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21,386,828 | Is inflammatory bowel disease associated with an increased incidence of cardiovascular events? | Patients with inflammatory bowel disease (IBD) present with several extraintestinal manifestations, including systemic inflammation and hypercoagulability. Limited studies have shown that patients with IBD may have a higher risk of developing atherosclerosis. The incidence of coronary artery disease (CAD) and the role of traditional CAD risk factors in IBD patients remain unclear. We sought to compare the rates of CAD events in patients with IBD with matched controls. We performed a longitudinal cohort study of patients with IBD compared with matched controls. The primary outcome was the development of CAD events. Traditional and nontraditional CAD risk factors were assessed. Cox proportional hazards model was used to assess the impact of each CAD risk factor on the outcomes. A total of 356 IBD patients and 712 matched controls were followed for a median of 53 and 51 months, respectively. The unadjusted hazard ratio (HR) for developing CAD in the IBD group was 2.85 (95% confidence interval (CI) 1.82-4.46). IBD patients had significantly lower rates of selected traditional CAD risk factors (hypertension, diabetes, dyslipidemia, and obesity; P<0.01 for all). Adjusting for these factors, the HR for developing CAD between groups was 4.08 (95% CI 2.49-6.70). Among nontraditional risk factors, an elevated white blood cell (WBC) count was a risk factor for CAD development in the IBD group (HR 1.23; 95% CI 1.15-1.33). | An increased incidence of CAD events was noted in IBD patients despite having a lower burden of traditional risk factors. Additionally, these risk factors had a lower impact on CAD development in the IBD group. Further investigation into how nontraditional risk factors, including WBC count, and the effect of attenuating systemic inflammation in IBD patients change CAD risk is warranted. |
20,973,264 | Does syndecan-1 overexpression promote tumor growth and angiogenesis in an endometrial cancer xenograft model? | Upregulation of syndecan-1, a member of the transmembranous proteoglycans that serves as a coreceptor for a wide pool of extracellular ligands, has been well documented in enabling the promotion of growth and invasion of endometrial cancer. As a step toward understanding a potential role for syndecan-1 in this process, we questioned whether syndecan-1 upregulates tumor-promoting characteristics, particularly, angiogenesis in an in vivo human xenograft tumor model. Human syndecan-1 was stably transfected into human endometrial adenocarcinoma 1A cells, and resulting transfectants were subcutaneously grafted into athymic mice; their outcomes were examined with respect to the enhancement of tumor growth and angiogenesis by immunohistochemistry, immunoblotting, and zymography. Overexpression of syndecan-1 promoted tumor growth concomitant with increased angiogenesis in tumor xenografts as evidenced by an increase in immunoreactivity for vascular endothelial growth factor and vascular endothelial cell marker CD34. Furthermore, zymographic studies revealed that syndecan-1 overexpression markedly enhanced activities of matrix metalloproteinases 2 and 9. | This is the first in vivo xenograft analysis providing evidence that supports that syndecan-1 has a critical role in carcinogenic progression, particularly, contributing to the development of angiogenesis and invasive phenotype in association with matrix metalloproteinases 2 and 9 activations in endometrial cancer. |
15,845,145 | Do stereophysicochemical variability plots highlight conserved antigenic areas in Flaviviruses? | Flaviviruses, which include Dengue (DV) and West Nile (WN), mutate in response to immune system pressure. Identifying escape mutants, variant progeny that replicate in the presence of neutralizing antibodies, is a common way to identify functionally important residues of viral proteins. However, the mutations typically occur at variable positions on the viral surface that are not essential for viral replication. Methods are needed to determine the true targets of the neutralizing antibodies. Stereophysicochemical variability plots (SVPs), 3-D images of protein structures colored according to variability, as determined by our PCPMer program, were used to visualize residues conserved in their physical chemical properties (PCPs) near escape mutant positions. The analysis showed 1) that escape mutations in the flavivirus envelope protein are variable residues by our criteria and 2) two escape mutants found at the same position in many flaviviruses sit above clusters of conserved residues from different regions of the linear sequence. Conservation patterns in T-cell epitopes in the NS3- protease suggest a similar mechanism of immune system evasion. | The SVPs add another dimension to structurally defining the binding sites of neutralizing antibodies. They provide a useful aid for determining antigenically important regions and designing vaccines. |
19,689,459 | Do fluvastatin and lovastatin inhibit granulocyte macrophage-colony stimulating factor-stimulated human eosinophil adhesion to inter-cellular adhesion molecule-1 under flow conditions? | Eosinophil accumulation in the lung is an important feature of airway inflammation in asthma. There is therefore much interest in developing novel therapies to prevent this process. Accumulating evidence suggests that statins have anti-inflammatory properties, including inhibition of leucocyte accumulation. We therefore assessed the ability of five statins to inhibit human eosinophil adhesion to recombinant human inter-cellular adhesion molecule (rhICAM)-1 under physiologically relevant flow conditions. Purified eosinophils were pre-treated with a panel of statins before elucidation of the adhesion profiles of resting and granulocyte macrophage-colony stimulating factor (GM-CSF)-stimulated cells to rhICAM-1-coated microchannels at a flow rate of 0.5 dynes/cm(2). Images were recorded in real-time at 1 min intervals and analysed using Ducocell software. Fluvastatin and lovastatin (both 10 nm) significantly inhibited GM-CSF-stimulated eosinophil adhesion to rhICAM-1 after 2 min (34.4+/-3.0% inhibition and 37.8+/-12.6% inhibition, respectively, n=4, P<0.05) but had no significant inhibitory effect on unstimulated eosinophil adhesion. Mevastatin, simvastatin, and pravastatin (all 10 nm) had no significant effect on GM-CSF-stimulated eosinophil adhesion to rhICAM-1. A concentration range of fluvastatin and lovastatin inhibited GM-CSF stimulated eosinophil adhesion with significant (P<0.05) inhibition observed at low concentrations of 1 nm for both drugs. Mevalonate (100 nm) reversed fluvastatin-mediated but not lovastatin-mediated inhibition of eosinophil adhesion. | Inhibition of eosinophil adhesion to ICAM-1 by fluvastatin and lovastatin under physiological shear stress represent novel actions by these drugs that may inform the development of anti-inflammatory therapy for allergic disease. |
21,966,512 | Does hepatitis E virus ORF2 protein activate the pro-apoptotic gene CHOP and anti-apoptotic heat shock proteins? | Hepatitis E virus (HEV) is a non-enveloped plus-strand RNA virus that causes acute hepatitis. The capsid protein open reading frame 2 (ORF2) is known to induce endoplasmic reticulum stress in ORF2 expressing cells. In this study we found that HEV ORF2 activates the expression of the pro-apoptotic gene C/EBP homologous protein (CHOP). ORF2 stimulates the CHOP promoter mainly through AARE (amino acid response elements) and to a minor extent the ERSE (endoplasmic reticulum stress response elements). Activating transcription factor 4 (ATF4) protein binds and activates the AARE regulatory sites of the CHOP promoter. ORF2 expression also leads to increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) that in turn initiates the translation of ATF4 mRNA. The pro-apoptotic gene CHOP is an important trigger to initiate endoplasmic reticulum stress induced apoptosis. However, the activation of CHOP by ORF2 in this study did not induce apoptosis, nor did BCL2-associated X protein (Bax) translocate to mitochondria. Microarray analysis revealed an ORF2 specific increased expression of chaperones Hsp72, Hsp70B', and co-chaperone Hsp40. Co-immunoprecipitation (Co-IP) and in silico molecular docking analysis suggests that HEV ORF2 interacts with Hsp72. In addition, Hsp72 shows nuclear accumulation in ORF2 expressing cells. | These data provide new insight into simultaneously occurring counter-acting effects of HEV ORF2 that may be part of a strategy to prevent host suicide before completion of the viral replication cycle. |
16,911,916 | Is p38 MAP kinase activity correlated with angiotensin II type 1 receptor blocker-induced left ventricular reverse remodeling in spontaneously hypertensive heart failure rats? | Angiotensin II type 1 receptor blocker L-158,809 (ARB) induces reverse left ventricular (LV) remodeling in spontaneously hypertensive heart failure (SHHF) rats. However, the signaling mechanism that mediates ARB-induced reverse LV remodeling remains unclear. The present study was to determine if changes in mitogen-activated protein kinase (MAPK, including ERK, JNK, and p38) signaling correlate with ARB-elicited reversal of cardiac hypertrophy in SHHF rats. In 1 set of experiments, 5-month-old lean female SHHF rats were treated with L-158,809 (ARB) or the vasodilator hydralazine (HYD) for 1 month, respectively. In a second set of experiments, 5-month-old SHHF rats were treated with ARB for 6 months or 1 month and then with HYD for 5 months. Either ARB or HYD normalized left ventricular end systolic pressure in SHHF rats relative to normotensive control Wistar Furth (WF) rats at both 6 and 11 months of age, but only ARB reduced heart-to-body weight ratio in SHHF rats to control level. Western blot analysis showed that cardiac p38 MAPK activity was markedly increased in 6-month-old SHHF rats, but dramatically reduced in 11-month-old SHHF rats compared with WF rats, as indicated by the levels of phosphorylated form of p38. The alterations in p38 activity were completely reversed by ARB treatment but not by HYD treatment. | ARB restored normal cardiac p38 activity, which coincided with ARB-induced reverse LV remodeling in SHHF rats, suggesting a strong correlation between p38 signaling and cardiac remodeling. |
8,378,957 | Is evidence from comparative investigations that impaired platelet activation specific for stroke-prone spontaneously hypertensive rats? | Platelet behavior of Sprague Dawley (SD), Wistar (WI), Wistar-Kyoto (WKY), spontaneously hypertensive (SHR), and stroke-prone spontaneously hypertensive rats (SHRSP) was studied in vivo to evaluate the importance of hypertension-related hemostatic disorders. The study was based on the model of stimulus-induced pulmonary microembolization of labeled platelets. After injection of 51Cr-labeled homologous platelets into urethane-anesthetized rats, the organ distribution of the platelets was continuously monitored by gamma detectors. Count rates of two detectors--one placed above the animals' thoraxes (C1), the other above their abdomens (C2)-and the ratio of C1:C2 were calculated. The following platelet activators were applied intravenously: adenosine diphosphate (ADP; 50 micrograms/kg), collagen (100 micrograms/kg), and thrombin (50 IU/kg). All three substances caused a reversible pulmonary accumulation of the labeled platelets and hence an increase in C1/C2 (delta C1/C2%). ADP induced a shift of 75% in SD, 52% in WI, 32% in WKY, 30% in SHR, and 31% in SHRSP. Thrombin-mediated shift was 79% in SD, 64% in WI, 58% in WKY, 48% in SHR, and 54% in SHRSP. Collagen induced a shift of 85% in SD, 96% in WI, 84% in WKY, 56% in SHR, and 62% in SHRSP. | Because indistinguishable results were observed in both hypertensive strains, we conclude that impaired platelet aggregation is not specific for SHRSP. Hence, it may not primarily be responsible for the increased occurrence of stroke in these animals. |
17,352,961 | Does oral intake of Lactobacillus fermentum CECT5716 enhance the effects of influenza vaccination? | We studied the coadjuvant capability of oral consumption of the breast-milk-isolated strain Lactobacillus fermentum (CECT5716) for an anti-influenza vaccine. A randomized, double-blinded, placebo-controlled human clinical trial including 50 volunteers (31 male and 19 female) was performed to address the immunologic effects of an intramuscular anti-influenza vaccine in adults (33.0 +/- 7.7 y old). Fifty percent of volunteers received an oral daily dose of methylcellulose (placebo) or probiotic bacteria (1 x 10(10) colony-forming units/d) 2 wk before vaccination and 2 wk after vaccination. Two weeks after vaccination there was an increase in the proportion of natural killer cells in the probiotic group but not in the placebo group. The vaccination induced an increase in T-helper type 1 cytokine concentrations and in T-helper and T-cytotoxic proportions in both groups; however, the probiotic group showed a significant higher induction in some of these parameters. Regarding the humoral effects, induction of antibody response in the placebo group could not be detected. In the case of the probiotic group, a significant increase in antigen specific immunoglobulin A was detected. Although an increase in total immunoglobulin M was observed, changes in anti-influenza antigen specific immunoglobulin M were not observed. The incidence of an influenza-like illness during 5 mo after vaccination (October to February) was lower in the group consuming the probiotic bacteria. | Oral administration of the strain L. fermentum CECT5716 potentates the immunologic response of an anti-influenza vaccine and may provide enhanced systemic protection from infection by increasing the T-helper type 1 response and virus-neutralizing antibodies. |
14,971,126 | Was it a good move? | This study examined whether transition from hospital to hostel improves patients' quality of life (QOL). In a longitudinal prospective study comparing the QOL of 16 patients who moved to a hostel with that of 20 who remained hospitalized, we posited that the former would exhibit improved QOL. We also assessed the reliability of psychiatric patients' reports by comparing them with staff reports. No changes were reported in the QOL of hospitalized patients, whereas those who moved to the hostel exhibited significant improvement in all aspects of life, as reflected in the World Health Organizations Quality of Life measure (WHOQOL-BREF), reports by patients and staff and subjective (but not objective) indicators in the TL30s questionnaire. Patients' reports reflect a higher QOL improvement than staff reports but both display similar trends regarding changes in QOL. | It was concluded that the move from the hospital to the hostel improved the QOL of the patients. |
25,735,513 | CT-guided Interstitial Brachytherapy of Hepatocellular Carcinoma before Liver Transplantation: an Equivalent Alternative to Transarterial Chemoembolization? | Transarterial chemoembolization (TACE) is established as bridging therapy of HCC listed for transplantation (LT). CT-guided brachytherapy (CTB) has not been evaluated as a bridging concept. We compared CTB and TACE for bridging before LT in HCC patients. Twelve patients with HCC received LT after CTB (minimal tumour dose, 15-20 Gy). Patients were matched (CTB:TACE, 1:2) by sex, age, number and size of lesions, and underlying liver disease with patients who received TACE before transplantation. Study endpoints were extent of necrosis at histopathology and recurrence rate after OLT. There were no significant differences between the CTB and TACE groups regarding Child-Pugh category (p = 0.732), AFP (0.765), time on waiting list (p = 0.659), number (p = 0.698) and size (p = 0.853) of HCC lesions, fulfilment of Milan-criteria (p = 0.638), or previous liver-specific treatments. CTB achieved higher tumour necrosis rates than TACE (p = 0.018). The 1- and 3-year recurrence rate in the CTB group was 10 and 10 % vs. TACE, 14 and 30 % (p = 0.292). | Our data show comparable or even better response and post-LT recurrence rates of CTB compared to TACE for treating HCC in patients prior to LT. CTB should be further evaluated as an alternative bridging modality, especially for patients not suited for TACE. |
27,746,201 | Are eosinophils in chronic obstructive pulmonary disease exacerbations associated with increased readmissions? | A subset of patients with chronic obstructive pulmonary disease (COPD) demonstrates eosinophilic inflammation either in their sputum or blood. Previous studies regarding the association between increased blood eosinophils and poor readmission outcomes are conflicting. Investigate outcomes following severe COPD exacerbations in patients with higher blood eosinophils. With an observational study design, hospitalizations for severe COPD exacerbation were retrospectively gathered. Patient health data previous to and up to one year following the index hospitalization were included. Patients were stratified into the eosinophilic group if the blood eosinophil level on admission was ≥200 cells/μL and/or ≥2% of the total white blood cell count. Clinical outcomes were 12-month COPD-related readmission, 12-month all-cause readmission, length of stay, and time to COPD-related readmission. These outcomes were analysed using logistic, negative binomial, and Cox regression models. A total of 167 patients were included: 55 with eosinophilia. Eosinophilia was associated with an increased risk of 12-month COPD-related readmission (OR 3.59 [1.65-7.82], p=0.0013), an increased risk of 12-month all-cause readmission (2.32 [1.10-4.92], p=0.0277), and a shorter time to first COPD-related readmission (HR 2.74 [1.56-4.83], p=0.0005). The length of stay was not statistically different between eosinophilic and non-eosinophilic patients. Sensitivity analyses using different eosinophilia definitions reveal a proportional increase in effect size with increasing eosinophil cell count definitions for predicting 12-month readmissions. | Blood eosinophils can be used as a biomarker in severe COPD exacerbations for predicting higher readmission rates. |
22,516,785 | Late post-partum dyspareunia: does delivery play a role? | To study whether post-partum dyspareunia one year after a delivery is associated with characteristics of delivery: perineal trauma, obstetric interventions and women's experience. A self-administered questionnaire on post-partum sexual function was mailed in May 2002 to all consecutive women who gave birth to a live-born term infant in a maternity unit, between January 2001 and June 2001. Obstetric data were abstracted from the hospital computerized medical database. Late dyspareunia was defined as pain during intercourse, one year after delivery. Multiple logistic regression modeling was used to select independent predictors of late post-partum dyspareunia. Seventy (27.6%) of the 254 women studied experienced late dyspareunia. There was no relation between late post-partum dyspareunia and neither the mode of delivery nor state of the perineum, including perineal laceration or episiotomy. Multiple logistic regression analysis showed that late post-partum dyspareunia was associated with dyspareunia before pregnancy, low satisfaction with delivery, and employment status. | Late post-partum dyspareunia seemed to be linked more with the mother's experience of childbirth than with perineal trauma. This hypothesis should be investigated further. |
18,226,130 | Can adiponectin predict abnormal glucose tolerance in Thai women with polycystic ovary syndrome? | A 75-g oral glucose tolerance test (OGTT) with fasting adiponectin and insulin (FI) blood sampling in 170 women with PCOS were performed consecutively. The prevalence of AGT was 45.9%. The body mass index (BMI), waist-to-hip ratio (WHR), fasting glucose and 2-h postload glucose were greater in the PCOS women with AGT than those without AGT (P<0.001). In addition, the PCOS women with AGT had more severe insulin resistance (IR) and lower adiponectin levels than those without AGT. However, the area under the ROC curve of adiponectin and insulin in predicting AGT was smaller than that of homeostatic model of IR (HOMA-IR) (P<0.01). The arbitrary cut-off values at 12 ug/mL of adiponectin, 10 microiu/mL of FI and 2 of HOMA-IR showed the sensitivity and specificity of 80.8% and 33.7%; 87.2% and 34.8%; and 89.7% and 31.5%, respectively. With these cut-off points, 46 (27.1%), 42 (24.7%) and 37 (21.8%) women, respectively, could be eliminated from performing OGTT. However, 15 (19.2%), 10 (12.8%) and 8 (10.3%), respectively, missed the diagnosis. In addition, with WHR and acanthosis nigricans adjustment, HOMA-IR, but not adiponectin, was a significant predictor of AGT. | Our study demonstrated that almost half of the women with PCOS had AGT. Adiponectin levels were significantly lower in the PCOS women with AGT than those without AGT. However, adiponectin was not shown to be as strong a predictive factor and might not be such an excellent screening test as FI and HOMA-IR. |
18,422,492 | Does circumcision make a difference to the sexual experience of gay men? | The relevance of circumcision in preventing male-to-male sexual transmission of HIV is poorly understood, in particular because any potential beneficial effect could be diminished by the impact of circumcision on sexual behavior.AIM: We examined the impact of circumcision on sexual experience. Univariate and multivariate logistic regressions were performed on data from 1,426 HIV-negative homosexually active men. We compared the sexual behaviors and preferences of circumcised with uncircumcised men, and men who were circumcised at infancy with those who were circumcised after infancy. Overall, 66% of men (N = 939) in the cohort were circumcised. After adjusting for age and ethnicity, we found no differences between circumcised and uncircumcised men in any insertive or receptive anal intercourse, difficulty using condoms, or sexual difficulties (e.g., loss of libido). Among the circumcised men, we compared those circumcised at infancy (N = 854) with those circumcised after infancy (N = 81). The majority cited phimosis (i.e., an inability to fully retract the foreskin) and parents' decision as the main reasons for circumcision after infancy. After adjusting for age and ethnicity, the men circumcised after infancy were more likely to practice any receptive anal sex (88% vs. 75%, P<0.05) and to experience erection difficulties (52% vs. 47%, P<0.05), but less likely to practice any insertive anal sex (79% vs. 87%, P<0.05) and to experience premature ejaculation (15% vs. 23%, P<0.05) than those circumcised at infancy. | Our data suggest that overall circumcision status does not affect the HIV-negative gay men's anal sexual behaviors, experience of condom use, or likelihood of sexual difficulties. However, there is some suggestion of differences in sexual practices and preferences among circumcised gay men depending on the age at circumcision. In particular, gay men circumcised later are more likely to engage in and prefer receptive anal intercourse. |
18,818,417 | Is notch3 a major regulator of vascular tone in cerebral and tail resistance arteries? | Notch3, a member of the evolutionary conserved Notch receptor family, is primarily expressed in vascular smooth muscle cells. Genetic studies in human and mice revealed a critical role for Notch3 in the structural integrity of distal resistance arteries by regulating arterial differentiation and postnatal maturation. We investigated the role of Notch3 in vascular tone in small resistance vessels (tail and cerebral arteries) and large (carotid) arteries isolated from Notch3-deficient mice using arteriography. Passive diameter and compliance were unaltered in mutant arteries. Similarly, contractions to phenylephrine, KCl, angiotensin II, and thromboxane A2 as well as dilation to acetylcholine or sodium nitroprusside were unaffected. However, Notch3 deficiency induced a dramatic reduction in pressure-induced myogenic tone associated with a higher flow (shear stress)-mediated dilation in tail and cerebral resistance arteries only. Furthermore, RhoA activity and myosin light chain phosphorylation, measured in pressurized tail arteries, were significantly reduced in Notch3KO mice. Additionally, myogenic tone inhibition by the Rho kinase inhibitor Y27632 was attenuated in mutant tail arteries. | Notch3 plays an important role in the control of vascular mechano-transduction, by modulating the RhoA/Rho kinase pathway, with opposite effects on myogenic tone and flow-mediated dilation in the resistance circulation. |
27,671,904 | Do non-modifiable factors predict discharge quality after robotic partial nephrectomy? | To identify predictors of poor discharge quality after robotic partial nephrectomy (RPN) at a large academic center. We queried our institutional RPN database for consecutive patients treated between 2011 and 2015. The primary outcome was poor discharge quality, defined as length of stay >3 days and/or unplanned readmission. The association between patient, disease, and provider factors and overall discharge quality was assessed using univariate and multivariable analyses. Of 791 cases, 219 (27.7 %) had poor discharge quality. On univariate analysis, factors associated with poor discharge quality were older age (p < .01), black race (p = .01), social insurance (p < .01), higher ASA score (p < .01), chronic kidney disease (p < .01), increased tumor size (p < .01), and higher tumor complexity (p = .01). Surgeon case volume did not predict discharge quality (p = .63). After adjustment for covariates on multivariable analysis, race (p = .01), ASA (p = .02), CKD (p < .01), tumor size (p = .02), and tumor complexity (p = .03) still predicted poor discharge quality. In particular, the odds of poor discharge quality were highest in the setting of CKD (OR 2.62, 95 % CI 1.72-4.01), black race (OR 2.17, 95 % CI 1.32-3.57), and higher ASA (OR 1.49, 95 % CI 1.07-2.08). | Non-modifiable patient and disease factors predict poor discharge quality after RPN. Risk adjustment for these factors will be important for determining future reimbursement for RPN providers. |
19,274,752 | Does extracellular matrix modulate sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor beta-induced apoptosis? | Hepatocytes in culture are a valuable tool to investigate mechanisms involved in the response of the liver to cytokines. However, it is well established that hepatocytes cultured on monolayers of dried stiff collagen dedifferentiate, losing specialized liver functions. In this study, we show that hepatocyte dedifferentiation is a reversible consequence of a specific signaling network constellation triggered by the extracellular matrix. A dried stiff collagen activates focal adhesion kinase (FAK) via Src, leading to activation of the Akt and extracellular signal-regulated kinase (ERK) 1/2 pathways. Akt causes resistance to transforming growth factor beta (TGF-beta)-induced apoptosis by antagonizing p38, whereas ERK1/2 signaling opens the route to epithelial-mesenchymal transition (EMT). Apoptosis resistance is reversible by inhibiting Akt or Src, and EMT can be abrogated by blocking the ERK1/2 pathway. In contrast to stiff collagen, a softer collagen gel does not activate FAK, keeping the hepatocytes in a state where they remain sensitive to TGF-beta-induced apoptosis and do not undergo EMT. In this culture system, inhibition of p38 as well as overexpression of constitutively active Akt causes apoptosis resistance, whereas constitutively active Ras induces EMT. Finally, we show that matrix-induced EMT is reversible by replating cells from dried stiff to soft gel collagen. Our results demonstrate that hepatocyte dedifferentiation in vitro is an active process driven by FAK-mediated Akt and ERK1/2 signaling. This leads to similar functional and morphological alterations as observed for regenerating hepatocytes in vivo and is reversible when Akt and/or ERK1/2 signaling pathways are antagonized. | Hepatocytes can exist in a differentiated and a dedifferentiated state that are reversible and can be switched by manipulating the responsible key factors of the signaling network. |
27,174,035 | Do hepatitis E virus mutations associated with ribavirin treatment failure result in altered viral fitness and ribavirin sensitivity? | Ribavirin monotherapy is the preferred treatment for chronic hepatitis E, although occasional treatment failure occurs. We present a patient with chronic hepatitis E experiencing ribavirin treatment failure with a completely resistant phenotype. We aimed to identify viral mutations associated with treatment failure and explore the underlying mechanisms. Viral genomes were deep-sequenced at different time points and the role of identified mutations was assessed in vitro using mutant replicons, antiviral assays, cell culture of patient-derived virus and deep-sequencing. Ribavirin resistance was associated with Y1320H, K1383N and G1634R mutations in the viral polymerase, but also an insertion in the hypervariable region comprising a duplication and a polymerase-derived fragment. Analysis of these genome alterations in vitro revealed replication-increasing roles for Y1320H and G1634R mutations and the hypervariable region insertion. In contrast, the K1383N mutation in the polymerase F1-motif suppressed viral replication and increased the in vitro sensitivity to ribavirin, contrary to the clinical phenotype. Analysis of the replication of mutant full-length virus and in vitro culturing of patient-derived virus confirmed that sensitivity to ribavirin was retained. Finally, deep-sequencing of hepatitis E virus genomes revealed that ribavirin is mutagenic to viral replication in vitro and in vivo. | Mutations Y1320H, G1634R and the hypervariable region insertion compensated for K1383N-associated replication defects. The specific role of the K1383N mutation remains enigmatic, but it appears to be of importance for the ribavirin resistant phenotype in this patient. |
20,080,980 | Does the DSM-IV clinical significance criterion for major depression reduce false positives? | To reduce false positive diagnoses, DSM-IV added a clinical significance criterion to many diagnostic criteria sets requiring that symptoms cause significant distress or impairment. The DSM-V Task Force is considering whether clinical significance should remain a diagnostic threshold or become a separate dimension, as it is in ICD. Yet, the criterion's effectiveness in validly reducing the prevalence of specific disorders remains unclear. Critics have argued that for some categories, notably major depression, the criterion is redundant with symptoms, which are inherently distressing or impairing. The authors empirically evaluated the criterion's effect on the prevalence of major depression in the community. This report also considers more broadly the relationship of symptoms to impairment in diagnosis. Subjects were respondents, aged 18 to 54 years, who participated in the National Comorbidity Survey Replication (N=6,707). The effect of the clinical significance criterion's distress and impairment components on major depression was assessed in this sample. Distress questions were administered to all respondents reporting persistent sadness (>or = 2 weeks) or the equivalent. Questions pertaining to role impairment were asked of all respondents satisfying major depression symptom-duration criteria. Of 2,071 individuals reporting persistent sadness or the equivalent, 97.2% (N=2,016) satisfied criteria for distress. Of 1,542 individuals satisfying depression symptom-duration criteria, 96.2% (N=1,487) satisfied criteria for impairment. | These findings support the redundancy thesis. Distress is virtually redundant with symptoms of persistent sadness, even in the absence of major depression, and impairment is almost always entailed by major depression-level symptoms. Thus, the clinical significance criterion does not substantially reduce the prevalence of major depression in the community. The DSM-V Task Force should consider eliminating the criterion and explore alternative ways to identify false positives in the diagnosis of depression. The criterion's status for other disorders should be evaluated on a disorder-by-disorder basis because the diagnostic relationship between symptoms and impairment varies across categories. |
16,671,449 | Does bolus tracer delivery measured by MRI confirm edema without blood-brain barrier permeability in diffuse traumatic brain injury? | Previous studies have shown that edema formation after diffuse traumatic brain injury (TBI) with secondary insult is cytotoxic and not vasogenic. This assumption is based on observations of reduced apparent diffusion coefficient (ADC) and lack of significant accumulation of intravascular tracer in brain tissue. However, ADC reduction does not exclude vasogenic edema, and intravascular tracer can only accumulate when it reaches the tissue and is not perfusion limited. This study aims to confirm tissue delivery of intravascular tracer and lack of BBB opening during a phase of rapid brain swelling after diffuse TBI. Rats were exposed to either TBI using the impact acceleration model combined with 30 minutes of hypoxia and hypotension, or sham injury. At 2 or 4 hours after injury, ADC and tissue water content were assessed using MRI. Gd-DTPA was given followed by a combination of rapid T2 imaging (60 seconds) and T1 imaging (30 minutes). Signal intensity changes were analyzed to determine a bolus effect (dynamic susceptibility contrast) and longer-term tissue accumulation of Gd-DTPA. Mean increase in cortical water content on the left was 0.8% at 2 hours, 2.1% at 4 hours; on the right it was 0.5% at 2 hours and 1.7% at 4 hours (p < 0.05). Mean ADC reduction over 4 hours was 0.04 x 10(-3) mm2/s on the left and 0.06 x 10(-3) mm2/s on the right. Kinetic analysis of signal intensity changes after Gd-DTPA showed no significant difference in inward transfer coefficient (BBB permeability) between sham injury and 2 or 4 hours post-injury. T2 imaging showed consistent tissue delivery of a bolus of Gd-DTPA to the tissue at 2 and 4 hours post-injury, comparable to sham animals. | Progressive cerebral edema formation after diffuse TBI occurred during ADC reduction and without continued BBB permeability. Tissue delivery of Gd-DTPA was confirmed, verifying that lack of tracer accumulation is due to an intact BBB and not to limited perfusion. |
26,837,315 | Does miR-320a mediate doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway? | Vascular homeostasis abnormalities may involve in doxorubicin induced cardiotoxicity. Enhanced cardiac miR-320a expression, reduced cardiac microvessel density and impaired cardiac function were observed in mice treated by anthracycline doxorubicin. To further explore the role of miR-320a in doxorubicin induced cardiotoxicity, microRNA mimics/inhibitor in vitro and rAAV administration in vivo were employed in mice. Knockdown of miR-320a not only resulted in enhanced proliferation and inhibited apoptosis in cultured endothelial cells, but also attenuated cardiac abnormalities induced by doxorubicin. On the contrary, overexpression of miR-320a enhanced apoptosis in vitro, and aggravated vessel abnormalities in heart and subsequent cardiac dysfunction in mice. Furthermore, Western blot assays showed that VEGF-A was a potential target of miR-320a, which was verified by anti-Ago2 co-immunoprecipitation. Moreover, as same as miR-320a, siRNA against VEGF-A reinforced doxorubicin induced endothelial cells injury. Finally, the negative effects of miR-320a on vascular homeostasis and cardiac function were alleviated by VEGF-A re-expression in doxorubicin treated mice. | Our observations demonstrate that miR-320a play important roles in doxorubicin induced cardiotoxicity via vessel homeostasis in heart and thus, inhibition of miR-320a may be applied to the treatment of cardiac dysfunction induced by anthracycline. |
17,314,069 | Does re-operation have an effect on outcome following heart transplantation? | Previous cardiac operation has traditionally been considered as a potential risk factor for patients undergoing heart transplantation. This study aimed to evaluate the outcome of patients undergoing heart transplantation as a second cardiac procedure and compare it with primary heart transplantation, using meta-analytical methodology. A literature search was undertaken to identify relevant comparative studies. Outcomes of interest were classified into four categories: (a) intra-operative times; (b) post-operative outcomes; (c) resources; (d) actuarial outcomes. Seven studies matched the selection criteria, reporting on 1004 patients. Six hundred and twenty-three had transplantation as primary operation and 381 as re-operation. The 1-year, 2-year, and 5-year mortality were similar for the two groups (HR=0.85, p=0.54; HR=0.97, p=0.88; and HR=1.04, p=0.92, respectively). Total operative, cold-ischaemic, by-pass, and cross-clamp times were significantly longer for the re-operation group by 59.44 (p<0.001), 14.62 (p=0.05), 25.24 (p<0.001), and 7.93 (p<0.001)min, respectively. Both ICU and hospital stay were longer for the re-operation group but only the former was statistically significant (WMD=1.37; p=0.02). Post-operative complications were similar, except re-exploration rate and blood transfusion requirement, which were higher in the re-operation group (OR=3.51; p<0.001 and WMD=2.21; p<0.001, respectively). | Heart transplantation following previous cardiac operation is technically demanding requiring longer operative times compared to primary heart transplantation. It does not, however, add a significant risk to the survival of the patient, and associated morbidity is not significantly compromised. |
21,542,908 | Does rostral growth of commissural axons require the cell adhesion molecule MDGA2? | Long-distance axonal growth relies on the precise interplay of guidance cues and cell adhesion molecules. While guidance cues provide positional and directional information for the advancing growth cone, cell adhesion molecules are essential in enabling axonal advancement. Such a dependence on adhesion as well as guidance molecules can be well observed in dorsal commissural interneurons, which follow a highly stereotypical growth and guidance pattern. The mechanisms and molecules involved in the attraction and outgrowth towards the ventral midline, the axon crossing towards the contralateral side, the rostral turning after midline crossing as well as the guidance along the longitudinal axis have been intensely studied. However, little is known about molecules that provide the basis for commissural axon growth along the anterior-posterior axis. MDGA2, a recently discovered cell adhesion molecule of the IgCAM superfamily, is highly expressed in dorsolaterally located (dI1) spinal interneurons. Functional studies inactivating MDGA2 by RNA interference (RNAi) or function-blocking antibodies demonstrate that either treatment results in a lack of commissural axon growth along the longitudinal axis. Moreover, results from RNAi experiments targeting the contralateral side together with binding studies suggest that homophilic MDGA2 interactions between ipsilaterally projecting axons and post-crossing commissural axons may be the basis of axonal growth along the longitudinal axis. | Directed axonal growth of dorsal commissural interneurons requires an elaborate mixture of instructive (guidance) and permissive (outgrowth supporting) molecules. While Wnt and Sonic hedgehog (Shh) signalling pathways have been shown to specify the growth direction of post-crossing commissural axons, our study now provides evidence that homophilic MDGA2 interactions are essential for axonal extension along the longitudinal axis. Interestingly, so far each part of the complex axonal trajectory of commissural axons uses its own set of guidance and growth-promoting molecules, possibly explaining why such a high number of molecules influencing the growth pattern of commissural interneurons has been identified. |
22,236,315 | Is distance to provider a barrier to care for medicaid patients with breast, colorectal, or lung cancer? | Distance to provider might be an important barrier to timely diagnosis and treatment for cancer patients who qualify for Medicaid coverage. Whether driving time or driving distance is a better indicator of travel burden is also of interest. Driving distances and times from patient residence to primary care provider were calculated for 3,917 breast, colorectal (CRC) and lung cancer Medicaid patients in Washington State from 1997 to 2003 using MapQuest.com. We fitted regression models of stage at diagnosis and time-to-treatment (number of days between diagnosis and surgery) to test the hypothesis that travel burden is associated with timely diagnosis and treatment of cancer. Later stage at diagnosis for breast cancer Medicaid patients is associated with travel burden (OR = 1.488 per 100 driving miles, P= .037 and OR = 1.270 per driving hour, P= .016). Time-to-treatment after diagnosis of CRC is also associated with travel burden (14.57 days per 100 driving miles, P= .002 and 5.86 days per driving hour, P= .018). | Although travel burden is associated with timely diagnosis and treatment for some types of cancer, we did not find evidence that driving time was, in general, better at predicting timeliness of cancer diagnosis and treatment than driving distance. More intensive efforts at early detection of breast cancer and early treatment of CRC for Medicaid patients who live in remote areas may be needed. |
12,657,967 | Does pancreatic somatostatin inhibit insulin secretion via SSTR-5 in the isolated perfused mouse pancreas model? | The function of pancreatic somatostatin in insulin secretion is controversial, and the receptor(s) mediating such event has not been exclusively investigated. To differentiate the specific role of SSTR5 in the mouse pancreas, we generated a mouse SSTR5 gene ablation model. Mice homozygous for the deletion (SSTR5-/-) and wild type (WT) littermate controls underwent whole pancreas perfusion to determine the effect of SSTR5 gene ablation on glucose-stimulated insulin secretion. The perfusion was done with and without octreotide added to the infusion buffer. Furthermore, pancreatic somatostatin was immunoneutralized by using a potent somatostatin monoclonal antibody to determine whether pancreatic somatostatin regulates insulin secretion in these mice. Results showed that at 3 months of age, there were no alterations in insulin secretion compared with WT controls. However, glucose-stimulated insulin secretion was significantly enhanced in 12-month-old SSTR5-/- mice compared with WT controls. The addition of octreotide to the perfusion significantly suppressed insulin secretion in WT controls, while it had no effect on SSTR5-/- mice. Immunoneutralization of pancreatic somatostatin resulted in enhanced glucose-stimulated insulin secretion in WT controls, but decreased levels of insulin secretion in SSTR5-/- mice. | These results suggest that, in the mouse, pancreatic somatostatin regulates insulin secretion through SSTR5, and that the effect is age-specific. |
20,608,900 | Does the diuretic bumetanide decrease autistic behaviour in five infants treated during 3 months with no side effects? | The inhibitory transmitter GABA has been suggested to play an important role in infantile autistic syndrome (IAS), and extensive investigations suggest that excitatory actions of GABA in neurological disorders are because of a persistent increase of [Cl(-) ](I) . To test the effects of the chloride co-transporter NKCC1 diuretic compound Bumetanide that reduces [Cl(-) ](I) on IAS. Bumetanide was administered daily (1mg daily) during a 3-month period and clinical and biological tests made. We used 5 standard IAS severity tests - Childhood Autism Rating Scale, Aberrant Behaviour Checklist, Clinical Global Impressions; Repetitive and Restrictive Behaviour and the Regulation Disorder Evaluation Grid. We report a significant improvement in IAS with no side effects. | Bumetanide decreases autistic behaviour with no side effects suggesting that diuretic agents may exert beneficial effects on IAS and that alterations of the actions of GABA may be efficient in IAS treatment calling for large scale randomized trials. |
27,538,686 | Urban rural differences in diet, physical activity and obesity in India: are we witnessing the great Indian equalisation? | The rising morbidity and mortality due to non-communicable diseases can be partly attributed to the urbanized lifestyle leading to unhealthy dietary practices and increasing physical levels of inactivity. The demographic and nutrition transition in India has also contributed to the emerging epidemic of non-communicable diseases in this country. In this context, there is limited information in India on dietary patterns, levels of physical activity and obesity. The aim of the present study was thus to assess the urban rural differences in dietary habits, physical activity and obesity in India. A household survey was done in the state of Punjab, India in a multistage stratified sample of 5127 individuals using the WHO STEPS questionnaire. No rural urban difference was found in dietary practices and prevalence of overweight and obesity except the fact that a significantly higher proportion of respondents belonging to rural area (15.6 %) always/often add salt before/when eating as compared to urban area (9.1 %). Overall 95.8 % (94.6-97.0) of participants took less than 5 servings of fruits and/or vegetables on average per day. No significant urban rural difference was noted in both sexes in all three domains of physical activity such as work, transport and recreation. However, rural females (19.1 %) were found to be engaged in vigorous activity more than the urban females (6.3 %). Males reported high levels of physical activity in both the settings. Absence of recreational activity was reported by more than 95 % of the subjects. Higher prevalence of obesity (asian cut offs used) was seen among urban females (34.3 %) as compared to their rural counterparts (23.2 %). Abdominal obesity was found to be significantly higher among females in both the settings compared to males (p < 0.001). | Poor dietary practices and physical inactivity seems to fuel the non-communicable disease epidemic in India. Non communicable disease control strategy need to address these issues with a gender equity lens. Rapid urbanization of rural India might be responsible for the absence of a significant urban rural difference. |
24,135,759 | Do orbital fibroblasts from thyroid eye disease patients differ in proliferative and adipogenic responses depending on disease subtype? | Thyroid eye disease (TED) patients are classified as type I (predominantly fat compartment enlargement) or type II (predominantly extraocular muscle enlargement) based on orbital imaging. Orbital fibroblasts (OFs) can be driven to proliferate or differentiate into adipocytes in vitro. We tested the hypothesis that type I OFs undergo more adipogenesis than type II OFs, whereas type II OFs proliferate more than type I OFs. We also examined the effect of cyclooxygenase (COX) inhibitors on OF adipogenesis and proliferation. Type I, type II, and non-TED OFs were treated with transforming growth factor-beta (TGFβ) to induce proliferation and with 15-deoxy-Δ(-12,14)-prostaglandin J2 (15d-PGJ2) to induce adipogenesis. Proliferation was measured using the [(3)H]thymidine assay, and adipogenesis was measured using the AdipoRed assay, Oil Red O staining, and flow cytometry. The effect of COX inhibition on adipogenesis and proliferation was also studied. Type II OFs incorporated 1.7-fold more [(3)H]thymidine than type I OFs (P < 0.05). Type I OFs accumulated 4.8-fold more lipid than type II OFs (P < 0.05) and 12.6-fold more lipid than non-TED OFs (P < 0.05). Oil Red O staining and flow cytometry also demonstrated increased adipogenesis in type I OFs compared to type II and non-TED OFs. Cyclooxygenase inhibition significantly decreased proliferation and adipogenesis in type II OFs, but not type I OFs. | We have demonstrated that OFs from TED patients have heterogeneous responses to proproliferative and proadipogenic stimulators in vitro in a manner that corresponds to their different clinical manifestations. Furthermore, we demonstrated a differential effect of COX inhibitors on type I and type II OF proliferation and adipogenesis. |
19,641,316 | Does induction of p14ARF by E2F1 contribute to 8-chloro-adenosine-induced apoptosis in human lung cancer H1299 cells? | 8-Chloro-adenosine (8-Cl-Ado) inhibits tumor cell proliferation by inducing cell-cycle arrest and apoptosis. We speculate that upregulation of p14ARF by E2F1 might contribute to 8-Cl-Ado-induced late apoptosis. Hoechst staining, cell proliferation and TUNEL assays, real-time quantitative PCR, Western blotting, chromatin immunoprecipitation and RNA interference were employed in investigating the role of induction of p14ARF by E2F1 in 8-Cl-Ado-induced apoptosis in human lung cancer H1299 cells. Exposure of H1299 to 8-Cl-Ado led to apoptosis after long exposure (48 h), revealed by the appearance of nucleus fragmentation and apoptotic bodies and the activation of procaspase-3 pathway. Western blotting and RT-PCR showed that the upregulation of p14ARF was in parallel with E2F1 expression during exposure. Furthermore, induction of p14ARF was attributed to increased E2F1 expression, evidenced by E2F1 transfection and chromatin immunoprecipitation/real-time quantitative PCR. Knockdown of p14ARF expression in H1299 decreased TUNEL-positive cell numbers and relatively increased survival cell numbers during 8-Cl-Ado exposure, indicating insensitivity of p14ARF-knocked down cells to 8-Cl-Ado. | Induction of p14ARF by E2F1 contributes to 8-Cl-Ado-induced late apoptosis. |
26,590,564 | Effects of total knee arthroplasty on ankle alignment in patients with varus gonarthrosis: Do we sacrifice ankle to the knee? | Total knee arthroplasty is one of the most commonly preferred surgical methods in the treatment of patients with varus gonarthrosis. In this study, we aimed to evaluate the radiological changes observed in the ankles after total knee arthroplasty. Between May 2012 and June 2013, 80 knees of 78 patients with varus deformity over 10° underwent total knee arthroplasty. For each patient, full-leg standing radiographs were obtained pre- and post-operatively. Mechanical and anatomical axes (HKA and AA), lateral distal femoral angle, medial proximal tibial angle, lateral distal tibial angle (LDTA), ankle joint line orientation angle (AJOA), tibial plafond talus angle (PTA) and talar shift were measured for each patient both pre- and post-operatively. Pre-operatively, the mean HKA was 16.6° and the mean AA was 10.41°, both in favour of varus alignment. Post-operatively, the mean HKA decreased to 3.6° and the mean AA to -2.1. The mean LDTA was 87.3°. Before the operation, the mean AJOA was -7.6°, opening to the medial aspect of the ankle, and it was 0.04° after the operation and opening to the lateral aspect (p < 0.05). | Our study reveals the changes occurring in the ankle after acute correction of long-standing varus deformity of the knee using total knee arthroplasty. In cases undergoing knee arthroplasty, effect of the acute change in the alignment of the knee on the ankle should be taken into consideration and the amount of correction should be calculated carefully in order not to damage the alignment of the ankle. |
9,497,506 | Does [ Gemfibrozil reduce elevated lipoprotein ( a ) levels in hypercholesterolemic patients ]? | To compare the effects of gemfibrozil and lovastatin in patients with hypercholesterolemia and increased lipoprotein(a) [Lp(a)] levels. Twenty-seven subjects with total cholesterol (TC) > 240 mg/dL, LDL-C > 160 mg/dL and Lp(a) > 25 mg/dL were studied. Patients were randomized to receive gemfibrozil 1200 mg/day, (n = 14, 54 +/- 7 years) or lovastatin 40-80 mg at night (n = 13, 55 +/- 9 years) for 12 weeks. Lipid profile and Lp(a) were determined at 4 and 12 weeks of treatment. Gemfibrozil reduced TC (-21%), LDL-C (-26%), triglycerides (TG)(-48%) and Lp(a) (-25%), increased HDL-C (+48%)(p < 0.001). Lovastatin reduced TC (-29%), LDL-C (-37%) and TG (-25%) (p < 0.001) however, it did not affect Lp(a). | Besides reducing plasma LDL-C, TG and increasing HDL-C, gemfibrozil effectively lowers Lp(a) levels. Lovastatin did not affect Lp(a) levels. |
26,303,678 | Does exercise Training protect Against Acute Myocardial Infarction via Improving Myocardial Energy Metabolism and Mitochondrial Biogenesis? | Acute myocardial infarction (AMI) represents a major cause of morbidity and mortality worldwide. Exercise has been proved to reduce myocardial ischemia-reperfusion (I/R) injury However it remains unclear whether, and (if so) how, exercise could protect against AMI. Mice were trained using a 3-week swimming protocol, and then subjected to left coronary artery (LCA) ligation, and finally sacrificed 24 h after AMI. Myocardial infarct size was examined with triphenyltetrazolium chloride staining. Cardiac apoptosis was determined by TUNEL staining. Mitochondria density was checked by Mito-Tracker immunofluorescent staining. Quantitative reverse transcription polymerase chain reactions and Western blotting were used to determine genes related to apoptosis, autophagy and myocardial energy metabolism. Exercise training reduces myocardial infarct size and abolishes AMI-induced autophagy and apoptosis. AMI leads to a shift from fatty acid to glucose metabolism in the myocardium with a downregulation of PPAR-α and PPAR-γ. Also, AMI induces an adaptive increase of mitochondrial DNA replication and transcription in the acute phase of MI, accompanied by an activation of PGC-1α signaling. Exercise abolishes the derangement of myocardial glucose and lipid metabolism and further enhances the adaptive increase of mitochondrial biogenesis. | Exercise training protects against AMI-induced acute cardiac injury through improving myocardial energy metabolism and enhancing the early adaptive change of mitochondrial biogenesis. |
25,158,912 | Are cardioprotective benefits of adenosine triphosphate-sensitive potassium channel opener diazoxide lost with administration after the onset of stress in mouse and human myocytes? | Adenosine triphosphate-sensitive (KATP) potassium channel opener diazoxide (DZX) maintains myocyte volume and contractility during stress via an unknown mechanism when administered at the onset of stress. This study was performed to investigate the cardioprotective potential of DZX when added after the onset of the stresses of hyperkalemic cardioplegia, metabolic inhibition, and hypo-osmotic stress. Isolated mouse ventricular and human atrial myocytes were exposed to control Tyrode's solution (TYR) for 10 to 20 minutes, test solution for 30 minutes (hypothermic hyperkalemic cardioplegia [CPG], CPG + 100uM diazoxide [CPG+DZX], metabolic inhibition [MI], MI+DZX, mild hypo-osmotic stress [0.9T], or 0.9T + DZX), with DZX added after 10 or 20 minutes of stress, followed by 20 minutes of re-exposure to TYR (±DZX). Myocyte volume (human + mouse) and contractility (mouse) were compared. Mouse and human myocytes demonstrated significant swelling during exposure to CPG, MI, and hypo-osmotic stress that was not prevented by DZX when administered either at 10 or 20 minutes after the onset of stress. Contractility after the stress of CPG in mouse myocytes significantly declined when DZX was administered 20 minutes after the onset of stress (p < 0.05 vs TYR). Contractility after hypo-osmotic stress in mouse myocytes was not altered by the addition of DZX. | To maintain myocyte volume homeostasis and contractility during stress (hyperkalemic cardioplegia, metabolic inhibition, and hypo-osmotic stress), KATP channel opener diazoxide requires administration at the onset of stress in this isolated myocyte model. These data have potential implications for any future clinical application of diazoxide. |
9,915,434 | Does comparison of digital rectal examination and biopsy result with the radical prostatectomy specimen? | Digital rectal examination is integral to staging prostate cancer. Ultrasound guided biopsy establishes the diagnosis, and it may provide useful information regarding disease grade and extent. Treatment decisions are largely based on information gained from digital rectal examination and biopsy but this information is only useful if it correlates with the radical prostatectomy specimen and prognosis. We correlated digital rectal examination and transrectal ultrasound guided biopsy results with a detailed analysis of the radical prostatectomy specimen. The accuracy of an abnormal digital rectal examination for predicting the location and extent of cancer was assessed in 89 patients thought to have clinical stage T2 disease. We evaluated 155 patients with clinical stages T1c and T2 disease to correlate the location of positive biopsies with the tumor site in the prostate. Radical prostatectomy specimens were completely sectioned at 2 mm. intervals, and tumor extent and location were recorded. In 85 patients a unilateral lesion was suspicious on digital rectal examination, that is stage cT2. The final pathological review revealed cancer on the suspicious side in 82 cases (96%) with tumor confined to the same lobe in only 23 (27%), bilateral disease in 59 (69%) and tumor confined to the contralateral lobe in 3 (4%). In 4 patients with a palpable bilateral abnormality a bilateral lesion was confirmed on final pathological evaluation. Digital rectal examination demonstrated a 36 and 31% incidence of extracapsular tumor extension and positive surgical margins, respectively, on the clinically benign side. In 100 patients only unilateral biopsy was positive. The final pathological evaluation revealed cancer in the biopsy positive side in 95 cases (95%) with tumor confined to the ipsilateral lobe in only 26 (26%), bilateral disease in 69 (69%) and tumor confined to the contralateral lobe in 5 (5%). In 46 of the 55 patients (84%) with bilateral positive biopsies tumor involved both sides but the pathologist did not identify cancer in both lobes in 9 (16%). While 100 patients had a unilateral negative biopsy, analysis of the prostatectomy specimen revealed carcinoma in the benign lobe in 74 (74%). Moreover, extracapsular tumor extension and a positive surgical margin were observed on the biopsy negative side in 31% of the patients. The degree to which digital rectal examination and biopsy results confirmed the final pathological evaluation was assessed using the kappa statistic, which revealed only slight agreement with each factor. The correlation of digital rectal examination and biopsy results with the location of extracapsular extension and positive margins was evaluated by the Spearman coefficient of correlation, which indicated poor agreement. When patients with unilateral versus bilateral positive biopsy were compared with respect to prognostic parameters, the difference was statistically significant for initial serum prostate specific antigen, the percentage of surface involved by tumor, biopsy and final Gleason scores, and the incidence of extracapsular extension of tumor. | Digital rectal examination and the interpretation of prostate biopsy are not accurate clinical tools for defining the location and extent of prostatic carcinoma. Bilateral positive biopsy may be useful as an adjunct to the current clinical staging system. |
25,559,034 | Does microRNA and messenger RNA profiling reveal new biomarkers and mechanisms for RDX induced neurotoxicity? | RDX is a well-known pollutant to induce neurotoxicity. MicroRNAs (miRNA) and messenger RNA (mRNA) profiles are useful tools for toxicogenomics studies. It is worthy to integrate MiRNA and mRNA expression data to understand RDX-induced neurotoxicity. Rats were treated with or without RDX for 48 h. Both miRNA and mRNA profiles were conducted using brain tissues. Nine miRNAs were significantly regulated by RDX. Of these, 6 and 3 miRNAs were up- and down-regulated respectively. The putative target genes of RDX-regulated miRNAs were highly nervous system function genes and pathways enriched. Fifteen differentially genes altered by RDX from mRNA profiles were the putative targets of regulated miRNAs. The induction of miR-71, miR-27ab, miR-98, and miR-135a expression by RDX, could reduce the expression of the genes POLE4, C5ORF13, SULF1 and ROCK2, and eventually induce neurotoxicity. Over-expression of miR-27ab, or reduction of the expression of unknown miRNAs by RDX, could up-regulate HMGCR expression and contribute to neurotoxicity. RDX regulated immune and inflammation response miRNAs and genes could contribute to RDX- induced neurotoxicity and other toxicities as well as animal defending reaction response to RDX exposure. | Our results demonstrate that integrating miRNA and mRNA profiles is valuable to indentify novel biomarkers and molecular mechanisms for RDX-induced neurological disorder and neurotoxicity. |
10,375,814 | Do tyrosine kinases participate in alpha 1A-adrenoceptor-mediated vasoconstriction in perfused rat hindlimb? | To determine whether or not tyrosine kinase is involved in the signal transduction of alpha 1A-adrenoceptors. Effects of various pharmacological probes on norepinephrine (NE)-induced vasopressor responses were determined in the perfused rat hindlimb. The putative tyrosine kinase inhibitors, genistein, and tyrphostin, significantly inhibited the vasopressor responses induced by NE but not that induced by KCl. The protein-tyrosine-phosphatase inhibitor, sodium orthovanadate, selectively potentiated the vasopressor responses induced by NE. Neither genistein nor tyrphostin had effect on the contraction elicited by phorbol 12-myristate 13-acetate. In contrast, both genistein and tyrphostin attenuated the vasopressor responses evoked by NaF. | The genistein- and tyrphostin-sensitive tyrosine kinases participate in alpha 1A-adrenoceptor-mediated vasoconstriction in perfused rat hindlimb. |
12,200,640 | Impaired coronary flow and left ventricular dysfunction after mechanical recanalization in acute myocardial infarction: role of neurohumoral activation? | Reopening of the infarct-related coronary artery is the treatment of choice in the clinical setting of acute myocardial infarction. Nevertheless the removal of the total occlusion obtained either by thrombolysis or by primary angioplasty is followed by the ischemia/reperfusion sequelae. One of many proposed mechanisms playing a role in ischemia/reperfusion damage is a persistent increase in vasoconstrictor tone, which reduces cardiac function and impairs myocardial blood flow during primary percutaneous coronary intervention in acute myocardial infarction (PAMI). To investigate early neurohumoral changes during PAMI we enrolled 18 patients, who were collated to 13 patients with stable angina undergoing elective PTCA. To evaluate angiotensin II (AngII), endothelin-1 (ET-1), vasopressin (AVP), norepinephrine (NE), troponin T (TNT), creatinephosphate kinase (CPKM) and isoenzyme MB (CPKMB), we collected blood from the pulmonary artery before and immediately after the infarct-related artery (IRA; TIMI 0 -->2-3) or culprit lesion revascularization. Hemodynamic and angiographic LV-function parameters were compared to biochemical data. Corrected TIMI-frame count (CTFC) was used as an index of coronary blood flow and correlated to the biochemical measurements. CTFC in the IRA correlated inversely (p = 0.03; r = -0.51) with left ventricular ejection fraction measured after 10 days, and positively (p = 0.03; r = 0.54) with the maximal amount of LDH released after onset of AMI. There was an abrupt and long lasting rise in ET-1 (+65 %; p<0.001) and an instant short lasting increase in AVP (+37 %; p<0.05), whereas NE concentrations were elevated prior to PAMI and remained elevated during reperfusion. Correlations with CTFC were found for ET-1 (p = 0.01; r = 0.61) and NE (p = 0.01; r = 0.58) during reperfusion. The extent of left ventricular dysfunction correlated with the concentrations of AVP and NE during reperfusion. | There is evidence for a distinct pattern of neurohumoral activation during early reperfusion in acute myocardial infarction. In particular, we documented substantial increases in AVP and ET-1. Left ventricular wall-stress appears to be involved in the release of AVP. Elevated levels of ET-1 and NE are associated with impaired angiographic reperfusion and increased myocardial damage after mechanical recanalization. |
20,662,989 | Do heat-stress responses modulate beta-adrenergic agonist and angiotensin II effects on the arrhythmogenesis of pulmonary vein cardiomyocytes? | Heat stress-induced responses reduce the occurrence of atrial fibrillation (AF). Pulmonary vein (PV) cardiomyocytes with pacemaker activity play a critical role in the pathophysiology of AF. In this study, we examined whether heat-stress responses alter the electrophysiological characteristics of PV cardiomyocytes and protect the PV against angiotensin II- or isoproterenol-induced arrhythmogenesis. We used whole-cell patch clamp techniques to investigate the spontaneous activity and ionic currents in single isolated rabbit PV pacemaker cardiomyocytes with or without (control) exposure to heat stress (43°C, 15 minutes) 5 ± 1 hours before the experiments. Compared to control cardiomyocytes, heat-stressed PV cardiomyocytes had slower beating rates. Heat-stressed PV cardiomyocytes had larger L-type calcium currents, transient outward currents, smaller inward rectifier potassium currents, but similar sodium-calcium exchanger currents. Additionally, heat-stressed PV cardiomyocytes had a lower incidence of pacemaker currents than control PV cardiomyocytes. Moreover, isoproterenol increased the beating rate of control cardiomyocytes but not heat-stressed PV cardiomyocytes. Similarly, angiotensin II also increased the beating rate of control cardiomyocytes, but not heat-stressed PV cardiomyocytes, in association with decreased expression of the angiotensin II type 1 receptor. | Heat-stress responses altered the electrophysiological characteristics of PV cardiomyocytes and attenuated the effects of isoproterenol and angiotensin II on PV arrhythmogenesis, which may play a role in the protective potential of heat-stress responses. |
17,992,647 | Is beta2-microglobulin-related amyloidosis of hemodialysis patients a multifactorial disease? | Beta2-microglobulin amyloidosis (Abeta(2)M) is one of the main long-term complications of dialysis treatment. The incidence and the onset of Abeta(2)M has been related to membrane composition and/or dialysis technique, with non-homogeneous results. This study was carried out to detect: i) the incidence of bone cysts and CTS from Abeta(2)M; ii) the difference in Abeta(2)M onset between cellulosic and synthetic membranes; iii) other risk factors besides the membrane. 480 HD patients were selected between 1986 to 2005 and grouped according to the 4 types of membranes used (cellulose, synthetically modified cellulose, synthetic low-flux, synthetic high-flux). The patients were analyzed before and after 1995, when the reverse osmosis treatment for dialysis water was started at our center, and the incidence of Abeta(2)M was compared between the two periods. Routine plain radiography, computer tomography (CT) and nuclear magnetic resonance imaging (MRI) as well as electromyography were used to investigate the clinical symptoms. Bone cysts occurred in 29.2% of patients before 1995 vs. 12.2% after 1995 (p<0.0001). CTS occurred in 24% of patients before 1995 vs. 7.1% after 1995 (p<0.0001). Bone cysts and CTS occurred in older patients, who began dialysis at a late age, with high CRP, low albumin, low residual GFR, and low Hb. Cox regression analysis showed that the risk factor for bone cysts was high CRP (RR 1.3, p<0.01), while albumin (RR 0.14, p<0.0001) and residual GFR (RR 0.81, p<0.0001) were revealed to be protective factors. Cox analysis for CTS confirmed CRP as a risk factor (RR 1.2, p<0.01), and albumin (RR 0.59, p<0.0001) and residual GFR (RR 0.75, p<0.0001) as protective factors. The comparison obtained between membranes did not suggest any protective effect on Abeta(2)M. | The findings that the inflammatory status as well as low albumin and the residual GFR of the uremic patient are predictive of Abeta(2)M lesions suggests that Abeta(2)M has a multifactorial origin rather than being solely a membrane- or technique-related side effect. |
24,619,759 | Is cSF-1R expression in tumor-associated macrophages associated with worse prognosis in classical Hodgkin lymphoma? | The aim of this study was to determine the prognostic relevance of colony-stimulating 1 receptor (CSF-1R) expression in both Hodgkin/Reed-Sternberg (HRS) cells and the surrounding cells (non-HRS cells) in patients with classical Hodgkin lymphoma (CHL) . Diagnostic tissues from 112 patients with CHL treated with doxorubicin, bleomycin, vinblastine, and dacarbazine were evaluated retrospectively by immunohistochemical analysis for CSF-1R and CD68 and CD163 for tissue-associated macrophages. High numbers (≥30%) of non-HRS cells expressing CSF-1R conferred inferior event-free survival and overall survival in univariate and multivariate analysis. High numbers of non-HRS cells expressing CSF-1R were significantly associated with a high number of tumor-associated macrophages as detected by CD163 expression (P < .001). In particular, coexpression of CSF-1R and CD163 was associated with a worse survival outcome than either CSF-1R or CD163 expression alone or no expression. | Our data demonstrate that a high number of non-HRS cells expressing CSF-1R are correlated with an increased tumor macrophage content and worse survival. |
8,076,753 | Does the distribution of novel intermediate filament proteins define subpopulations of myenteric neurons in rat intestine? | Recent studies with neurofilament antibodies as neuronal markers have shown subpopulations of myenteric neurons that do not contain neurofilament proteins. Novel neuronal intermediate filament proteins alpha-internexin, peripherin, and nestin have been identified. The aim of this study was to examine the distribution of these novel intermediate filaments in comparison with neurofilaments in myenteric plexus neurons. Using indirect immunofluorescence techniques in whole-mount cryostat sections from neonate and adult rat small intestine and in primary cultures of myenteric neurons, the distribution of neurofilaments, alpha-internexin, peripherin, and nestin was studied in comparison with the neuronal marker protein gene product (PGP) 9.5 in myenteric neurons. Sixty-five percent of neurons contained neurofilament triplet proteins. alpha-Internexin and/or peripherin were found in the neurofilament-negative neurons. PGP 9.5 was present in 80% of the myenteric neurons. Of the neurons that were PGP negative, > 95% contained peripherin or alpha-internexin. Nestin was not found in either neonate or adult myenteric neurons but was seen in glial cells in culture. | The results suggest that a subpopulation of myenteric neurons lacks neurofilament triplet proteins but contains either peripherin, alpha-internexin, or both. This selective distribution of intermediate filaments in subpopulations of enteric neurons may support differential roles in these structurally unique neurons. |
25,480,913 | Do mutations in LZTR1 add to the complex heterogeneity of schwannomatosis? | We aimed to determine the proportion of individuals in our schwannomatosis cohort whose disease is associated with an LZTR1 mutation. We used exome sequencing, Sanger sequencing, and copy number analysis to screen 65 unrelated individuals with schwannomatosis who were negative for a germline NF2 or SMARCB1 mutation. We also screened samples from 39 patients with a unilateral vestibular schwannoma (UVS), plus at least one other schwannoma, but who did not have an identifiable germline or mosaic NF2 mutation. We identified germline LZTR1 mutations in 6 of 16 patients (37.5%) with schwannomatosis who had at least one affected relative, 11 of 49 (22%) sporadic patients, and 2 of 39 patients with UVS in our cohort. Three germline mutation-positive patients in total had developed a UVS. Mosaicism was excluded in 3 patients without germline mutation in NF2, SMARCB1, or LZTR1 by mutation screening in 2 tumors from each. | Our data confirm the relationship between mutations in LZTR1 and schwannomatosis. They indicate that germline mutations in LZTR1 confer an increased risk of vestibular schwannoma, providing further overlap with NF2, and that further causative genes for schwannomatosis remain to be identified. |
20,419,832 | Do natural epitope variants of the hepatitis C virus impair cytotoxic T lymphocyte activity? | To understand how interactions between hepatitis C virus (HCV) and the host's immune system might lead to viral persistence or effective elimination of HCV. Nucleotides 3519-3935 of the non-structural 3 (NS3) region were amplified by using reverse transcription polymerase chain reaction (PCR). PCR products of the HCV NS3 regions were integrated into a PCR((R)) T7TOPO((R)) TA vector and then sequenced in both directions using an automated DNA sequencer. Relative major histocompatibility complex binding levels of wild-type and variant peptides were performed by fluorescence polarization-based peptide competition assays. Peptides with wild type and variant sequences of NS3 were synthesized locally using F-moc chemistry and purified by high-performance liquid chromatography. Specific cytotoxic T lymphocytes (CTLs) clones toward HCV NS3 wild-type peptides were generated through limiting dilution cloning. The CTL clones specifically recognizing HCV NS3 wild-type peptides were tested by tetramer staining and flow cytometry. Cytolytic activity of CTL clones was measured using target cells labeled with the fluorescence enhancing ligand, DELFIA EuTDA. The pattern of natural variants within three human leukocyte antigen (HLA)-A2-restricted NS3 epitopes has been examined in one patient with chronic HCV infection at 12, 28 and 63 mo post-infection. Results obtained may provide convincing evidence of immune selection pressure for all epitopes investigated. Statistical analysis of the extensive sequence variation found within these NS3 epitopes favors a Darwinian selection model of variant viruses. Mutations within the epitopes coincided with the decline of CTL responses, and peptide-binding studies suggested a significant impact of the mutation on T cell recognition rather than peptide presentation by HLA molecules. While most variants were either not recognized or elicited low responses, such could antagonize CTL responses to target cells pulsed with wild-type peptides. | Cross-recognition of CTL epitopes from wild-type and naturally-occurring HCV variants may lead to impaired immune responses and ultimately contribute to viral persistence. |
18,090,011 | Does a fentanyl-based pain management protocol provide early analgesia for adult trauma patients? | In the past two decades, a number of reports have identified inadequate treatment of pain among emergency department patients. No study has evaluated the frequency or effectiveness of early analgesia in the trauma patient. The objective of this study was to determine the effect of a protocol-driven pain management scheme on time to initiation of analgesia among trauma patients. A fentanyl-based protocol was developed with patients being assigned to one of three treatment arms based on hemodynamics and Glasgow Coma Scale (GCS) score. Using an institutional review board-approved before and after study design, patients over the age of 14 and meeting trauma system activation criteria at the Dartmouth-Hitchcock Medical Center were eligible. Results were compared with a retrospective chart review of eligible patients treated during a matched preprotocol time period in 2002. The primary outcome measure was time to initiation of analgesia. Secondary outcome measures included (1) the proportion of patients receiving their first analgesia dose within 30 minutes, (2) the number of patients receiving multiple doses of analgesia in the trauma bay, and (3) adverse events. Pain level was assessed using either a Numeric Pain Scale (for patients with a GCS score of 15) or a Behavioral Pain Assessment Scale (GCS score <15). Implementation of the protocol resulted in a decrease in the mean time to initiation of analgesia from 53.61 minutes +/- 6.88 minutes to 27.94 minutes +/- 3.34 minutes (p = 0.001). The protocol also increased the percentage of patients receiving analgesia within the first 30 minutes of arrival from 44.4% to 74.6% (p < 0.001). There were no differences between the two groups in terms of baseline characteristics or adverse events. | The implementation of a fentanyl-based pain management protocol resulted in a marked reduction in time to initial analgesia among trauma patients. There was no evidence of an increase in adverse events. This tool has the potential to be easily extrapolated and applied to other trauma systems. |
24,635,851 | Are we getting the critical view? | At laparoscopic cholecystectomy, most surgeons have adopted the operative approach where the 'critical view of safety' (CVS) is achieved prior to dividing the cystic duct and artery. This prospective study evaluated whether an adequate critical view was achieved by scoring standardized intra-operative photographic views and whether there were other factors that might impact on the ability to obtain an adequate critical view. One hundred consecutive patients undergoing a laparoscopic cholecystectomy were studied. At each operation, two photographs were taken. Two independent experienced hepatobiliary surgeons scored the photographs on whether a critical view of safety was achieved. Inter-observer agreement was calculated using the weighted kappa coefficient. The Cochran-Mantel-Haenszel test was used to analyse the scores with potential confounding clinical factors. The kappa coefficient for adequate display of the cystic duct and artery was 0.49; 95% confidence interval (CI) 0.33 to 0.64; P = 0.001. No bias was detected in the overall scorings between the two observers (χ(2) 1.33; P = 0.312). Other clinical factors including surgeon seniority did not alter the outcome [odds ratio (OR) 0.902; 95% confidence interval 0.622 to 1.264]. | Heightened awareness of the CVS through mandatory documentation may improve both trainee and surgeon technique. |
19,359,662 | Is glucose 6-phosphate dehydrogenase regulated through c-Src-mediated tyrosine phosphorylation in endothelial cells? | Glucose 6-phosphate dehydrogenase (G6PD) maintains cellular NADPH levels, which are essential for cellular functions, such as vascular endothelial growth factor (VEGF)-induced angiogenesis. The molecular mechanisms regulating G6PD in angiogenesis are not fully understood. Because tyrosine phosphorylation is a key regulatory pathway for VEGF-mediated endothelial cell (EC) responses, we investigated tyrosine phosphorylation of G6PD and the role of the nonreceptor tyrosine kinase Src. VEGF increased G6PD membrane translocation as measured by a plasma membrane sheet assay, whereas tyrosine kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyramidine) decreased G6PD translocation by 100%. Furthermore, G6PD tyrosine phosphorylation and plasma membrane activity were increased by VEGF. In resting ECs, tyrosine kinase inhibitors PP2 and herbimycin A decreased basal G6PD activity by approximately 25%, whereas transfection with kinase inactive Src (KD-Src) decreased basal activity by approximately 30%. In mouse embryonic fibroblasts, Src-deficient (SYF) cells showed approximately 22% lower basal G6PD activity than Src-expressing S(+)YF cells. In addition, Src directly phosphorylated G6PD assayed by in vitro kinase assay. In ECs transfected with the G6PD mutants Y428F, Y507F (presumptive sites for Src-phosphorylation) or double mutant Y428F/Y507F, G6PD tyrosine phosphorylation was significantly decreased. Finally, G6PD tyrosine mutants (Y428F, Y507F, and Y428F/Y507F) decreased VEGF-mediated Akt phosphorylation and EC migration. | G6PD activity and membrane association are regulated by Src-mediated tyrosine phosphorylation, which contributes to VEGF-mediated cellular responses in EC. |
20,367,824 | Does the organization of care processes affect outcomes in patients undergoing total joint replacement? | Surgeons realize that safe and efficient care processes for total joint replacement requires more than just well-performed operations. Orthopaedic teams are reorganizing care process to improve efficacy and shorten length of stay. Little is known on the impact of organizational changes on patient outcome. This paper studies the relation between the organization of care processes and patient outcomes in hip and knee. Clinical pathways are used as one of the methods to structure the care process. Although evidence is available on the effect of pathways in total joint replacement, their impact with the organization of the care process has not been studied previously. A cross-sectional multicentre study was performed on 39 care processes and 737 consecutive patients. Regression models were used to analyse the relation between the organization of the care process and risk-adjusted patient outcomes. The use of pathways and the organization of the care process, measured by the Care Process Self Evaluation Tool (CPSET), were measured at organizational level. Length of stay, pain, mobility and elapsed time to discharge were measured at patient level. The use of pathways had a positive effect on four out of five subscales and the overall CPSET score. Using pathways decreased length of stay (P = 0.014), pain (P = 0.052) and elapsed time to discharge (P = 0.003). The CPSET subscale communication was related with three risk adjusted outcomes. Multivariate analysis demonstrated a significant effect by three different variables on the length of stay; (1) use of pathways; (2) coordination of care processes; and (3) communication with patients and family. Both the use of pathways and coordination of the care process were determinants for the elapsed time to discharge. A significant interaction effect was found between use of pathways and coordination of the care process. | This large multicentre study revealed the relation between the use of pathways, organization of the care process and patient outcomes. This information is important for both clinicians and managers to understand and further improve the organization of orthopaedic care. |
15,253,026 | Can energy drinks affect the effects of alcoholic beverages? | The pattern of use of energy drinks, alone or combined with alcoholic beverages, was evaluated in a criteria sample. 136 volunteers aged 24 +/- 6 years, who had reported at least one previous use of energy drinks, answered a questionnaire on their pattern of use of energy drinks and alcoholic beverages. Most of the sample (76%) reported using energy drinks in combination with alcoholic beverages, preferably whisky (90%), vodka (37%) and beer (13%). Most of the sample (79%) also reported using energy drinks alone. In the latter case, 61% of them reported not feeling any effect, 10% reported happiness, 9% euphoria, 9% insomnia, 7% uninhibited behavior and 24% increase in physical vigor. Out of those who reported combined use with alcohol, 14% told not to feel different, 38% increase happiness, 30% euphoria, 11% insomnia, 27% uninhibited behavior and 24% increase of physical vigor. High level of variability was observed in the number of lifetime uses of energy drinks (14 +/- 16). However, there was certain constancy in the number of cans ingested per occasion (1.5 +/- 0.7). | It was observed that the effects of energy drinks are variable, probably depending on the dose and individual sensitivity. Some reports suggest interaction with alcohol, expressed as an increase in the excitatory effects or reduction in the depressive effects. The possible pharmacological mechanisms underlying this interaction are discussed. |
17,545,513 | Is interaction between cancer cells and stromal fibroblasts required for activation of the uPAR-uPA-MMP-2 cascade in pancreatic cancer metastasis? | Interaction between tumor cells and surrounding stromal fibroblast (SF) plays a critical role in tumor growth and invasion. The aim of the study is to determine the role of SF in regulating the invasive behaviors of pancreatic cancer by evaluating the mode of SF activating the urokinase plasminogen activator (uPA)-plasmin-matrix metalloproteinase (MMP)-2 cascade. The expression patterns of uPA, MMP-2, and uPA receptor (uPAR) in human metastatic pancreatic cancer were analyzed by immunohistochemistry and the roles of SF in activation of the uPA-plasmin-MMP-2 cascade were evaluated by coculturing pancreatic cancer cell lines with SF. uPA expression and fibroblastic uPAR expression were correlated with liver metastasis of human pancreatic cancer. MMP-2 rather than MMP-9 was activated in the metastatic pancreatic cancer. In the in vitro culture system, the coculture of peritumor fibroblasts with metastatic pancreatic cancer BxPc3 cells resulted in activation of MMP-2 and up-regulation of uPAR expression. In this coculture system, the uPA-plasminogen cascade was involved in MMP-2 activation. This activation required a direct interaction between SF and cancer cells. In the coculture system, intergrin alpha(6)beta(1) expression was increased in BxPc3 cells, and blocking the function of integrin alpha(6)beta(1) decreased the activation of uPA and MMP-2. This suggests that interaction between integrins of cancer cells and the uPARs of the SF might be involved in the activation of the uPAR-uPA-MMP-2 cascade. | Our results suggest that SF plays a role in promoting pancreatic cancer metastasis via activation of the uPA-plasminogen-MMP-2 cascade. |
11,722,026 | Involvement of apoptosis in neurological injury after hypothermic circulatory arrest: a new target for therapeutic intervention? | This study was undertaken to evaluate the role of apoptosis in neurological injury after hypothermic circulatory arrest (HCA). Twenty-one pigs (27 to 31 kg) underwent 90 minutes of HCA at 20 degrees C and were electively sacrificed at 6, 24, 48, and 72 hours, and at 7, 10, and 12 days after HCA, and compared with unoperated controls. In addition, 3 animals that had HCA at 10 degrees C, and 3 treated with cyclosporine A (CsA) in conjunction with HCA at 20 degrees C, were examined 72 hours after HCA. After selective perfusion and cryopreservation, all brains were examined to visualize apoptotic DNA fragmentation and chromatin condensation on the same cryosection of the hippocampus: fluorescent in situ end labeling (ISEL) was combined with staining with a nucleic acid-binding cyanine dye (YOYO). In addition to apoptosis, which was seen at a significantly higher level (p = 0.05) after HCA than in controls, two other characteristic degenerative morphological cell types (not seen in controls) were characterized after HCA. Cell death began 6 hours after HCA and reached its peak at 72 hours, but continued for at least 7 days. Compared with the standard protocol at 20 degrees C, HCA at 10 degrees C and CsA treatment both significantly reduced overall cell death after HCA, but not apoptosis. | The data establish that significant neuronal apoptosis occurs as a consequence of HCA, but at 20 degrees C, other pathways of cell death, probably including necrosis, predominate. Although preliminary results suggest that the neuroprotective effects of lower temperature and of CsA are not a consequence of blockade of apoptotic pathways, inhibition of apoptosis nevertheless seems promising as a strategy to protect the brain from the subtle neurological injury that is associated with prolonged HCA at clinically relevant temperatures. |
22,192,149 | Does idebenone increase mitochondrial complex I activity in fibroblasts from LHON patients while producing contradictory effects on respiration? | Leber's hereditary optic neuropathy (LHON) is caused by mutations in the complex I subunits of the respiratory chain. Although patients have been treated with idebenone since 1992, the efficacy of the drug is still a matter of debate. We evaluated the effect of idebenone in fibroblasts from LHON patients using enzymatic and polarographic measurements. Complex I activity was 42% greater in treated fibroblasts compared to controls (p = 0.002). Despite this complex I activity improvement, the effects on mitochondrial respiration were contradictory, leading to impairment in some cases and stimulation in others. | These results indicate that idebenone is able to compensate the complex I deficiency in LHON patient cells with variable effects on respiration, indicating that the patients might not be equally likely to benefit from the treatment. |
20,714,111 | Do heavy-chain complementarity-determining regions determine conformation selectivity of anti-aβ antibodies? | Amyloid-β (Aβ) protofibrils are neurotoxic soluble intermediates in the Aβ aggregation process eventually forming senile plaques in Alzheimer's disease. This Aβ species is a potential biomarker for Alzheimer's disease and also a promising target for immunotherapy. In this study, we investigated the characteristics of conformation-dependent Aβ antibodies specific for Aβ protofibrils. Mice were immunized with Aβ protofibrils to generate hybridomas producing Aβ-specific monoclonal antibodies. Binding of antibodies to different Aβ conformations was investigated with inhibition ELISA. The antibodies' complementarity-determining region (CDR) sequences were determined and compared. A majority of the antibodies were of the IgM class, all selectively binding to aggregated Aβ. Two IgG antibodies were generated: one with selective affinity for Aβ protofibrils and the other bound Aβ in all conformations. A high degree of similarity between the heavy-chain CDRs of the conformation-dependent antibodies was found, and all high-affinity Aβ antibodies displayed a high degree of sequence similarity in the light-chain CDRs. | Sequence similarity in the heavy-chain CDRs is associated with conformation selectivity of the antibodies, while sequence similarity in the light-chain CDRs correlates with the affinity for Aβ. |
9,662,190 | Do two doses of PMPA protect newborn macaques against oral simian immunodeficiency virus infection? | Simple and affordable intervention strategies are needed to reduce the rate of HIV transmission from mother to infant in developing countries. Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is considered to be a useful model of human pediatric HIV infection. To investigate whether short-term 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) administration can protect newborn rhesus macaques against perinatal SIV infection. Eight newborn macaques were inoculated orally with highly virulent SIVmac within the first 3 days of life. Four of these animals were untreated controls. The other four animals were given one dose of PMPA (30 mg/kg subcutaneously) 4 h before oral SIV inoculation, and were then given a second and final dose of PMPA 24 h later. All four untreated control animals were persistently SIV-positive within 2 weeks after virus inoculation. In contrast, no virus could be detected in the four animals that received two doses of PMPA; these animals were seronegative and healthy at 10 months. | Two doses of PMPA prevented SIV infection of newborn macaques. Our data suggest that short-term administration of PMPA to HIV-infected pregnant women at the onset of labor and to their newborns after delivery may reduce the rate of intrapartum HIV transmission. |
17,913,758 | Is the degree of cognitive impairment in patients with Alzheimer's disease related to their capacity to appoint an enduring power of attorney? | Clinicians are often asked to retrospectively assess a patient's capacity to create an Enduring Power of Attorney (EPA). This study will investigate if capacity to create an EPA is significantly related to the degree of cognitive impairment in Alzheimer patients, and whether Mini Mental State Examination score (MMSE) is a good predictor of a patient's capacity. It also considers if socio-demographic factors are related to a patient's capacity to create an EPA. Participants with a DSM-IV diagnosis of Alzheimer's disease were recruited from the Old Age Psychiatric service at the Queen Elizabeth Psychiatric Hospital, Birmingham, UK. A cognitive assessment of each patient was performed using the MMSE, followed by two independent assessments of their capacity to create an EPA made using a semi-structured interview. There was a significant association between level of cognitive impairment and capacity to create an EPA: chi(2) = 35.15 (P<0.0001). MMSE score significantly predicted capacity status (OR=1.6, 95% CI 0.863-0.979). Optimal sensitivity (86.6%, CI 67.4-95.5%) and specificity (82.2% CI 67.4-91.5%) were obtained using a cutoff MMSE score of 18. Positive predictive value (PPV): 75.8% (95% CI 57-88%), negative predictive value (PNV): 90.2% (CI 76-97%). No socio-demographic factors were significantly associated with capacity to create an EPA. | The MMSE could be used as a screening tool to help inform a clinical capacity assessment in patients with Alzheimer's disease. It is important that patients always undergo individual clinical assessments where possible, but in situations where direct assessment is not possible MMSE score could be used to aid retrospective assessments of capacity to create an EPA. |
24,733,028 | Is a high normal ankle-brachial index associated with proteinuria in a screened cohort of Japanese : the Okinawa Peripheral Arterial Disease Study? | We hypothesized that ankle-brachial index (ABI) increased with age as a result of arterial stiffness, and decreased when flow-limiting atherosclerotic stenosis occurred in the lower limbs. As arterial stiffness is associated with proteinuria, we investigated the relationship between ABI and prevalence of proteinuria. A cross-sectional study of ABI and proteinuria with 13,193 participants aged 21-89 years (53% women) from health checkups between July 2003 and March 2010 was conducted. ABI was measured using the automatic oscillometric method, and stratified into four groups: ABI ≤ 0.9 (low); 0.9 < ABI <1.0 (borderline low); 1.0 ≤ ABI <1.2 (normal); and 1.2 ≤ ABI <1.4 (high normal). In participants with ABI at least 1.0, ABI was positively correlated with SBP, pulse pressure, and brachial-ankle pulse wave velocity. In participants with ABI less than 1.0, all indices were negatively correlated with ABI. The prevalence of proteinuria, defined as ≥ 1+ by dipstick, was significantly higher in low (23%) and high normal ABI (10%) compared with borderline low (6%) and normal ABI (7%). In participants at least 60 years, proteinuria was significantly associated with only low ABI [odds ratio (OR) 3.22, 95% confidence interval 1.34-7.41] compared with normal ABI before and after multivariable adjustment. In participants less than 60 years, adjusted OR for proteinuria was only significantly associated with high normal ABI (OR 1.32, 95% confidence interval 1.01-1.74). | High normal ABI in younger participants may be a result of arterial stiffness and associated with proteinuria. |
22,409,214 | Does pravastatin and simvastatin improve acetylsalicylic acid-mediated in vitro blood platelet inhibition? | Insight into the pathophysiology of atherothrombosis indicates that an integrated risk factor approach, focusing particularly on the management of dyslipidaemia (with statins) and thrombosis (with ASA), may constitute an optimal therapeutic approach. We investigated whether pravastatin, simvastatin and atorvastatin may directly modulate under in vitro conditions the reactivity of blood platelets originating from healthy volunteers. In addition, we analysed the influence of statins on the platelet sensitivity to ASA under such conditions. We monitored collagen- or ADP-induced platelet aggregation, CD36, PAC-1 and CD62 expression on platelet surface and thromboxane generation after incubation with pravastatin, simvastatin, atorvastatin and/or ASA. The incubation of whole blood with simvastatin and pravastatin significantly decreased CD36 expression. In the presence of 50 μM ASA, simvastatin and pravastatin significantly reduced the PAC-1 expression (30% reduction for simvastatin, P < 0·01, and 15% reduction for pravastatin, P < 0·01), platelet aggregation (20% reduction for both statins, P < 0·01) and thromboxane generation (35% reduction for simvastatin, P < 0·001, and 30% reduction for pravastatin, P < 0·001) compared to ASA alone. Atorvastatin changed neither baseline platelet aggregation nor ASA-mediated platelet inhibition. | Our results suggested that statins may directly interact with platelet membranes or may modulate a signalling pathway in platelets (the pleiotropic effects of statins). It is possible that the statin effect on CD36 and ASA-mediated protein acetylation can be reached by the modulation of a distribution or a function of membrane-associated proteins. Further studies are certainly needed to better elucidate the mechanism(s) underlying the statins' effects on platelet sensitivity to ASA. |
25,227,639 | Does BMI predict recurrence or complications after reoperative reflux surgery? | Obese patients who fail primary surgical management of gastroesophageal reflux present a significant challenge. We reviewed our outcomes with reoperative reflux surgery in obese (body mass index (BMI)>30) and nonobese patients to identify predictors of failure and complications and evaluate whether reoperative fundoplication is the ideal solution for obese patients. We conducted a retrospective review of consecutive patients undergoing reoperation for failed anti-reflux surgery between 1994 and 2013. Medical record review identified preoperative, intraoperative, and postoperative characteristics. Short- and long-term outcomes for obese and nonobese patients were compared using descriptive statistics and logistic regression. One hundred and nine interventions were identified in 95 patients. Clinical characteristics were similar between obese and nonobese patients. Eighty-eight (83.8%) patients underwent laparoscopic repair, 87 (79.8%) of whom had a Nissen fundoplication. Obese patients were more likely to fail via a slipped wrap (64.7 vs. 40.0%; p = 0.02). No differences were seen in short- or long-term symptomatic relief or major complications. In bivariate analysis, short-term outcomes were predicted by preoperative albumin<3.5 mg/dL (odds ratio (OR), 0.27 (confidence interval (CI), 0.08-0.96); p = 0.04) and laparoscopic conversion (OR, 0.19 (CI, 0.04-1.03); p = 0.05). Laparoscopic conversion was associated with major complications (OR, 7.33 (CI, 1.33-40.55); p = 0.02). BMI was a significant predictor for long-term outcome (p = 0.03) as a continuous variable in sensitivity analyses. | Obese patients with recurrence after failed anti-reflux operation may be safely treated with a repeat operation. Our data indicate no difference in outcomes for patients with BMI>30, underscoring the importance of preoperative discussion as to the best approach: reoperative fundoplication or a gastric bypass. |
19,095,097 | Factors influencing time between biopsy and definitive surgery for malignant melanoma: do they impact clinical outcome? | Whether time between biopsy and surgery for malignant melanoma affects clinical outcomes is sparsely defined. This study evaluated factors influencing surgical interval and surgical interval effect on outcomes. We performed a review of a prospective 10-year, single-institution database. There were 473 patients treated for 478 malignant melanomas. The mean surgical interval was 30.5 days. The mean thickness was 2.1 mm; 46% of patients had a surgical interval of more than 28 days whereas 8% had a surgical interval of more than 56 days. Residual melanoma was found at excision in 170 (36%) patients. Age, sex, and referral source significantly affected surgical interval, however, lesion thickness, sentinel lymph node status, ulceration, and residual melanoma at excision did not. In univariate Cox models, neither a surgical interval of 28 or less nor less than 56 days showed better overall survival (OS) or disease-free survival (DFS). In multivariate Cox models of OS and DFS including lesion thickness, sentinel lymph node status, ulceration, and residual melanoma at excision, neither a surgical interval of 28 days or fewer nor a surgical interval of 56 days or fewer significantly affected outcomes. | Age, sex, referral source, and lesion thickness were associated with surgical interval. Immediate surgery for malignant melanoma does not significantly impact OS or DFS. |
17,298,984 | Histopathological assessment of lymph nodes in upper gastrointestinal cancer: does triple levelling detect significantly more metastases? | For cancers of the upper gastrointestinal tract it is standard to examine one section/level, from paraffin blocks containing lymph node tissue, for metastatic tumour. To determine whether significantly more metastases can be detected by assessing two additional levels. 101 archival upper gastrointestinal cancers were evaluated. All negative lymph nodes were examined at two additional levels separated by 100 microm and stained by H&E. The slides were examined for the presence of metastases. 1143 lymph nodes, that were originally clear of metastases, were examined at a further two levels (three levels in total); 23 additional metastases were identified in 17 patients. Eleven of these patients were already stage N1 before examination of the additional levels. However, six patients were originally N0, and were therefore upgraded to N1. | Examining lymph nodes at three levels did detect more metastatic deposits than examination of one section/level. In six patients this changed the N stage from N0 to N1. This would have significant prognostic and management implications. |
27,718,524 | Do antisense locked nucleic acids targeting agrA inhibit quorum sensing and pathogenesis of community-associated methicillin-resistant Staphylococcus aureus? | Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is commonly associated with nonnosocomial skin and soft tissue infections due to its virulence, which is mainly controlled by the accessory gene regulator (agr) quorum sensing (QS) system. In this study (KFF) Two PLNAs were designed, and synthesized, after predicting the secondary structure of agrA mRNA. The influence on bacterial growth was tested using a growth curve assay. RT-qPCR, haemolysis assay, lactate dehydrogenase release assay and chemotaxis assay were used to evaluate the effects of the PLNAs on inhibiting agr QS. A mouse skin infection model was employed to test the protective effect of the PLNAs in vivo. None of the PLNAs were found to be bacteriostatic or bactericidal in vitro. However, one PLNA, PLNA34, showed strong ability to suppress expression of agrA and the effector molecule RNAIII in USA300 LAC strain. Furthermore, PLNA34 inhibited the expression of virulence genes that are upregulated by agr, including hla, psmα, psmβ and pvl. The haemolytic activity of the supernatants from PLNA34-treated bacteria was also dramatically reduced, as well as the capacity to lyse and recruit neutrophils. Moreover, PLNA34 showed high levels of protection in the CA-MRSA mouse skin infection model. | The anti-agrA PLNA34 can effectively inhibit the agr QS and suppress CA-MRSA pathogenicity. |
18,251,181 | Is p53 an indicator of tumor progression in early but not advanced gastric carcinomas? | p53 plays an important role in the development of gastric carcinomas through its effect on apoptosis. Its use as a biomarker of tumorigenesis and progression in clinical tissue is currently under consideration. This project assessed its value in early and advanced stage gastric carcinomas. The characteristics of positive staining for p53 was evaluated in 202 gastric adenocarcinomas classified into early stage (T1) (127 cases) and advanced stage (T2, 3 and 4) (75 cases) using the tumor-node-metastasis classification. Four subgroups (classified as p53 negative, +, ++ and +++ according to the level of positivity) were investigated for relationships with apoptosis (morphology) or cell proliferation (Ki-67). The mucosa of early stage and both mucosa and subserosa of advanced cancers were examined. p53-positive early stage cancers had more apoptosis but also more proliferation than p53-negatives (P<0.05), perhaps indicating conferral of a growth advantage. In advanced cancers, there was no correlation between apoptosis and extent of p53 positivity. p53 positivity had no correlation with cell proliferation in the mucosa and subserosa of these cancers. | p53 may be useful as an indicator of development and progression in early stage gastric cancers but this is not the case for advanced stage gastric cancers. |
27,293,336 | Are mutations in GABRG2 receptor gene a major factor in the pathogenesis of mesial temporal lobe epilepsy in Indian population? | This study is focused on GABRG2 gene sequence variations in patients with mesial temporal lobe epilepsy (mTLE). The GABAAreceptor is a heteropentameric receptor and alpha-1 beta-2 gamma-2 subunits combination is most abundant and present in almost all regions of the brain. The gamma-2 subunit (GABRG2) gene mutations have been reported in different epilepsy pathologies. In the present study we have looked for GABRG2 gene sequence variations in patients with mTLE. Twenty patients (12 females and eight males, age 4.6-38 years) with MTLE were recruited for this investigation. Patients were recommended for epilepsy surgery after all clinical investigations as per the epilepsy protocol. Ethnically matched glioma or meningioma patients were considered as nonepileptic controls. During temporal lobectomy of amygdalohippocampectomy, hippocampal brain tissue samples were resected guided by intraoperative electrocorticography (ECoG) activity. All 11 exons of GABRG2 gene with their flanking intronic regions were amplified by polymerase chain reaction (PCR) and screened by DNA sequencing analysis for sequence variations. Comparison of allele frequencies between patient and control groups was determined using a c(2) test. | Total five DNA sequence variations were identified, three in exonic regions (c.643A > G, rs211035), (c.T > A, rs424740), and (c.C > T, rs418210) and two in intronic regions (c.751 + 41A > G, rs211034) and (c.751 + 52G > A, rs 34281163). Allele frequencies of variants identified in this study did not differ between patients and normal controls. Thus, we conclude that GABRG2 gene may not be playing significant role in the development of epilepsy or as a susceptibility gene in patients with MTLE in Indian population. |
11,287,775 | Does urinary prostaglandin D synthase ( beta-trace ) excretion increase in the early stage of diabetes mellitus? | Circulating levels of lipocalin-type prostaglandin D synthase (L-PGDS)/beta-trace reportedly increase in renal failure as well as in cardiovascular injuries. We investigated the alterations of L-PGDS in urine and plasma in the early stage of type-2 diabetic patients. Thirty-six type-2 diabetic patients and 29 normal subjects were studied. Overnight spot urine and plasma samples were obtained in the morning. L-PGDS was measured by ELISA method using anti-L-PGDS antibody. Variables indicating renal function were determined. Plasma L-PGDS concentration was slightly higher in the patients with diabetes mellitus than in the control subjects, whereas the urinary L-PGDS excretion almost doubled in the diabetic patients as compared with that in the control subjects. Plasma L-PGDS was determined by plasma creatinine (Cr) concentration while urinary L-PGDS excretion was correlated solely with urinary protein excretion. There was no relationship between plasma L-PGDS concentration and urinary L-PGDS excretion. The averaged plasma concentration of L-PGDS in the diabetics with a normal Cr level in plasma, corresponding to that in the controls, was determined by the plasma Cr concentration. On the other hand, the urinary L-PGDS excretion was determined by the amount of proteinuria and greater in the diabetics with a normal Cr level in plasma than in the controls even when the patients exhibited urinary protein excretion equal to that in the control subjects. | Urinary L-PGDS excretion increased in the early stage of kidney injury in patients with type-2 diabetes mellitus. The urinary excretion was correlated independently with urinary protein excretion even when there was no difference in urinary protein or albumin excretions, thereby suggesting that urinary L-PGDS excretion is possibly a more sensitive indicator of renal injuries than proteinuria. Urinary L-PGDS may thus predict the progression of renal injuries in diabetic patients. |
27,456,959 | Too much sitting and all-cause mortality: is there a causal link? | Sedentary behaviours (time spent sitting, with low energy expenditure) are associated with deleterious health outcomes, including all-cause mortality. Whether this association can be considered causal has yet to be established. Using systematic reviews and primary studies from those reviews, we drew upon Bradford Hill's criteria to consider the likelihood that sedentary behaviour in epidemiological studies is likely to be causally related to all-cause (premature) mortality. Searches for systematic reviews on sedentary behaviours and all-cause mortality yielded 386 records which, when judged against eligibility criteria, left eight reviews (addressing 17 primary studies) for analysis. Exposure measures included self-reported total sitting time, TV viewing time, and screen time. Studies included comparisons of a low-sedentary reference group with several higher sedentary categories, or compared the highest versus lowest sedentary behaviour groups. We employed four Bradford Hill criteria: strength of association, consistency, temporality, and dose-response. Evidence supporting causality at the level of each systematic review and primary study was judged using a traffic light system depicting green for causal evidence, amber for mixed or inconclusive evidence, and red for no evidence for causality (either evidence of no effect or no evidence reported). The eight systematic reviews showed evidence for consistency (7 green) and temporality (6 green), and some evidence for strength of association (4 green). There was no evidence for a dose-response relationship (5 red). Five reviews were rated green overall. Twelve (67 %) of the primary studies were rated green, with evidence for strength and temporality. | There is reasonable evidence for a likely causal relationship between sedentary behaviour and all-cause mortality based on the epidemiological criteria of strength of association, consistency of effect, and temporality. |
25,752,486 | Does phase analysis detect heterogeneity of myocardial deformation on cine MRI? | Myocardial scar will lead to heterogeneous left ventricular deformation. We hypothesized that a myocardial scar will display an elevated standard deviation (SD) of phase and that this effect could be compared with mechanical dispersion. Thirty patients (three women and 27 men) were investigated over 4-8 weeks after ST-elevation myocardial infarction treated with percutaneous coronary intervention. Seventeen had a scar area > 75% in at least one antero- or inferoseptal segment (scar) and 13 had a scar area < 1% (non-scar). The phase delays of velocity, displacement, and strain were measured in the longitudinal direction, tangential to the endocardial outline, and in the radial direction, perpendicular to the tangent. The SD of phase in radial measurements differentiated scar patients from those without scar (p < 0.01), while longitudinal measurements did so only for longitudinal strain. Likewise, the SD for radial measurements of time to peak for segmental velocity, displacement, and strain performed better than longitudinal measurements and equal to the results of phase. | Phase dispersion in deformation imaging may be used for detecting heterogeneous left ventricular contraction. |
23,866,848 | Is operative diagnosis for revision total hip arthroplasty associated with patient-reported outcomes ( PROs )? | Little is known about the impact of the reason for revision total hip arthroplasty (THA) on the outcomes following revision THA. In this study, our objective was to assess the association of operative diagnosis with patient-reported outcomes (PROs) after revision THA. We used prospectively collected data from the Mayo Clinic Total Joint Registry that collects pre- and post-operative pain and function outcomes using a validated Hip questionnaire, on all revision THAs from 1993-2005. We used logistic regression to assess the odds of moderate-severe index hip pain and moderate-severe limitation in activities of daily living (ADLs) 2- and 5-years after revision THA. We calculated odds ratios (OR) and 95% confidence intervals (CIs). For the 2- and 5-year cohorts, the operative diagnosis was loosening/wear/osteolysis in 73% and 75%; dislocation/bone or prosthesis fracture/instability or non-union in 17% and 15%; and failed prior arthroplasty with components removed/infection in 11% and 11%, respectively. In multivariable-adjusted analyses that included preoperative ADL limitations, compared to patients with loosening/wear/osteolysis, patients with dislocation/fracture/instability/non-union had OR of 2.2 (95% CI, 1.3-3.5; p = 0.002) for overall moderate-severe ADL limitation and those with failed prior arthroplasty/infection had OR of 1.6 (95% CI, 1.0-2.8; p = 0.06). At 5-years, ORs were lower and differences were no longer significant. Moderate-severe pain did not differ significantly by diagnosis, at 2- or 5-years in multivariable adjusted analyses, with one exception, i.e. failed prior arthroplasty/infection had a trend towards significance with odds ratio of 1.9 (95% CI, 0.9-3.8; p = 0.07). | Operative diagnosis is independently associated with ADL limitations, but not pain, at 2-years after revision THA. Patients should be informed of the risk of poorer short-term outcomes based on their diagnosis. |
20,132,554 | Are caspase 8 and maspin downregulated in breast cancer cells due to CpG site promoter methylation? | Epigenetic changes associated with promoter DNA methylation results in silencing of several tumor suppressor genes that lead to increased risk for tumor formation and for progression of the cancer. Methylation specific PCR (MSP) and bisulfite sequencing were used for determination of proapoptotic gene Caspase 8 (CASP8) and the tumor suppressor gene maspin promoter methylation in four breast cancer and two non-tumorigenic breast cell lines. Involvement of histone H3 methylation in those cell lines were examined by CHIP assay. The CpG sites in the promoter region of CASP8 and maspin were methylated in all four breast cancer cell lines but not in two non-tumorigenic breast cell lines. Demethylation agent 5-aza-2'-deoxycytidine (5-aza-dc) selectively inhibits DNA methyltransferases, DNMT3a and DNMT3b, and restored CASP8 and maspin gene expression in breast cancer cells. 5-aza-dc also reduced histone H3k9me2 occupancy on CASP8 promoter in SKBR3cells, but not in MCF-7 cells. Combination of histone deacetylase inhibitor Trichostatin A (TSA) and 5-aza-dc significant decrease in nuclear expression of Di-methyl histone H3-Lys27 and slight increase in acetyl histone H3-Lys9 in MCF-7 cells. CASP8 mRNA and protein level in MCF-7 cells were increased by the 5-aza-dc in combination with TSA. Data from our study also demonstrated that treatment with 5-FU caused a significant increase in unmethylated CASP8 and in CASP8 mRNA in all 3 cancer lines. | CASP8 and maspin expression were reduced in breast cancer cells due to promoter methylation. Selective application of demethylating agents could offer novel therapeutic opportunities in breast cancer. |
16,955,408 | Does presence of prostate cancer metastasis correlate with lower lymph node reactivity? | Several reports suggest that the dissemination of neoplastic cells and cancer progression are associated with the generation of an immunosuppressive environment. In this report, we investigated immunological effects of prostate cancer by comparing metastastic and non-metastatic pelvic lymph nodes (LNs) from 25 patients with carcinomatous involvement of LNs to the non-metastatic LNs from 26 control patients with no metastatic involvement by immunohistochemistry and histological analyses. Our results showed a decreased abundance of CD20+ B lymphocytes (P = 0.031), CD38+ activated lymphocytes (P = 0.038), and CD68+ macrophages (P < 0.001), and less evidence of follicular hyperplasia (P = 0.014), sinus hyperplasia (P < 0.001), and fibrosis (P=0.028) in metastatic LNs comparatively to control LNs. Finally, we observed that metastatic LNs were significantly smaller than control LNs (P = 0.005). | Our results suggest that the development of prostate cancer LN metastasis is accompanied with smaller LN size and decreased LN reactivity suggesting the development of an immununosuppressive microenvironment. |
20,233,800 | Cancer and the media: how does the news report on treatment and outcomes? | Cancer receives a great deal of news media attention. Although approximately half of all US patients with cancer die of their illness or of related complications, it is unknown whether reports in the news media reflect this reality. To determine how cancer news coverage reports about cancer care and outcomes, we conducted a content analysis of US cancer news reporting in 8 large-readership newspapers and 5 national magazines. Trained coders determined the proportion of articles reporting about cancer survival, cancer death and dying, aggressive cancer treatment, cancer treatment failure, adverse events of cancer treatment, and end-of-life palliative or hospice care. Of 436 articles about cancer, 140 (32.1%; 95% confidence interval [CI], 28%-37%) focused on survival and only 33 (7.6 %; 5%-10%) focused on death and dying (P<.001, chi(2) test). Only 57 articles (13.1%; 10%-17%) reported that aggressive cancer treatments can fail, and 131 (30.0%; 26%-35%) reported that aggressive treatments can result in adverse events. Although most articles (249 of 436 [57.1%]; 95% CI, 52%-62%) discussed aggressive treatments exclusively, almost none (2 of 436; [0.5%]; 0%-2%) discussed end-of-life palliative or hospice care exclusively (P<.001, chi(2) test), and only a few (11 of 436 [2.5%]; 1%-6%) discussed aggressive treatment and end-of-life care. | News reports about cancer frequently discuss aggressive treatment and survival but rarely discuss treatment failure, adverse events, end-of-life care, or death. These portrayals of cancer care in the news media may give patients an inappropriately optimistic view of cancer treatment, outcomes, and prognosis. |
24,107,313 | Is switching from brand name to generic formulations of phenobarbital associated with loss of antiepileptic efficacy? | In human medicine, adverse outcomes associated with switching between bioequivalent brand name and generic antiepileptic drug products is a subject of concern among clinicians. In veterinary medicine, epilepsy in dogs is usually treated with phenobarbital, either with the standard brand name formulation Luminal(®) or the veterinary products Luminal(®) vet and the generic formulation Phenoleptil(®). Luminal(®) and Luminal(®) vet are identical 100 mg tablet formulations, while Phenoleptil(®) is available in the form of 12.5 and 50 mg tablets. Following approval of Phenoleptil(®) for treatment of canine epilepsy, it was repeatedly reported by clinicians and dog owners that switching from Luminal(®) (human tablets) to Phenoleptil(®) in epileptic dogs, which were controlled by treatment with Luminal(®), induced recurrence of seizures. In the present study, we compared bioavailability of phenobarbital after single dose administration of Luminal(®) vet vs. Phenoleptil(®) with a crossover design in 8 healthy Beagle dogs. Both drugs were administered at a dose of 100 mg/dog, resulting in 8 mg/kg phenobarbital on average. Peak plasma concentrations (Cmax) following Luminal(®) vet vs. Phenoleptil(®) were about the same in most dogs (10.9 ± 0.92 vs. 10.5 ± 0.77 μg/ml), and only one dog showed noticeable lower concentrations after Phenoleptil(®) vs. Luminal(®) vet. Elimination half-life was about 50 h (50.3 ± 3.1 vs. 52.9 ± 2.8 h) without differences between the formulations. The relative bioavailability of the two products (Phenoleptil(®) vs. Luminal(®) vet.) was 0.98 ± 0.031, indicating that both formulations resulted in about the same bioavailability. | Overall, the two formulations did not differ significantly with respect to pharmacokinetic parameters when mean group parameters were compared. Thus, the reasons for the anecdotal reports, if true, that switching from the brand to the generic formulation of phenobarbital may lead to recurrence of seizures are obviously not related to a generally lower bioavailability of the generic formulation, although single dogs may exhibit lower plasma levels after the generic formulation that could be clinically meaningful. |
27,541,328 | Do fluctuations in Global Brain Activity Are Associated With Changes in Whole-Brain Connectivity of Functional Networks? | The aim of this study was to explore the relationship between global brain activity, changes in whole-brain connectivity, and changes in brain states across subjects using resting-state functional magnetic resonance imaging. We extended current methods that use a sparse set of coactivation patterns to extract critical time points in global brain activity. Critical activity time points were defined as points where the global signal is greater than one standard deviation above or below the average global signal. Four categories of critical points were defined along dimensions of global signal intensity and trajectory. Voxel-based methods were used to interrogate differences in connectivity between these critical points. Several differences in connectivity were found in functional resting-state networks (RSNs) as a function of global activity. RSNs associated with cognitive functions in frontal, parietal, and subcortical regions exhibited greater whole-brain connectivity during lower global activity states. Meanwhile, RSNs associated with sensory functions exhibited greater whole-brain connectivity during the higher global activity states. Moreover, we present evidence that these results depend in part upon the standard deviation threshold used to define the critical points, suggesting critical points at different thresholds represent unique brain states. | Overall, the findings support the hypothesis that the brain oscillates through different states over the course of a resting-state study reflecting differences in RSN connectivity associated with global brain activity. |
7,824,730 | Prenatally detected fetal myelomeningocele: is karyotype analysis warranted? | To determine the prevalence of karyotype abnormalities in fetuses with prenatally detected spina bifida and evaluate the ability of prenatal sonography to enable prediction of chromosomal abnormalities. Sonograms from 63 fetuses with prenatally detected spina bifida were reviewed, and associated sonographic abnormalities were recorded. Sonographic findings were correlated with autopsy or clinical findings when possible. Associated sonographic abnormalities were present in 15 (24%) of fetuses with spina bifida. Among 52 fetuses with known karyotypes, the prevalence of chromosome abnormalities was 17%. Karyotype abnormalities included trisomy 18, trisomy 13, triploidy, and translocation. Twenty-two percent of chromosomally abnormal fetuses had sonographically isolated spina bifida. | Prenatal sonography can help predict most karyotypically abnormal fetuses with spina bifida, but approximately 20% will be missed with this technique alone in the second trimester. The authors believe cytogenetic analysis is justified in the setting of prenatally detected spina bifida. |
18,811,691 | Cicatricial marginal alopecia: is it all traction? | In a specialized hair loss clinic, a group of patients was identified with focal or complete hair loss at the scalp periphery, with a normal scalp surface. Biopsy revealed complete loss of individual hair follicles, indicative of scarring alopecia. Not all patients had a history supportive of a diagnosis of traction alopecia. To identify and characterize further patients with scarring alopecia of the scalp margin using a retrospective review. All biopsies of scarring alopecia carried out by a single clinician between 1 January 1999 and 29 September 2006 were reviewed. Patients in whom the hair loss was located at the periphery of the scalp were selected for retrospective chart review. A total of 15 patients met the study criteria, which included histological scarring alopecia and hair loss of the scalp margin. Six of the patients gave a history of relaxing or straightening their hair. Six denied hair care practices sufficient to cause traction alopecia. In three patients, the hair care history was unknown. Occipital hair loss was a common clinical finding, mimicking alopecia areata. The presence of scarring was often subtle histologically. | A group of patients with moderate to severe cicatricial alopecia of the scalp margin is described. The presence of scarring is difficult to diagnose both clinically and histologically. The lack of a history of severe traction or harsh styling practices in half the patients casts doubt on whether or not traction is the only pathogenic factor. |
23,839,873 | Is clipping superior to cauterization in the treatment of palmar hyperhidrosis? | Endoscopic thoracic sympathectomy has been accepted as the most effective treatment for palmar hyperhidrosis (PH). However, there is a debate regarding the surgical techniques in terms of effectiveness, recurrence, and reversibility. In this study, sympathetic chain disruptions were compared in terms of whether the clipping or ablation technique had an effect on the long-term outcomes of patients who underwent thoracic sympathectomy for primary PH. All patients who underwent video-thoracoscopic sympathectomy for PH between May 2008 and October 2011 were included. Single-port bilateral sympathectomy was performed depending on the sweat distribution. As a standard approach, rib-based terminology was used to describe the blockade level of the sympathetic ganglia, and single-level R3 sympathectomy (between R3 and R4) was performed in all patients. The type of sympathectomy was changed. Monopolar electrocautery was first performed and 5-mm clips were then used for nerve disruption. Both techniques were evaluated and compared in terms of effectiveness, reversibility, and recurrence. Cauterization of the sympathetic chain was applied in 28 (47%) (Group A) patients and clipping in 32 (53%) patients (Group B). CH was the most common adverse effect and was observed in 43 (71.6%) patients (Group A, 71.4%; Group B, 71.8%; p = 0.8). The success rate was 93% for Group A and 100% for Group B (p = 0.15). The satisfaction rate for Group A was 83% and for Group B was 86% (p = 0.77). In Group A two patients (7%), and in Group B three patients (9%) requested reversibility because of severe compensatory hyperhidrosis. Overly dry hands were the other most common side effect and were identified in 12 (25%) patients. Recurrences were observed in 11 patients in Group A and 4 patients in Group B (19 vs. 6%; p = 0.01). The mean follow-up time was 33 ± 10.5 months (range, 13-53 months). | Both clipping and cauterization are highly effective for the treatment of PH. The methods are comparable in terms of effectiveness and side effects despite the fact that the recurrence rate was higher in the cauterization group. Potential reversibility of compensatory sweating was not observed in our series. Identification of ideal candidates for surgery and education of patients about the permanent side effects of sympathectomy might make these techniques more convenient. |
26,063,958 | Do serum Enzyme Profiles Differentiate Five Types of Muscular Dystrophy? | Differentiation among types of muscular dystrophy (MD) has remained challenging. In this retrospective study, we sought to develop a methodology for differentiation of MD types using analysis of serum enzyme profiles. The serum levels of enzymes from 232 patients, including 120 with DMD, 36 with BMD, 36 with FSHD, 46 with LGMD, and 11 with EDMD, were evaluated. The characteristic profiles of serum enzymes facilitated differentiation of these five types of MD. DMD was characterized by simultaneous elevation of ALT, AST, LDH, and ALP; BMD and LGMD were characterized by elevation of ALT, AST, and LDH; and FSHD and EDMD were characterized by a lack of abnormal serum enzyme levels. We further developed discriminant functions to distinguish BMD and LGMD. For LGMD, LGMD2B patients had significantly higher ALP levels than non-LGMD2B patients (98 ± 59 U/L versus 45 ± 9 U/L, resp., p < 0.05). | Our approach enabled the determination of MD subtypes using serum enzyme profiles prior to genetic testing, which will increase the chance a mutation will be found in the first gene analyzed. |
19,184,268 | "Pathologic" fractures: should these be included in epidemiologic studies of osteoporotic fractures? | Pathologic fractures are often excluded in epidemiologic studies of osteoporosis. Using Medicare administrative data, we identified persons with vertebral and hip fractures. Among these, 48% (vertebral) and 3% (hip) of the fractures were coded as pathologic. Only 25% and 66% of persons with these pathologic fractures had evidence for malignancy. Analyses of osteoporosis-related fractures that use administrative data often exclude pathologic fractures (ICD-9 733.1x) due to concern that these are caused by cancer. We examined "pathologic" fractures of the vertebrae and hip to evaluate their contribution to fracture incidence and assessed the evidence for a malignancy. We studied US Medicare beneficiaries age>or =65 with new fractures identified using ICD-9 diagnosis codes 733.13 (pathologic vert), 805.0, 805.2, 805.4, 805.8 (nonpathologic vert); and 733.14 (pathologic hip), 820.0, 820.2, 820.8 (nonpathologic hip). We further examined the proportion of cases with a diagnosis of a malignancy proximate to the fracture. We identified 44,120 individuals with a vertebral fracture and 60,354 with a hip fracture. Approximately 48% of vertebral fractures and 3% of hip fractures were coded as pathologic. For only approximately 25% of persons with a "pathologic" vertebral fracture ICD-9 code, but 66% of persons with a "pathologic" hip fracture, there was evidence of a possible cancer diagnosis. | Among US Medicare beneficiaries, one fourth of pathologic vertebral fracture and two thirds of pathologic hip fracture cases had evidence for a malignancy. Particularly for vertebral fractures, excluding persons with pathologic fractures in epidemiologic analyses that utilize administrative claims data substantially underestimates the burden of fractures due to osteoporosis. |
11,500,700 | Growth hormone: do we have a national perspective of indications for its use? | Presentation of indications for growth hormone use in children, from the view of physicians practising in Saudi Arabia. A questionnaire containing a list of common possible indications of growth hormone use was collected from 52 physicians practising in Saudi Arabia who were attending a didactic endocrinology course. All (100%) physicians considered growth hormone deficiency to be an indication. Sixty four and 29% considered Turner's syndrome and chronic renal failure to be indications. Other indications included Russell-Silver syndrome in 23%, X-linked hypophosphatemic rickets in 10%, Achondroplasts in 10%, Sickle cell anemia in 10% and Bartter's syndrome in 2%. Genetic and constitutional short stature were considered in 17 and 19%. Only 65% did not advocate the use of growth hormone for short non-growth hormone-deficient children. | Indications of growth therapy are not clearly defined in Saudi Arabia. It is indicated to define this by a clear, national decided criteria which should take into consideration the internationally approved indications, availability and cost of this hormone. |
25,287,489 | Is paired box gene 8 ( PAX8 ) expression associated with sonic hedgehog ( SHH ) /wingless int ( WNT ) subtypes , desmoplastic histology and patient survival in human medulloblastomas? | The paired box gene 8 (PAX8) plays crucial roles in organ patterning and cellular differentiation during development and tumorigenesis. Although its function is partly understood in vertebrate development, there is poor data concerning human central nervous system (CNS) development and brain tumours. We investigated developing human (n = 19) and mouse (n = 3) brains as well as medulloblastomas (MBs) (n = 113) for PAX8 expression by immunohistochemistry. Human MB cell lines were assessed for PAX8 expression using polymerase chain reaction and immunoblotting and analysed for growth and migration following PAX8 knock-down by small interfering ribonucleic acid (siRNA). PAX8 protein expression was associated with germinal layers in human and murine forebrain and hindbrain development. PAX8 expression significantly decreased over time in the external granule cell layer but increased in the internal granule cell layer. In MB subtypes, we observed an association of PAX8 expression with sonic hedgehog (SHH) and wingless int subtypes but not with group 3 and 4 MBs. Beyond that, we detected high PAX8 levels in desmoplastic MB subtypes. Univariate analyses revealed high PAX8 levels as a prognostic factor associated with a significantly better patient prognosis in human MB (overall survival: Log-Rank P = 0.0404, Wilcoxon P = 0.0280; progression-free survival: Log-Rank P = 0.0225; Wilcoxon P = 0.0136). In vitro assays revealed increased proliferation and migration of MB cell lines after PAX8 siRNA knock-down. | In summary, high PAX8 expression is linked to better prognosis in MBs potentially by suppressing both proliferative and migratory properties of MB cells. The distinct spatio-temporal expression pattern of PAX8 during brain development might contribute to the understanding of distinct MB subtype histogenesis. |
25,307,975 | Does delirium affect length of hospital stay after lung transplantation? | Delirium is relatively common after lung transplantation, although its prevalence and prognostic significance have not been systematically studied. The purpose of the present study was to examine pretransplant predictors of delirium and the short-term impact of delirium on clinical outcomes among lung transplant recipients. Participants underwent pretransplant cognitive testing using the Repeatable Battery for the Assessment of Neuropsychological Status and the Trail Making Test. After transplant, delirium was assessed using the Confusion Assessment Method until discharge. Sixty-three patients were transplanted between March and November 2013, of which 23 (37%) developed delirium. Among transplanted patients, 48 patients completed pretransplant cognitive testing. Better pretransplant cognitive function was associated with lower risk of delirium (odds ratio, 0.69 [95% confidence interval 0.48, 0.99], P = .043); and demographic and clinical features including native disease (P = .236), the Charlson comorbidity index (P = .581), and the lung allocation score (P = .871) were unrelated to risk of delirium, although there was a trend for women to experience delirium less frequently (P = .071). The presence (P = .006) and duration (P = .027) of delirium were both associated with longer hospital stays. | Delirium occurs in more than one-third of patients after lung transplantation. Delirium was associated with poorer pretransplant cognitive functioning and longer hospital stays, after accounting for other medical and demographic factors. |
20,050,352 | Does incremental value of using Medicaid claim file to study comorbid conditions and treatments in dually eligible beneficiaries? | Although investigations using Medicare claims files are ubiquitous in the health services research literature, Medicaid claims files are used less frequently. Nonetheless, Medicaid is the major payer for healthcare among low-income persons. To assess the added value of Medicaid claim files for identifying comorbid conditions and cancer treatments in a dually eligible sample. Data were obtained from linked statewide tumor registries from 2 contiguous Midwestern states (Michigan and Ohio), Medicare and Medicaid enrollment files, and Medicare and Medicaid claims files. We estimated the prevalence of Charlson Comorbidity Index conditions by counting the number of patients with these conditions in the Medicare claims files alone. We then estimate the expected percent increase in the prevalence of comorbid conditions (along with the 95% confidence interval) that could be obtained by using both Medicare and Medicaid claim files. We followed a similar procedure to identify treatments provided to dually eligible patients. Medicaid claims added very few individuals with comorbid conditions over those identified through Medicare claim files. The increase in the prevalence of comorbid conditions was between 0% and 2.5%. Likewise, Medicaid claims identified few individuals with cancer treatments who were not already identified through Medicare claim files, although variations were noted between the 2 states. | This study suggests that the incremental value of Medicaid inpatient, outpatient, and carrier claims is relatively small over what can be obtained from Medicare claims data. |
20,016,184 | Is vitamin E use associated with improved survival in an Alzheimer 's disease cohort? | Vitamin E at a dose of 2,000 IU per day has been shown to delay Alzheimer's disease (AD) progression, but recent studies have questioned the safety of this dose level and the overall efficacy of vitamin E in AD treatment. We analyzed the survival history of 847 probable or mixed AD patients followed in a research center between 1990 and the censoring date of December 31, 2004. Standard practice during this period was to recommend vitamin E at 1,000 IU twice daily to all patients. We used Cox proportional hazards modeling to assess the association of vitamin E alone, or in combination with a cholinesterase inhibitor (ChEI), with all-cause mortality, adjusting for important covariates. Approximately two thirds of the patients took vitamin E with a ChEI, 10% took vitamin E alone, and 15% took no antidementia drug. The adjusted hazard ratio (HR) associated with vitamin E (with or without a ChEI) was 0.71 (95% CI: 0.57-0.89; p = 0.003). Compared to the no drug treatment group, the HR for vitamin E alone or with another drug was 0.77 (95% CI: 0.60-1.0); the HR for ChEI use alone was 1.2 (95% CI: 0.87-1.60). | The results do not support a concern over increased mortality with high-dose vitamin E supplementation. |
22,021,910 | Does mechanical stretch induce the apoptosis regulator PUMA in vascular smooth muscle cells? | The expression of PUMA (p53-up-regulated modulator of apoptosis), an apoptosis-regulating gene, increases during endoplasmic reticulum stress. The mechanisms by which cyclic stretch influences the regulation of PUMA in vascular smooth muscle cells (VSMCs) during apoptosis remain unclear. We hypothesized that cyclic stretch enhances PUMA expression in VSMCs undergoing apoptosis. Human VSMCs grown on a Flexcell I flexible membrane base were stretched via vacuum to 20% of elongation at a frequency of 1 Hz. An in vivo model of volume overload with aorta-caval shunt and pressure overload with aortic banding in adult rats was used to study PUMA expression. Cyclic stretch markedly enhanced PUMA protein and gene expression after stretch. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125 and interferon-γ (IFN-γ) antibody 30 min before stretch inhibited PUMA expression. Gel shift assay demonstrated that stretch increased the DNA binding activity of interferon regulatory factor-1 (IRF-1). SP600125, JNK small interfering RNA, and IFN-γ antibody attenuated the DNA binding activity induced by stretch. PUMA-Mut plasmid, SP600125, and IRF-1 antibody attenuated the promoter activity. Stretch increased secretion of IFN-γ from VSMCs, and conditioned media from stretched VSMCs increased PUMA protein expression. The in vivo model of aorta-caval shunt and aortic banding also showed increased PUMA protein expression in the aorta. | Cyclic mechanical stretch increases PUMA expression in cultured human VSMCs. The PUMA expression induced by stretch is mediated by IFN-γ, JNK, and IRF-1 pathways. These findings suggest that PUMA is an important mediator in VSMC apoptosis induced by stretch. |
22,527,071 | Is knee area tissue oxygen saturation predictive of 14-day mortality in septic shock? | Thenar eminence tissue oxygen saturation (StO(2)) was developed to assess organ perfusion. However, mottling, a strong predictor of mortality in septic shock, develops preferentially around the knee. We aimed to evaluate the prognostic value of StO(2) measured around the knee in septic shock patients and compare it to thenar StO(2). This was a prospective observational study in a tertiary teaching hospital. All consecutive patients with septic shock were included. Parameters were recorded when vasopressors were started (H0) and every 6 h during 24 h. Their predictive value was assessed on 14-day mortality. Fifty-two patients were included. SOFA score was 11 (9-15) and SAPS II was 56 (40-72). At 6 h after ICU admission (H6), mean arterial pressure, cardiac index, and central venous pressure were not different between non-survivors and survivors; but non-survivors had higher arterial lactate level (8.8 ± 5.0 vs. 2.2 ± 1.5 mmol/l, P < 0.001), lower urinary output (0.22 ± 0.45 vs. 0.70 ± 0.50 ml/kg/h, P < 0.001) and ScvO(2) (62 ± 20 vs. 72 ± 9 %, P = 0.03). At H6, StO(2) was lower in non-survivors; this difference was not significant for thenar StO(2) (70 ± 15 vs. 77 ± 12 %, P = 0.10) but was very pronounced for knee StO(2) (39 ± 23 vs. 71 ± 12 %, P < 0.001). At H6, a low knee StO(2) was associated with a higher mottling score (P < 0.01), a higher lactate level (P < 0.002, R (2) = 0.2), and a lower urinary output (P = 0.02, R (2) = 0.12). | After initial septic shock resuscitation, StO(2) measured around the knee is a strong predictive factor of 14-day mortality. |
18,725,871 | Is research presented at the scoliosis research society annual meeting influenced by industry funding? | All abstracts submitted to the 2006 SRS annual meeting were reviewed. To determine the rate of funding in abstracts submitted for presentation at the 2006 Annual Scoliosis Research Society (SRS) meeting and whether funding produced bias toward a positive outcome. Financial conflicts of interest have been attributed to bias in research. Three members the SRS Program Committee reviewed 610 abstracts submitted for presentation at the 2006 annual meeting. The committee's average grade was correlated with type of funding (industry, professional society, university); abstract conclusions (favorable, unfavorable, or only descriptive); and subject category [adolescent idiopathic scoliosis (AIS), motion preservation, etc.]. Of the 610 submitted articles, 72% (n = 440) were unfunded. Of the 170 funded articles, 140 were supported by industry, 7 by government agency, 8 by professional societies, 4 by universities, and 11 by private foundations. There was no statistically significant difference between the reviewers' grades of funded versus unfunded articles (P = 0.39). Comparing AIS articles to all the other categories, the number of funded articles were significantly greater only in motion preservation (P<0.001) and genetics (P = 0.039). When a consultant/employee relationship was present, there was a significant difference in the proportion of funded articles and favorable findings (P = 0.048). | The higher percentage of funded articles in motion preservation and genetics compared to AIS articles could reflect a bias in those 2 areas. However, although there were more funded articles in those 2 areas there were not more funded, favorable articles (motion preservation P = 0.059, and genetics P = 0.3). Thus, certain categories attracted more funding than others but there was not a bias toward favorable findings within the funded articles unless the funding was due to a consultant/employee relationship. |
10,809,269 | Are calcitonin precursors reliable markers of sepsis in a medical intensive care unit? | The diagnosis of infection in critically ill patients is challenging because traditional markers of infection are often misleading. For example, serum concentrations of calcitonin precursors are increased in patients with infections. However, their predictive accuracy for the diagnosis of sepsis in unselected patients in a medical intensive care unit (ICU) is unknown. Therefore, we compared the usefulness of serum concentrations of calcitonin precursors, C-reactive protein, interleukin-6, and lactate for the diagnosis of sepsis in consecutive patients suffering from a broad range of diseases with an anticipated stay of > or =24 hrs in a medical ICU. Prospective cohort study. Medical intensive care unit in a university medical center. 101 consecutive critically ill patients. None. Blood samples were collected at various time points during the course of the disease. Systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock were diagnosed according to standardized criteria, and patients were reclassified daily without prior knowledge of the serum concentrations of calcitonin precursors or interleukin-6. At admission, 99% of the patients had systemic inflammatory response syndrome, 53% had sepsis, and 5% developed sepsis during their stay in the ICU. Calcitonin precursors, C-reactive protein, interleukin-6, and lactate levels increased with the severity of infection (p < .01, one-way analysis of variance). In a receiver operating characteristic curve analysis, calcitonin precursors were found to be the most reliable laboratory variable for the diagnosis of sepsis as compared with C-reactive protein, interleukin-6, and lactate (p < .01, for each comparison). Calcitonin precursor concentrations of >1 ng/mL had sensitivity of 89% and specificity of 94% for the diagnosis of sepsis. High serum concentrations of calcitonin precursors were associated with poor prognosis (p = .01). | In a medical ICU, serum calcitonin precursor concentrations are more sensitive and are specific markers of sepsis as compared with serum C-reactive protein, interleukin-6, and lactate levels. |
24,606,068 | Do peripheral monocytes of obese women display increased chemokine receptor expression and migration capacity? | The activation of peripheral immune cells and the infiltration of immune cells into adipose tissue in obesity are implicated in the development of type 2 diabetes mellitus. The aim of the study was to compare peripheral immune cells from obese and normal-weight women with regard to composition of immune cell subpopulations, surface expression of the chemokine receptors (CCRs) CCR2, CCR3, CCR5, and CXCR3 (chemokine (C-X-C motif) receptor 3) and cell-intrinsic migration capacity. This was a case-control study. The study was conducted at a university clinical study center. Obese females and normal-weight females were included for fluorescence-activated cell sorting analysis and migration assays. Peripheral blood mononuclear cells were prepared from fasting blood samples and used for fluorescence-activated cell sorting analysis and migration assays. An increase in the percentages of CD14(+)CD16(+) monocytes was observed in obese subjects compared with controls. The CCR profile of monocytes differed significantly in the obese state; in particular, CCR2 levels were increased. In addition, a higher chemotactic activity of monocytes from obese subjects was observed in a migration assay, which was associated with both insulin resistance and CCR2 expression. | Our results suggest that the enhanced intrinsic migratory capacity of peripheral monocytes in obese women may be due to the increased CCR expression, further supporting a link between peripheral immune cell dysfunction and obesity. |
9,428,224 | Does endothelin 1 induce leukocyte adhesion in submucosal venules of the rat small intestine? | The release of endothelin 1 (ET-1) and the activation of leukocytes are involved in the pathophysiology of gastrointestinal ischemia/reperfusion injuries. The aim of this study was to define the in vivo relation between ET-1 and endothelial cell-leukocyte interactions. Anesthetized rats were studied to characterize the microvascular effects of increasing doses of local and systemic infusions of ET-1 in all layers of an ileal segment. Leukocyte-endothelial interactions were monitored with intravital fluorescence videomicroscopy. The ETA receptor-selective antagonist BQ 610, the novel ETA-receptor antagonist ETR-PI/fl peptide, and the ETB-receptor antagonist IRL 1038 were used to investigate the roles of receptor subtypes. The functional capillary density of the mucosa was significantly decreased by 3 nmol/kg intravenous ET-1. After 30 minutes the rolling fraction of leukocytes reached 90% in the postcapillary venules, and the number of adherent leukocytes was significantly increased after 90 minutes. ETR-PI/fl peptide inhibited leukocyte rolling by 88%, BQ 610 by 73%, and IRL 1038 by 30%. Both ETA-receptor antagonists prevented ET-1-induced firm adhesion. The ETA-receptor antagonists but not IRL 1038 inhibited the ET-1-induced lymphatic muscle and mucosal capillary perfusion failure. | ET-1 induces leukocyte rolling and adherence through a predominantly ETA receptor-mediated mechanism in the submucosal venules of the intestinal microcirculation. |
26,842,697 | Are ratios of central venous-to-arterial carbon dioxide content or tension to arteriovenous oxygen content better markers of global anaerobic metabolism than lactate in septic shock patients? | To evaluate the ability of the central venous-to-arterial CO2 content and tension differences to arteriovenous oxygen content difference ratios (∆ContCO2/∆ContO2 and ∆PCO2/∆ContO2, respectively), blood lactate concentration, and central venous oxygen saturation (ScvO2) to detect the presence of global anaerobic metabolism through the increase in oxygen consumption (VO2) after an acute increase in oxygen supply (DO2) induced by volume expansion (VO2/DO2 dependence). We prospectively studied 98 critically ill mechanically ventilated patients in whom a fluid challenge was decided due to acute circulatory failure related to septic shock. Before and after volume expansion (500 mL of colloid solution), we measured cardiac index, VO2, DO2, ∆ContCO2/∆ContO2 and ∆PCO2/∆ContO2 ratios, lactate, and ScvO2. Fluid-responders were defined as a ≥15 % increase in cardiac index. Areas under the receiver operating characteristic curves (AUC) were determined for these variables. Fifty-one patients were fluid-responders (52 %). DO2 increased significantly (31 ± 12 %) in these patients. An increase in VO2 ≥ 15 % ("VO2-responders") concurrently occurred in 57 % of the 51 fluid-responders (45 ± 16 %). Compared with VO2-non-responders, VO2-responders were characterized by higher lactate levels and higher ∆ContCO2/∆ContO2 and ∆PCO2/∆ContO2 ratios. At baseline, lactate predicted a fluid-induced increase in VO2 ≥ 15 % with AUC of 0.745. Baseline ∆ContCO2/∆ContO2 and ∆PCO2/∆ContO2 ratios predicted an increase of VO2 ≥ 15 % with AUCs of 0.965 and 0.962, respectively. Baseline ScvO2 was not able to predict an increase of VO2 ≥ 15 % (AUC = 0.624). | ∆ContCO2/∆ContO2 and ∆PCO2/∆ContO2 ratios are more reliable markers of global anaerobic metabolism than lactate. ScvO2 failed to predict the presence of global tissue hypoxia. |
25,977,233 | Predischarge Transthoracic Echocardiography after Surgery for Congenital Heart Disease: A Routine with a Reason? | Predischarge (pre-d/c) transthoracic echocardiography (TTE) is routine after surgery for congenital heart disease, but how it affects clinical care is unknown. The aim of this study was to test the hypothesis that pre-d/c TTE frequently reveals findings associated with short-term clinical course through a systematic review of findings on pre-d/c TTE and clinical events that followed. Clinical outcomes of mortality, hospitalization, catheterization, and surgery at 1 year were examined for pediatric patients undergoing pre-d/c TTE between June 2010 and June 2012. Using logistic regression, a multivariate model was generated associating clinical, pre-d/c transthoracic echocardiographic, and demographic variables with unplanned postdischarge cardiac events (UCEs) within 1 year. Of 462 patients who underwent pre-d/c TTE, there were 265 male patients (57%) and 197 female patients (43%); the median age was 0.8 years (range, 0-33 years). Two hundred thirty-seven patients (51%) had findings (valve regurgitation, hemodynamic obstruction, ventricular dysfunction, unintended shunt, or pericardial effusion) on pre-d/c TTE, 57 of which were of more than mild severity. Agreement between pre-d/c TTE and postoperative transesophageal echocardiographic findings was only fair to moderate (κ = 0.27-0.43). Sixty-four patients (14%) had UCEs. Univariate analysis revealed that UCE were more frequent in patients with diagnoses and surgical procedures of high complexity. After accounting for these confounding nonechocardiographic variables, pre-d/c transthoracic echocardiographic findings, specifically valve regurgitation of more than mild severity, and ventricular dysfunction and obstructions of any severity were independently associated with UCEs (odds ratios, 1.90, 1.99, and 1.85, respectively). | Findings on pre-d/c TTE are frequent, commonly discordant with postoperative transesophageal echocardiographic results, and associated with adverse clinical events after surgery for congenital heart disease. These data would strongly support the practice of pre-d/c TTE after surgery for congenital heart disease. |
24,365,985 | Do preliminary assessment of zolpidem pharmacokinetics in pediatric burn patients? | Severely burned patients frequently experience sleep fragmentation and insomnia. This study evaluated the population pharmacokinetics of the sleep-enhancing agent zolpidem among burned children. Zolpidem was administered according to the following age-based dosing schedule: 2.5 mg per dose for 2-4 year olds, 5.0 mg per dose for 5-10 year olds, and 10 mg per dose for older than 10 years. Serum samples were collected before and 1, 2, 4, 5, 6, and 8 hours after dosing. The population pharmacokinetic analysis modeled zolpidem concentrations using nonlinear mixed effects models. Eleven patients with a mean (±SD) age of 8.3 ± 4.0 years and a mean total burn surface area of 56% ± 22% were recruited. Seventy-three zolpidem concentrations were measured with a mean Cmax of 291 ± 140 ng/mL. A 2-compartment model with first-order absorption best described the data. Zolpidem clearance was estimated at 0.03 L·h(-1)·kg(-1) (relative standard error, 55%) and increased with body weight (P < 0.05). The central compartment volume of distribution was estimated at 0.05 L/kg (relative standard error, 25%), which was inversely related to the proportion of the body surface with third-degree burns (P < 0.001). | A population pharmacokinetic model has been developed that reliably characterized the pharmacokinetic parameters of zolpidem when used as a sleep-enhancing agent among pediatric burn patients. Additional studies are needed to link this pharmacokinetic model with pharmacodynamic data, which may include an assessment of the effects of higher zolpidem doses and/or more frequent administration upon sleep architecture. |
27,616,634 | Are patients on basal insulin attaining glycemic targets? | To investigate treatment patterns and achievement of glycemic targets in patients with type 2 diabetes mellitus treated with basal insulin in a real-world setting, and to determine physicians' beliefs and practices regarding these patients. This study had two components; a retrospective analysis using a US claims database of patient and treatment data, and a survey of physicians' beliefs and practices. A total of 39,074 patients treated with basal insulin were included in this analysis. The proportion of patients achieving HbA1c<7.0% (53mmol/mol) was similar in ongoing basal insulin users at baseline (26%) and at 3months follow-up (27%). The number of new initiators achieving HbA1c<7.0% (53mmol/mol) increased from baseline (11%) to 3months (27%). In the physician survey component, the majority of physicians indicated they would continue to increase basal insulin dose as long as was needed to reach HbA1c/fasting blood glucose goals (85% of physicians treating 'not on-goal' patients, 78% of physicians treating 'on-goal' patients). Physician-perceived barriers to insulin intensification included patient's lifestyle, non-adherence, and concerns about out-of-pocket costs. | A large proportion of patients on insulin-based therapy fail to reach glycemic goals. More education of clinicians may improve insulin intensification rates and increase the proportion of patients reaching glycemic targets. |
22,565,242 | Does Medicaid pay more to a program of all-inclusive care for the elderly (PACE) than for fee-for-service long-term care? | In rebalancing from nursing homes (NHs), states are increasing access of NH-certified dually eligible (Medicare/Medicaid) patients to community waiver programs and Programs of All-Inclusive Care for the Elderly (PACE). Prior evaluations suggest Medicaid's PACE capitation exceeds its spending for comparable admissions in alternative care, although the latter may be underestimated. We test whether Medicaid payments to PACE are lower than predicted fee-for-service outlays in a long-term care admission cohort. Using grade-of-membership methods, we model health deficits for dual eligibles aged 55 or more entering waiver, PACE, and NH in South Carolina (n = 3,988). Clinical types, membership vectors, and program type prevalences are estimated. We calculate a blend, fitting PACE between fee-for-service cohorts, whose postadmission 1-year utilization was converted to attrition-adjusted outlays. PACE's capitation is compared with blend-based expenditure predictions. Four clinical types describe population health deficits/service needs. The waiver cohort is most represented in the least impaired type (1: 47.1%), NH entrants in the most disabled (4: 38.5%). Most prevalent in PACE was a dementia type, 3 (32.7%). PACE's blend was waiver: 0.5602 (95% CI: 0.5472, 0.5732) and NH: 0.4398 (0.4268, 0.4528). Average Medicaid attrition-adjusted 1-year payments for waiver and NH were $4,177 and $77,945. The mean predicted cost for PACE patients in alternative long-term care was $36,620 ($35,662 and $37,580). PACE's Medicaid capitation was $27,648-28% below the lower limit of predicted fee-for-service payments. | PACE's capitation was well under outlays for equivalent patients in alternative care-a substantial savings for Medicaid. Our methods provide a rate-setting element for PACE and other managed long-term care. |
16,100,158 | Does bosentan improve exercise tolerance and Tei index in patients with pulmonary hypertension and prostanoid therapy? | Pulmonary arterial hypertension (PAH) is a progressive disease with a bad prognosis. Prostanoids are well established in the medical treatment of this disease. Treatment of patients with progressive disease despite prostanoids remains a therapeutic challenge. In this study, we examined the effect of adding bosentan, an endothelin antagonist, to existing prostanoid therapy on exercise capacity (6-min walking distance [6MWD]) and right ventricular (RV) function (Tei index) in patients with progressive pulmonary hypertension. Prospective, nonrandomized, open-label study. University hospital. Sixteen patients with pulmonary hypertension (PAH, n = 10; pulmonary hypertension due to other cause, n = 6) with progressive disease receiving either beraprost (n = 3), inhaled iloprost (n = 10), or iloprost IV (n = 3). Combination therapy with bosentan (final dosage, 125 mg bid) was initiated following an interval of 3-months minimum of unchanged prostanoid therapy. Tei index, 6MWD, and New York Heart Association (NYHA) functional class were assessed prior to the initiation of combination therapy (baseline), at 6 months after initiation of combination therapy, and every 3 months thereafter. Two patients were followed up for 6 months only; all remaining patients reached a mean follow-up period (+/- SD) of 13.5 +/- 5.0 months (range, 9 to 22 months). 6MWD increased by 42.5 +/- 66 m at 6 months and 44.6 +/- 66 m at the last follow-up (both time points vs baseline, p < 0.001), and Tei index improved by -0.13 +/- 0.08 at 6 months and - 0.13 +/- 0.11 at the last follow-up (both time points vs baseline, p < 0.001). All patients reported subjective improvements. Nine of 16 patients exhibited improvement in NYHA functional class at 6 months. No side effects occurred that required dose adjustment or discontinuation of the study medication. | Bosentan administered to patients with progressive pulmonary hypertension receiving prostanoids resulted in an increased exercise capacity and an improved RV function. Bosentan therefore appears to be well suited for combination therapy with prostanoids in selected patients pending results of ongoing randomized trials. |
24,406,064 | Do the O-linked glycans of human von Willebrand factor modulate its interaction with ADAMTS-13? | O-linked glycans (OLGs) are clustered on either side of the von Willebrand factor (VWF) A1 domain and modulate its interaction with platelets; however, their influence on the VWF interaction with ADAMTS-13 is unknown. To assess the role of the OLGs in VWF susceptibility to ADAMTS-13 proteolysis, which would help to explain their specific distribution. OLG sites were mutated individually and as clusters on either and both sides of the A1 domain, and expressed in HEK293T cells. First, their proteolysis by ADAMTS-13 was assayed in the presence of urea. Next, a parallel-flow chamber was used to analyze VWF-mediated platelet capture on collagen in the presence and absence of ADAMTS-13 under a shear stress of 1500 s(-1) . The decrease in platelet capture in the presence ADAMTS-13 was used as a measure of VWF proteolysis. Initially, we found that, under denaturing conditions, the C-terminal S1486A and Cluster 2 and double cluster (DC) variants were less susceptible to ADAMTS-13 proteolysis than wild-type VWF. Next, we showed that addition of ADAMTS-13 diminished VWF-mediated platelet capture on collagen under flow; surprisingly, this was more pronounced with the S1486A, Cluster 2 and DC variants than with wild-type VWF, indicating that these are proteolyzed more rapidly under shear flow. | OLGs provide rigidity to peptide backbones, and our findings suggest that OLG in the A1-A2 linker region regulates VWF conformational changes under shear. Importantly, the impact of OLGs on ADAMTS-13 cleavage under shear stress is the opposite of that under denaturing conditions, highlighting the non-physiologic nature of in vitro cleavage assays. |
25,319,009 | Does tGFβ1 protect cells from γ-IR by enhancing the activity of the NHEJ repair pathway? | Several groups have reported that TGFβ1 regulates cellular responses to γ-irradiation; however, the exact mechanism has not been fully elucidated. In the current study, the role of TGFβ1 in cellular responses to γ-irradiation was investigated in detail. The data indicate that TGFβ1 pretreatment decreased the aftermath of ionizing radiation (IR)-induced DNA damage in a SMAD-dependent manner. To determine the underlying mechanism for these effects, the extent of IR-induced DNA repair activity in the presence or absence of TGFβ1 was examined. Studies reveal that TGFβ1 upregulated DNA ligase IV (Lig4), augmented IR-induced nuclear retention of the DNA ligase, and enhanced nonhomologous end-joining (NHEJ) repair activity. In addition, knockdown of Lig4 reduced the TGFβ1-induced protection against IR. Overall, these data indicate that TGFβ1 facilitates the NHEJ repair process upon γ-irradiation and thereby enhances long-term survival. | These findings provide new insight and a possible approach to controlling genotoxic stress by the TGFβ signaling pathway. |
25,850,356 | Does neoflavonoid dalbergiphenol from heartwood of Dalbergia sissoo act as bone savior in an estrogen withdrawal model for osteoporosis? | Dalbergiphenol (DGP) is a neoflavonoid isolated from heartwood of Dalbergia sissoo. Effects of DGP on skeletal health remain to be elucidated. The objective of the present study was to investigate the biological effects of DGP on bone loss in ovariectomized mice. Adult BALB/c mice were ovariectomized and administered DGP (1 and 5 mg/kg/d) or 17β-estradiol (E2) orally for 6 weeks. The sham group and the ovariectomy (OVX) + vehicle group served as controls. Eight female BALB/c mice were taken for each group. Uterine estrogenicity, bone microarchitecture, biomechanical strength, new bone formation (based on bone formation rate and mineral apposition rate), and skeletal expression of osteogenic and resorptive gene markers were studied. OVX resulted in a marked increase in body weight and a decrease in femoral and vertebral trabecular bone volume that were prevented by DGP or E2 treatment. DGP treatment increased bone biomechanical strength and new bone formation rate in ovariectomized mice, comparable with E2 treatment. However, increase in uterine weight and estrogenicity were observed in E2-treated ovariectomized mice, but not in response to DGP treatment. Treatment with DGP increased messenger RNA expression of runt-related transcription factor 2, osterix, and collagen type I, and decreased messenger RNA expression of tartrate-resistant acid phosphatase and the osteoprotegerin-to-receptor activator of nuclear factor-κB ligand ratio in the femur of ovariectomized mice. | Overall findings suggest that DGP treatment can effectively prevent OVX-induced increase in bone loss and decrease in bone strength possibly by increasing osteoblastic activities and by decreasing osteoclastic activities. |
23,327,622 | Does lactoferrin knockout mice demonstrate greater susceptibility to Aggregatibacter actinomycetemcomitans-induced periodontal disease? | Among the innate defense mechanisms in the oral cavity, lactoferrin (LF) is a vital antimicrobial that can modify the host response against periodontopathogens. Aggregatibacter actinomycetemcomitans is the main periodontopathogen of localized aggressive periodontitis. The aim of this study is to evaluate the role of LF during A. actinomycetemcomitans-induced periodontitis. Differences in the expression levels of cytokines, chemokines, chemokine receptors, and bone loss markers between wild-type (WT) and LF knockout mice (LFKO(-/-)) were evaluated by real time-PCR. Serum IgG and LF levels were quantified by ELISA. Alveolar bone loss among the groups was estimated by measuring the distance from cemento-enamel junction (CEJ) to the alveolar bone crest (ABC) at 20 molar sites. Oral infection with A. actinomycetemcomitans increased LF levels in periodontal tissue (P = 0.01) and saliva (P = 0.0004) of wild-type infected (WTI) mice compared to wild-type control mice. Pro-inflammatory cytokines such as interferon-γ, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-12 were increased in the infected LF knockout (LFKO(-/-)I) mice compared to the WTI mice, whereas the anti-inflammatory cytokines IL-4 and IL-10 were decreased. Chemokines and chemokine receptors showed different expression patterns between WTI and LFKO(-/-)I mice. The LFKO(-/-)I mice developed increased bone loss (P = 0.002), in conjunction with increased expression of receptor activator of nuclear factor-κB ligand and decrease in osteoprotegerin, compared to WTI mice. | These results demonstrate that the infected LFKO(-/-) mice were more susceptible to A. actinomycetemcomitans-induced alveolar bone loss, with different patterns of immune responses compared to those of WTI mice. |
26,630,432 | Is Cervical Sagittal Imbalance a Risk Factor for Adjacent Segment Pathomechanics After Multilevel Fusion? | A biomechanical study using human spine specimens. The aim of this study was to assess whether the presence of cervical sagittal imbalance is an independent risk factor for increasing the mechanical burden on discs adjacent to cervical multilevel fusions. The horizontal offset distance between the C2 plumbline and C7 vertebral body (C2-C7 Sagittal Vertical Axis (SVA)) or the angle made with vertical by a line connecting the C2 and C7 vertebral bodies (C2-C7 tilt angle) are used as radiographic measures to assess cervical sagittal balance. There is level III clinical evidence that sagittal imbalance caused by kyphotic fusions or global spinal sagittal malalignment may increase the risk of adjacent segment pathology. Thirteen human cadaveric cervical spines (Occiput-T1; age: 50.6 years; range: 21-67) were tested first in the native intact state and then after instrumentation across C4-C6 to simulate in situ two-level fusion. Specimens were tested using a previously validated experimental model that allowed measurement of spinal response to prescribed imbalance. The effects of fusion on segmental angular alignments and intradiscal pressures in the C3-C4 and C6-C7 discs, above and below the fusion, were evaluated at different magnitudes of C2-C7 tilt angle (or C2-C7 SVA). When compared with the pre-fusion state, in situ fusion across C4-C6 segments required increased flexion angulation and resulted in increased intradiscal pressure at the C6-C7 disc below the fusion in order to accommodate the same increase in C2-C7 tilt angle or C2-C7 SVA (P < 0.05). The adjacent segment mechanical burden due to fusion became greater with increasing C2-C7 tilt angle or SVA. | Cervical sagittal imbalance arising from regional and/or global spinal sagittal malalignment may play a role in exacerbating adjacent segment pathomechanics after multilevel fusion and should be considered during surgical planning. |
26,808,136 | Is Long-Term Low-Dose Aspirin Therapy Associated with Renal Dysfunction in Patients with Type 2 Diabetes? | Low-dose aspirin is widely recommended for patients at high risk for cardiovascular disease (CVD); however, it remains uncertain whether long-term treatment adversely affects renal function in patients with diabetes. We investigated whether long-term low-dose aspirin affects renal dysfunction in patients with diabetes. We conducted a randomized controlled trial (RCT), the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, to evaluate low-dose aspirin as primary prevention for CVD in patients with type 2 diabetes. We followed the patients with negative urine dipstick albumin of the JPAD trial in a cohort study after the RCT period was completed. Patients were randomly allocated to receive aspirin (81 mg or 100 mg daily, aspirin group) or no aspirin (no aspirin group). After the RCT, the treating physician decided whether to administer aspirin. We evaluated the incidence of positive urine dipstick albumin and annual changes in estimated glomerular filtration rate (eGFR). Positive urine dipstick albumin developed in 297 patients in the aspirin group (n = 1,075) and 270 patients in the no aspirin group (n = 1,098) during follow-up (median, 8.5 years). Intention-to-treat analysis showed low-dose aspirin did not increase the incidence of positive urine dipstick albumin (hazard ratio [HR], 1.17; 95% confidence interval [CI], 0.995-1.38). On-treatment analysis yielded similar results (HR, 1.08; 95% CI, 0.92-1.28). Multivariable analysis showed the incidence of positive urine dipstick albumin was higher among the elderly and those with elevated serum creatinine, high hemoglobin A1c, or high blood pressure; however, low-dose aspirin did not increase the risk of positive urine dipstick albumin. There were no significant differences in annual changes in eGFR between the groups (aspirin, -0.8 ± 2.9; no aspirin, -0.9 ± 2.5 ml/min/1.73 m(2)/year). | Long-term low-dose aspirin does not affect eGFR and positive urine dipstick albumin in patients with type 2 diabetes. |
22,419,854 | Are differences in corneal phenotypes between destrin mutants due to allelic difference and modified by genetic background? | Mutations in destrin (Dstn) cause corneal abnormalities in mice. A null mutation, Dstn(corn1), results in corneal epithelial hyperproliferation, inflammation, and neovascularization in the A.BY background (A.BY Dstn(corn1)). Homozygosity for a point mutation, Dstn(corn1-2J), results in mild thickening of the corneal epithelium but no corneal neovascularization in a C57BL/6 (B6) background (B6 Dstn(corn1-2J)). The goal of this study was to determine whether phenotypic differences are due to allelic differences between Dstn(corn1) and Dstn(corn1-2J), or are the result of genetic background effects. We generated two congenic (Cg) mouse lines, B6.Cg-Dstn(corn1) and A.BY.Cg-Dstn(corn1-2J), to compare to the original A.BY Dstn(corn1) and B6 Dstn(corn1-2J) lines. We performed immunohistochemistry to assay F-actin accumulation, neovascularization, proliferation, and inflammation. By western blot analysis we tested the expression of serum response factor (SRF), a known regulator of the Dstn(corn1) phenotype. The Dstn(corn1) mutation leads to neovascularization, hyperproliferation, and inflammation in the cornea of A.BY Dstn(corn1) as well as B6.Cg-Dstn(corn1) mice. We did not observe significant corneal neovascularization or hyperproliferation in either A.BY.Cg-Dstn(corn1-2J) or B6 Dstn(corn1-2J) mice. Actin accumulation, neovascularization, epithelial proliferation and inflammation in B6.Cg-Dstn(corn1) cornea are significantly reduced when compared to A.BY Dstn(corn1)cornea. SRF changes are consistent in Dstn(corn1) mutants, regardless of genetic background. | Differences in the abnormal phenotypes of Dstn mutants result from allelic differences between Dstn(corn1) and Dstn(corn1-2J) . Moreover, phenotypes of Dstn(corn1) mice are modified by genetic background, suggesting the existence of genetic modifiers. Protein analysis suggests that a genetic modifier affects phenotypic severity functionally downstream from or in a pathway independent from SRF. These data demonstrate that natural genetic variation affects phenotypic severity in Dstn(corn1) mice. |
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