Dipeptide vinyl sultams: synthesis via the Wittig-Horner reaction and activity against papain, falcipain-2 and Plasmodium falciparum.

The synthesis of phosphonate derivatives of N-phenyl- and N-benzyl-gamma- and delta-sultams, and their application in the Wittig-Horner reaction with N-Boc-L-phenylalanine aldehyde to afford E- and Z-isomers, are described. These compounds were further processed to provide five dipeptide vinyl sultams, which were found to be inactive against papain at concentrations up to 50 microM. In contrast, vinyl sultams demonstrated weak activity against recombinant falcipain-2 and Plasmodium falciparum W2.

Predictors of chloroquine treatment failure in children and adults with falciparum malaria in Kampala, Uganda.

Chloroquine-resistant falciparum malaria is a serious problem in much of sub-Saharan Africa. However, it is desirable to continue to use chloroquine as first-line therapy for uncomplicated malaria where it remains clinically effective. To identify predictors of chloroquine treatment failure, a 14-day clinical study of chloroquine resistance in patients with uncomplicated falciparum malaria was performed in Kampala, Uganda.

Corticotropin-releasing hormone stimulates P450 17alpha-hydroxylase/17,20-lyase in human fetal adrenal cells via protein kinase C.

CRH directly stimulates dehydroepiandrosterone sulfate (DHEAS) production in human fetal adrenal cells. In the human fetal and adult pituitary, CRH acts via protein kinase A (PKA). We determined the CRH signal transduction pathway in fetal adrenal cells, i.

Proteases of protozoan parasites.

Proteolytic enzymes seem to play important roles in the life cycles of all medically important protozoan parasites, including the organisms that cause malaria, trypanosomiasis, leishmaniasis, amebiasis, toxoplasmosis, giardiasis, cryptosporidiosis and trichomoniasis. Proteases from all four major proteolytic classes are utilized by protozoans for diverse functions, including the invasion of host cells and tissues, the degradation of mediators of the immune response and the hydrolysis of host proteins for nutritional purposes. The biochemical and molecular characterization of protozoan proteases is providing tools to improve our understanding of the functions of these enzymes.

Identification of tyrosine phosphorylation sites in the CD28 cytoplasmic domain and their role in the costimulation of Jurkat T cells.

The cytoplasmic domain of CD28 contains four tyrosine residues. Because signal transduction by CD28 appears to involve its tyrosine phosphorylation, we determined sites of CD28 tyrosine phosphorylation using mutants of mouse CD28 that retained tyrosine at one position, with the remaining three positions mutated to phenylalanine. When expressed in Jurkat cells and stimulated by mAb, only the mutants with tyrosine at position 170 or 188 were tyrosine phosphorylated.

Prevention of reflex natriuresis after acute unilateral nephrectomy by melanocortin receptor antagonists.

gamma-Melanocyte-stimulating hormone (gamma-MSH), atrial natriuretic peptide (ANP), and oxytocin have been identified as candidate hormonal mediators of the reflex natriuresis that follows acute unilateral nephrectomy (AUN). Pharmacological characterization of the third melanocortin receptor (MC3-R) indicates that it uniquely responds to physiological concentrations of gamma-MSH. We tested the roles of gamma-MSH, ANP, and oxytocin in the postnephrectomy natriuresis by carrying out AUN during continuous intrarenal infusion of specific antagonists for their cognate receptors.

Pharmacodynamics of acute tolerance to multiple nicotinic effects in humans.

Tolerance is an important determinant of addiction as well as therapeutic and/or toxic effects of drugs. The development of acute tolerance to various effects of nicotine was studied in nine healthy smokers who were abstaining from tobacco. Nicotine was infused rapidly to reach a concentration of about 25 ng/ml, followed by a computer-controlled infusion to maintain that concentration.

Venous bleeding during transsphenoidal surgery: its association with pre- and intraoperative factors and with cavernous sinus and central venous pressures.

Venous bleeding during transsphenoidal surgery for resection of pituitary tumors is a common problem that interferes with the performance of the surgical procedure. In this study, data were collected prospectively from 50 patients to determine whether there were pre- or intraoperative factors (e.g.

Hemoglobin catabolism and iron utilization by malaria parasites.

Erythrocytic malaria parasites transport large quantities of erythrocyte cytoplasm to an acidic food vacuole, where hemoglobin is degraded. Globin is hydrolysed to free amino acids, which are subsequently incorporated into parasite proteins. Potentially toxic heme moieties are polymerized to hemozoin and also probably provide necessary parasite iron.

Rescue therapy with mycophenolate mofetil. Mycophenolate Mofetil Renal Refractory Rejection Study Group.

In three international phase III trials, MMF has been demonstrated to reduce the frequency and severity of acute renal allograft rejection episodes. As a treatment for acute refractory renal allograft rejection, MMF is also now showing strong promise in phase I and phase II trials. The mechanism of MMF to selectively inhibit purine synthesis in T- and B-lymphocytes results in a number of pathways in which it can interfere with deleterious immune responses in solid-organ transplant patients: inhibiting T- and B-cell activation and proliferation, inhibiting the glycosylation of adhesion molecules, and inhibiting the production of antibodies and possibly cytokines.

Plantar puncture wounds: a survey to determine the incidence of infection.

Objective: To determine the incidence of plantar puncture wound infections.

Methods: Ambulatory emergency patients were surveyed with regard to a previous history of plantar puncture wounds and any subsequent infections.

Results: 200 questionnaires were analysed.

Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors.

We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number of vinyl sulfones strongly inhibited falcipain, a Plasmodium falciparum cysteine proteinase that is a critical hemoglobinase. In studies of cultured parasites, nanomolar concentrations of three vinyl sulfones inhibited parasite hemoglobin degradation, metabolic activity, and development.

Greater ozone-induced inflammatory responses in subjects with asthma.

In order to test the hypothesis that ozone (O3)-induced changes in lung function and respiratory tract injury/inflammation are greater in subjects with asthma than in normal subjects, we exposed 18 asthmatic subjects, on separate days, to O3 (0.2 ppm) and filtered air for 4 h during exercise. Symptom questionnaires were administered before and after exposure, and pulmonary function tests (FEV1, FVC, and specific airway resistance [SRaw]) were performed before, during, and immediately after each exposure.

Phosphodiesterase inhibitors correct resistance to natriuretic peptides in rats with Heymann Nephritis.

Experimental nephrotic syndrome is characterized by abnormal sodium metabolism, reflected in a blunted natriuretic response both to volume expansion and to infused atrial natriuretic peptide (ANP). The studies presented here examined the relationships among plasma ANP concentration and urinary sodium (VNaV) and cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruil and inner medullary collecting duct (IMCD) cells to ANP and urodilatin (renal natriuretic peptide; RNP) in vitro in rats with Heymann nephritis, an immunologically mediated model of nephrotic syndrome. Nine to 14 days after Ip injection of anti-Fx1A antiserum, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline (2% body weight, given over 5 min).

Pulmonary complications of HIV infection.

Pulmonary disease is a major source of morbidity and mortality in HIV-infected persons. Pneumocystis carinii pneumonia has decreased substantially during the last eight years, but in the United States it remains the most common disorder that announces the onset of AIDS. In contrast, tuberculosis is by far the most important AIDS-associated indicator disease in developing countries.

Expression of the integrin subunit alpha 9 in the murine embryo.

The alpha 9 integrin subunit is expressed in adult skeletal muscle, visceral smooth muscle, hepatocytes, squamous epithelium, and airway epithelium. The in vivo function of this protein is unknown. Thus far, only a single alpha 9-containing integrin has been identified (alpha 9 beta 1) and only a single ligand (tenascin) has been found for this integrin.

The consequences of a positive prenatal HIV antibody test for women.

As more women of childbearing age are affected by the human immunodeficiency virus (HIV), many providers have demanded routine perinatal HIV screening, arguing that the medical benefits of testing outweigh the socioeconomic, medical, and psychological risks of a positive HIV test for women. In this primarily urban poor population, we used a semistructured interview to evaluate differences in health care discrimination, economic losses, risk behaviors, relationships changes, and psychological status in 20 HIV-positive and 20 HIV-negative mothers matched for HIV risk, race, income, and delivery date. Many (35%) seropositive and no seronegative women cited health care discrimination due to HIV status.

Extraluminal, transluminal, and observational treatment for vertebral artery injuries.

Injury to the vertebral artery following penetrating trauma is rare and treatment is usually surgical ligation. Recent liberal use of angiography in the evaluation of penetrating neck trauma has identified increasing numbers of patients with this challenging injury. This report describes our recent experience in treating patients with vertebral artery injuries.

Intensive care for patients with AIDS: clinical and ethical issues.

Pneumocystis carinii pneumonia (PCP) remains a common and morbid infection among patients with the acquired immunodeficiency syndrome (AIDS). Most patients who die of PCP do so because of respiratory failure. The survival after intubation and mechanical ventilation for PCP and respiratory failure has gone through three eras: Era I (1981-85), when the survival rate to hospital discharge was about 10%; Era II (1986-88), when the hospital survival rate rose to about 40%; and Era III (1989-present), when the hospital survival rate fell again to about 25%.

Functional expression of falcipain, a Plasmodium falciparum cysteine proteinase, supports its role as a malarial hemoglobinase.

Erythrocytic malaria parasites degrade hemoglobin as a principal source of amino acids for parasite protein synthesis. We have previously shown that a Plasmodium falciparum trophozoite cysteine proteinase, now termed falcipain, is required for hemoglobin degradation, and we have hypothesized that this proteinase is responsible for initial cleavages of hemoglobin. To further evaluate the biological role of falcipain, we expressed the enzyme in bacterial and viral expression systems.

Fetal cerebral ventricular atrium: difference in size according to sex.

Purpose: To determine whether the diameter of the fetal lateral ventricular atrium is larger in male than in female fetuses.

Materials And Methods: The atrial diameter in 219 fetuses retrospectively identified from a consecutive group of healthy newborns was measured without knowledge of the subject's sex.

Results: Atrial size demonstrated a near-normal distribution, with mean size for all subjects 6.

HIV infection in homosexual and bisexual men 18 to 29 years of age: the San Francisco Young Men's Health Study.

Objectives: Recent studies suggest very high human immunodeficiency virus (HIV) infection rates in some populations of younger homosexual men, but these studies may represent only particularly high-risk populations. The current study obtained population-based data on the HIV epidemic in young homosexual/bisexual men.

Methods: A household survey of unmarried men 18 through 29 years of age involved a multistage probability sample of addresses in San Francisco.

Transforming growth factor-beta 1 lowers the CD14 content of monocytes.

Marked elevation of transforming growth factor-beta 1 (TGF-beta 1) has been demonstrated clinically following injury and in sepsis. While alterations in the monocyte binding site (CD14) for the lipopolysaccharide (LPS)-lipopolysaccharide binding protein (LBP) complex have been noted with exposure to LPS, immune complexes, gamma-interferon, and IL-4, it is not known whether TGF-beta 1 can alter CD14 expression. To study the effect of TGF-beta 1 on monocyte CD14 expression, human leukocytes were isolated from healthy donors with discontinuous gradient centrifugation and incubated at 37 degrees C for 2 and 24 hr with increasing doses of purified human platelet TGF-beta 1.