Ischemic heart disease,factor predisposing to Barrett's adenocarcinoma: A case control study

AIM:To define the significance of ischemic heart disease(IHD)(stable angina to infarction) co-existance in Barrett esophagus(BE) patients and patients with esophageal adenocarcinoma(AdE).METHODS: All BE/AdE patients in Blackpool-Wyre-Fylde area and Trikala prefecture identified from medical records. Patient clinical details were obtained from hospital and General Practitioner records. Additional information was gathered from validated questionnaire.RESULTS: Forty(33%) AdE and 83(19%) BE patients had IHD(P = 0.002). Eighteen(15%) AdE and 34(8%) BE patients had suffered a myocardial infarction(P = 0.03). Three(3%) AdE and 7(2%) BE patients had severe heart failure(P = 0.82). Thirty-nine(47%) BE with IHD and 8(20%) AdE patients with IHD consumed aspirin daily(P = 0.004). Seventh-seven(93%) BE patients with IHD and 36(90%) AdE patients with IHD were on statins(P = 0.86). Logistic regression analysis: AdE was more frequent in the elderly,with long termreflux,long BE and concurrent IHD(odds ratio: 2.086,P = 0.001) not consuming statins. Eighteen(22%) BE patients with IHD [16(84%) with myocardial infarction] vs 33(10%) without IHD died from non-neoplastic causes within 24 mo from BE diagnosis(P = 0.005). CONCLUSION: IHD is more prevalent in AdE than BE patients. Increased prevalence of AdE is related with the presence of myocardial infarction but not severe heart failure,possibly because patients with BE and se-vere IHD have low life expectancy.     

Glutamine synthetase deficiency in murine astrocytes results in neonatal death

Glutamine synthetase (GS) is a key enzyme in the “glutamine‐glutamate cycle” between astrocytes and neurons, but its function in vivo was thus far tested only pharmacologically. Crossing GS^fl/lacZ or GS^fl/fl mice with hGFAP‐Cre mice resulted in prenatal excision of the GS^fl allele in astrocytes. “GS‐KO/A” mice were born without malformations, did not suffer from seizures, had a suckling reflex, and did drink immediately after birth, but then gradually failed to feed and died on postnatal day 3. Artificial feeding relieved hypoglycemia and prolonged life, identifying starvation as the immediate cause of death. Neuronal morphology and brain energy levels did not differ from controls. Within control brains, amino acid concentrations varied in a coordinate way by postnatal day 2, implying an integrated metabolic network had developed. GS deficiency caused a 14‐fold decline in cortical glutamine and a sevenfold decline in cortical alanine concentration, but the rising glutamate levels were unaffected and glycine was twofold increased. Only these amino acids were uncoupled from the metabolic network. Cortical ammonia levels increased only 1.6‐fold, probably reflecting reduced glutaminolysis in neurons and detoxification of ammonia to glycine. These findings identify the dramatic decrease in (cortical) glutamine concentration as the primary cause of brain dysfunction in GS‐KO/A mice. The temporal dissociation between GS^fl elimination and death, and the reciprocal changes in the cortical concentration of glutamine and alanine in GS‐deficient and control neonates indicate that the phenotype of GS deficiency in the brain emerges coincidentally with the neonatal activation of the glutamine‐glutamate and the associated alanine‐lactate cycles. © 2010 Wiley‐Liss, Inc.     

Cost–utility analysis of an advanced pressure ulcer management protocol followed by trained wound,ostomy, and continence nurses

The high prevalence of severe pressure ulcers (PUs) is an important issue that requires to be highlighted in Japan. In a previous study, we devised an advanced PU management protocol to enable early detection of and intervention for deep tissue injury and critical colonization. This protocol was effective for preventing more severe PUs. The present study aimed to compare the cost‐effectiveness of the care provided using an advanced PU management protocol, from a medical provider's perspective, implemented by trained wound, ostomy, and continence nurses (WOCNs), with that of conventional care provided by a control group of WOCNs. A Markov model was constructed for a 1‐year time horizon to determine the incremental cost‐effectiveness ratio of advanced PU management compared with conventional care. The number of quality‐adjusted life‐years gained, and the cost in Japanese yen (¥) ($US1 = ¥120; 2015) was used as the outcome. Model inputs for clinical probabilities and related costs were based on our previous clinical trial results. Univariate sensitivity analyses were performed. Furthermore, a Bayesian multivariate probability sensitivity analysis was performed using Monte Carlo simulations with advanced PU management. Two different models were created for initial cohort distribution. For both models, the expected effectiveness for the intervention group using advanced PU management techniques was high, with a low expected cost value. The sensitivity analyses suggested that the results were robust. Intervention by WOCNs using advanced PU management techniques was more effective and cost‐effective than conventional care.     

Target-induced death by apoptosis in human lymphokine-activated natural killer cells

Activated human natural killer (NK) cells undergo rapid apoptotic cell death after ligand binding to the Fc receptor (CD16). We examined whether human NK cells die after engagement in cytolytic functions. Peripheral blood NK cells, with and without prior activation in vitro with interleukin-2 (IL-2), were tested for the occurrence of cell death after incubation with K562, the prototype NK-sensitive target cell. A proportion (15.2%) of NK cells that were stimulated for 3 days with IL- 2 and then incubated for 4 hours with K562 cells showed rapid cell death, but NK cells not stimulated with IL-2 did not. This cell death was found to involve nuclear condensation and fragmentation and DNA cleavage, all of which are characteristic of apoptosis. These data indicate that a proportion of activated human NK cells undergo apoptosis as they engage in target cell lysis. Target-induced NK cell death may represent an important mechanism for regulation of inflammatory processes involving NK cells.     

Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia

Despite expectations that 2-chlorodeoxyadenosine (2-CdA) would prove active primarily in lymphoproliferative diseases, early reports suggested unexpected high activity of this drug in heavily pretreated children with acute myeloblastic leukemia (AML) at a maximally tolerated dose of 8.9 mg/m2/day for 5 days. In view of these findings, we conducted an escalating dose trial of 2-CdA in adult patients with relapsed or resistant AML. Thirty-six patients who had received extensive prior therapy were treated at 9 dose levels of 2-CdA at daily doses ranging from 5 to 21 mg/m2 for 5 days. 2-CdA eliminated leukemic blasts from the peripheral blood in 32 of 36 cases; however, bone marrow hypoplasia was seen only at daily dose levels > or = 15 mg/m2. We observed a total of 3 complete remissions: 1 at the 15 mg/m2/d dose level and 2 at the 21 mg/m2/d dose level; these responses persisted for 3, 2, and 3 months, respectively. Although prolonged myelosuppression would have been dose-limiting at 21 mg/m2/d for 5 days, the most important adverse effect was the development of a sensorimotor peripheral neuropathy. This reaction, whose onset was substantially delayed after completion of drug treatment, was observed in 2 of 5 patients at the 19 mg/m2/d level and in 4 of 4 evaluable patients at the 21 mg/m2/d level. Pathologically, this process was characterized by axonal degeneration and secondary demyelination. Other side effects included reactivation of a posttransplant Epstein-Barr virus-related lymphoma in 1 patient and tumor lysis syndrome. We conclude that the maximally tolerable dose of 2-CdA in adult patients (17 mg/m2/d for 5 days) in approximately twofold in excess of that previously reported in children and that the limiting toxic effect is a degenerative neuropathic disorder. We confirm that this drug has definite activity in AML, but the magnitude of this effect needs to be determined in larger numbers of patients who have received less extensive therapy. This agent deserves further evaluation in patients with both AML and acute lymphoblastic leukemia at these higher doses and perhaps as part of a preparative regimen for patients undergoing bone marrow transplantation.