Correlation of enzyme-linked immunosorbent assays for serum human immunodeficiency virus antigen and antibodies to recombinant viral proteins with subsequent clinical outcomes in a cohort of asymptomatic homosexual men.

A cohort of asymptomatic homosexual men at a Boston community health center was screened for the presence of human immunodeficiency virus (HIV) serum antigen and antibodies to recombinant proteins containing portions of the envelope and the gag (core) gene products. Of 196 asymptomatic men screened, 149 were antigen-negative/antibody-negative, 41 were antigen-negative/antibody-positive, and six were antigen-positive/antibody-positive. All three men in whom the acquired immune deficiency syndrome (AIDS) developed over the next year were antigen-positive at enrollment. Although a larger portion of the men who were antigen-positive and did not demonstrate progression to AIDS after one year had thrush, zoster, or generalized lymphadenopathy, the associations were not statistically significant. Whereas all of the seropositive men had antibody to viral envelope antigens, about a quarter did not have detectable antibodies to recombinant core antigens. However, all of these men had detectable antibody to core antigens by Western blot. Titers to recombinant core and envelope antigens tended to be lower in the men with AIDS. HIV-infected persons who are more likely to have enhanced immuno-compromise may be identified by these newer tests, but further longitudinal studies will be necessary to fully understand their prognostic value.

Cholinergic activity of acetylenic imidazoles and related compounds.

A series of acetylenic imidazoles related to oxotremorine (1a) were prepared and evaluated as cholinergic agents with in vitro binding assays and in vivo pharmacological tests in mice. 1-[4-(1H-Imidazol-1-yl)-2-butynyl]-2-pyrrolidinone (1b) was a cholinergic agonist with one-half the potency of oxotremorine. Analogues of 1b with a 5- or 2-methyl substituent in the imidazole ring (compounds 1c and 1g) were cholinergic partial agonists. Analogues of 1b with a methyl substituent at the 5-position in the pyrrolidinone ring (7b) or at the alpha-position in the acetylenic chain (8b) were antagonists. Various analogues of these imidazole acetylenes where the pyrrolidinone ring was replaced by an amide, carbamate, or urea residue were prepared. Several compounds which contained 5-methylimidazole as the amine substituent were partial agonists. The activities of the imidazole compounds are compared with those of the related pyrrolidine and dimethylamine analogues. Agonist and antagonist conformations for these compounds at muscarinic receptors are proposed.

Dopaminergic and serotonergic activities of imidazoquinolinones and related compounds.

The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij] quinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described. Dopaminergic activity is associated with the (R)-enantiomer of 5; the (S)-enantiomer shows no dopaminergic activity. A series of analogues where the imidazolone ring was modified to various 5- or 6-membered heterocyclic rings were prepared. Some of these compounds showed a combination of dopaminergic and serotonergic activity, while one compound, 6-(dipropylamino)-1,2,6,7-tetrahydro-3H,5H-pyrido[3,2,1- ij]quinazolin-3-one (24), was a selective serotonergic agonist. Various analogues of 5 where the dipropylamine substituent was modified were prepared. Most of these showed reduced dopaminergic activity, while several were as potent as 5 at the serotonin 5HT1A receptor. Orientations for the new compounds at dopamine and serotonin receptors are proposed and compared with those of other tricyclic ligands known to have high affinity at these receptors.

Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.

The imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.

Analgesic activities of spinal cord substance P antagonists implicate substance P as a neurotransmitter of pain sensation.

Substance P (SP) injected into intraspinal (i.s.) spaces caused mice to vigorously scratch and bite their skins in an apparent reaction to a perceived cutaneous sensation. The scratching behavior was similar to the reciprocal hindlimb-scratching syndrome (RHS) described for intracranial (i.c.) SP injections. Radiotracer experiments, as well as potency and latency measurements, demonstrated that SP-induced scratching, whether induced by the i.c. or i.s. route, was due to SP receptor stimulation in the cervicothoracic cord. Similarly, biting was due to SP stimulation of the lumbosacral spinal cord. Mice coated with capsaicin, an irritant chemical, scratched and bit the coated areas in a manner similar to animals injected with i.s. SP. Standard analgesics depressed this scratching behavior elicited by topical capsaicin. Non-analgesic drugs, with the exception of amphetamine, did not affect capsaicin-induced pain. It is concluded that i.s. SP induces a painful sensory experience. Some piperazinone derivatives of substance P's C-terminal hexapeptide are shown to specifically antagonize the scratching induced by i.s. SP with little or no effect on motor behavior. These antagonists depressed scratching elicited by topical capsaicin and were analgesic on the hot-plate test. It is concluded that SP is a natural neurotransmitter for pain and that antagonism of endogenous SP systems causes analgesia.

Pharmacology of U-91356A, an agonist for the dopamine D2 receptor subtype.

U-91356A [(R)-5,6-dihydro-5-(propylamino)4H-imidazo[4,5,1-ij]quinolin -2-(1H)-one, monohydrochloride], bound with highest affinity to the dopamine D2 receptor subtype, although it also bound with somewhat lower affinities to the dopamine D3 and D4, as well as the 5-HT1A receptor subtypes. In addition to depressing dopamine synthesis and turnover, injection of U-91356A increased striatal acetylcholine concentrations. U-91356A also depressed firing rates of dopamine neurons. In mice, this compound stimulated cage climbing and locomotor activity in reserpinized animals; it also antagonized D-amphetamine-stimulated locomotor activity. It produced contralateral turning in rats with unilateral lesions of the substantia nigra. These data are consistent with roles for the dopamine D2 receptor subtype as a dopamine autoreceptor and as a stimulatory, postsynaptic dopamine receptor.

Dopamine D2 receptor binding properties of [3H]U-86170, a dopamine receptor agonist.

U-86170F, an imidazoguinolinone, is a potent dopamine D2 agonist, binding with high affinity to the dopamine D2 receptor. A Kd of 0.99 nM was determined in membranes from Chinese hamster ovarian (CHO) cells transfected with the D2 receptor and a Kd of 1.72 nM was obtained in rat striatal homogenates. GTP sensitivity was demonstrated when its addition (300 microM) reduced [3H]U-86170 binding by 60%. This agonist ligand is especially effective in identifying agonists and partial agonists, as well as antagonists, and affords a more precise evaluation of their affinity for the dopamine D2 receptor, without the use of multiple site analysis, than does an antagonist [3H]-ligand.

Pre- and postsynaptic dopaminergic activities of U-86170F.

The biochemical, endocrine, receptor binding, and behavioral effects of the putative dopamine autoreceptor agonist, U-86170F, were evaluated in various in vivo and in vitro models. U-86170F and apomorphine were shown to cause a significant reversal of the effects of gamma-butyrolactone (GBL) on dopamine accumulation in mouse striata. In contrast to apomorphine, U-86170F had a ceiling effect on the extent of the reversal of GBL effects (55%), whereas apomorphine had an 82% reversal. The effect on striatal homovanillic acid (HVA) levels was also monitored, and both compounds exerted a similar and significant reduction in striatal HVA. A comparison was made between the effects of intraperitoneal (i.p.) and oral administration of U-86170F in the alpha-methyl-p-tyrosine (alpha-MPT)/prolactin model in rats. When administered by the i.p. route, U-86170F suppressed the effects of alpha-MPT on prolactin level increase, having an ED50 of about 0.03 mg/kg, and when administered by the oral route, its ED50 was approximately 0.1 mg/kg. U-86170F has been shown to be a potent dopamine autoreceptor agonist in the GBL, prolactin, and HVA models, with an effective i.p. dose of approximately 0.03 mg/kg. When evaluated for postsynaptic dopaminergic activity in the reserpinized mouse model, and compared to apomorphine, U-86170F was found to increase locomotor activity, but its maximum effect was only 65% of that attained with apomorphine. Higher doses were needed for postsynaptic effects. In receptor binding studies using cloned D2 receptor preparations, U-86170F was found to exhibit agonist binding properties similar to dopamine as demonstrated by their inhibition of 3H-raclopride binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Reliability of self-reported sexual behavior risk factors for HIV infection in homosexual men.

This study was undertaken to determine the reliability of self-reported sexual behavior using the test and retest technique when used with self-reported sexual behavior. The subjects were 116 asymptomatic homosexual men who participated in another study (an examination of behavioral and demographic determinants of HIV antibody status). The subjects were asked to complete two questionnaires. The first contained demographic and sexual behavior questions. The second, administered an average of 6 weeks later, used a subset of the questions in the first questionnaire. The reliability of the test-retest procedure was measured by the Kappa statistic, which assesses the proportion of agreement between two data items, accounting for the amount of agreement expected by chance. The highest degree of reliability as measured by Kappa was found with demographic information, smoking history, and sexual orientation. Self-reported sexual behaviors for the previous 6 months generally had the next highest degree of reliability as measured by Kappa. Questions examining change over the previous 5 years had the lowest reliability. Behavior changes during the time between questionnaires, subjectivity of the answer categories, and social desirability of the answers are three factors that may result in a lack of reliability in this self-reported sexual behavior questionnaire. This raises methodological concerns about the measurement of behavioral risk factors for AIDS and the ability to assess meaningfully subjective reports of behavioral change.

alpha-Methyl analogues of acetylenic amines as striatal muscarinic antagonists.

The effect of acetylenic amines, with or without alpha-methyl substitution, on striatal acetylcholine (ACh) concentration in rats was investigated. Oxotremorine, oxotremorine-1, and U-77053 (trimethyl (4-(1-pyrrolidinyl)-2 butynyl)-urea), the unsubstituted amines, increased striatal ACh concentration. On the other hand, the corresponding alpha-methyl substituted analogues, alpha-methyl-oxotremorine, BM-5, and alpha-methyl U-77053, decreased the concentration of ACh in the striatum. The results indicate that substitution of alpha-methyl in acetylenic amines converts compounds from agonists to antagonists for striatal muscarinic receptors.

Correlates of HIV risk in a random sample of street youths in San Francisco.

In a random sample of 203 street youths recruited in the Haight-Ashbury neighborhood of San Francisco, the authors found significant differences between those who reported that they could go home if they wanted to compared to those who perceived that they could not go back home. Those who could not go home were significantly more likely to report having been away from home for more than 3 years, having run away before age 13, having been kicked out of their home, and not being in touch with their parents compared to the other group. Those who could not go home reported significantly more-injection drug use, which puts them at high risk for HIV. Health care providers can identify street youths at highest risk by asking the question "Could you go back home today if you wanted to do so?"

Caring for the adolescent with HIV infection or AIDS in the critical care setting.

Caring for the adolescent with HIV infection or AIDS in the critical care setting is challenging. This article discusses medical treatments for HIV, aspects of adolescent development that influence their behaviors, certain behaviors that put adolescents at risk for HIV acquisition, ethical and legal concerns for caring for this population, nursing implications for care, and the needs of nurses caring for this population.

Children with HIV becoming adolescents: caring for long-term survivors.

As children infected with HIV live longer, pediatric nurses who care for these patients need to be familiar with adolescent development and to anticipate physiologic and behavioral changes that will occur in this population. Concerns regarding confidentiality, autonomy, medication needs and compliance may become paramount. Learning how to interview adolescents and becoming comfortable with adolescent sexuality issues will enhance the patient-provider relationship.

Comparison of diamond-like carbon-coated nitinol stents with or without polyethylene glycol grafting and uncoated nitinol stents in a canine iliac artery model.

OBJECTIVE: Neointimal hyperplasia is a major complication of endovascular stent placement with consequent in-stent restenosis or occlusion. Improvements in the biocompatibility of stent designs could reduce stent-associated thrombosis and in-stent restenosis. We hypothesised that the use of a diamond-like carbon (DLC)-coated nitinol stent or a polyethylene glycol (PEG)-DLC-coated nitinol stent could reduce the formation of neointimal hyperplasia, thereby improving stent patency with improved biocompatibility. METHODS: A total of 24 stents were implanted, under general anaesthesia, into the iliac arteries of six dogs (four stents in each dog) using the carotid artery approach. The experimental study dogs were divided into three groups: the uncoated nitinol stent group (n = 8), the DLC-nitinol stent group (n = 8) and the PEG-DLC-nitinol stent group (n = 8). RESULTS: The mean percentage of neointimal hyperplasia was significantly less in the DLC-nitinol stent group (26.7±7.6%) than in the nitinol stent group (40.0±20.3%) (p = 0.021). However, the mean percentage of neointimal hyperplasia was significantly greater in the PEG-DLC-nitinol stent group (58.7±24.7%) than in the nitinol stent group (40.0±20.3%) (p = 0.01). CONCLUSION: Our findings indicate that DLC-coated nitinol stents might induce less neointimal hyperplasia than conventional nitinol stents following implantation in a canine iliac artery model; however, the DLC-coated nitinol stent surface when reformed with PEG induces more neointimal hyperplasia than either a conventional or DLC-coated nitinol stent.

Hemocompatibility of surface-modified, silicon-incorporated, diamond-like carbon films.

The hemocompatibility of plasma-treated, silicon-incorporated, diamond-like carbon (Si-DLC) films was investigated. Si-DLC films with a Si concentration of 2at.% were prepared on Si (100) or Nitinol substrates using a capacitively coupled radiofrequency plasma-assisted chemical vapor deposition method using a mixed gas of benzene (C(6)H(6)) and diluted silane (SiH(4):H(2)=10:90). The Si-DLC films were then treated with O(2), CF(4) or N(2) glow discharge for surface modification. The plasma treatment revealed an intimate relationship between the polar component of the surface energy and its hemocompatibility. All in vitro characterizations, i.e. protein absorption behavior, activated partial thromboplastin time measurement and platelet adhesion behavior, showed improved hemocompatibility of the N(2-)- or O(2)-plasma-treated surfaces where the polar component of the surface energy was significantly increased. Si-O or Si-N surface bonds played an important role in improving hemocompatibility, as observed in a model experiment. These results support the importance of a negatively charged polar component of the surface in inhibiting fibrinogen adsorption and platelet adhesion.

The relation between nitrite inhalants, unprotected receptive anal intercourse, and the risk of human immunodeficiency virus infection.

The role of nitrite was evaluated between 1985 and 1988 in a study of sexual transmission of the human immunodeficiency virus (HIV) among homosexual male couples in Boston, Massachusetts. Initial enrollment data suggested that a history of unprotected receptive anal intercourse (odds ratio (OR) = 2.3, 95% confidence interval (CI) 1.4-3.6) and a history of nitrite use (OR = 1.7, 95% CI 1.1-2.5) were independent risk factors for HIV infection. In addition, interaction between nitrite use and unprotected receptive anal intercourse was observed (OR = 5.5, 95% CI 2.8-11.1) after controlling for number of unprotected receptive anal sex partners and history of sexually transmitted diseases. Since it was felt that nitrite use might be a marker for unprotected receptive anal sexual activity, a supplemental questionnaire was administered to obtain information on simultaneous nitrite use and unprotected receptive anal intercourse. The supplemental data suggested a strong interaction between nitrite use and unprotected receptive anal intercourse in increasing the risk of HIV infection. In the adjusted analyses, the odds ratio for HIV infection was considerably greater among men who always used nitrites during unprotected receptive anal intercourse (OR = 31.8, 95% CI 12.9-76.7) compared with men who sometimes (OR = 7.1, 95% CI 2.1-23.6) or never (OR = 9.0, 95% CI 2.5-32.1) used them. These findings have preventive public health implications and may add insight into our understanding of the mechanism by which HIV infection spread rapidly among homosexual men in the early 1980s.

Cloning and expression of the ccpA gene encoding catabolite control protein from Thermoactinomyces sp. E79.

The gene ccpA encoding the catabolite control protein A (CcpA) of Thermoactinomyces sp. E79 has been cloned and characterized. Nucleotide sequence analysis of the CcpA clone showed that the cloned fragment contained the full structural gene for a protein of 346 amino acids. The predicted amino acid sequence shows similarity to the transcriptional regulators of the Lacl-GalR family; a highly conserved helix-turn-helix motif, which might bind to DNA, was identified through comparison with regulator proteins in this family. The highest sequence identity was obtained when it was compared with the CcpA of Bacillus subtilis (60%) or Bacillus megaterium (60%). The expression of ccpA in Thermoactinomyces sp. E79 was dependent on glucose, which is contrast to the cases of B. subtilis, B. megaterium and S. xylosus. The complementation experiment with the B. megaterium ccpA mutant indicated that the cloned gene was a ccpA.

Medicinal chemistry of imidazoquinolinone dopamine receptor agonists.

(R)-5-(Dipropylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]-quinolin-2( 1H)-on e (1a, U-86170), a potent high intrinsic activity dopamine (D2) agonist, has been prepared in eleven steps from quinoline. In several tests, the compound showed dopamine autoreceptor agonist activity at low doses. It showed postsynaptic agonist activity at somewhat higher doses, reversing the effects of reserpine in mice and increasing striatal acetylcholine levels. The compound showed some serotonergic (5HT1A) activity, but was inactive at other receptors. The related monopropylamine 2 (U-91356), also showed good dopaminergic agonist activity, and had improved metabolic stability and oral bioavailability in the rat and monkey when compared to 1a. Compounds 1a and 2 have been prepared in tritiated form, and [3H]1a (69 Ci/mmol) has found use as a D2 agonist radioligand in binding assays. The dopaminergic (D2) and serotonergic (5HT1A) activities of a series of compounds related to 1a have been evaluated using this ligand, [3H]raclopride, and [3H]8-OH DPAT.