Mechanisms of disease: Helicobacter pylori-related gastric carcinogenesis--implications for chemoprevention

Gastric adenocarcinoma is the second most common cause of cancer-related mortality worldwide. Infection with Helicobacter pylori is the single most common cause of adenocarcinoma of the distal stomach. Cancer risk is believed to be related to differences among H. pylori strains and inflammatory responses governed by host genetics. In particular, specific interactions between host factors that modulate the response to the infection, and bacterial virulence factors that can directly cause tissue damage seem to have a major pathogenic role in the development of gastric cancer. In addition, environmental factors can modify key growth signaling pathways within the gastric mucosa, which leads to the alteration of epithelial cell growth. Preventive strategies represent the most promising means of decreasing cancer risk, and must be aimed at the control of H. pylori infection, improvement of environmental conditions, and the identification of subjects who are genetically predisposed to the development of cancer in response to H. pylori infection. Understanding the intracellular signaling pathways that are specifically affected by H. pylori and that promote phenotypic and genotypic changes that might ultimately progress to malignant transformation could enable physicians to focus eradication therapy appropriately and design interventions targeted at the molecular level to prevent the development of gastric cancer.     

Broad copy neutral‐loss of heterozygosity regions and rare recurring copy number abnormalities in normal karyotype‐acute myeloid leukemia genomes

We analyzed, by the latest high‐resolution SNP arrays, 19 Normal Karyotype (NK)‐AML patients at diagnosis (Dx) and remission (R) phases, to determine the number of tumor‐associated copy number abnormalities (CNAs) and copy neutral‐loss of heterozygosity (CN‐LOH) regions per patient and to identify possible recurring genomic abnormalities. The number of tumor‐associated CNAs was determined after comparison of matched Dx/R samples using stringent conditions able to reduce the number of false positive CNAs. With the exception of a single outlier case, a low number of CNAs per patient was detected (median value of 1 somatic loss or gain per patient). However, a high prevalence of CNAs (60–70% of the patients showed at least one tumor‐associated gain or loss) and few recurring CNAs were observed, thus providing new hints towards identification of cooperating mutations. An extensive search of all tumor‐associated CN‐LOH regions >1 Mb revealed only three broad regions (terminal 12Mb of 22q, terminal 27Mb of 1p and the whole chromosome 21) in three patients out of 19 (16%). CN‐LOH of the whole chromosome 21 was responsible for homozygosity of a missense mutation (R80C) of RUNX1/AML1. Our study suggests that a relative submicroscopic copy number stability NK‐AML genomes is associated with low recurrence of specific CNAs and CN‐LOH in NK‐AML patient population. Sequencing of candidate genes in the identified CNAs and CN‐LOH regions should be considered a priority in the search of novel driver mutations of AML. © 2010 Wiley‐Liss, Inc.     

Timing, setting and incidence of cardiovascular complications in patients with acute myocardial infarction submitted to primary percutaneous coronary intervention

Background: At the Istituto di Clinica Medica Generale e Cardiologia (Florence, Italy), the widespread use of percutaneous coronary intervention (PCI) has markedly changed the hospital course of patients with acute myocardial infarction (AMI). These patients are typically transferred to the coronary care unit (CCU) only after primary PCI, whereas during the thrombolytic era, patients were first admitted to CCU before reperfusion. Objectives and Methods: The incidence, timing and setting of complications from symptom onset to hospital discharge in 689 consecutive AMI patients undergoing PCI were evaluated. Results: Ventricular fibrillation occurred in 11% of patients, and most episodes (94.7%) occurred before or during PCI. Of all patients, 6.3% developed complete atrioventricular block (CAVB), and in 86.3% of these cases, the CAVB occurred before or during PCI; in 94.5%, a CAVB resolution occurred in the catheterization laboratory (CL). Thirty-one patients (4.5%) had impending shock on admission to the CL. Cardiogenic shock developed in 2 9 patients (4.2%), mostly in the prehospital phase or in the CL. Only four patients (less than 1%) developed cardiogenic shock later during their hospital course. Similarly, circulatory and ventilatory support, as well as temporary pacing and cardiac defibrillation, were used mostly in the prehospital phase or in the CL. During the CCU stay, 45 patients (6.5%) had hemorrhagic or vascular complications, and the incidence of post-PCI ischemia and early reocclusion of the culprit vessel were low (2.1% and 0.6%, respectively). Thus, cardiac complications usually associated with AMI were observed mainly before hospital admission or in the CL during the reopening of the target vessel. These complications were rarely observed after a successful PCI. Conclusions: For AMI patients, the CL is not only the site of PCI, it is also where most life-threatening cardiac complications are observed and treated.     

Thymic function in severely immunodeficient HIV type 1-infected patients receiving stable and effective antiretroviral therapy

The role of the thymus in long-term immune reconstitution has not been addressed in HIV patients who were severely immunodeficient prior to successful treatment with combination antiretroviral therapy (ART). Adult HIV-1 patients (n = 78) with nadir CD4+ T cell counts <100 T cells/microl, at least 12 months on ART and 6 months of complete viral suppression (<50 HIV RNA copies/ml) were selected from a patient database. The cohort was divided according to current CD4+ T cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. Thymic volume was assessed by spiral computed tomography. Naive (CD45RA+CD62L+) and replicating (Ki67+) T cells were quantitated by flow cytometry, T cell receptor excision circles (TREC) were assessed by real-time PCR, and serum IL-7 and testosterone by immunoassay. Patients with low CD4+ T cell counts had smaller thymuses [0(0-5.3) vs. 3.5(0-15.6) cm(3), p = 0.04] and were more likely to have no detectable thymus. They had similar proportions of replicating cells, but fewer naive CD4+ and CD8+ T cells and less TREC in CD4+ and CD8+ T cells/ml of blood than patients with high CD4+ T cell counts. However, some patients with no detectable thymus had high numbers of naive and TREC-bearing T cells. Thus, the recovery of CD4+ T cells in severely immunodeficient HIV patients with a virological response to ART is probably limited by thymic function. However, the data are consistent with extrathymic T cell production contributing to the naive T cell pool in some patients.     

Clearance of irretrievable bile duct and pancreatic duct stones by extracorporeal shockwave lithotripsy, using a transportable device: effectiveness and medium-term results

BACKGROUND AND GOALS: Extracorporeal shockwave lithotripsy (ESWL) is an established treatment of irretrievable biliary and pancreatic stones, but the cost of the shockwave generators limits its widespread use. We revised data about the effectiveness of our treatment for refractory stones using a transportable shockwave generator. STUDY: We retrospectively evaluated the short and medium-term outcomes of patients who underwent ESWL using a transportable electromagnetic shockwave generator between 1998 and 2003 at our unit, for the treatment of irretrievable bile duct or pancreatic duct stones. All patients received intravenous conscious sedation and antibiotic prophylaxis. RESULTS: Complete stone clearance was achieved in 70/82 patients (85.4%), in 66 of the patients (94.2%) with 1 session of ESWL. Despite the insertion of a stent in the bile duct, 2 patients had moderate cholangitis, while they waited for the next ESWL session. We did not record any moderate-severe complication of ESWL, but 2 patients underwent surgery owing to perforation/bleeding during endoscopic removal of residual fragments. A symptomatic recurrence of stones was recorded in 10/69 (14.5%) patients, who had been previously cleared and whose follow-up data (median follow-up 29 mo; range 7 to 66) were available. CONCLUSIONS: We obtained satisfactory stone clearance by using a transportable shockwave generator. Most patients required 1 session. Our experience confirmed the safety of the treatment, even though patients may experience cholangitis while awaiting definitive treatment. The use of a transportable ESWL generator may be a valuable option in centers, while ensuring a sufficient proficiency in biliary endoscopy.     

Effects of potassium on nitrate mediated alterations of osmoregulation in marine crabs

Determining the acute nitrate tolerance of marine animals is important for conservation as high levels of nitrate may be discharged into aquatic ecosystems via various anthropogenic sources. Typically, sodium nitrate (NaNO(3)) is used to determine the acute nitrate toxicity of marine animals. The standard procedure involves dissolving NaNO(3) salt in distilled water to create a stock solution, which is then diluted in seawater to obtain the desired nitrate concentration for the toxicity test. However, due to the relatively low toxicity of NO(3)(-), large volumes of the stock solution are required to create high NaNO(3)-N concentrations in the test solutions for LC(50) (median lethal concentration) calculations. As the stock solution contains no other elements, other than Na(+) and NO(3)(-), this can lead to drastically altered Na(+)/K(+) ratios (compared to natural seawater) of the test solutions, which could significantly affect the osmo-ionoregulation of the animals, and subsequently bias survival data. Consequently, experiments were performed to determine if incorporating potassium chloride (KCl), at a K(+) level equaling natural seawater at 30 per thousand, to the NaNO(3)-N stock solution influences the haemolymph osmolality, ion composition and LC(50) values of two commercially important crab species, the mud crab Scylla serrata and the blue swimmer crab Portunus pelagicus. In each experiment with S. serrata and P. pelagicus, a total of 20 replicate crabs were exposed to NaNO(3)-N concentrations of 2000, 3000, 4000, 5000 and 6000 mgl(-1) with and without incorporated KCl. Mortality observations were made at 12-h interval for 96-h. After 96-h, the haemolymph osmolality, Na(+), K(+) and Ca(2+) of the surviving crabs were measured. The 96-h LC(50) values for early juveniles of S. serrata and P. pelagicus were 3601 (3314-3902) mg l(-1) versus 4339 (4056-4518) mg l(-1) and 3355 (3085-3620) mg l(-1) versus 4132 (3864-4409) mg l(-1), respectively for the treatments without and with incorporated KCl. Statistical analysis showed that the sole utilisation of NaNO(3) led to a significantly (p<0.01) lower LC(50) value for both crabs, likely a consequence of their significantly lower (p<0.05) haemolymph K(+) levels. In contrast, no significant differences (p>0.05) in haemolymph K(+) was detected between crabs from the control and the treatment with incorporated KCl. It is therefore likely that previously reported acute nitrate toxicity tests have substantially underestimated the nitrate tolerances of marine animals. To avoid this problem, we propose incorporating KCl to the NaNO(3)-N stock solution as a standard protocol for future acute nitrate toxicity experiments on marine animals.