Biomedical subjects

M A Jarvis

Publications and source records attributed to M A Jarvis.

15 recordsLinked to original sources

PubMed2000

A protein-based therapeutic for human cytomegalovirus infection.

Current antiviral strategies target viral gene products. Although initially successful, their severe toxicity and susceptibility to circumvention by the generation of drug-resistant variants limit their usefulness. By contrast, the central role of the host cell serine endoprotease furin in the proteolytic activation of numerous pathogens points to the endoprotease as a strategic target for therapeutics. Herein, we show that the production of infectious human cytomegalovirus is dramatically reduced by exogenous addition of a bioengineered serpin, alpha(1)-PDX. This protein is a potent and selective furin inhibitor (K(i) = 0.6 nM) and is 10-fold more effective than currently used antiherpetic agents in cell-culture models. The requirement of furin for the processing of envelope glycoproteins from many pathogenic viruses and for the activation of several bacterial toxins suggests that selective inhibitors of furin have potential as broad-based anti-pathogens.

Blotting, Western↗

PubMed2000

The kinetics of specific immune responses in rhesus monkeys inoculated with live recombinant BCG expressing SIV Gag, Pol, Env, and Nef proteins.

Development of an effective preventive or therapeutic vaccine against HIV-1 is an important goal in the fight against AIDS. Effective virus clearance and inhibition of spread to target organs depends principally on the cellular immune response. Therefore, a vaccine against HIV-1 should elicit virus-specific cytotoxic lymphocyte (CTL) responses to eliminate the virus during the cell-associated stages of its life cycle. The vaccine should also be capable of inducing immunity at the mucosal surfaces, the primary route of transmission. Recombinant Bacille Calmette-Guérin (BCG) expressing viral proteins offers an excellent candidate vaccine in view of its safety and ability to persist intracellularly, resulting in the induction of long-lasting immunity and stimulation of the cellular immune response. BCG can be administered orally to induce HIV-specific immunity at the mucosal surfaces. The immunogenicity of four recombinant BCG constructs expressing simian immunodeficiency virus (SIV) Gag, Pol, Env, and Nef proteins was tested in rhesus macaques. A single simultaneous inoculation of all four recombinants elicited SIV-specific IgA and IgG antibody, and cellular immune responses, including CTL and helper T cell proliferation. Our results demonstrate that BCG recombinant vectors can induce concomitant humoral and cellular immune responses to the major proteins of SIV.

Animals↗

PubMed2000

Reliability of Allen's test in selection of patients for radial artery harvest.

BACKGROUND: Allen's test is widely used to assess the ulnar collateral blood supply of the hand before radial artery harvest for coronary bypass surgery. This study was performed to determine the optimum cut-off point for a positive Allen's test and the clinical reliability of Allen's test in this role. METHODS: Patients undergoing coronary artery bypass surgery were examined by independent observers using both Allen's test and a Doppler ultrasound test of the ulnar collateral circulation. RESULTS: We examined 93 hands in 47 patients; mean age was 63.6 years. Receiver operating characteristic analysis found that at a conventional cut-off of 6 seconds on Allen's test had a sensitivity of 54.5%, specificity of 91.7%, and diagnostic accuracy of 78.5%. At a cut-off of 5 seconds diagnostic accuracy was maximal (79.6%), with sensitivity of 75.8% and specificity of 81.7%; 100% sensitivity occurred at a cut-off of 3 seconds, with specificity of 27% and diagnostic accuracy of 52%. CONCLUSIONS: At no cut-off point does Allen's test perform satisfactorily as a discriminatory test. It should be replaced by more objective tests, such as Doppler ultrasound.

Aged↗

PubMed1999

Role of the primary care physician in problems of substance abuse.

Patients with substance abuse problems are common in general medical practice and include people of all ages and socioeconomic groups. Initial diagnosis and treatment of addiction problems are often done by the primary care practitioner before referral to a specialist. This article provides information to help in recognition of addiction, guidelines for treatment of intoxication and withdrawal of various drugs of abuse (such as opioids, sedative-hypnotics, stimulants, hallucinogens, and volatile inhalants), and techniques for brief intervention as well as long-term care of substance-abusing patients. The physician can be a powerful influence for getting the patient to accept treatment, especially when the physician is empathic without being judgmental. Addiction is a chronic disorder with remissions and relapses like any other chronic disease, so exacerbations should not be seen as failures but as time to intensify treatment. Patients with substance abuse problems can be frustrating to treat, but it can also be a rewarding experience when a physician helps a substance-abusing patient return to normal and productive functioning in society.

Acute Disease↗

PubMed1999

Human cytomegalovirus infection of caco-2 cells occurs at the basolateral membrane and is differentiation state dependent.

Epithelial cells are known to be a major target for human cytomegalovirus (HCMV) infection; however, the analysis of virus-cell interactions has been difficult to approach due to the lack of in vitro models. In this study, we established a polarized epithelial cell model using a colon epithelial cell-derived cell line (Caco-2) that is susceptible to HCMV infection at early stages of cellular differentiation. Infection of polarized cells was restricted to the basolateral surface whereas virus was released apically, which was consistent with the apical and not basolateral surface localization of two essential viral glycoproteins, gB and gH. HCMV infection resulted in the development of a cytopathology characteristic of HCMV infection of colon epithelium in vivo, and infection did not spread from cell to cell. The inability of HCMV to infect Caco-2 cells at late stages of differentiation was due to a restriction at the level of viral entry and was consistent with the sequestration of a cellular receptor for HCMV. These observations provide the first evidence that restriction of HCMV replication in epithelial cells is due to a receptor-mediated phenomenon.

Caco-2 Cells↗

PubMed1999

Alterations in methadone metabolism during late pregnancy.

Traditionally, methadone maintenance therapy has been a once-daily dosing schedule. The current study evaluates the effectiveness of this regimen during pregnancy. A total of 23 pregnant and 16 non-pregnant opioid-dependent patients were studied in two phases to evaluate pregnancy-dependent changes in methadone pharmacokinetics. In the first phase, pregnant patients had a statistically significant higher elimination rate constant (k) and lower half-life compared to non-pregnant controls. In the second phase, the apparent clearance (Cl/F) was significantly greater during pregnancy, with preliminary data suggesting that this observation results from a decrease in the fraction of dose absorbed (F). The implications of these findings on dosing regimens during pregnancy is discussed.

Adult↗

PubMed1996

Induction of human factor VIII inhibitors in rats by immunization with human recombinant factor VIII: a small animal model for humans with high responder inhibitor phenotype.

Hemophilia A is a clotting disorder that is due to reduced or absent coagulation factor VIII (FVIII) activity. In approximately 25% of people with severe hemophilia A, standard treatment with intravenous plasma-derived or recombinant FVIII (rFVIII) induces anti-FVIII antibodies that inhibit FVIII activity (inhibitors). We describe the development of a rat model to study the formation of inhibitors. Immunization of rats with human rFVIII in adjuvant induced an anti-human rFVIII antibody response characteristic of an anti-FVIII inhibitor response in hemophilia A patients. The rats exhibited a rapid, polyclonal secondary antibody response to human rFVIII. These antibodies were reactive against epitopes located in the heavy and light chains. All the rFVIII-immunized rats developed antibodies against the FVIII C2 domain, a region of major reactivity in hemophilia A patients with inhibitors. Furthermore, competition ELISAs demonstrated that rat and human anti-FVIII antibodies recognized identical or overlapping epitopes of the FVIII molecule. The rat anti-FVIII antibodies also functioned as human FVIII inhibitors with titers ranging from 120 to 2048 Bethesda Units (B.U.). We propose that this rat model may be useful to investigate immune responses to FVIII and may lead to better therapies for FVIII inhibitors.

Animals↗

PubMed1995