Willingness to participate in cardiac trials

The elderly, women, and minorities are all less likely to be enrolled in randomized clinical trials (RCTs). Whether differential patient interest in RCTs contributes to these disparities is unclear. The authors surveyed 660 patients' willingness to consider two potential cardiac RCTs of medical therapy vs. percutaneous coronary angioplasty or coronary artery bypass surgery, respectively. The cohort's mean age was 67 years (43% aged ≥70 years; 35% women; and 28% nonwhite). Compared with younger patients, those aged ≥70 years were equal or more likely to consider both the percutaneous coronary angioplasty (46% vs. 41%) and coronary artery bypass surgery RCTs (35% vs. 31%). Race also had no significant impact on trial enrollment, yet women were significantly less likely than men to participate in either RCT. In conclusion, patient willingness to consider RCT participation does not explain underenrollment of elderly and minority patients. Women, however, were more reluctant to consider RCTs, an area requiring further study.     

Mechanisms of insulin resistance in cultured fibroblasts from a patient with leprechaunism: Impaired post-binding actions of insulin and multiplication-stimulating activity

The binding and action of insulin and of the insulin-like growth factor, multiplication-stimulating activity (MSA), were studied in cultured skin fibroblasts from an infant with leprechaunism and associated insulin resistance. Three actions of insulin were reduced in the leprechaun cells: activation of glycogen synthase was 30% as great as in control fibroblasts, the increase in 2-deoxyglucose transport was 33% of the control value, and the uptake of alpha-aminoisobutyric acid was sevenfold less sensitive to enhancement. On a molar basis, MSA was at least as effective as insulin in activating glycogen synthase in control fibroblasts; in the patient's cells there was a reduction in activation that paralleled the changes observed with insulin. To localize the site of insulin resistance, the binding of both [125I]-insulin and [125I]-MSA to fibroblasts was measured and found to be reduced in the leprechaun cells. However, the impairment of the actions of insulin and MSA in the patient's cells was not explained solely by the diminished binding of the two polypeptides. Since the hexose transport system and the terminal enzymes studied thus far are intact, the defect is postulated to involve the post-binding coupling mechanism and mediator formation.     

Barriers to interferon-alpha therapy are higher in intravenous drug users than in other patients with acute hepatitis C

BACKGROUND/AIMS: Treatment with interferon-alpha (IFN-alpha) may eradicate HCV in most acute hepatitis C patients, thus preventing chronic hepatitis and avoiding less efficacious combination therapy. METHODS: In a prospective study, we evaluated the impact of barriers to successful start and completion of treatment of acute and subacute (<12 months from infection) hepatitis C with pegylated IFN-alpha2b, 1.5 microg/kg, QW, for 24 weeks. RESULTS: Out of 27 patients (22 were active intravenous drug users [IVDU]), 5 cleared HCV spontaneously. Antiviral treatment was indicated in 22 patients: six refused therapy for fear of side effects, whereas two others were lost to observation. Eight patients completed the treatment or received >80% of the scheduled drug: seven (88%) were sustained virological responders 24 weeks after the end of treatment. Six patients (all IVDU) stopped prematurely due to side effects: only one had a sustained virological response. Based on an intent-to-treat analysis, and considering all 14 patients in whom at least one dose of drug was administered, only 8 (57%) became sustained virological responders. CONCLUSIONS: Treatment of acute hepatitis C with pegylated IFN-alpha is highly beneficial, but its effectiveness is affected by a poor rate of acceptance and/or adherence to currently available regimens, especially in IVDU and women.     

A unique case of death by MDPHP with no other co-ingestion: a forensic toxicology case

International Journal of Legal Medicine - Synthetic cathinones are a class of psychoactive drugs that have become, in recent years, of quite common observation in medical and toxicological forensic...     

Co-administration of nitric oxide-aspirin (NCX-4016) and aspirin prevents platelet and monocyte activation and protects against gastric damage induced by aspirin in humans

OBJECTIVES: The goal of this study was to test the hypothesis that NCX-4016 may have broader anti-inflammatory and antithrombotic effects as well as better gastric tolerability than aspirin in humans. BACKGROUND: NCX-4016 is an aspirin derivative containing a nitric oxide-releasing moiety that prevents platelet activation and modulates tissue factor (TF) expression and cytokine release from lipopolysaccharide (LPS)-stimulated monocytes. METHODS: This was a blind-observer, placebo-controlled, parallel-group study in which 48 healthy subjects were randomized to receive NCX-4016 800 mg twice a day, NCX-4016 800 mg twice a day plus aspirin 325 mg, aspirin 325 mg, or placebo for 21 days. RESULTS: Similar to aspirin alone, NCX-4016 effectively inhibited platelet aggregation induced by 0.6 mmol/ arachidonic acid, clot-stimulated thromboxane (TX) B2 generation in whole blood, and urinary excretion of 11-dehydro-TXB2. Unlike aspirin alone, the administration of NCX-4016 significantly inhibited TF expression in monocytes stimulated ex vivo with 10 micromol/l LPS (determined by flow-cytometry analysis of TF on CD14 positive cells). NCX-4016 also inhibited the rapid TF expression induced in monocytes by a proteinase activated receptor agonist (thrombin receptor activator protein, 2 micromol/l) as well as LPS-induced expression of CD11b . Ex vivo, release of MCP-1 and interleukin-6 were significantly inhibited by NCX-4016, but not by aspirin. NCX-4016 was not associated with gastric damage, and significantly reduced gastric injury when co-administered with aspirin, although both drugs reduced gastric PGE2 production to the same extent. CONCLUSIONS: NCX-4016 is equally effective as aspirin in inhibiting cyclooxygenase activity. However, NCX-4016 causes less gastric damage and prevents monocyte activation. Larger multicenter trials are warranted to establish clinical efficacy and safety of NCX-4016.     

Pancreatic metastases: observations of three cases and review of the literature.

BACKGROUND: The aim of the study is to analyze pancreatic metastases and their clinical, radiological, therapeutic and prognostic features. METHODS: Three cases of pancreatic metastases observed and a world literature review of 333 cases were recorded. RESULTS: Pancreatic metastases are due more frequently to renal cell carcinoma; they are usually metachronous and characterized by a long period of time between the resection of the primary tumor and their detection. The differential diagnosis with other pancreatic masses is difficult, but an accurate anamnesis, some peculiar findings of imaging techniques and percutaneous fine needle aspiration could allow preoperative diagnosis. Pancreatic resections are the treatment of choice allowing the better palliation and improving survival. 150/234 pancreatic metastases underwent pancreatic resections (resectability index = 64.1%); 88/132 patients are alive with a mean follow-up of 27.1 months; of the 44 dead patients the mean survival time was 21.3 months. Among pancreatic metastases the primary tumor with better prognosis is renal cell carcinoma. CONCLUSION: Pancreatic metastases are rare; their preoperative diagnosis is difficult but useful and possible. Surgical resection is suggested because the patient still may have a prolonged survival.     

Impairment of antipyrine clearance in humans by propranolol

The effect of propranolol on antipyrine clearance in humans was evaluated in six healthy volunteers who received single 1.4 to 1.5 g doses of intravenous antipyrine on two occasions. The first (control) antipyrine trial was without concurrent drug administration; the second trial was done during treatment with therapeutic doses of propranolol (40 mg every 4 to 6 hours). Antipyrine elimination half-life (t1/2), volume of distribution (Vd), and total clearance were determined after each trial. In all subjects isoproterenol sensitivity decreased markedly during propranolol treatment, indicating a high degree of beta blockade produced by the drug. Mean antipyrine t1/2 during the propranolol treatment period was significantly prolonged, and total clearance significantly reduced, over the control values. Twenty-four-hour urinary excretion of 4-hydroxyantipyrine, the major metabolite of antipyrine, likewise was reduced from 23.6% of the dose on the control trial to 14.8% of the dose during propranolol coadministration (0.1 less than P less than 0.2). Vd however, was nearly identical during both trials (0.62 L/kg). Thus propranolol prolongs the half-life and reduces the clearance or biotransformation rate of antipyrine, a drug whose clearance is independent of hepatic blood flow. Propranolol may influence the activity of hepatic microsomal enzymes responsible for drug hydroxylation.     

Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis

Chronic eosinophilic leukemia is a neoplastic condition with persistent eosinophilia as the major hematological abnormality and with the eosinophils being part of the neoplastic clone. Some cases can be recognized by traditional hematological criteria, but many can be recognized only when a clonal cytogenetic or molecular genetic abnormality is demonstrated. A range of cytogenetic and molecular genetic abnormalities has been recognized, including both those seen in other myeloid malignancies (such as trisomy 8, monosomy 7, and 20q-) and those that are particularly linked to eosinophil differentiation (such as rearrangements of PDGFRB, FGFR1, and PDGFRA, the latter with formation of a FIP1L1-PDGFRA fusion gene). The discovery of the FIP1L1-PDGFRA fusion gene has led to the recognition that many patients who would previously have been regarded as having idiopathic hypereosinophilia actually have chronic eosinophilic leukemia. The same fusion gene has also been found in patients with hypereosinophilia and atypical bone marrow mast cells but whether this syndrome should be regarded as a variant of eosinophilic leukemia or as a variant of systemic mastocytosis remains to be established.     

Adoptive T-cell therapy for EBV-associated post-transplant lymphoproliferative disease

Increased understanding of the mechanisms by which T lymphocytes recognize virus and tumor-specific antigens has fueled the use of adoptive immunotherapy for viral and malignant diseases. An ideal candidate for such treatment is Epstein-Barr virus (EBV). EBV-associated post-transplant lymphoproliferative disorder (PTLD) is a serious complication post-solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). The disease is essentially the result of suppression of cytotoxic T-cell function and despite various treatment strategies the course may still be fulminant and lethal. Therefore, an adoptive immunotherapeutic approach using ex vivo derived EBV-specific CTL offers a promising solution not only for the treatment but also as prophylaxis for PTLD. The infusion of EBV-CTL has been demonstrated to be safe and effective in allogeneic HSCT recipients and their use post-SOT is being evaluated.