Expression of bcl-xL can confer a multidrug resistance phenotype

It has been suggested that genes that regulate apoptotic cell death may play an important role in determining the sensitivity of tumor cells to chemotherapy. We have recently cloned a member of the bcl-2 family, bcl- x. To test whether bcl-XL expression affects the sensitivity of tumor cells to chemotherapy, we have created stable cell lines overexpressing bcl-XL and have tested these cells for resistance to cell death induced by metabolic inhibitors and chemotherapeutic agents. Bcl-XL expression dramatically reduces the cytotoxicity of bleomycin, cisplatin, etoposide, vincristine, hygromycin B, and mycophenolic acid for up to 4 days in culture. Bcl-XL does not prevent cells from undergoing cell cycle arrest in response to these drugs, but rather prevents treated cells from undergoing apoptosis. Cell-cycle analysis on cells treated with the chemotherapeutic agents bleomycin, cisplatin, etoposide, and vincristine, show that the drugs cause growth arrest in different positions within the cell cycle. Bcl-XL expressing cells treated with chemotherapeutic drugs retain their proliferative ability after the drugs are removed. Interestingly, vincristine-treated cells expressing bcl-XL become polyploid after drug removal. These data show that bcl-XL protects cells from a wide variety of apoptotic stimuli, acts in multiple positions within the cell cycle, and confers a multidrug resistance phenotype. The ability of bcl-XL to prevent apoptotic cell death in response to chemotherapy-induced DNA damage and cell-cycle arrest may contribute to the accumulation of chromosomal aberrations within tumors. The expression of bcl-XL in tumor cells is likely to be an important indicator of chemotherapeutic efficacy.     

Psychological problems in gastroenterology outpatients: A South Australian experience. Psychological co-morbidity in IBD,IBS and hepatitis C

Background

In independent studies, IBD, IBS and HCV have each been associated with a substantially increased risk of psychological problems such as depression and anxiety and impairment of quality of life compared to the general healthy population. However, the relative psychological burden for each of these diagnoses is unknown as it has never been compared contemporaneously at one institution. Current local data are therefore needed to enable an evidence-based allocation of limited clinical psychological resources.

Methods

Overall, 139 outpatients (64 IBD, 41 HCV, and 34 IBS) were enrolled in this cross-sectional study. The HADS, SCL90, SF-12 and appropriate disease-specific activity measures were administered. Differences between groups were assesed with ANOVA, the Chi-Square test and the independent samples t-test (two-tailed).

Results

Each of the three groups had significantly lower quality of life than the general population (p < 0.05). Overall, a total of 58 (42%) participants met HADS screening criteria for anxiety and 26 (19%) participants for depression. The HCV group had a significantly higher prevalence of depression than either of the other groups (HCV = 34%, IBS = 15% and IBD = 11%, p = 0.009). In the SCL90, the three disease groups differed on 7 out of 12 subscales. On each of these subscales, the HCV group were most severely affected and differed most from the general population.

Conclusion

Patients with these common chronic gastrointestinal diseases have significant impairment of quality of life. Anxiety is a greater problem than depression, although patients with HCV in particular, should be regularly monitored and treated for co-morbid depression. Evaluation of specific psychological interventions targeting anxiety is warranted.

     

Push enteroscopy in the investigation of small-intestinal disease

We report our experience with small-bowel push enteroscopy in 50 patients. The indications for push enteroscopy were: anaemia/occult gastrointestinal bleeding (22 patients); overt gastrointestinal bleeding (17 patients); abnormal small-bowel radiology (8 patients) and miscellaneous (3 patients). In those with undiagnosed gastrointestinal bleeding/anaemia, abnormalities were detected in 24/39 patients (62%): small bowel arteriovenous malformations (AVMs) were detected in 19 (49%), and five (13%) had lesions in the upper gastrointestinal tract. Seventeen patients had heater-probe ablation therapy of vascular lesions: nine patients had small-intestinal lesions, four patients gastric lesions, and four patients combined gastric and small- intestinal lesions. In those with abnormal small-bowel radiology, abnormalities were detected in 6/8 patients. We conclude that (i) push enteroscopy can establish a diagnosis in a high proportion of patients with gastrointestinal bleeding; (ii) heater-probe ablation therapy of vascular lesions can be performed routinely at the time of enteroscopy; (iii) a significant proportion of patients (9/50) referred for enteroscopy with undiagnosed gastrointestinal bleeding have lesions in the stomach/proximal duodenum missed at diagnostic endoscopy. Push enteroscopy is a valuable diagnostic and therapeutic endoscopic procedure.      

Efficacy and safety of biphasic insulin aspart 30 combined with pioglitazone in type 2 diabetes poorly controlled on glibenclamide (glyburide) monotherapy or combination therapy: an 18-week, randomized, open-label study

BACKGROUND: Few large randomized controlled trials have assessed the value of adding insulin to an oral antidiabetic drug regimen. OBJECTIVE: This trial compared the efficacy and safety of biphasic insulin aspart 30/70 (BIAsp 30) plus pioglitazone (n = 93), glibenclamide (glyburide) plus pioglitazone (n = 91), or BIAsp 30 monotherapy (n = 97). METHODS: This 18-week, multinational, multicenter, randomized, open-label, parallel-group trial involved 281 patients with type 2 diabetes (60% male; mean age, 56 years; mean body mass index, 29.5 kg/m2) with inadequate glycemic control (mean glycosylated hemoglobin [HbA(1c)], 9.5%; range, 7.4%-14.7%) on glibenclamide monotherapy or combination therapy. The primary objective was to compare end-of-trial HbA(1c) among the 3 treatment groups. Fasting and mean 7- and 8-point blood glucose profiles, blood lipid levels, plasminogen activator inhibitor levels, adverse events, and hypoglycemia frequency were also compared. Patients using BIAsp 30 (alone or with pioglitazone) were injected twice daily (immediately before breakfast and dinner). Pioglitazone (30 mg/d) and glibenclamide (5-15 mg/d) were taken orally once daily with or immediately after breakfast. RESULTS: At the end of the trial, HbA(1c) was significantly lower for the BIAsp 30 plus pioglitazone group than for the glibenclamide plus pioglitazone group (mean [SD], -0.64% [0.23%]; P = 0.005) and the BIAsp 30 monotherapy group (-0.60% [0.22%]; P = 0.008). Mean (SD) fasting blood glucose (before breakfast) was significantly lower for BIAsp 30 plus pioglitazone than for glibenclamide plus pioglitazone (153 [45] mg/dL vs 169 [65] mg/dL, respectively; P = 0.012). Each time point on the 8-point blood glucose profile was lower for BIAsp 30 plus pioglitazone than for glibenclamide plus pioglitazone (P < 0.001 to P < 0.05). No major hypoglycemic episodes were reported, and the absolute rate of hypoglycemic events was low (<1 event/patient-week) in the BIAsp-only group. Edema was reported in < or =9% of patients in each treatment group, but no occurrence was classified as serious. Weight gain (mean, 4.0 kg) was more common in the BIAsp plus pioglitazone group (8%); however, this was consistent with improved glycemic control and is similar to that reported in other pioglitazone trials. CONCLUSIONS: BIAsp 30 plus pioglitazone provided an efficacious and well-tolerated treatment alternative to glibenclamide plus pioglitazone or BIAsp 30 alone in this population of patients who previously were not well controlled on glibenclamide monotherapy or combination therapy.     

A randomized double-blind placebo-controlled crossover study of subcutaneous sumatriptan in general practice

Objective. To evaluate the therapeutic response to sumatriptan in the acute migraine attack. Material and methods. Two hundred and thirty migraineurs diagnosed by their general practitioners in accordance with their usual practice were included in the study. The patients treated two migraine attacks at home by subcutaneous injection of sumatriptan or placebo for the first attack and the alternative medication, i.e. placebo or sumatriptan, for the second attack (crossover). Following treatment, a neurology resident interviewed and examined the patients, Results. When sumatriptan was compared to placebo, significantly more of the 209 evaluable patients reported headache relief at I h (56% vs 8%, p < 0.001) and 2 h (62% vs 15%, p < 0.001) after the first injection. Resolution of nausea, photophobia, and phonophobia was significantly more common in patients on sumatriptan than in those on placebo ( p < 0.001 for all comparisons). The adverse events were usually transient and of mild or moderate severity; however, three patients withdrew due to adverse events. Ninety-five percent of patients evaluated by a neurology resident met the IHS criteria for migraine. Conclusion. In general practice, sumatriptan taken subcutaneously using an autoinjector at home was an effective and well tolerated acute treatment for migraine.     

PSEUDOHYPERPHOSPHATAEMIA AND MONOCLONAL GAMMOPATHY

SUMMARY A case is reported of pseudohyperphosphataemia in association with a monoclonal gammopathy of undetermined significance.     

Diverging associations of an intended early invasive strategy compared with actual revascularization, and outcome in patients with non-ST-segment elevation acute coronary syndrome: the problem of treatment selection bias

AIMS: In several observational studies, revascularization is associated with substantial reduction in mortality in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS). This has strengthened the belief that routine early angiography would lead to a reduction in mortality. We investigated the association between actual in-hospital revascularization and long-term outcome in patients with nSTE-ACS included in the ICTUS trial. METHODS AND RESULTS: The study population of the present analysis consists of ICTUS participants who were discharged alive after initial hospitalization. The ICTUS trial was a randomized, controlled trial in which 1200 patients were randomized to an early invasive or selective invasive strategy. The endpoints were death from hospital discharge until 4 year follow-up and death or spontaneous myocardial infarction (MI) until 3 years. Among 1189 patients discharged alive, 691 (58%) underwent revascularization during initial hospitalization. In multivariable Cox regression analyses, in-hospital revascularization was independently associated with a reduction in 4 year mortality and 3 year event rate of death or spontaneous MI: hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.37-0.96] and 0.46 (95% CI 0.31-0.68). However, when intention-to-treat analysis was performed, no differences in cumulative event rates were observed between the early invasive and selective invasive strategies: HR 1.10 (95% CI 0.70-1.74) for death and 1.27 (95% CI 0.88-1.85) for death or spontaneous MI. CONCLUSION: The ICTUS trial did not show that an early invasive strategy resulted in a better outcome than a selective invasive strategy in patients with nSTE-ACS. However, similar to retrospective analyses from observational studies, actual revascularization was associated with lower mortality and fewer MI. Whether an early invasive strategy leads to a better outcome than a selective invasive strategy cannot be inferred from the observation that revascularized patients have a better prognosis in non-randomized studies.     

Biliary drainage of the common bile duct with an enteral metal stent

In this case report we present an elderly patient who was referred to our hospital with recurrent episodes of cholangitis that persisted after placement of five metal stents for a distal common bile duct （CBD） stenosis.All metal stents were endoscopically removed from the CBD by forceps after balloon dilatation of the papilla. A profoundly dilated CBD with sludge and concrements was seen. To ensure adequate bile drainage an enteral metal stent was inserted in the CBD. This case shows that proximally migrated uncovered metal stents in the CBD can be safely removed endoscopically under certain circumstances. We suggest that in the case of a CBD drainage problem due to an extremely dilated CBD, placement of an enteral metal stent in the CBD could be considered, especially in patients who are unfit for surgery.