Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants.

Initial biologic events that underlie sexual transmission of HIV-1 are poorly understood. To model these events, we exposed human immature Langerhans cells (LCs) within epithelial tissue explants to two primary and two laboratory-adapted HIV-1 isolates. We detected HIV-1(Ba-L) infection in single LCs that spontaneously emigrated from explants by flow cytometry (median of infected LCs = 0.52%, range = 0.08-4.77%). HIV-1-infected LCs downregulated surface CD4 and CD83, whereas MHC class II, CD80, and CD86 were unchanged. For all HIV-1 strains tested, emigrated LCs were critical in establishing high levels of infection (0.1-1 microg HIV-1 p24 per milliliter) in cocultured autologous or allogeneic T cells. HIV-1(Ba-L) (an R5 HIV-1 strain) more efficiently infected LC-T cell cocultures when compared with HIV-1(IIIB) (an X4 HIV-1 strain). Interestingly, pretreatment of explants with either aminooxypentane-RANTES (regulated upon activation, normal T cell expressed and secreted) or cellulose acetate phthalate (potential microbicides) blocked HIV-1 infection of LCs and subsequent T cell infection in a dose-dependent manner. In summary, we document HIV-1 infection in single LCs after exposure to virus within epithelial tissue, demonstrate that relatively low numbers of these cells are capable of inducing high levels of infection in cocultured T cells, and provide a useful explant model for testing of agents designed to block sexual transmission of HIV-1.

Comparative biochemistry and drug design for infectious disease.

In the past two decades, biochemistry and molecular biology have demonstrated the existence of potentially exploitable biochemical differences between etiologic agents of disease and their hosts. Known differences between organism and host with respect to metabolism and polymer structure point to the detailed characterization of key proteins as the focus for the development of potential inhibitors. In the last decade, the methodology of the isolation, characterization, and inactivation of proteins and enzymes has been advanced. The present scientific and technological base suggests that new efforts toward the development of selective chemotherapeutic agents for infections caused by bacteria, viruses, protozoa, and higher eukaryotes should exploit the known differences in proteins or other specific biopolymers serving crucial structural or metabolic roles in the economy of the parasite.

Manufacturing innovation and american industrial competitiveness.

An erosion of manufacturing capacities has contributed substantially to America's trade problems. The difficulty lies not in U.S. machines and technology, but in U.S. strategies for automation and the goals American firms seek to achieve through production innovation. Mass production and administrative hierarchies created the basis for American industrial preeminence in the years after World War II. There is substantial evidence that American firms have been unable to adopt or adapt to the production innovations emerging abroad. A sustained weakness in manufacturing capabilities could endanger the technology base of the country.

Two approaches that increase the activity of analogs of adenine nucleosides in animal cells.

Deamination of many analogs of adenine nucleosides results in the loss of their chemotherapeutic efficacy. Two approaches have been used in this study to overcome this problem. First, some adenine nucleotides, which are resistant to mammalian adenosine deaminase, are more toxic to animal cells than are the respective nucleosides. For toxic to animal cells than are the respective nucleosides. For example, 9-beta-D-arabinofuranosyladenine 5'-phosphate, a molecule that penetrates the cell without degradation, has a more sustained toxicity against mouse fibroblasts (L-cells) than does 9-beta-D-arabinofuranosyladenine (ara-A). Furthermore, L-cells treated with 2',3'-dideoxyadenosine 5'-phosphate are extensively killed after 48 hr, whereas 2',3'-dideoxyadenosine is almost nontoxic to L-cells. Specific inhibition of adenosine deaminase by nontoxic concentrations of erythro-9-(2-hydroxy-3-nonyl)adenine greatly potentiates the biological activity of both ara-A and 3'-deoxyadenosine (cordycepin). Simultaneous administration of cytostatic concentrations of ara-A and the inhibitor of adenosine deaminase to L-cells killed greater than 99.9 percent of cells in 36 hr. A similar concentration of ara-A plus the deaminase inhibitor also markedly extended the mean survival of mice bearing Ehrlich ascites carcinoma as compared to ara-A alone. A cytostatic concentration of cordycepin 1 x 10-4 M), administered in the presence of deaminase inhibitor, killed greater than 99.9 percent of cultured L-cells in only 8 hr. During the latter incubation, accumulation of uridine in acid-insoluble material reached a maximum after 30 min, and incorporation of thymidine into acid-insoluble material was almost totally arrested after 2 hr.

Synthesis and the lethality of bleomycin in bacteria.

The bleomycins are antitumor agents composed of various cationic amides of a common inactive bleomycinic acid. At 1 mug/ml at 37 degrees, the naturally occurring spermidine derivative of bleomycin (A5) was far more lethal to Escherichia coli than were several other bleomycins tested. An exponential loss of viability was produced for 2 hr in various strains of E. coli growing in a synthetic medium. In the stringent E. coli, strain 15 TAU (thymine-arginine-uracil) rel A+ (arginine), withholding thymine did not affect the rate of killing. However, uracil starvation completely blocked killing by the antibiotic. Arginine deprival partially inhibited bleomycin killing in the stringent cell but had little effect on the lethality of the antibiotic in a relaxed isogenic strain actively synthesizing RNA. Similar results were obtained with another isogenic pair, stringent CP78 and relaxed CP79. Thus, the lethality of the antitumor agent, bleomycin, which is reported to produce breaks in bacterial and animal cell DNA in vivo and in vitro appeared totally dependent on RNA synthesis in E. coli. Nevertheless, chloramphenicol, which blocks protein synthesis and relaxes RNA synthesis in the stringent strains, also significantly inhibited the lethal action of the antibiotic, reducing the exponential rate of killing.

No evidence of human herpesvirus 8 infection in patients with paraneoplastic pemphigus, pemphigus vulgaris, or pemphigus foliaceus.

Paraneoplastic pemphigus has been associated with both malignancies and multicentric Castleman's disease; the latter is a rare angiolymphoproliferative disorder that has also been linked with human herpesvirus 8 (HHV8) infection. Other diseases definitively associated with HHV8 include Kaposi's sarcoma and primary effusion lymphoma. In a search for additional HHV8-associated diseases, patients with paraneoplastic pemphigus, as well as patients with pemphigus vulgaris and pemphigus foliaceus, were studied. Using an immunofluorescence assay able to specifically detect antibodies directed against lytically induced HHV8 antigens, HHV8 antibodies were not detected in sera from 24 patients with paraneoplastic pemphigus (including 10 with concomitant Castleman's disease) nor from 19 patients with pemphigus vulgaris. Sera from patients with Kaposi's sarcoma and from healthy U.S. blood donors were positive (25 of 26) and negative (none of 20), respectively. In addition, HHV8 DNA was not found in frozen lesional skin of five patients with pemphigus vulgaris and five patients with pemphigus foliaceus by nested polymerase chain reaction (lower limit of detection = 10 copies viral DNA per microg total cellular DNA). Finally, tissue sections of lesional skin from 10 patients with pemphigus vulgaris were negative for HHV8 by in situ hybridization, using probes able to detect both latently and lytically expressed HHV8 genes in Kaposi's sarcoma tissue. In summary, no evidence of HHV8 infection was found in all types of pemphigus using a variety of methods. These findings do not support a general role for HHV8 in skin diseases associated with immunosuppression.

The utilization of nucleotides by animal cells.

We have extended our studies on the toxicity of several arabinosyl nucleotides to L cells. In contrast to a short-term toxic effect of 9-beta-D-arabinofuranosyladenine (araA), both 9-beta-D-arabinofuranosyladenine 5'-phosphate (araAMP) and 9-beta-D-arabinofuranosyladenine 3',5'-cyclic phosphate produced sustained killing of the fibroblasts. 9-beta-D-Arabinofuranosyladenine 2',5'-cyclic phosphate and 9-beta-D-arabinofuranosyladenine-N1-oxide-5'-phosphate were not toxic, whereas 9-beta-D-arabinofuranosylhypoxanthine 5'-phosphate and adenosine 3',5'-cyclic phosphate had relatively slight effects on cell growth. 2',3'-Dideoxyadenosine 5'-phosphate was lethal to L cells, whereas 2',3'-dideoxyadenosine inhibited growth only slightly. The survival time of mice bearing Ehrlich ascites carcinoma was prolonged beyond controls equally well by treatment with either araAMP or araA. To explore the mechanism of nucleotide toxicity, we studied the metabolism of exogenous [3H, 32P]-araAMP. The double-labeled compound entered the cells very slowly and accumulated in both acid-soluble and acid-insoluble materials. 32P and 3H were associated with the adenine nucleotide fractions in ratios similar to that of the exogenous compound. After dephosphorylation of the acid-soluble fraction, greater than 85% of the 3H was associated with araA. Following degradation of the adenine-containing triphosphates with apyrase, all of the 32P and 97% of the 3H were associated with araAMP. Only small quantities of each label were associated with RNA and DNA. Following enzymatic degradation of DNA to 5'-monophosphates, most of both 3H and 32P were associated with the dAMP fraction in a ratio that was similar to that of the exogenous araAMP. After dephosphorylation of the 5'-monophosphates, greater than 90% of the 3H was contained in arabinosyl nucleosides. DNA was also enzymatically degreded to 3'-monophosphates. 3H was found primarily in the 3'-adenine nucleotide fraction with a slight amount in the nucleoside, whereas 32P was distributed among all the 3'-mononucleotides. After dephosphorylation of the 3'-monophosphates, 93% of the 3H was associated with araA. These results indicate that a small amount of araAMP penetrated the cell as the intact nucleotide, was phosphyorlated to the triphosphate and was subsequently incorporated within DNA.

Parents, peers, and the acquisition of an STD. Developmental changes in girls.

PURPOSE: The purpose of this study was to examine the relationship between age and number of sexually transmitted diseases (STD) episodes in sexually active girls with their perceptions of the interpersonal implications of STD acquisition. METHODS: The sample consisted of 248 girls (mean age = 16.9 years); 74% had an STD history. Adolescents responded to statements using a five-point Likert scale regarding their interpersonal expectations, and rated the perceived prevalence of STD among their friends and among all adolescents. RESULTS: The results of logistic regression analyses indicated that older girls were less likely to tell their parents but did not perceive parental support differently than younger girls. Older girls were more likely to tell their partners and to be more embarrassed by the acquisition. Those with a greater number of STD episodes perceived the acquisition as a less negative event. Girls with a greater number of STD episodes perceived the prevalence of STD to be significantly greater among their friends and among all adolescents than those girls with fewer episodes. Overall, the perceived prevalence among friends (40%) was significantly lower than the perceived prevalence among teens in general (74%). CONCLUSIONS: Future research and practice in aiding adolescent girls to manage STD acquisition must incorporate developmental theory, and, when appropriate, methods to involve families while preserving privacy.

Developmental sophistication among adolescents of negotiation strategies for condom use.

Condoms are an important method of reducing the risk of sexually transmitted disease among sexually active adolescents. This study used a developmental approach to examine the negotiation of condom use. The Interpersonal Negotiation Strategy Interview was administered to adolescents using two vignettes that were focused on the negotiation of "safer sex" behaviors. The sample consisted of 196 girls and 92 boys recruited from their primary care clinic or Job Corps. The mean scores for each problem-solving step were at the subjective, unilateral stage, which indicates that problems are resolved through one-way methods. Current educational strategies and the lack of mutuality in adolescents' sexual relationships influence the level of negotiation skills. Interventions need to be at the appropriate developmental level but also need to encourage progress toward collaborative relationships.

PIP: 92 young men and 196 young women aged 12-22 years of mean age 16.3-18.1 were recruited either from an urban primary care clinic for adolescents or a Job Corps site to participate in a study exploring the negotiation of condom use. More than 75% of the participants were African-American. Following a developmental approach, the Interpersonal Negotiation Strategy Interview was administered using two vignettes focused upon the negotiation of safer sex behaviors. The mean scores for each problem-solving step were at the subjective, unilateral stage, indicating that problems are resolved through one-way methods. The authors conclude that current educational strategies and the lack of mutuality in adolescents' sexual relationships influence their ability to negotiate. Accordingly, interventions need to be at the appropriate developmental level, but should also encourage progress toward collaborative relationships.

Family involvement in the gynecologic care of adolescents.

The purpose of this paper is to address the issues of family involvement in gynecologic care for adolescent girls. This is accomplished by reviewing pertinent literature and its implication for health-care delivery. Specific aspects of adolescent development including changes in cognitive development and relationships are reviewed. In addition, the implications of communication between parent and adolescent, degree of parental monitoring, and the type of parenting style are discussed. Using this information as a background, recommendations for family involvement in gynecologic care are given. Methods for handling appointments are addressed; including the structure and content of the appointment and also the follow-up appointment, especially for high-risk families. Issues of confidentiality for both adolescent and parent are discussed. This information should aid clinicians in supporting those features of families that promote positive growth in adolescent girls.

PNPs as catalysts in child care policymaking.

Dramatic socioeconomic changes in American family life, along with welfare reform, school readiness initiatives, and research on the relationship between child development and child care, have generated new interest in child care policy. Pediatric nurse practitioners and other pediatric nurses have much to contribute to the formulation of national, state, and local child care policies, especially if they are knowledgeable of key policies and regulatory issues. This article outlines these concepts with an eye toward promoting how pediatric nurses might reclaim their role as catalysts for promoting high-quality child care.

Advancing health policy in nursing education through service learning.

Knowledge of health policy is an increasingly important aspect of nursing practice and education, especially as nurses strive to improve the rapidly changing health care delivery system. At the same time, many educators, researchers, foundations, and government officials are touting the benefits of service learning. In particular, service learning offers ways to enhance partnerships between academia and community agencies and to extend learning beyond the traditional classroom. We present a model for educating nurses as advanced practice nurses in health policy that links service learning with a framework for the political development of nurses. Under the rubric of service learning, the curriculum is based on the overlap among health policy, the role of the nurse as consultant, and community-based care. After discussing the importance of health policy for graduate nursing education and reviewing the essentials of service learning, we describe a three-semester graduate sequence in health policy service learning. The focus is on the clinical and classroom components of both individual and group practica and their relationship to stages of nursing's political development. The article concludes with evaluation considerations and the implications of our work for nursing theory, research, practice, and education.

Promoting the nurse practitioner role in managed care.

Managed care poses opportunities for nurse practitioners, providing they successfully negotiate new health care systems. This requires being familiar with Medicaid waivers and state policies regarding health insurance. In addition, knowledge of credentialing and compensation mechanisms under managed care enhances nurse practitioners' ability to forge provider roles. Because of the overlap between priorities of nurse practitioner practice and managed care, nurse practitioners have the potential to strengthen their roles as primary and specialty care providers in traditional and nontraditional settings.

Issues related to the sexual decision-making of inner-city adolescent girls.

To be effective in reducing the risks of sexual activity in adolescent girls, the context of adolescent sexuality needs to be understood. Two focus groups of high-risk inner-city African-American and Caucasian adolescent girls (15 to 16 years of age) were organized to explore issues related to sexual decision-making. The transcripts of the groups were reviewed for recurrent themes the girls discussed in regard to sexual decision-making, and their views of relationships and images of males. Verbatim examples are presented to exemplify each category. These adolescents experienced multiple pressures to engage in intercourse at young ages, but utilizing the presence of others was described as a helpful means to avoid engaging in sexual activities. The lack of mutual trusting relationships also was an important aspect for the these girls. Interventions which reduce the pressures to engage in sexual behaviours, develop methods for coping with these pressures, and facilitate the ability to establish mutual relationships will aid the healthy psychosexual development of adolescent girls.

Strategies for coping with sexually transmitted diseases by adolescent females.

Coping strategies of adolescent girls in response to the acquisition of a sexually transmitted disease (STD) were evaluated. Perceptions of control over acquisition of an STD and emotional impact were assessed. The sample consisted of 177 adolescent girls recruited from their source of primary care (mean age = 16.8). There were no differences in the use of coping strategies by age group or STD history. Subjects used a wide variety of coping strategies; those who viewed the future acquisition of an STD more negatively used more strategies. Wishful thinking was used by most of the subjects, but was not felt to be helpful; despite this, adolescents with a previous STD were no less likely to use wishful thinking. It was concluded that adolescent health care providers must understand girls' responses to STD and help them develop effective coping skills to reduce the incidence of STD.

Managed care organizations' arrangements with nurse practitioners.

Thirty-four of 67 MCOs in New York and Connecticut responded to requests for information on the roles, participation, and listing of nurse practitioners as primary care providers or in other capacities. MCO executives report a high degree of satisfaction with NPs who serve as their primary care providers, especially in women's health and geriatrics, as they spend more time teaching and explaining procedures than physicians. Ongoing lack of up-to-date information and/or confusion about the scope of NP practice exists among both health care professionals and the public. Perceived differences in the scope of care provided by NPs was related to state regulations, physician practice patterns, and availability of primary care physicians. Eighty-five percent of MCO executives thought their organizations should encourage the use of NPs.

The OR suite as a unique trauma resuscitation bay.

Trauma is the fourth leading cause of death in the United States, and trauma injuries affect more than 50 million Americans annually. Inadequate care of trauma patients can cause unnecessary patient deaths. To decrease death and disability caused by trauma, one Denver hospital developed a trauma OR based on the "Golden Hour" principle (ie, the sooner a patient receives treatment, the more likely the patient will survive). Since 1977, this hospital has performed 1,838 trauma resuscitations in the trauma OR suite. This article discusses the importance of triage and recants the history of trauma patient transportation. The authors detail the trauma procedures at their hospital, including the specific roles of trauma team members and the necessary equipment, and provide demographic information on the trauma resuscitations performed at the hospital since 1988. The article also discusses the extensive and continuous orientation necessary for trauma team members and explains the quality improvement strategies implemented by this hospital.

Focus groups reveal perils and promises of managed care for nurse practitioners.

Decades of practice and research suggest that nurse practitioners (NPs) provide cost-effective and high-quality care. Managed care's emphasis on prevention and cost savings led some policy makers to view NPs as a way to meet the need for primary care providers. However, access to and utilization of NPs has increasingly been controlled by managed care organizations (MCOs) through their selection of providers for primary care panels. This study employed qualitative methodology to examine NPs' experiences with MCOs. Three focus groups, comprising 27 NPs in New York and Connecticut, revealed NPs' mixed reactions to managed care and a range of sentiments regarding NPs' efforts to be listed as primary care providers. The results reflected NPs' concerns about their perceived "invisibility," as well as their sense of "invincibility" in the ways in which NPs are responding to the barriers posed by MCOs. They identified barriers to, as well as ways to facilitate, being listed by MCOs, and described the importance of NPs working individually and collectively in negotiating with MCOs.