Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure

Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-alpha in heart failure (HF) rats. TNF-alpha and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E2 by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle (drinking water). Eplerenone-treated HF rats had lower plasma TNF-alpha, interleukin (IL)-1beta and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity (indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-alpha, IL-1beta, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+vehicle versus sham+vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF+eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E2 in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.     

The use of erythropoiesis-stimulating agents in patients with non-myeloid hematological malignancies: a systematic review

The effectiveness of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with non-myeloid hematological malignancies needs to be assessed as the response to their administration is not uniform and their cost is high. We conducted a systematic review (SR) of the literature to identify reports of the effect of ESAs on survival, quality of life (QOL), transfusion requirements, and anemia. The entries to MEDLINE, EMBASE, and the Cochrane Library databases, and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology and the American Society of Hematology were searched. Seventeen reports and five abstracts of randomized trials fulfilled prospective criteria for inclusion. Five trials reported on survival; three failed to detect differences between groups and two demonstrated inferior survival in patients allocated to an ESA. Seven trials and three abstracts reported on QOL with four articles and three abstracts describing improvements in patients allocated to erythropoietin. However, important methodologic limitations were identified in these reports. Seven randomized controlled trials reported a reduction in the proportion of patients transfused. The absolute risk reduction in transfusions ranged from 15% to 24%. This is the only SR that assesses the use of erythropoiesis-stimulating agents specifically in patients with hematological malignancies. We conclude that available data evaluating ESAs in patients with hematologic malignancies demonstrate that these agents reduce transfusion requirements. Limitations of these data preclude conclusions that these agents improve QOL. More data are required to confirm the inferior survival associated with ESAs.     

Susceptibility of Haemophilus influenzae Type b to Cefatrizine, Ampicillin, and Chloramphenicol

The susceptibility of 269 isolates of Haemophilus influenzae type b to cefatrizine (BL-S640), ampicillin, and chloramphenicol was evaluated by disk diffusion susceptibility tests, using a modified Bauer-Kirby method. Broth dilution susceptibility tests were performed on 88 of these isolates, including all isolates resistant by disk to cefatrizine or ampicillin. Six of the isolates were resistant by disk to cefatrizine (zone size, <16 mm), four were resistant to ampicillin (zone size, <19 mm), and none were resistant to chloramphenicol (zone size, <17 mm). Only two of the six isolates of H. influenzae that were resistant to cefatrizine by disk were resistant to more than 4 mug of drug per ml. The four organisms resistant to ampicillin on disk were resistant, when tested by the broth method, to >128 mug/ml. These four ampicillin-resistant H. influenzae were susceptible to <4 mug of cefatrizine per ml. The two isolates resistant to >4 mug of cefatrizine per ml were susceptible to 0.5 and 2 mug of ampicillin, respectively, per ml. The activity of cefatrizine appears to be comparable in vitro to ampicillin against H. influenzae.     

Yersinia pseudotuberculosis disseminates directly from a replicating bacterial pool in the intestine

Dissemination of Yersinia pseudotuberculosis within mice after oral inoculation was analyzed. Y. pseudotuberculosis translocated to organs such as the liver and spleen shortly after oral inoculation, but was quickly cleared. In contrast, a second temporally distinct bacterial translocation event resulted in successful hepatosplenic replication of the bacteria. Replicating pools of bacteria could be established in these organs in mouse mutants that lacked Peyer's patches. These animals frequently had sterile mesenteric lymph nodes, a finding consistent with translocation taking place independently of regional lymph node colonization. In further contradiction to accepted models for dissemination of enteropathogens, clonal analysis revealed that bacteria causing disease in the spleen and liver of C57BL/6J mice were derived from populations located outside the intestinal lymph nodes. Replication of bacteria in the intestine before translocation appeared critical for dissemination, as transient selective suppression by streptomycin of bacterial growth in the intestine delayed dissemination of Y. pseudotuberculosis. These results collectively indicate that hepatosplenic colonization appears intimately connected with the ability of Y. pseudotuberculosis to successfully establish replication in the intestinal lumen and does not result from ordered spread leading from the intestine to regional lymph nodes before dissemination.     

Regional Myocardial Perfusion Rates in Patients with Coronary Artery Disease

Regional myocardial perfusion rates were estimated from the myocardial washout of (133)Xenon in 24 patients with heart disease whose coronary arteriograms were abnormal and 17 similar subjects whose coronary arteriograms were judged to be normal. Disappearance rates of (133)Xe from multiple areas of the heart were monitored externally with a multiple-crystal scintillation camera after the isotope had been injected into a coronary artery and local myocardial perfusion rates were calculated by the Kety formula.The mean myocardial perfusion rates in the left ventricle exceeded those in the right ventricle or atrial regions in subjects without demonstrable coronary artery disease. In this group there was a significant lack of homogeneity of local perfusion rates in left ventricular myocardium; the mean coefficient of variation of left ventricular local perfusion rates was 15.8%.In the patients with radiographically demonstrable coronary artery disease, a variety of myocardial perfusion patterns were observed. Local capillary blood flow rates were depressed throughout the myocardium of patients with diffuse coronary disease but were subnormal only in discrete myocardial regions of others with localized occlusive disease. Local myocardial perfusion rates were similar to those found in the group with normal coronary arteriograms in patients with slight degrees of coronary disease and in those areas of myocardium distal to marked coronary constrictions or occlusions which were well supplied by collateral vessels.In subjects with right coronary disease, the mean right ventricular perfusion rates were significantly subnormal; in seven subjects of this group perfusion of the inferior left ventricle by a dominant right coronary artery was absent or depressed. The average mean left ventricular perfusion rate of 12 subjects with significant disease of two or more branches of the left coronary artery was significantly lower than that of the group with normal left coronary arteriograms. In the patients with abnormal left coronary arteriograms, the average coefficient of variation of local left ventricular perfusion rates was significantly increased (24.8%).The studies provide evidence that coronary artery disease is associated with increased heterogeneity of local myocardial perfusion rates. They indicate that radiographically significant vascular pathology of the right or left coronary artery may be associated with significant reductions of myocardial capillary perfusion in the region supplied by the diseased vessel.     

Insulin Resistance, ��-Cell Dysfunction, and Conversion to Type 2 Diabetes in a Multiethnic Population: The Insulin Resistance Atherosclerosis Study

OBJECTIVE

Insulin resistance and β-cell function are major predictors of type 2 diabetes, but studies using direct methods of insulin resistance and secretion are few and relatively small. Furthermore, the strength of these associations has not been tested in different ethnic groups and various states of glucose tolerance, family history of diabetes, and obesity.

RESEARCH DESIGN AND METHODS

Predictors of incident diabetes were evaluated in Hispanic, non-Hispanic white, and African American participants in the Insulin Resistance Atherosclerosis Study (aged 40–69 years). In 557 participants with normal glucose tolerance and 269 with impaired glucose tolerance (IGT), insulin sensitivity (insulin sensitivity index [S^I]) and first-phase insulin secretion (acute insulin response [AIR]) were directly measured using the frequently sampled intravenous glucose tolerance test.

RESULTS

At the 5-year follow-up examination, 128 (15.5%) individuals had developed diabetes. Both S^I (odds ratio × 1 SD 0.50 [95% CI 0.37–0.68]) and AIR (0.51 [0.40–0.65]) were independent predictors of incident diabetes even after adjustment for age, sex, ethnicity, center, IGT, family history of diabetes, and BMI. The strength of the relation of S^I and AIR to incident diabetes was not significantly affected by potential interactions of age, sex, ethnicity, glucose tolerance, BMI, or family history of diabetes (P ≥ 0.15).

CONCLUSIONS

Both insulin sensitivity and β-cell function predict conversion to diabetes in different ethnic groups and various states of glucose tolerance, family history of diabetes, and obesity. The prevention of type 2 diabetes should focus on interventions that improve both insulin resistance and insulin secretion.Insulin resistance and insulin secretion are major predictors of type 2 diabetes, but much of the evidence is the result of studies that use surrogate measures of insulin resistance and β-cell function (1–4). There are few studies that have measured insulin resistance and secretion by direct methods. These studies have enrolled relatively few participants and have targeted individuals from a single ethnic group. In the study by Martin et al. (5), there were 25 incident cases of diabetes among 151 offspring of white parents who both had type 2 diabetes. In a subsequent report by Goldfine et al. (6), this cohort of individuals was compared with a cohort of 181 subjects with normal glucose tolerance (NGT) with only 6 incident cases of diabetes during a mean follow-up of 25 years (6). In the Pima Indian report, 200 subjects were studied and 38 developed type 2 diabetes (7). In a more recent study from the Netherlands, 101 white individuals with impaired glucose tolerance (IGT) were enrolled and 35 developed diabetes (8). Risk of progression to IGT and diabetes associated with direct measures of insulin sensitivity and secretion was also examined in 399 Pima Indians (9) and in 81 first-degree relatives of African Americans with type 2 diabetes (10). None of these studies adjusted their results for glucose tolerance status and adiposity. Furthermore, there are few data on how insulin resistance and secretion perform in different ethnic groups and various states of glucose tolerance, family history of diabetes, and obesity.Because the significance of insulin resistance and secretion could differ by ethnic group, parental history of diabetes, and obesity, we examined the heterogeneity of the relation of insulin resistance and β-cell function to future development of type 2 diabetes. The Insulin Resistance Atherosclerosis Study (IRAS) is a large epidemiological study on insulin resistance and cardiovascular risk factors among individuals of three ethnic groups (African Americans, Hispanics, and non-Hispanic whites) (11). Insulin sensitivity and first-phase insulin secretion were directly measured using the frequently sampled intravenous glucose tolerance test with MINMOD analysis.     

CT differentiation of enlarged mediastinal lymph node due to anthracosis from metastatic lymphadenopathy: a comparative study proven by endobronchial US-guided transbronchial needle aspiration

PURPOSE

Anthracosis often results in mediastinal nodal enlargement. The aim of this comparative study was to evaluate if it is possible to differentiate endobronchial ultrasound-guided trans-bronchial needle aspiration (EBUS-TBNA) proven anthracotic lymph nodes from malignant lymph node enlargement by means of multislice computed tomography (MSCT).

METHODS

We compared the MSCT findings of 89 enlarged lymph nodes due to anthracosis with 54 malignant lymph nodes (non-small cell lung cancer 75.9%, small cell lung cancer 18.5%, and non-Hodgkin lymphoma 5.6%). The lymph nodes were assessed for density (calcification, fat, and necrosis), shape (oval, round), contrast enhancement, and contour (sharp, ill-defined).

RESULTS

Malignant lymph nodes showed significantly greater axis diameters (P < 0.001). Both anthracotic and malignant nodes were most often oval (86.5% of all malignant nodes vs. 81.5% of all anthracotic nodes, P = 0.420) and showed confluence in a remarkable percentage (28.1% vs. 42.6%, P = 0.075). Anthracotic nodes showed calcifications more often (18% vs. 0%, P < 0.001). Malignant lymph nodes showed a significantly greater short and long axis diameter (P < 0.001), and they had a higher frequency of ill-defined contours (27.8% vs. 2.2%, P < 0.001) and contrast enhancement (27.8% vs. 5.6%, P < 0.001). Nodal necrosis, which appeared in one third of the malignant nodes, was not observed in anthracosis (35.2% vs. 0%, P < 0.001). Confluence of enlarged lymph nodes was seen in malignant lymph nodes (42.6%), as well as in lymph node enlargement due to anthracosis (28.1%, P = 0.075).

CONCLUSION

Our results show that there are significant differences in MSCT findings of malignant enlarged lymph nodes and benign lymph node enlargement due to anthracosis.Anthracosis is characterized by alterations not only of the lung parenchyma and bronchioles but also of the lymphatic system, resulting in chronic lymphadenopathy and nodal enlargement (1). Since finding of enlarged mediastinal lymph nodes on computed tomography (CT) may raise the suspicion of metastasis in patients with a known primary neoplasm (2, 3), and lymph node anthracosis may appear as false positive on positron emission tomography (PET) (4–6), it can confuse clinicians in staging of lung cancer patients.The aim of this comparative study of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and chest CT was to evaluate whether it is possible to differentiate enlarged anthracotic lymph nodes from malignant lymph node enlargement by means of CT. To the best of our knowledge, this study seems to be the first to deal with the differential diagnosis of enlarged anthracotic and malignant lymph nodes in this setting.