Effects of bile acids on ventricular muscle contraction and electrophysiological properties: studies in rat papillary muscle and isolated ventricular myocytes

Summary The effects of sodium salts of various bile acids on the contractile force and the electrophysiological properties of rat ventricular muscle were studied in vitro. Primary, conjugated, and secondary bile acids were studied in a concentration range of 10^–9–10^–6 mol/l, which corresponds to concentrations found in the plasm of patients with cholestatic jaundice. In general, the bile acid induced a negative inotropic effect which was manifested as a reduction in active tension, maximum rate of tension activation, and maximum rate of tension relaxation. Twitch duration and time to peak tension were unaffected by the bile acids. The negative inotropism was associated with a reduction in ventricular action potential duration. Resting potential, action potential amplitude, and maximum upstroke velocity of phase 0 depolarization were unaffected. Voltage clamp experiments in rat ventricular myocytes demonstrated that sodium taurocholate decreased the slow inward current and slightly increased the outward potassium current. Hence, these effects on the membrane currents are probably responsible for the negative inotropic effect. Send offprint requests to O. Binah at the above address     

Pesticide-related health problems and farmworkers

1. Migrant and seasonal farmworkers are primarily ethnic minorities who are excluded from federal laws that protect other workers. Farmworkers live and work under substandard conditions that place them at increased risk of pesticide-related illness. 2. Agriculture uses 80% of all pesticides in the U.S. Handlers who mix, load and apply pesticides as well as workers cultivating and harvesting crops sprayed with them are at risk of acute poisoning or even death from their exposures. Drift and run-off of agricultural pesticides pollute the air, soil and water, creating additional hazards to workers' families, community residents, and the environment. 3. Chronic effects, including cancer in adults and children, adverse reproductive outcomes, delayed neuropathy and neurobehavioral effects, are also associated with occupational and environmental exposure to pesticides.     

Bactericidal/permeability-increasing protein in host defense and its efficacy in the treatment of bacterial sepsis

The 55-kD bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived polypeptide belonging to a family of lipid and endotoxin binding proteins. BPI is composed of two functionally distinct structural domains: a potently antibacterial and antiendotoxin ∼ 20-kD aminoterminal half, and an opsonic carboxy-terminal portion. In multiple animal models, a recombinant amino-terminal fragment of BPI (rBPI₂₁) is nontoxic and protects against gram-negative bacteria and endotoxin. In humans, rBPI₂₁ is also nontoxic and nonimmunogenic and has undergone phase II/III clinical trials with apparent therapeutic benefit.     

Alterations of paraoxonase and platelet-activating factor acetylhydrolase activities in patients on peritoneal dialysis.

OBJECTIVE: The more atherogenic lipid profile seen in peritoneal dialysis (PD) patients cannot fully explain the increased incidence of atherosclerosis in this population. Oxidative modification of low-density lipoproteins (LDL) is considered to play a central role in the atherogenic process, whereas high-density lipoprotein (HDL) protects LDL from oxidation. On the other hand, it has been suggested that the LDL and HDL of PD patients are more resistant to oxidation than those of control subjects, while PD-HDL equally protects LDL from oxidation compared to control-HDL. Two HDL-associated enzymes have been shown to protect both LDL and HDL from oxidation: paraoxonase (PON1) and HDL-associated platelet-activating factor acetylhydrolase (HDL-PAF-AH). Furthermore, low PON1 activity and high total plasma PAF-AH concentration, which represents mainly the LDL-associated enzyme, have been shown to be independent risk factors for coronary artery events in the general population. However, there are limited data regarding possible alterations of these enzymes in PD patients. The aim of our study was to examine the possible alterations of PON1 and PAF-AH activities in patients undergoing PD. DESIGN: A cross-sectional study. SETTING: A university medical center. PARTICIPANTS: 56 PD patients of Caucasian origin and 86 matched controls were studied. MEASUREMENTS: In all subjects, serum PON1 activity toward paraoxon (paraoxonase) and phenylacetate (arylesterase), as well as total serum and HDL-PAF-AH activities were measured; PON1 genetic polymorphisms known to influence PON1 activity (Q192R and M55L) were determined. RESULTS: The PD patients exhibited significantly increased serum PON1 (paraoxonase) and PON1 (arylesterase) activities compared to controls, regardless of the PON1 polymorphisms or the levels of HDL cholesterol. Additionally, PD patients had significantly elevated activities of total serum PAF-AH and HDL-PAF-AH, independently of the levels of LDL or HDL cholesterol. The ratio of HDL-PAF-AH/ total PAF-AH, which has recently been suggested to be a potential marker of atherogenicity, was decreased in these patients compared to controls. Moreover, no difference in the prevalence of PON1 polymorphisms between PD patients and controls was found. CONCLUSION: The elevated activities of PON1 and HDL-PAF-AH could explain the increased resistance of PD-HDL to oxidation; the higher activity of total PAF-AH and the decreased HDL-PAF-AH/ total PAF-AH ratio could contribute to the increased incidence of atherosclerosis in these patients.     

Adenocarcinoma arising in a chondroid syringoma of vulva.

Chondroid syringoma of the vulva is an extremely rare tumor. Of the previously reported cases, only one was clinically malignant. The authors describe a case of chondroid syringoma of the right labium majus from which arose a papillary adenocarcinoma. A right inguinal lymph node was replaced with metastatic adenocarcinoma.     

Antiviral immune responses modulate the nature of central nervous system (CNS) disease in a murine model of multiple sclerosis

Summary: In animals and in humans, T-cell therapy can cure advanced disseminated leukemia that would otherwise be fatal. The therapeutic effect of immune T cells is quantitative. As the dose of effector T cells is increased, survival is proportionately increased. Therefore, effective T-cell therapy is predicated on the ability to procure large numbers of immune effector T cells. By using cultured T cells, the number of immune T cells can be increased in vivo substantially above che level achievable by vaccination. The survival of cultured T ceils in vivo is dependent upon both the culture conditions used and the therapeutic regimens employed. Under appropriate conditions, cultured T ceils can proliferate in vivo in response to stimulation by antigen, distribute widely and survive long term to provide effector function and immunologic memory. Given that T cells recognize peptides. the need for immunization with tumor can be circumvented by immunization with peptide. Peptide-specific T cells and the progeny of single T-cell clones can provide the necessary cellular functions to eradicate disseminated murine leukemia. The ability of cloned T cells to similarly provide substantial measurable immunity in humans has been validated in clinical trials. By priming with peptides and by using established culture conditions, T-cell therapy can now be directed against virtually any antigen within the host T-cell repertoire. The major remaining question to be answered is which proteins and which peptides are the most suitable targets for T-cell therapy trials.