Evaluation of the role of ionized calcium in sodium fluoroacetate (“1080”) poisoning

Fluoroacetate, which is an inhibitor of the tricarboxilic acid cycle, is widely used as a rodenticide. Fluoroacetate is converted in the body to fluorocitrate, which is an inhibitor of the enzyme aconitate hydrase. As a result, energy production goes down, and citrate accumulates. As citrate is a potent chelator of calcium ion, we postulated that ionized calcium concentration in the blood would drop. Fluoroacetate, 0.03 mmol/kg, was injected iv into anesthetized cats. Ionized calcium concentration in anaerobically drawn arterial blood samples was measured with an ion-exchange electrode. Samples were taken immediately before and 40 min after the poisoning, after which the animals were either used as controls (six cats) or treated with an infusion of iv CaCl₂ (another six cats), so as to restore ionized calcium levels to normal values. Forty minutes after fluoroacetate injection, the ionized calcium levels fell by an average of 27.2%, from 1.09 ± 0.07 to 0.79 ± 0.14 mM. There was a corresponding prolongation of the QTc interval of the ECG (r = 0.82). Treatment with CaCl₂ significantly prolonged the life of the treated animals as compared to the control animals (p < 0.0016 by the Mann-Whitney rank sum test). Our findings suggest that reduced levels of ionized calcium play an important role in the pathogenesis of fluoroacetate poisoning. The reduced levels of Ca²⁺ are an adequate explanation for the toxic effects of fluoroacetate, and may be the missing link between the biochemistry of the poisoning and the clinical manifestations.     

The common prothrombotic factors in nulliparous women do not compromise blood flow in the feto-maternal circulation and are not associated with preeclampsia or intrauterine growth restriction

OBJECTIVE: In this study we evaluated the associations between common prothrombotic factors and increased blood flow resistance in the feto-maternal circulation, intrauterine growth restriction, small for gestational age, or preeclampsia. STUDY DESIGN: A prospective study was conducted in healthy nulliparous women with spontaneous singleton pregnancy. Blood was tested for the common prothrombotic factors, i.e., factor V Leiden, factor II G20210A, methylenetetrahydrofolate reductase C677T, anticardiolipin, and lupus anticoagulant. Blood flow resistance in the uterine, placental, and umbilical arteries were assessed by multigate Doppler and compared between women with and without prothrombotic factors. The maternal, fetal, and neonatal clinical courses were also compared among these subgroups. RESULTS: Prothrombotic factors were detected in 191 of 637 (30%) subjects. No significant difference in resistance to blood flow in the feto-maternal unit was discernible between women with and without prothrombotic factors. Pregnancy-induced hypertension or preeclampsia occurred in 10 of 191 (5.2%) and in 19 of 446 (4.3%) of women with and without a prothrombotic factor respectively ( P = .59). Intrauterine growth restriction was detected at 31 weeks in 13 of 164 (7.9%) and in 42 of 377 (11.1%) fetuses of women with and without a prothrombotic factor ( P = .26), and small for gestational age at delivery was observed in 19 of 187 (10.2%) and in 41 of 413 (9.9%) of mothers with and without prothrombotic markers, respectively. CONCLUSION: The presence of prothrombotic factors in healthy nulliparous women does not compromise blood flow in the feto-maternal unit, nor is it associated with preeclampsia, intrauterine growth restriction, or small for gestational age .     

Predictors of cardiac and noncardiac mortality among 14,697 patients with coronary heart disease

The decrease in mortality from ischemic heart disease during the last 25 years may partly reflect improvement in diagnosis and treatment of patients with coronary heart disease. These patients, therefore, are experiencing morbidity and mortality due to other causes. The aim of our study was to describe the incidence and causes of cardiac mortality (CM) and noncardiac mortality (NCM) and to identify predictive factors. A cohort of 14,697 patients with coronary heart disease was merged with the Central Population Registry to identify mortality records from 1990 to 1996. Among the 1,839 deaths, 1,055 (57.4%) were cardiac, 626 (34.0%) were noncardiac, and 158 deaths (8.6%) were due to unknown causes as classified in the International Classification of Diseases-Ninth Edition (ICD). The 3 most significant predictors were age for a 10-year increment (odds ratios 1.75 and 2.25 for CM and NCM, respectively), chronic obstructive pulmonary disease (odds ratios 1.67 and 1.71), and current smoking (odds ratios 1.29 and 1.66). A history of cancer was a predictor of NCM, but not of CM, whereas peripheral vascular disease predicted CM but not NCM. As the number of predictive factors increased from none to >or=5, the risk of NCM gradually increased from 1.9% to 15.5%. Similar predictors expose subjects with coronary disease to CM and NCM, but smoking plays a more pronounced role in the prediction of NCM, whereas past myocardial infarction, lower levels of high-density lipoprotein cholesterol, and peripheral vascular disease are mainly associated with CM. Because of the similarity of antecedent predictors, treatment of risk factors among patients with coronary heart disease should prove valuable for the prevention of all-cause mortality.     

A Comparison of One- and Two-Stage Laparoscopic Sleeve Gastrectomy Following Failed Laparoscopic Adjustable Gastric Banding Using the BAROS Score

Obesity Surgery - Revision of a failed band can be done by laparoscopic sleeve gastrectomy (LSG). It can be performed synchronously with band removal or during two separate procedures. Comparing...     

Optimism During Hospitalization for First Acute Myocardial Infarction and Long-Term Mortality Risk: A Prospective Cohort Study

Objective

To assess the association between dispositional optimism, defined as generalized positive expectations about the future, and long-term mortality in young survivors of myocardial infarction (MI).

Xenotransplantation and ABO incompatible transplantation: the similarities they share.

Transplantation of kidney allografts across the ABO barrier has been feasible with the development of technologies for removal of anti-blood group antibodies from the circulation of the recipent. The recipients of ABO incompatible grafts display tolerance, accommodation or rejection of the graft. Understanding the factors that determine the outcome of the immune response against incompatible blood group antigens has required the study of an appropriate experimental animal model. The model used is that of knockout (KO) mice for the alpha1,3galactosyltransferase gene, lacking the alpha-gal epitopes and transplanted with wild type mouse heart expressing the alpha-gal epitope. The alpha-gal epitope (Galalpha1-3Galbeta1-(3)4GlcNAc-R) is one of the most abundant carbohydrate epitopes on cells of non-primate mammals and New World monkeys, where it is synthesized by the glycosylation enzyme alpha1,3galactosyltransferase. In humans, apes and Old World monkeys, this epitope is absent due to an evolutionary event that led to the inactivation of the alpha1,3galactosyltransferase gene in ancestral Old World primates. Instead, humans, apes and Old World monkeys produce a natural antibody, the anti-Gal antibody, that is the most abundant natural antibody in humans (approximately 1% of circulating immunoglobulins) and which specifically interacts with alpha-gal epitopes. The interaction between anti-Gal and alpha-gal epitopes is a major immunologic barrier in xenotransplantation, preventing transplantation of pig organs or tissues (i.e. xenografts) into humans. Anti-Gal antibodies also comprise a large proportion of anti-blood group B activity in A and O individuals. Moreover, in recipients of ABO incompatible grafts, much of the elicited anti-A and anti-B antibodies are in fact anti-Gal antibodies capable of binding also to the incompatible blood group antigens. Since the alpha-gal epitope is very similar in its structure to blood groups A and B, understanding anti-Gal response to alpha-gal epitopes is likely to provide information on the immune response to ABO incompatible antigens. Studies on the immune response to alpha-gal epitopes in KO mice have indicated that this epitope can not activate T cells. Anti-Gal B cells engaging alpha-gal epitopes on transplated wild type mouse heart can be activated to produce their antibodies only if they receive help from T cells that are activated by allogeneic or xenogeneic peptides. If T cell help is not available for several days the B cells are induced to differentiate into cells capable of producing accommodating antibodies. Accommodating anti-Gal antibodies bind to the incompatible carbohydrate antigen but do not induce rejection. Prolonged exposure of anti-Gal B cells to the incompatible alpha-gal epitope on the wild type mouse heart graft induces tolerance due to the deletion of these B cells. These studies imply that similar variation in the availability of T cell help in recipients of ABO incompatible grafts result in rejection, accommodation or tolerance, to the blood group antigen. The studies on immune response to incompatible alpha-gal epitopes have further indicated that tolerance to incompatible blood group antigens can be achieved by gene therapy with autologous bone marrow cells or autologous lymphocytes engineered to express the incompatible blood group antigen. Studies in the mouse model suggest that administration into the patient such autologous cells engineered to express the incompatible transplantation carbohydrate antigen induces deletion of anti-blood group B cells and induction of tolerance, provided that the anti-blood group antibodies are removed. Such tolerance is perpetuated indefinitely by the subsequent transplantation of the organ expressing the incompatible blood group antigen.     

Intravenous nitroglycerin in the treatment of decompensated heart failure: potential benefits and limitations

Acute decompensated heart failure (ADHF) is a common cause of hospitalizations. Intravenous nitroglycerin is widely used in the treatment of this condition. The use of this drug is based on its nitric oxide-mediated vasodilatory effect, which can lead to beneficial hemodynamic effects as well as improvement of myocardial ischemia and reduction of mitral regurgitation. However, information regarding the use of nitroglycerin for ADHF is limited to mostly hemodynamic evaluations in small groups of patients without cardiovascular outcome data. A single randomized, placebo controlled study that evaluated commonly used doses of nitroglycerin in patients with ADHF was disappointing and failed to show a significant hemodynamic effect or improvement of symptoms compared with placebo. The potential benefit of nitroglycerin seems to be limited by a decreased vasodilatory response in patients with heart failure, which requires an active titration of the drug and the use of high doses (>120 microg/min). In addition, the initial beneficial hemodynamic effect achieved with the appropriate dose of nitroglycerin is associated with neurohumoral activation and limited by an early development of nitrate tolerance that leads to a marked attenuation of the initial effect. More information obtained in large-scale studies that are appropriately designed to evaluate the effect of variable doses of nitroglycerin on short- and long-term cardiovascular outcome, with and without interventions shown to prevent nitrate tolerance, is needed before intravenous nitroglycerin can be recommended as a standard therapy for ADHF.     

Liver-targeted gene therapy by SV40-based vectors using the hydrodynamic injection method

Efficient reconstitution of defective genes in hepatocytes could be used to treat various liver and systemic diseases through gene therapy. To explore the potential of SV40-based vectors in liver gene therapy, we constructed SV/luc, an SV40 T-antigen replacement transduction vector, that was propagated on COS and COT cells, which supply the SV40 T-antigen in trans. For liver targeting, BALB/C mice were injected via the tail vein with SV/luc stocks containing 3 x 10(6) to 10(8) transducing units in a volume of 1-2 ml. Luciferase activity was monitored with a light-detection cooled charged-coupled device (CCCD) camera, which enables continuous in vivo measurement of luc expression. The SV40 vector proved to be efficient in gene delivery to the liver, leading to long-term (> or =107 days) transgene expression in hepatocytes. Optimal results were obtained with 3 x 10(6) to 3 x 10(7) transducing units. The hydrodynamic vector delivery method caused transient liver inflammatory changes, with full recovery within days. Low levels of SV40-neutralizing antibodies were detected in the sera of treated mice; however, there was no indication of vector or transgene-specific cellular immune responses. Vectors packaged in vitro, using recombinant capsid proteins and plasmid DNA, were also effective in liver transduction. These results suggest that SV40 vectors may be useful for liver gene therapy.