Effect of D,L‐threo‐1‐phenyl‐2‐decanoylamino‐3‐morpholino‐1‐propanol and tetrandrine on the reversion of multidrug resistance in K562/A02 cells

Abstract

We studied the clinical impact of CD38 expression in 226 chronic lymphocytic leukemia patients (CLL) at disease presentation and during follow up to determine its prognostic significance, progression free survival (PFS) and overall survival (OS), and to verify whether this parameter changed over time. Various patients' characteristics were studied including gender, Rai and Binet stages, immunoglobulin light chain expression, lymphocyte doubling time and CD38 expression. After a median follow up of 53 months (range 6–282), 62% CD38 positive(+) patients required therapy. PFS and OS at 84 months were significantly lower for CD38(+) patients: 20 and 71% respectively, compared to CD38 negative(?): 70 and 96%. At multivariate analysis CD38(+) showed to be the best factor for predicting progression: HR 3·3, 95%CI 2·10–5·14, p = 0·000. Its expression did not change in 98% re-evaluated patients. We confirm that CD38(+) is a stable parameter for the identification of CLL patients with a more aggressive disease course.     

N‐Acetylcysteine Treatment Protects Against VEGF‐Receptor Blockade‐Related Emphysema

Administration of the VEGF receptor blocker SU5416 to rats causes alveolar septal cell apoptosis and emphysema; both can be prevented by a superoxide dismutase mimetic. Here we show that SU5416 induces the expression of heme oxygenase‐1 in the lung tissue and that administration of antioxidant N‐acetyl‐l‐cysteine protects alveolar septal cells against apoptosis, as demonstrated by caspase‐3 lung immunohistochemistry, and against emphysema.     

A Cost‐Effectiveness Analysis of a Peak Flow‐Based Asthma Education and Self‐Management Plan in a High‐Cost Population

Background. Asthma education and action plans (AP) have been recognized as important components in the optimal management of asthma. Studies have differed on the importance of a peak flow‐based self‐management plans in reducing health care costs and use due to asthma exacerbation. Objective. To analyze the cost‐effectiveness of peak flow‐based action plans in reducing costs associated with ER visits and hospitalizations due to acute asthma exacerbation in a population of high‐risk and high‐cost patients, defined as patients with moderate to severe asthma with a history of recent urgent treatment in the ER or hospitalization due to asthma. Methods. A literature review of randomized clinical trials comparing peak flow‐based (PFB) action plans, symptom‐based (SB) action plans, and usual care/no action plan (NAP) was performed. Probability values regarding the effectiveness of each alternative (as measured by increase/decrease in ER visits and hospitalizations over a 6‐month period) were derived. Incremental cost‐effectiveness and cost‐benefit ratios were calculated for each alternative. Sensitivity analyses were performed. Results. For high‐risk and high‐cost asthma patients, our analysis revealed that the most cost‐effective alternative for reducing ER visits was a peak flow‐based self‐management plan. The peak flow‐based self‐management program had an incremental cost‐effectiveness (C/E) ratio of $ 60.57 per ER visit averted compared to usual care/NAP and a C/E ratio of $31.46 compared to the SB‐AP. The PFB‐AP was also the most cost‐effective in reducing asthma hospitalization costs with an incremental C/E ratio of $300 per hospitalization prevented, compared with usual care and a C/E ratio of $311, compared to a SB‐AP. Analysis yielded a cost‐benefit ratio of 13.79 for the PFB‐AP compared to NAP; the SB‐AP had a cost‐benefit ratio of 11.53 compared to NAP. Conclusion. Cost‐effectiveness and cost‐benefit analyses reveal that for high‐cost patients, a peak flow‐based asthma education and self‐management plan program is the most cost‐effective alternative in reducing costs associated with ER visits and hospitalizations due to asthma exacerbation. Further refinements to this cost‐effectiveness analysis including measuring changes in drug use and costs and patients' productivity losses need to be pursued and may demonstrate additional cost‐savings due to peak flow‐based asthma education plans.     

The Short‐Term Effects and Unintended Long‐Term Consequences of Binge Drinking in College: A 10‐Year Follow‐Up Study

This study addresses binge drinking in college as a risk factor for heavy drinking and alcohol dependence after college. A national probability sample of 1972 college students from the National Longitudinal Surveys of Youth (NLSY79) was interviewed in 1984 and reinterviewed again as adults in 1994. The short‐term effects of binge drinking in college were assessed as well as the extent to which experiences of negative effects in college predicted patterns of alcohol use across the transition from college into postcollege years. As expected, college binge drinkers were comparatively more likely than nonbinge drinkers to experience one or more alcohol‐related problems while in college. In addition, weighted estimates of DSM‐IV‐defined diagnostic criteria in logistic regression models indicated that the binge drinking patterns exhibited during the college years, for some former college students of both genders, posed significant risk factors for alcohol dependence and abuse 10 years after the initial interview, in conjunction with evidence of academic attrition, early departure from college and less favorable labor market outcomes.     

Intravenous n‐acetylcysteine,ascorbic acid and selenium‐based anti‐oxidant therapy in severe acute pancreatitis

Background: To observe outcome in a cohort of patients with severe acute pancreatitis receiving multiple anti‐oxidant therapy. Methods: An observational study was carried out in 46 consecutive patients with acute pancreatitis fulfilling current Atlanta consensus criteria for severe disease. All patients received multiple anti‐oxidant therapy based on intravenous selenium, N‐acetylcysteine and ascorbic acid plus β‐carotene and α‐tocopherol delivered via nasogastric tube. Principal outcomes were the effect of anti‐oxidant supplementation on anti‐oxidant levels, morbidity and mortality in patients on anti‐oxidant therapy, case‐control analysis of observed survival compared to predicted survival derived from logistic organ dysfunction score (LODS), logistic regression analysis of factors influencing outcome and side effect profile of anti‐oxidant therapy. Results: Paired baseline and post‐supplementation data were available for 25 patients and revealed that anti‐oxidant supplementation restored vitamin C (P?=?0.003) and selenium (P?=?0.028) toward normal. In univariate survival analysis, patient survival to discharge was best predicted by admission APACHE‐II score with relative risk of death increasing 12.6% for each unit increase (95% CI 6.0% to 19.6%). The mean LODS calculated on admission to hospital was 3.7 (standard error of the mean 4.1) giving a predicted mortality for the cohort of 21%. The observed in‐hospital mortality was 43%. Conclusions: Case‐control analyses do not appear to demonstrate any benefit from the multiple anti‐oxidant combination of selenium, N‐acetylcysteine and ascorbic acid in severe acute pancreatitis.     

Long‐term survival after resection for non‐pancreatic periampullary cancer followed by adjuvant intra‐arterial chemotherapy and concomitant radiotherapy

BackgroundThere is no consensus regarding the optimal adjuvant treatment after resection of non‐pancreatic periampullary adenocarcinoma (NPPC; distal common bile duct, ampulla, duodenum).ObjectivesThe present study was conducted to evaluate the impacts on longterm survival and recurrence of adjuvant intra‐arterial chemotherapy (IAC) and concomitant radiotherapy (RT) in patients submitted to resection for NPPC or pancreatic ductal adenocarcinoma (PDAC) in a randomized controlled trial.MethodsA total of 120 patients with PDAC (n = 62) or NPPC (n = 58) were prestratified at a ratio of 1:1 for tumour origin and randomized. Half of these patients were treated with adjuvant IAC/RT and the other half were treated with surgery alone. Follow‐up was completed for all patients up to 5 years after resection or until death.ResultsThere was no survival benefit in either the whole group (primary endpoint) or the PDAC group after IAC/RT. In the NPPC group, longterm survival was observed in 10 patients in the IAC/RT group and five patients in the control group: median survival was 37 months and 28 months, respectively. The occurrence of liver metastases was reduced by IAC/RT from 57% to 29% (P = 0.038). Cox regression analysis revealed a substantial effect of IAC/RT on survival (hazard ratio: 0.44, 95% confidence interval 0.23–0.83; P = 0.011).ConclusionsThis longterm analysis shows that median and longterm survival were improved after IAC/RT in patients with NPPC, probably because of the effective and sustained reduction of liver metastases. The present results illustrate that NPPC requires an adjuvant approach distinct from that in pancreatic cancer and indicate that further investigation of this issue is warranted.     

Bone mineral density in patients with inflammatory bowel disease: A population‐based prospective two‐year follow‐up study

Background: Bone loss and osteoporosis are commonly reported in inflammatory bowel disease (IBD), especially Crohn disease (CD). The aims of the present study were to evaluate changes in bone mineral density (BMD) in IBD patients during a 2‐year follow‐up period, and to investigate the role played by possible contributing factors in bone loss. Methods: Sixty patients with CD and 60 with ulcerative colitis (UC) were studied initially. Fifty‐five CD and 43?UC patients were re‐examined after 1 year, and 50?CD and 44?UC patients after 2 years. Lumbar spine, femoral neck and total body BMD were measured by dual X‐ray absorptiometry (DXA), and Z scores were obtained by comparison with age‐matched and sex‐matched healthy subjects. Biochemical variables were assessed at inclusion and at the 1‐year follow‐up visit. Results: Mean BMD values were unchanged in both CD and UC patients. In patients with repeated measurements, significant differences in Z scores (Δ Z score) were found for femoral neck and total body in CD and for total body in UC. Significant bone loss occurred in 11?CD (22%) and 12?UC (27%) patients. A significant increase in BMD was found in 21?CD (42%) and 20?UC (46%) patients. In CD patients the initial BMD values for lumbar spine and femoral neck were inversely correlated to BMD changes at the same sites and the change in body mass index (BMI) was positively correlated to change in the total body BMD. C‐reactive protein was significantly higher in CD patients with bone loss. Biochemical markers of bone metabolism could not be used to predict BMD changes. Although it was not significant, there was a relationship between corticosteroid therapy and bone loss in CD. Conclusions: Only minor changes in BMD were observed in both CD and UC patients during a 2‐year period. The multifactorial pathogenesis of bone loss in IBD makes it difficult to assess the importance of each single contributing factor. However, our results indicate that disease activity and corticosteriod therapy are involved in bone loss in CD patients.     

What We Owe to α1‐Antitrypsin and to Carl‐Bertil Laurell

The archetypal status of α₁‐antitrypsin in biology and medicine grew from the finding, thirty years ago, by Carl‐Bertil Laurell, of the association of its deficiency with emphysema. In biology, α₁‐antitrypsin now provides the model for both the structure and the remarkable mechanism of the serpin protease inhibitors that control the key proteolytic pathways of the body. In medicine, the plasma deficiency of α₁‐antitrypsin has drawn attention to protease‐antiprotease imbalance as a contributory cause of chronic obstructive pulmonary disease. But even more significantly, the finding that the common genetic deficiency of α₁‐antitrypsin was also associated with the development of liver cirrhosis introduced the new entity of the conformational diseases. The proposal that the same general mechanism was responsible for the best known of the conformational diseases, the common late‐onset dementias, was controversial. It was vindicated however by the recent finding that a mutation, which results in the liver aggregation of α₁‐antitrypsin, also results in a typical late‐onset dementia when it occurs in a brain‐specific homologue of α₁‐antitrypsin. The extensive development of such diverse fields of studies, each based on α₁‐antitrypsin, is a measure of the encouragement Laurell gave to younger colleagues in the field. It also reflects the great advantage of linked contributions from clinical as well as basic sciences. Time after time, scientific controversies and deadlocks have been solved by landmark clinical cases, which have revealed unexpected findings and insights, within and beyond the fields of study.     

Incidence,etiology and bone marrow characteristics of non‐chemotherapy‐induced agranulocytosis

Abstract

Objective: Agranulocytosis is a rare but fatal condition. The majority of cases are associated with drugs. However, in‐patient incidences and the relationship between clinical outcomes and bone marrow characteristics have not been established.

Methods: We conducted a retrospective study in a university hospital. A total of 38 in‐patients diagnosed with agranulocytosis were analyzed.

Results: The average incidence of agranulocytosis in Songklanagarind Hospital between 1993 and 2007 was 0·98 cases per 10?000 admissions per year. Antimicrobial agents were the most common etiology (63% of patients) and antithyroid agents were the second most common (13·6%). Two patterns of bone marrow were noted: type I was characterized by a left‐shifted granulopoiesis and type II was recognized as having hypocellular bone marrow with markedly reduced granulocyte precursors. A significantly higher mortality was associated with type II.

Conclusion: Antimicrobial agents are the most common cause and the rare granulocyte precursors in bone marrow are associated with higher mortality rates.     

Drug‐eluting versus third‐generation bare metal stents: The US strategy

Drug‐eluting stents have rapidly come to dominate the field of coronary intervention, constituting 85% of the US market just one year after introduction. The current utilization of bare metal stents in coronary intervention in the US is quite limited. This article will review technological advances in third‐generation bare metal stents, which optimize procedural performance by means of improved flexibility, lower crossing profile, and thinner struts while maintaining fluoroscopic visibility and may portend a continued role for bare metal stents in some settings. This article will review data pertaining to outcomes with new generation bare metal stents and discuss current options for utilization of drug eluting stents versus bare metal stents in the US.     

Anti‐CagA and anti‐VacA antibodies in Helicobacter pylori‐infected patients with and without peptic ulcer disease in Serbia and Montenegro

Background: The expression of two Helicobacter pylori proteins, CagA and VacA, is associated with more severe pathogenesis and clinical outcomes of the infection. However, this association varies among geographical regions and ethnic groups. We therefore evaluated CagA and VacA seroprevalence in H. pylori‐positive dyspeptic patients in Serbia and Montenegro. Methods: In 173 consecutive dyspeptic patients referred to endoscopy (67M, mean age 49?±?15, 76 smokers), immunoblot assay was used to detect serum antibodies against CagA and VacA. Presence of H. pylori infection was assessed using a rapid urease test (RUT), routine histology and serology (anti‐IgG ELISA). Duodenal ulcer (DU) was diagnosed in 28, gastric ulcer (GU) in 3 and non‐ulcer dyspepsia (NUD) in the remaining 142 patients. Results: 129 (74.6%) patients were H. pylori‐positive, 27 (96.4%) with DU, 3 (100%) with GU and 99 (69.7%) with NUD (P?P?Conclusions: In Serbia and Montenegro there is high seroprevalence of CagA‐positive H. pylori strains in dyspeptic patients with and without peptic ulcer, while VacA‐positive strains are more closely related to peptic ulcer disease.     

Establishment of T‐Helper‐2 immune response based gerbil model of enteric infection

Background: The reciprocal antagonism of T‐helper‐1 (Th‐1) and Th‐2 type immune responses suggests that helminth parasitic infection may ameliorate disease where a Th‐1 type response dominates. The Mongolian gerbil has been useful in the investigation of the pathogenesis of gastric cancer, since long‐term infection of gerbils with Helicobacter pylori induces adenocarcinoma. In this study the kinetics of worm expulsion and associated immune responses in gerbils infected with Trichinella spiralis were investigated in an attempt to establish an animal model of parasitic infection that could be helpful when investigating the effect of a Th‐2 type response on Th‐1‐based intestinal disorders. Methods: Gerbils were infected with various doses of infective T. spiralis larvae and were euthanized on different days after infection to investigate the intestinal worm recovery, goblet cell population, eosinophil response and serum IgG1 responses. Results: The number of worms recovered from the intestine was dependent on the number of larvae used for the infection. Almost all worms were expelled spontaneously by day 26 post‐infection, when the gerbils had been infected with 375 or 750 larvae. The number of intestinal goblet cells, eosinophils and the serum IgG1 level significantly increased following infection compared with the control. Conclusion: This is the first comprehensive report on the time‐course of T. spiralis infection in gerbils. The data indicate that the T. spiralis‐infected gerbil could be used as a model of the Th‐2‐based response to investigate the effect of a parasite‐induced Th‐2 response on various Th‐1‐mediated intestinal disorders such as H. pylori‐induced gastritis and gastric carcinoma.     

Colitis up‐regulates local glucocorticoid activation and down‐regulates inactivation in colonic tissue

Background: Pro‐inflammatory processes are counteracted by anti‐inflammatory factors such as glucocorticoids. The response of target cells to glucocorticoids depends on several factors including prereceptor modulation of glucocorticoid signals via local glucocorticoid metabolism. This is determined by two isoforms of 11β‐hydroxysteroid dehydrogenase (11βHSD); 11βHSD1 operates in vivo as a reductase converting inactive 11‐oxo glucocorticoids to active glucocorticoids cortisol or corticosterone, whereas 11βHSD2 catalyses oxidation of active glucocorticoids to their inactive 11‐oxo derivatives. The aim of this study was to investigate the changes in local metabolism of glucocorticoids and in the expression of 11βHSD1 and 11βHSD2 mRNA during colonic inflammation. Methods: Acute colitis was induced by intracolonic administration of 2,4,6‐trinitrobenzenesulphonic acid (TNBS) or by drinking a dextran sodium sulphate (DSS) solution. Metabolism of glucocorticoids was measured in tissue fragments in vitro and 11βHSD1 and 11βHSD2 mRNA abundance was quantified using real‐time RT‐PCR one week after administration of TNBS and 10 days after drinking the DSS solution. Results: In both models of inflammatory bowel disease we observed down‐regulation of corticosterone oxidation to 11‐dehydrocorticosterone by 64% (TNBS) and 53% (DSS) and reciprocal stimulation of reduction of 11‐dehydrocorticosterone to corticosterone by 83% and 54%, respectively. A similar pattern was observed at the level of mRNA; 11βHSD1 mRNA was significantly higher (TNBS: increase by 660%; DSS: increase by 760%) and 11βHSD2 mRNA lower (TNBS: decrease by 85%; DSS: decrease by 60%) during inflammation. Conclusions: Colitis induces local glucocorticoid activation from 11‐oxo steroids and decreases glucocorticoid inactivation; i.e. inflammation increases local tissue ratio of active and inactive glucocorticoids. The results indicate that the changes in local metabolism of glucocorticoids could contribute to the control of an overshoot of inflammation processes in the colon.     

Duodenal intraepithelial lymphocyte‐count revisited

Background: The number of intraepithelial lymphocytes in the duodenum was determined 30 years ago, the suggested normal upper limit being 40 lymphocytes per 100 epithelial cells. Methods: Duodenal mucosa was analysed from 18 healthy individuals and 56 consecutive patients biopsied because of epigastralgia (17 cases), diarrhoea (10 cases), oesophagitis (10 cases), iron‐deficiency (9 cases) and B12‐deficiency (10 cases) showing normal histology, along with 10 cases of active coeliac disease. The biopsies were fixed in 4% formalin overnight and embedded in paraffin. Three micrometre thick sections were stained with haematoxylin and eosin and CD3. At least 300 epithelial cells were counted, the number of intraepithelial lymphocytes was given as the mean/100 epithelial cells. Extensive statistical analyses were performed. Results: In the healthy individuals the mean number (s) of intraepithelial lymphocytes/100 epithelial cells was 10.8 (2.6) and 13.2 (3.8) in H&E and CD3 stained sections, respectively. The upper limit of the confidence interval for CD3 staining was 29. There was no significant difference between normal individuals and the clinical groups, with the exception of coeliac disease. Conclusion: Two‐step analysis of intraepithelial lymphocyte‐determination is suggested: (a) semiquantitative estimate on H&E‐stained sections (normal ratio of 1:5 between lymphocytes and enterocytes; upper normal limit 20 lymphocytes) and (b) CD3‐staining and counting if intraepithelial lymphocytosis is suspected. The upper normal range of intraepithelial lymphocytes is set at 25 CD3+ lymphocytes/100 epithelial cells. Values between 25 and 29 are regarded as ‘borderline’ and 30 or more represent pathologic intraepithelial lymphocytosis in the duodenum.     

Activity of Angiotensin‐Converting Enzyme After Treatment with L‐Arginine in Renovascular Hypertension

The renin‐angiotensin system plays a role in the pathophysiology of renovascular hypertension. In addition, some studies have demonstrated a beneficial effect of L‐arginine (L‐Arg), the precursor of nitric oxide (NO), in this model of hypertension. This study was designed to investigate the effects of L‐Arg on cardiovascular parameters and on the activity of the angiotensin‐converting enzyme (ACE), after 14 days of renovascular hypertension. The experiments were performed on conscious male Wistar rats. Two‐kidney, one‐clip renovascular hypertension (2K1C) was initiated in rats by clipping the left renal artery during 14 days, while control rats were sham‐operated. One group was submitted to a similar procedure and treated with L‐Arg (10 mg/ml; average intake of 300mg/day) from the 7th to the 14th day after surgery, whereas the respective control group received water instead. At the end of the treatment period, the mean arterial pressure (MAP) was measured in conscious animals. The rats were sacrificed and the ACE activity was assayed in heart and kidneys, using Hip‐His‐Leu as substrate. In a separate group, the heart was removed, the left ventricle (LV) was weighed and the LV/body weight ratios (LV/BW) were determined. We observed significant differences in MAP between the L‐Arg‐treated and untreated groups (129 ± 7 vs. 168 ± 6 mmHg; P < 0.01). The cardiac hypertrophy described for this model of hypertension was attenuated in the 2K1C‐L‐Arg‐treated group (14th day, wet LV/BW: 2K1C‐L‐Arg = 1.88 ± 0.1; 2K1C = 2.20 ± 0.1 mg/g; P < 0.05). L‐Arg administration caused an important decrease in cardiac ACE activity (2K1C‐L‐Arg: 118 ± 15; 2K1C: 266 ± 34 µmol/min/mg; P < 0.01). L‐Arg also decreased the ACE activity in the clipped kidney by 47% (P < 0.01), but not in the nonclipped kidney. These data suggest that increased NO formation and reduced angiotensin II formation are involved in the anthihypertensive effect of orally administered L‐arginine.