Heparin-steroid conjugates: new angiogenesis inhibitors with antitumor activity in mice.

Inhibitors of angiogenesis hold potential in the treatment of cancer and other diseases where the disease is caused or maintained by the inappropriate growth of blood vessels. In the present study, a novel inhibitor of angiogenesis was synthesized by covalently linking a nonanticoagulating derivative of heparin, heparin adipic hydrazide (HAH), by an acid-labile bond to the antiangiogenic steroid, cortisol. The rationale was that the heparin derivative, which binds to sulfated polyanion receptors on endothelial cells, should concentrate the steroid on the surface of vascular endothelial cells. Endocytosis of the conjugate and decomposition of the acid-labile linkage inside lysosomes and other acidic intracellular compartments should then lead to release of the cortisol and expression of its antiproliferative activity. Analysis of the stability of HAH-cortisol showed that it was stable at pH 7.4 and broke down rapidly (t1/2 15 min) at pH 4.8 at 37 degrees C. Treatment of murine pulmonary capillary endothelial cells with HAH-cortisol at 10(-5) M (with respect to cortisol) suppressed their DNA synthesis by 50% and inhibited their migration into wounded areas of confluent monolayers. HAH-cortisol at 10(-4) M (with respect to cortisol) did not suppress the DNA synthesis of Lewis lung carcinoma cells. Daily i.p. injections of HAH-cortisol into mice bearing s.c. sponge implants retarded vascularization of the sponge, and injections directly into the sponge abolished vascularization for as long as the injections were continued. Daily i.v. injections of HAH-cortisol at doses causing no apparent toxicity retarded the growth of solid s.c. Lewis lung carcinomas in mice by up to 65%. In all of these assays, equivalent treatments with a mixture of the HAH plus cortisol was significantly less effective. The antiproliferative effect of HAH-cortisol on endothelial cells appeared independent of the glucocorticoid activity of the steroid since HAH conjugated to 5 beta-pregnane-3 alpha,17 alpha,21-triol-20-one, a steroid lacking glucocorticoid or mineralocorticoid activity, was even more effective at inhibiting DNA synthesis by murine pulmonary capillary endothelial cells than was HAH-cortisol. In conclusion, HAH-cortisol represents the prototype of a new class of angiogenesis inhibitors for the treatment of cancer and other angiogenic diseases.

Characteristics of women who refuse an offer of prenatal diagnosis: data from the California maternal serum alpha fetoprotein blood test experience.

This paper presents data from the California maternal serum alpha fetoprotein (MSAFP) program in order to explore the effect and interaction of various factors, especially ethnicity, abortion history and attitudes, religion, and religiosity on MSAFP test decision. The intent is to describe which women are more likely to reject MSAFP screening and also to understand the reasons for refusal and the meanings associated with it. We obtained data on sociodemographics and reproductive history from 595 obstetrical patient charts; we conducted semistructured interviews with an additional 158 pregnant women who were European-American, English-speaking Latina, or Spanish-speaking Latina. All of the women had been offered screening within the context of California's MSAFP Program. We found that women who had never terminated a pregnancy, Spanish-speaking Latinas, and women who scored high on a religiosity scale were significantly more likely to refuse testing. However, we found that all of those factors were strongly mediated by the effects of ethnicity and acculturation, producing different patterns of association in different groups of women.

Categorizing genetic tests to identify their ethical, legal, and social implications.

Practice standards in medical genetics provide an implicit guide to the ethical, legal, and social implications (ELSI) of genetic tests. The common use of nondirective counseling reflects the principle that many testing decisions should be determined by personal values. Yet geneticists make test recommendations in some circumstances, e.g., RET mutation testing for MEN2 and newborn screening for phenylketonuria (PKU). Conversely, many geneticists recommend against testing for Apolipoprotein E (ApoE) alleles to predict Alzheimer disease (AD) risk. Taken together, these examples suggest that genetic tests can be categorized by a joint consideration of clinical validity and availability of effective treatment for persons who test positive. For genetic tests with high clinical validity/no treatment (e.g., presymptomatic testing for Huntington disease), the predominant concern is adequate nondirective counseling to ensure an informed, autonomous decision. By contrast, the predominant concern for tests with high clinical validity/effective treatment (e.g., PKU) is assuring access to care for eligible persons. For tests with limited clinical validity/no treatment (e.g., ApoE), recommending against test use can be justified on the principle of avoiding harm. For a fourth category, tests with limited clinical validity/effective treatment (e.g., HFE mutation testing for hereditary hemochromatosis), net benefit is the issue: the balance between potential benefits of treatment and potential harms of genetic labeling must be weighed. Where uncertainty exists concerning both clinical validity and effectiveness of treatment, as in the case of BRCA 1/2 mutation testing, the value of testing may vary according to different testing contexts. This approach to test categorization allows a rapid determination of the predominant ELSI concerns for different kinds of genetic tests and identifies the data most urgently needed for test evaluation.

Women's interest in genetic testing for breast cancer susceptibility may be based on unrealistic expectations.

We report on results of an interview study assessing women's attitudes toward and hypothetical interest in genetic susceptibility testing for breast cancer. Data are from 246 interviews with women of varying ethnicity (African American, European American, Native American, and Ashkenazi Jewish), family history of breast cancer (negative, positive, and borderline), and educational level. Semistructured interviews included questions on general health beliefs; attitudes, experiences, and concerns about breast cancer; and hypothetical interest in genetic testing. Influence of specific test characteristics was assessed with 14 Likert scales varying negative and positive predictive value, timing of disease, possible medical interventions following a positive result. Results reported include both statistical and qualitative analysis. We found that women had a high level of interest in testing which, in general, did not vary by ethnicity, level of education, or family history. Interest in testing appeared to be shaped by an exaggerated sense of vulnerability to breast cancer, limited knowledge about genetic susceptibility testing, and generally positive views about information provided through medical screening. However, study participants were most interested in a test that didn't exist (high positive predictive value followed by effective, noninvasive, preventive therapy) and least interested in the test that does exist (less than certain positive predictive value, low negative predictive value, and limited, invasive, and objectionable therapeutic options). Our data suggest that without a careful counseling process, women could easily be motivated toward interest in a test which will not lead to the disease prevention they are seeking.

Screening for cystic fibrosis carrier state.

Carrier screening for cystic fibrosis as part of reproductive health care, including prenatal care, is not the standard of practice at this time. However, a recent National Institutes of Health Consensus Development Conference recommended that cystic fibrosis carrier screening should be offered to adults with a family history of cystic fibrosis, partners of individuals with cystic fibrosis, couples planning a pregnancy, and couples seeking prenatal testing. A workshop convened to discuss the implementation of these recommendations concluded that several issues must be resolved before these recommendations can be implemented. This commentary reviews the discussions that occurred and the conclusions that were reached at this workshop. Some of the subjects considered by the workshop participants were: the goals and outcomes of carrier screening; the continuum from making a test available to offering that test; to whom, when, and how cystic fibrosis testing should be offered; laboratory practice and quality assurance; provider and patient education; and insurance issues. The workshop participants concluded that those populations to whom carrier screening should be offered might include individuals and couples in high-risk groups who seek preconception counseling, infertility care, or prenatal care. High-risk groups include individuals of white northern European or of Ashkenazi-Jewish descent, those whose partners have cystic fibrosis, and those with a family history of cystic fibrosis. Before screening can be offered systematically to these individuals or couples, practice guidelines, educational materials for providers and patients, informed-consent protocols, and laboratory standards for testing must be developed.

Why women say yes to prenatal diagnosis.

Despite considerable concern of bioethicists, disabilities rights activists, feminists and others about the spread of prenatal diagnostic technologies, their routine acceptance in many parts of the world continues at a rapid pace. Yet, there is wide variation by country and region in rates of acceptance of prenatal diagnosis. We draw on John McKinlay's model of how a medical innovation becomes routinized to explore the circumstances that led to the widespread use of one prenatal diagnostic screen-the maternal serum alpha fetoprotein (MSAFP) test for the detection of neural tube defects and other developmental disabilities. As predicted by McKinlay's model, analysis of published data suggests that strong institutional or provider support is the best predictor of women's level of MSAFP test acceptance. Data collected at a health maintenance organization in California illuminate the processes through which medico-legal and institutional forces affect the use of MSAFP screening. By examining the language women use to talk about MSAFP screening, we show how providers also shape women's understandings of the meaning and purpose of MSAFP screening. These data ultimately shed light on how the very ethical issues which concern critics of prenatal diagnosis become obscured in the processes by which this screening test becomes accepted as routine.

'Because of the risks': how US pregnant women account for refusing prenatal screening.

Most research on prenatal fetal testing in general, and maternal alpha-fetoprotein (AFP) screening in particular, has focused on women who accept and even actively seek prenatal diagnosis. Much of this work suggests that agreeing to prenatal diagnosis is inextricably linked to the processes associated with the 'medicalization' of reproduction and that most women do not see refusal as an option. In contrast, little attention has been paid to women who decline fetal diagnosis. Instead, it is generally assumed that women who do so are resisting this thrust toward medicalization and/or are opposed to abortion. Our research is designed to address this imbalance. We analyze how a group of US women who refused the offer of AFP screening account for their decisions and compare their explanations with those of women who took the test. Contrary to our expectations, we found that refusal did not signify rejection of and/or resistance to the offerings of science and technology. Rather, women who refused often employed biomedical categories, particularly the concept of 'risk', to reject its very offerings. Furthermore, refusers and acceptors were more alike than different in their views on abortion, medicalization and pregnancy. We conclude that the key difference between the two groups lies in their interpretation and application of biomedical concepts and modern risk-assessment.

Pentafuside (Trimeris).

Pentafuside (T-20) is a 36 amino acid peptide compound under development by Trimeris for the potential treatment of HIV infection, for which it received US FDA fast track designation in February 1999 [313596,182694]. It corresponds to amino acids 638 to 673 of HIV-1(LA1) transmembrane protein, gp41 [238873]. Pentafuside blocks HIV infection, uniquely, by preventing membrane fusion, an essential process in viral replication. In preclinical studies it blocked infection of cells by HIV and prevented the fusion of one HIV-infected cell with another [171217]. In March 1998, Trimeris signed a letter of intent with DuPont Merck Pharm Co to conduct trials of Merck's efavirenz in combination with pentafuside. The trial planned to enroll up to 48 HIV-infected individuals at three sites in the US, who have begun to fail their existing triple combination therapy. Prior exposure to non-nucleoside reverse transcriptase inhibitors and protease inhibitors, other than indinavir, will be among the exclusion criteria for the study. The first 10 days of the study is a dose-optimization period that will assess the safety, pharmacokinetics and antiviral activity of multiple ascending doses of pentafuside. After completion of this period, subjects will be eligible to participate in an extension period of at least six months, during which pentafuside will be administered in combination with efavirenz and two protease inhibitors [281696]. The use of pentafuside and truncated peptides in combination with other antiviral agents is claimed in WO-09640191.

Unstable angina associated with sertraline.

An 81-year-old woman reported with chest pain occurring shortly after initiating treatment with sertraline. She had no prior history of cardiovascular disease. She developed nausea and malaise 4 h after her first dose, which resulted in avoidance of further treatment. After voluntarily reinitiating sertraline 10 days later, she again developed nausea and malaise but persisted with treatment. On the second day, her gastrointestinal symptoms were accompanied by crushing retrosternal chest pain radiating to both arms and resolving spontaneously after 10 mins. Following the third dose of sertraline, the patient experienced severe and persistent crushing retrosternal chest pain radiating to both arms. She was hospitalized with a diagnosis of unstable angina and treated with acetylsalicylic acid, intravenous heparin and nitroglycerin. The temporal relationship of chest pain onset following ingestion of sertraline is strongly suggestive of an adverse medication effect.

The effects of ethnicity, education and an informational video on pregnant women's knowledge and decisions about a prenatal diagnostic screening test.

Prenatal screening for genetic disease and developmental disabilities is rapidly becoming a routine part of the management of low-risk pregnancies. Yet research on how to best inform pregnant women about these tests and their special ethical entailments remains sparse. We asked 130 low-risk pregnant women of diverse ethnic and social class backgrounds a series of questions about a prenatal test they had been offered within the previous 3 months. All had been given an informational booklet about the test at the time it was offered; about half also saw a video. We found that neither group of women retained much of the information they had received about the prenatal screening but that those who saw the video remembered more. Information-retention also varied significantly by ethnicity and level of education.

Respiratory failure associated with the lipodystrophy syndrome in an HIV-positive patient with compromised lung function.

Protease inhibitors, used as treatment in human immunodeficiency virus (HIV) infection, are associated with a syndrome of peripheral lipodystrophy, central adiposity, hyperlipidemia and insulin resistance. An HIV-positive patient with chronic obstructive pulmonary disease is presented who developed the lipodystrophy syndrome that is associated with the use of protease inhibitors. It is postulated that the lipodystrophy syndrome further compromised his lung function, leading to respiratory failure. Patients who have pulmonary disease and are taking protease inhibitors require monitoring of clinical status and pulmonary function tests.

The production of authoritative knowledge in American prenatal care.

Using Jordan's concept of authoritative knowledge, this article describes some of the ways that the prenatal care practices of a group of U.S. women help to consolidate biomedical hegemony. We analyze the considerations that the women took into account when deciding whether or not to accept specific prenatal care recommendations as authoritative, focusing on when and how they used their own "embodied" knowledge and experience as a standard against which to assess the validity of clinical recommendations. The data provide insight into medicalization processes and the role patients themselves play in furthering biomedical hegemony.

Debating clinical utility.

The clinical utility of genetic tests is determined by the outcomes following test use. Like other measures of value, it is often contested. Stakeholders may have different views about benefits and risks and about the importance of social versus health outcomes. They also commonly disagree about the evidence needed to determine whether a test is effective in achieving a specific outcome. Questions may be presented as factual disagreements, when they are actually debates about what information matters or how facts should be interpreted and used in clinical decision-making. Defining the different issues at stake is therefore an important element of policy-making. Key issues include evidence standards for test use, and in particular, the circumstances under which prospective controlled data should be required, as well as evidence on feasibility, cost and equitable delivery of testing; the goals of population-based screening programs, and in particular, the role of social outcomes in evaluating test value; and the appropriate uses and funding of tests that inform non-medical actions. Addressing each of these issues requires attention to stakeholder values and methods for effective deliberation that incorporate consumer as well as health professional perspectives.

A common intracellular allosteric binding site for antagonists of the CXCR2 receptor.

BACKGROUND AND PURPOSE: We have previously shown that SB265610 (1-(2-bromo-phenyl)-3-(7-cyano-3H-benzotriazol-4-yl)-urea) behaves as an allosteric, inverse agonist at the C-X-C chemokine (CXCR)2 receptor. The aim of this study was to determine whether SB265610, in addition to two other known antagonists, bind to either of the two putative, topographically distinct, allosteric binding sites previously reported in the Literature. EXPERIMENTAL APPROACH: Ten single point mutations were introduced into the CXCR2 receptor using site-directed mutagenesis. Three CXCR2 antagonists were investigated, SB265610, Pteridone-1 (2-(2,3 difluoro-benzylsulphanyl)-4-((R)-2-hydroxy-1-methyl-ethylamino)-8H-pteridin-7-one) and Sch527123 (2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1enylamino}-benzamide), and the effect of these mutations on their binding affinity and ability to inhibit interleukin-8-stimulated binding of [(35)S]GTPgammaS was examined. KEY RESULTS: Seven of the nine mutations introduced into the C-terminal domain and intracellular loops of the receptor produced a significant reduction in affinity at least one of the antagonists tested. Of those seven mutations, three produced a significant reduction in the affinity of all three antagonists, namely K320A, Y314A and D84N. In all but one mutation, the changes observed on antagonist affinity were matched with effects on inhibition of interleukin-8-stimulated [(35)S]GTPgammaS binding. CONCLUSIONS AND IMPLICATIONS: These antagonists bind to a common intracellular, allosteric, binding site of the CXCR2 receptor, which has been further delineated. As many of these mutations are close to the site of G protein coupling or to a region of the receptor that is responsible for the transduction of the activation signal, our results suggest a molecular mechanism for the inhibition of receptor activation.

Prophylaxis for infective endocarditis. Who needs it? How effective is it?

OBJECTIVE: To review guidelines for using antibiotic prophylaxis to prevent infective endocarditis, and to present recent changes and controversies regarding these guidelines. QUALITY OF EVIDENCE: Data are from physiologic and in vitro studies, as well as studies of animal models, and from retrospective analyses of human endocarditis cases. Systematic reviews and guidelines are also examined. As no randomized clinical trials have examined prophylaxis for bacterial endocarditis, many recommendations presented are based on consensus guidelines. MAIN MESSAGE: Antibiotic prophylaxis to prevent bacterial endocarditis should be used in high- and moderate-risk patients with cardiac disease. It should be given before procedures in which bacteremias are likely with organisms that cause endocarditis, such as viridans streptococci. For most procedures, a single dose of amoxicillin (2 g by mouth 1 hour before the procedure) is sufficient to ensure adequate serum levels before and after the procedure. CONCLUSION: Infective endocarditis continues to have high rates of morbidity and mortality. Antibiotic prophylaxis, therefore, is important to combat this preventable disease. For high- and moderate-risk patients with cardiac disease, the cost-benefit ratio favours prophylaxis.

Evaluation and management of chylous ascites.

Twenty-eight cases of chylous ascites occurring over the past 20 years are analyzed for clinical presentation, cause, yield of diagnostic procedure used, and response to therapy. Malignancies were responsible for 21 of 24 adult cases of chyloperitoneum, with lymphomas predominating (13 cases). The dismal prognosis in adult cases (12 patients died within 3 months) shows the need for appropriate diagnostic assessment including early lymph node biopsy or laparotomy, or both, when indicated. Surgery, chemotherapy, or radiation therapy should be instituted promptly except in cases resulting from surgical trauma to lymphatics, which frequently resolve with conservative management. Three of the four pediatric cases of chylous ascites resulted from congenital lymphatic anomalies; the fourth case resulted from operative trauma. Aggressive diagnostic and therapeutic interventions are not warranted in childhood cases of chylous ascites until conservative management (paracentesis, low-fat diet, medium-chain triglyceride supplementation) has failed; neoplasia is rarely implicated and many cases resolve within a few months.

Hemochromatosis: genetics helps to define a multifactorial disease.

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder that can result in iron overload and a wide range of clinical complications, including hepatic cirrhosis, diabetes mellitus, hypopituitarism, hypogonadism, arthritis, and cardiomyopathy. People with HH can be detected at an asymptomatic stage of the disease by abnormalities in serum iron measures. Early detection is desirable, because periodic phlebotomy provides effective treatment for iron overload and may prevent complications of the disorder. The natural history of HH is poorly understood, however, and the proportion of people detected by screening who will develop serious complications of HH is unknown. The genetics of HH may help to resolve these questions. The gene, HFE, and two mutations, C282Y and H63D, have been identified: the C282Y mutation has a higher penetrance than the H63D mutation, and appears to result in a greater loss of HFE protein function. Most people with HH are C282Y homozygotes, a small proportion are compound heterozygotes or H63D homozygotes, and some have no identifiable HFE mutation or are HFE heterozygotes, suggesting that additional mutations associated with HH are yet to be found. Gender and environmental agents, such as alcohol and dietary iron, influence phenotypic expression of HH. The severity of HH is thus determined by an interaction between genotype and modifying factors. HFE mutations also appear to increase the likelihood of iron overload in inherited anemias and to promote the clinical manifestations of porphyria cutanea tarda. HH is an important paradigm for medical genetics because it offers an opportunity to explore the complexity of gene gene and gene environment interactions.