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PubMed1983

Selective anxiolytics: are the actions related to partial "agonist" activity or a preferential affinity for benzodiazepine receptor subtypes?

Both pharmacological and biochemical evidence support the existence of BZ receptor subtypes. Determination of the molecular basis of BZ receptor heterogeneity requires additional research. The physiological significance of BZ receptor subtypes is not currently understood. One hypothesis presented to explain the unique pharmacological effects of CL 218872 suggests that CL 218872 has preferential affinity for a BZ receptor subtype (i.e., type I sites) that mediates the anxiolytic effects of the clinically active BZs. An alternative hypothesis has been proposed to account for these observations and is based upon the possibility that CL 218872 may act as a partial agonist at the BZ receptor. The partial agonist theory is supported by behavioral evidence and the relatively small differences in affinity of the BZ receptor subtypes discriminated by CL 218872 at physiological temperatures. In addition, in vivo binding studies suggest that occupancy of type II BZ receptor subtypes (i.e., those with low affinity for CL 218872) is necessary for CL 218872 to produce minimal anticonflict activity (4). Unlike certain other neurotransmitter systems, it is difficult to correlate the heterogeneous binding properties of BZ receptor ligands with their agonist/antagonist potential at BZ receptor. For example, CL 218872 discriminates BZ receptor subtypes and acts as an agonist at the BZ receptor. Beta-carbolines such as PCC also discriminate receptor subtypes, yet they act as antagonists at the BZ receptor. Compounding the complexity, neither the nature nor the existence of an endogenous ligand is known. So, the designation of agonist or antagonist effects is made on a purely functional basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex.

Reuptake plays an important role in regulating synaptic and extracellular concentrations of glutamate. Three glutamate transporters expressed in human motor cortex, termed EAAT1, EAAT2, and EAAT3 (for excitatory amino acid transporter), have been characterized by their molecular cloning and functional expression. Each EAAT subtype mRNA was found in all human brain regions analyzed. The most prominent regional variation in message content was in cerebellum where EAAT1 expression predominated. EAAT1 and EAAT3 mRNAs were also expressed in various non-nervous tissues, whereas expression of EAAT2 was largely restricted to brain. The kinetic parameters and pharmacological characteristics of transport mediated by each EAAT subtype were determined in transfected mammalian cells by radio-label uptake and in microinjected oocytes by voltage-clamp measurements. The affinities of the EAAT subtypes for L-glutamate were similar, with Km determinations varying from 48 to 97 microM in the mammalian cell assay and from 18 to 28 microM in oocytes. Glutamate uptake inhibitors were used to compare the pharmacologies of the EAAT subtypes. The EAAT2 subtype was distinguishable from the EAAT1/EAAT3 subtypes by the potency of several inhibitors, but most notably by sensitivity to kainic acid (KA) and dihydrokainic acid (DHK). KA and DHK potently inhibited EAAT2 transport, but did not significantly affect transport by EAAT1/EAAT3. Using voltage-clamp measurements, most inhibitors were found to be substrates that elicited transport currents. In contrast, KA and DHK did not evoke currents and they were found to block EAAT2-mediated transport competitively. This selective interaction with the EAAT2 subtype could be a significant factor in KA neurotoxicity. These studies provide a foundation for understanding the role of glutamate transporters in human excitatory neurotransmission and in neuropathology.

Amino Acid Sequence↗
PubMed1995

Human prostate muscarinic receptor subtypes.

The alpha adrenergic receptor subtypes of the human prostate have been intensively investigated, while the muscarinic receptor subtypes and their function have yet to be determined in this tissue. [3H]-QNB binding to muscarinic receptors was performed on membrane homogenates of adenoma from six prostatectomy specimens resulting in an average total receptor density of 46 fMol/mg protein. Pirenzepine, hexahydrosiladifenidol, and para-fluoro-hexahydrosiladifenidol, drugs with high affinity for the M1 subtype, were significantly more potent inhibitors of [3H]-QNB binding than the M2 selective drug methoctramine. Immunoprecipitation studies were done using antisera raised to individual M1-M5 receptor subtypes. Approximately 75% of the solubilized receptors in the adenoma specimens were immunoprecipitated with the anti-M1 antibody, in contrast to 5% or less with antibodies against M2, M3 or M4 subtypes. These immunoprecipitation studies confirm the preponderance of the M1 subtype in prostate adenoma suggested by the high affinity pirenzepine binding. M1 receptors, when incubated with agonist, coimmunoprecipitated with the alpha subunits of the guanine nucleotide binding regulatory proteins Gi alpha, Gq/11 alpha and G16 alpha. Immunohistochemical staining with the anti-M1 antibody demonstrates the M1 receptor to be localized to the glandular epithelium. The human prostate is the first peripheral tissue in which a preponderance of the M1 subtype of muscarinic receptors has been demonstrated.

Adult↗
PubMed1995

Cloning of the human alpha 1d-adrenergic receptor and inducible expression of three human subtypes in SK-N-MC cells.

We have cloned the human alpha 1d-adrenergic receptor (AR) and compared the pharmacological properties of the three recombinant human alpha 1-AR subtypes in SK-N-MC cells. SK-N-MC cells natively express a mixture of alpha 1-AR subtypes, and the use of an inducible expression system allowed us to directly compare the recombinant and native subtypes without concern for cell-specific processing or microenvironment. The human alpha 1d-AR was expressed from a cDNA/gene fusion construct cloned from human SK-N-MC cell cDNA and human genomic libraries. This receptor is deduced to contain 572 amino acids with 98% identity to the rat alpha 1d-AR in the transmembrane domains and, when expressed in human embryonic kidney 293 cells, has alpha 1-AR binding properties similar to those of the rat alpha 1d-AR. Norepinephrine increased inositol phosphate formation and mobilized intracellular Ca2+ in transfected 293 cells. Reverse transcription-polymerase chain reaction analysis of the three cloned human subtypes (alpha 1a, alpha 1b, and alpha 1d) in mRNA from SK-N-MC cells, which natively express alpha 1A- and alpha 1B-like pharmacology, showed abundant alpha 1a and alpha 1d but fewer alpha 1b transcripts. The three human clones were expressed in SK-N-MC cells using isopropyl-beta-D-thiogalactoside-inducible vectors. Upon induction, alpha 1-AR density was increased with the recombinant subtype comprising 67-80% of total alpha 1-ARs. Inhibition curves for (+)-niguldipine and 5-methylurapidil fit best to a two-site model in uninduced cells, indicating significant receptor heterogeneity. Isopropyl-beta-D-thiogalactoside induction altered the potencies of both compounds, causing most inhibition curves to fit best to a one-site model. (+)-Niguldipine was 100-fold more potent at the alpha 1a-AR than at alpha 1b- or alpha 1d-ARs, whereas 5-methylurapidil had similar potencies at alpha 1a- and alpha 1d-ARs and about 10-fold lower affinity at the alpha 1b-AR. We conclude that the complex alpha 1A- and alpha 1B-like pharmacology observed in native SK-N-MC cells is due to expression of all three subtypes in different proportions, independently of cell-specific processing or environmental factors, and that the alpha 1a-AR cDNA encodes the pharmacologically defined alpha 1A subtype.

Adrenergic alpha-Antagonists↗
PubMed1994

Cloning, expression, and tissue distribution of the rat homolog of the bovine alpha 1C-adrenergic receptor provide evidence for its classification as the alpha 1A subtype.

Three alpha 1-adrenergic receptors (ARs) have been cloned, i.e., the alpha 1B-, alpha 1C-, and alpha 1D-ARs. Compared with the alpha 1B subtype, the alpha 1A subtype in tissue is described as being insensitive to chloroethylclonidine and sensitive to SZL-49 and having a 10-100-fold higher affinity for a number of agonists and antagonists. The alpha 1A subtype is also expressed in a variety of rat tissues (as assessed by pharmacology), with greatest abundance in the cerebral cortex, hippocampus, vas deferens, and submaxillary gland. The cloned bovine alpha 1C-AR, though having an alpha 1A-AR pharmacology, was first reported as not being expressed in any rat tissue (as determined by Northern analysis) and was therefore designated as a new subtype. We report the cloning, expression, and characterization of the rat homolog of the bovine alpha 1C-AR. Using a human alpha 1C-AR probe obtained by polymerase chain reaction screening of a neuroblastoma cell line (SK-N-MC), both exon 1 and exon 2 of the rat alpha 1C-AR gene were cloned from a rat genomic library. These two exons were spliced together and cloned into the expression vector pMT2'. Transfection into COS-1 cells and analysis of the ligand-binding profile of the expressed protein receptor using 125I-HEAT revealed a 10-100-fold higher affinity for the alpha 1-AR antagonists 5-methylurapidil, (+)-niguldipine, WB-4101, and phentolamine and the agonists oxymetazoline and methoxamine, compared with the alpha 1B-AR. This ligand-binding profile is similar to that for endogenously expressed tissue alpha 1A-ARs. In addition, the rat alpha 1C-AR was the least sensitive of the three cloned subtypes to the alkylating effects of chloroethylclonidine but was the most sensitive to the alkylating prazosin analog SZL-49, properties also observed for the tissue alpha 1A subtype. Furthermore, by three different techniques, i.e., RNase protection assays, reverse transcription-polymerase chain reaction Northern blotting, and in situ hybridization histochemistry, the rat alpha 1C-AR mRNA was localized to alpha 1A-AR-rich tissues, such as rat vas deferens, hippocampus, aorta, and submaxillary gland. Taken together, these data suggest that this receptor may actually represent the alpha 1A subtype.

Amino Acid Sequence↗
PubMed1993

Expression of mRNA for the serotonin 5-hydroxytryptamine1D beta receptor subtype in human and bovine cerebral arteries.

Serotonin [5-hydroxytryptamine (5-HT)] has been implicated in the pathophysiology of migraine, and the clinical efficacy of the 5-HT1B/5-HT1D receptor agonist sumatriptan points to neural and/or vascular 5-HT1D receptors as relevant targets in migraine therapy. We characterized the human and/or bovine 5-HT1D receptor subtype in cerebral blood vessels pharmacologically by correlation analysis and molecularly by Northern blot hybridization of cerebrovascular RNA extracts. Pharmacological analysis showed that sumatriptan was less potent than 5-HT in inducing contraction in freshly isolated human cerebral arteries and revealed an overall pharmacological profile positively and significantly correlated with that published for the 5-HT1D alpha (r = 0.746, p = 0.021) and 5-HT1D beta (r = 0.942, p = 0.0001) cloned human receptor subtypes. These results are suggestive of a contractile 5-HT1D beta receptor subtype but are not conclusive. However, Northern blots revealed the presence of mRNA transcripts for the 5-HT1D beta subtype, but not the 5-HT1D alpha subtype, in bovine (approximately 2.2 kilobases) and human (approximately 4.5 kilobases) cerebral blood vessels. Expression of either subtype could not be detected in intraparenchymal microvessels or capillaries isolated from bovine or human cerebral cortex. These results clearly indicate that the beneficial effect of sumatriptan in migraine attack, if vascularly related, is mediated by contractile 5-HT1D beta receptors most likely located on cerebral blood vessels at the surface of the brain. This study points to the 5-HT1D beta receptor subtype as the putative cerebrovascular target for migraine therapeutic agents.

Animals↗
PubMed1993

Development of natriuretic peptide analogs selective for the atrial natriuretic factor-R1A receptor subtype.

A pharmacological characterization of subtypes of the atrial natriuretic factor (ANF) receptor ANF-R1, found in bovine adrenal cortex and rat papillary membrane preparations, has been carried out using various chimeric analogs based on rat ANF(99-126) [rANF(99-126)] and porcine brain natriuretic peptide 32 (pBNP32). Receptor binding and cGMP production assays in bovine adrenal cortex indicate that replacement of the amino-terminal segment of pBNP32 with that of rANF(99-126) enhances the affinity of the peptide for the ANF-R1A receptor subtype and its stimulation of associated guanylate cyclase activity. In rat kidney papillae, the substitution of amino- and/or carboxyl-terminal portions of pBNP32 with those of rANF(99-126) also results in a large increase in the affinity and agonistic potency for the ANF-R1A subtype but in only modest changes in those for the ANF-R1B receptor subtype. Interestingly, in this preparation the chimeric analogs could discriminate by their differential affinities and cGMP production potencies between the two receptor subtypes. In particular, pBNP1, obtained by combining the ring structure of pBNP32 with the amino- and carboxyl-terminal portions of rANF(99-126), is the most selective analog. pBNP1 displays higher affinity and agonistic potency for ANF-R1A receptor than for ANF-R1B receptor, with selectivity ratios between these two subtypes of 632- and 504-fold, respectively. Moreover, an excellent correlation is observed between the affinity of the peptides for the ANF-R1A receptor and their stimulation of particulate guanylate cyclase activity in bovine adrenal cortex (r = 0.99, p < 0.01) and rat papillary (r = 0.97, p < 0.01) membrane preparations. In addition, all the chimeric analogs in this study show affinities similar to those of rANF(99-126) and pBNP32 for the ANF-R2 receptor in NIH-3T3 membrane preparations. Importantly, the chimeric analogs pBNP1 and pBNP3, which contain the core of pBNP32 and the amino-terminal segment of rANF(99-126), display higher affinities for the ANF-R1A receptor type than for the ANF-R2 receptor type. These results indicate that the analogs combining the ring structure of pBNP32 with the amino- and/or carboxyl-terminal segments of rANF(99-126) are more selective for the ANF-R1A receptor subtype than are the natural peptides rANF(99-126) and pBNP32.

3T3 Cells↗
PubMed1996

Intracellular trafficking of the muscarinic acetylcholine receptor: importance of subtype and cell type.

Agonist-induced decrease of surface muscarinic receptor number occurs in a number of cell lines. Recent work has suggested that some muscarinic receptor subtypes undergo internalization, whereas others do not. We investigated the agonist-induced trafficking of various muscarinic receptor subtypes transfected into CHO cells and compared it with the trafficking of receptors expressed natively in neuronal cells, fibroblasts, or epithelial cells. SH-SY5Y neuroblastoma cells, which express predominantly the m3 receptor subtype, show qualitatively similar changes in surface receptor number in response to agonist stimulation to those occurring in NG108-15 cells, which express predominantly the m4 subtype. The rate constants for internalization, however, were considerably different, indicating that receptors in SH-SY5Y cells show a much faster turnover than those in NG108-15 cells. In the transfected cells, the muscarinic receptor subtypes m1 and m3, which are coupled to second messenger systems via Gq/11, showed little agonist-induced loss of surface receptors. In contrast, the muscarinic receptor subtypes m2 and m4, which are coupled via Gi or G(o), showed a substantial loss of surface receptors after treatment with agonist. An interesting implication of this result is that agonist-induced receptor trafficking can still occur efficiently, even at very high receptor densities. Significant agonist-induced internalization also occurs in a fibroblast line (HeLa) and an epithelial cell line (HT29), both of which express predominantly m3 receptors. Our results suggest that the extent and rate of the loss of receptors from the cell surface in response to agonist stimulation are governed by both the receptor subtype and the cell type in which it is expressed.

Animals↗
PubMed1996

Inducible expression of beta 1- and beta 2-adrenergic receptors in rat C6 glioma cells: functional interactions between closely related subtypes.

We examined the role of beta 1- and beta 2-adrenergic receptor (AR) density and ratio in catecholamine-stimulated cAMP responses in rat C6 glioma cells. These cells, which normally express both subtypes, were stably transfected with an isopropylthio-beta-D-galactoside-inducible vector containing either beta 1AR or beta 2AR coding sequences, and receptor expression was controlled by the time and concentration of isopropylthio-beta-D-galactoside exposure. Induction of the dominant beta 1AR subtype increased the potencies of isoproterenol (ISO) and other agonists in stimulating cAMP accumulation by 20-40-fold without changing maximal response. Induction of beta 2AR expression caused 7-13-fold increases in the potency of ISO, epinephrine, and zinterol, but not of norepinephrine, and a 20-40% loss in maximal response to all agonists. Selective antagonists showed that both subtypes contributed in a nonadditive manner in the response to ISO under different conditions. After beta 2AR induction, the effects of ISO were not blocked by the beta 1-selective antagonist CGP 20712A but were shifted 100-fold to the right by the beta 2-selective antagonist ICI 118,551. However, in the presence of ICI 118,551, CGP 20712A caused an additional 100-fold decrease in ISO potency, and Schild analysis revealed complex interactions between the two subtypes. Each antagonist alone caused smaller shifts to the right in the dose-response curve to NE and, when present simultaneously, completely abolished the NE response. We conclude that beta 1ARs and beta 2ARs have different efficiencies in activating cAMP accumulation in C6 glioma cells. Activation of coexisting subtypes results in complex and sometimes synergistic interactions between the two subtypes, which vary with agonist concentration, selectivity, subtype density, and ratio.

Adrenergic beta-Agonists↗
PubMed1996

Subtype B isolates of human immunodeficiency virus type 1 detected in Australia.

The human immunodeficiency virus type 1 (HIV-1) can be subtyped on the basis of nucleotide sequence variability. Knowledge of circulating HIV-1 genotypes or subtypes allows understanding of the origin and spread of HIV-1 in different geographical regions, and is required for rational vaccine development. A study was undertaken to determine the predominant HIV-1 subtype in Australia. Part of the HIV-1 envelope gene (including the variable domain, V3) was sequenced directly from DNA extracted from peripheral blood mononuclear cells of 17 HIV-1 seropositive people in Sydney, Australia. Phylogenetic analysis based on nucleotide sequence suggested that all patients (including individual cases acquired in New Zealand, Papua New Guinea and Thailand) were infected with HIV-1 subtype B. Octapeptides from the HIV-1 envelope V3 loop tip indicated variation but included a predominance of the most common subtype B octapeptides HIGPGRAF (4 cases), NIGPGRAF (3 cases) and PIGPGRAF (1 case). These data suggest that subtype B is the major HIV-1 strain in Australia (and probably in New Zealand and Papua New Guinea), although the importation of HIV-1 acquired overseas is likely to lead to the detection and dissemination of other subtypes in Australia.

Australia↗
PubMed1997

Differences in age and body site distribution of the histological subtypes of basal cell carcinoma. A possible indicator of differing causes.

OBJECTIVE: To assess if there are any significant differences in the sex, anatomical site, and age distribution of patients with different histological subtypes of basal cell carcinoma (BCC). DESIGN: Histopathology reports were analyzed with respect to the subtype of BCC, site of a tumor, and age and sex of a patient. SETTING: Histopathology reports were reviewed from 1 private laboratory that derived its cases from general practitioners, surgeons, and dermatologists. PATIENTS: Patients with BCC (N = 3885) for whom case data were received by the pathology laboratory from January 2, 1991, to June 12, 1991, were included in the study. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Superficial BCCs differed from other subtypes of BCC by occurring more commonly on the trunk and in younger patients. RESULTS: The mean age (56.8 years) of the patients with superficial BCCs was significantly lower than that of the patients with other subtypes of BCC who were examined (P < .001); the mean ages of the patients with these other subtypes were as follows: nodulosuperficial BCC, 62.9 years; nodular BCC, 63.9 years; nodulomorpheic BCC, 66.1 years; and morpheic BCC, 66.0 years. The majority of superficial BCCs occurred on the trunk and limbs (73.3%), while the majority of all other subtypes occurred on the head and neck. CONCLUSIONS: Superficial BCC differs from the other subtypes of BCC in terms of patient age and tumor site, and these findings may reflect differences in the etiology.

Adolescent↗
PubMed1998

Sequencing of porA from clinical isolates of Neisseria meningitidis defines a subtyping scheme and its genetic regulation.

Subtyping Neisseria meningitidis by methods that rely on monoclonal antibody (mAb) reactivity results in an unusually high number of strains that are not subtypeable. To subtype 48 strains isolated (1993-1994) in the province of Quebec that were not subtypeable by mAb-based techniques, we used DNA sequencing of the variable regions of porA, a gene that encodes the class 1 outer membrane protein. We assigned subtypes to all the previously nonserosubtypeable isolates and identified some novel subtypes. Because our sequencing strategy included the promoter region of porA, different isolates were compared in their sequences of the porA promoter region. A poly(G) stretch lies between the -10 and -35 regions of the promoter; replacement of a G residue by an A residue in this region resulted in loss of expression of porA. No correlation was found between the number of G residues in the poly(G) stretch and the level of expression; a minimum of 10 G residues is required in this stretch for expression of porA. One isolate expressed no class 1 outer membrane protein because of the insertion sequence IS1301 in the coding region of porA. Another isolate did not express the protein owing to a frame-shift mutation within the coding region of porA. Sequencing of porA allowed assignments of subtypes to previously uncharacterized isolates and provided insights about the regulation of expression of this gene in N. meningitidis.

Amino Acid Sequence↗
PubMed1997

Differential distribution of hepatitis C virus subtypes in Asia: comparative study among Thailand, Indonesia, the Philippines and Japan.

Hepatitis C virus (HCV) is currently classified into at least six major genotypes, each of which is further divided into a number of subtypes. It has been reported that prevalence of each subtype varies among different geographical regions of the world and that severity of liver disease and sensitivity to interferon treatment varies with different subtypes. The purpose of this study was to determine and compare the prevalence of each subtype among HCV isolates in different areas in Asia such as southern (Hat Yai) and northern (Chiang Mai) parts of Thailand, Indonesia (Surabaya), the Philippines (Manila) and Japan (Kobe). Sera were obtained from various groups of patients and tested for antibodies against HCV using second and/or third generation ELISA kits. RNA was extracted from anti-HCV-positive sera and reverse-transcribed into cDNA. The cDNA-preparations were subjected to nested PCR to amplify NS5B and 5'-untranslated region (5'UTR) sequences. Amplified fragments were sequenced and subtypes of the isolates were determined based on sequence similarities with reported sequences. In Chiang Mai and Hat Yai, Thailand, HCV-3a, HCV-1a and HCV-1b were common in various populations. HCV type 6 variants were commonly found among blood donors and drug addicts in Chiang Mai, but not in Hat Yai. In Surabaya, Indonesia, HCV-2a was frequently detected in blood donors, but less frequently in patients with chronic liver disease. In blood donors, HCV-1a, HCV-1b and HCV-1d were more strongly associated with elevation of serum aminotransferase levels than HCV-2a. HCV-1a was significantly more common in patients on maintenance hemodialysis than in blood donors or patients with chronic liver disease. HCV-1d was detected exclusively in Indonesia. Another unique subtype HCV-3g was found also in Indonesia, though less frequently than HCV-1d. In the Philippines, a vast majority of the isolates were either HCV-1a or HCV-1b. Thus, HCV subtype prevalence varies among different regions of Asia.

Hepacivirus↗
PubMed1998

Angiotensin AT1 receptor subtypes in the rabbit pulmonary artery. A ligand binding study.

The present ligand binding study showed that the rabbit pulmonary artery contained two subtypes of losartan-sensitive angiotensin receptor. The two receptor subtypes are differentially distributed. The high affinity receptor subtype is located predominantly in the cardia end of the artery while the low affinity receptor subtype is found mainly in the pulmonary portion of the artery. The Kd for the high and low affinity receptors for sar1, Ile8-angiotensin II was found to be 0.25 +/- 0.005 and 0.88 +/- 0.02 nM, respectively; and for angiotensin II to be 0.43 +/- 0.001 and 0.96 +/- 0.02 nM, respectively. In the presence of 1 mM GppNHp, the high affinity receptor subtype was converted to the low affinity subtype, indicating that it is G-protein coupled. 1 mM GppNHp had no effect on the low affinity receptor subtype. The present data support the findings of an earlier functional study which also showed the existence and similar differential distribution of two losartan-sensitive angiotensin receptors in the rabbit pulmonary artery. However, the significance of these findings in regard to the regulation of pulmonary circulation in normal and pathological conditions remains to be investigated.

Angiotensin I↗
PubMed1998

HIV vaccine development: a subtype E-specific strategy.

The pandemic of HIV/AIDS consists of multiple foci with distinct epidemiological characteristics. Among the approximately one million Southeast Asians infected with HIV, subtype (clade) E infections predominate. This subtype, a recombinant virus comprised of a clade A core (gag) gene and a mosaic clade A/clade E envelope (env) gene, became broadly epidemic in Thailand beginning in 1989. Since then, subtype E HIV has become increasingly prevalent throughout Southeast Asia. Consistent with the recent introduction of clade E HIV, the diversity of Southeast Asian subtype E viruses is narrow (6% nucleotide diversity across env). Since neutralizing antibodies may play a protective role against HIV infection, and are relatively clade specific for genotype E viruses, a subtype E-derived candidate vaccine tested in Southeast Asia would provide an optimal test of vaccine concept. It would also provide, for the first time to a developing region of the world, a non-B clade candidate vaccine designed specifically for the local epidemic. A consortium of industry (Chiron Vaccines and Pasteur Merieux Connaught), academic (Mahidol and Chiang Mai Universities) and military (United States and Royal Thai Army Medical Departments) medicine is working together to develop and test HIV vaccines for the genotype E epidemic. A genotype B recombinant glycoprotein (rgp)120 candidate vaccine has undergone phase I/II testing in Thailand and confirmed to be safe and immunogenic in this ethnic group. An rgp120 (E) has been produced and a phase I/II trial of the bivalent product (B/E) is in the final stages of approval. This vaccine construct is designed to elicit humoral immune responses. To augment these antibody responses with CD8+ CTL responses, an E-specific, live-vectored vaccine is being developed which will be used in conjunction with rgp120 in a second vaccine approach. Canarypox (ALVAC) constructs containing multiple HIV genes (gag/pol/env) currently designed for the subtype B epidemics will be modified to contain a clade E env gene sequence. After predetermined milestones have been met, these two subtype E-specific candidate vaccines will be assessed for protection in a large collaborative efficacy trial. Since neither animal models nor laboratory assays are validated as predictive of HIV vaccine efficacy, it must be through such a phase III trial that vaccine-induced protection and immunologic correlates will be determined.

AIDS Vaccines↗
PubMed2001

Detection of prostaglandin EP(1), EP(2), and FP receptor subtypes in human sclera.

PURPOSE: To examine the expression of five prostaglandin (PG) receptors, EP(1), EP(2), EP(3), EP(4), and FP and their corresponding mRNA transcripts in human sclera and cultured human scleral fibroblasts (HSFs). METHODS: Primary cultures of HSFs were established from donor eyes. Also, sclera from human donor eyes was snap frozen and sectioned. Immunocytochemistry was performed on HSFs and tissue sections with subtype-specific antibodies to the EP(1), EP(2), EP(3), EP(4), and FP receptors. The presence of mRNA for the receptor subtypes was examined from total RNA obtained from human sclera and confirmed with restriction digest analysis. RESULTS: Positive EP(1) and FP receptor immunoreactivity was observed in fibroblasts within the sections from human sclera. In primary cultures of HSFs, EP(1) and FP labeling was observed over the entire cell surface. EP(2) immunoreactivity within HSFs was mostly present in the juxtanuclear region. RT-PCR analysis of total RNA isolated from human sclera and HSFs confirmed the presence of EP(1), EP(2), and FP receptor subtypes. The identity of the polymerase chain reaction products was confirmed by restriction enzyme analysis. No mRNA or immunoreactivity above basal levels was detected for the EP(3) and EP(4) prostanoid receptor subtypes in tissue sections or primary cultures. CONCLUSIONS: The EP(1), EP(2), and FP receptor subtypes are present in HSFs, suggesting that these cells may respond to endogenous PGs and their structural analogues through interaction with these receptor subtypes.

Adult↗
PubMed2002

Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues.

PURPOSE: To determine the expression and precise cellular and subcellular localization of the EP prostanoid receptor subtypes EP(1) through EP(4) and the FP receptor in normal human ocular tissues on the protein and mRNA levels. METHODS: Expression of EP and FP receptor proteins was examined by immunohistochemistry on the light microscopic level, using subtype-specific antibodies on frozen and paraffin-embedded tissue sections of 10 normal human donor eyes. The subcellular distribution of the receptor proteins was studied by electron microscopic immunogold labeling. mRNA expression in various ocular tissues was analyzed by reverse transcription-polymerase chain reaction, using subtype-specific primers. RESULTS: The highest expression of the EP(1) receptor protein was found in the epithelia of the cornea, conjunctiva, lens, and the ciliary body; trabecular cells; iris vessels; and retinal ganglion cells. EP(2) receptor labeling was most prominent in the corneal epithelium and choriocapillaries. EP(3) and EP(4) receptor labeling was primarily observed in the corneal endothelium and keratocytes, trabecular cells, ciliary epithelium, and conjunctival and iridal stroma cells, and EP(3) was found, in addition, in retinal Müller cells. The highest expression of FP receptor protein was found in the corneal epithelium, ciliary epithelium, the circular portion of ciliary muscle, and iris stromal and smooth muscle cells. Immunoelectron microscopy showed a subcellular distribution of all prostanoid receptors along plasma membranes and the nuclear envelope. EP and FP receptor mRNA expression largely paralleled the proteins' expression patterns. CONCLUSIONS: The findings demonstrate a wide distribution but differential expression of FP and EP prostanoid receptor subtypes in human ocular tissues. EP(1) through EP(4) receptor subtype expression in human outflow pathways could be significant for future pharmacologic management strategies for the glaucomas.

Adolescent↗
PubMed2025

Coronary Artery Disease-Based Polygenic Risk Score in Early-Onset Acute Myocardial Infarction Subtypes.

BACKGROUND: The coronary artery disease-based polygenic risk score (PRS-CAD) estimates risk of acute myocardial infarction (AMI), but its performance across AMI subtypes in younger individuals, especially women, remains uncertain. OBJECTIVES: The authors assessed PRS-CAD's performance in AMI subtypes. METHODS: We included 2,079 AMI patients aged 18 to 55 years with a 2:1 female-to-male ratio from the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients) study and 3,761 controls from the MESA (Multi-Ethnic Study of Atherosclerosis) study. AMI subtypes were classified using the VIRGO taxonomy. We evaluated PRS-CAD's association with AMI subtypes using multinomial logistic regression and with 1-year outcomes in AMI subtypes using Cox regression. RESULTS: PRS-CAD was significantly associated with MI due to coronary artery disease (N = 1,876; OR: 1.82 per 1-SD increase; 95% CI: 1.67-1.97; P < 0.001) but not with MI with nonobstructive coronary artery disease (N = 188; OR: 1.13 per 1-SD increase; 95% CI: 0.96-1.34; P = 0.14). PRS-CAD's performance did not differ by sex. A 1-SD increase in PRS-CAD was associated with higher risk of 1-year hospitalization or death in patients with MI with nonobstructive coronary artery disease (HR: 1.50; 95% CI: 1.08-2.10; P = 0.02) but not in patients with MI due to coronary artery disease (HR: 0.98; 95% CI: 0.91-1.07; P = 0.67). CONCLUSIONS: PRS-CAD's association with AMI varied by subtype but not by sex in young adults, warranting caution in application.

acute myocardial infarction↗