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Are antibodies to the amino-terminal domain of desmoglein 1 retained during transition from pemphigus vulgaris to pemphigus foliaceus? | Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two blistering skin diseases mediated by antibodies to desmoglein 3 (Dsg3) and/or Dsg1. Phenotypic transition from PV to PF is rarely reported. To determine the immune response to extracellular (EC) domains of Dsgs during this transition. We report two PV patients who subsequently developed a PF phenotype. To map the conformational epitopes in these cases, we examined the reactivity of the sera of two patients by immunoprecipitation-immunoblotting analysis, using five Dsg1/Dsg3 domain-swapped molecules on a backbone of Dsg2. Reactivity exclusively with the EC1 domain of Dsg1 was maintained in both PV and PF stages. No reactivity to Dsg3 in the PF stage was found in patient 1. Various changes in immunoreactivity to Dsg3 were found and the EC1 and EC2 domains of Dsg3 reacted weakly to serum taken at remission and PF stages in patient 2. | Women have poorer outcomes after vascular surgery as compared to men as shown by studies recently. Frailty is also an independent risk factor for postoperative morbidity and mortality. This study examines the interplay of gender and frailty on outcomes after infrainguinal vascular procedures. The American College of Surgeons National Surgical Quality Improvement Program database was used to identify all patients who underwent infrainguinal vascular procedures from 2005-2012. Frailty was measured using a modified frailty index (mFI; derived from the Canadian Study of Health and Aging). Univariate and multivariate analysis were performed to investigate the association of preoperative frailty and gender, on postoperative outcomes. Of 24,645 patients (92% open, 8% endovascular), there were 533 deaths (2.2%) and 6198 (25.1%) major complications within 30 d postoperatively. Women were more frail (mean mFI = 0.269) than men (mean mFI = 0.259; P < 0.001). Women and frail patients (mFI>0.25) were more likely to have a major morbidity (P < 0.001) or mortality (P < 0.001) with the highest risk in frail women. On multivariate logistic regression analysis, female gender and increasing mFI were independently significantly associated with mortality (P < 0.05) as well as major complications. The interaction of gender and frailty in multivariate analysis showed the highest adjusted 30-d mortality and morbidity in frail females at 2.8% and 30.1%, respectively and that was significantly higher (P < 0.001) than nonfrail males, nonfrail females and frail males. |
Is oxytocin secretion related to measures of energy homeostasis in young amenorrheic athletes? | Oxytocin has been implicated in the modulation of energy metabolism in animals. Oxytocin knockout mice develop obesity without a change in food intake, suggesting that a lack of oxytocin may reduce metabolic rate. Furthermore, administration of oxytocin centrally reduces food intake in rats, an effect reversed by an oxytocin antagonist, implying that oxytocin may regulate appetite and energy intake. We have previously demonstrated that young female athletes (in a higher energy expenditure state than nonathletes) have low nocturnal oxytocin compared with nonathletes. Whether oxytocin is associated with measures of energy homeostasis in athletes is unknown. We hypothesized that oxytocin, a signal for energy availability, would be associated with other measures of energy homeostasis in young female athletes. We performed a cross-sectional study of 45 females, aged 14-21 years [15 amenorrheic athletes (AA), 15 eumenorrheic athletes, and 15 nonathletes] of comparable body mass index. Dual x-ray absorptiometry was performed to assess body composition. Indirect calorimetry was used to measure resting energy expenditure (REE). Fasting levels of oxytocin, energy homeostasis hormones irisin and fibroblast growth factor-21, and appetite-regulating hormone peptide YY were obtained. In AA, oxytocin secretion was positively correlated with surrogate measures of energy availability, including weight (r = 0.65, P = .009) and body mass index (r = 0.61, P = .016). Furthermore, oxytocin was associated with REE (r = 0.80, P = .0003), independent of lean mass, and with irisin (r = 0.74, P = .002) and fibroblast growth factor-21 (r = 0.58, P = .024). In eumenorrheic athletes, oxytocin was associated with REE (r = 0.59, P = .021), independent of lean mass. In nonathletes, oxytocin secretion was not significantly associated with measures of energy homeostasis. | We evaluated whether detecting prostate cancer cells by the nested reverse transcriptase-polymerase chain reaction (RT-PCR) in lymph nodes has predictive value for serum prostate specific antigen (PSA) recurrence in patients undergoing radical prostatectomy. We assessed the presence of prostate cancer cells by RT-PCR for prostate specific membrane antigen and PSA assay in lymph nodes dissected from 38 patients with localized prostate cancer treated with radical prostatectomy. The results of nested RT-PCR assay were compared with biochemical recurrence. Nested RT-PCR was positive in the lymph nodes of 2 of 18 patients (11%) with stage pT2a and 5 of 20 (25%) with stage pT2b disease. All 7 patients had biochemical recurrence. We noted a significant difference in the Kaplan-Meier recurrence-free actuarial probability curve in those with positive and negative nested RT-PCR results for prostate specific membrane antigen, PSA and prostate specific membrane antigen-PSA in the lymph nodes (p = 3.02x10(-7), 2.23x10(-7) and 3.02x10(-7), respectively). Multivariate analysis of serum PSA, Gleason score and preoperative RT-PCR assay in peripheral blood showed that nested RT-PCR for prostate specific membrane antigen, PSA and prostate specific membrane antigen-PSA in the lymph nodes were independent predictors of recurrence (p = 0.0089, 0.0075 and 0.0089, respectively). |
Does interferon-γ enhance the efficacy of autogenous bone grafts by inhibiting postoperative bone resorption in rat calvarial defects? | Interferon (IFN)-γ is a major cytokine produced by immune cells that plays diverse roles in modulating both the immune system and bone metabolism, but its role in autogenous bone grafting remains unknown. Here, we present that local IFN-γ administration improved the efficacy of autogenous bone graft treatment in an experimental rat model. An autogenous bone graft model was prepared with critically sized rat calvariae defects. Four weeks (w) after bone graft implantation, rats were treated locally with IFN-γ or were not treated. The effect of IFN-γ on bone formation was evaluated for up to 8w with micro-computed tomography, quantitative histomorphometry, and Von Kossa staining. Osteoclastogenesis was assessed by tartrate-resistant acid phosphatase staining. Immunohistochemistry staining or quantitative polymerase chain reactions were used to estimate the expression of osteoclast differentiation factor and inflammatory cytokines including tumor necrosis factor (TNF)-α, a well-known stimulant of osteoclastogenesis and an inhibitor of osteoblast activity, in defects. Newly formed bone gradually replaced the autogenous bone grafts within 4w, although severe bone resorption with osteoclastogenesis and TNF-α expression occurred after 6w in the absence of IFN-γ administration. IFN-γ administration markedly attenuated bone loss, osteoclastogenesis, and TNF-α expression, while it enhanced bone formation at 8w. | Diastolic dysfunction, manifested by impaired left ventricular (LV) relaxation, is prevalent among individuals with metabolic disorders. The objective of this study was to evaluate the extent to which plasma triglyceride (TG) levels are related to LV diastolic function. A total of 424 subjects (age 49 +/- 12 years) had fasting plasma TG levels measured and underwent echocardiography for assessment of LV structure and function: LV ejection fraction and LV mass indexed to height (LVM/Ht(2.7)); transmitral inflow early diastolic peak velocity (E wave) and late diastolic peak velocity (A wave), and E wave to A wave ratio (E/A); deceleration time; and Doppler tissue imaging early diastolic myocardial velocity (EM), an index of LV relaxation. All subjects had normal LV ejection fraction, 48% had hypertension, 16% had increased LVM/Ht(2.7), 11% had type 2 diabetes mellitus, 37% were obese, and 27% had hypertriglyceridemia (TG > 150 mg/dL). Univariate analysis showed significant relationships between TG level and E/A, deceleration time, and Em (P < or = .001 for all). After adjustment for potential confounders in multivariate models (eg, age, systolic blood pressure, and LVM/Ht(2.7)), TG levels remained predictive of E/A, deceleration time, and Em (P < or = .05, <.001, and < or =.0001, respectively). Stepwise multivariate analysis showed that after age and body mass index, the TG level was the next most predictive variable of Em. |
Does systemic propranolol act centrally to reduce conditioned fear in rats without impairing extinction? | Previous work has implicated noradrenergic beta-receptors in the consolidation and reconsolidation of conditioned fear. Less is known, however, about their role in fear expression and extinction. The beta-receptor blocker propranolol has been used clinically to reduce anxiety. With an auditory fear conditioning task in rats, we assessed the effects of systemic propranolol on the expression and extinction of two measures of conditioned fear: freezing and suppression of bar-pressing. One day after receiving auditory fear conditioning, rats were injected with saline, propranolol, or peripheral beta-receptor blocker sotalol (both 10 mg/kg, IP). Twenty minutes after injection, rats were given either 6 or 12 extinction trials and were tested for extinction retention the following day. The effect of propranolol on the firing rate of neurons in prelimbic (PL) prefrontal cortex was also assessed. Propranolol reduced freezing by more than 50%, an effect that was evident from the first extinction trial. Suppression was also significantly reduced. Despite this, propranolol had no effect on the acquisition or retention of extinction. Unlike propranolol, sotalol did not affect fear expression, although both drugs significantly reduced heart rate. This suggests that propranolol acts centrally to reduce fear. Consistent with this, propranolol reduced the firing rate of PL neurons. | Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism and sudden death. Thus, it is important to consider the pathophysiology of DVT. Recently, iron has been reported to be associated with thrombotic diseases. Hence, in this study, we investigate the effects of dietary iron restriction on the process of thrombus resolution in a rat model of DVT. We induced DVT in 8-week-old male Sprague-Dawley rats by performing ligations of their inferior venae cavae. The rats were then given either a normal diet (DVT group) or an iron-restricted diet (DVT+IR group). Thrombosed inferior venae cavae were harvested at 5 days after ligation. The iron-restricted diet reduced venous thrombus size compared to the normal diet. Intrathrombotic collagen content was diminished in the DVT+IR group compared to the DVT group. In addition, intrathrombotic gene expression and the activity of matrix metalloproteinase-9 were increased in the DVT+IR group compared to the DVT group. Furthermore, the DVT+IR group had greater intrathrombotic neovascularization as well as higher gene expression levels of urokinase-type plasminogen activator and tissue-type plasminogen activator than the DVT group. The iron-restricted diet decreased intrathrombotic superoxide production compared to the normal diet. |
Does extremes of shock index predict death in trauma patients? | We noted a bimodal relationship between mortality and shock index (SI), the ratio of heart rate to systolic blood pressure. To determine if extremes of SI can predict mortality in trauma patients. Retrospective evaluation of adult trauma patients at a tertiary care center from 2000 to 2012 in the United States. We examined the SI in trauma patients and determined the adjusted mortality for patients with and without head injuries. Descriptive statistics and multivariable logistic regression. SI values demonstrated a U-shaped relationship with mortality. Compared with patients with a SI between 0.5 and 0.7, patients with a SI of <0.3 had an odds ratio for death of 2.2 (95% confidence interval [CI] 21.2-4.1) after adjustment for age, Glasgow Coma score, and injury severity score while patients with SI >1.3 had an odds ratio of death of 3.1. (95% CI 1.6-5.9). Elevated SI is associated with increased mortality in patients with isolated torso injuries, and is associated with death at both low and high values in patients with head injury. | Alzheimer's disease (AD) is characterized by cerebral deposition of β-amyloid peptide (Aβ). Aβ is produced by sequential cleavage of the Amyloid Precursor Protein (APP) by β- and γ-secretases. Many studies have demonstrated that the internalization of APP from the cell surface can regulate Aβ production, although the exact organelle in which Aβ is produced remains contentious. A number of recent studies suggest that intracellular trafficking also plays a role in regulating Aβ production, but these pathways are relatively under-studied. The goal of this study was to elucidate the intracellular trafficking of APP, and to examine the site of intracellular APP processing. We have tagged APP on its C-terminal cytoplasmic tail with photoactivatable Green Fluorescent Protein (paGFP). By photoactivating APP-paGFP in the Golgi, using the Golgi marker Galactosyltranferase fused to Cyan Fluorescent Protein (GalT-CFP) as a target, we are able to follow a population of nascent APP molecules from the Golgi to downstream compartments identified with compartment markers tagged with red fluorescent protein (mRFP or mCherry); including rab5 (early endosomes) rab9 (late endosomes) and LAMP1 (lysosomes). Because γ-cleavage of APP releases the cytoplasmic tail of APP including the photoactivated GFP, resulting in loss of fluorescence, we are able to visualize the cleavage of APP in these compartments. Using APP-paGFP, we show that APP is rapidly trafficked from the Golgi apparatus to the lysosome; where it is rapidly cleared. Chloroquine and the highly selective γ-secretase inhibitor, L685, 458, cause the accumulation of APP in lysosomes implying that APP is being cleaved by secretases in the lysosome. The Swedish mutation dramatically increases the rate of lysosomal APP processing, which is also inhibited by chloroquine and L685, 458. By knocking down adaptor protein 3 (AP-3; a heterotetrameric protein complex required for trafficking many proteins to the lysosome) using siRNA, we are able to reduce this lysosomal transport. Blocking lysosomal transport of APP reduces Aβ production by more than a third. |
Does ciclosporin reduce paracellin-1 expression and magnesium transport in thick ascending limb cells? | Renal magnesium (Mg2+) wasting is one of the ciclosporin (CsA) tubular effects. The major site of Mg2+ transport is the thick ascending limb (TAL), where 70% of the ultrafiltrable Mg2+ is reabsorbed paracellularly. Paracellin-1 is a tight junction protein, which regulates the paracellular Mg2+ transport in the TAL. We hypothesize that CsA reduces the expression and function of paracellin-1 and accounts for the observed renal Mg2+ wasting. We established an immortalized cultured cortical TAL (cTAL) cell line from L-PK/Tag1 transgenic mice by microdissection. The cultured cells expressed paracellin-1 and the characteristics of cTAL cells. Real-time PCR and western blotting were used to test the CsA effects on paracellin-1 expression of cultured cTAL cells. Cytosolic-free Mg2+ concentration [Mg2+]i change with time in a single cTAL cell was used as an indicator of transcellular Mg2+ transport and assessed by using fluorescence dye Mag-fura-2 AM. Paracellular Mg2+ transport was measured by cells grown in porous filters. The results showed that CsA significantly reduced paracellin-1 mRNA and protein expression in a dose-dependent manner. CsA (100 ng/ml) incubation for 24 h induced a decrease of paracellin-1 mRNA by 89.4% and paracellin-1 protein by 75.4%. CsA (100 ng/ml) did not change transcellular Mg2+ transport, but paracellular Mg2+ transport was decreased in CsA-treated cTAL cells by 74.4%. | Hostility may be associated with greater systemic inflammation. However, contradictory evidence exists. Certain individuals or dimensions of hostility may be more susceptible to these effects. Main and interactive effects of hostility with sex and/or age were evaluated on markers of inflammation, independently of traditional risk factors for coronary artery disease. 199 healthy men (81) and women (118), aged 20-64 years (M=41 ± 11 years) were recruited. Hostility was assessed using the Cook-Medley Hostility Inventory (CMHo) and ecological momentary assessments (EMA) of quarrelsome behavior and angry affect in daily living. Blood samples were drawn to measure inflammatory activity (Il-6, TNF-α, hsCRP, Il-8, Il-10, Il-18, MCP-1) and lipid oxidation (Myeloperoxidase; MPO). Correlations and hierarchical regression analyses were performed controlling for pertinent behavioral, psychological, medical, and socio-demographic factors. Significant univariate associations emerged between CMHo and Il-6, TNF-α, MCP-1 (p<.05). Hierarchical regressions showed interactions of hostility with sex (Il-6, TNF-α; p<.05) and age (hsCRP, Il-6, TNF-α; p<.05). For example, in simple slope analyses, hostility was positively related to TNF-α in women (b=0.009, p=0.006) but not men. Greater hostility was also related to greater Il-6 levels among younger women (b=. 027, p=0.000). |
Do sensory neuro-immune interactions differ between irritable bowel syndrome subtypes? | The gut is a major site of contact between immune and sensory systems and evidence suggests that patients with irritable bowel syndrome (IBS) have immune dysfunction. Here we show how this dysfunction differs between major IBS subgroups and how immunocytes communicate with sensory nerves. Peripheral blood mononuclear cell supernatants from 20 diarrhoea predominant IBS (D-IBS) patients, 15 constipation predominant IBS (C-IBS) patients and 36 healthy subjects were applied to mouse colonic sensory nerves and effects on mechanosensitivity assessed. Cytokine/chemokine concentration in the supernatants was assessed by proteomic analysis and correlated with abdominal symptoms, and expression of cytokine receptors evaluated in colonic dorsal root ganglia neurons. We then determined the effects of specific cytokines on colonic afferents. D-IBS supernatants caused mechanical hypersensitivity of mouse colonic afferent endings, which was reduced by infliximab. C-IBS supernatants did not, but occasionally elevated basal discharge. Supernatants of healthy subjects inhibited afferent mechanosensitivity via an opioidergic mechanism. Several cytokines were elevated in IBS supernatants, and levels correlated with pain frequency and intensity in patients. Visceral afferents expressed receptors for four cytokines: IL-1β, IL-6, IL-10 and TNF-α. TNF-α most effectively caused mechanical hypersensitivity which was blocked by a transient receptor potential channel TRPA1 antagonist. IL-1β elevated basal firing, and this was lost after tetrodotoxin blockade of sodium channels. | To examine the association between serum lipoprotein(a) and angiographically assessed coronary artery disease progression without new myocardial infarction. 85 patients with coronary artery disease who underwent serial angiography with an interval of at least two years were studied. Progression of coronary artery disease was defined as an increase in diameter stenosis of 15% or more. Vessels on which angioplasty had been performed were excluded from the analysis. The patients were classified into two groups: a progression group without new myocardial infarction (n = 48) and non-progression group (n = 37). Risk factors including lipoprotein(a) were evaluated to see how they were related to progression without myocardial infarction. There were no differences between the two groups in the following factors: age, gender, the time interval between the angiographic studies, the distribution of the analysed coronary arteries, and history of well established coronary risk factors. Univariate analysis showed that serum lipoprotein(a) (P = 0.0002), cigarette smoking between the studies (P = 0.002), serum high density lipoprotein (P = 0.003), and serum low density lipoprotein (P = 0.01) were related to progression without myocardial infarction. Multivariate analysis selected two independent factors for progression without myocardial infarction: serum lipoprotein(a) (P = 0.003) and serum high density lipoprotein (P = 0.03). |
Is transthoracic ultrasonography an alternative to subxyphoid ultrasonography for the diagnosis of hemopericardium in penetrating precordial trauma? | Surgeon-performed ultrasonography is increasingly becoming part of the initial evaluation of patients after blunt or penetrating trauma. Currently, most institutions obtain a subxyphoid or subcostal view of the heart and pericardial space, and a three-view ultrasonogram of the abdomen to detect blood in the pericardial sac or in three dependent abdominal areas. A left parastemal standard transverse transthoracic view is described in addition to the aforementioned views. This facilitates the visualization of the pericardial sac when a subxyphoid or subcostal view cannot be obtained because of anatomical reasons (narrow subxyphoid space) or local factors (pain, fractures, subcutaneous emphysema, or chest wall contusion). The transthoracic view can be useful in patients where the subxyphoid view is difficult to obtain through the conventional approach. In most patients an excellent view of the pericardial sac and ventricles can be obtained and, therefore, expedites the diagnosis and treatment of patients with hemopericardium. | Protein arginine methyltransferase 5 (PRMT5), is thought to play a role in epigenetic reprogramming of mouse germ cells. However, up to now there has been little information concerning its expression profile and effects on generation of induced pluripotent stem cells (iPSCs) from somatic cells, in livestock. Here, we have explored PRMT5 expression profiles in dairy goats and its consequences to derivation of iPSCs from dairy goat embryonic fibroblasts (GEFs). We investigated effects of PRMT5 on iPS-like cells production in vitro. alkaline phosphatase (AP) staining, QRT-PCR and western blotting analysis of expression of related markers were used to evaluate efficiency of generation of iPSCs derived from GEFs. These showed PRMT5 to be a conservative gene widely expressed in various tissues and different-aged testes. PRMT5 overexpression in combination with OCT3/4, SOX2, KLF4 and C-MYC (POSKM) significantly increased number of AP positive iPS-like colony-derived GEFs compared to OSKM alone, in our dairy goats. Moreover, our results demonstrated that PRMT5 overexpression stimulated GEF proliferation and down-regulated p53, p21 (a target gene of p53) and the apoptotic marker caspase 3, to enhance somatic cell reprogramming. |
Does hepatic HMOX1 expression positively correlate with Bach-1 and miR-122 in patients with HCV mono and HIV/HCV coinfection? | To analyze the expression of HMOX1 and miR-122 in liver biopsy samples obtained from HCV mono-and HIV/HCV co-infected patients in relation to selected clinical parameters, histological examination and IL-28B polymorphism as well as to determine whether HMOX1 expression is dependent on Bach-1. The study group consisted of 90 patients with CHC: 69 with HCV mono and 21 with HIV/HCV co-infection. RT-PCR was used in the analysis of HMOX1, Bach-1 and miR-122 expression in liver biopsy samples and in the assessment of IL-28B single-nucleotide polymorphism C/T (rs12979860) in the blood. Moreover in liver biopsy samples an analysis of HO-1 and Bach-1 protein level by Western Blot was performed. HCV mono-infected patients, with lower grading score (G<2) and higher HCV viral load (>600000 IU/mL) demonstrated higher expression of HMOX1. In patients with HIV/HCV co-infection, the expression of HMOX1 was lower in patients with lower lymphocyte CD4 count and higher HIV viral load. IL28B polymorphism did not affect the expression of either HMOX1 or miR-122. Higher HMOX1 expression correlated with higher expression of Bach-1 (Spearman's ρ = 0.586, p = 0.000001) and miR-122 (Spearman's ρ = 0.270, p = 0.014059). | We sought to evaluate the impact of the speed of recanalization on the evolution of diffusion- weighted imaging (DWI) lesions and outcome in stroke patients treated with tissue-type plasminogen activator (tPA). We evaluated 113 consecutive stroke patients with a middle cerebral artery occlusion who were treated with intravenous tPA. All patients underwent multiparametric magnetic resonance imaging studies, including DWI and perfusion-weighted imaging before and 36 to 48 hours after administration of a tPA bolus. Patients were continuously monitored with transcranial Doppler during the first 2 hours after tPA administration. The pattern of recanalization on transcranial Doppler was defined as sudden (<1 minute), stepwise (1 to 29 minutes), or slow (>30 minutes). During transcranial Doppler monitoring, 13 (12.3%) patients recanalized suddenly, 32 (30.2%) recanalized in a stepwise manner, and 18 (17%) recanalized slowly. Baseline clinical and imaging parameters were similar among recanalization subgroups. At 36 to 48 hours, DWI lesion growth was significantly (P=0.001) smaller after sudden (3.23+/-10.5 cm(3)) compared with stepwise (24.9+/-37 cm(3)), slow (46.3+/-38 cm(3)), and no (51.7+/-34 cm(3)) recanalization. The slow pattern was associated with greater DWI growth (P=0.003), lesser degree of clinical improvement (P=0.021), worse 3-month outcome (P=0.032), and higher mortality (P=0.003). |
Does sodium intake affect urinary albumin excretion especially in overweight subjects? | To examine the relationship between sodium intake and urinary albumin excretion, being an established risk marker for later cardiovascular morbidity and mortality. Cross-sectional cohort study using linear regression analysis. Setting. University hospital outpatient clinic. A cohort drawn from the general population, consisting of 7850 subjects 28-75 years of age, all inhabitants of the city of Groningen, the Netherlands. The cohort is enriched for the presence of subjects with elevated urinary albumin concentration. The results show a positive relationship between dietary sodium intake and urinary albumin excretion. The association was independent of other cardiovascular risk factors (such as sex, age, blood pressure, body mass index (BMI), waist-to-hip ratio, serum cholesterol, plasma glucose and smoking) and other food constituents (calcium, potassium and protein). The relationship between sodium intake and urinary albumin excretion was steeper in subjects with a higher BMI compared with a lower BMI. | Mesenchymal stem cells may offer therapeutic potential for asthma due to their immunomodulatory properties and host tolerability, yet prior evidence suggests that bloodborne progenitor cells may participate in airway remodeling. Here, we tested whether mesenchymal stem cells administered as anti-inflammatory therapy may favor airway remodeling and therefore be detrimental. Adipose tissue-derived mesenchymal stem cells were retrovirally transduced to express green fluorescent protein and intravenously injected into mice with established experimental asthma induced by repeat intranasal house dust mite extract. Controls were house dust mite-instilled animals receiving intravenous vehicle or phosphate-buffered saline-instilled animals receiving mesenchymal stem cells. Data on lung function, airway inflammation, and remodeling were collected at 72 h after injection or after 2 weeks of additional intranasal challenge. The mesenchymal stem cells homed to the lungs and rapidly downregulated airway inflammation in association with raised T-helper-1 lung cytokines, but such effect declined under sustained allergen challenge despite a persistent presence of mesenchymal stem cells. Conversely, airway hyperresponsiveness and contractile tissue underwent a late reduction regardless of continuous pathogenic stimuli and inflammatory rebound. Tracking of green fluorescent protein did not show mesenchymal stem cell integration or differentiation in airway wall tissues. |
Does performance-oriented mobility assessment ( POMA ) balance score indicate need for assistive device? | To determine (1) if older adults using an assistive device (AD) score lower on the Performance-Oriented Mobility Assessment (POMA) balance subscale (B-subscale) than individuals not using an AD; and (2) if a cut-score of 12 would indicate the need to use an AD. Elderly persons (n = 82, mean age = 82.1 years) were surveyed about AD use, health status, activity level and fall history. A one-time assessment of balance was conducted using the B-subscale. The 'arising task' was repeated to evaluate performance on the sit-to-stand task without using hands. A significant difference in B-subscale scores was observed between the two groups (AD; no AD), (P < 0.001). AD use was associated with lower activity level and health status. A cut-score of 12 points indicated device use (P = 0.000). The repeated 'arising task' demonstrated that 76.8% performed the task without using hands for support. | The development of transplant coronary artery disease is associated with neovascularization in the thickened neointima. We previously reported that captopril inhibits neointimal proliferation in a rat allograft model. We postulated that angiogenic inducers are upregulated post-transplantation and captopril ameliorates transplant coronary artery disease by suppressing the angiogenic activity of coronaries. Animals received no treatment or captopril (50 mg/kg/day). Allograft hearts were analyzed at post-transplantation Days 0, 14, and 21 and angiogenic inducer, plasma platelet-activating factor, determined. The conditioned media from coronaries and myocardium were tested for vascular endothelial growth factor, thrombospondin-1 and angiogenic activity using an endothelial migration assay and rat corneal neovascularization assay. The captopril-treated group had reduced plasma platelet-activating factor and coronary media revealed earlier upregulation of thrombospondin-1 secretion, diminished vascular endothelial growth factor and no angiogenic activity. At Day 0, the coronary and myocardial conditioned medium had inhibitory activity due to thrombospondin-1, and circulating levels of platelet-activating factor were negligible. By 21 days post-transplantation, plasma platelet-activating factor was elevated and the conditioned medium from untreated coronaries had significantly higher angiogenic activity due to increased vascular endothelial growth factor whereas the myocardium remained non-angiogenic. |
Does anxiety-like state associate with taste to produce conditioned taste aversion? | The interactions among experience, emotion, and memory are considered to be instrumental in the ontogeny and maintenance of acquired emotional and behavioral disorders (e.g., phobias). Here we address the question whether an anxiety-like state can associate with taste to produce conditioned taste aversion (CTA). We have used an anxiogenic agent, the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP), to induce an anxiety-like emotional state in rats after consumption of an unfamiliar tastant. The anxiogenic agent induced CTA. The mCPP-induced CTA could be prevented by concomitant administration of ethanol, which is known to reverse mCPP-induced anxiety-like behavior, at a concentration that had no effect on CTA memory. In contrast, ethanol did not prevent LiCl-induced CTA. Administration of mCPP before the consumption of the tastant had no effect on the preference for that tastant. | Although "clinical remission" has been a realistic goal of treatment in rheumatoid arthritis (RA), there is evidence that subclinical synovitis is associated with ongoing structural damage even after clinical remission is achieved. In the study reported here, we assessed whether ultrasonography (US) can predict progressive joint destruction during clinical remission of RA. Thirty-one patients with RA in clinical remission based on the disease activity score in 28 joints were recruited for this study. Bilateral wrists and all of the metacarpophalangeal and proximal interphalangeal (PIP) joints were examined by power Doppler (PD) ultrasonography (US), and the PD signals were scored semiquantitatively in each joint. The total PD score was calculated as the sum of individual scores for each joint. Among 22 RA patients who maintained clinical remission during the 2-year follow-up period, seven showed radiographic progression. Radiographic progression was strongly associated with total PD score at entry, with all patients showing radiographic progression having a total PD score of ≥ 2 at entry and none of the patients with a total PD score of ≤ 1 showing any radiographic progression. There was no significant association of therapeutic agents with progressing or non-progressing cases. |
Does mesenchymal stem cell application improve tendon healing via anti-apoptotic effect ( Animal study )? | The aim of this study was to determine the effects of mesenchymal stem cell (MSC) application and the possible pathways of MSC's effects on tendon strength and healing after tendon repair. The study included 40 Wistar albino rats. Mesenchymal stem cells were obtained from the femurs and tibias of 6 rats. Achilles tendons of the remaining 34 rats were cut and repaired with open surgical procedures. Rats were divided into 2 groups. Percutaneous MSCs were applied to the study group (n=17) and physiological serum only was applied to the control group (n=17) at the 4th week. Rats were sacrificed using the cervical dislocation method under ether anesthesia at the 12th week and samples were analyzed by histological and immunohistochemical methods. For biomechanical analysis, a traction force was applied at 10 mm/min and load to failure was recorded for each specimen in Newtons. Histologically, there was no significant difference between groups (p>0.05). In the immunohistochemical studies, MSCs were located more intensively at the repair zone. Apoptosis was minimally present in the study group and was clearly increased in the control group. Increase in tendon strength was significantly higher in the study group than in the control group at the 12th week (p<0.05). | Published yields of pH monitoring for suspected laryngopharyngeal reflux (LPR) vary greatly. Hypopharyngeal pH artifacts may be responsible for these inconsistencies. To determine the impact of potential artifacts on pH monitoring of the hypopharynx and esophagus. Patients with suspected LPR were prospectively studied. Single-catheter, triple-sensor pH monitoring was performed off antireflux therapy. Subjects recorded meal times and marked liquid swallows outside of meals on the data recorder. Results were analyzed by excluding six potential pH artifacts individually and all together. Positive pH test was defined as three or more reflux episodes in hypopharynx, total percent of time pH less than 4 was 1.0% or greater in the proximal esophagus, and total percent of time pH less than 4 was 4.2% or greater in the distal esophagus. Wilcoxon rank sum and chi-square tests were used. Thirty-eight subjects (24 females; median age, 47 yr) completed the study. A total of 2,225 hypopharyngeal pH drops less than 4 were identified; 48% were short pH drops at less than 5 seconds, 17% within meal periods, 16% liquid swallows outside of meals, 16% isolated proximal pH drops, 12% pH out of range, and 5% pH drift. Eighty percent of the hypopharyngeal pH drops were at least one of the potential pH artifacts. The yield of the hypopharyngeal sensor was reduced by 45% (from 92% to 47%) after all potential pH artifacts were excluded. Yields of proximal and distal esophageal pH sensors were reduced by 19% and 8%, respectively, significantly less than the hypopharyngeal sensor (P < .01). |
Does ginsenoside Rd attenuate DNA Damage by Increasing Expression of DNA Glycosylase Endonuclease VIII-like Proteins after Focal Cerebral Ischemia? | Ginsenoside Rd (GSRd), one of the main active ingredients in traditional Chinese herbal Panax ginseng, has been found to have therapeutic effects on ischemic stroke. However, the molecular mechanisms of GSRd's neuroprotective function remain unclear. Ischemic stroke-induced oxidative stress results in DNA damage, which triggers cell death and contributes to poor prognosis. Oxidative DNA damage is primarily processed by the base excision repair (BER) pathway. Three of the five major DNA glycosylases that initiate the BER pathway in the event of DNA damage from oxidation are the endonuclease VIII-like (NEIL) proteins. This study aimed to investigate the effect of GSRd on the expression of DNA glycosylases NEILs in a rat model of focal cerebral ischemia. NEIL expression patterns were evaluated by quantitative real-time polymerase chain reaction in both normal and middle cerebral artery occlusion (MCAO) rat models. Survival rate and Zea-Longa neurological scores were used to assess the effect of GSRd administration on MCAO rats. Mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damages were evaluated by the way of real-time analysis of mutation frequency. NEIL expressions were measured in both messenger RNA (mRNA) and protein levels by quantitative polymerase chain reaction and Western blotting analysis. Apoptosis level was quantitated by the expression of cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling assay. We found that GSRd administration reduced mtDNA and nDNA damages, which contributed to an improvement in survival rate and neurological function; significantly up-regulated NEIL1 and NEIL3 expressions in both mRNA and protein levels of MCAO rats; and reduced cell apoptosis and the expression of cleaved caspase-3 in rats at 7 days after MCAO. | There is debate about whether intraoperative cholangiography (IOC) should be performed routinely or selectively during laparoscopic cholecystectomy (LC) in patients with suspected choledocholithiasis. The timing of endoscopic retrograde cholangiopancreatography (ERCP) in these patients also is an issue. We reviewed the experience in our center, where a management algorithm limiting ERCP in relation to LC was adopted. We retrospectively reviewed every LC performed by one surgeon during 6 years and the related ERCPs. A total of 264 LCs were performed. In 30 patients, stones were cleared or excluded by preoperative ERCP. In the remaining 234 LCs, 31 of 34 IOCs were successfully performed. Two of 31 IOCs were positive for bile duct stones; stone removal was successful in each patient at subsequent ERCP. Only 10 of 201 patients who did not have IOC required postsurgical ERCP within 10 weeks of LC, 3 of whom had common bile duct stones at ERCP. |
Does long-term pharmacological activation of PPARgamma prevent left ventricular remodeling in dogs with advanced heart failure? | Peroxisome proliferator-activated receptor gamma (PPARgamma) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPARgamma activator, GW347845 (GW), on the progression of heart failure. Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n = 7), low-dose GW (3 mg/Kg daily, n = 7), or no therapy (control, n = 7). In control dogs, EF significantly decreased (28 +/- 1 vs. 22 +/- 1%, p < 0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the follow-up period (64 +/- 4 vs. 76 +/- 5; p = 0.003, 46 +/- 3 vs. 59 +/- 4 ml, p = 0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69 +/- 4 vs.81 +/- 5 ml, p = 0.01), whereas ESV remained statistically unchanged (50 +/- 3 vs. 54 +/- 3 ml, p = 0.10) resulting in modestly increased ejection fraction (27 +/- 1 vs. 32 +/- 3%, p = 0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72 +/- 4 vs. 79 +/- 5 ml, p = 0.04; 53 +/- 3 vs. 62 +/- 5 ml, p = 0.04) and EF decreased (26 +/- 1 vs. 23 +/- 1%, p = 0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPARgamma, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy. | To verify an impact of a lymph node revealing solution (LRS) on the number of lymph nodes (LN) revealed in colorectal resection specimens. Fifty-nine cases of rectosigmoid carcinomas divided into two subgroups-stage pT2&3 (20 cases) and ypT2&3 (with pre-operative radiotherapy-39 cases)-were formalin fixed for 42-72 h, serially sectioned and re-fixed in LRS containing ethanol, diethyl ether, glacial acetic acid, and formalin for 24 h. The number of LNs was matched to a control group consisting of 34 cases of colorectal carcinoma, 14 pT2&3 and 20 ypT2&3 rectosigmoid carcinomas examined routinely. Results were statistically tested by Student's t-test. In the study group the total number of revealed LNs was 869, range 1-48, average 14.7 per specimen, median 15. In the control group the number of LNs was 200, range 0-13, average 5.9 per specimen, median 6. The difference between the study and the control group was statistically significant (P = 0.05). |
Are nutrient intake and iron status of urban poor and rural poor without access to rice fields affected by the emerging economic crisis : the case of pregnant Indonesian women? | We evaluated the adequacy of nutrient intake in comparison with the Indonesian Estimated Average Requirement (EARs) among pregnant Indonesian women and explain the short-term effect of economic crisis on nutrient intake and iron status. Cross-sectional study. Purworejo District, Central Java, located 60 km west of Yogyakarta Province, Indonesia. During the period from 1996 to 1998, up to six 24 h recalls were performed during the second trimester of pregnancy among 450 women. Nutrient intake and iron status was evaluated in relation to date of data collection relative to the economic crisis that emerged in August 1997. A computer program (Inafood) was developed to calculate nutrient intake. : Forty percent of the pregnant women were at risk of inadequate intake of energy and protein, and 70% were at risk of inadequate intake of vitamin A, calcium and iron even before the crisis. Our results also demonstrate an effect of short-term economic crisis on nutrient intake and iron status. When the crisis emerged, urban poor experienced a decrease in intake of most nutrients. During the crisis, rich women experienced a significant decrease in fat (P<0.05). Negative changes in fat density during crisis were experienced by the rich and the rural, poor, and access to rice field subgroups (P<0.01). A significant increase in carbohydrate densities was seen for the rich and rural, poor, and access to rice fields groups (P<0.05). Urban poor experienced decreased serum ferritin concentration (P<0.05), whereas rich women experienced a significant increase (P<0.05). | Salivary gland adenoid cystic carcinoma (ACC) is one of the most common malignant tumours in the oral and maxillofacial region, and has high aggressive potential. Tumour and stroma interactions are critical in determining the biological characteristics of malignancy. The aim of this study was to investigate the presence of myofibroblasts and their roles in the invasive characteristics of ACC. Immunohistochemistry was used to detect the expression of vimentin (VIM), α-smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP2) and CD34 in ACCs and normal salivary gland controls. A significant difference in α-SMA expression was found between normal controls and ACCs, suggesting the presence of myofibroblasts in ACCs. Immunohistochemical staining also demonstrated higher MMP2 expression in the stroma of ACCs than in the controls (P < 0.001). Primary culture of myofibroblasts from one ACC showed great invasive activity, with high expression of MMP2 and C-X-C motif chemokine 12 (CXCL12) by reverse transcription polymerase chain reaction (RT-PCR) analysis. |
Is telephone-based low intensity therapy after crisis presentations to the emergency department associated with improved outcomes? | In Australia there is an overwhelming need to provide effective treatment to patients presenting to the Emergency Department (ED) in mental health crisis. We adapted Improving Access to Psychological Therapies service model (IAPT) from the National Health Service (NHS) method for the large scale delivery of psychological therapies throughout the United Kingdom to an Australian ED setting. This telephone-based low intensity therapy was provided to people presenting in crisis to the EDs with combinations of anxiety, depression, substance use, and suicidal thinking. This uncontrolled study utilised session-by-session, before-and-after measures of anxiety and depression via Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder-7 (GAD-7). Of 347 eligible post-crisis ED referred patients, 291 (83.9%) engaged with the IAPT team. Most patients (65%) had attended the ED previously on an average of 3.9 (SD = 6.0) occasions. Two hundred and forty one patients received an average of 4.1 (SD = 2.3) contacts of low-intensity psychological therapies including 1.2 (SD = 1.7) community outreach visits between 20th Oct 2011 and 31st Dec 2012. Treated patients reported clinically significant improvements in anxiety, depression and suicidal ideation. Uncontrolled effect sizes were moderate for anxiety (0.6) and depression (0.6). | Somatic cells in vitro have a finite life expectancy before entering a state of senescence, but it is unclear whether this state occurs in vivo in kidney development, growth, and aging. We previously showed that human kidney cortex displays telomere shortening with age. In this study, we compared the structural and functional changes in rat kidney with age to phenomena associated with cellular senescence in vitro. We assessed the changes in Fischer 344 rat kidneys from age 1 to 9 months to define growth and development and from age 9 to 24 months to define aging. Rat kidney telomeres were approximately 35 to 40 kb long and did not shorten significantly. Expression of mRNA for p16INK4a, a characteristic senescence gene in vitro, was undetectable in most young rats but rose 27 fold during growth and a further 72-fold during aging. p16INK4a protein was localized to the nucleus and increased with age. p16INK4a mRNA also increased in other tissues. Lipofuscin and senescence-associated beta-galactosidase increased in epithelium with growth and aging and their occurrence was significantly associated with each other. Lipofuscin was particularly found in atrophic nephrons. |
Do matrix metalloproteinase-8 inhibitors mitigate sepsis-induced myocardial injury in rats? | Sepsis-induced myocardial injury (SIMI) is caused by a variety of mechanisms. The aim of the study is to investigate the effects of metalloproteinase-8 (MMP-8) on SIMI and its mechanisms in rats. Forty male Sprague Dawley rats were randomly divided into four groups: MMP-8 inhibitor (M8I), dexamethasone (DEX), sepsis, and sham groups. The sepsis model was established by cecal ligation and puncture (CLP). Rats in the M8I group immediately received an intraperitoneal injection of M8I (0.1 mg/kg) after CLP. Rats in the DEX group immediately received an intraperitoneal (IP) injection of DEX (2 mg/kg). Rats in the sepsis and sham groups received intraperitoneal injections of normal saline. Rats were sacrificed 12 hours after CLP. Paraffin sections were stained with hematoxylin and eosin to observe the myocardium. The myocardial ultrastructure was observed with transmission electron microscopy. MMP-8, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were detected by immunohistochemistry. The expression of MMP-8 was measured by Western blotting. TNF-α and IL-1β levels in serum and myocardial tissue were determined by enzyme-linked immunosorbent assay. Compared with the sham group, the myocardium in the sepsis group was seriously injured. MMP-8, TNF-α and IL-1β expression was higher in the sepsis group than in the sham group. Treatment with M8I or DEX, however, attenuated sepsis induced histopathological changes in the heart, and was associated with significant reductions in serum and myocardial levels of TNF-α and IL-1β (P < 0.05). M8I significantly inhibited MMP-8 expression in myocardial tissue (P < 0.05). In addition, treatment with DEX was not associated with a change in myocardial levels of MMP-8 (P > 0.05). | To characterize seasonal variation in the myopic progression of Chinese children. Myopia progression data are presented for a total of 85 Chinese children, aged 6 to 12 years, with baseline myopia of -0.75 D to -3.50 D sphere and astigmatism ≤-1.50 D, who wore traditional single-vision spectacles in two clinical trials (trial A: n = 37, trial B: n = 48). Refractive error and axial length data were obtained at 6-month intervals using cycloplegic autorefraction and partial coherence interferometry, respectively. Progression rates for right eyes were defined for the first and second 6 months of the studies and classified in terms of "summer," "autumn," "winter," or "spring" based on the mid-point of the 6-month period between visits. The mean 6-month spherical equivalent progression was -0.31 ± 0.25 D for summer, -0.40 ± 0.27 D for autumn, -0.53 ± 0.29 D for winter, and -0.42 ± 0.20 D for spring (p < 0.001). Mean axial elongation was 0.17 ± 0.10 mm for summer, 0.24 ± 0.09 mm for autumn, 0.24 ± 0.09 mm for winter, and 0.15 ± 0.08 mm for spring (p < 0.001). Post hoc analysis indicated that data for summer and winter were different from each other at p < 0.05 for both myopia progression and axial elongation after adjusting for age. |
Does cyclosporine suppress cell growth and collagen production in hepatic stellate cells? | In HCV-related graft hepatitis, immunosuppression has been implicated in rapid progression to cirrhosis, a serious clinical issue. We investigated the effects of cyclosporine or tacrolimus on cell growth and collagen production by hepatic stellate cells (HSC), which play a role in hepatic fibrosis. Cultured rat HSCs and human HSC-derived TWNT-4 cells were evaluated for proliferation, type I collagen, phosphorylation states of mitogen-activated protein kinases extracellular signal-regulated kinase 1/2; [MAPKs Erk1/2], c-Jun N-terminal kinase (JNK, p38), as well as the expression of collagen, matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) genes. Cyclosporine suppressed cell growth and collagen production in a concentration-dependent manner. At clinically relevant concentrations of 0.125 micromol (150 ng/mL) cyclosporine significantly reduced collagen production per cell by more than 50%. Similarly, tacrolimus also reduced both collagen concentration and cell number; however, tacrolimus at a clinically relevant concentration of 12.5 nmol (10 ng/mL) did not significantly reduce collagen production. Treatment with cyclosporine reduced type I collagen and TIMP-1 expression and enhanced MMP-1 expression. Cyclosporine also inhibited phosphorylation strongly for JNK and p38, and weakly inhibited for Erk1/2. | The association between environmental lead exposure and blood pressure variability, an important risk factor for cardiovascular disease, is unexplored and unknown. The objective of the study was to test the hypothesis that lead exposure is associated with blood pressure variability. American participants 17 years of age or older from National Health and Nutrition Examination Survey III were included in the analysis. Participants' blood lead concentrations expressed as micrograms per deciliter were determined. The standard deviations of visit-to-visit systolic and diastolic blood pressure were calculated to determine blood pressure variability. Multivariable regression analyses adjusted for age, gender, race, smoking and socioeconomic status were employed. The participants' mean age and mean blood lead concentration were 42.72 years and 3.44 mcg/dl, respectively. Systolic blood pressure variability was significantly associated with environmental lead exposure after adjusting for the effect of the confounders. The unadjusted and adjusted means of visit-to-visit systolic blood pressure variability and the β coefficient of lead exposure were 3.44, 3.33 mcg/dl, β coefficient = 0.07, P < 0.01. |
Is splenectomy modifying the vascular remodeling of thrombosis? | Splenectomy is a clinical risk factor for complicated thrombosis. We hypothesized that the loss of the mechanical filtering function of the spleen may enrich for thrombogenic phospholipids in the circulation, thereby affecting the vascular remodeling of thrombosis. We investigated the effects of splenectomy both in chronic thromboembolic pulmonary hypertension (CTEPH), a human model disease for thrombus nonresolution, and in a mouse model of stagnant flow venous thrombosis mimicking deep vein thrombosis. Surgically excised thrombi from rare cases of CTEPH patients who had undergone previous splenectomy were enriched for anionic phospholipids like phosphatidylserine. Similar to human thrombi, phosphatidylserine accumulated in thrombi after splenectomy in the mouse model. A postsplenectomy state was associated with larger and more persistent thrombi. Higher counts of procoagulant platelet microparticles and increased leukocyte-platelet aggregates were observed in mice after splenectomy. Histological inspection revealed a decreased number of thrombus vessels. Phosphatidylserine-enriched phospholipids specifically inhibited endothelial proliferation and sprouting. | CENTRAL, Medline, Embase, Web of Science, LILACS and BBO databases, the Brazilian database of thesis and dissertations (Banco de Teses CAPES), a Brazilian register of ethically approved projects involving human beings (SISNEP) and two registers of ongoing trials (Current Controlled Trials and Clinical-Trials.gov). Reference lists were also scanned for relevant papers. Study authors were contacted for additional information. Individual or cluster-randomised or quasi-randomised controlled trials conducted in children under seven were included. Study selection and data abstraction were conducted by two reviewers independently. Risk of bias assessment was undertaken using the Cochrane Collaboration tool. Meta-analyses of prevented fractions (PF) were performed to assess the effect of fluoride toothpaste on the dmft and dmfs. Meta-analyses were also performed to obtain a pooled relative risk (RR) to assess the effect of fluoride toothpastes on the proportion of children developing caries. Eight studies were included. When standard F toothpastes were compared to placebo or no intervention, significant caries reduction at surface (PF = 31%; 95% CI 18-43; 2644 participants in five studies), tooth (PF = 16%; 95% CI 8-25; 2555 participants in one study) and individual (RR = 0.86; 95% CI 0.81-0.93; 2806 participants in two studies) level were observed. Low F toothpastes were effective only at surface level (PF = 40%; 95% CI 5-75; 561 participants in two studies). |
Does zinc transporter-1 concentrate at the postsynaptic density of hippocampal synapses? | Zinc concentrates at excitatory synapses, both at the postsynaptic density and in a subset of glutamatergic boutons. Zinc can modulate synaptic plasticity, memory formation and nociception by regulating transmitter receptors and signal transduction pathways. Also, intracellular zinc accumulation is a hallmark of degenerating neurons in several neurological disorders. To date, no single zinc extrusion mechanism has been directly localized to synapses. Based on the presence of a canonical PDZ I motif in the Zinc Transporter-1 protein (ZnT1), we hypothesized that ZnT1 may be targeted to synaptic compartments for local control of cytosolic zinc. Using our previously developed protocol for the co-localization of reactive zinc and synaptic proteins, we further asked if ZnT1 expression correlates with presynaptic zinc content in individual synapses. Here we demonstrate that ZnT1 is a plasma membrane protein that is enriched in dendritic spines and in biochemically isolated synaptic membranes. Hippocampal CA1 synapses labelled by postembedding immunogold showed over a 5-fold increase in ZnT1 concentration at synaptic junctions compared with extrasynaptic membranes. Subsynaptic analysis revealed a peak ZnT1 density on the postsynaptic side of the synapse, < 10 nm away from the postsynaptic membrane. ZnT1 was found in the vast majority of excitatory synapses regardless of the presence of vesicular zinc in presynaptic boutons. | Obesity has been described as a predictor of cardiovascular mortality, and some studies have reported an association with obesity and increased aortic stiffness. Other studies have not identified obesity to be an independent risk factor. Therefore, the purpose of our study was to determine the association between aortic stiffness and obesity in the Brazilian population. A cross-sectional study recruited 1,662 individuals aged 25-64 years from the population of Vitória, Brazil following the guidelines of the MONICA-WHO Project. Anthropometric, clinical, and hemodynamic measurements and analyses of aortic stiffness (using carotid-femoral pulse wave velocity <PWV) were obtained in 1,608 subjects. PWV correlated positively with age, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure, heart rate (HR), body mass index (BMI), waist circumference (WC), cholesterol levels, triglyceride levels, and blood glucose levels. A multivariate regression analysis demonstrated that the mean BP (β = 0.405, P < 0.01), age (β = 0.314, P < 0.01), HR (β = 0.107, P < 0.01), BMI (β = -103, P < 0.01), and blood glucose levels (β = 0.093, P < 0.01) explained nearly 37% of the PWV variability. A multivariate regression analysis using the WC instead of the BMI failed to reveal any significant effect of this parameter on the PWV. |
Does interleukin-6 stimulate rat myometrial contractions in an in vitro model? | Interleukin-6 (IL-6) increases in culture-positive amniotic fluid in women with preterm labor. IL-6 stimulates the production of prostaglandins leading to increased uterine activity. We tested the hypothesis that IL-6 increases myometrial activity through release of uterotonic mediators. We studied the effect of IL-6 on uterine contractions in the absence and presence of fetal membranes to determine if the effect was on myometrium alone or was mediated through fetal membranes/decidua. IL-6 in concentrations of 100, 10, 0.1 or 0 ng/ml was added to the maternal side of the dual chamber-fetal membrane-uterine muscle in vitro model. We found that 10 ng/ml of IL-6 alone, without fetal membranes, caused a significant decrease in uterine contractions over time (P < or = 0.01). This decrease was not observed with the addition of term, nonlabored fetal membranes. | A large body of research suggests that light or moderate alcohol consumption is associated with reduced all-cause mortality. However, concerns remain that the observed relationship is due to selection bias, misclassification of ex-drinkers, or residual confounding. The association between alcohol consumption and all-cause mortality was analyzed using Cox regression. The analysis was performed using data from the Health and Retirement Study, a longitudinal cohort of 24,029 individuals from a nationally representative sample of US adults aged more than 50 years. Drinking level was based on alcohol consumption measured at 3 points over the 4 years before the start of follow-up. Occasional drinkers-those who reported drinking on at least 1 occasion, but always less than once per week-served as the reference category. There was extensive adjustment for sociodemographic variables, health status, and functional status. During 206,966 person-years of follow up, 7902 individuals died. No level of regular alcohol consumption was associated with reduced all-cause mortality. The hazard ratio and 95% confidence interval in fully adjusted analyses was 1.02 (0.94-1.11) for <7 drinks/week, 1.14 (1.02-1.28) for 7 to <14 drinks/week, 1.13 (0.96-1.35) for 14 to <21 drinks/week, and 1.45 (1.16-1.81) for ≥ 21 drinks/week. |
Does downstream Toll-like receptor signaling mediate adaptor-specific cytokine expression following focal cerebral ischemia? | Deletion of some Toll-like receptors (TLRs) affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT), MyD88(-/-) and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO). Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve) and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. IL-6, keratinocyte chemoattractant (KC), granulocyte colony-stimulating factor (G-CSF) and IL-10 were significantly decreased in MyD88(-/-) mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88(-/-) mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1 α was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. MyD88(-/-) mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO. | No polymorphisms affecting serum FSH levels have been described in the human FSHB gene. We have identified a potential regulatory single nucleotide polymorphism (SNP, rs10835638; G/T) 211 bp upstream from the FSHB mRNA transcription start-site, located within a highly conserved region among placental mammals. We aimed to determine the correlation of carrier status of rs10835638 alternative alleles with serum FSH level in men, and testicular and hormonal parameters. A quantitative genetic association study using a cohort of healthy men (n = 554; age 19.2 +/- 1.7 years) visiting the Centre of Andrology, Tartu University Hospital, Estonia. Rs10835638 (allele frequencies: G 87.6%, T 12.4%) was significantly associated with serum FSH level (analysis of variance: F = 13.0, P = 0.0016, df = 1; regression testing for a linear trend: P = 0.0003). Subjects with the GG genotype exhibited higher FSH levels (3.37 +/- 1.79 IU/l, n = 423) compared with heterozygotes (2.84 +/- 1.54 IU/l, n = 125) (P = 0.0005), the group of T-allele carriers (GT+TT, 2.78 +/- 1.51 IU/l, n = 131) (P = 0.0005) and TT-homozygotes (2.02 +/- 0.81 IU/L, n = 6) (P = 0.031). Rs10835638 was also associated with significant (P < 0.05) reduction in free testosterone index and testes volume, but increased semen volume, sex hormone-binding globulin, serum testosterone and estradiol. LH and inhibin-B levels did not differ significantly between groups. |
Is sLC25A22 a novel gene for migrating partial seizures in infancy? | To identify a genetic cause for migrating partial seizures in infancy (MPSI). We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22. In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport. | The aim of this study was to investigate the association of the expression of tumor necrosis factor-α (TNF-α) with asymptomatic inflammatory prostatitis National Institutes of Health (NIH) category IV and prostatic calculi, in patients with obstructive benign prostatic hyperplasia (BPH) treated by transurethral electroresection of the prostate (TURP). Ninety-six patients with obstructive BPH and TURP were evaluated in a prospective study. Based on a preoperative transrectal ultrasound examination of the prostate gland, patients were divided into two groups, one with prostatic calculi (n = 31) and one without (n = 65). Prostatitis NIH category IV was classified according to Irani's histological grading system (Irani et al. J Urol 1997;157:1301-3). Associations between the incidence of prostatic calculi, histological prostatitis, TNF-α expression, prostate-specific antigen, uric acid, cholesterol, triglycerides, C-reactive protein, International Prostate Symptom Score (IPSS), the International Index for Erectile Function (IIEF-5) and the NIH-Chronic Prostatitis Symptom Index Score (NIH-CPSI) were analyzed. Prostatitis was confirmed by histological investigation in 71.9% of patients: 83.9% of those with prostatic calculi versus 66.1% of those without (p < 0.04). TNF-α expression was significantly higher in patients with prostatic calculi. Association calculations yielded significant values for the severity (histological grading) of inflammation (p < 0.029), TNF-α expression (p < 0.007), uric acid (p < 0.005), cholesterol (p < 0.028) and the NIH-CPS subdomain of urinary symptoms (p < 0.044) in patients with prostatic calculi. |
Is recruitment of HP1β to UVA-induced DNA lesions independent of radiation-induced changes in A-type lamins? | The optimal repair of DNA lesions is fundamental for physiological processes. We asked whether the recruitment of HP1β, 53BP1 and BMI1 proteins to ultraviolet (UVA)-induced DNA lesions requires functional A-type lamins. We found that UVA irradiation of nuclear lamina abolished the fluorescence of mCherry-tagged A-type lamins and destroyed the nuclear lamina as also observed by electron microscopy studies. Similarly, an absence of endogenous A- and B-type lamins was found in irradiated regions by UVA. However, irradiation did not affect the recruitment of HP1β, 53BP1 and BMI1 to DNA lesions. The UVA-induced shrinkage of the nuclear lamina, which anchors chromatin, explains why UVA-micro-irradiated chromatin is relaxed. Conversely, additional experiments with γ-irradiation showed that the nuclear lamina remained intact and the genome-wide level of HP1β was stable. Fluorescence intensity of HP1β and BMI1 in UVA-induced DNA lesions and level of HP1β after γ-irradiation were unaffected by deficiency in A-type lamins, whereas those parameters of 53BP1 were changed. | The prognostic role of low sputum eosinophils in steroid-naïve, symptomatic asthmatic patients is controversial. To verify whether low sputum eosinophils predict poor response to treatment with inhaled corticosteroids. Sixty-seven symptomatic asthmatic patients with moderate asthma were examined before and after 2 weeks and 4 weeks of treatment with beclomethasone dipropionate, 500 microg bid. None received corticosteroids in the 3 months preceding the study. At each visit, all patients underwent spirometry, methacholine challenge, and sputum induction. The patients recorded symptom scores and peak expiratory flow (PEF) throughout the study. Seventeen patients had low sputum eosinophils despite being symptomatic. Patients with high (> 3%) sputum eosinophils at baseline showed significant improvement in symptoms, pulmonary function, and bronchial hyperresponsiveness after treatment, whereas patients with low sputum eosinophils showed no significant improvement in most clinical and functional outcomes. Among the baseline indexes examined, sputum eosinophils had the highest negative predictive value but low positive predictive value for the response to treatment. Multiple stepwise regression showed that only baseline FEV(1) and sputum eosinophil percentages significantly correlated with changes in FEV(1) after treatment. |
Is aRT an alternative for restoring occlusoproximal cavities in primary teeth - evidence from an updated systematic review and meta-analysis? | A previous systematic review showed that atraumatic restorative treatment (ART) can be an option to restore the occlusoproximal cavities in primary teeth; however, few studies fulfilled the criteria of inclusion to generate a high level of evidence. To update the existing systematic review and address questions regarding survival rate of ART restorations compared to the conventional approach in occlusoproximal cavities in primary molars. The search was extended beyond the original search through the PubMed/MEDLINE database up to February 2016. Furthermore, Web of Science and EMBASE were searched. The inclusion criteria were subjects related to the scope of the systematic review. After selection by title and abstract, potentially eligible articles were read in full and included in accordance with exclusion criteria. Meta-analysis was carried out with the outcome being the survival rate of restorations. The search strategy identified 560 potentially relevant studies, in addition to 127 from the original systematic review. A total of four articles were included in the qualitative and quantitative analyses. Meta-analysis showed no statistically significant difference between ART and conventional approaches in survival rate of occlusoproximal cavities (OR = 0.887, 95% CI: 0.574-1.371). | Paraneoplastic syndromes are serious immune caused diseases of the peripheral and/or central nervous system associated with malignant neoplasm. Symptoms develop when antibodies against antigens expressed by tumor cells cross-react with neuronal proteins. Antineuronal antibodies are usually examined in patient's sera while examination of the cerebrospinal fluid (CSF) often fails. Furthermore, the few previous reports describing CSF data summarized different antineuronal antibodies and/or regarded patients with different neurological symptoms as one group. We retrospectively evaluated data of 18 patients with paraneoplastic syndromes due to anti-Hu antibodies. The study aimed to differentiate patients with peripheral neuropathy and encephalitis by cerebrospinal fluid (CSF) parameters including anti-Hu antibody titers. Our results confirm previous observations that serum titers of anti-Hu antibodies and standard CSF values do not differ between patients with neuropathy and encephalitis. However, analysis of CSF anti-Hu titers and calculating the intrathecal synthesis helped to discriminate between both groups. |
Is low prevalence of depression and anxiety linked to statutory retirement ages rather than personal work exit : a national survey? | Common mental disorder prevalence decreases substantially around the conventional retirement age for men in the UK, but trends for older women are more continuous. Prevalence changes in depression and anxiety around retirement are less clear, as is the role of risk factors. The aim of this study was to establish whether work status, age or other known risk factors account for the reduced prevalence of depressive episode and anxiety disorder around retirement ages for men and for women. The British Psychiatric Morbidity Survey (BPMS) 2000 was analysed, including 1875 men and 2253 women aged 45-75 years. Diagnoses were from the Revised Clinical Interview Schedule (CIS-R). Logistic models were adjusted for sociodemographic factors, social network, work status, life events, physical illness and disability. There are marked reductions in the prevalence of depressive episode after 60 years for women [60% lower prevalence, 95% confidence interval (CI) 40-80] and 65 years for men (90% lower prevalence, 95% CI 70-100), compared to the youngest age groups. For anxiety disorder, the reduction in prevalence was 80% (95% CI 60-90) for men and 40% (95% CI 20-60) for women. In fully adjusted multivariate models, the strong association between diagnoses and age groups remained, for both genders. Work status was a significant factor for men but not for women. | Tissue-plasminogen activator (tPA) demonstrated beneficial effects on peritoneal adhesion formation; however, its short half-life limits its continual fibrinolytic effect. Therefore, we delivered adenovirus encoding tPA to prevent adhesions. Rats were subjected to peritoneal injury and assigned to two protocols. In de novo adhesion protocol, adenovirus encoding human tPA gene (Ad-htPA) was instilled after peritoneal injury in group 1 (n = 22), whereas group 2 received phosphate-buffered saline (PBS) (n = 24). In recurrent adhesion protocol, group 1 (n = 15) received the same Ad-htPA dose after adhesiolysis and group 2 (n = 13) received PBS. Adhesion severity was scored 1 week after ad-htPA instillation. Adhesions were analyzed for htPA mRNA by reverse transcription-polymerase chain reaction and levels of htPA, and fibrinolytic inhibitors PAI-1, TIMP-1, and TGF-beta1 were measured using enzyme-linked immunosorbent assay. htPA mRNA and protein were only expressed in adhesions from treated groups. A reduction in adhesion scores (P < .01) and in fibrinolytic inhibitors (P < .001) occurred in the treatment groups. Also, negative correlation was found (r = -.69, P < .01) between adhesion scores and htPA protein, but a positive correlation was found (r = .90, P < .01) between adhesion score and fibrinolytic inhibitors. No bleeding or wound complications were encountered. |
Does american Brachytherapy Society recommend no change for prostate permanent implant dose prescriptions using iodine-125 or palladium-103? | In 2004, the American Association of Physicists in Medicine (AAPM) issued a report outlining recommended 125I and 103Pd datasets for consistency in calculating brachytherapy dose distributions. In 2005, to aid evaluating the clinical impact of implementing these datasets, the AAPM assessed the historical dependence of how prescribed doses differed from administered doses for 125I and 103Pd for permanent implantation of the prostate. Consequently, the American Brachytherapy Society (ABS) considered the nature of these changes towards issuing recommended dose prescriptions for 125I and 103Pd interstitial brachytherapy implants for monotherapy and standard boosts. An investigation was performed of the 2005 AAPM analysis to determine changes in administered dose while affixing prescribed dose using 2004 AAPM 125I and 103Pd brachytherapy dosimetry datasets for prostate implants. For 125I and 103Pd, administered dose would change by +1.4% and +4.2%, respectively. The biological and societal impact of changing prescribed dose was considered. Based on the need for clinical constancy and in recognition of overall uncertainties, the ABS recommends immediate implementation of the 2004 AAPM consensus brachytherapy dosimetry datasets and no changes to 125I and 103Pd dose prescriptions at this time. | The antiphospholipid antibody syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). We recently demonstrated that Toll-like receptor 2 (TLR2) and CD14 contribute to monocyte activation of aPLA. To study the mechanisms of cell activation by aPLA, leading to pro-coagulant and pro-inflammatory responses. For this study, we used purified antibodies from the plasmas of 10 different patients with APS and healthy donors. We demonstrate that aPLA, but not control IgG, co-localizes with TLR2 and TLR1 or TLR6 on human monocytes. Blocking antibodies to TLR2, TLR1 or TLR6, but not to TLR4, decreased TNF and tissue factor (TF) responses to aPLA. Pharmacological and siRNA approaches revealed the importance of the clathrin/dynamin-dependent endocytic pathway in cell activation by aPLA. In addition, soluble aPLA induced NF-κB activation, while bead-immobilized aPLA beads, which cannot be internalized, were unable to activate NF-κB. Internalization of aPLA in monocytes and NF-κB activation were dependent on the presence of CD14. |
Does probucol inhibit in-stent thrombosis and neointimal hyperplasia by promoting re-endothelialization? | Evidence suggests that delayed re-endothelialization is responsible for in-stent thrombosis. Probucol inhibits neointimal thickening in animals via enhanced re-endothelialization and is the only oral drug that consistently inhibits restenosis after coronary angioplasty in humans. Here, we examined the effects of probucol on re-endothelialization and neointimal formation in a stent model. New Zealand White rabbits were fed a hypercholesterolemic diet with probucol (1%) or without (control) (n=11 each) for 6 weeks. At 2 weeks, endothelial denudation and stenting of the iliac artery was performed. Iliac arteries were harvested at week 6, and stented segments sectioned and analyzed. Compared with control, probucol increased in-stent re-endothelialization (74+/-6% in controls versus 93+/-3% in probucol-treated; P=0.008), and decreased average luminal stenosis (58+/-27 versus 31+/-16%; P=0.01) and stent depth (619+/-310 versus 314+/-158 microm; P=0.009). Compared with control, probucol also decreased accumulation of macrophages in the neointima. Furthermore, none of the probucol-treated rabbits had in-stent thrombosis, whereas four of eleven control rabbits showed thrombosis (P=0.04). | To use clinical and genetic analyses to determine the mutation causing autosomal recessive nonsyndromic hearing loss (ARNSHL) segregating in two consanguineous Iranian families. Family study. Members of each family received otologic and audiometric examination for the type and extent of hearing loss. Linkage mapping using Affymetrix 50K GeneChips and short tandem repeat (STRP) analysis localized the hearing loss in both families to the DFNB3 locus. Direct sequencing of the MYO15A gene was completed on affected members of both families. Family L-3165 segregated a novel homozygous missense mutation (c.6371G>A) that results in a p.R2124Q amino acid substitution in the myosin XVa protein, while family L-896 segregated a novel homozygous missense (c.6555C>T) mutation resulting in a p.P2073S amino acid change. |
Does prefrontal and temporal gray matter density decrease in opiate dependence? | There have been only a few structural brain-imaging studies, with varied findings, of opiate-dependent subjects. Voxel-based morphometry (VBM) is suitable for studying whole brain-wise structural brain changes in opiate-dependent subjects. The objective of the current study is to explore gray matter density in opiate-dependent subjects. Gray matter density in 63 opiate-dependent subjects and 46 age- and sex-matched healthy comparison subjects was compared using VBM. Relative to healthy comparison subjects, opiate-dependent subjects exhibited decreased gray matter density in bilateral prefrontal cortex [Brodmann areas (BA) 8, 9, 10, 11, and 47], bilateral insula (BA 13), bilateral superior temporal cortex (BA 21 and 38), left fusiform cortex (BA 37), and right uncus (BA 28). | Exploitation of antigen-specific regulatory T cells (Tregs) as critical regulators in the control of chronic inflammatory diseases is hampered by the obscure nature of most disease-relevant autoantigens. Heat shock proteins (Hsp) are possible targets for Tregs due to their enhanced expression in inflamed (stressed) tissues and there is evidence that Hsp can induce anti-inflammatory immunoregulatory T-cell responses. Recent publications showing that exogenous administration of stress proteins has induced immunoregulation in various models of inflammatory disease have also been shown to be effective in first clinical trials in humans. Now, in the light of a growing interest in T-cell regulation, it is of interest to further explore the mechanisms through which Hsp can be utilized to trigger immunoregulatory pathways, capable of suppressing such a wide and diversified spectrum of inflammatory diseases. |
Are clinical Experiences Predictive of Outcomes on the NATABOC Examination? | To determine the efficacy of the National Athletic Trainers' Association Board of Certification (NATABOC) clinical experience requirements and individual student characteristics to predict candidate outcomes on the NATABOC certification examination. For all subjects, we gathered survey information and examination scores. The survey information included age, sex, route to certification, previous athletic training and allied health experience, and clinical education experiences. A total of 269 subjects, 22.25% of all first-time candidates for the June and November 1993 NATABOC examinations, were included in this study. Data were analyzed for standard descriptive statistics and parametric linear regression and correlational relationships. Total clinical hours, high-risk sport experiences, and previous athletic training experience were not predictive of examination outcomes. Although our results indicated a relationship between previous allied health experience and both outcome on the written section of the examination and age and outcome on the oral/practical section, these characteristics also were not predictive of examination outcomes. | To assess BGC823 gastric cancer (GC) cell metastasis after knockdown of liver-intestine cadherin (CDH17) and the therapeutic value of CDH17-RNAi-lentivirus in vivo. We evaluated primary tumor growth and assessed local infiltration and systemic tumor dissemination using an orthotopic implantation technique. The therapeutic value of CDH17 knockdown was examined by intratumoral administration of CDH17-RNA interference (RNAi)-lentivirus in an established GC tumor xenograft mouse model. Furthermore, a comparative proteomic approach was utilized to identify differentially expressed proteins in BGC823 and lenti-CDH17-miR-neg cells following CDH17 knockdown. Metastases in the liver and lung appeared earlier and more frequently in animals with tumors derived from BGC823 or lenti-CDH17-miR-neg cells than in tumors derived from lenti-CDH17-miR-B cells. Average tumor weight and volume in the CDH17-RNAi-lentivirus-treated group were significantly lower than those in the control group (tumor volume: 0.89 ± 0.04 cm³ vs 1.16 ± 0.06 cm³, P < 0.05; tumor weight: 1.15 ± 0.58 g vs 2.09 ± 0.08 g, P < 0.05). Fifteen differentially expressed proteins were identified after CDH17 silencing in BGC823 cells, including a variety of cytoskeletal and chaperone proteins as well as proteins involved in metabolism, immunity/defense, cell proliferation and differentiation, cell cycle, and signal transduction. |
Does contralateral prophylactic mastectomy provide no survival benefit in young women with estrogen receptor-negative breast cancer? | Several studies have shown that contralateral prophylactic mastectomy (CPM) provides a disease-free and overall survival (OS) benefit in young women with estrogen receptor (ER)-negative breast cancer. We utilized the National Cancer Data Base to evaluate CPM's survival benefit for young women with early -stage breast cancer in the years that ER status was available. We selected 14,627 women ≤45 years of age with American Joint Committee on Cancer stage I-II breast cancer who underwent unilateral mastectomy or CPM from 2004 to 2006. Five-year OS was compared between those who had unilateral mastectomy and CPM using the Kaplan-Meier method and Cox regression analysis. A total of 10,289 (70.3 %) women underwent unilateral mastectomy and 4,338 (29.7 %) women underwent CPM. Median follow up was 6.1 years. After adjusting for patient age, race, insurance status, co-morbidities, year of diagnosis, ER status, tumor size, nodal status, grade, histology, facility type, facility location, use of adjuvant radiation and chemohormonal therapy, there was no difference in OS in women <45 years of age who underwent CPM compared towith those who underwent unilateral mastectomy (hazard ratio [HR] = 0.93; p = 0.39). In addition, Tthere was no improvement in OS in women <45 years of age with T1N0 tumors who underwent CPM versus unilateral mastectomy (HR = 0.85; p = 0.37) after adjusting for the aforementioned factors. Among women ≤45 years of age with ER-negative tumors who underwent CPM, there was no improvement in OS compared with women who underwent unilateral mastectomy (HR = 1.12; p = 0.32) after adjusting for the same aforementioned factors. | The link between Parkinson's disease (PD) and Gaucher disease (GD), the most common lysosomal storage disease associated with loss of glucocerebrosidase (GBA) activity, can be explained by abnormal accumulation of oligomeric alpha-synuclein (α-Syn) species resulting from mutations in the GBA gene. However, in GD, the relationship between GBA activity and α-Syn accumulation in biological fluids has not been investigated. We analyzed plasma oligomeric α-Syn levels, leucocyte GBA activity, and plasma chitotriosidase activity in 21 patients with GD. Negative correlation between plasma oligomeric α-Syn levels, and leucocyte GBA activity was observed in patients with GD (R(2) = 0.487; P < 0.001). |
Do hip- and knee-strength assessments using a hand-held dynamometer with external belt-fixation are inter-tester reliable? | In football, ice-hockey, and track and field, injuries have been predicted, and hip- and knee-strength deficits quantified using hand-held dynamometry (HHD). However, systematic bias exists when testers of different sex and strength perform the measurements. Belt-fixation of the dynamometer may resolve this. The aim of the present study was therefore to examine the inter-tester reliability concerning strength assessments of isometric hip abduction, adduction, flexion, extension and knee-flexion strength, using HHD with external belt-fixation. Twenty-one healthy athletes (6 women), 30 (8.6) (mean (SD)) years of age, were included. Two physiotherapy students (1 female and 1 male) performed all the measurements after careful instruction and procedure training. Isometric hip abduction, adduction, flexion, extension, and knee-flexion strength were tested. The tester-order and hip-action order were randomised. No systematic between-tester differences (bias) were observed for any of the hip or knee actions. The intra-class correlation coefficients (ICC 2.1) ranged from 0.76 to 0.95. Furthermore, standard errors of measurement in per cent (SEM %) ranged from 5 to 11 %, and minimal detectable change in per cent (MDC %) from 14 to 29 % for the different hip and knee actions. | Krüpple-like factor 5 (KLF5) is a transcription factor that is highly expressed in the proliferative compartment of the intestinal crypt. There, it is thought to regulate epithelial turnover and homeostasis. In this study, we sought to determine the role for Klf5 in the maintenance of cellular proliferation, cytodifferentiation, and morphology of the crypt-villus axis. Tamoxifen-induced recombination directed by the epithelial-specific Villin promoter (in Villin-CreERT2 transgenic mice) was used to delete Klf5 (in Klf5 (loxP/loxP) mice) from the adult mouse intestine and analyzed by immunostaining and RT-qPCR. Control mice were tamoxifen-treated Klf5 (loxP/loxP) mice lacking Villin-CreERT2. Three days after tamoxifen-induced recombination, the mitosis marker phospho-histone H3 was significantly reduced within the Klf5-mutant crypt epithelium, coincident with increased expression of the apoptosis marker cleaved-caspase 3 within the crypt where cell death rarely occurs normally. We also observed a reduction in Chromagranin A expressing enteroendocrine cells, though no significant change was seen in other secretory or absorptive cell types. To examine the long-term repercussions of Klf5 loss, we killed mice 5, 14, and 28 days post recombination and found reemerging expression of KLF5. Furthermore, we observed restoration of cellular proliferation, though not to levels seen wildtype intestinal crypts. Reduction of apoptosis to levels comparable to the wildtype intestinal crypt was also observed at later time points. Analysis of cell cycle machinery indicated no significant perturbation upon deletion of Klf5; however, a reduction of stem cell markers Ascl2, Lgr5, and Olfm4 was observed at all time points following Klf5 deletion. |
Do novel MSH6 mutations in treatment-naïve glioblastoma and anaplastic oligodendroglioma contribute to temozolomide resistance independently of MGMT promoter methylation? | The current standard of care for glioblastoma (GBM) involves a combination of surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance to temozolomide is largely mediated by expression of the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation of MSH6 and other mismatch repair proteins plays an important role in temozolomide resistance. Here, we investigate endogenous MSH6 mutations in GBM, anaplastic oligodendroglial tumor tissue, and corresponding brain tumor-initiating cell lines (BTIC). MSH6 sequence and MGMT promoter methylation were determined in human tumor samples and BTICs. Sensitivity to temozolomide was evaluated in vitro using BTICs in the absence and presence of O(6)-benzylguanine to deplete MGMT. The influence of MGMT and MSH6 status on in vivo sensitivity to temozolomide was evaluated using intracranial BTIC xenografts. We identified 11 previously unreported mutations in MSH6 in nine different glioma samples and six paired BTIC lines from adult patients. In addition, MSH6 mutations were documented in three oligodendrogliomas and two treatment-naïve gliomas, both previously unreported findings. These mutations were found to influence the sensitivity of BTICs to temozolomide both in vitro and in vivo, independent of MGMT promoter methylation status. | Transmission-based precautions (TBPs) are infection control measures designed to interrupt pathogen transmission. Success relies on early recognition of patients with potentially infectious syndromes, then the implementation of appropriate TBPs. We are aware of no literature evaluating interventions to facilitate healthcare workers (HCWs) in implementing TBPs. To evaluate the impact of a TBP guidance summary card on HCWs' decision-making about the appropriate implementation of TBPs. A prospective audit was carried out to assess HCWs' ability to make decisions about TBP implementation. Following the first audit phase, staff were issued with a guidance card summarizing local TBP guidelines, identifying and addressing relevant TBP measures for infectious syndromes and specific organisms. The audit cycle was then completed to assess the impact of this intervention. Baseline knowledge of appropriate TBP measures was low. Provision of a TBP summary card was significantly associated with the ability of staff carrying the card to correctly decide what TBPs are required in a variety of clinical situations, including Clostridium difficile infection [N = 107; odds ratio (OR): 27.0; 95% confidence interval (CI): 8.37-86.8; P < 0.0001], norovirus diarrhoea and vomiting (N = 107; OR: 94.3, 95% CI: 25.0-356; P < 0.0001), influenza-like illness (N = 107; OR: 85.2; 95% CI: 4.94-1470; P < 0.0001) and the difference between surgical and FFP3 masks (N = 107; OR: 412; 95% CI: 23.4-7246; P < 0.0001). |
Does coadministration of esomeprazole with fosamprenavir have no impact on steady-state plasma amprenavir pharmacokinetics? | To evaluate the drug interaction between fosamprenavir (FPV) and esomeprazole (ESO) after repeated doses in healthy adults. Subjects received ESO 20 mg once daily (qd) for 7 days followed by either ESO 20 mg qd + FPV 1400 mg twice daily (bid) or ESO 20 mg qd + FPV 700 mg bid + ritonavir (RTV) 100 mg bid for 14 days in arms 1 and 2, respectively. After a 21- to 28-day washout, subjects received either FPV 1400 mg bid for 14 days (arm 1) or FPV 700 mg bid + RTV 100 mg bid for 14 days (arm 2). Pharmacokinetic sampling was conducted on the last day of each treatment. Simultaneous coadministration of ESO 20 mg qd with either FPV 1400 mg bid or FPV 700 mg bid + RTV 100 mg bid had no effect on steady-state amprenavir pharmacokinetics. The only effect on plasma ESO exposure was a 55% increase in area under the plasma concentration-time curve during a dosing interval, tau[AUC0-tau], after coadministration of ESO 20 mg qd with FPV 1400 mg bid. | Mesenchymal stem cells (MSCs) under favorable conditions secrete a spectrum of cytokines that promote the survival of surrounding cells via paracrine mechanisms. We explored the impact of rat pancreatic extract (RPE) on cytokine secretion by MSCs and examined the influence of administration of conditioned media of MSCs treated with RPE on blood glucose levels in diabetic rats. Cytokine levels (IGF-1, VEGF, bFGF) in conditioned media of MSCs treated with RPE were measured using enzyme-linked immunosorbent assays. We estimated blood glucose levels of STZ-induced diabetic rats following intraperitoneal injection of conditioned media from RPE-treated MSCs. We analyzed histopathology of pancreatic islets by insulin immunostaining and apoptosis through a TUNEL assay. Levels of IGF-1, VEGF, and bFGF were significantly increased in RPE-CM compared with control media. Administration of conditioned media of RPE-treated MSCs significantly lowered the blood glucose levels of diabetic rats. After RPE treatment the insulin-positive area was increased and apoptosis of pancreatic beta cells decreased. |
Do sugar-Sweetened Beverages Are the Main Sources of Added Sugar Intake in the Mexican Population? | Sugar intake has been associated with an increased prevalence of obesity, other noncommunicable diseases, and dental caries. The WHO recommends that free sugars should be <10% of total energy intake (TEI) and that additional health benefits could be obtained with a reduction below 5% of TEI. The objective of this study was to estimate the total, intrinsic, and added sugar intake in the Mexican diet and to identify the food groups that are the main sources of these sugars. We used data from a national probabilistic survey [ENSANUT (National Health and Nutrition Survey) 2012], which represents 3 geographic regions and urban and rural areas. Dietary information was obtained by administering a 24-h recall questionnaire to 10,096 participants. Total sugar intake was estimated by using the National Institute of Public Health (INSP) food-composition table and an established method to estimate added sugars. The mean intakes of total, intrinsic, and added sugars were 365, 127, and 238 kcal/d, respectively. Added sugars contributed 13% of TEI. Sugar-sweetened beverages (SSBs) were the main source of sugars, contributing 69% of added sugars. Food products high in saturated fat and/or added sugar (HSFAS) were the second main sources of added sugars, contributing 25% of added sugars. | Space-consuming mediastinal tumors can create respiratory failure. We are reporting on a case of mediastinal lymphoma, which created respiratory failure in our patient. IV steroid therapy was used in our patient, who presented with end-stage respiratory failure. Conservative management of our patient was possible without the application of ECMO. |
Does 24-h smoking abstinence potentiate fMRI-BOLD activation to smoking cues in cerebral cortex and dorsal striatum? | Exposure to smoking-related cues can trigger relapse in smokers attempting to maintain abstinence. In the present study, we evaluated the effect of 24-h smoking abstinence on brain responses to smoking-related cues using functional magnetic resonance imaging (fMRI). Eighteen adult smokers underwent fMRI scanning following smoking as usual (satiated condition) and following 24-h abstinence (abstinent condition). During scanning, they viewed blocks of photographic smoking and control cues. Following abstinence, greater activation was found in response to smoking cues compared to control cues in parietal (BA 7/31), frontal (BA 8/9), occipital (BA 19), and central (BA 4) cortical regions and in dorsal striatum (putamen) and thalamus. In contrast, no smoking cue greater than control cue activations were observed following smoking as usual. Direct comparisons between conditions (satiated vs. abstinent) showed greater brain reactivity in response to smoking cues following abstinence. In addition, positive correlations between pre-scan craving in the abstinent condition and smoking cue activation were observed in right dorsomedial prefrontal cortex (dmPFC) including superior frontal gyrus (BA 6/10), anterior cingulate gyrus (BA 32), and supplementary motor area (BA 6). | Minimal-change nephrotic syndrome is an idiopathic disease in which protein leaks through podocytes into the urine. We used proteomic tools to examine differences of plasma protein expression in healthy rats and rats with doxorubicin-induced nephropathy treated with or without prednisone. Healthy three-month-old Sprague-Dawley male rats were randomly chosen for one injection of doxorubicin (5.5 mg/kg) through the caudal vein to induce nephropathy (n = 50) or the same volume of saline (control, n = 20). After 1 week, 25 rats in the nephropathy group received topical prednisone (5.5 mg/kg/day) for 21 days and another 25 rats (untreated nephropathy) and the control rats received topical water. At 4 weeks, protein chips generated from rat plasma samples were analyzed by surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS) to obtain mass-to-charge ratios (m/z) of proteins of 2-50 kDa. Relative to control rats, untreated nephropathic rats had four significantly higher and seven significantly lower m/z peaks. Prednisone treatment significantly normalized the intensities of peaks 9069 and 15005 (which correspond to cortexin-1 and interleukin-17A, respectively, according to Swiss Prot database) by increasing the expression of 9069 but reducing expression of 15005. |
Does inferior vena cava ligation rapidly induce tissue factor expression and venous thrombosis in rats? | Although stasis is important in the pathogenesis of deep vein thrombosis (DVT), how it contributes to thrombogenesis is largely unknown. To gain mechanistic insight, we used a rat model of inferior vena cava (IVC) ligation. Rats were subjected to IVC ligation for 15 to 60 minutes. Ligation resulted in rapid IVC dilatation and by 60 minutes, thrombi were detected in all rats. Small thrombi were detected in the IVC of most rats after 15 minutes of ligation. Thrombi were rich in fibrin, contained aggregated platelets as well as trapped leukocytes and red cells, and most originated at sites of localized endothelial denudation. Immunohistochemical analysis revealed tissue factor (TF)-expressing leukocytes within the thrombi and adherent to the vessel wall. Despite a largely intact vessel wall, endothelial cells also stained for TF. The expression of TF colocalized with that of protein disulfide isomerase (PDI), an enzyme implicated in TF decryption. | We sought to identify whether stable single nucleotide polymorphisms (SNPs) of various endocrine and immune molecules could be used as biomarkers associated with specific immune alterations and chronic stress measures in normal humans. A total of 207 volunteer participants answered stress questionnaire and gave peripheral blood cells for identification of SNPs in genes coding for glucocorticoid receptor (GR), beta 2 adrenergic receptor (B2AR), interferon-gamma receptors (IFNGR1, IFNGR2), and interleukin-4 receptor (IL4R). Immunoregulatory profiles were measured by flow cytometry and genotyping assays were performed by allelic discrimination real-time PCR. Several significant differences were revealed in associations between stress marker and immune indicators based on SNP categories. For instance, Th1 levels of the minor alleles of GR TthIIII (AA) and IFNGR2 Q64R (Arg/Arg) groups were positively associated with chronic stress (PSS) (p = 0.024 and 0.005, respectively) compared with wild type (WT) and negatively associated with PSS in the heterozygous genotypes of GR BclI and IL4R Ile50Val (p = 0.040 and p = 0.052, respectively). Treg levels of the minor alleles of BclI (GG) and IFNGR1 T-56C (CC) groups were positively associated with PSS (p = 0.045 and p = 0.010, respectively) and negatively associated in the minor allele (Val/Val) of IL4R Ile50Va and the heterozygous genotype of IL4R Q576R (p = 0.041 and p = 0.017, respectively) compared to WT. |
Do mortality rates differ among patients prescribed various vitamin D agents? | Limited well-controlled research exists examining the impact of different formulations of oral vitamin D on clinical outcomes in dialysis patients, specifically those on peritoneal dialysis. For this retrospective mortality analysis, we compared mortality rates of patients on 3 of the most commonly prescribed vitamin D agents. We examined 2 years (7/1/2008 to 6/30/2010) of oral medication records of peritoneal dialysis patients from a large US dialysis organization. Patients were identified whose physicians prescribed a single form of vitamin D (calcitriol, paricalcitol, or doxercalciferol) for ≥ 90% of all patient-months. We excluded incident patients (< 90 days on dialysis) and patients whose physicians treated < 5 peritoneal dialysis patients at a dialysis facility, and we assessed mortality. The analysis inclusion criteria identified 1,707 patients. The subset in this analysis included 12.6% of all prevalent peritoneal dialysis patients and 11.8% of prevalent patient-months. Patients with physicians who predominately prescribed calcitriol had a lower mortality rate: 9.33 (confidence interval (CI) 7.06, 11.60) deaths per 100 patient-years than the doxercalciferol, 12.20 (CI 9.34, 15.06) or paricalcitol, 12.27 (CI 9.27, 15.28) groups. However, these differences were not statistically significant. A Cox proportional hazards model, adjusting for differences in age, vintage, gender, race, body mass index, and comorbidities also showed no significant differences. | To evaluate the effect of uterine leiomyomas on the endometrium using molecular markers of endometrial receptivity: HOXA10, HOXA11, LIF, and BTEB1. Case-control study. University medical center. Thirty reproductive-aged women with submucosal, intramural, or no uterine myomas who underwent hysteroscopy or hysterectomy. Proliferative phase endometrial sampling was performed at the time of surgery. In uteri with a submucosal myoma, directed endometrial biopsies were obtained over the myoma and over normal myometrium. Endometrial HOXA10 expression was evaluated as a primary endpoint using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. HOXA11, BTEB1, and LIF were evaluated using real-time RT-PCR. Endometrial HOXA10 and HOXA11 messenger RNA (mRNA) expression were significantly decreased in uteri with submucosal myomas compared with controls and with uteri with intramural myomas. A similar trend was seen in BTEB1 mRNA expression; however, no difference was found in LIF mRNA expression. Immunohistochemistry localized the decrease in endometrial HOXA10 protein expression to stroma. In the presence of a submucosal myoma, there were no regional differences in gene expression. |
Are polymorphisms of estrogen metabolism-related genes ESR1 , UGT2B17 , and UGT1A1 associated with osteoporosis in surgically menopausal Japanese women? | Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life. This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated. No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations. | Inhalation of antigen in atopic asthma induces early (EAR) and late asthmatic responses (LARs), inflammatory cell infiltration and airways hyperresponsiveness (AHR). Previously, we have established a protocol of sensitisation and subsequent ovalbumin (Ova) inhalation challenge in guinea-pigs which induced these 4 features (Smith & Broadley, 2007). However, the responses of guinea-pigs to Ova challenge have recently declined, producing no LAR or AHR and diminished EAR and cells. By making cumulative modifications to the protocol, we sought to restore these features. Guinea-pigs were sensitised with Ova (i.p. 100 or 150 μg) on days 1 and 5 or days 1, 4 and 7 and challenged with nebulised Ova (100 or 300 μg/ml, 1h) on day 15. Airway function was measured in conscious guinea-pigs by whole-body plethysmography to record specific airway conductance (sGaw). Airway responsiveness to aerosolized histamine (0.3mM) was determined before and 24h after Ova challenge. Bronchoalveolar lavage was performed for total and differential inflammatory cell counts. Lung sections were stained for counting of eosinophils. Lack of AHR and LAR with the original protocol was confirmed. Increasing the Ova challenge concentration from 100 to 300 μg/ml restored AHR and eosinophils and increased the peak of the EAR. Increasing the number of sensitisation injections from 2 to 3 did not alter the responses. Increasing the Ova sensitisation concentration from 100 to 150 μg significantly increased total cells, particularly eosinophils. A LAR was revealed and lymphocytes and eosinophils increased when either the Al(OH)3 concentration was increased or the duration between the final sensitisation injection and Ova challenge was extended from 15 to 21 days. |
Are urine but not plasma nitric oxide metabolites decreased in women with preeclampsia? | Nitric oxide is a potent vasorelaxant produced by endothelial cells. We tested the hypothesis that urinary and perhaps plasma nitric oxide metabolites would be reduced in women with preeclampsia. Plasma and urine from 14 women meeting strict clinical criteria for the diagnosis of preeclampsia and 20 normal nulliparous women were assayed for the stable metabolites of nitric oxide, nitrate and nitrite. There was no significant difference of plasma concentrations of nitrate and nitrite between women with preeclampsia and women with normal pregnancies (32.7 +/- 3.1 vs 25.8 +/- 2.4 micromol/L). Plasma creatinine levels were elevated in women with preeclampsia (0.85 +/- 0.09 vs 0.66 +/- 0.02 mg/dl, p<0.01), indicating a reduced glomerular filtration rate. Urine concentrations of nitrate and nitrite normalized by creatinine excretion were significantly lower in women with preeclampsia compared with normal pregnant women (0.37 +/- 0.06 vs 0.69 +/- 0.11 micromol of nitrite per milligram creatinine, p. <0.05). | Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, after basal cell carcinoma, and its incidence is dramatically rising. CSCC is rarely problematic, but given its high frequency, the absolute number of complicated cases is also high. It is necessary to identify molecular markers to recognize those CSCC with poor prognosis. There is controversy concerning the role of EGFR (epidermal growth factor receptor) as a marker of prognosis in CSCC. In addition, EGFR-targeted therapies have emerged in recent years and a better understanding of the role of EGFR in CSCC may help some patients in predicting prognosis and guide curative management. We evaluated clinical and histopathological features, including events of bad clinical evolution, in a series of 94 CSCC. We also analysed EGFR expression by immunohistochemistry, FISH and QPCR. We detected EGFR in 85 (90.4%) cases, with overexpression in 33 (35.1%) cases, and aberrant EGFR expression in the cytoplasm in 50 (53.1%) cases. EGFR overexpression in the primary tumours was associated with lymph node progression, TNM stage progression and proliferation (Ki-67 staining) in CSCC. EGFR overexpression and poor grade of differentiation were the strongest independent variables defining lymph node metastasis and progression in CSCC in a logistic regression model. |
Does hospital attendance prediction tool also identify impaired quality of life in adults with asthma in general practice? | To assess the ability of an adult risk screening questionnaire (RSQ), previously shown to predict attendance at hospital emergency departments, to identify impaired quality of life in adult patients with asthma in general practice. Baseline data from an RCT of asthma clinics in general practice, using the St. George Respiratory Questionnaire (SGRQ) to measure quality of life. Twelve general practices in Adelaide, Australia. A total of 184 adult asthmatics were recruited, with a mean (standard deviation) age of 50.3 years (16.6 years). Age, gender, weight, number of comorbidities, smoking status, FEV1 and percent predicted FEV1 (pre-and post-bronchodilator), peak flow (pre and post), and RSQ were independently related to SGRQ scores. After adjusting for potential confounders, an RSQ score predictive of hospital attendance was also associated with an average increase (worsening) in SGRQ total score of 11.9 (95% CI: 7.6, 16.3), an average increase in activity score of 9.0 (2.5, 15.5), symptom score of 14.8 (8.6, 21.0), and impact score of 13.1 (8.6, 17.6). These represent clinically significant differences. | Nogo-A is a myelin-associated neurite outgrowth inhibitory protein that limits elongation of central nerve fibers, neuronal regeneration and plasticity. We investigated the effect of delivering an inhibitory peptide that neutralizes Nogo-A on neuronal recovery following mild cortical contusion injury. 41 rats were allocated into the control and NEP1-40 treatment groups. PBS was applied following trauma over the parietal cortex after opening the dura in the control group. NEP1-40 solution was immediately applied following trauma after opening the dura in the treatment group. Each group was further divided into 3 subgroups and sacrificed on the third, eighth, and 21st days after injury. The brains were removed for analysis. Immunohistochemical staining of the injured cortex for pan-cadherin revealed a significant increase in staining in the NEP 1-40 treatment group at the 8th and 21st days after injury. Electron microscopic evaluation revealed better cytoarchitectural preservation in the axons of the animals treated with NEP 1-40. |
Is up-regulation of TDAG51 a dependent factor of LPS-induced RAW264.7 macrophages proliferation and cell cycle progression? | As a component of the outer membrane in Gram-negative bacteria, lipopolysaccharide (LPS)-induced proliferation and cell cycle progression of monocytes/macrophages. It has been suggested that the proapoptotic T-cell death-associated gene 51 (TDAG51) might be associated with cell proliferation and cell cycle progression; however, its role in the interaction between LPS and macrophages remains unclear. We attempted to elucidate the role(s) of TDAG51 played in the interaction between LPS and macrophages. We investigated TDAG51 expression in RAW264.7 cells stimulated with LPS and examined the effects of RNA interference-mediated TDAG51 down-regulation. We used CCK-8 assay and flow cytometry analysis to evaluate the interaction between TDAG51 and LPS-induced proliferation and cell cycle progression in RAW264.7 cells. Our findings indicate that TDAG51 is up-regulated in LPS-stimulated RAW264.7 cells, the TDAG51 siRNA effectively reduced TDAG51 protein up-regulation following LPS stimulation in RAW264.7 cells, the significant changes of the proliferation and cell cycle progression of RAW264.7 cells in TDAG51 Knockdown RAW264.7 cells treated with LPS were observed. | To study the impact of the new pharmacological treatment strategies in Parkinson's disease by analysis of the sales of dopaminergic drugs in Sweden 1990-2001. Invoice statistics and statistics on prescription sales of dopaminergic drugs 1990-2001 were obtained from the 906 public pharmacies and the 89 hospital pharmacies in Sweden. The Swedish Diagnosis and therapy survey was used to study the diagnosis the drugs were prescribed for. During the period the sales expressed in DDD/1000 inhabitants and day increased from 1.75 to 1.86 (6%) for levodopa and from 0.04 to 0.27 (575%) for dopamine agonists. The increase in sales of dopamine agonists occurred after 1997 and consisted entirely of the sales of the new agonists, cabergoline, pramipexole and ropinirole. In Swedish crowns the total sales of dopaminergic drugs increased with 126% during the period. The cost for the dopamine agonists was 8% of the total cost for dopaminergic drugs in 1990 and 23% in 2001. The prescription sales figures of levodopa and dopamine agonists for the different Swedish counties in 2001 varied between 1.52 and 2.44 and 0.13 and 0.74 DDD/1000 inhabitants and day, respectively. There was no correlation, whether positive or negative, between the sales of dopamine agonists, levodopa and COMT inhibitors or between the sales and the densities of neurologists. |
Is full-length cytokeratin-19 released by human tumor cells : a potential role in metastatic progression of breast cancer? | We evaluated whether CK19, one of the main cytoskeleton proteins of epithelial cells, is released as full-length protein from viable tumor cells and whether this property is relevant for metastatic progression in breast cancer patients. EPISPOT (EPithelial ImmunoSPOT) assays were performed to analyze the release of full-length CK19 by carcinoma cells of various origins, and the sequence of CK19 was analyzed with mass spectrometry. Additional functional experiments with cycloheximide, Brefeldin A, or vincristine were done to analyze the biology of the CK19-release. CK19-EPISPOT was used to detect disseminated tumor cells in bone marrow (BM) of 45 breast cancer patients who were then followed up over a median of 6 years. CK19 was expressed and released by colorectal (HT-29, HCT116, Caco-2) and breast (MCF-7, SKBR3, and MDA-MB-231) cancer cell lines. The CK19-EPISPOT was more sensitive than the CK19-ELISA. Dual fluorescent EPISPOT with antibodies against different CK19 epitopes showed the release of the full-length CK19, which was confirmed by mass spectrometry. Functional experiments indicated that CK19 release was an active process and not simply the consequence of cell death. CK19-releasing cells (RCs) were detectable in BM of 44% to 70% of breast cancer patients. This incidence and the number of CK19-RCs were correlated to the presence of overt metastases, and patients with CK19-RCs had a reduced survival as compared with patients without these cells (P = 0.025, log-rank test; P = 0.0019, hazard ratio, 4.7; multivariate analysis). | To compare ambulatory blood pressure (ABP) in nonoverweight, prepubertal children with and without primary snoring (PS), and to investigate whether PS is a part of the dose-response relationship between sleep-disordered breathing (SDB) and BP in children. This was a cross-sectional community-based study involving 190 children age 6 to 13 years. Each participant underwent an overnight sleep study and ABP monitoring after completing a validated sleep symptoms questionnaire. Individual systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial BP were calculated for wake and sleep periods. Subjects were hypertensive if mean SBP or DBP was > 95th percentile (relative to sex and height) of reference. A total of 56 nonsnoring controls, 46 children with PS, 62 children with an apnea-hypopnea index (AHI) of 1 to 3, and 26 children with an AHI > 3 were identified. The daytime and nighttime BP increased across the severity spectrum of SDB. The dose-response trends for the proportion of subjects with nighttime systolic and diastolic hypertension also were significant. Nighttime DBP was significantly higher in the children with PS compared with controls after adjusting for age, sex, and body mass index. |
Does multimedia-driven teaching significantly improve students ' performance when compared with a print medium? | In this study, we compared the educational value of a multimedia module about aortic valve replacement as a preparation for the operating room with a print medium of identical content. One hundred twenty-six students were randomly assigned in a prospective study to either use the multimedia course (n = 69) or a print version (n = 57). A 20-item multiple-choice test was performed before and after learning with the respective medium. Both groups participated in an operation during which they were evaluated with 28 standardized tasks and questions. Individual motivation, computer literacy, and didactic quality of both media were assessed with psychometric tests. There were no significant differences in the multiple-choice pretest (multimedia, 30.6% +/- 12.4% versus print, 27.9% +/- 11.4%) and posttest responses (multimedia, 76.7% +/- 13.3% versus print, 76.9% +/- 11.1). Mean percentage of correct answers during the operation was 82.9% +/- 10% in the online group and 64.7% +/- 12% in the print group (p < 0.0001). The multimedia group needed significantly (p < 0.001) less study time (105 +/- 24 minutes) when compared with the text group (122 +/- 30 minutes). There were no statistically significant differences in motivation, computer literacy, and didactic quality of either medium. | P2X1 receptors play an important role in platelet function as they can induce shape change, granule centralization and are also involved in thrombus formation. As platelets have no nuclei, the level of P2X1 expression depends on transcriptional regulation in megakaryocytes, the platelet precursor cell. Since nothing is known about the molecular mechanisms regulating megakaryocytic P2X1 expression, this study aimed to identify and functionally characterize the P2X1 core promoter utilized in the human megakaryoblastic cell line MEG-01. In order to identify cis-acting elements involved in the transcriptional regulation of P2X1 expression, the ability of 4.7 kb P2X1 upstream sequence to drive luciferase reporter gene expression was tested. Low promoter activity was detected in proliferating MEG-01 cells. This activity increased 20-fold after phorbol-12-myristate-13-acetate (PMA) induced differentiation. A transcription start site was detected 365 bp upstream of the start codon by primer extension. Deletion analysis of reporter constructs indicated a core promoter located within the region -68 to +149 bp that contained two Sp1 sites (named Sp1a and Sp1b) and an NF-1 site. Individual mutations of Sp1b or NF-1 binding sites severely reduced promoter activity whereas triple mutation of Sp1a, Sp1b and NF-1 sites completely abolished promoter activity in both untreated and PMA treated cells. Sp1/3 and NF-1 proteins were shown to bind their respective sites by EMSA and interaction of Sp1/3, NF-1 and TFIIB with the endogenous P2X1 core promoter in MEG-01 cells was demonstrated by chromatin immunoprecipitation. Alignment of P2X1 genes from human, chimp, rat, mouse and dog revealed consensus Sp1a, Sp1b and NF-1 binding sites in equivalent positions thereby demonstrating evolutionary conservation of these functionally important sites. |
Do neural crest stem cells from hair follicles and boundary cap have different effects on pancreatic islets in vitro? | Neural crest stem cells derived from the boundary cap (bNCSCs), markedly promote survival, proliferation and function of insulin producing β-cells in vitro and in vivo after coculture/transplantation with pancreatic islets [ 1, 2 ]. Recently, we have shown that beneficial effects on β-cells require cadherin contacts between bNCSCs and β-cells [ 3, 4 ]. Here we investigated whether hair follicle (HF) NCSCs, a potential source for human allogeneic transplantation, exert similar positive effects on β-cells. We established cocultures of HF-NCSCs or bNCSCs from mice expressing enhanced green fluorescent protein together with pancreatic islets from DxRed expressing mice or NMRI mice and compared their migration towards islet cells and effect on proliferation of β-cells as well as intracellular relations between NCSCs and islets using qRT-PCR analysis and immunohistochemistry. Whereas both types of NCSCs migrated extensively in the presence of islets, only bNCSCs demonstrated directed migration toward islets, induced β-cell proliferation and increased the presence of cadherin at the junctions between bNCSCs and β-cells. Even in direct contact between β-cells and HF-NCSCs, no cadherin expression was detected. | Lower respiratory tract infection is a common cause of consultation and antibiotic prescription in paediatric practice. The misuse of antibiotics is a major cause of the emergence of multidrug-resistant bacteria. The aim of this study was to evaluate the frequency, changes over time, and determinants of non-compliance with antibiotic prescription recommendations for children admitted in paediatric emergency department (PED) with community-acquired pneumonia (CAP). We conducted a prospective two-period study using data from the French pneumonia network that included all children with CAP, aged one month to 15 years old, admitted to one of the ten participating paediatric emergency departments. In the first period, data from children included in all ten centres were analysed. In the second period, we analysed children in three centers for which we collected additional data. Two experts assessed compliance with the current French recommendations. Independent determinants of non-compliance were evaluated using a logistic regression model. The frequency of non-compliance was compared between the two periods for the same centres in univariate analysis, after adjustment for confounding factors. A total of 3034 children were included during the first period (from May 2009 to May 2011) and 293 in the second period (from January to July 2012). Median ages were 3.0 years [1.4-5] in the first period and 3.6 years in the second period. The main reasons for non-compliance were the improper use of broad-spectrum antibiotics or combinations of antibiotics. Factors that were independently associated with non-compliance with recommendations were younger age, presence of risk factors for pneumococcal infection, and hospitalization. We also observed significant differences in compliance between the treatment centres during the first period. The frequency of non-compliance significantly decreased from 48 to 18.8 % between 2009 and 2012. The association between period and non-compliance remained statistically significant after adjustment for confounding factors. Amoxicillin was prescribed as the sole therapy significantly more frequently in the second period (71 % vs. 54.2 %, p < 0.001). |
Does inhibition of autophagy enhance the cytotoxic effect of PA-MSHA in breast cancer? | PA-MSHA, a genetically engineered Pseudomonas aeruginosa (PA) strain, is currently under investigation as a new anti-cancer drug. It can induce cell cycle arrest and apoptosis in different human cancer cells, including hormone receptor negative breast cancer cells. However, the underlying mechanism of tumor lethality mediated by PA-MSHA remains to be fully investigated. The effect of PA-MSHA on human hormone receptor negative breast cancer cells was analyzed by morphological measurement, western blot, cell proliferation assay and mouse xenograft model. PA-MSHA was found to induce endoplasmic reticulum (ER) stress in breast cancer cell lines through the IRE1 signaling pathway. Inhibiting autophagy potentiated the cytotoxic effect of PA-MSHA while treating breast cancer cell lines. In mouse xenograft model, PA-MSHA produced more pronounced tumor suppression in mice inoculated with IRE1 gene knockdown. MDA-MB-231HM cells. | Mark/recapture (or capture-recapture) is a simple technique commonly applied to estimate the hypothetical total (including undercount) in a register composed of cases from two or more independent and separately incomplete case lists. This paper seeks to illustrate serious drawbacks in the use of the mark/recapture technique when applied to injuries. Northumbrian children under 15 years of age who were seriously injured in motor vehicle accidents (MVAs) over a five year period ascertained from two data sources: police reports and hospital inpatient records. Individuals (n) appearing in both police (S) and hospital (H) case lists are identified using various matching criteria. The separate and combined influence of age, sex, and casualty class (cyclist, passengers, pedestrians) on the probability of such matching is estimated using multivariate techniques. The hypothetical total incidence of child MVA victims (N) is calculated from N = (S x H)/n. Estimates of the incidences of "serious" injuries in MVAs under various conditions of stratification and matching. The overall procedure is tested for conformity with accepted criteria for valid use of mark/recapture. About one third of the 1009 police and 836 hospital records could be exactly matched. There were significant variations in matching proportions by class of accident (pedestrian v passenger v cyclist). This selective recapture or "heterogeneity" was not affected by sex, but was independently influenced by the age of the child. Further uncertainty was introduced when matching criteria were slightly relaxed. Estimates of the total population of children with serious injuries vary accordingly from 1729 to 2743. A number of plausible reasons why these two data sources might not be unbiased or mutually independent samples of the total target population are proposed as explanations for this heterogeneity. |
Is hepatitis B virus replication regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones? | HBV covalently closed circular DNA (cccDNA), the replicative intermediate responsible for persistent HBV infection of hepatocytes, is the template for transcription of all viral mRNAs. Nuclear cccDNA accumulates as a stable episome organized into minichromosomes by histone and nonhistone proteins. In this study we investigated, by a newly developed sensitive and specific assay, the relationship between viral replication and HBV chromatin assembly, transcription, and interaction with viral and cellular regulatory proteins. To achieve this aim we coupled a quantitative chromatin immunoprecipitation (ChIP) technique to an established method that allows the amplification of virion-encapsidated HBV genomes after transfection of linear HBV DNA into human hepatoma HuH7 cells. The cccDNA-ChIP technique was also applied to study HBV minichromosome transcriptional regulation in liver tissue from HBV-infected patients. The use of anti-acetyl-H4/-H3 specific antibodies to immunoprecipitate transcriptionally active chromatin revealed that HBV replication is regulated by the acetylation status of the cccDNA-bound H3/H4 histones. Class I histone deacetylases inhibitors induced an evident increase of both cccDNA-bound acetylated H4 and HBV replication. Finally, histones hypoacetylation and histone deacetylase 1 recruitment onto the cccDNA in liver tissue correlated with low HBV viremia in hepatitis B patients. | fibromyalgia is a chronic disease characterized by generalized pain, stiffness, poor physical conditioning, non-restorative sleep and poor health-related quality of life. Ganoderma lucidum a type of mushroom that has demonstrated several benefits in different populations. Ceratonia siliqua is a natural therapy rich in antioxidants with potential benefits on health. to evaluate the effects of 6-week treatment of Ganoderma lucidum and Ceratonia siliqua on physical fitness in patients suffering from fibromyalgia. sixty-four women with fibromyalgia participated in the study. They took 6 g of Ganoderma lucidum or Ceratonia siliqua per day for 6 weeks. Different fitness tests were selected in order to evaluate functional capacity. after the 6-week treatment period, Ganoderma lucidum significantly improved aerobic endurance, lower body flexibility, and velocity (p < .05). No significant improvement in any physical test was observed in the Ceratonia siliqua group. |
Does noble-Collip Drum Trauma induce Disseminated Intravascular Coagulation But Not Acute Coagulopathy of Trauma-Shock? | There are two opposing possibilities for the main pathogenesis of trauma-induced coagulopathy: an acute coagulopathy of trauma shock and disseminated intravascular coagulation with the fibrinolytic phenotype. The objective of this study was to clarify the main pathogenesis of trauma-induced coagulopathy using a rat model of Noble-Collip drum trauma. Eighteen rats were divided into the control, trauma 0, and trauma 30 groups. The trauma 0 and 30 groups were exposed to Noble-Collip drum trauma. Blood samples were drawn without, immediately after, and 30 min after Noble-Collip drum trauma in the control, trauma 0, and trauma 30 groups, respectively. Coagulation and fibrinolysis markers were measured. Thrombin generation was assessed according to a calibrated automated thrombogram. Spontaneous thrombin bursts resulting from circulating procoagulants were observed in the nonstimulated thrombin generation assay immediately after trauma. Soluble fibrin levels (a marker of thrombin generation in the systemic circulation) were 50-fold greater in the trauma groups than in the control group. The resultant coagulation activation consumed platelets, coagulation factors, and antithrombin. Endogenous thrombin potential and factor II ratio were significantly negatively correlated with antithrombin levels, suggesting insufficient control of thrombin generation by antithrombin. High levels of active tissue-type plasminogen activator induced hyperfibrin(ogen)olysis. Soluble thrombomodulin increased significantly. However, activated protein C levels did not change. | DNA-based microbiological studies are moving beyond studying healthy human microbiota to investigate diverse infectious diseases, including chronic respiratory infections, such as those in the airways of people with cystic fibrosis (CF) and non-CF bronchiectasis. The species identified in the respiratory secretion microbiota from such patients can be classified into those that are common and abundant among similar subjects (core) versus those that are infrequent and rare (satellite). This categorization provides a vital foundation for investigating disease pathogenesis and improving therapy. However, whether the core microbiota of people with different respiratory diseases, which are traditionally associated with specific culturable pathogens, are unique or shared with other chronic infections of the lower airways is not well studied. Little is also known about how these chronic infection microbiota change from childhood to adulthood. We sought to compare the core microbiota in respiratory specimens from children and adults with different chronic lung infections. We used bacterial 16S rRNA gene pyrosequencing, phylogenetic analysis, and ecological statistical tools to compare the core microbiota in respiratory samples from three cohorts of symptomatic children with clinically distinct airway diseases (protracted bacterial bronchitis, bronchiectasis, CF), and from four healthy children. We then compared the core pediatric respiratory microbiota with those in samples from adults with bronchiectasis and CF. All three pediatric disease cohorts shared strikingly similar core respiratory microbiota that differed from adult CF and bronchiectasis microbiota. The most common species in pediatric disease cohort samples were also detected in those from healthy children. The adult CF and bronchiectasis microbiota also differed from each other, suggesting common early infection airway microbiota that diverge by adulthood. The shared core pediatric microbiota included both traditional pathogens and many species not routinely identified by standard culture. |
Is volume overhydration related to endothelial dysfunction in continuous ambulatory peritoneal dialysis patients? | In dialysis patients, volume overhydration is common and is related to increased risk of cardiovascular morbidity and mortality. However, it remains unclear whether volume overload imposes those detrimental effects through endothelial dysfunction. In this cross-sectional study, 81 stable patients on continuous ambulatory peritoneal dialysis in a single center were recruited. Volume status was evaluated by extracellular water, assessed by bioimpedance analysis, and normalized to individual height (nECW). Endothelial function was estimated by endothelial-dependent flow-mediated dilatation (FMD) of the brachial artery and expressed as percentage change relative to baseline diameter. There were 37 male and 44 female patients (mean age 61 +/- 12 years, dialysis vintage 20 +/- 23 months). FMD in female patients was significantly higher than that in male patients (9.17% +/- 6.23% vs 6.31% +/- 5.01%, p < 0.05). FMD was negatively correlated with weight (r = -0.308, p < 0.01), body mass index (r = -0.242, p < 0.05), systolic blood pressure (r = -0.228, p < 0.05), ECW (r = -0.404, p < 0.001), and nECW (r = -0.418, p < 0.001). No correlation was found between FMD and other variables. In multiple stepwise regression analysis, calcium x phosphate product (beta = 0.422, p < 0.001), nECW (beta = -0.343, p < 0.01), and dialysis vintage (beta = -0.237, p < 0.05) were independent determinants of FMD (adjusted R(2) = 0.327 for this model). | To demonstrate that in APPswe/PS1DeltaE9 transgenic mice, gene gun mediated Abeta42 gene vaccination elicits a high titer of anti-Abeta42 antibodies causal of a significant reduction of Abeta42 deposition in brain. Gene gun immunization is conducted with transgenic mice using the Abeta42 gene in a bacterial plasmid with the pSP72-E3L-Abeta42 construct. Enzyme-linked immunoabsorbent assays (ELISA) and Western blots are used to monitor anti-Abeta42 antibody levels in serum and Abeta42 levels in brain tissues. Enzyme-linked immunospot (ELISPOT) assays are used for detection of peripheral blood T cells to release gamma-interferon. Immunofluorescence detection of Abeta42 plaques and quantification of amyloid burden of brain tissue were measured and sections were analyzed with Image J (NIH) software. Gene gun vaccination with the Abeta42 gene resulted in high titers of anti-Abeta42 antibody production of the Th2-type. Levels of Abeta42 in treated transgenic mouse brain were reduced by 60-77.5%. The Mann-Whitney U-test P=0.0286. |
Are oxysterols increased in plasma of end-stage renal disease patients? | Oxidative stress occurs in chronic renal failure patients undergoing hemodialysis (HD). The objective of our study was to measure oxidation products of cholesterols, so-called oxysterols, in the serum of HD patients in comparison to healthy control persons. In 42 HD patients, plasma oxysterols were measured before and after HD. The values were compared with those in 40 healthy controls. The following cholesterol derivatives were analyzed: dienes, 7beta-OH, beta-epoxy, alpha-epoxy, 20alpha-OH, alpha-triol, and 7-keto cholesterol. In HD patients, serum levels of oxysterols are increased in comparison to controls. The highest values were measured for beta-epoxy cholesterol and for 20alpha-OH cholesterol. During HD oxysterol concentrations increased, obviously by water removal and concentration of nondialyzable compounds. | Immunohistochemical 4 (IHC4) score plus Clinical Treatment Score (CTS) is an inexpensive tool predicting risk of distant recurrence in women with early breast cancer (EBC). IHC4 score is based on ER, PR, HER2 and Ki67 index. This study explores the role of the combined score (IHC4 + CTS) in predicting risk of locoregional recurrence (LRR) in women with EBC who had breast conservation surgery (BCS) without adjuvant radiotherapy (study group). The secondary objective was to evaluate the clinicopathological differences between our study group and women who had adjuvant radiation following BCS (control group). Patients were selected from the local database over a 13-year period. IHC testing was done where results were missing. Combined scores were calculated using the appropriate formulae. Patients in the study group (81 patients) had favorable clinicopathological features compared to the control group (1406 patients). The Cox regression indicated a statistically significant association between the combined score and the risk of LRR (p = 0.03). The incidence of LRR was zero, 20% and 33.3% in the low, intermediate and high risk groups respectively (p = 0.007). Margin status was the only variable not included in the combined score. The Cox regression analysis demonstrated that the combined score (p = 0.02) and the ordinal measure of margins (p = 0.03) were significant independent predictors of LRR. |
Does nitroglycerin decrease medial smooth muscle cell proliferation after arterial balloon injury? | Nitroglycerin and its effector molecules nitric oxide and cyclic guanosine monophosphate decrease smooth muscle cell proliferation in vitro. We examined the in vivo effect of nitroglycerin on intimal hyperplasia. We treated rats after carotid artery balloon injury with nitroglycerin delivered paraarterially with a miniosmotic pump for 1 week. High nitroglycerin serum levels were achieved, and the level of cyclic guanosine monophosphate in the carotid artery wall was significantly increased (1.48 +/- 0.37 vs 0.86 +/- 0.39 pmol/mg protein; p < 0.05) in the nitroglycerin-treated group. Cellular proliferation in the arterial wall was assessed by incorporation of 5-bromo-2'-deoxyuridine 6 days after the injury and was lower in the nitroglycerin-treated group (15.2 +/- 3.4 vs 36.3 +/- 5.5 positive cells/section; p < 0.005). This was due to a decrease in the number of proliferating cells in the media (6.3 +/- 1.2 vs 21.8 +/- 4.5; p < 0.005), whereas in the budding neointima, the difference in the number of proliferating cells was not significant. Neointimal lesions 21 days after the injury did not differ in cross-sectional intimal area, in intimal/medial area ratio, and in cell density. | HLA-DR2 (15) and 14 (6) have been recently proposed as susceptibility alleles for the development of sarcoidosis and HLA-DR15 as a marker of poor outcome, but validation in other populations is necessary. Employing serological techniques, we HLA-typed 103 Irish sarcoidosis patients and 105 ethnically-matched healthy controls for class I A and B and II DR and DQ alleles. HLA-B5 (10% vs. 2%, p = 0.018) and DR2 (45% vs. 27%, p = 0.007) were positively associated and B15 (0% vs. 7%, p = 0.01) negatively associated with sarcoidosis compared to control subjects. Seventy-five patients were followed > 2 years and 47 (63%) had chronic and 28 (37%) non-chronic disease. HLA-DR2 (55% vs. 27%, p = 0.001) and DR11 (26% vs. 5%, p<0.0001) were significantly more frequent in chronic disease vs. controls, in contrast to HLA-DR3 (13% vs. 38%, p = 0.002), which had a significant negative association. HLA-B5 (11% vs. 2%, p = 0.029) and DR3 (64% vs. 38%, p = 0.005) were significantly more frequent in non-chronic disease. Of the 29 patients achieving spontaneous remission, 24 (83%) were HLA-DR3 -positive and DR3-positivity was associated with significantly greater carbon monoxide diffusion at follow-up compared to DR3-negative patients (90% vs. 82% predicted, p = 0.027). |
Is activation of zebrafish Src family kinases by the prion protein an amyloid-β-sensitive signal that prevents the endocytosis and degradation of E-cadherin/β-catenin complexes in vivo? | Prions and amyloid-β (Aβ) oligomers trigger neurodegeneration by hijacking a poorly understood cellular signal mediated by the prion protein (PrP) at the plasma membrane. In early zebrafish embryos, PrP-1-dependent signals control cell-cell adhesion via a tyrosine phosphorylation-dependent mechanism. Here we report that the Src family kinases (SFKs) Fyn and Yes act downstream of PrP-1 to prevent the endocytosis and degradation of E-cadherin/β-catenin adhesion complexes in vivo. Accordingly, knockdown of PrP-1 or Fyn/Yes cause similar zebrafish gastrulation phenotypes, whereas Fyn/Yes expression rescues the PrP-1 knockdown phenotype. We also show that zebrafish and mouse PrPs positively regulate the activity of Src kinases and that these have an unexpected positive effect on E-cadherin-mediated cell adhesion. Interestingly, while PrP knockdown impairs β-catenin adhesive function, PrP overexpression enhances it, thereby antagonizing its nuclear, wnt-related signaling activity and disturbing embryonic dorsoventral specification. The ability of mouse PrP to influence these events in zebrafish embryos requires its neuroprotective, polybasic N-terminus but not its neurotoxicity-associated central region. Remarkably, human Aβ oligomers up-regulate the PrP-1/SFK/E-cadherin/β-catenin pathway in zebrafish embryonic cells, mimicking a PrP gain-of-function scenario. | To evaluate the relationship between temperature and hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) levels in Harbin of China and analyze whether these would affect diagnosis and control of diabetes. Two groups were investigated: 1. Routine patients come from outpatients, 2. Research subjects including 224 healthy volunteers and 391 diabetic patients, who had 5 blood specimens collected between February and June 2010. Fasting plasma glucose and hemoglobin A1c were detected. In non-diabetic patients, mean HbA1c concentrations for all temperature categories were not significantly different, but mean FPG level was higher at cooler temperatures (p < 0.05). In the diabetic group, mean HbA1c concentrations were higher at cool temperatures than at very cold temperatures (p < 0.05), but mean FPG level was higher at cold temperature than at other temperature categories (p < 0.05). Both the within- and the between-subject coefficients of variation (CVs) for HbA1c were smaller than for FPG. |
Do botulinum toxin type a injections into the trigone to treat idiopathic overactive bladder induce vesicoureteral reflux? | We assessed the generation of vesicoureteral reflux before and after injection of botulinum toxin A into the trigone of patients with nonneurogenic overactive bladder, and evaluated its short-term efficacy. Adults with nonneurogenic overactive bladder resistant to behavioral treatments, pelvic floor exercises, medication and neuromodulation were included in the study. The initial evaluation (history, physical examination, 3-day urinary diary, V8 score, flowmetry and post-void residual) was repeated 6 weeks after botulinum toxin A injection. Videourodynamic study was performed 1 hour before injection and 6 weeks later. Botulinum toxin A (200 units) was injected into the detrusor in 10 sites over the bladder base including the trigone. The primary outcome was the presence or absence of vesicoureteral reflux before and 6 weeks after botulinum toxin A injection. The secondary outcomes were clinical and urodynamic parameter changes. Values were compared using the Wilcoxon test. A total of 12 women were enrolled in the study (median age 76 years). The duration of symptoms was 7.5 years. One patient was excluded from analysis because of a urinary tract infection. There were 10 women with no vesicoureteral reflux at baseline and 1 had bilateral vesicoureteral reflux (grade 2 right, grade 1 left). At 6 weeks there was no induced vesicoureteral reflux and the patient with vesicoureteral reflux at baseline showed no change in vesicoureteral reflux grade. No local or systemic side effects related to botulinum toxin A were reported. In terms of efficacy, at direct questioning 6 weeks after treatment 4 of 11 patients reported an improvement that made them ask for another injection. | In 1970, Breslow described his eponymously named thickness measurement. No-one has sought to enhance the Breslow thickness (BT). The aim of this study was to demonstrate a proof of concept that the density of melanoma cells at the position where the BT is measured is a morphological prognostic biomarker, which we name the Breslow density (BD). The hypothesis was that the BD has prognostic value for overall survival (OS) and is independent of the BT. We analysed 100 cutaneous melanomas, and followed REMARK guidelines. The BD was the estimated percentage dermal area occupied by melanoma cells in a specified location. The BT and BD had a strong correlation (P = 2.1 × 10 |
Does prolonged TASER use on exhausted humans worsen markers of acidosis? | There are safety concerns about TASER conducted electrical weapon (CEW) use on humans, and there have been media reports of adverse human outcomes after CEW exposure. Conducted electrical weapons are often used on physically exhausted subjects. A single CEW application of a CEW is generally accepted to be 5 seconds of exposure. Some exposures in reality involve more than 5 seconds. We sought to determine if a prolonged (15 seconds) CEW exposure on exhausted humans caused acidosis, hyperkalemia, serum lactate change, or troponin change. This was a prospective study of generally healthy human volunteers. Medical histories and baseline serum values were obtained, and several of the volunteers did have acute or chronic medical problems. Subjects underwent an exercise protocol until subjective exhaustion. Exhaustion was defined by the volunteer no longer being able to perform the exercise at a given pace. Blood was drawn immediately (defined as within 20 seconds) after exercise and was immediately followed by a 15-second CEW exposure. Blood was drawn immediately after exposure and again at 16 to 24 hours after exposure. Blood was analyzed for pH, pco(2), potassium, lactate, and troponin. Data were compared using Wilcoxon signed rank tests. There were 38 subjects enrolled with an average age of 39 years. The following health conditions were reported among the volunteers: hypertension (2), gastritis/reflux (2), active respiratory tract infections (3), asthma (2), chronic muscular pain conditions (4), pituitary adenoma (1) and glaucoma (1). Sixteen volunteers reported use of prescription medication at the time of their participation. The median initial pH of 7.38 (interquartile range [IQR], 7.35-7.40) decreased to 7.23 (IQR, 7.19-7.31) immediately after exercise. Immediately after exposure, median pH was 7.22 (IQR, 7.18-7.25). It was 7.39 (IQR, 7.37-7.43) at 24 hours. The pCO2 increased from 46.3 (IQR, 43.0-54.5) to 57.4 (IQR, 49.9-67.7) immediately after exercise, decreased to 51.3 (IQR, 44.4-65.0) immediately after exposure, and was 46.3 (IQR, 42.7-51.7) at 24 hours. Lactate increased from a median of 1.65 (IQR, 1.14-2.55) to 8.39 (IQR, 6.98-11.66) immediately after exercise, increased to 9.85 (IQR, 7.70-12.87) immediately after exposure, and was 1.02 (IQR, 0.91-1.57) at 24 hours. Serum potassium increased from 3.9 (IQR, 3.8-4.4) to 4.2 (IQR, 4.0-4.9) immediately after exercise, decreased to 3.8 (IQR, 3.7-4.4) immediately after exposure, and was 4.1 (IQR, 3.9-4.6) at 24 hours. No troponin elevations were detected. | The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown. To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis. Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis. |
Does heme oxygenase-2 gene deletion attenuate oxidative stress in neurons exposed to extracellular hemin? | Hemin, the oxidized form of heme, accumulates in intracranial hematomas and is a potent oxidant. Growing evidence suggests that it contributes to delayed injury to surrounding tissue, and that this process is affected by the heme oxygenase enzymes. In a prior study, heme oxygenase-2 gene deletion increased the vulnerability of cultured cortical astrocytes to hemin. The present study tested the effect of HO-2 gene deletion on protein oxidation, reactive oxygen species formation, and cell viability after mixed cortical neuron/astrocyte cultures were incubated with neurotoxic concentrations of hemin. Continuous exposure of wild-type cultures to 1-10 microM hemin for 14 h produced concentration-dependent neuronal death, as detected by both LDH release and fluorescence intensity after propidium iodide staining, with an EC50 of 1-2 microM; astrocytes were not injured by these low hemin concentrations. Cell death was consistently reduced by at least 60% in knockout cultures. Exposure to hemin for 4 hours, a time point that preceded cell lysis, increased protein oxidation in wild-type cultures, as detected by staining of immunoblots for protein carbonyl groups. At 10 microM hemin, carbonylation was increased 2.3-fold compared with control sister cultures subjected to medium exchanges only; this effect was reduced by about two-thirds in knockout cultures. Cellular reactive oxygen species, detected by fluorescence intensity after dihydrorhodamine 123 (DHR) staining, was markedly increased by hemin in wild-type cultures and was localized to neuronal cell bodies and processes. In contrast, DHR fluorescence intensity in knockout cultures did not differ from that of sham-washed controls. Neuronal death in wild-type cultures was almost completely prevented by the lipid-soluble iron chelator phenanthroline; deferoxamine had a weaker but significant effect. | Ezetimibe as monotherapy or in combination with statins effectively lowers low-density lipoprotein cholesterol (LDL-C). However, there are few reports of ezetimibe's effect when added to ongoing non-statin lipid-lowering drugs or combination lipid-lowering therapy. To evaluate the impact of preexisting lipid therapy on LDL-C response to ezetimibe. We performed a retrospective review of all patients started on ezetimibe therapy at the Veterans Affairs Long Beach Healthcare System between March 1, 2003, and March 1, 2005. We calculated the ezetimibe-induced percent change in LDL-C in patients without concomitant changes in other lipid-lowering medications. We then stratified the population according to the type and number of preexisting lipid therapies and compared the LDL-C-lowering efficacy of ezetimibe among these groups. Overall, ezetimibe was associated with a 23.0% reduction in LDL-C. Patients with preexisting statin monotherapy had significantly greater LDL-C reduction with ezetimibe than did those with preexisting non-statin drugs (-26.1% vs -9.3%; p = 0.0138). In patients with no preexisting lipid therapy (n = 58), monotherapy (n = 115), double therapy (n = 36), or triple therapy (n = 9), ezetimibe decreased LDL-C by 17.3%, 21.4%, 33.5%, and 38.1%, respectively. This stepwise trend in increased ezetimibe efficacy was statistically significant, even with adjustments for baseline LDL-C. |
Is siglec-10 associated with survival and natural killer cell dysfunction in hepatocellular carcinoma? | The interaction between Siglec-10 and its ligand, CD24, selectively represses tissue damage-caused immune responses. However, the nature of Siglec-10 and CD24 in human hepatocellular carcinoma (HCC) is still poorly defined. Hereon, the expression, function, and regulation of CD24 and Siglec-10 in HCC were investigated in the present study. Flow cytometry was performed to examine the expression of Siglec-10 in HCC tissues and adjacent non-tumor tissues of HCC patients. To further determine whether Siglec-10 expression is associated with the clinical characteristics and survival, conventional immunohistochemistry was performed in 96 HCC patients. Additionally, the role of Siglec-10 in the regulation of natural killer (NK) cell dysfunction was evaluated. Finally, CD24 expression in HCC was also assessed. Siglec-10 was expressed most on NK cells in HCC (40.7 ± 4.5%). Compared with surrounding non-tumor tissues, tumor tissues had higher Siglec-10 expression (31.0 ± 1.7% versus 40.7 ± 4.5%, n = 10, P < 0.05), and the expression was negatively associated with patient survival. Siglec-10(+)CD56(+) NK cells exhibited reduced effector function, as shown by decreased granules and cytokine expressions compared with Siglec-10(-)CD56(+) NK cells. Moreover, the number of CD24(+)CD45(-) cells in HCC tissues was higher than that in adjacent non-tumor tissues (9.4 ± 0.9% versus 3.1 ± 0.9%, n = 15, P < 0.05). | The left dorsolateral prefrontal cortex (DLPFC) is the most commonly used target for transcranial magnetic stimulation (TMS) in the treatment of depression. The "5-cm rule" is an empiric method used for probabilistic targeting of the DLPFC in most clinical trials. This rule may be suboptimal, as it does not account for differences in skull size or variations in prefrontal anatomy relative to motor cortex location. This study is a post hoc analysis of data from a large repetitive TMS (rTMS) trial in which we examined the variability of coil placement and how it affects antidepressant efficacy. Fifty-four depressed subjects enrolled in a randomized, single-site trial received either active rTMS or sham for 3 weeks. Prior to treatment initiation, investigators placed vitamin E capsules at the point of stimulation and used a high-resolution magnetic resonance imaging (MRI) scan to image these fiducials relative to anatomy. We employed a semiautomated imaging-processing algorithm to localize the cortical region stimulated. Active TMS significantly reduced Hamilton Depression Rating Scale (HDRS) scores. A linear model for this improvement involving the coordinates of the stimulated cortex location, age, and treatment condition was highly significant. Specifically, individuals with more anterior and lateral stimulation sites were more likely to respond. |
Is biomechanical efficiency decreased in heart failure during low-level steady state and maximal ramp exercise? | Previous studies of biomechanical efficiency (external work/energy input--Watt/O(2) consumed) in heart failure (HF) using cardiopulmonary exercise testing (CPET) and magnetic resonance spectroscopy (MRS) have had discordant results with increased efficiency by CPET and decreased efficiency by MRS. Compare biomechanical efficiency of HF subjects and normal controls during steady state (SS=35 W for 6 min) and ramp cycle ergometer exercise. The hypothesis was that HF subjects would have impaired biomechanical efficiency that correlated with HF symptoms. Biomechanical efficiency used the actual Vo(2) during exercise and recovery. Gross (Vo(2) above zero), Net (Vo(2) above the resting Vo(2)) and Work (Vo(2) above the unloaded pedaling Vo(2)) efficiencies were calculated. HF subjects had an 18% higher Vo(2) during SS exercise (P=0.029). Biomechanical efficiency was reduced during SS exercise (gross -15%, P=0.019, net -15%, P=0.062, and work -35%, P=0.002). Gross Efficiency during SS exercise had the strongest correlation with HF symptoms (r=0.55). During ramp exercise gross (-26%), net (-10%) and work (-8%) biomechanical efficiency were all reduced (all P<0.05). The slope of the Vo(2)/Watt relationship during ramp exercise had the best correlation with HF symptoms (r=0.46). | Presence of intratumoral T-cell infiltration has been linked to improved survival in ovarian cancer patients. We questioned whether antibody immunity specific for ovarian cancer tumor antigens would predict disease outcome. We evaluated humoral immune responses against ovarian cancer antigens p53, HER-2/neu, and topoisomerase IIalpha. Serum was collected from 104 women (median age, 59 years; range, 34 to 89 years) at the time of their initial definitive surgery for ovarian cancer. Serum was analyzed by enzyme-linked immunosorbent assay for antibodies to p53, HER-2/neu, and topoisomerase IIalpha proteins. Antibody immunity to tetanus toxoid was assessed as a control. The incidence of humoral immunity at the time of diagnosis to any of these three antigens was tabulated. For patients with advanced-stage disease (III/IV), correlation was made between the presence of tumor-specific immunity at the time of diagnosis and overall survival. Patients were followed for a median of 1.8 years. Multivariate analysis showed the presence of p53 antibodies to be an independent variable for prediction of overall survival in advanced-stage patients. Overall survival was significantly higher for patients with antibodies to p53 when compared with patients without p53 antibodies (P = .01). The median survival for p53 antibody-positive patients was 51 months (95% CI, 23.5 to 60.5 months) compared with 24 months (95% CI, 19.4 to 28.6 months) for patients without antibodies to p53. |
Does branched-chain amino acid-enriched nutrient increase blood platelet count in patients after endoscopic injection sclerotherapy? | Protein and energy malnutrition is a severe problem for patients with liver cirrhosis (LC) and fasting often induces starvation which is a vitally important outcome. Dietary restriction is essential for endoscopic injection sclerotherapy (EIS) in patients with risky esophageal varices, thereby creating the possible exacerbation of nutritional state and inducing liver dysfunction. Whether EIS induces nutritional deficiency in LC patients and the effects of branched-chain amino acid (BCAA)-enriched nutrient are prospectively investigated. A total of 61 LC patients were randomly divided into an EIS monotherapy group (non-BCAA group, n = 31) and an EIS combined with BCAA therapy group (n = 30). Platelet count, blood chemistry and somatometry values were prospectively measured at five time points. The platelet counts before treatment were at the same level in both groups (P = 0.72). Three months after treatment, the counts decreased in the non-BCAA group; however, they increased in the BCAA group (P = 0.019). Body mass index, triceps skin fold thickness and arm muscle circumference significantly decreased in both groups. The BCAA and tyrosine ratio value increased only in the BCAA group (P < 0.01). The skeletal muscle volume measured by InBody720 significantly decreased in the non-BCAA group (P < 0.001). | The molecular mechanisms underlying dysregulation of microRNAs have been documented in nasopharyngeal carcinoma (NPC). Our previous study demonstrated that plasma miR-124 was down-regulated in NPC using microarray analysis and quantitative PCR validation. Though growing studies showed that down-regulated miR-124 was closely related to tumourigenesis in various types of cancers, the role of miR-124 in NPC remains largely unknown. The expression level of miR-124 was evaluated in NPC cell lines and patient specimens using quantitative reverse transcription-PCR (Real-time qPCR). The clinicopathological significance of the resultant data was later analyzed. Then, we explored the role of miR-124 in NPC tumorigenesis by in vitro and in vivo experiments. Homo sapiens forkhead box Q1 (Foxq1) was confirmed as a novel direct target gene of miR-124 by the dual-luciferase assay and western bolt. We found that miR-124 was commonly down-regulated in NPC specimens and NPC cell lines. The expression of miR-124 was inversely correlation with clinical stages and marked on T stages. Then, the ectopic expression of miR-124 dramatically inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as tumor growth and metastasis in vivo. Furthermore, we identified Foxq1 as a novel direct target of miR-124. Functional studies showed that knockdown of Foxq1 inhibited cell growth, migration and invasion, whereas Foxq1 overexpression partially rescued the suppressive effect of miR-124 in NPC. In clinical specimens, Foxq1 was commonly up-regulated in NPC, and the level increased with clinical stages and T stages. Additionally, the level of Foxq1 was inversely correlated with miR-124. |
Are extensive dysregulations of oligodendrocytic and astrocytic connexins associated with disease progression in an amyotrophic lateral sclerosis mouse model? | Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which glial cells play significant roles in disease progression. Connexins (Cxs) form homotypic or heterotypic gap junctions (GJs) and allow direct intercellular communications among nervous tissue cells. The role of Cxs in motor neuron disease has never been investigated; therefore, we aimed to evaluate alterations of Cxs in mSOD1-transgenic (mSOD1-Tg) mice in comparison with their non-transgenic (non-Tg) littermates at the same ages. We pathologically evaluated temporal changes to astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 immunoreactivities at presymptomatic, disease-progressive, and end stages, relative to aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-2 (EAAT2), myelin-oligodendrocyte glycoprotein (MOG), and Nogo-A immunoreactivities, and observed neuronal loss by NeuN and neurofilament immunostaining, and microglial response by Iba-1 immunostaining. We also performed quantitative immunoblotting and real-time PCR analyses for Cxs. The mSOD1-Tg mice showed neuronal and axonal loss in the anterior horns of the lumbar spinal cord accompanied by increased activation of microglia compared with non-Tg mice at the disease-progressive and end stages. Expression patterns of Cxs were not different between mSOD1-Tg and non-Tg mice at the presymptomatic stage, but immunoreactivities for GFAP, Cx43, Cx30 and AQP4 were increased in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. By contrast, Cx47 and Cx32 immunoreactivities were markedly diminished in Nogo-A-positive oligodendrocytes in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages, especially in oligodendrocytes showing SOD1 accumulation. EAAT2 immunoreactivity was also diminished in the anterior horns of mSOD1-Tg mice at the disease-progressive and end stages. Quantitative immunoblotting revealed a significant reduction in Cx47 and Cx32 protein levels in mSOD1-Tg mice at the disease-progressive and end stages. The levels of Cx47 and Cx32 mRNAs were also decreased at these stages. | Low sex hormone levels have been associated with the metabolic syndrome (MetS). Our objective was to determine whether the association between sex hormone levels and MetS varies by race/ethnicity among men and to investigate the relationship of sex hormones and individual components of MetS. We conducted a population-based observational survey. A multistage stratified design was used to recruit a random sample of 2301 racially/ethnically diverse men age 30-79 yr. Blood samples were obtained on 1899 men. Analyses were conducted on 1885 men with complete data on total testosterone (T), free T, and SHBG. There were no interventions. MetS was defined using a modification of the Adult Treatment Panel III guidelines. The association between MetS and sex hormone levels was assessed using odds ratios and 95% confidence intervals estimated using logistic regression models. A strong inverse association was observed, in both bivariate and multivariate analyses, between hormone levels and MetS. The odds of MetS increased about two-fold with a 1 sd decrease in hormone levels. The association between sex hormones and MetS was statistically significant across racial/ethnic groups. Although the magnitude of this association was largest among White men, racial/ethnic differences were not statistically significant. The strength of the association of sex hormones with individual components of MetS varied; stronger associations were observed with waist circumference and dyslipidemia and more modest associations with diabetes and elevated blood sugar. |
Does a novel survival-based tissue microarray of pancreatic cancer validate MUC1 and mesothelin as biomarkers? | One-fifth of patients with seemingly 'curable' pancreatic ductal adenocarcinoma (PDA) experience an early recurrence and death, receiving no definable benefit from a major operation. Some patients with advanced stage tumors are deemed 'unresectable' by conventional staging criteria (e.g. liver metastasis), yet progress slowly. Effective biomarkers that stratify PDA based on biologic behavior are needed. To help researchers sort through the maze of biomarker data, a compendium of ∼2500 published candidate biomarkers in PDA was compiled (PLoS Med, 2009. 6(4) p. e1000046). Building on this compendium, we constructed a survival tissue microarray (termed s-TMA) comprised of short-term (cancer-specific death <12 months, n = 58) and long-term survivors (>30 months, n = 79) who underwent resection for PDA (total, n = 137). The s-TMA functions as a biological filter to identify bona fide prognostic markers associated with survival group extremes (at least 18 months separate survival groups). Based on a stringent selection process, 13 putative PDA biomarkers were identified from the public biomarker repository. Candidates were tested against the s-TMA by immunohistochemistry to identify the best markers of tumor biology. In a multivariate model, MUC1 (odds ratio, OR = 28.95, 3+ vs. negative expression, p = 0.004) and MSLN (OR = 12.47, 3+ vs. negative expression, p = 0.01) were highly predictive of early cancer-specific death. By comparison, pathologic factors (size, lymph node metastases, resection margin status, and grade) had ORs below three, and none reached statistical significance. ROC curves were used to compare the four pathologic prognostic features (ROC area = 0.70) to three univariate molecular predictors (MUC1, MSLN, MUC2) of survival group (ROC area = 0.80, p = 0.07). | To analyze the effect of retinoic acids (RA) on HIV-1 expression and correlate this effect with expression levels of RA receptors (RARs) in T-lymphoid and monocytoid cell lines. The effect of all-trans and 9-cis RA on HIV-1 production in T-lymphoid (H9, CEM) and monocytoid (U937,THP-1) cell lines was measured during acute and chronic infection. The expression levels of human RAR alpha (hRAR alpha, receptor for all-trans RA) and the human retinoid-X receptor alpha (hRXR alpha receptor for 9-cis RA) were determined by Northern blot analysis. Both all-trans and 9-cis RA inhibited virus replication in HIV-1 IIIB-infected monocytoid cells, in the presence and absence of the co-stimulatory agent phorbol myristate acetate (PMA). The retinoids had weak or no stimulatory effects on HIV production by T-cell lines. HIV production by PMA-stimulated T-cell lines was inhibited by these retinoids. The 9-cis RA was generally more effective than all-trans RA in inhibiting HIV production and in combination generally more effective than the single agents alone. Human RAR alpha was expressed in H9, U937 and THP-1 cells, but almost undetectable in CEM cells. Human RXR alpha was significantly expressed in U937 and THP-1 cells, weakly expressed in H9 cells and not detectable in CEM cells. After stimulation by PMA, RXR alpha expression increased in H9 and U937 cells but not in CEM cells. Human RAR alpha expression was unchanged in H9 and CEM cells, and elevated in U937 cells, after PMA stimulation. |
Is serum Matrix Metalloproteinase-7 an independent prognostic biomarker in advanced bladder cancer? | Urine markers have been studied extensively but there is a lack of blood prognostic markers in bladder cancer. MMP-7 is produced by stromal cells and by tumor cells and is overexpressed in a variety of epithelial and mesenchymal tumors. In this study, we assessed with an immunoassay we developed, the prognostic value of serum MMP-7 in a series of patients with advanced bladder cancer. Serum samples were collected from 56 patients with advanced bladder cancer who were treated at the Montpellier Cancer Institute between March 2003 and December 2004. MMP-7 was quantified in serum samples by using a homogeneous sandwich fluoroimmunoassay we developed based on the time resolved amplified cryptate emission (TRACE) technology. The median overall survival of the study population was 2.2 years (95% CI, 1.4 to 3.0) with 1- and 5-year survival rates of 73% (95% CI, 59% to 82%) and 25% (95% CI, 14% to 37%), respectively. High MMP-7 serum levels were associated with poor survival. Using a cut-off value of 11.5 ng/mL, the median overall survival was 3.0 years (95% CI, 1.5 to 5.1) for patients with MMP-7 serum level <11.5 ng/mL and 1.3 years (95% CI, 0.8 to 2.5) for patients with serum level ?11.5 ng/mL. Multivariate analysis identified high MMP-7 serum concentration as an independent prognostic factor for survival in patients with advanced bladder cancer (R?=?2.1, 95% CI, 1.1 to 4.4). | Electroacupuncture (EA) is reported to be an effective treatment for obesity, but its mechanism is unclear. This study aimed to investigate the relationship between hypothalamic LKB1-AMPK-ACC signaling and EA. Fifty male Sprague-Dawley rats were divided into two groups fed either chow (chow-fed group) or high-fat diet (HF group). After 4 weeks of feeding, obese rats in the HF group (defined as weighing 20% or more than rats in the chow-fed group) were randomly allocated into an EA or Diet-induced obesity (DIO) group. The EA group was given EA on bilateral ST25-ST36 for 4 weeks, while the DIO group received no further intervention. Body weight of the chow-fed, DIO, and EA groups were measured weekly. mRNA and protein levels of the hypothalamic LKB1-AMPK-ACC signaling pathway were detected using real-time (RT)-PCR and western blot, respectively. After 4 weeks of EA treatment, the weight growth trend of rats in the EA group was inhibited compared with those in the DIO group. RT-PCR and western blotting showed that EA upregulated the transcription of Adenosine 5'-monophosphate-activated protein kinase α2 (AMPKα2), promoted protein expression of Liver kinase B1 (LKB1) and AMPKα1, and inhibited acetyl-CoA carboxylase (ACC) protein expression in the hypothalamus. |
Is risk of malignancy index sensitive in detecting non-epithelial ovarian cancer and borderline ovarian tumor? | To determine the value of risk of malignancy index in detection of ovarian cancer and referral of adnexal masses. Patients scheduled for surgery due to adnexal mass between May 2008 and August 2009 were prospectively included in the study. Risk of malignancy index (RMI) was calculated for each patient with a published formula (RMI=Ultrasonic score X menopausal status X Ca-125 (IU/ml) level). RMI >200 was accepted as positive for malignancy and the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of RMI in detecting malignant cases were calculated. One hundred consecutive patients of whom 80 (80%) had benign ovarian cyst, 4 (4%) had borderline lesion and 16 (16%) had invasive ovarian cancer were included in the study. Forty-five percent (9/20) of malignant cases were epithelial ovarian cancer, 20% (4/20) were borderline ovarian tumor, 30% (6/20) were non-epithelial ovarian tumor and 5% (1/20) was a metastasis from the appendix. All the cases with epithelial ovarian cancer had positive RMI but only 1 of 4 borderline lesions, 2 of 6 non-epithelial ovarian cancers had positive RMI. The sensitivity of RMI was 60%, specificity was 88.8%, PPV was 57.1% and NPV was 89.9% for all cases. When the cancer cases other than epithelial ovarian cancers were excluded, the sensitivity, specificity, PPV and NPV of RMI was 76.92%, 88.75%, 52.63% and 95.95% respectively. | Total parenteral nutrition (TPN) impairs host immunocompetence, a mechanism possibly underlying the high morbidity of infectious complications in critically ill patients. Our recent study demonstrated TPN to reduce the number and function of hepatic mononuclear cells (MNCs) and to worsen survival after intraportal Pseudomonas challenge in mice. The present study examined the duration of enteral nutrition (EN) needed to reverse TPN-induced changes in hepatic MNCs in a murine model. Male ICR mice (6 weeks) received 5 days of TPN followed by 0 (TPN), 12 (EN12), 24 (EN24), 48 (EN48) or 72 (EN72)h of chow feeding. Control mice (Control) were given chow with intravenous saline infusions for 5 days. After nutritional support, hepatic MNCs were isolated and counted. Lipopolysaccharide (LPS) receptor expressions (CD14 and TLR4/MD2) on Kupffer cells were analyzed by flowcytometry. In addition, TPN, EN12, EN48 and control mice were given intraportal Pseudomonas challenge and survival was monitored. The TPN group was significantly lower in hepatic MNC number and LPS receptor expressions than the Control group. However, EN quickly reversed TPN-induced hepatic impairments in MNC loss within 12h, CD14 expression within 48 h and TLR4/MD2 expression within 24h. Survival of the EN48 group was significantly improved as compared with the TPN and EN12 groups. |
Is suppression of plasma estrogen levels by letrozole and anastrozole related to body mass index in patients with breast cancer? | To investigate whether suppression of plasma estradiol and estrone sulfate levels by the aromatase inhibitors (AIs) anastrozole and letrozole is related to body mass index (BMI) in postmenopausal women with early estrogen receptor (ER) -positive breast cancer. Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI. This effect with high BMI might hypothetically be a result of reduced inhibition of aromatase and suppression of plasma estrogen levels and might be overcome by the use of an increased dose of anastrozole or, alternatively, the use of a more potent AI such as letrozole. Plasma estradiol and estrone sulfate levels from a highly sensitive radioimmunoassay were available for 44 postmenopausal patients who received anastrozole (1 mg per day) for 3 months followed by letrozole (2.5 mg per day) for 3 months or the opposite sequence. Correlations between the estrogen suppression by each AI and BMI were assessed. Baseline values of estradiol and estrone sulfate were significantly correlated with BMI (r = 0.57; P < .001, and r = 0.38; P = .006, respectively). Levels of estrogen in patients receiving treatment were greater at higher levels of BMI with both AIs, but although this was significant with letrozole (r = 0.35; P = .013, and r = 0.30; P = .035 for estradiol and estrone sulfate, respectively), it was not with anastrozole. Suppression of both estrogen types was greater with letrozole across the full range of BMIs in this study. | The susceptibility of neonates to pulmonary and systemic infection has been associated with the immaturity of both lung structure and the immune system. Surfactant protein (SP) D is a member of the collectin family of innate immune molecules that plays an important role in innate host defense of the lung. We tested whether treatment with recombinant human SP-D influenced the response of the lung and systemic circulation to intratracheally administered Escherichia coli lipopolysaccharides. After intratracheal lipopolysaccharide instillation, preterm newborn lambs were treated with surfactant and ventilated for 5 h. Survival rate, physiologic lung function, lung and systemic inflammation, and endotoxin level in plasma were evaluated. In control lambs, intratracheal lipopolysaccharides caused septic shock and death associated with increased endotoxin in plasma. In contrast, all lambs treated with recombinant human SP-D were physiologically stable and survived. Leakage of lipopolysaccharides from the lungs to the systemic circulation was prevented by intratracheal recombinant human SP-D. Recombinant human SP-D prevented systemic inflammation and decreased the expression of IL-1beta, IL-8, and IL-6 in the spleen and liver. Likewise, recombinant human SP-D decreased IL-1beta and IL-6 in the lung and IL-8 in the plasma. Recombinant human SP-D did not alter pulmonary mechanics following endotoxin exposure. Recombinant human SP-D was readily detected in the lung 5 h after intratracheal instillation. |
Are gene-rich large deletions overrepresented in POAG patients of Indian and Caucasian origins? | Large copy number variations (CNV) can contribute to increased burden for neurodegenerative diseases. In this study, we analyzed the genome-wide burden of large CNVs > 100 kb in primary open angle glaucoma (POAG), a neurodegenerative disease of the eye that is the largest cause of irreversible blindness. Genome-wide analysis of CNVs > 100 kb were analyzed in a total of 1720 individuals, including an Indian cohort (347 POAG cases and 345 controls) and a Caucasian cohort (624 cases and 404 controls). All the CNV data were obtained from experiments performed on Illumina 660W-Quad (infinium) arrays. We observed that for both the populations CNVs > 1 Mb was significantly enriched for gene-rich regions unique to the POAG cases (P < 10(-11)). In the Indian cohort CNVs > 1 Mb (39 calls) in patients influenced 125 genes while in controls 31 such CNVs influenced only 5 genes with no overlap. In both cohorts we observed 1.9-fold gene enrichment in patients for deletions compared to duplications, while such a bias was not observed in controls (0.3-fold). Overall duplications > 1 Mb were more than deletions (Del/Dup = 0.82) confirming that the enrichment of gene-rich deletions in patients was associated with the disease. Of the 39 CNVs > 1 Mb from Indian patients, 28 (72%) also were implicated in other neurodegenerative disorders, like autism, schizophrenia, sensorineural hearing loss, and so forth. We found one large duplication encompassing CNTN4 gene in Indian and Caucasian POAG patients that was absent in the controls. | The present study tested the hypothesis that the anesthetic technique will influence the changes in regional blood flow (RBF) during intraoperative cardiac tamponade. Twenty-four dogs were divided into three equal groups: Group I, anesthesia was maintained with ketamine (25 mg.kg(-1).hr(-1)); Group II, with fentanyl and midazolam (F-M; 10 mug.kg(-1).hr(-1) and 0.5 mg.kg(-1).hr(-1), respectively); Group III with 1 minimum alveolar concentration (MAC; 1.4%) isoflurane. Radioactive microspheres were used to measure RBF in myocardium, brain, spinal cord, abdominal viscera, skeletal muscle and skin. Cardiac output (CO) was measured by thermodilution and arterial pressure with a catheter situated in the thoracic aorta. Catheters were introduced into the pericardial cavity to infuse isotonic saline and to measure intrapericardial pressure (IPP). Measurements were obtained under control conditions and during tamponade, as defined by an increase in IPP sufficient to reduce mean arterial pressure by 40%. Tamponade caused decreases in CO and RBF that were comparable under the three anesthetics, except that RBF in subcortical regions of the brain and in the spinal cord were maintained under isoflurane but decreased under ketamine or F-M. |
Do liver myofibroblasts up-regulate monocyte CD163 expression via PGE2 during hepatitis B induced liver failure? | Although patients with liver failure exhibit a generalized inflammatory-imbalance status, substantial evidence indicates that this immunosuppressive or anti-inflammatory state may be deleterious. Increased expression of CD163 (known to be involved in several anti-inflammatory functions of the immune system) in patients with liver failure is significantly correlated with a fatal outcome. However, little is known of the regulatory mechanisms that influence the expression of CD163. We assessed the expression of CD163 on monocytes from both circulating cells and the liver tissues of patients with hepatitis B induced liver failure using flow cytometry and isolated the myofibroblasts from diseased livers. The ability of human liver myofibroblasts to regulate CD163 expression on monocytes was studied in vitro. We showed that CD163⁺ monocytes were enriched primarily in diseased livers and that they were associated with liver myofibroblasts in the same area. Accordingly, liver myofibroblasts were significantly superior to normal skin fibroblasts in inducing the expression of CD163 on monocytes in vitro. Moreover, we found that liver myofibroblasts triggered the activation of monocytes by secreting PGE2. Inhibition of PGE2 production in liver myofibroblasts using NS-398 markedly reduced CD163 expression in vitro. | Determination of left ventricular hypertrophy (LVH) via electrocardiogram (ECG) is a known independent risk factor for cardiovascular morbidity and mortality in hypertension (HTN). Dietary sodium and HTN are both associated with unfavorable alterations in left ventricular mass, however, to what extent their interplay affects ECG screening for LVH is unclear. The effects of controlled dietary sodium manipulation on ECG determinants of LVH in hypertensive subjects were evaluated using well-established voltage criteria for LVH. ECGs from 80 hypertensive subjects were evaluated following random sequence assignment to 7 days of high sodium (HS) intake (200 mEq/24 h), and then 7 days of low sodium (LS) intake (10 mEq/24 h). Sodium restriction over 7 days resulted in significant decreases in overall, and LVH-specific, ECG voltages. Most subjects exhibited decrements in overall ECG voltage with sodium restriction (72%); however, a smaller subset displayed higher voltages when on LS intake (28%). The prevalence of ECG-determined LVH was significantly lowered with LS diet (HS diet 22/80 (28%) vs. LS diet 8/80 (10%), P < 0.05). Subjects exhibiting reversal of LVH status with sodium restriction were younger, demonstrated salt sensitivity of blood pressure, and lower LVH-specific ECG voltage. |
Do compound heterozygotes for filaggrin gene mutations always show severe atopic dermatitis? | Mutations in FLG, which encodes profilaggrin, cause ichthyosis vulgaris (IV) and are an important predisposing factor for atopic dermatitis (AD). IV shows autosomal hemidominant (semidominant) inheritance, and patients with bi-allelic FLG mutations tend to have severe IV phenotypes. However, the effect of bi-allelic FLG mutations on AD incidence and severity remains a subject of controversy. In this study, we studied individuals with bi-allelic null FLG mutations to elucidate the effect of bi-allelic FLG mutations on AD incidence and severity. Six individuals with bi-allelic FLG null mutations from three families of IV/AD were investigated. We report the detailed clinical features of the individuals. The phenotype was confirmed by the clinical examinations and the severity of IV and AD was scored using ichthyosis score and Eczema Area and Severity Index (EASI). It was found that five of the six patients had severe IV, and the remaining patient showed moderate IV. Two of the six had moderate AD and three of the six had mild AD. The remaining patient had no AD. | Postoperative day-case patients are usually allowed to recover from anaesthesia in a postanaesthesia care unit (PACU) before transfer back to the day surgical unit (DSU). Bypassing the PACU can decrease recovery time after day surgery. Cost savings may result from a reduced nursing workload associated with the decreased recovery time. This study was designed to evaluate the effects of bypassing the PACU on patient recovery time and nursing workload and costs. Two hundred and seven consenting outpatients undergoing day surgery procedures were enrolled. Anaesthesia was induced and maintained with a standardized technique and the electroencephalographic bispectral index was monitored and maintained at 40-60 during anaesthetic maintenance. At the end of surgery, patients were randomly assigned to either a routine or fast-tracking (FT) group. Patients in the FT group were transferred from the operating room to the DSU (i.e. bypassing the PACU) if they achieved the FT criteria. All other patients were transferred to the PACU and then to the DSU. Nursing workload was evaluated using a patient care hour chart based on the type and frequency of nursing interventions in the PACU and DSU. A cost associated with the nursing workload was calculated. The overall time from end of anaesthesia to discharge home was significantly decreased in the fast-tracking group. However, overall patient care hours and costs were similar in the two recovery groups. |
Is routine intravascular ultrasound scanning guidance of coronary stenting associated with improved clinical outcomes? | The purpose of the current study was to determine whether there is any incremental benefit to routine intravascular ultrasound (IVUS) guidance of percutaneous coronary intervention. We compared the outcome of 796 patients who underwent an IVUS study (IVUS group) during the index stent procedure with 8274 patients who did not have an IVUS study (angiography group). The primary end point was the composite end point of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months of the index stent procedure. There were statistically significant differences in multiple procedural characteristics. Most importantly, those patients who underwent an IVUS study had a larger postprocedural minimal lumen diameter and smaller postprocedural percent diameter stenosis. However, there was no significant difference between the IVUS group and the angiography group with respect to the primary end point (RR 1.10, 95% CI 0.91, 1.32) or any of the individual clinical end points. Adjustment for multiple clinical and procedural characteristics did not significantly alter these findings. | Rotenone is an environmental neurotoxin that induces accumulation of α-synuclein and degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc), but the molecular mechanisms are not fully understood. We investigated whether rotenone induced impairment of autophagic flux and lysosomal functions. Autophagy flux, accumulation of α-synuclein, lysosomal membrane integrity and neurodegeneration were assessed in the rotenone-treated rat model and PC12 cells, and the effects of the autophagy inducer trehalose on rotenone's cytotoxicity were also studied. Rotenone administration significantly reduced motor activity and caused a loss of tyrosine hydroxylase in SNpc of Lewis rats. The degeneration of nigral dopaminergic neurons was accompanied by the deposition of α-synuclein aggregates, autophagosomes and redistribution of cathepsin D from lysosomes to the cytosol. In cultured PC12 cells, rotenone also induced increases in protein levels of α-synuclein, microtubule-associated protein 1 light chain 3-II, Beclin 1, and p62. Rotenone increased lysosomal membrane permeability as evidenced by leakage of N-acetyl-beta-d-glucosaminidase and cathepsin D, the effects were blocked by reactive oxygen species scavenger tiron. Autophagy inducer trehalose enhanced the nuclear translocation of transcription factor EB, accelerated the clearance of autophagosomes and α-synuclein and attenuated rotenone-induced cell death of PC12 cells. Meanwhile, administration of trehalose to rats in drinking water (2%) decreased rotenone-induced dopaminergic neurons loss in SNpc. |
Is neuronal loss an early component of subacute sclerosing panencephalitis? | We performed diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) studies in a group of patients with subacute sclerosing panencephalitis (SSPE) in order to estimate the pathologic process underlying the phenotypic variability. Patients with SSPE who had MRI including DTI and MRS examinations were evaluated according to their clinical status as determined by the SSPE Scoring System and their mental age as determined by tests appropriate for age and developmental level. Comparisons of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values and metabolite ratios of frontal periventricular white matter, parieto-occipital periventricular white matter, and globus pallidus in both hemispheres were made between control and SSPE groups, and between SSPE subgroups. Control (n = 18) and SSPE (n = 39) groups differed in all DTI and MRS parameters except FA, choline (Cho), and Cho/creatine (Cr). SSPE cases had higher ADC and lower N-acetylaspartate (NAA), NAA/Cho, and NAA/Cr in all regions of interest, suggesting cell loss. Disease progression rate and neurologic deficit appeared to be associated with the degree of ADC elevation and NAA reduction: the group with severe global deterioration had the lowest NAA (230.75 ± 197.97 in forceps minor), and rapid progression was associated with acute reduction in NAA. | Three-year colonoscopic surveillance after initial polypectomy may not be required for all patients. Those with multiple baseline polyps and large adenomas, implicated as predictors of colon cancer, merit close observation. Conversely, patients with single small adenomas may be subjected to early endoscopic surveillance unnecessarily. From our Adenoma Registry we evaluated patient and adenoma characteristics in 697 patients. All had an adenoma recurrence within 3 years of a positive baseline colonoscopy. Potential risk factors studied were age, gender, number of adenomas, size of largest adenoma and histology. We defined a significant outcome as size of 1 cm or greater, tubulovillous or villous histology, high-grade dysplasia, carcinoma in situ, invasive cancer, or 4 or more adenomas. Having 3 or more adenomas on initial colonoscopy with at least 1 measuring 1 cm or larger greatly increased the chance of a significant finding on the first surveillance colonoscopy. Conversely, patients with 1 or 2 adenomas all measuring less than 1 cm were at extremely low risk of an important outcome within 3 years. |
Do myeloid-derived suppressor cells reveal radioprotective properties through arginase-induced l-arginine depletion? | High arginase-1 (Arg) expression by myeloid-derived suppressor cells (MDSC) is known to inhibit antitumor T-cell responses through depletion of l-arginine. We have previously shown that nitric oxide (NO), an immune mediator produced from l-arginine, is a potent radiosensitizer of hypoxic tumor cells. This study therefore examines whether Arg(+) overexpressing MDSC may confer radioresistance through depleting the substrate for NO synthesis. MDSC and Arg expression were studied in preclinical mouse CT26 and 4T1 tumor models and further validated in rectal cancer patients in comparison with healthy donors. The radioprotective effect of MDSC was analyzed in hypoxic tumor cells with regard to l-arginine depletion. In both mouse tumors and cancer patients, MDSC expansion was associated with Arg activation causing accelerated l-arginine consumption. l-Arginine depletion in turn profoundly suppressed the capacity of classically activated macrophages to synthesize NO resulting in impaired tumor cell radiosensitivity. In advanced cT3-4 rectal cancer, circulating neutrophils revealed Arg overexpression approaching that in MDSC, therefore mounting a protumor compartment wherein Arg(+) neutrophils increased from 17% to over 90%. | During lower limb lengthening, distraction-induced muscle pain and surrounding joint contractures are frustrating complications for which few effective treatments are available. We evaluated Botulinum Toxin Type A (BtX-A) injection in the calf muscles during human tibial distraction osteogenesis. We hypothesized that it may decrease calf pain and increase ROM of the surrounding joints by reducing muscle stiffness. Between April 2010 and January 2011, we evaluated 36 patients undergoing bilateral tibia lengthening who met prespecified inclusion criteria. All patients underwent stature lengthening with lengthening over a nail or lengthening and then nailing. BtX-A (200 IU) was injected at the calf muscle only in one leg for each patient and the same amount of sterile normal saline was injected into the other leg as a control. Selection of the leg receiving the toxin was randomized. Clinical evaluation included a VAS score for calf pain and measurement of ROM of the knees and ankles and calf circumference, with evaluations performed in a double-blinded manner. Side-to-side differences were analyzed until the end of consolidation phase. Minimum followup was 24 months (mean, 30 months; range, 24-39 months). The distraction rate and the final length gain were similar in the treated and control limbs. A priori power analysis suggested that 34 legs were required to achieve statistical significance of 0.05 with 80% of power to detect a 50% difference in treatment effect between treatment and control groups. There were no differences in calf pain, knee and ankle ROM, and maximal calf circumferences between the two legs at each time point. |
Do bRAF-V600 mutations have no prognostic impact in stage IV melanoma patients treated with monochemotherapy? | The impact of BRAF tumor mutations on the natural course of disease of melanoma patients is controversial. We analyzed the mutational status and overall survival of 215 patients receiving treatment with dacarbazine or temozolomide. All patients who started first-line treatment at our institution between 2000 and 2010 were included to prevent selection and bias due to thereafter arising therapeutic options. No patient received BRAF- or MEK-inhibitors during follow-up. Survival was associated with the pattern of visceral involvement, the presence of brain metastases and the serum lactate dehydrogenase level (all p<0.001). The BRAF-V600 mutational status was not associated with survival and no differences in overall survival were detected according to age, gender or to the cytotoxic agent used for therapy. In Cox regression analysis the presence of brain metastases (hazard ratio 2.3; p<0.001) and an elevated serum LDH (hazard ratio 2.5; p<0.001) were the only factors, which independently predicted survival. | During real-time monitoring of the ultrafiltration coefficient (Kuf) in haemodiafiltration (HDF), it was noticed that the ultrafiltration performance of polysulphone membrane dialysers increased when hypertonic glucose (D50%) was administered through the venous blood return. This observation was explored in six non-diabetic chronic dialysis patients during 48 HDF sessions using 1.8 m(2) polysulphone membrane dialysers. In all six patients, 24 sessions were performed with glucose supplementation (as a continuous D50% (500 g/l) infusion at 40 ml/h) and 24 sessions without supplementation. Glucose supplementation led to a marked increase in Kuf from 22.8+/-2.2 (without D50%, n=24) to 32. 1+/-3.9 ml/h/mmHg (with D50%, n=24) (P<0.0001). An increase in percentage reduction ratios for urea and creatinine were also consistently observed during the sessions with glucose administration (from respective mean values of 75+/-5 and 68+/-4% to 79+/-4 and 74+/-10%). Mean double-pool Kt/V, calculated from serum urea concentrations, rose from 1.65+/-0.24 (n=24) to 1.86+/-0.24 (n=24) (P<0.005). Similar results were observed in a subgroup of 18 HDF sessions (nine with glucose and nine without) monitored with an on-line urea sensor of spent dialysate. No detrimental effects were induced at any time. |
Do diabetic conditions modulate the adenosine monophosphate-activated protein kinase of podocytes? | Adenosine monophosphate-activated protein kinases (AMPKs), as a sensor of cellular energy status, have been known to play an important role in the pathophysiology of diabetes and its complications. Because AMPKs are known to be expressed in podocytes, it is possible that podocyte AMPKs could be an important contributing factor in the development of diabetic proteinuria. We investigated the roles of AMPKs in the pathological changes in podocytes induced by high-glucose (HG) and advanced glycosylation end products (AGEs) in diabetic proteinuria. We prepared streptozotocin-induced diabetic renal tissues and cultured rat and mouse podocytes under diabetic conditions with AMPK-modulating agents. The changes in AMPKα were analyzed with confocal imaging and Western blotting under the following conditions: (1) normal glucose (5mM, =control); (2) HG (30mM); (3) AGE-added; or (4) HG plus AGE-added. The density of glomerularphospho-AMPKα in experimental diabetic nephropathy decreased as a function of the diabetic duration. Diabetic conditions including HG and AGE changed the localization of phospho-AMPKα from peripheral cytoplasm to internal cytoplasm and peri- and intranuclear areas in podocytes. HG reduced the AMPKα (Thr172) phosphorylation of rat podocytes, and similarly, AGEs reduced the AMPKα (Thr172) phosphorylation of mouse podocytes. The distributional and quantitative changes in phospho-AMPKα caused by diabetic conditions were preventable using AMPK activators, metformin, and 5-aminoimidazole-4-carboxamide-1β-riboside. | Data sources The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Embase. Randomised controlled trials (RCTs) of orthodontic treatment to correct prominent lower front teeth were included. Study screening, risk of bias assessment and data extraction were carried out independently by two reviewers. The mean differences with 95% confidence intervals were calculated for continuous data. Meta-analysis was undertaken when studies of similar comparisons reported comparable outcome measures. A fixed-effect model was used. The l(2) statistic was used as a measure of statistical heterogeneity. Seven RCTs (339 patients) were included in this review. One study was assessed as at low risk of bias, three at high risk of bias and three at unclear risk. Four studies reported on the use of a facemask, two on the chin cup, one on the tandem traction bow appliance and one on mandibular headgear.One study reported on both the chin cup and mandibular headgear appliances. One study (n = 73, low quality evidence), comparing a facemask to no treatment, reported a mean difference (MD) in overjet of 4.10 mm (95% confidence interval (CI) 3.04 to 5.16; P value < 0.0001) favouring the facemask treatment.Three studies (n = 155, low quality evidence) reported ANB differences immediately after treatment with a facemask when compared to an untreated control. The pooled data showed a statistically significant MD in ANB in favour of the facemask of 3.93° (95% CI 3.46 to 4.39; P value < 0.0001). There was significant heterogeneity between these studies (I2 = 82%). This is likely to have been caused by the different populations studied and the different ages at the time of treatment.One study (n = 73, low quality evidence) reported outcomes of the use of the facemask compared to an untreated control at three years follow-up. This study showed that improvements in overjet and ANB were still present three years post-treatment. In this study, adverse effects were reported, but due to the low prevalence of temporomandibular (TMJ) signs and symptoms no analysis was undertaken.Two studies (n = 90, low quality evidence) compared the chin cup with an untreated control. Both studies found a statistically significant improvement in ANB, and one study also found an improvement in the Wits appraisal. Data from these two studies were not suitable for pooling.A single study of the tandem traction bow appliance compared to untreated control (n = 30, very low quality evidence) showed a statistically significant difference in both overjet and ANB favouring the intervention group. The remaining two studies did not report the primary outcome of this review. |
Does the Tardieu Scale differentiate contracture from spasticity whereas the Ashworth Scale is confounded by it? | To compare the Tardieu Scale as a clinical measure of spasticity after stroke with the Ashworth Scale. Cross-sectional study. Sixteen people, living in the community three years after their stroke. The Ashworth Scale and Tardieu Scale as well as laboratory measures of spasticity (stretch-induced electromyographic (EMG) activity) and contracture (maximum passive joint excursion) were collected from the affected elbow flexors and extensors and ankle plantarflexors and dorsiflexors by three examiners who were blinded to the results of the other measures. The percentage exact agreement (PEA) between the Tardieu Scale and a laboratory measure of spasticity was 100% for both the elbow flexors and ankle plantarflexors. This was significantly (P= 0.02) greater than the PEA of 63% for both muscles between the Ashworth Scale and the same laboratory measure of spasticity. For contracture, the PEA between the Tardieu Scale and a laboratory measure was 94% for both the elbow flexors and the ankle plantarflexors. Pearson correlation coefficients between the Tardieu Scale and laboratory measures of spasticity were 0.86 for the elbow flexors and 0.62 for the ankle plantarflexors and between the Tardieu Scale and laboratory measures of contracture were 0.89 for the elbow flexors and 0.84 for the ankle plantarflexors. | Nitric oxide (NO) has previously been shown to inhibit human rhinovirus (HRV) replication in airway epithelial cells and to inhibit rhinovirus-induced epithelial cytokine and chemokine production independently of its effects on viral replication by modulating nuclear translocation and binding of transcription factors. To define the molecular mechanisms by which NO inhibits HRV-16-induced epithelial production of CXCL10 by affecting nuclear translocation and binding of nuclear factor-kappaB (NF-kappaB) and IFN regulatory factor 1 (IRF-1). Cultured human airway epithelial cells were infected with HRV-16 in the absence or presence of a NO donor, or were preincubated with 2 highly selective inhibitors of inhibitor of kappaB kinase (IKK)beta and then infected with HRV-16. Effects on the NF-kappaB and IRF-1 pathways were examined by using electrophoretic mobility shift assays, Western blotting, and real-time RT-PCR. Nitric oxide directly inhibited the binding of both recombinant NF-kappaB p50 protein and recombinant IRF-1 to their recognition sequences from the CXCL10 promoter. NO also inhibited phosphorylation of the NF-kappaB inhibitor, IkappaBalpha, in HRV-16-infected cells. In addition, both NO and inhibitors of IKKbeta inhibited viral induction of IRF-1 mRNA and protein. |
Does the secretome of endothelial progenitor cells promote brain endothelial cell activity through PI3-kinase and MAP-kinase? | Angiogenesis and vascular remodelling are crucial events in tissue repair mechanisms promoted by cell transplantation. Current evidence underscores the importance of the soluble factors secreted by stem cells in tissue regeneration. In the present study we investigated the effects of paracrine factors derived from cultured endothelial progenitor cells (EPC) on rat brain endothelial cell properties and addressed the signaling pathways involved. Endothelial cells derived from rat brain (rBCEC4) were incubated with EPC-derived conditioned medium (EPC-CM). The angiogenic response of rBCEC4 to EPC-CM was assessed as effect on cell number, migration and tubular network formation. In addition, we have compared the outcome of the in vitro experiments with the effects on capillary sprouting from rat aortic rings. The specific PI3K/AKT inhibitor LY294002 and the MEK/ERK inhibitor PD98059 were used to study the involvement of these two signaling pathways in the transduction of the angiogenic effects of EPC-CM. Viable cell number, migration and tubule network formation were significantly augmented upon incubation with EPC-CM. Similar findings were observed for aortic ring outgrowth with significantly longer sprouts. The EPC-CM-induced activities were significantly reduced by the blockage of the PI3K/AKT and MEK/ERK signaling pathways. Similarly to the outcome of the rBCEC4 experiments, inhibition of the PI3K/AKT and MEK/ERK pathways significantly interfered with capillary sprouting induced by EPC-CM. | The diagnosis of acute-onset autoimmune hepatitis (AIH) has been difficult because patients do not always show clinicopathological features typical of AIH. We examined the important requirements for a definitive diagnosis of acute-onset AIH. Clinical, biochemical, and pathological features of 18 acute-onset AIH patients (16 women, 2 men; mean age, 54.3 +/- 12.3 years) with no history of liver disease and no signs of chronicity were examined. Mean ALT was 679 +/- 431 IU/l, and mean T-Bil was 2.4 +/- 2.9 mg/dl. Mean IgG was 1801 +/- 446 mg/dl, with 7 patients (39%) showing normal levels. Antinuclear antibody was <or=1: 40 in 7 (39%). Liver histology showed severe activity in 17 (94%) of the patients and severe acute hepatitis in 7 (39%). Centrizonal necrosis and plasma cell accumulation were characteristic for acute-onset AIH. AIH score ranged from 7 to 18 (13.2 +/- 3.8) before treatment. All patients were diagnosed and treated early and responded completely to therapy. |
Do metabolite findings in tumefactive demyelinating lesions utilizing short echo time proton magnetic resonance spectroscopy? | To use MR spectroscopy to aid in the diagnosis of demyelinating disease and to help differentiate tumefactive demyelinating lesions from neoplastic processes. MR imaging of the brain was obtained in 4 patients who presented clinically with focal neurologic deficits. MR imaging initially revealed parenchymal mass lesions. Single-voxel MR spectroscopy was then performed utilizing a point-resolved spectroscopy sequence protocol with a short echo time (30 msec). MR imaging revealed a focal ring-enhancing mass in one patient, multiple ring-enhancing lesions in the second patient, a large area of edema and mass effect without associated enhancement in the third patient, and multiple solid and peripherally enhancing lesions in the fourth patient. MR spectroscopic results in all 4 patients demonstrated marked elevation of the glutamate and glutamine peaks (2.1-2.5 ppm). Other nonspecific (and in a sense confounding) findings included elevation of the choline peak (3.2 ppm), elevation of the lactate peak (1.3 ppm), elevation of the lipid peak (0.5-1.5 ppm), and decrease in the N-acetylaspartate peak (2.0 ppm). All 4 patients were eventually given the diagnosis of multiple sclerosis based on CSF analysis, brain biopsy, and/or clinical follow-up. | To develop a model to predict which newborns >/=34 weeks gestation with respiratory distress will die or will require prolonged (>3 days) assisted ventilation. Retrospective cohort study using data from Northern California newborns >/=34 weeks gestation who presented with respiratory distress. We split the cohort into derivation and validation datasets. Bivariate and multivariate data analyses were performed on the derivation dataset. After developing a simple score on the derivation dataset, we applied it to the original as well as to a second validation dataset from Massachusetts. Of 2276 babies who met our initial eligibility criteria, 203 (9.3%) had the primary study outcome (assisted ventilation >3 days or death). A simple score based on gestational age, the lowest PaO 2 /FIO 2 , a variable combining lowest pH and highest PaCO 2 , and the lowest mean arterial blood pressure had excellent performance, with a c-statistic of 0.85 in the derivation dataset, 0.80 in the validation dataset, and 0.80 in the secondary validation dataset. |
Are better physician-patient relationships associated with higher reported adherence to antiretroviral therapy in patients with HIV infection? | There is little evidence to support the widely accepted assertion that better physician-patient relationships result in higher rates of adherence with recommended therapies. To determine whether and which aspects of a better physician-patient relationship are associated with higher rates of adherence with antiretroviral therapies for persons with HIV infection. Cross-sectional analysis. Twenty-two outpatient HIV practices in a metropolitan area. Five hundred fifty-four patients with HIV infection taking antiretroviral medications. We measured adherence using a 4-item self-report scale (alpha= 0.75). We measured core aspects of physician-patient relationships using 6 previously tested scales (general communication, HIV-specific information, participatory decision making, overall satisfaction, willingness to recommend physician, and physician trust; alpha > 0.70 for all) and 1 new scale, adherence dialogue (alpha= 0.92). For adherence dialogue, patients rated their physician at understanding and solving problems with antiretroviral therapy regimens. Mean patient age was 42 years, 15% were female, 73% were white, and 57% reported gay or bisexual sexual contact as their primary HIV risk factor. In multivariable models that accounted for the clustering of patients within physicians' practices, 6 of the 7 physician-patient relationship quality variables were significantly (P < .05) associated with adherence. In all 7 models worse adherence was independently associated (P < .05) with lower age, not believing in the importance of antiretroviral therapy, and worse mental health. | Inflammation and reactive oxygen species (ROS) are important in the development of perinatal brain injury. The ROS-generating enzyme NADPH oxidase (Nox2) is present in inflammatory cells and contributes to brain injury in adult animal models. NADPH oxidase contributes to ROS formation and development of injury in the immature brain and inhibition of NADPH oxidase attenuates perinatal brain injury. We used animal models of term hypoxia-ischemia (HI) (P9 mice) as well as ibotenate-induced excitotoxic injury (P5 mice) mimicking features of periventricular leukomalacia in preterm infants. In vitro microglia cell cultures were used to investigate NADPH oxidase-dependent ROS formation. In vivo we determined the impact 1) of HI on NADPH oxidase gene expression 2) of genetic (gp91-phox/Nox2 knock-out) and 3) of pharmacological NADPH oxidase inhibition on HI-induced injury and NMDA receptor-mediated excitotoxic injury, respectively. Endpoints were ROS formation, oxidative stress, apoptosis, inflammation and extent of injury. Hypoxia-ischemia increased NADPH oxidase subunits mRNA expression in total brain tissue in vivo. In vitro ibotenate increased NADPH oxidase-dependent formation of reactive oxygen species in microglia. In vivo the inhibition of NADPH oxidase did not reduce the extent of brain injury in any of the animal models. In contrast, the injury was increased by inhibition of NADPH oxidase and genetic inhibition was associated with an increased level of galectin-3 and IL-1beta. |
Does prophylactic hemodialysis prevent contrast-induced nephropathy after cardiac catheterization in patients with chronic renal insufficiency? | In Japan, prophylactic hemodialysis has been considered useful for preventing contrast-induced nephropathy (CIN). To assess whether hemodialysis prevented CIN, 391 patients (age: 69 +/- 8 years, 63 females) with chronic renal insufficiency (CRI, serum creatinine level (Scr) > or = 1.3 mg/dl) who underwent cardiac catheterization, were retrospectively analyzed. Patients were divided into 3 categories based on Scr: L (1.3 > or = Scr < 2.0 mg/dl, n = 332); M (2.0 > or = Scr < 3.0 mg/dl, n = 49); and H (Scr > or = 3.0 mg/dl, n = 10). To prevent CIN, 35 category M patients and all category L patients received hydration alone, whereas 14 category M patients and all category H patients received hemodialysis. CIN developed in 48 patients. The incidence of CIN in category H was significantly higher than that in category L or M (H, 40% vs L, 11% or M, 16% (p < 0.05)). In category M patients treated with hemodialysis, Scr increased from 2.4 +/- 0.3 to 3.0 +/- 0.5 mg/dl (p < 0.05) within 7 days, and 29% of patients developed CIN. However, in category M patients who did not receive hemodialysis, the Scr did not change (pre, 2.3 +/- 0.2 mg/dl to post, 2.2 +/- 0.4 mg/dl), and the incidence of CIN was 11%. | We hypothesized that dietary polyunsaturated fatty acids (PUFA) could affect the expression of serum fatty acid binding protein 5 (FABP5) and CD36 levels and also fatty acid synthase (FAS), and estrogen receptor (ER) expressions in breast cancer cells. A rat mammary cancer model was induced by injection i.p., with 50 mg MNU/kg body weight. Low (13.8% energy) or high-fat (42.5% energy) diets composed mainly of n-6 or n-3 PUFAs originating either from linoleic acid or linolenic acid, respectively, were given for eight weeks. After sacrifice at week 8, serum FABP5 level was examined and immunostainings of CD36, FAS, and ER of breast cancer tissue were observed. By week 8, there was no statistical difference of tumor formation rate between each group. The level of serum FABP5 in the high n-3 group was significantly lower than the low n-6 and high n-6 groups. Immunohistochemistry results showed that there was a significant difference of CD36 expression between the low n-3 group and high n-6 group (p < 0.05). Although the high n-3 group had the most inhibition on FAS and ER expression, there was no statistical difference between each group. |
Does atorvastatin inhibit osteoclastogenesis by decreasing the expression of RANKL in the synoviocytes of rheumatoid arthritis? | Statins, hydroxymethylglutaryl-coenzyme A reductase inhibitors, have been reported to have antiinflammatory and/or immunomodulatory effects and prophylactic and therapeutic effects in collagen-induced arthritis, an experimental model of rheumatoid arthritis (RA). The authors undertook to determine the effect of atorvastatin on the expressions of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) in RA fibroblast-like synoviocytes (FLSs), to identify the mechanisms responsible for these effects, and to determine whether the statin inhibits osteoclastogenesis. FLSs isolated from five RA patients were cultured in the presence of 20 ng/ml of tumor necrosis factor-α (TNF-α) with or without atorvastatin. RANKL expressions were assayed with Western blotting and enzyme-linked immunosorbent assay. RANKL, RANK, and OPG expression were assayed with reverse transcription-polymerase chain reaction (RT-PCR). Osteoclast formation was assayed by counting cells after staining for tartrate-resistant acid phosphatase in cocultures of peripheral blood mononuclear cells (PBMCs) and RA FLSs. Atorvastatin inhibited the expression of RANKL in RA FLSs in a dose-dependent manner, and the suppression of RANKL was prevented by mevalonate. However, OPG expression was not affected by atorvastatin in RA FLSs, and atorvastatin did not affect RANK expression in CD14⁺ cells. Conversely, atorvastatin suppressed TNF-α-induced p38 phosphorylation in RA FLSs and significantly reduced TRAP-positive multinucleated osteoclast formation in the coculture of PBMCs and RA FLSs. | The present study examined the effects of intraportal infusion of L-arginine on ischemia/reperfusion injury (I/RI) in pig livers, by observing changes in the liver function, liver cell morphology, and changes in the mitochondrial ultrastructure. The involvement of the nitric oxide (NO) pathway in the reperfusion-ischemic phenomenon is complex and not fully understood. Likewise, little is known about the possible benefit of intraportal infusion of L-arginine (substrate for the NO synthesis) on liver I/RI. A pig model consisting of 90 min of hepatic ischemia and 180 min of reperfusion was employed. Eighteen female hybrid pigs were randomly divided into three groups: sham-operated, non-preconditioned, and pharmacologically preconditioned group (intraportal infusion of L-arginine 400 mg/kg) 10 min before being subjected to ischemia and reperfusion. Serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), thiobarbituric acid reactive substances (TBARS), and the bile flow were measured. Liver biopsies were taken 180 min after reperfusion for histology, caspase-3 immunohistochemistry, and ultrastructural examination of mitochondria. In the pharmacologically preconditioned group, we observed increased bile flow (P < 0.01) and improved serum AST levels (P < 0.01) relative to the non-preconditioned group. Serum concentrations of TBARS did not differ between the groups. Sinusoidal congestion (P = 0.02) was more evident in the non-preconditioned group than in the sham operated group. Infiltrating PMNs (P = 0.01) were more evident in the non-preconditioned group than in the sham and pharmacologically preconditioned group. The pharmacologically preconditioned group showed an approximately 2.5-fold decrease in caspase-3 activity relative to the non-preconditioned group (P < 0.01). Notably, damage to the mitochondrial ultrastructure in the pharmacologically preconditioned group was reduced relative to the other groups (P < 0.01). |
Is metabolic syndrome associated with increased risk of Barrett esophagus : A meta-analysis? | Barrett esophagus (BE) is considered precursor condition of esophageal adenocarcinoma. Its incidence and prevalence are increasing in general population. Studies reported that metabolic syndrome (MS) or diabetes mellitus (DM) is related to increased risk of BE. Current study was to assess and better understand the relationship between MS /DM and BE. Electronic search was conducted in the database Pubmed/Medline (-December, 2015), Embase (-December, 2015), Cochrane Library (-December, 2015), and Web of Knowledge (-December, 2015). Studies included were assessed with summary odds ratios (ORs) with 95% confidence intervals (CIs) and compared exposure group with control group. The heterogeneity was examined by the funnel plot and the Egger's test. Subgroup analyses and sensitive analyses were performed for the detection of possible heterogeneity and impact on stability of analysis results. Twelve publications met the criteria and included 355,311 subjects were analyzed. The pooled results showed MS was closely associated with increased risk of BE (OR = 1.23; 95%CI 1.03-1.47; P = 0.024), and yet DM did not significantly increase the risk of BE (OR = 1.07; 95%CI 0.82-1.38; P = 0.627). Substantial heterogeneities were detected. No significant publication bias was detected by Egger's test (P = 0.23). | Coordinated muscle synergies in the human upper limb are controlled, in part, by a neural distribution network located in the cervical spinal cord, known as the cervical propriospinal system. Studies in the cat and non-human primate indicate the cerebellum is indirectly connected to this system via output pathways to the brainstem. Therefore, the cerebellum may indirectly modulate excitability of putative propriospinal neurons (PNs) in humans during upper limb coordination tasks. This study aimed to test whether anodal direct current stimulation (DCS) of the cerebellum modulates PNs and upper limb coordination in healthy adults. The hypothesis was that cerebellar anodal DCS would reduce descending facilitation of PNs and improve upper limb coordination. Transcranial magnetic stimulation (TMS), paired with peripheral nerve stimulation, probed activity in facilitatory and inhibitory descending projections to PNs following an established protocol. Coordination was tested using a pursuit rotor task performed by the non-dominant (ipsilateral) hand. Anodal and sham DCS were delivered over the cerebellum ipsilateral to the non-dominant hand in separate experimental sessions. Anodal DCS was applied to a control site lateral to the vertex in a third session. Twelve right-handed healthy adults participated. Pairing TMS with sub-threshold peripheral nerve stimulation facilitated motor evoked potentials at intensities just above threshold in accordance with the protocol. Anodal cerebellar DCS reduced facilitation without influencing inhibition, but the reduction in facilitation was not associated with performance of the pursuit rotor task. |
Does prognostic significance of MSI2 predict unfavorable outcome in adult B-acute lymphoblastic leukemia? | The Musashi-2 gene (MSI2) is implicated in leukemogenesis, and high MSI2 expression has been associated with decreased survival in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), suggesting its use as a new prognostic marker. We aimed to validate the prognostic significance of MSI2 in ALL. MSI2 expression was measured by real-time polymerase chain reaction in 140 adult B-ALL patients and compared to controls. MSI2 expression level in patients was significantly higher when compared to the control group (P = 0.001). High MSI2 expression did not correlate with the clinical characteristics of patients. However, patients with high MSI2 expression had significantly lower incidence of complete remission (CR) (P = 0.03), inferior overall survival (P = 0.018), and shorter disease-free survival (P = 0.001). Multivariate analysis revealed that high MSI2 expression was an independent prognostic factor for adult BCR-ABL1-negative B-ALL patients. | : During ankle block performance, anesthetizing the sural nerve is important for generating complete anesthesia of the lateral aspect of the foot. We hypothesized that an ultrasound-guided perivascular approach, utilizing the lesser saphenous vein as a reference, would prove more successful than a conventional approach based on surface landmarks. : Eighteen healthy volunteers were prospectively randomized into this controlled and blinded study. Each subject was placed prone and the right ankle was randomized to receive either an ultrasound-guided perivascular sural nerve block (group US) or a traditional landmark-based sural nerve block (group TRAD). The subject's left ankle then received the alternate approach. The ultrasound technique relied on injecting local anesthetic circumferentially around the lesser saphenous vein. All blocks were performed with 5 mL of 3% chloroprocaine. We evaluated sensory block to ice and pinprick. Secondary outcome variables included performance times, number of needle passes, participant satisfaction, and presence of any complications. : At the midfoot position, testing at 10 minutes after block placement revealed a loss of sensation to ice in 94% (complete in 78% and partial in 16%) in the US group versus 56% in the TRAD group (complete in 28%, partial in 28%) (P <.01). Complete loss of sensation to ice persisted in 33% of the US group as compared with 6% in the TRAD group at 60 minutes (P <.05). A similar pattern was observed when the blocks were tested with pinprick. Ultrasound-guided blocks took longer to perform on average than the traditional blocks (mean difference of 102 seconds, P <.001). The ultrasound block was subjectively felt to be denser by 88% of the subjects (P =.001). |
Are food insecurity and gender risk factors for obesity? | Examine relationships between adult obesity, childhood overweight, and food insecurity. Cross-sectional retrospective study. Community settings in Hartford, Connecticut. Convenience sample of 200 parents and their 212 children, aged 2-12. Adult obesity (Body Mass Index [BMI] > 30), childhood overweight (BMI-for-age > 95(th) percentile), and household food security (U.S. Department of Agriculture module). Chi-square tests between weight status and socioeconomic characteristics. Multinomial regression analyses to determine risk factors for adult obesity and childhood overweight. Over half of parents (51%) were obese, and almost one-third of children (31.6%) were overweight. Over half of households were food insecure. Food insecure adults were significantly more likely to be obese as those who were food secure (Odds Ratio [OR]=2.45, p = .02). Being a girl and having an obese parent doubled the likelihood of children being overweight (OR=2.56, P = .01; OR=2.32, P = .03). Children with family incomes below 100% of poverty were half as likely to be overweight as those with higher incomes (OR=.47, P = .05). Food insecurity did not increase odds of childhood overweight. | To explore the effect of artesunate (ART) on cell differentiation and cell cycle distribution of the prostate cancer cell line PC-3 in vitro. PC-3 cells were cultivated with ART from logarithmic growth phase. After 48-hour treatment, the cell cycles were detected by flow cytometry (FCM), and enzyme linked immunosorbent assay was used to detect the level of prostate specific antigen (PSA) in cell culture supernatant. The change of cellular morphology was observed under a transmission electron microscope (TEM). In comparison with the blank control group, the rate of G(0)/G(1) plus S stages of PC-3 cells was significantly decreased in the high-dose ART group. The PC-3 cell was arrested in G(2)/M by ART. The rates of G(2)/M of the high-dose ART group and the medium-dose ART group were obviously higher than those of the blank control group and the cisplatin group (P<0.05). The levels of PSA in the three ART groups were significantly lower than that of the normal control group (P<0.05, P<0.01). In the ART groups, TEM showed that some vacuoles appeared in endochylema, cell polarity was enhanced, cell nucleus leaned to one side of the cell, and microvilli increased on the other side of the cell. |
Is carotid inflammation unaltered by exercise in hypercholesterolemic Swine? | Reduction of vascular inflammation might contribute to the beneficial effects of exercise. We hypothesized that 1) exercise would reduce carotid endothelial vascular cell adhesion molecule-1 (VCAM-1) and that 2) in vivo detection of carotid inflammation can be achieved in a large animal model using contrast-enhanced ultrasound (CEU) with VCAM-1-targeted microbubbles (MBs). Familial hypercholesterolemic (FH) swine were divided into sedentary (Sed) and exercise-trained (Ex) groups. Ex pigs underwent 16-20 wk of treadmill aerobic exercise. At the end of the study, in vivo CEU with VCAM-1-targeted MBs and assessment of endothelial-dependent dilation (EDD) were performed in carotid arteries. VCAM-1 mRNA and protein expression were compared with markers of atherosclerotic disease and health, and in vitro EDD was assessed in carotid arteries. Exercise training neither reduced inflammation nor improved EDD in carotid arteries of FH swine. Markers of atherosclerosis including VCAM-1 were prominent in the bifurcation compared with the proximal or distal common carotid artery and inversely associated with phosphorylated and total endothelial nitric oxide synthase. Signal intensity from VCAM-1-to-control MBs positively correlated with carotid VCAM-1 protein expression, validating our technique. | Primary androgen deprivation therapy (PADT) is the most effective systemic therapy for patients with metastatic prostate cancer. Nevertheless, once PSA progression develops, the prognosis is serious and mortal. We sought to identify factors that predicted the prognosis in a series of patients with metastatic prostate cancer. Two-hundred eighty-six metastatic prostate cancer patients who received PADT from 1998 to 2005 in Nara Uro-Oncology Research Group were enrolled. The log-rank test and Cox's proportional hazards model were used to determine the predictive factors for prognosis; rate of castration-resistant prostate cancer (CRPC) and overall survival. The median age, follow-up period and PSA level at diagnosis were 73 years, 47 months and 174 ng/mL, respectively. The 5-year overall survival rate was 63.0%. The multivariable analysis showed that Gleason score (Hazard ratio [HR]:1.362; 95% confidence interval [C.I.], 1.023-1.813), nadir PSA (HR:6.332; 95% C.I., 4.006-9.861) and time from PADT to nadir (HR:4.408; 95% C.I., 3.099-6.271) were independent prognostic factors of the incidence of CRPC. The independent parameters in the multivariate analysis that predicted overall survival were nadir PSA (HR:5.221; 95% C.I., 2.757-9.889) and time from PADT to nadir (HR:4.008; 95% C.I., 2.137-7.517). |
Does iL-15 expression on RA synovial fibroblasts promote B cell survival? | The purpose of this study was to examine the role of RA Synovial Fibroblast (RASFib) IL-15 expression on B cell survival. Magnetically sorted peripheral blood memory B cells from 15 healthy subjects were cocultured with RASFib. RASFib constitutively expressed membrane IL-15. Survival of isolated B cells cultured for 6 days, below 5%, was extended in coculture with RASFib to 52+/-8% (p<0.001). IL-15 neutralizing agents but not isotype controls, reduced this rate to 31+/-6% (p<0.05). Interestingly, rhIL-15 had no effect on isolated B cells but significantly increased their survival in coculture with RASFib. In parallel, B cell IL-15R chains were upregulated in cocultures. BAFF and VCAM-1, that are expressed on RASFib, were tested as potential candidates involved in upregulating B cell IL-15R. Culture of B cells in the presence of rhBAFF or rhVCAM-1 resulted in significantly increased survival, together with upregulation of all three IL-15R chains; in parallel, rhIL-15 potentiated the anti-apoptotic effect of BAFF and VCAM-1. Both BAFF and VCAM-1 neutralizing agents downmodulated the effect of RASFib on B cell survival and IL-15R expression. In parallel, rhIL-15 had a lower effect on the survival of B cells cocultured with RASFib in the presence of BAFF or VCAM-1 neutralizing agents. Peripheral blood B cells from 15 early RA patients demonstrated an upregulated IL-15R and increased survival in cocultures. | Hypoadiponectinemia is associated with cardiovascular morbidity and diabetes mellitus. We hypothesize that adiponectin may be downregulated in sleep apnea through various mechanisms, contributing to cardiometabolic risks. This study investigated the relationship between serum adiponectin and sleep disordered breathing and its potential determinants. Cross-sectional study. Adult men without prevailing medical comorbidity from the sleep clinic in a teaching hospital. One hundred thirty-four men underwent polysomnography, with mean age of 43.9 (9.8) years, and median apnea-hypopnea index (AHI) of 17.1 (5.7, 46.6). Overnight urine samples for catecholamines and blood samples for analyses of insulin, glucose and adiponectin levels from fasting subjects were taken. Insulin resistance was estimated by homeostasis model assessment (HOMA-IR). Magnetic resonance imaging was performed to quantify the amount of abdominal visceral fat. Serum adiponectin level, adjusted for age, body mass index, and visceral fat volume, was significantly lower in subjects with severe obstructive sleep apnea (AHI > or =30) compared with those with an AHI of less than 30: 4.0 (3.1, 5.4) versus 5.4 (3.6, 7.9) microg/mL, P = 0.039. After we adjusted for adiposity, adiponectin levels remained negatively correlated with AHI (P = 0.037), arousal index (P = 0.022), HOMA-IR/fasting insulin (P < 0.001), and urinary norepinephrine and normetanephrine (P < 0.008). In a multiple stepwise regression model, the independent determinants of adiponectin after adjustment for adiposity were HOMA-IR (P < 0.001) and urinary norepinephrine and normetanephrine (P = 0.037). |
Do axes of astigmatism in fellow eyes show mirror rather than direct symmetry? | Most astigmats have a similar level of astigmatism in each eye. However, there is controversy over whether the astigmatic axes in fellow eyes typically show direct or mirror symmetry. We carried out a statistical analysis designed to address this issue. The median absolute difference in the astigmatic axes of fellow eyes was calculated for a sample of 50 995 astigmats (subjects with at least 0.25 D of astigmatism in each eye). This was done, firstly, for a 'direct symmetry model' in which the difference in axis was calculated as |AxisR - AxisL| and secondly, for a 'mirror symmetry model' in which the difference in axis was calculated as |AxisR - (180 - AxisL)|. Under the direct symmetry model, the median absolute difference in the axis of astigmatism between fellow eyes was 20 degrees. Under the mirror symmetry model, the median absolute difference in the axis of astigmatism between fellow eyes was significantly lower, at 10 degrees (p < 10e-100). Comparable results were found when the analysis was restricted to subjects with: lower levels of astigmatism (< or =1.00 D), higher levels of astigmatism (>1.00 D), against-the-rule astigmatism, with-the-rule astigmatism or oblique astigmatism (all p < 10e-100). | Sepsis is associated with immunosuppression (characterized by a reduced capacity of circulating monocytes to release proinflammatory cytokines), which has been implicated in late mortality. Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast Asia with a mortality of up to 40%. Previous in vitro and murine studies have suggested a key role for the so-called negative regulators of the toll-like receptor (TLR) signaling pathway in immunosuppression. In this study, we investigated the expression of these negative TLR regulators in patients with septic melioidosis in association with the responsiveness of peripheral blood leukocytes of these patients to lipopolysaccharide and B. pseudomallei. Ex vivo study. Academic research laboratory. Thirty-two healthy controls and 34 patients with sepsis caused by B. pseudomallei. None. 1) Plasma cytokine levels; 2) ex vivo cytokine production capacity of whole blood; and 3) purified mononuclear cell-derived messenger RNA (mRNA) levels of key inhibitory molecules of the TLR-signaling cascade were investigated. In accordance with an immunosuppressed state, whole blood of patients demonstrated a strongly decreased capacity to release the proinflammatory cytokines tumor necrosis factor-[alpha], interleukin-1[beta], and the chemokine interleukin-8 after ex vivo stimulation with lipopolysaccharide or B. pseudomallei. Analysis of myeloid-differentiation-88-short, interleukin-1R-associated-kinase (IRAK)-M, IRAK-1, suppressor-of-cytokine signaling-3, Src-homology-2-domain-containing inositol-5-phosphatase-1, single-immunoglobulin-interleukin-1R-related-molecule, and A20 mRNA expression in purified mononuclear cells showed decreased IRAK-1 and elevated IRAK-M expression in patients with septic melioidosis. Immunosuppression was correlated with mortality; furthermore, patients who eventually died had higher IRAK-M mRNA levels on admission than the patients who survived. |
Is chronic rhinosinusitis with and without nasal polyps associated with decreased expression of glucocorticoid-induced leucine zipper? | Chronic rhinosinusitis without nasal polyps (CRSsNP) and with nasal polyps (CRSwNP) is characterized by persistent inflammation of sinonasal mucosa. Glucocorticoid-induced leucine zipper (GILZ) is a recently described anti-inflammatory mediator. Here we analysed the expression of GILZ in CRSsNP and CRSwNP, its association with response to surgery, and its cytokine-driven expression regulation in the upper airways. Methods The messenger RNA (mRNA) and protein expression of GILZ in 33 CRSsNP, 32 CRSwNP, and 11 control samples was assessed by means of a quantitative RT-PCR and immunohistochemistry, respectively. Nasal explant culture was used to investigate the effect of IFN-gamma, IL-4, IL-13, IL-1beta, and TNF-alpha on GILZ mRNA expression in normal sinonasal mucosa. The GILZ mRNA and protein expression was significantly suppressed in both CRSsNP and CRSwNP patients compared with controls. No significant difference in GILZ expression was found between CRSsNP and CRSwNP patients. Comparing patients responsive and patients recalcitrant to surgery, a significant further decrease of GILZ expression was found in recalcitrant patients both in the CRSsNP and in the CRSwNP group. IL-1beta, TNF-alpha, IL-4, and IL-13 reduced, whereas IFN-gamma enhanced GILZ mRNA levels in the sinonasal mucosa. | The aim of this study was to determine the association between 25-hydroxyvitamin D (25(OH)D) and neuroimaging correlates of cerebral small vessel disease. We identified 759 consecutive patients with acute ischemic stroke or transient ischemic attack. Lacunes, white matter hyperintensity, and cerebral microbleed (CMB) were assessed using MR images. Deep CMB was defined as the presence of CMB in basal ganglia, thalamus, or brain stem. The association between 25(OH)D and small vessel disease was tested using linear and logistic regression analyses. Mean age was 68 (±13) years. Mean level of 25(OH)D was 34.1±17.8 nmol/L. On bivariate analysis, a 25-nmol/L decrease in 25(OH)D was associated with lacunes (regression coefficient, 0.23; 95% confidence interval [CI], 0.02-0.45), severe white matter hyperintensity (odds ratio, 2.05; 95% CI, 1.41-3.08), and deep CMB (odds ratio, 1.28; 95% CI, 1.01-1.63). Also, 25(OH)D deficiency (≤25 nmol/L) was associated with lacunes (regression coefficient, 0.5; 95% CI, 0.04-0.95), severe white matter hyperintensity (odds ratio, 2.74; 95% CI, 1.31-6.45), and deep CMB (odds ratio, 1.68; 95% CI, 1.03-2.78). The association remained significant even after multivariable adjustment and in the subgroup of previously healthy patients. |
Is fgf2 expressed in human and murine embryonic choroid plexus and affects choroid plexus epithelial cell behaviour? | Although fibroblast growth factor (Fgf) signalling plays crucial roles in several developing and mature tissues, little information is currently available on expression of Fgf2 during early choroid plexus development and whether Fgf2 directly affects the behaviour of the choroid plexus epithelium (CPe). The purpose of this study was to investigate expression of Fgf2 in rodent and human developing CPe and possible function of Fgf2, using in vitro models. The application of Fgf2 to brain in vivo can affect the whole tissue, making it difficult to assess specific responses of the CPe. Expression of Fgf2 was studied by immunohistochemistry in rodent and human embryonic choroid plexus. Effects of Fgf2 on growth, secretion, aggregation and gene expression was investigated using rodent CPe vesicles, a three-dimensional polarized culture model that closely mimics CPe properties in vivo, and rodent CPe monolayer cultures. Fgf2 was present early in development of the choroid plexus both in mouse and human, suggesting the importance of this ligand in Fgf signalling in the developing choroid plexus. Parallel analysis of Fgf2 expression and cell proliferation during CP development suggests that Fgf2 is not involved in CPe proliferation in vivo. Consistent with this observation is the failure of Fgf2 to increase proliferation in the tri-dimensional vesicle culture model. The CPe however, can respond to Fgf2 treatment, as the diameter of CPe vesicles is significantly increased by treatment with this growth factor. We show that this is due to an increase in cell aggregation during vesicle formation rather than increased secretion into the vesicle lumen. Finally, Fgf2 regulates expression of the CPe-associated transcription factors, Foxj1 and E2f5, whereas transthyretin, a marker of secretory activity, is not affected by Fgf2 treatment. | Total bilirubin (TB) was recently recognized as an endogenous anti-inflammatory and anti-oxidant molecule. Uric acid (UA) takes part in cardiovascular diseases by inducing oxidative stress, inflammation, and endothelial dysfunction. We assessed the relationship between serum TB levels, serum UA levels, and inflammatory status assessed by neutrophil-to-lymphocyte ratio (N/L) and arterial stiffness and arterial wave reflection in patients with a clinical diagnosis of coronary artery disease (CAD). We included 145 consecutive patients admitted with stable angina pectoris (SAP) or acute coronary syndrome (ACS). Blood samples were drawn at admission for complete blood count and biochemistry. Non-invasive pulse waveform analysis for the determination of augmentation index (AIx) and carotid-femoral pulse wave velocity (PWV) measurements were performed with the commercially available SphygmoCor system. When patients were divided into tertiles of PWV and AIx, median N/L and median serum UA levels were the highest and mean TB levels were the lowest in the third tertile (p<0.001 for all). AIx and PWV were positively associated with serum UA and N/L and negatively associated with serum TB levels (p<0.001 for all). After adjustments for age, gender, heart rate, systolic blood pressure, and presence of diabetes, significant correlations persisted for N/L, UA, and TB in ACS patients (p<0.05). In the SAP group, TB was significantly negatively correlated with AIx and PWV, and UA was significantly positively correlated with PWV (p<0.05). |
Is antibody immunity to the p53 oncogenic protein a prognostic indicator in ovarian cancer? | Presence of intratumoral T-cell infiltration has been linked to improved survival in ovarian cancer patients. We questioned whether antibody immunity specific for ovarian cancer tumor antigens would predict disease outcome. We evaluated humoral immune responses against ovarian cancer antigens p53, HER-2/neu, and topoisomerase IIalpha. Serum was collected from 104 women (median age, 59 years; range, 34 to 89 years) at the time of their initial definitive surgery for ovarian cancer. Serum was analyzed by enzyme-linked immunosorbent assay for antibodies to p53, HER-2/neu, and topoisomerase IIalpha proteins. Antibody immunity to tetanus toxoid was assessed as a control. The incidence of humoral immunity at the time of diagnosis to any of these three antigens was tabulated. For patients with advanced-stage disease (III/IV), correlation was made between the presence of tumor-specific immunity at the time of diagnosis and overall survival. Patients were followed for a median of 1.8 years. Multivariate analysis showed the presence of p53 antibodies to be an independent variable for prediction of overall survival in advanced-stage patients. Overall survival was significantly higher for patients with antibodies to p53 when compared with patients without p53 antibodies (P = .01). The median survival for p53 antibody-positive patients was 51 months (95% CI, 23.5 to 60.5 months) compared with 24 months (95% CI, 19.4 to 28.6 months) for patients without antibodies to p53. | The appetite-stimulating properties of cannabis are well documented and have been predominantly attributed to the hyperphagic activity of the psychoactive phytocannabinoid, ∆(9)-tetrahydrocannabinol (∆(9)-THC). However, we have previously shown that a cannabis extract devoid of ∆(9)-THC still stimulates appetite, indicating that other phytocannabinoids also elicit hyperphagia. One possible candidate is the non-psychoactive phytocannabinoid cannabigerol (CBG), which has affinity for several molecular targets with known involvement in the regulation of feeding behaviour. The objective of the study was to assess the effects of CBG on food intake and feeding pattern microstructure. Male Lister hooded rats were administered CBG (30-120 mg/kg, per ora (p.o.)) or placebo and assessed in open field, static beam and grip strength tests to determine a neuromotor tolerability profile for this cannabinoid. Subsequently, CBG (at 30-240 mg/kg, p.o.) or placebo was administered to a further group of pre-satiated rats, and hourly intake and meal pattern data were recorded over 2 h. CBG produced no adverse effects on any parameter in the neuromotor tolerability test battery. In the feeding assay, 120-240 mg/kg CBG more than doubled total food intake and increased the number of meals consumed, and at 240 mg/kg reduced latency to feed. However, the sizes or durations of individual meals were not significantly increased. |
Do interrater reliability of Sensory Integration and Praxis Tests ( SIPT ) score interpretation? | This study examined interrater reliability of score interpretation on the Sensory Integration and Praxis Tests (SIPT). Using SIPT scores of two complex cases, 20 trained participants independently rated each case for presence of sensory integrative dysfunction and for relevance of specific patterns of dysfunction. They also provided comments to justify their ratings. Agreement on the presence of sensory integrative dysfunction was 70% for Case A and 100% for Case B. Reliability was more variable for dysfunctional pattern ratings, ranging from 50% to 100% agreement for Cases A and B, respectively. Participants consistently appeared to use configural decision-making strategies to guide their ratings. | To explore the role of hepatitis C virus (HCV) envelope protein 2 (E2) in the induction of apoptosis. A carboxyterminal truncated E2 (E2-661) was transiently expressed in several cultured mammalian cell lines or stably expressed in Chinese hamster ovary (CHO) cell line. Cell proliferation was assessed by 3H thymidine uptake. Apoptosis was examined by Hoechst 33258 staining, flow cytometry and DNA fragmentation analysis. Reduced proliferation was readily observed in the E2-661 expressing cells. These cells manifested the typical features of apoptosis, including cell shrinkage, chromatin condensation and hypodiploid genomic DNA content. Similar apoptotic cell death was observed in an E2-661 stably expressing cell line. |
Does plantar cutaneous input modulate differently spinal reflexes in subjects with intact and injured spinal cord? | Spinal reflex excitability study in sensory-motor incomplete spinal cord-injured (SCI) and spinal intact subjects. To investigate the effects of plantar cutaneous afferent excitation on the soleus H-reflex and flexion reflex in both subject groups while seated. Rehabilitation Institute of Chicago and City University of New York, USA. The flexion reflex in SCI subjects was elicited by non-nociceptive stimulation of the sural nerve. In normal subjects, it was also elicited via innocuous medial arch foot stimulation. In both cases, reflex responses were recorded from the ipsilateral tibialis anterior muscle. Soleus H-reflexes were elicited and recorded via conventional methods. Both reflexes were conditioned by plantar cutaneous afferent stimulation at conditioning test intervals ranging from 3 to 90 ms. Excitation of plantar cutaneous afferents resulted in facilitation of the soleus H-reflex and late flexion reflex in SCI subjects. In normal subjects, the soleus H-reflex was depressed while the late flexion reflex was absent. The early flexion reflex was irregularly observed in SCI patients, while in normal subjects a bimodal reflex modulation pattern was observed. | The aim of this study was to investigate the expression of ubiquitin-specific peptidase 9, X-linked (USP9X) in non-small cell lung cancer (NSCLC) patients and to evaluate the relevance of USP9X expression to tumor prognosis. Ninety-five patients who underwent surgical resection for clinical stage I-IIIA NSCLC between July 2008 and July 2011 were included in this study. Immunohistochemical analysis of USP9X expression was performed on 95 NSCLC tissues and 32 adjacent normal lung parenchymal tissues from these patients. The Chi-squared test was used to compare the clinicopathological characteristics between different groups. Kaplan-Meier analysis and a Cox regression model were used to determine the independent prognostic factors. A P value <0.05 was considered to be significant. The expression of USP9X was found to be significantly higher in NSCLC tissue (44.2%) than in adjacent normal lung parenchymal tissue (6.3%) (P<0.001). High USP9X expression was significantly associated with positive lymph node metastasis (P<0.001), clinical stage (P<0.001) and a reduced overall survival rate (P=0.001) in patients with NSCLC. Based on the multivariate analysis, the elevated expression of the USP9X protein was a significant predictor of poor prognosis for NSCLC patients (HR =2.244, P=0.028). |
Does non-adherence to the rule of 3 increase the risk of adverse events in esophageal dilation? | Although the rule of 3 is recommended to minimize the risk of perforation when esophageal dilation is performed using bougie dilators, there are no data to validate its use. Our aim was to investigate the association between the rule of 3 and adverse events (AEs) in esophageal dilation. A retrospective chart review in patients who underwent esophageal bougie or balloon dilation between December 1991 and February 2013 at a tertiary hospital was performed. Data collection included patient demographics, stricture and procedural characteristics, AEs, and follow-up. Univariate logistic regression models were used to assess the risk of AEs and perforations. A total of 297 patients (median age, 63 years; 60% men) underwent 2216 esophageal bougie or balloon dilations. Major AEs occurred in 22 (1%) dilation sessions, including 11 (0.5%) perforations, 4 (0.2%) fistulas, 3 (0.1%) hospitalizations for pain management, 2 (0.09%) clinically significant hemorrhages, 1 (0.04%) fever, and 1 (0.04%) tracheoesophageal voice prosthesis leak. Mean duration of treatment was 43.2 months (standard deviation, 47.7 months). Most strictures were benign (n = 275; 93%) and complex in nature (n = 198; 67%). Non-adherence to the rule of 3 occurred in 190 (13%) dilations with bougie dilators. Non-adherence was not associated with a higher rate of major AEs (1/190, 0.5% vs 15/953, 1.6%; P = .18) and perforations (0/190, 0% vs 7/952, 0.7%; P = .18). Gender, complex strictures, location of the stricture, type of dilator, and additional interventions were also not associated with major AEs or perforations. However, malignant strictures were associated with an increased risk of major AEs (odds ratio, 3.5; 95% confidence interval, 1.1-12.0) and perforations (odds ratio, 8.3; 95% confidence interval, 2.2-31.9). | In vivo proton magnetic resonance spectroscopy (1H-MRS) studies of HIV-infected humans have demonstrated significant metabolic abnormalities that vary by brain region, but the causes are poorly understood. Metabolic changes in the frontal cortex, basal ganglia and white matter in 18 SIV-infected macaques were investigated using MRS during the first month of infection. Changes in the N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), creatine (Cr) and glutamine/glutamate (Glx) resonances were quantified both in absolute terms and relative to the creatine resonance. Most abnormalities were observed at the time of peak viremia, 2 weeks post infection (wpi). At that time point, significant decreases in NAA and NAA/Cr, reflecting neuronal injury, were observed only in the frontal cortex. Cr was significantly elevated only in the white matter. Changes in Cho and Cho/Cr were similar across the brain regions, increasing at 2 wpi, and falling below baseline levels at 4 wpi. MI and MI/Cr levels were increased across all brain regions. |
Do rNA binding proteins regulate anabolic and catabolic gene expression in chondrocytes? | Regulation of anabolic and catabolic factors is considered essential in maintaining the homoeostasis of healthy articular cartilage. In this study we investigated the influence of RNA binding proteins (RNABPs) in this process. Using small interfering RNA (siRNA), RNABP expression was knocked down in SW1353 chondrosarcoma cells and human articular chondrocytes. Gene expression and messenger RNA (mRNA) decay of anabolic (SOX9, Aggrecan) and catabolic (matrix metalloproteinase (MMP)13) factors were analysed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). RNA-electromobility shift assays (EMSAs) were used to investigate RNABP interactions with the SOX9 mRNA 3' untranslated region (UTR). Immunohistochemical localisation of MMP13 and the RNABP human antigen R (HuR) was performed in E13.5 and E16.5 mouse embryo sections. SOX9 mRNA, mRNA half-life and protein expression were increased with siRNA targeting the RNABP tristetraprolin (TTP) in both HACs and SW1353s. TTP knockdown also stimulated aggrecan mRNA expression but did not affect its stability. RNA-EMSAs demonstrated that adenine uracil (AU)-rich elements in the SOX9 mRNA 3'UTR interacted with chondrocyte proteins with three specific elements interacting with TTP. HuR knockdown significantly increased MMP13 expression and also regulated the expression of a number of known transcriptional repressors of MMP13. HuR was ubiquitously expressed within mouse embryos yet displayed regional down-regulation within developing skeletal structures. | Fluoroquinolone (FQ) exposure before tuberculosis (TB) diagnosis is common, but its effect on outcomes, including mortality, is unclear. Among TB patients reported to the Tennessee Department of Health from 2007 to 2009, we assessed FQ exposure within 6 months before TB diagnosis. The primary outcome was the combined endpoint of death at the time of TB diagnosis and during anti-tuberculosis treatment. Among 609 TB cases, 214 (35%) received FQs within 6 months before TB diagnosis. A total of 71 (12%) persons died; 10 (2%) were dead at TB diagnosis and 61 (10%) died during anti-tuberculosis treatment. In multivariable logistic regression analysis, factors independently associated with death were older age (OR 1.05 per year, 95%CI 1.04-1.07), human immunodeficiency virus infection (OR 8.08, 95%CI 3.83-17.06), US birth (OR 3.03, 95%CI 1.03-9.09), and any FQ exposure before TB diagnosis (OR 1.82, 95%CI 1.05-3.15). Persons with FQ exposure before TB diagnosis were more likely to have culture- and smear-positive disease than unexposed persons. |
Is a retinoblastoma orthologue a major regulator of S-phase , mitotic , and developmental gene expression in Dictyostelium? | The retinoblastoma tumour suppressor, Rb, has two major functions. First, it represses genes whose products are required for S-phase entry and progression thus stabilizing cells in G1. Second, Rb interacts with factors that induce cell-cycle exit and terminal differentiation. Dictyostelium lacks a G1 phase in its cell cycle but it has a retinoblastoma orthologue, rblA. Using microarray analysis and mRNA-Seq transcriptional profiling, we show that RblA strongly represses genes whose products are involved in S phase and mitosis. Both S-phase and mitotic genes are upregulated at a single point in late G2 and again in mid-development, near the time when cell cycling is reactivated. RblA also activates a set of genes unique to slime moulds that function in terminal differentiation. | This study sought to examine whether plasma brain natriuretic peptide levels can predict prognosis after myocardial infarction. It has been suggested that concentrations of plasma brain natriuretic peptide reflect left ventricular function. Although the prognosis after myocardial infarction depends on residual left ventricular function, it is not known whether plasma levels of brain natriuretic peptide after the onset of myocardial infarction can be used to predict long-term outcome. Plasma brain natriuretic peptide and atrial natriuretic peptide levels as well as invasive hemodynamic variables were measured in 70 patients with acute myocardial infarction (53 men, 17 women; mean age 65 years). Measurements were obtained on admission (mean 6 h after onset) and on day 2 after onset. Mean follow-up period was 18 months. Plasma brain natriuretic peptide levels measured on admission and day 2 correlated significantly with hemodynamic variables, which are influenced by left ventricular function. However, plasma atrial natriuretic peptide levels correlated with none of the hemodynamic variables measured on admission; and of those measured on day 2, plasma atrial natriuretic peptide levels correlated only with left atrial filling pressure. During the follow-up period (mean 18 +/- 7 months), 11 patients died of cardiac causes. By Kaplan-Meier analysis, it was found that patients with plasma brain natriuretic peptide levels higher than the median level, both on admission and on day 2, had significantly higher mortality rates than those with the submedian level (on admission, p < 0.01; on day 2, p < 0.05). However, only the plasma atrial natriuretic peptide level obtained immediately after admission was significantly related to survival (p < 0.01). By Cox proportional hazards model analysis of the noninvasive variables, it was found that plasma brain natriuretic peptide concentration was more closely related to survival after myocardial infarction (p = 0.0001). |
Do [ Growth behavior of spiral ganglion explants on cochlear implant electrodes and their materials ]? | With the increasing use of cochlear implants (CIs), the insertion of alloplastic material into the inner ear is nowadays an established treatment for severe to profound hearing loss in children and adults. Beyond its widespread use, the biocompatibility of the CI electrode and its interaction with the neural structures of the cochlea is not yet established. To investigate the survival and growth behavior of spiral ganglion neurons on different CI materials, spiral ganglion explants from newborn rats were cultured on silicone and platinum, on a surface combination of silicone and platinum, and, finally, on a CI electrode. The results of this study indicate that the growth of spiral ganglion neurons in vitro is strongly influenced by the different materials and their arrangement, with platinum exhibiting the highest degree of biocompatibility with respect to neurite extension. Level differences in the surface structure between silicone and platinum lead to inhibition of neurite outgrowth. Furthermore, the culturing of spiral ganglion explants on a CI electrode leads to neurite sprouting toward the electrodes made of platinum. | To clarify the lowering effect of metabolic syndrome (MetS) on serum prostate-specific antigen (PSA) levels in a Chinese screened population. A total of 45 540 ostensibly healthy men aged 55-69 years who underwent routine health check-ups at Beijing Shijitan Hospital between 2008 and 2015 were included in the study. All the men underwent detailed clinical evaluations. PSA mass density was calculated (serum PSA level × plasma volume ÷ prostate volume) for simultaneously adjusting plasma volume and prostate volume. According to the modified National Cholesterol Education Programme-Adult Treatment Panel (NCEP-ATP) III criteria, patients were dichotomized by the presence of MetS, and differences in PSA density and PSA mass density were compared between groups. Linear regression analysis was used to evaluate the effect of MetS on serum PSA levels. When larger prostate volume in men with MetS was adjusted for, both PSA density and PSA mass density in men with MetS were significantly lower than in men without MetS, and the estimated difference in mean serum PSA level between men with and without MetS was greater than that before adjusting for prostate volume. In the multivariate regression model, the presence of MetS was independently associated with an 11.3% decline in serum PSA levels compared with the absence of MetS. In addition, increasing number of positive MetS components was significantly and linearly associated with decline in serum PSA levels. |
Does transfusion of sex-mismatched and non-leukocyte-depleted red blood cells in cardiac surgery increase mortality? | To examine the mortality risk of blood transfusions when donor information, postdonation treatment, and a wide selection of risk factors are taken into account. A retrospective study was performed on 9907 patients who underwent coronary artery bypass grafting and/or aortic valve replacement. Several transfusion-related risk factors, including age of blood products, sex of donor, ABO group, Rh group, posttransfusion treatment, and sex matching, were included in the analysis. A wide selection of preoperative comorbidities were included as well. A Cox proportional hazards analysis was performed to determine significant risk factors. Patients were followed for a period of up to 12 years posttransfusion. We found an excess mortality for transfusions of sex-mismatched red blood cells (RBCs) per unit transfused (hazard ratio [HR], 1.083; 95% confidence interval [CI] 1.028-1.140; P = .003). In addition, we found a significant risk during the first year for transfusing 1 to 2 units of non-leukocyte-depleted RBCs (HR, 1.426; 95% CI, 1.004-2.024; P = .047). Transfusion of 1 to 2 units of leukocyte-depleted RBCs was not associated with increased risk (HR, 0.981; 95% CI, 0.866-1.110; P = not significant). The age of blood products was not associated with increased mortality. | Enteric glial cells (EGCs) play important roles in enteric integrity and regulation of gastrointestinal function. However, whether EGCs undergo pathophysiological changes in stress-associated gastrointestinal disorders is unknown. We investigated structural and functional alterations in colonic EGCs and their roles in colonic contraction in an irritable bowel syndrome (IBS) model. As a chronic stress, male Wistar rats underwent 3-h maternal separation during postnatal days 2-14. As an acute stress, we used water-immersion stress (4 h) in adulthood (at 8 weeks). We quantitatively and morphologically evaluated enteric neurons and EGCs using whole-mount longitudinal muscle-myenteric plexus preparations. Colonic contraction was analyzed with electrical field stimulation (EFS). Glial fibrillary acidic protein (GFAP) expression and the number of total, cholinergic, and nitrergic neurons were unchanged in maternally separated rats with acute stress (combined stress: an IBS model) compared with controls. However, the density of GFAP-positive EGC processes that apparently overlapped with the neurons and the extent of bulbous swelling of terminals increased according to the stress intensity: control, acute stress, maternal separation, and combined stress. EFS-induced colonic contractions were significantly greater in the combined stress rats than in controls. Higher dose of fluorocitrate, a selective inhibitor of EGC metabolism, was required to inhibit both EFS-induced contraction and EGCs activation in the combined stress rats than in controls. |
Do bacterial communities on classroom surfaces vary with human contact? | Humans can spend the majority of their time indoors, but little is known about the interactions between the human and built-environment microbiomes or the forces that drive microbial community assembly in the built environment. We sampled 16S rRNA genes from four different surface types throughout a university classroom to determine whether bacterial assemblages on each surface were best predicted by routine human interactions or by proximity to other surfaces within the classroom. We then analyzed our data with publicly-available datasets representing potential source environments. Bacterial assemblages from the four surface types, as well as individual taxa, were indicative of different source pools related to the type of human contact each surface routinely encounters. Spatial proximity to other surfaces in the classroom did not predict community composition. | The synergistic effects of the combined ACE and NEP inhibition is based both on the blockade of angiotensin II synthesis and degradation of vasoactive peptides and NEP substrates (ANP, arginine, endothelial cells, guanylat cyclase etc.), including bradykinine and the natriuretic peptides, which contribute to vasodilatation, diuresis and improvement of myocardial function. This study was undertaken to asses the hypotensive effect of a dual ACE/NEP inhibitor (omapatrilat) in comparison to a NEP inhibitor (candoxatril) and ACE inhibitor (enalapril) in SHRS. The study was performed in 130 male spontaneously hypertensive rats (SHRS) that were divided into 4 groups and treated orally by a gastric tube for 14 days according to the following dosage regimen: omapatrilat (40 mg/kg b.w./24 h); candoxatril (30 mg/kg b.w./24 h); enalapril (20 mg/kg b.w./ 24 h) and control (water). Systolic blood pressure values were determined at the beginning of the study by the tail-cuff pletysmographic method, at the 7th and 14th day of the treatment, as well as 14 days after the end of the drug administration. For evaluation of the effect of omapatrilat, candoxatril and enalapril on the investigated parameters (plasma atrial natriuretic peptide and serum ACE), 10 animals from the control group were sacrificed at the beginning of the study, and afterwards 10 animals from each group were also sacrificed on the 7th and 14th day of the treatment, as well as 14 days after the end of the drug administration (28th day). The dual ACE/NEP inhibitor, omapatrilat and the ACE inhibitor, enalapril lowered SBP more effectively than the NEP inhibitor, candoxatril at all time points of the experiment (p < 0.01). Omapatrilat was slightly more effective than the enalapril treatment. |
Does inhibition of HMG CoA reductase reveal an unexpected role for cholesterol during PGC migration in the mouse? | Primordial germ cells (PGCs) are the embryonic precursors of the sperm and eggs. Environmental or genetic defects that alter PGC development can impair fertility or cause formation of germ cell tumors. We demonstrate a novel role for cholesterol during germ cell migration in mice. Cholesterol was measured in living tissue dissected from mouse embryos and was found to accumulate within the developing gonads as germ cells migrate to colonize these structures. Cholesterol synthesis was blocked in culture by inhibiting the activity of HMG CoA reductase (HMGCR) resulting in germ cell survival and migration defects. These defects were rescued by co-addition of isoprenoids and cholesterol, but neither compound alone was sufficient. In contrast, loss of the last or penultimate enzyme in cholesterol biosynthesis did not alter PGC numbers or position in vivo. However embryos that lack these enzymes do not exhibit cholesterol defects at the stage at which PGCs are migrating. This demonstrates that during gestation, the cholesterol required for PGC migration can be supplied maternally. | Endothelin-1 (ET-1), a powerful vasoconstrictor, is a 21 amino acid peptide produced by endothelium. It negatively affects pulmonary, cardiac, hepatic, and renal function. It also constricts bronchial and gut smooth muscle. This peptide also stimulates monocytes to produce prostaglandin E2 (PGE2), tumor necrosis factor, interleukin-6 and 8, and substances that stimulate neutrophil superoxide production. Plasma levels of ET-1 also increase in shock, low flow states, ischemia, and sepsis. Fourteen patients between the ages of seven and 72 years were admitted to the Bridgeport Hospital Burn Unit and resuscitated with a modified Parkland formula. Plasma was drawn on admission, at 12, 24, and 48 hours. Endothelin-1 and PGE2 were measured by radioimmunoassay. Endothelin-1 levels increased ten- to 20-fold in all patients. Prostaglandin E2 levels increased five- to 40-fold in all patients. There was no correlation between plasma ET-1 or PGE2 levels with either size of burn, inhalation injury, patient age, organ dysfunction, or survival in this small study of early burn injury. |
Is a thymic stromal lymphopoietin gene variant associated with asthma and airway hyperresponsiveness? | The epithelial cell-derived protein thymic stromal lymphopoietin stimulates dendritic and mast cells to promote proallergic T(H)2 responses. Studies of transgenic expression of thymic stromal lymphopoietin and its receptor knockout mice have emphasized its critical role in the development of allergic inflammation. Association of genetic variation in thymic stromal lymphopoietin with IgE levels has been reported for human subjects. The aim of this study was to evaluate the relationship between variants of thymic stromal lymphopoietin and asthma and related phenotypes. We selected 6 single nucleotide polymorphisms in thymic stromal lymphopoietin and genotyped 5565 individuals from 4 independent asthma studies and tested for association with asthma, atopy, atopic asthma, and airway hyperresponsiveness by using a general allelic likelihood ratio test. P values were corrected for the effective number of independent single nucleotide polymorphisms and phenotypes. The A allele of rs1837253, which is 5.7 kb upstream of the transcription start site of the gene, was associated with protection from asthma, atopic asthma, and airway hyperresponsiveness, with the odds ratios and corrected P values for each being 0.79 and 0.0058; 0.75 and 0.0074; and 0.76 and 0.0094, respectively. Associations between thymic stromal lymphopoietin and asthma-related phenotypes were the most statistically significant observations in our study, which has to date examined 98 candidate genes. Full results are available online at http://genapha.icapture.ubc.ca/. | To determine the impact of two apparent diffusion coefficient (ADC) measurement techniques on diffusion-weighted magnetic resonance images (DW MRI) on the assessment of rectal cancer response to neoadjuvant chemoradiotherapy (CRT). ADC values were measured prospectively with two different techniques - the first, which measures ADCs in the most cellular tumor parts, and the second, which measures the entire tumor area, in 58 patients with locally advanced rectal cancer on pre-CRT and post-CRT image sets. Areas under the receiver operating characteristic curves (AUCs) and parameters of diagnostic accuracy were calculated for pre- and post-CRT ADC values and numeric and percent ADC change for each technique to determine their performance in tumor response evaluation using histopathological tumor-regression grade as the reference standard. The second technique yielded higher AUCs (0.935 vs 0.704, P<.001), percent-change (0.828 vs 0.636, P<0.001), and numeric-change (0.866 vs 0.653, P<0.001) than the first technique for post-CRT ADC. Accuracies for post-CRT ADC assessment were 62% for the first and 88% for the second technique (cut-off values: 0.98 and 1.29×10(-3) mm2/s, respectively) and for ADC change assessment, both numeric and percent, 59% and 74%, respectively (cut-off values: increase of 0.18 and 0.28×10(-3) mm(2)/s; increase of 24% and 37%, respectively). |
Does transcutaneous vagus nerve stimulation modulate tinnitus-related beta- and gamma-band activity? | The ability of a treatment method to interfere with tinnitus-related neural activity patterns, such as cortical gamma rhythms, has been suggested to indicate its potential in relieving tinnitus. Therapeutic modulation of gamma-band oscillations with vagus nerve stimulation has been recently reported in epileptic patients. The aim of this study was to investigate the effects of transcutaneous vagus nerve stimulation (tVNS) on neural oscillatory patterns. We calculated the power spectral density and synchrony of magnetoencephalography recordings during auditory stimulation in seven tinnitus patients and eight normal-hearing control subjects. Comparisons between subject groups were performed to reveal electrophysiological markers of tinnitus. tVNS-specific effects within each group were studied by comparing recording blocks with and without tVNS. We also investigated the correlation of each measure with individual ratings of tinnitus distress, as measured by the tinnitus handicap inventory questionnaire. Tinnitus patients differed from controls in the baseline condition (no tVNS applied), measured by both cortical oscillatory power and synchronization, particularly at beta and gamma frequencies. Importantly, we found tVNS-induced changes in synchrony, correlating strongly with tinnitus handicap inventory scores, at whole-head beta-band (r = -0.857, p = 0.007), whole-head gamma-band (r = -0.952, p = 0.0003), and frontal gamma-band (r = -0.952, p = 0.0003). | Interaction of macrophages with aggregated matrix-anchored lipoprotein deposits is an important initial step in atherogenesis. Aggregated lipoproteins require different cellular uptake processes than those used for endocytosis of monomeric lipoproteins. In this study, we tested the hypothesis that engagement of aggregated LDL (agLDL) by macrophages could lead to local increases in free cholesterol levels and that these increases in free cholesterol regulate signals that control cellular actin. AgLDL resides for prolonged periods in surface-connected compartments. Although agLDL is still extracellular, we demonstrate that an increase in free cholesterol occurs at sites of contact between agLDL and cells because of hydrolysis of agLDL-derived cholesteryl ester. This increase in free cholesterol causes enhanced actin polymerization around the agLDL. Inhibition of cholesteryl ester hydrolysis results in decreased actin polymerization. |
Is a high-fat diet associated with otitis media with effusion? | An association between obesity and otitis media with effusion (OME) has been previously reported. The aim of this study was to evaluate the association between dietary intake and OME when adjusting obesity. We analyzed the differences in dietary intake between children with/without OME who were 4 through 13 years of age using data from a large population-based survey - the Korea National Health and Nutrition Examination Survey - from 2008 through 2012. Data from 4359 participants were analyzed using simple and multiple logistic regression analyses with complex sampling. The BMI category, the proportion of total calorie intake, protein intake, water intake, and Na intake (intake/recommendation), and the distribution of carbohydrate intake were not associated with OME. The distribution of fat intake was associated with OME (each 10% increase of fat calories/total calories: unadjusted odds ratio [OR]=1.331, 95% confidence interval [CI]=1.016-1.744, P=0.038; age- and sex-adjusted OR=1.359, 95% CI=1.028-1.797, P=0.031; adjusted for age, sex and other factors OR=1.392, 95% CI=1.054-1.839, P=0.020). Based on BMI subgroup analysis, the distribution of fat intake was associated with OME in the healthy weight group (each 10% increase of fat calories/total calories: unadjusted OR=1.393, 95% CI=1.017-1.909, P=0.039; adjusted OR=1.470, 95% CI=1.051-2.055, P=0.024) but not in the obese group. | The restoration of coronary flow after transient ischemia immediately induces life-threatening ventricular tachyarrhythmias. Although most of these arrhythmias disappear spontaneously, some of them induce serious hemodynamic changes. This retrospective study investigates the efficacy of therapy with intracoronary verapamil to terminate reperfusion-induced ventricular tachyarrhythmias in patients with acute myocardial infarction (AMI). Between February 1992 and February 2003, 390 patients with a diagnosis of AMI were enrolled into the study. All patients received mechanical revascularization therapy within 6 h of onset of symptoms, and 109 patients experienced reperfusion-induced tachyarrhythmias. A subset of these patients was treated with intracoronary verapamil (0.25 to 1.0 mg) to terminate the reperfusion-induced tachyarrhythmia. They were evaluated for immediate termination of the tachyarrhythmias, hemodynamic changes, resumption rates, and major complications. Thirty-one patients (28%) were treated with intracoronary verapamil for the immediate termination of reperfusion-induced ventricular tachyarrhythmias. These tachyarrhythmias included 6 premature ventricular contractions, 19 accelerated idioventricular rhythms, 3 ventricular tachycardias, 2 ventricular fibrillations (VFs), and 1 torsades de pointes. Intracoronary verapamil was effective in rapidly terminating all reperfusion-induced arrhythmias except for VFs. The side effects of treatment included temporary hypotension (two patients) and bradycardia (one patient), although all patients recovered spontaneously. No major complications were induced by the intracoronary use of verapamil, and no resumptions of arrhythmias were documented. |
Do personality and choice of coping predict quality of life in head and neck cancer patients during follow-up? | The aim of the present study was to investigate to what extent personality and choice of coping predicted self-reported quality of life (QoL) in successfully treated head and neck squamous cell carcinoma (HNSCC) patients. We determined QoL by the European Organization for Research and Treatment of Cancer Quality of life Questionnaire (EORTC-QLQ) C30/H&N35, personality by the Eysenck Personality Inventory and coping by the COPE questionnaire. All patients younger than 80 years who had been diagnosed with HNSCC in Western Norway in the period from 1992 to1997, and who had survived until 1999, were sampled. Ninety-six patients (90% response rate) were included 48+/-2 months after diagnosis. Fifty-five of 58 eligible patients were interviewed a second time 47+/-1 months after the first interview where neuroticism and QoL questionnaires were answered. Numerical T stage was inversely associated with the second QoL scores (CV: 10-24%). High neuroticism generally predicted low secondary QoL scores both directly (common variance: 17-25%) and adjusted by the QoL values measured simultaneously as the neuroticism (CV: 11-25%). Avoidance focused, problem focused, drinking to cope and coping by humor all predicted QoL scores (CV: 8.5-15%). The present association pattern could still be shown when adjusted for gender, age and educational level when studied by multiple regression analyses. | Although clinical investigations indicate that the limit of reversibility of rotator cuff muscles fibers type I and II atrophy is grade 2 of fatty degeneration (FD) according to the Goutallier computed tomography classification, little is known about the morphometric verification of these findings. The supraspinatus tendon was detached from the greater tubercle and the infraspinatus and subscapularis in 12 rabbits, and a 12-week observation period followed. This proved to be sufficient for development of grade >2 FD of the supraspinatus tendon. The tendon was then reinserted. The animals were euthanized 24 weeks after tendon reconstruction. The sections of middle part of supraspinatus were stained for adenosine triphosphatase reaction, and morphometric measurements were taken of type I and II muscle fiber diameters. The contralateral shoulders served as controls. The macroscopic inspection of the supraspinatus tendons revealed complete healing in all cases. No statistically significant differences were found between controls and operated-on shoulders for type I (P = .13) and type II (P = .55) muscle fibers. |
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