(-1) for 5 hours. Treatment with catecholamines, mechanical ventilation, and IABP was kept constant throughout the study. Within 10 minutes of L-NMMA administration, mean arterial blood pressure (MAP) increased from 76+/-9 to 109+/-22 mm Hg (+43%). Urine output increased within 5 hours from 63+/-25 to 156+/-63 cc/h (+148%). Cardiac index decreased during the steep increase in MAP from 2. 0+/-0.5 to 1.7+/-0.4 L/(min. m(2)) (-15%); however, it gradually increased to 1.85+/-0.4 L/(min. m(2)) after 5 hours. The heart rate and the wedge pressure remained stable. Twenty-four hours after L-NMMA discontinuation, MAP (+36%) and urine output (+189%) remained increased; however, cardiac index returned to pretreatment level. No adverse events were detected. Ten out of eleven patients could be weaned off mechanical ventilation and IABP. Eight patients were discharged from the coronary intensive care unit, and seven (64%) were alive at 1-month follow-up. | Developmental dyslexia (DD) is a complex heritable condition associated with impairments in multiple neurocognitive domains. Substantial heritability has been reported for DD and related phenotypes, and candidate genes have been identified. Recently, a candidate gene for human cognitive processes, that is, GRIN2B, has been found to be associated significantly with working memory in a German DD sample. In this study, we explored the contribution of six GRIN2B markers to DD and key DD-related phenotypes by association analyses in a sample of Italian nuclear families. Moreover, we assessed potential gene-by-environment interactions on DD-related phenotypes. We carried out a family-based association study to determine whether the GRIN2B gene influences both DD as a categorical trait and its related cognitive traits in a large cohort of 466 Italian nuclear families ascertained through a proband affected by DD. Moreover, we tested the role of the selected GRIN2B markers and a set of commonly described environmental moderators using a test for G×E interaction in sib pair-based association analysis of quantitative traits in 178 Italian nuclear families. Evidence for a significant association was found with the categorical diagnosis of DD, performance intelligence quotient, phonemic elision, and auditory short-term memory. No significant gene-by-environment effects were found. |
Do posttraumatic stress disorder and substance use disorder in adolescent bipolar disorder? | Anxiety disorders such as posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are increasingly recognized as comorbid disorders in children with bipolar disorder (BPD). This study explores the relationship between BPD, PTSD, and SUD in a cohort of BPD and non-BPD adolescents. We studied 105 adolescents with BPD and 98 non-mood-disordered adolescent controls. Psychiatric assessments were made using the Kiddie Schedule for Affective Disorders and Schizophrenia-Epidemiologic Version (KSADS-E), or Structured Clinical Interview for DSM-IV (SCID) if 18 years or older. SUD was assessed by KSADS Substance Use module for subjects under 18 years, or SCID module for SUD if age 18 or older. Nine (8%) BPD subjects endorsed PTSD and nine (8%) BPD subjects endorsed subthreshold PTSD compared to one (1%) control subject endorsing full PTSD and two (2%) controls endorsing subthreshold PTSD. Within BPD subjects endorsing PTSD, seven (39%) met criteria for SUD. Significantly more SUD was reported with full PTSD than with subthreshold PTSD (chi(2) = 5.58, p = 0.02) or no PTSD (chi(2) = 6.45, p = 0.01). Within SUD, the order of onset was BPD, PTSD, and SUD in three cases, while in two cases the order was PTSD, BPD, SUD. The remaining two cases experienced coincident onset of BPD and SUD, which then led to trauma, after which they developed PTSD and worsening SUD. | Studies indicate the dramatic reduction of shear stress (SS) within the rapamycin eluting stent (RES) segment of coronary arteries. It remains unclear about the role of rapamycin in endothelialization of stented arteries where SS becomes low. Since mTOR (mammalian target of rapamycin) pathway is involved in the antioxidative sestrins expression, we hypothesized that rapamycin attenuated low SS (LSS) induced endothelial dysfunction through mTOR and sestrin1 associated redox regulation. To mimic the effect of LSS on the stented arteries, a parallel plate flow chamber was used to observe the interplay of LSS and rapamycin on endothelial cells (ECs). The results showed LSS significantly induced EC apoptosis which was mitigated by pretreatment of rapamycin. Rapamycin attenuated LSS induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) production via prohibition of sestrin1 downregulation. Activities of mTORC1 and mTORC2 were detected contradictorily modulated by LSS. Inhibition of rictor expression by target small interfering RNA (siRNA) transfection prohibited sestrin1 downregulation induced by LSS, but inhibition of raptor did not. |
Is density and duration of pneumococcal carriage maintained by transforming growth factor β1 and T regulatory cells? | Nasopharyngeal carriage of Streptococcus pneumoniae is a prerequisite for invasive disease, but the majority of carriage episodes are asymptomatic and self-resolving. Interactions determining the development of carriage versus invasive disease are poorly understood but will influence the effectiveness of vaccines or therapeutics that disrupt nasal colonization. We sought to elucidate immunological mechanisms underlying noninvasive pneumococcal nasopharyngeal carriage. Pneumococcal interactions with human nasopharyngeal and bronchial fibroblasts and epithelial cells were investigated in vitro. A murine model of nasopharyngeal carriage and an experimental human pneumococcal challenge model were used to characterize immune responses in the airways during carriage. We describe the previously unknown immunological basis of noninvasive carriage and highlight mechanisms whose perturbation may lead to invasive disease. We identify the induction of active transforming growth factor (TGF)-β1 by S. pneumoniae in human host cells and highlight the key role for TGF-β1 and T regulatory cells in the establishment and maintenance of nasopharyngeal carriage in mice and humans. We identify the ability of pneumococci to drive TGF-β1 production from nasopharyngeal cells in vivo and show that an immune tolerance profile, characterized by elevated TGF-β1 and high nasopharyngeal T regulatory cell numbers, is crucial for prolonged carriage of pneumococci. Blockade of TGF-β1 signaling prevents prolonged carriage and leads to clearance of pneumococci from the nasopharynx. | Metabolic syndrome (MetS) and depression have become two prevalent diseases worldwide, whose interaction needs further investigation. Dietary treatment for weight loss in patients with MetS may improve depressive manifestations, however, the precise interactive pathways remain uncertain. Therefore, the aim of this study was to examine the effects of a hypocaloric diet designed to reduce MetS features on self-perceived depression and the possible underlying factors. Sixty subjects (Age: 50 ± 1 y; BMI: 36.1 ± 0.6 kg/m(2)) with MetS were selected from the RESMENA study (control and intervention) after they completed the 6-months hypocaloric treatment and rated for depressive symptoms using the Beck Depression Inventory (BDI). Anthropometric and biochemical measurements including leptin, C-reactive protein (CRP) and insulin levels were evaluated. Depressive symptoms decreased during the weight loss intervention, with no differences between both dietary groups (control group -4.2 ± 0.8 vs RESMENA group -3.2 ± 0.6, P = 0.490). The number of criteria of the MetS was higher among subjects with more somatic-related depressive symptoms at baseline (B = 1.032, P-trend = 0.017). After six months of dietary treatment, body weight decreased in all subjects (-8.7%; confidence interval (95% CI) = 7.0-9.7) and also self-perceived depression (-37.9%; 95% CI = 2.7-4.9), as well as circulating leptin (-20.1%; 95% CI = 1.8-6.8), CRP (-42.8%; 95% CI = 0.6-3.0) and insulin (-37.7%; 95% CI = 4.1-7.2) concentrations. The decrease in BDI was significantly associated with declines in body fat mass (B = 0.34, 95% CI = 0.11-0.56) and also with the decrease in leptin (B = 0.16, 95% CI = 0.04-0.28) and CRP (B = 0.24, 95% CI = 0.01-0.46) concentrations. |
Does age correlate with increased frequency of high risk factors in elderly patients with thyroid cancer? | Age and certain pathologic features (ie, follicular histology, vascular invasion, and extracapsular extension) are reported to impact on prognosis in thyroid cancer, but the relationship between these two factors remains incompletely defined. Clinical, pathologic, therapeutic, prognostic, and outcome data were retrospectively collected and compared among three groups of patients with thyroid cancer: group 1 (age 21 to 50), group 2 (age 51 to 70), and group 3 (age greater than 70). There was a statistically significant age-related decrement in survival: 10-year survival was 92% in group 1, 77% in group 2, and 48% in group 3. Follicular histology, vascular invasion, and extracapsular extension were more frequently observed in group 3 versus group 2 and in group 2 versus group 1 (all differences statistically significant except for vascular invasion). Although survival was significantly less for group 3 versus group 2 versus group 1, only vascular invasion and extracapsular extension independently predicted outcome by multivariate analysis. | Inadequate response of the innate immune system to bacterial antigens present in the intestinal flora may play a role in the development of necrotizing enterocolitis (NEC). Pattern recognition receptors such as CD14, toll-like receptor (TLR) 4, and caspase-recruitment domain (CARD) 15 bind bacterial lipopolysaccharide and peptidoglycan, and their activation leads to production of inflammatory cytokines. Our aim was to evaluate whether single nucleotide polymorphisms (SNPs) of CD14, TLR4, and CARD15 are associated with the risk of NEC in very low birth weight (VLBW) infants. We determined the CD14 C-260T, TLR4 A +896G, C +1196T, and CARD15 G +2722C, C +2104T, 3020insC functional SNPs in dried blood samples from 118 VLBW infants (of those, 41 developed NEC) and from 146 healthy term newborns using polymerase chain reaction and restriction fragment length polymorphism methods. We tested the association between genotype and risk of NEC. No significant differences were found in the prevalence of CD14 -260T, TLR4 +896G, +1196T, and CARD15 +2722C, +2104T, 3020insC alleles between VLBW infants and healthy term newborns (P = NS). The frequencies of investigated genotypes were similar in infants with and without NEC (P = NS). Furthermore, we did not find any association between genotype and prematurity or sepsis, which are important risk factors of NEC. |
Does aqueous humor stimulate the migration of human trabecular meshwork cells in vitro? | Depletion of trabecular meshwork cell numbers is a feature of the outflow system in aging and in primary open-angle glaucoma. It is possible that migration stimulated by factors present in aqueous humor may contribute to the cell loss. This investigation assessed the chemoattractant potential of glaucomatous and nonglaucomatous human aqueous humor and fibronectin, one of its constituents, on a range of cultured trabecular meshwork cell lines. Migration was assessed in 48-well modified Boyden chambers. The potential migratory stimulants were soluble fibronectin and glaucomatous and nonglaucomatous aqueous humor. The glaucomatous aqueous samples were collected from patients undergoing trabeculotomy for primary open-angle glaucoma and the normal aqueous from normal bovine eyes and patients undergoing cataract surgery. The target cell types were normal human and bovine meshwork cells grown from explants and two human transformed meshwork cell lines from a normal (HTM-5) and a glaucomatous (HTM-3) source. Soluble fibronectin stimulated all the target cells to migrate with an optimal concentration ranging from 1 to 30 microg/ml, and Zigmond Hirsch checkerboard analysis indicated that both chemotaxis and chemokinesis took place. All the aqueous humor samples stimulated migration of the meshwork cell lines at an optimal concentration of 200 microl/ml. Glaucomatous aqueous humor stimulated a greater migratory response than nonglaucomatous aqueous for two of the four target cell types (P < or = 0.03). Neutralization of the fibronectin content of nonglaucomatous and glaucomatous aqueous by addition of excess anti-fibronectin antibody indicated that fibronectin could account for 35% to 80% of the migratory activity of the aqueous. | Previous research has suggested that childhood emotional abuse, physical abuse, and sexual abuse are associated with an increased risk for ischemic heart disease. Our objective was to examine whether childhood abuse predicted incident metabolic syndrome, a precursor to heart disease, in midlife women. Participants were 342 (114 Black, 228 White) women from the Pittsburgh site of the Study of Women's Health Across the Nation (SWAN). SWAN included a baseline assessment of premenopausal or early perimenopausal women in midlife (mean age = 45.7), and women were evaluated for presence of the metabolic syndrome over 7 annual follow-up visits. Women were classified as having metabolic syndrome if they met 3 of the following criteria: waist circumference >88 cm, triglycerides ≥150 mg/dl, HDL <50 mg/dl, SBP ≥130 or DBP ≥85 mmHg or on blood pressure medication, and fasting glucose ≥110 mg/dl or diabetic. The Childhood Trauma Questionnaire is a standardized measure that retrospectively assesses 3 domains of abuse in childhood and adolescence: emotional, physical, and sexual abuse. Approximately 34% of the participants reported a history of abuse. Cox model survival analysis showed that physical abuse was associated with incident metabolic syndrome over the course of 7 years (HR = 2.12, p = .02), adjusted for ethnicity, age at baseline, and time-dependent menopausal status. Sexual abuse and emotional abuse were unrelated to the metabolic syndrome. |
Does a retrospective analysis of the impact of 18F-FDG PET scan on clinical management of 133 breast cancer patients? | While it is well-known that there is 18F-FDG uptake in breast tumors, clinical impact of (18)F-FDG PET in managing breast cancer patients is not well-studied. One hundred and thirty-three consecutive breast cancer patients from May 1996 to June 2000 were studied. All patients were treated and being followed. Reasons of referral included equivocal conventional studies, staging/re-staging, clinical suspicion of recurrence, and elevated serum tumor markers. Clinical status at 6 months postPET is used as the gold standard in lesions of worsening versus stable or improving. PET was 69% sensitive and 80% specific in predicting clinical stage at 6 months. This 69% of the patients who got worse at 6 months was PET positive and 80% of the patients who were stable or improving at 6 months were PET negative. There was a significant association between PET results and clinical outcome, after adjusting for stage of disease (P=0.04), or for the treatment patients received (P<0.01). Negative PET results changed therapy as often as positive ones did. PET influenced treatment decisions in 74% of the patients referred for study. | Low Birth Weight (LBW) is one of the major risk factor for death in early life. However, little is known about predictors of LBW in sub-Saharan Africa. Therefore, the aim of this study was to measure the incidence and determinants of LBW in a rural population of Ethiopia. An observational cohort study on pregnant women was conducted from December 2009 to November 2010. During the study period 1295 live birth were registered and the weights of 956 children were measured within 24 hours after birth. Socio-demographic, economic, maternal and organizational factors were considered as a predicators of LBW, defined as birth weight below 2500g. Logistic regression was used to analyze the data, odds ratio (OR) and confidence intervals (CI) are reported. The incidence of LBW was 28.3%. It is significantly associated with poverty [OR 2.1; 95% CI: 1.42, 3.05], maternal Mid Upper Arm Circumference (MUAC) less than 23 cm [OR 1.6; 95% CI: 1.19, 2.19], not attending ANC [OR 1.6; 95% CI: 1.12, 2.28], mother's experience of physical violence during pregnancy [OR 1.7; 95% CI: 1.12, 2.48], and longer time to walk to health facility [OR 1.6; 95% CI: 1.11, 2.40]. |
Does quantification of skeletal metastases in castrate-resistant prostate cancer predict progression-free and overall survival? | To report a simplified and effective method for substratification of M1 castrate-resistant prostate cancer (CRPC) by correlating progression-free (PFS) and overall survival (OS) with simple quantification of skeletal metastases. In all, 561 men with M1 CRPC were studied longitudinally. Individual bone scan disease burden, quantified by counting bone metastasis number, was correlated with clinical outcome using specific threshold points of 1-4, 5-20 and >20 detectable lesions. Patients with a higher metastasis number had a shorter PFS and OS (hazard ratio [HR] 2.0, 95% confidence interval [CI] 1.7-2.4; P < 0.001). Patients with 1-4 metastases had much better PFS and OS than those with 5-20 metastases. The median PFS and OS in the latter was 10.9 (95% CI 8.4-12.8) and 22.1 (95% CI: 18.5-24.5) months, respectively. PFS and OS for patients with >20 metastases were shorter still [median 5.3 (95% CI 3.4-6.9) months and 13.3 (95% CI 11.3-17.6) months, respectively]. Dichotomising into cohorts with 1-4 and ≥5 metastases, the latter group had considerably poorer PFS [8.4 (95% CI 6.8-10.3) months; P < 0.001) and OS [18.7 (95% CI 17.5-22.1) months; P < 0.001]. | Exposure to environmental tobacco smoke (ETS) has been shown to increase symptoms of allergic bronchial asthma, but direct effects on the expression of inflammatory markers have not been demonstrated thus far. The aim of this study was to assess the correlation of ETS exposure with the expression of proinflammatory mediators in airway secretions, including IFN-gamma and IL-12, as well as IL-5 and IL-13, in allergic asthmatic schoolchildren and healthy control subjects. By using the nasopharyngeal aspiration technique, airway secretions were collected from 24 atopic children with asthma (age, 6-16 years) and 26 healthy control subjects, and the concentration of cytokines was measured with immunoenzymatic methods. IL-13 levels were highly increased in patients with asthma (P < .005), and parental tobacco smoke resulted in a significant increase in airway IL-13 secretion in these children compared with that seen in nonexposed children and healthy control subjects (median, 860 pg/mL vs 242 pg/mL and 125 pg/mL, respectively). Furthermore, a positive correlation between IL-13 levels and serum IgE concentrations (r(s) = 0.55) was found in children with allergic asthma. |
Is enhancement of in vitro activity of tuberculosis drugs by addition of thioridazine reflected by improved in vivo therapeutic efficacy? | Assessment of the activity of thioridazine towards Mycobacterium tuberculosis (Mtb), in vitro and in vivo as a single drug and in combination with tuberculosis (TB) drugs. The in vitro activity of thioridazine as single drug or in combination with TB drugs was assessed in terms of MIC and by use of the time-kill kinetics assay. Various Mtb strains among which the Beijing genotype strain BE-1585 were included. In vivo, mice with TB induced by BE-1585 were treated with a TB drug regimen with thioridazine during 13 weeks. Therapeutic efficacy was assessed by the change in mycobacterial load in the lung, spleen and liver during treatment and 13 weeks post-treatment. In vitro, thioridazine showed a concentration-dependent and time-dependent bactericidal activity towards both actively-replicating and slowly-replicating Mtb. Thioridazine at high concentrations could enhance the activity of isoniazid and rifampicin, and in case of isoniazid resulted in elimination of mycobacteria and prevention of isoniazid-resistant mutants. Thioridazine had no added value in combination with moxifloxacin or amikacin. In mice with TB, thioridazine was poorly tolerated, limiting the maximum tolerated dose (MTD). The addition of thioridazine at the MTD to an isoniazid-rifampicin-pyrazinamide regimen for 13 weeks did not result in enhanced therapeutic efficacy. | The purpose of this study was to evaluate patient-specific outcomes and satisfaction using dental implants in a population affected with ectodermal dysplasia. Patient-based data were collected using a self-reported survey instrument sent to patients belonging to a private patient foundation and/or treated previously at a government clinic. A standardized survey instrument was developed to evaluate patient satisfaction, outcomes, and potential complications using dental implants. The survey instrument was mailed to 253 affected individuals self-reported to have various forms of ectodermal dysplasia and who were voluntarily participants in the National Foundation for Ectodermal Dysplasias and/or were participants in the US National Institute for Dental Craniofacial Research Intramural Ectodermal Dysplasia clinical research program. A total of 109 responses were obtained (43% response rate). The duration following completion of implant therapy ranged from to 1 to 23 years. Of the 109 participants, 50% reported either an implant or prosthetic complication with implant treatment, and 24% reported some form of failure with implant therapy. However, 91% of participants reported being either satisfied or very satisfied with dental implants, and 95% reported that the treatment was worth the time and cost. |
Does fasting protect liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice? | Fasting and calorie restriction are associated with a prolonged life span and an increased resistance to stress. The protective effects of fasting have been exploited for the mitigation of ischemic organ injury, yet the underlying mechanisms remain incompletely understood. Here, we investigated whether fasting protects liver against ischemia reperfusion (IR) through energy-preserving or anti-inflammatory mechanisms. Fasted C57BL6 mice were subjected to partial hepatic IR. Injury was assessed by liver enzymes and histology. Raw264-7 macrophage-like cells were investigated in vitro. Sirt1 and HMGB1 were inhibited using Ex527 and neutralizing antibodies, respectively. Fasting for one, but not two or three days, protected from hepatic IR injury. None of the investigated energy parameters correlated with the protective effects. Instead, inflammatory responses were dampened in one-day-fasted mice and in starved macrophages. Fasting alone led to a reduction in circulating HMGB1 associated with cytoplasmic HMGB1 translocation, aggregate formation, and autophagy. Inhibition of autophagy re-elevated circulating HMGB1 and abolished protection in fasted mice, as did supplementation with HMGB1. In vitro, Sirt1 inhibition prevented HMGB1 translocation, leading to elevated HMGB1 in the supernatant. In vivo, Sirt1 inhibition abrogated the fasting-induced protection, but had no effect in the presence of neutralizing HMGB1 antibody. | Interobserver and intraobserver correlation between the colposcopic phenomenon ridge sign and its association with cervical intraepithelial neoplasia (CIN) 2 or 3, with a specific human papillomavirus (HPV) type, and with the age of the patient. Colpophotographs, cervical smears, and histologic results of punch or cone biopsies of 592 patients were evaluated. Colpophotographs were analyzed retrospectively for the presence or absence of an opaque acetowhite ridge at the squamocolumnar junction (ridge sign) by 3 gynecologists of different experience. Interobserver reliability for colposcopic grading of CIN was between 18.2% and 82.3%. Concerning the ridge sign, interobserver agreement varied between 25.3% and 49.4% according to the observers' experience, and intraobserver reliability varied between 56.4% and 67.5% (Cohen kappa=0.310-0.469). In 83 (14.0%) of 592 patients, a ridge sign was diagnosed by the most experienced investigator. Cervical intraepithelial neoplasia 2 or 3 was confirmed histologically in 53 of these 83 women (63.8%). Sensitivity of ridge sign for detection of CIN 2 or 3 was 33.1%; specificity was 93.1%. Women with ridge sign were significantly younger than women with no ridge sign (p< .001). Ridge sign was associated with the presence of HPV 16 (p< .001). |
Does sT segment elevation differ depending on the method of measurement? | The literature seldom specifies the location or method of measurement of ST segment elevation (STE) for determining eligibility in reperfusion trials. The objective of this study was to assess if different methods of measurement of STE in precordial leads of patients with anterior acute myocardial infarction due to left anterior descending occlusion result in significantly different scores. This was a retrospective review of diagnostic electrocardiograms (ECGs) of consecutive patients presenting to our emergency department with acute myocardial infarction who had emergent primary percutaneous coronary intervention, left anterior descending occlusion, and no bundle branch block. STE was measured at the J point and at 60 milliseconds after the J point, relative to the PR segment, in leads V1-V6. STE by the two methods was compared for each lead, as were ST scores (sum of STE in leads V1-V6) and the sum of the STE in V2-V4. Eligibility for reperfusion therapy using 1-mm and 2-mm STE criteria in two consecutive anterior leads, as well as ST scores and the sum of the STE in V2-V4, were evaluated. Thirty-seven ECGs were analyzed. Mean ST measurements in every lead were significantly lower when measured at the J point versus 60 milliseconds after the J point, as were ST scores (9.7 +/- 2.14 mm vs. 14.9 +/- 2.69 mm; p < 0.00001). Fewer ECGs met enrollment criteria when based on STE at the J point versus at 60 milliseconds after the J point. Fewer ECGs met an ST score of 6 mm when measured at the J point (70% vs. 88%). | Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown. Four isogenic cell lines C2/C2VHL and 786-O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2α knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student's T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival. Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2α is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ERα) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated α-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset. |
Is the diagnosis of inflammatory bowel disease often unsupported in clinical practice? | The diagnosis of inflammatory bowel disease can be challenging and requires the efforts of a multidisciplinary team. We performed a retrospective analysis with the aim of evaluating the adequacy of the prerequisites for arriving at an accurate histological diagnosis. The following parameters were considered as prerequisites for a diagnosis of inflammatory bowel disease: clinical and endoscopic data; proper sampling and handling of biopsies; and elementary microscopic lesions. We collected 345 cases from 13 centres. The date of onset and treatment were available for 13% and 16% of the cases, respectively. Endoscopy information was accessible for 77% of the cases. Endoscopic mapping was completed in 13% of the cases. In no cases were the biopsies oriented on acetate strips. The diagnosis was conclusive in 47% of the cases. Activity, epithelial disruption and crypt distortion were described in 35% of the reports with a conclusive diagnosis. | Paired electrical stimulation and postextrasystolic potentiation (PESP) of contractility has been extensively studied in ventricular myocardium, but less is known about PESP of atrial contractility. Our aim was to determine whether PESP of atrial contractility could augment left ventricular (LV) preload and improve LV systolic performance. A paired electrical stimulus closely following the pacing stimulus was applied to isolated atrial and ventricular myocardium from 4 dog hearts, and the interval dependent force potentiation was examined. In isolated atrial myocardium, paired pacing increased the active tension from a baseline of 1.36 +/- 0.23 to 2.60 +/- 0.57 g/mm(2); in ventricular myocardium active tension increased from 2.58 +/- 0.42 to 3.81 +/- 0.27 g/mm(2) (both P <.01). Then, LV pressure (micromanometer) and segment length (ultrasonic crystals) were measured in the intact hearts of 7 anesthetized dogs in which premature stimuli were applied to the atrium. In intact hearts, paired pacing of the atrium (coupling interval 200 ms) increased LV end-diastolic pressure from 3.8 +/- 1.0 to 6.4 +/- 1.0 mm Hg; systolic pressure increased from 105 +/- 6 to 112 +/- 7 mm Hg (both P <.05). LV pressure-length loop area (regional stroke work) increased 10.5 +/- 0.2%. |
Does leflunomide prevent alveolar fluid clearance inhibition by respiratory syncytial virus? | Previously, we demonstrated that intranasal infection of BALB/c mice with respiratory syncytial virus (RSV) resulted in an early 40% reduction in alveolar fluid clearance (AFC), an effect mediated via P2Y purinergic receptors. To confirm that RSV-induced inhibition of AFC is mediated by uridine triphosphate (UTP), and to demonstrate that inhibition of de novo pyrimidine synthesis with leflunomide prevents increased UTP release after RSV infection, and thereby also prevents inhibition of AFC by RSV. BALB/c mice were infected intranasally with RSV strain A2. AFC was measured in anesthetized, ventilated mice by instillation of 5% bovine serum albumin into the dependent lung. Some mice were pretreated with leflunomide or 6-mercaptopurine. RSV-mediated inhibition of AFC is associated temporally with a 20-nM increase in UTP and ATP content of bronchoalveolar lavage fluid, hypoxemia, and altered nasal potential difference. RSV-mediated nucleotide release, AFC inhibition, and physiologic sequelae thereof can be prevented by pretreatment of mice with the de novo pyrimidine synthesis inhibitor leflunomide, which is not toxic to the mice, and which does not affect RSV replication in the lungs. In contrast, pretreatment of mice with 6-mercaptopurine, an inhibitor of de novo purine synthesis, has no beneficial effect on AFC or other indicators of disease progression. Finally, RSV-mediated inhibition of AFC is prevented by volume-regulated anion channel inhibitors. | To determine whether insulin resistance (IR calculated using the HOMA model) has a dominant role in the clustering of cardiovascular risk factors in the Asian Indian population. A total of 654 non-diabetic subjects aged > or =40 years (male 396: female 258) were selected from a population survey. They had estimates of fasting and 2 h plasma glucose, insulin levels, body mass index (BMI), waist-to-hip ratio (WHR) and blood pressure. Factor analysis was carried out using the principle components analysis (PCA) with varimax orthogonal rotation of continuously distributed variables, considered to represent the components of insulin resistance syndrome including the calculated IR. There were three major clusters of cardiovascular disease (CVD) risk variables in men and four clusters in women. Insulin resistance, 2 h plasma glucose, insulin and obesity aggregated as the major domain. Insulin resistance was not linked with hypertension. BMI was a common link for all the three factors in men, and for three of the four in women. |
Does spinal hemiepiphysiodesis decrease the size of vertebral growth plate hypertrophic zone and cells? | Hemiepiphysiodesis is a potential method to treat idiopathic juvenile scoliosis early. The purpose of the present study was to investigate a mechanism of curve creation in the pig thoracic model of spinal hemiepiphysiodesis by determining whether the structure of the vertebral growth plate varied with distance from the stapled, concave side of the spine. The hypotheses were that the heights of the hypertrophic zone, hypertrophic cells, and disc would be decreased on the treated side of the treated level as compared with both an unstapled control level and the side opposite the staple. Custom spine staples were implanted into six midthoracic vertebrae in each of five skeletally immature pigs. After eight weeks, the spines were harvested and histological sections were prepared. Hypertrophic zone height, hypertrophic cell height and width, and disc height were measured at discrete coronal plane locations at stapled and unstapled thoracic levels. Differences between stapled and unstapled levels and locations were compared with use of mixed linear modeling for repeated measures, followed by regression models to determine growth plate intercept and slope across the plane by thoracic level. Zone height, cell height, and cell width were lowest on the stapled side of the stapled level, with significant differences in the overall statistical model (p < 0.02). Disc heights were significantly reduced (p < 0.0001) at the stapled levels across the coronal plane. | miRNAs have been implicated in the regulation of key metabolic, inflammatory, and malignant pathways; hence, they might be considered both predictors and players of cancer development. Using a case-control study design nested in the ORDET prospective cohort study, we addressed the possibility that specific mRNAs can serve as early predictors of breast cancer incidence in postmenopausal women. We compared leukocyte miRNA profiles of 133 incident postmenopausal breast cancer cases and profiles of 133 women who remained healthy over a follow-up period of 20 years. The analysis identified 20 differentially expressed miRNAs, 15 of which were downregulated. Of the 20 miRNAs, miR145-5p and miR145-3p, each derived from another arm of the respective pre-miRNA, were consistently and significantly downregulated in all the databases that we surveyed. For example, analysis of more than 1,500 patients (the UK Metabric cohort) indicated that high abundance of miR145-3p and miR145-5p was associated with longer, and for miR145-3p also statistically significant, survival. The experimental data attributed different roles to the identified miRNAs: Although the 5p isoform was associated with invasion and metastasis, the other isoform seems related to cell proliferation. |
Does serum creatine kinase predict ectopic pregnancy? | To evaluate the discriminatory ability of maternal serum creatine kinase (SCK) as a test for ectopic pregnancy (EP). Serum creatine kinase concentrations were obtained prospectively from symptomatic patients being evaluated for early abnormal pregnancy. Serum creatine kinase concentrations from all patients and from a subset of these patients with maternal serum beta-hCG concentrations < 6,500 mIU/mL (conversion factor to SI unit, 1.00) were analyzed with descriptive statistics, receiver operator characteristic (ROC) curve analysis, and calculations of predictive values. A university hospital emergency room. Fifty-six patients with intrauterine gestations (25 with beta-hCG concentrations < 6,500 mIU/mL) and 23 patients with EP (20 with beta-hCG concentrations < 6,500 mIU/mL) were studied. For all patients and the subgroup with beta-hCG concentrations < 6,500 mIU/mL, mean SCK levels were not significantly different between ectopic and intrauterine gestations. For all patients and the subgroup with beta-hCG concentrations < 6,500 mIU/mL, the areas under the ROC curves did not demonstrate discriminatory ability of the SCK test. The highest positive predictive value of an elevated SCK for EP was 52% using the SCK concentration of 70 U/L, and this was seen in the subgroup of patients with beta-hCG values < 6,500 mIU/mL. | With the advancement of biomedical technology, artificial materials have been developed to replace diseased, damaged or nonfunctional body parts. Among such materials, ultra high molecular weight alkane or modified alkyl polymers have been extensively used in heart valves, stents, pacemakers, ear implants, as well as total joint replacement devices. Although much research has been undertaken to design the most non-reactive biologically inert polyethylene derivatives, strong inflammatory responses followed by rejection and failure of the implant have been noted. Purification of the alkane polymers from the site of inflammation revealed extensive "in vivo" oxidation as detected by fourier transformed infra-red spectroscopy. Herein, we report the novel observation that oxidized alkane polymers induced activation of TLR1/2 pathway as determined by ligand dependent changes in intrinsic tyrosine fluorescence intensity and NF-kappaB luciferase gene assays. Oxidized polymers were very effective in activating dendritic cells and inducing secretion of pro-inflammatory cytokines. Molecular docking of the oxidized alkanes designated ligand specificity and polymeric conformations fitting into the TLR1/2 binding grooves. |
Is contractile function preserved in unloaded hearts despite atrophic remodeling? | Recent studies have shown that mechanically unloading a failing heart may induce reverse remodeling and functional improvement. However, these benefits may be balanced by an unloading-related remodeling including myocardial atrophy that might lead to decrease in function. Using a model of heterotopic heart transplantation, we aimed to characterize the myocardial changes induced by long-term unloading. Macroscopic as well as cellular and functional changes were followed in normal hearts unloaded for a 3-month period. Microscopic parameters were evaluated with stereologic methodology. Myocardial contractile function was quantified with a Langendorff isolated, perfused heart technique. Atrophy was macroscopically obvious and accompanied by a 67% reduction of the myocyte volume and a 43% reduction of the interstitial tissue volume, thus accounting for a shift of the myocyte/connective tissue ratio in favor of noncontractile tissue. The absolute number of cardiomyocyte nuclei decreased from 64.7 +/- 5.1 x 10(7) in controls to 22.6 +/- 3.7 x 10(7) (30 days) and 21.6 +/- 3.1 x 10(7) (90 days) after unloading (P < .05). The numeric nucleic density in the unloaded myocardium, as well as the mean cardiomyocyte volume per cardiomyocyte nucleus, remained constant throughout the 90 days of observation. Functional data indicated an increase in ventricular stiffness, although contractile function was preserved, as confirmed by unaltered maximal developed pressure and increased contractility (maximum rate of left ventricular pressure development) and relaxation (minimum rate of left ventricular pressure development). | This meta-analysis investigated the association between functional COX-2 gene polymorphisms and the risk of oral cancer. Several electronic databases were searched for published studies using combinations of keywords related to COX-2 gene polymorphisms and oral cancer. After selection of relevant studies, following strict inclusion and exclusion criteria, data was performed using STATA 12.0 software. We retrieved 83 studies from database search using specific search terms. After multiple rounds of selection and elimination, 7 studies were finally identified as suitable to be included in our present meta-analysis, based on their relevance and data integrity. These 7 studies contained a combined total of 2,296 oral cancer patients and 3,647 healthy controls. Our findings demonstrated that +837 T > C (rs5275) polymorphism in COX-2 showed statistically significant differences in gene frequencies in case and control groups in allele model and dominant model. Similar results were obtained with COX-2 gene polymorphism 765 G > C (rs20417). On the other hand, 1195 A > G (rs689466) polymorphism in COX-2 did not confer susceptibility to oral cancers. |
Does dihydroartemisinin ( DHA ) induce caspase-3-dependent apoptosis in human lung adenocarcinoma ASTC-a-1 cells? | Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, isolated from the traditional Chinese herb Artemisia annua, is recommended as the first-line anti-malarial drug with low toxicity. DHA has been shown to possess promising anticancer activities and induce cancer cell death through apoptotic pathways, although the molecular mechanisms are not well understood. In this study, cell counting kit (CCK-8) assay was employed to evaluate the survival of DHA-treated ASTC-a-1 cells. The induction of apoptosis was detected by Hoechst 33258 and PI staining as well as flow cytometry analysis. Collapse of mitochondrial transmembrane potential (DeltaPsim) was measured by dynamic detection under a laser scanning confocal microscope and flow cytometry analysis using Rhodamine123. Caspase-3 activities measured with or without Z-VAD-fmk (a broad spectrum caspase inhibitor) pretreatment by FRET techniques, caspase-3 activity measurement, and western blotting analysis. Our results indicated that DHA induced apoptotic cell death in a dose- and time-dependent manner, which was accompanied by mitochondrial morphology changes, the loss of DeltaPsim and the activation of caspase-3. | To study the association between impaired fasting glucose (IFG) and arterial stiffness in older adults. Cross-sectional population-based study. The Rotterdam Study, a Dutch population-based cohort study. Two thousand nine hundred eighty-seven subjects aged 60 and older. Arterial stiffness assessed by measuring common carotid arterial distensibility and glucose status classified into three categories: normal fasting glucose (NFG) (fasting glucose <6.1 mmol/L), IFG (fasting glucose 6.1-6.9 mmol/L), and diabetes mellitus (DM). In the total cohort, common carotid distensibility decreased with increasing impairment of glucose metabolism. Subjects younger than 75 with IFG were comparable with subjects with NFG with respect to arterial stiffness. Subjects aged 75 and older with IFG had stiffer arteries than subjects with NFG, reaching the same arterial stiffness as subjects with DM. For subjects younger than 75, mean difference in distensibility coefficient between subjects with NFG and with IFG was 0.1 (95% confidence interval (CI)=-0.04-0.05, P=.88) and between subjects with NFG and with DM was 1.2 (95% CI=0.7-1.7, P<.001). For subjects aged 75 and older, the mean difference between these groups was 0.7 (95% CI=0.2-1.2, P=.007) and 0.8 (0.3-1.4; P=.002), respectively. In the total cohort, fasting glucose was strongly associated with carotid distensibility (beta-coefficient=-0.29, P<.001). |
Is a functional synonymous coding variant in the IL1RN gene associated with survival in septic shock? | Death from infection is a highly heritable trait, yet there are few genetic variants with known mechanism influencing survival during septic shock. We hypothesized that a synonymous coding variant in the IL-1 receptor antagonist gene (IL1RN), rs315952, previously associated with reduced risk for acute respiratory distress syndrome, would be functional and associate with improved survival in septic shock. We used a human endotoxin (LPS) model of evoked inflammatory stress to measure plasma IL-1 receptor antagonist (IL1RA) following low-dose Food and Drug Administration-grade LPS injection (1 ng/kg) in 294 human volunteers. RNA sequencing of adipose tissue pre- and post-LPS was used to test for allelic imbalance at rs315952. In the Vasopressin and Septic Shock Trial cohort, we performed a genetic association study for survival, mortality, and organ failure-free days. Adipose tissue displayed significant allelic imbalance favoring the rs315952C allele in subjects of European ancestry. Consistent with this, carriers of rs315952C had slightly higher plasma IL1RA at baseline (0.039) and higher evoked IL1RA post-LPS (0.011). In the Vasopressin and Septic Shock Trial cohort, rs315952C associated with improved survival (P = 0.028), decreased adjusted 90-day mortality (P = 0.044), and faster resolution of shock (P = 0.029). | The 1997 TNM staging system for prostatic carcinoma and the 2002 revision thereof classified prostatic carcinoma with bladder neck involvement classified as pT4 disease. This classification is based on the belief that tumors that invade surrounding structures are more aggressive and warrant higher staging than tumors that do not invade surrounding structures. Recent reports in the literature suggested that microscopic involvement of the bladder neck does not carry independent prognostic significance. Therefore, resection specimens with bladder neck involvement should not be classified as pT4. The current study prospectively examined the prognostic significance of bladder neck involvement by prostatic carcinoma. The authors analyzed the totally embedded and whole-mounted radical prostatectomy specimens from 364 consecutive patients. The mean patient age was 66 years (range, 41-77 years). The bladder neck, which had been coned from the specimen, was cut in a perpendicular fashion. Involvement of the bladder neck was defined as the presence of neoplastic cells within the smooth muscle bundles of the coned bladder neck. The data were prospectively collected. Bladder neck involvement was analyzed in relation to age, preoperative prostate-specific antigen (PSA) level, prostate weight, Gleason score, final pathologic classification, tumor volume, surgical margin status, the presence of high-grade prostate intraepithelial neoplasm, multifocality, seminal vesicle invasion, extraprostatic extension, perineural invasion, and PSA recurrence. Bladder neck involvement was found in 22 (6%) of 364 patients. Univariate results indicated that bladder neck involvement versus no bladder neck involvement was significantly associated with preoperative PSA (P < 0.001), higher pathologic classification (P < 0.001), larger tumor volume (P < 0.001), extraprostatic extension (P < 0.001), positive surgical margins (P < 0.001), and PSA recurrence (P = 0.003). In a multivariate logistic regression model controlling for pathologic classification, Gleason score, and surgical margin status, bladder neck involvement was an independent predictor of PSA recurrence (P = 0.04). The adjusted odds ratio for bladder neck involvement was 3.3 (95% confidence interval, 1.04-10.03). |
Does ketamine inhibit proliferation of neural stem cell from neonatal rat hippocampus in vitro? | Ketamine is a widely used anesthetic in obstetric and pediatric anesthesia. In the developing brain, the widespread neuron apoptosis triggered by ketamine has been demonstrated. However, little is known about its effect on neural stem cells (NSCs) function. This study aimed to investigate the effect of ketamine on proliferation of NSCs from neonatal rat hippocampus. Neural stem cells were isolated from the hippocampus of Sprague-Dawley rats on postnatal day 3. In dose-response experiments, cultured neural stem cells (NSCs) were exposed to different concentrations of ketamine (0-1000 µM) for 24 hrs. The proliferative activity of NSCs was evaluated by 5-Bromo-2'-deoxyuridine (BrdU) incorporation assay. Apoptosis of neural stem cells were assessed using caspase-3 by western blot. The intracellular Ca(2+) concentration ([Ca(2+)]i) in NSCs was analyzed by flow cytometry. The activation of protein kinase C-α (PKCα) and the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) were measured by western blot analysis. Clinical relevant concentration of ketamine (10, 20 and 50 µM) did not markedly alter the proliferation of NSCs from neonatal rat hippocampus in vitro. However, ketamine (200, 500, 800 and 1000μM) significantly inhibited the proliferation of NSCs and did not affect the expression of caspase-3. Meanwhile, ketamine (200, 500, 800 and 1000μM) also markedly decreased [Ca(2+)]i as well as suppressed PKCα activation and ERK1/2 phosphorylation in NSCs. A combination of subthreshold concentrations of ketamine (100 μM) and Ca(2+) channel blocker verapamil (2.5 μM), PKCα inhibitor chelerythrine (2.5 μM) or ERK1/2 kinase inhibitor PD98059 (5 μM) significantly produced suprathreshold effects on PKCα activation, ERK1/2 phosphorylation and NSC proliferation. | As wearable sensors/devices become increasingly popular to promote physical activity (PA), research is needed to examine how and which components of these devices people use to increase their PA levels. (1) To assess usability and level of engagement with the Fitbit One and daily SMS-based prompts in a 6-week PA intervention, and (2) to examine whether use/ level of engagement with specific intervention components were associated with PA change. Data were analyzed from a randomized controlled trial that compared (1) a wearable sensor/ device (Fitbit One) plus SMS-based PA prompts, and (2) Fitbit One only, among overweight/ obese adults (N = 67). We calculated average scores from Likert-type response items that assessed usability and level of engagement with device features (e.g., tracker, website, mobile app, and SMS-based prompts), and assessed whether such factors were associated with change in steps/day (using Actigraph GT3X+). Participants reported the Fitbit One was easy to use and the tracker helped to be more active. Those who used the Fitbit mobile app (36%) vs. those who did not (64%) had an increase in steps at 6-week follow-up, even after adjusting for previous web/app use: +545 steps/ day ( |
Does the intervertebral disc contain intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration? | The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration. Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue-specific deletion of the core clock gene Bmal1. Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1β but not tumour necrosis factor α. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs. | To avoid the use of unnecessary broad-spectrum antibiotics, empirical therapy of bacteraemia should be adjusted according to the results of blood cultures. To investigate whether the results of blood cultures led to changes in antibiotic use and costs in a tertiary-care university hospital in Norway. Medical records from all patients with positive blood cultures in 2001 were analysed retrospectively. Factors predisposing to infections, results of blood cultures, antibiotic use and outcome were recorded. The influence of blood culture results on antibiotic treatment and costs were analysed. The antibiotic use in 226 episodes of bacteraemia in 214 patients was analysed. According to the guidelines empirical antibiotic treatment should be adjusted in 166 episodes. Antibiotic use was adjusted in 146 (88%) of these 166 episodes, which led to a narrowing of therapy in 118 (80%) episodes. Compared with empirical therapy there was a 22% reduction in the number of antibiotics. Adjustment of therapy was more often performed in Gram-negative bacteraemia and polymicrobial cultures than in Gram-positive bacteraemia. In bacteraemia caused by ampicillin-resistant Escherichia coli, ampicillin was mostly replaced by ciprofloxacin. The cost for 7 days adjusted therapy in 146 episodes was euro19,800 (23%) less than for 7 days of empirical therapy. |
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