Service delivery for patients with HIV in a rural state: the Vermont model.

The incidence of human immunodeficiency virus (HIV) infection is increasing rapidly in rural areas of the United States. Barriers to health-care delivery for this patient population include the complexity of this rapidly changing field, inexperienced rural physicians, long travel distances to receive expert care, lack of psychosocial support systems, and concerns about confidentiality. Models of HIV care for rural areas have not been developed that remove these barriers. We present the philosophy, structure, implementation, and services of a model of care in Vermont that is designed to remove many of these barriers and bring HIV expertise into the rural areas of the state. Three HIV specialty clinics have been developed in regional hospitals throughout the state. The clinic team includes an HIV-trained nurse practitioner and social worker from the hospital, a client consultant from the regional AIDS service organization, and an infectious disease specialist who travels to each of the clinics monthly. Patient care will be centralized in these regionally located clinics. The dispersion of HIV care among numerous and inexperienced rural providers will be obviated. Confidentiality will be emphasized within the hospital environment. The model has the potential to provide a complete continuum of medical care and psychosocial case management, integrate patient care and regional provider education, and increase community awareness. Patients will be able to receive their care in their own community, avoiding long travel distances. This may encourage patients to seek care earlier in their illness. The model may be adaptable to other rural areas of the United States.

Building comprehensive HIV/AIDS care services.

This article presents the experiences of three innovative programs for HIV/AIDS-related health care funded by the Health Resources and Services Administration (HRSA) Special Projects of National Significance (SPNS) Program. The Comprehensive Healthcare projects were funded as part of a larger initiative for innovative HIV service delivery models, consisting of 27 grantees, the funding agency (HRSA), and an Evaluation and Dissemination Center. These projects--the University of Nevada School of Medicine's Early Nutrition Intervention in HIV and AIDS project, the University of Vermont and State Agricultural College's Rural HIV Service Delivery project, and Washington University School of Medicine's Helena Hatch Special Care Center for Women--have developed specialized medical care models within the context of a continuum of services in a medical clinic. This article serves to describe the initial experiences of these three service demonstration projects, and some of the lessons learned as a result of their implementation. All of these projects share the goal of providing integrated services, such as medical care, nutrition, case management, and social and mental health services to people living with HIV/AIDS. However, the projects target different populations, (e.g., those in rural areas versus those in a large inner city), and use contrasting service delivery models of comprehensive HIV care. These projects have undertaken diverse activities and have used numerous effective strategies to increase their ability to provide a continuum of care and services for people living with HIV/AIDS. Based on the valuable lessons that the Comprehensive Healthcare projects learned during the first 2 years of funding, a number of collective recommendations have been made. It is expected that these suggestions will prove extremely useful to other programs that consider offering comprehensive health-care services to people living with HIV/AIDS or other complex medical conditions.

Determining physicians' knowledge and attitudes when prescribing drugs to treat gastrointestinal disorders.

OBJECTIVE: Peptic ulcer disease (PUD) affects 10% to 15% of the US population. The causes of PUD are many, including high acid production, low bicarbonate secretion, and infection due to Helicobacter pylori. In 1992, the Vermont Medicaid Program noted a significant increase in prescription drug expenditures, particularly in the area of treatment of PUD. The purpose of this study was to review Medicaid prescription data and to use focus group methodology to gain an understanding of rural nonacademic and semiurban academic physicians' prescribing decisions regarding the treatment of PUD. METHODS: Pharmaceutical data from 1991 and 1992, provided by the Department of Social Welfare, Medicaid Division, was reviewed. Focus group discussions were held with primary-care providers from rural and semiurban regions with Vermont. RESULTS: Pharmaceutical review revealed that expenditures increased 21% for gastrointestinal drugs from 1991 to 1992. Drug utilization review of pharmaceutical prescriptions revealed that H2 antagonists were being prescribed for greater than the recommended 6 to 8 weeks in 60% of the cases. Focus group discussions showed that rural nonacademic and urban academic physicians had similar concerns and management plans in regard to their patients with peptic ulcer disease. However, differences existed in physician perceptions regarding pharmaceutical effectiveness of various agents for the treatment of PUD. CONCLUSIONS: Physician education outreach programs should be designed to standardize treatment methodology for PUD throughout the state. This standardization of treatment could have a significant impact on healthcare costs and the ease with which patients can eradicate this disease.

Alternative medicine in Vermont--a census of practitioners: prevalence, patterns of use, and national projections.

The number of alternative/holistic practitioners in Vermont was estimated by two methods: scanning advertisements (yellow pages, newspaper and magazine ads, brochures), and by word-of-mouth canvassing. We located 897 Vermonters who derive most of their annual income practicing at least 1 of 97 different types of alternative medicine and therapy. Most practitioners were female and most practiced more than one type of healing. Bodyworkers were the most prevalent practitioners, followed by chiropractors, acupuncturists, herbalists, and holistic psychotherapists. On a per-capita basis, there is 1 alternative practitioner per 652 Vermonters (or 153 practitioners per 100,000 population). This census nearly equals that of Vermont's M.D. population. Extrapolating this Vermont census to a nationwide estimate of alternative practitioners suggests there are over 403,000 full-time alternative/holistic healers practicing in the United States.

Cholesterol screening in the elderly: changing attitudes.

The purpose of this study was to assess an elderly population's (60-80 years old) attitudes toward health prevention and life-style change with a particular emphasis on cholesterol screening and management. A free cholesterol screen was offered to participants in exchange for completion of a 21-item questionnaire (including medical history, risk factors, attitudes on preventive health, eating patterns and demographic information). This study provides evidence for increasing awareness of elevated cholesterol levels as a risk factor for coronary heart disease. It also demonstrates that there is an attitude of willingness to modify dietary cholesterol and fat intake within this mobile elderly population.

Ca2+ release by inositol 1,4,5-trisphosphate is blocked by the K(+)-channel blockers apamin and tetrapentylammonium ion, and a monoclonal antibody to a 63 kDa membrane protein: reversal of blockade by K+ ionophores nigericin and valinomycin and purification of the 63 kDa antibody-binding protein.

Ins(1,4,5)P3-induced Ca2+ release from platelet membrane vesicles was blocked by apamin, a selective inhibitor of low-conductance Ca(2+)-activated K+ channels, and by tetrapentylammonium ion, and was weakly inhibited by tetraethylammonium ion. Other K(+)-channel blockers, i.e. charybdotoxin, 4-aminopyridine and glybenclamide were ineffective. A monoclonal antibody (mAb 213-21) obtained by immunizing mice with the InsP3-sensitive membrane fraction from platelets also blocked Ca2+ release by InsP3 from membrane vesicles obtained from platelets, cerebellum, aortic smooth muscle, HEL cells and sea-urchin eggs. ATP-dependent Ca2+ uptake and binding of [3H]InsP3 to platelet membranes was unaffected by either K(+)-channel blockers or mAb 213-21. Blockade of Ca2+ release by apamin, tetrapentylammonium and mAb 213-21 was not affected by the Na+/H+ carrier monensin or the protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), but could be completely reversed by the K+/H+ ionophore nigericin and partially reversed by the K+ carrier valinomycin. The antibody-binding protein (ABP) solubilized from platelets, cerebellum, and smooth muscle chromatographed identically on gel filtration, anion-exchange and heparin-TSK h.p.l.c. ABP was purified to apparent homogeneity from platelets and aortic smooth muscle as a 63 kDa protein by immunoaffinity chromatography on mAb 213-21-agarose. These results suggest that optimal Ca2+ release by InsP3 from platelet membrane vesicles may require the tandem function of a K+ channel. A counterflow of K+ ions could prevent the build-up of a membrane potential (inside negative) that would tend to oppose Ca2+ release. The 63 kDa protein may function to regulate K+ permeability that is coupled to the Ca2+ efflux via the InsP3 receptor.

Effects of modification of tyrosines 3 and 62 (63) on enzymatic and toxicological properties of phospholipases A2 from Naja nigricollis and Naja naja atra snake venoms.

Previously we selectively modified His (48), Arg, Lys, Asp, Glu and Trp residues in the basic phospholipase A2 from Naja nigricollis and the acidic phospholipase A2 from N. n. atra snake venoms. Evidence was obtained for the existence of separate but perhaps overlapping sites responsible, respectively, for their enzymatic and pharmacological properties. We have now modified one or two (Tyr 3, Tyr 62 [63], Tyr 3 + 62 [63]) out of the nine tyrosine residues in these enzymes using p-nitrobenzenesulfonyl fluoride. The derivatives were separated by HPLC, and modified residues determined by amino acid analysis. Enzymatic activity was tested on lecithin--Triton mixed micelles, egg yolk and heart and diaphragm homogenates. The N. nigricollis modified derivatives retained a greater percentage of their enzymatic activities than did the N. n. atra derivatives and also a greater percentage of their activity on natural substrates than on lecithin--Triton mixed micelles. The greatest loss in activity resulted when both tyrosines were modified and the least when tyrosine 3 was modified. Modification of tyrosine 62 of N. nigricollis caused a much greater loss of intraventricular lethal potency than of enzymatic activity, whereas modification of tyrosine 3 of N. n. atra increased lethal potency over six-fold while enzymatic activity decreased about 60%. Examples of dissociation between enzymatic and pharmacological potencies were also noted when hemolytic, anticoagulant and cardiotoxicity on isolated ventricular muscle were measured. The extents of phospholipid hydrolysis were relatively low in brain homogenates, synaptic plasma membranes and heart ventricular muscle. However, they were similar for the native enzymes and all of the tyrosine modified derivatives. These tyrosines do not appear to be part of the enzymatic active site, even though they are thought to be associated with substrate and calcium binding. These results strengthen our earlier conclusion that some pharmacological effects of phospholipase A2 are not due to enzymatic hydrolysis, and that there are separate but perhaps partly overlapping sites for enzymatic and pharmacological activities.

Cardiotoxicity of Naja nigricollis phospholipase A2 is not due to alterations in prostaglandin synthesis.

The basic phospholipase A2 from Naja nigricollis snake venom is cardiotoxic, causing decreased contractility and arrhythmias at concentrations which induce low levels of phospholipid hydrolysis. Cardiac tissue has a high content of arachidonic acid at the sn-2 position of the major membrane phospholipids, thus increased prostaglandin synthesis might contribute to the cardiotoxic effects of N. nigricollis phospholipase A2. Intracellular action potentials and cardiac contractility were monitored in the isolated right ventricular wall of the rat heart exposed for 1 hr to N. nigricollis phospholipase A2, with or without indomethacin, or to arachidonic acid. The tissues were homogenized, prostaglandins extracted and the 6-keto PGF1 alpha and PGE2 content of the hearts determined. The physiologic effects and prostaglandin content of hearts treated with N. nigricollis phospholipase A2 were not altered by indomethacin nor mimicked by concentrations of arachidonic acid comparable to that present in N. nigricollis phospholipase A2-treated tissue. These results support our previous suggestion that exogenously applied N. nigricollis phospholipase A2 causes cardiotoxic effects by a mechanism that is independent of phospholipid hydrolysis.

Effect of alkylation of tryptophan residues on the enzymatic and pharmacological properties of snake venom phospholipase A2.

Snake venom phospholipases A2 show a remarkable degree of amino acid sequence homology yet differ markedly in enzymatic and pharmacological activities. The basic phospholipase A2 from Naja nigricollis venom has much greater lethal potency, cardiotoxicity, hemolytic and anticoagulant activity than the acidic or neutral enzymes from Naja naja atra or Hemachatus haemachatus venoms, respectively, even though it has lower enzymatic activity than the latter two enzymes. Previous studies in which we selectively modified lysine and free carboxyl groups suggested that the pharmacological and enzymatic active sites are not identical. Tryptophan residues have been suggested as being involved in substrate binding although some phospholipases have no tryptophan. We investigated the effect of alkylating the tryptophans in N. nigricollis, N. n. atra, and H. haemachatus phospholipases A2 with 2-hydroxy-5-nitrobenzyl bromide. Chemical modification caused decreases in enzymatic activity, although the extent of inactivation varied with the enzyme and with the substrate (lecithin micelles, egg yolk, heart homogenates). The specificity of the enzymes for individual phospholipid substrates was not affected. Alkylation of the tryptophans also caused decreases in lethal, hemolytic, anticoagulant, and cardiotoxic potencies, which were similar to the extents of decrease in enzymatic activity. Our results suggest that tryptophans are not specifically associated with either the enzymatic or the pharmacological active site nor are essential for either activity.

Effect of carboxylate group modification on enzymatic and cardiotoxic properties of snake venom phospholipases A2.

By treating Naja nigricollis and Naja naja atra phospholipase A2 with carbodiimide and semicarbazide, we obtained derivatives having varied numbers of modified carboxylate groups. When tested on artificial and natural substrates, derivatives of both enzymes with a modified carboxylate group at the active site (Asp-49) retained little enzymatic activity (1/41 to 10%). However, the derivatives of N. nigricollis also lost most of their lethal potency (5% of native), while those of N. n. atra retained considerable lethality (29%). Carboxyl modification with protection of Asp-49 in N. n. atra enzyme resulted in a derivative with lethal potency equal to or greater than the native enzyme and enzymatic activity which was low on all substrates (12-17% of native). Similar protection of Asp-49 at the active site in N. nigricollis enzyme produced a derivative with decreased enzymatic activity on artificial substrate (22% of native) and decreased lethality (17-33% of native), but with full enzymatic activity on natural substrates. When tested on electrical and mechanical properties of the isolated perfused heart and the isolated ventricle muscle wall, the derivatives of both enzymes retained considerably more of the cardiotoxic activity than would have been expected based on their residual enzymatic activity. The one exception occurred with the least modified N. nigricollis derivative which had an unaltered Asp-49, this enzyme retained both cardiotoxic activity and full enzymatic activity on natural substrates. The extent of phospholipid hydrolysis following treatment was measured in the isolated heart preparation and in hearts removed from mice following i.v. injection of the phospholipases. Very low levels of phospholipid hydrolysis were observed and no correlation could be made between the extent of hydrolysis and the pharmacological potencies of these enzymes. Modification of the enzymatic active site, whether of Asp-49 in this study of His-48 in prior studies, leads to a large decrease in both enzymatic activity and lethal potency. Asp and Glu residues outside of the enzymatic site contribute significantly to the lethal potency of the N. nigricollis enzyme and to the enzymatic activity of the N. n. atra enzyme. Based on these and previous data we conclude that changes in isoelectric points are not responsible for altered lethal potencies following chemical modification and that some pharmacological effects of snake venom phospholipases A2 are due to a non-enzymatic action, suggesting two distinct but perhaps overlapping active sites.

Dissociation of pharmacological and enzymatic activities of snake venom phospholipases A2 by modification of carboxylate groups.

The carboxylate groups in an acidic and in a basic phospholipase A2 (PLA2) enzyme, purified, respectively, from Naja naja atra and Naja nigricollis snake venoms, were modified with carbodiimide and semicarbazide. The derivatives modified at pH 3.5 and pH 5.5 had less than 1% (N. nigricollis) or 2% (N. n. atra) residual enzymatic activity, whereas 12-16% enzymatic activity remained following modification at pH 5.5 in the presence of Ca2+. In marked contrast, these derivatives retained variable, but significantly greater, levels of lethal potency, hemolytic and anticoagulant activities, and abilities to block indirectly and directly induced contractions of the diaphragm. By this modification of aspartic and glutamic acid residues we have, for the first time, obtained derivatives of PLA2 which selectively retain greater pharmacological activity relative to enzymatic activity. Previously, we had found that modification of lysine and arginine residues produced derivatives which retain enzymatic activity but show a loss of pharmacological properties. These findings suggest that some pharmacological effects of snake venom PLA2 enzymes are due to a non-enzymatic action, suggesting two distinct but perhaps overlapping active sites.

Effect of methylation of histidine-48 on some enzymatic and pharmacological activities of snake venom phospholipases A2.

The effects on some pharmacological and enzymatic properties were determined following methylation of histidine at the enzymatic active site of the basic relatively toxic Naja nigricollis and the acidic relatively non-toxic Naja naja atra phospholipases A2. Following methylation a very low residual enzymatic activity (0.4-1% of control) was accompanied by a parallel loss in intraventricular lethality, anticoagulant potency, direct hemolytic action and ability to block directly and indirectly evoked contractions of the mouse phrenic nerve-diaphragm preparation. Since methylation does not impair the enzyme's ability to bind monomeric or micellar substrates or Ca2+, the results suggest that the pharmacologically active region of the molecule is different from the micellular substrate binding site but strongly influenced by the invariant histidine-48 located at the enzymatic active site.