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Selected AbstractsPromoter hypermethylation of CDH13 is a common, early event in human esophageal adenocarcinogenesis and correlates with clinical risk factorsINTERNATIONAL JOURNAL OF CANCER, Issue 10 2008Zhe Jin Abstract Although the CDH13 gene has been shown to undergo epigenetic silencing by promoter methylation in many types of tumors, hypermethylation of this gene in Barrett's-associated esophageal adenocarcinogenesis has not been studied. Two hundred fifty-nine human esophageal tissues were therefore examined for CDH13 promoter hypermethylation by real-time methylation-specific PCR. CDH13 hypermethylation showed discriminative receiver-operator characteristic curve profiles, sharply demarcating esophageal adenocarcinoma (EAC) from esophageal squamous cell carcinoma (ESCC) and normal esophagus (NE) (p < 0.0001). CDH13 normalized methylation values (NMV) were significantly higher in Barrett's esophagus (BE), dysplastic BE (D) and EAC than in NE (p < 0.0000001). CDH13 hypermethylation frequency was 0% in NE but increased early during neoplastic progression, rising to 70% in BE, 77.5% in D and 76.1% in EAC. Both CDH13 hypermethylation frequency and its mean NMV were significantly higher in BE with than without accompanying EAC. In contrast, only 5 (19.2%) of 26 ESCCs exhibited CDH13 hypermethylation. Furthermore, both CDH13 hypermethylation frequency and its mean NMV were significantly higher in EAC than in ESCC, as well as in BE or D vs. ESCC. Interestingly, mean CDH13 NMV was significantly lower in short-segment than in long-segment BE, a known clinical risk factor for neoplastic progression. Similarly, BE segment length was significantly lower in specimens with unmethylated than with methylated CDH13 promoters. 5-aza-2,-deoxycytidine treatment of OE33 EAC and KYSE220 ESCC cells reduced CDH13 methylation and increased CDH13 mRNA expression. These findings suggest that hypermethylation of CDH13 is a common, tissue-specific event in human EAC, occurs early during BE-associated neoplastic progression, and correlates with known clinical neoplastic progression risk factors. © 2008 Wiley-Liss, Inc. [source] Reliability of the assessment of preventable adverse drug events in daily clinical practice,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 7 2008Jasperien E. van Doormaal PharmD Abstract Purpose To determine the reliability of the assessment of preventable adverse drug events (ADEs) in daily practice and to explore the impact of the assessors' professional background and the case characteristics on reliability. Methods We used a combination of the simplified Yale algorithm and the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) scheme to assess on the one hand the causal relationship between medication errors (MEs) and adverse events in hospitalised patients and on the other hand the severity of the clinical consequence of MEs. Five pharmacists and five physicians applied this algorithm to 30 potential MEs. After individual assessment, the pharmacists reached consensus and so did the physicians. Outcome was both MEs' severity (ordinal scale, NCC MERP categories A,I) and the occurrence of preventable harm (binary outcome, NCC MERP categories A,D vs. E,I). Kappa statistics was used to assess agreement. Results The overall agreement on MEs' severity was fair for the pharmacists (,,=,0.34) as well as for the physicians (,,=,0.25). Overall agreement for the 10 raters was fair (,,=,0.25) as well as the agreement between both consensus outcomes (,,=,0.30). Agreement on the occurrence of preventable harm was higher, ranging from ,,=,0.36 for the physicians through ,,=,0.49 for the pharmacists. Overall agreement for the 10 raters was fair (,,=,0.36). The agreement between both consensus outcomes was moderate (,,=,0.47). None of the included case characteristics had a significant impact on agreement. Conclusions Individual assessment of preventable ADEs in real patients is difficult, possibly because of the difficult assessment of contextual information. Best approach seems to be a consensus method including both pharmacists and physicians. Copyright © 2008 John Wiley & Sons, Ltd. [source] Heat shock protein 101 effects in A. thaliana: genetic variation, fitness and pleiotropy in controlled temperature conditionsMOLECULAR ECOLOGY, Issue 6 2008S. J. TONSOR Abstract The Hsp100/ClpB heat shock protein family is ancient and required for high temperature survival, but natural variation in expression and its phenotypic effects is unexplored in plants. In controlled environment experiments, we examined the effects of variation in the Arabidopsis cytosolic AtHsp101 (hereafter Hsp101). Ten wild-collected ecotypes differed in Hsp101 expression responses across a 22 to 40 °C gradient. Genotypes from low latitudes expressed the least Hsp101. We tested fitness and pleiotropic consequences of varying Hsp101 expression in ,control' vs. mild thermal stress treatments (15/25 °C D/N vs. 15/25° D/N plus 3 h at 35 °C 3 days/week). Comparing wild type and null mutants, wt Columbia (Col) produced ~33% more fruits compared to its Hsp101 homozygous null mutant. There was no difference between Landsberg erecta null mutant NIL (Ler) and wt Ler; wt Ler showed very low Hsp101 expression. In an assay of six genotypes, fecundity was a saturating function of Hsp101 content, in both experimental treatments. Thus, in addition to its essential role in acquired thermal tolerance, Hsp101 provides a substantial fitness benefit under normal growth conditions. Knocking out Hsp101 decreased fruit production, days to germination and days to bolting, total dry mass, and number of inflorescences; it increased transpiration rate and allocation to root mass. Root : total mass ratio decayed exponentially with Hsp101 content. This study shows that Hsp101 expression is evolvable in natural populations. Our results further suggest that Hsp101 is primarily an emergency high-temperature tolerance mechanism, since expression levels are lower in low-latitude populations from warmer climates. Hsp101 expression appears to carry an important trade-off in reduced root growth. This trade-off may select for suppressed expression under chronically high temperatures. [source] Timing of autologous stem cell transplantation from last chemotherapy affects lymphocyte collection and survival in non-Hodgkin lymphomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2006Shernan G. Holtan Summary Autograft absolute lymphocyte count (A-ALC) is a prognostic factor for survival in non-Hodgkin lymphoma (NHL) after autologous stem cell transplantation (ASCT). An A-ALC is dependent upon the preaphaeresis absolute lymphocyte count (PA-ALC) at the time of aphaeresis. It was hypothesised that the time interval from last chemotherapy (TILC) to aphaeresis affects PA-ALC. One hundred and sixty consecutive NHL patients who underwent ASCT at the Mayo Clinic between 1996 and 2001 were evaluated. A strong correlation between TILC and PA-ALC (r = 0·67, P < 0·0001) was identified. Higher PA-ALC was observed in TILC ,55 d compared with TILC <55 d [median: 7·0 vs. 3·8 × 109/l], P < 0·0001). TILC as a continuous variable was identified as a prognostic factor for overall survival (OS) [hazard ratio (HR) = 0·989, P < 0·01] and progression-free survival (PFS) (HR = 0·992, P < 0·0492). Median OS and PFS were longer in the TILC ,55 d vs. TILC <55 d group (not reached vs. 21 months, P < 0·0008; 76 vs. 9 months, P < 0·0025, respectively). Multivariate analysis demonstrated TILC to be an independent prognostic indicator for OS and PFS. These findings suggest that the immune status of the host at the time of aphaeresis may predict survival after ASCT. [source] Basiliximab in association with tacrolimus and steroids in caucasian cadaveric renal transplanted patients: significant decrease in early acute rejection rate and hospitalization timeCLINICAL TRANSPLANTATION, Issue 2 2004Gianluca Leonardi Abstract:, Safety and tolerability of basiliximab in renal transplantation have been proven in different immunosuppressive regimens. Few informations are available about the association of basiliximab with tacrolimus and steroids. We present a retrospective analysis performed in Caucasian cadaveric renal transplant recipients, comparing a basiliximab, tacrolimus and steroids induction protocol (GrA: 51 patients) with a tacrolimus and steroids protocol (GrB: 46 patients). A significant decrease in acute rejection rate in the first 3 months (2.0% vs. 17.4%; p < 0.01) was noted. Interestingly, the recipients in GrA were at major immunologic risk for the younger age of recipients, the greater number of mismatches and the higher rate of second transplants. The hospitalization times resulted reduced of 5.3 d in GrA vs. GrB (20.8 d vs. 26.1 d; p < 0.05). The adverse events patterns and profiles were similar in the two treatments groups. One patient in each group had a post-transplant lymphoprolipherative disorder. No significant difference was found in patient and graft survival. According to the results of this study, in a Caucasian adult population, basiliximab in association with tacrolimus and steroids is a safe and efficacious tool for acute rejection prevention and it is cost saving by reducing the hospitalization times. [source] Impact of in vivo complement activation and cryoglobulins on graft outcome of HCV-infected renal allograft recipientsCLINICAL TRANSPLANTATION, Issue 1 2004Stefan M Weiner Abstract:, Background:, Chronic hepatitis C virus (HCV) infection is closely associated with mixed cryoglobulinemia. Cryoglobulins can activate complement leading to vascular damage. We examined whether cryoglobulinemia and complement turnover is associated with HCV infection in renal transplant recipients and whether this has an adverse effect on graft outcome. Methods:, Sera and fresh plasma from 31 HCV-RNA-positive patients after renal transplantation (group I) were studied for cryoglobulins, complement hemolytic activity (CH50), and complement split product C3d. In total, 80 HCV-negative renal transplant recipients (group II) and 72 untreated patients with chronic hepatitis C (group III) without renal transplantation served as controls. Results:, Cryoglobulins were detected in 45, 28, and 26% of the patients in group I, II, and III, respectively. A high cryocrit (>5%) was present only in patients of group III (p < 0.01%). Mean CH50 values were lower and C3d levels higher in HCV-positive patients (group I and III) compared with HCV-negative patients (p < 0.0001). Cryoglobulins were not associated with extrahepatic manifestations or graft dysfunction, except in five patients of group III demonstrating cryoglobulinemic vasculitis. HCV-positive renal transplant recipients with signs of complement activation showed a significantly greater increase of serum creatinine (0.88 ± 1.14 mg/dL) when compared with baseline than patients without complement activation (0.34 ± 0.37 mg/dL; p = 0.035). There was also a tendency toward a higher extent of proteinuria in patients with complement activation (1.38 ± 2.17 g/d vs. 0.50 ± 0.77 g/d; p = 0.25, NS). Conclusions:, Cryoglobulins are common in renal allograft recipients, but do not affect graft function. However, complement activation appears to be involved in chronic allograft dysfunction in HCV-infected recipients. [source] Chronic allograft nephropathy and nephrotic range proteinuriaCLINICAL TRANSPLANTATION, Issue 3 2005Venkataraman Ramanathan Abstract:, While the association between post-transplant nephrotic range proteinuria (PTx-NP) and chronic allograft nephropathy (CAN) has been described, the factors that determine graft survival in such patients are unclear. We retrospectively identified 30 patients with biopsy-proven CAN who presented with PTX-NP between 1988 and 2002. Patients were stratified into two groups according to PTX-NP onset: <1 yr vs. >1 yr post-transplantation. Both groups were comparable with respect to the degree of renal dysfunction (serum creatinine 4.3 ± 2.5 mg/dL vs. 3.4 ± 1.5 mg/dL) and proteinuria (4.7 ± 1.6 gm/d vs. 5.8 ± 3 gm/d). After a mean follow-up of 14 months post-biopsy, 87% of patients had lost their grafts in both groups (89% vs. 83%, p = NS). Overall, patients with serum creatinine ,2 mg/dL had better graft survival during follow-up than patients with serum creatinine >2 mg/dL (75% vs. 4%, Fisher Exact Probability p = 0.0038). Using Kaplan,Meier estimate, the 5-yr graft survival rate was 100% for patients with serum creatinine ,2 mg/dL and 40% in those with >2 mg/dL (p = 0.06). The magnitude of proteinuria beyond 3 gm/d did not influence graft survival. One-half of the patients (n = 15) received therapy with angiotensin converting enzyme inhibitors (ACEI). Graft survival, however, was not different between the patients who received ACEI compared with the patients who did not receive ACEI (13% vs. 13%). PTx-NP related to CAN was associated with poor allograft survival, irrespective of the time of onset of presentation, especially when renal function was reduced at the time of biopsy. [source] | ||||||||||