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PubMed1977

Geographical distribution of the subtype of hepatitis B surface antigen in Chinese.

Using the much more sensitive hemagglutination inhibition assay for subtyping of hepatitis B surface antigen (HBsAg), we examined the determinants a, d, w and r in 192 from 228 HBsAg positive adults who had been found after screening with reversed passive hemagglutination method. Sixty-four subtypable cases were asymptomatic carriers and the remaining 128 were liver disease patients. Among them there was no significant difference of the subtypes, invariably with adw as the main subtype. Geographical difference was evident: adr was the main subtype (78 per cent) among the northern Chinese; while adw was dominant (76 per cent) among the southern Chinese with the Yangtze River as a boundary. Eight of the 18 adr-subtyped northern Chinese were born and live in Taiwan where 91 per cent of HBsAg positive Taiwanese were adw-subtyped. This was an indirect evidence that intra-familial spreading from parents played an important role in hepatitis B virus infection.

Acute Disease↗
PubMed2004

Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells.

Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of human beta-adrenergic receptors in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds.

Adenylyl Cyclases↗
PubMed2002

Characteristic MRI findings in multiple system atrophy: comparison of the three subtypes.

We reviewed MRI findings in 29 patients with probable multiple system atrophy (MSA) to see whether there were common and or less common neuroradiological findings in the various clinical subtypes. We divided the patients into three clinical subtypes according to initial and predominant symptoms: 14 with olivopontocerebellar atrophy (OPCA), eight with the Shy-Drager syndrome (SDS) and seven with striatonigral degeneration (SND). The patients showed atrophy of the brain stem and cerebellum, high signal on T2-weighted images of the base of the pons and middle cerebellar peduncles, high and low signal on T2-weighted images of the putamen and atrophy of frontal and parietal lobes. The degree of atrophy of the middle cerebellar peduncle and cerebellum was greater in OPCA patients and a high-signal lateral rim to the putamen more frequent in SND. However, all findings were observed in all subtypes, and the degrees of atrophy of the putamen and pons and the frequency of high signal in the base of the pons were similar in the subtypes. We also found atrophy of the cerebral hemispheres, especially the frontal and parietal lobes, but its degree was not significantly different in the various subtypes. Our findings suggest that, although MSA can be divided clinically into three subtypes, most of the features on MRI are common and overlap in the subtypes, independently of the clinical presentation.

Brain↗
PubMed1996

Subtyping of human T-lymphotropic virus type I by amplification of long terminal repeat sequences and restriction fragment length polymorphism analysis in carriers with multiple transfusions.

Five major subtypes of human T-lymphotropic virus type I (HTLV-I) have been proposed: cosmopolitan, Japanese, West African, Central African, and Melanesian. Based on nucleotide variations specific to particular subtypes, it was possible to genotype HTLV-I rapidly by restriction fragment length polymorphism (RFLP) studies following polymerase chain reaction (PCR). In this study, the restriction patterns of two LTR fragments were analyzed using eight restriction endonucleases (AvaI, Eco57I, BsoFI, NdeI, SacI, DraI, MaeII, and MaeIII). Genotyping of HTLV-I was done in nine patients with adult T-cell leukemia or HTLV-I-associated myelopathy/tropical spastic paraparesis, in three prostitutes, and in 19 carriers with multiple transfusion in Taiwan. The subtyping results of RFLP studies using these eight restriction endonucleases were in accordance with those of phylogenetic analysis. A substitution of G by A at nucleotide position 503, which creates the DraI site but suppresses the SacI site, was found not only in the Japanese subtype but also in a minority of the cosmopolitan subtype. A mutation near the position of subtype-specific nucleotide variations might suppress the restriction site and lead to unexpected restriction patterns. Amplification of more than one proviral fragment and RFLP studies with a group of appropriate restriction endonucleases may provide rapid and accurate genotyping of HTLV-I. More carriers are required to evaluate the possibility of mixed infection with different HTLV-I subtypes.

Base Sequence↗
PubMed2004

Liposarcoma subtypes: identification with computed tomography and ultrasound-guided percutaneous needle biopsy.

The purpose of the study was to evaluate the feasibility of image-guided percutaneous needle biopsy to enable specific subtype classification of liposarcoma in patients with previously diagnosed disease and compare the yield of fine and large needle techniques for each subtype. We reviewed the medical records and pathology reports of 69 fine (20 g) needle and large (15, 16 g) needle biopsies performed in 44 patients enrolled in a clinical trial evaluating the effect of a novel therapy for advanced liposarcoma in the abdomen and pelvis. Cytopathologists and surgical pathologists identified features that enabled them to classify the tumor into one of four subtypes: well differentiated, myxoid/round cell, pleomorphic and dedifferentiated. The pre-study open surgical biopsy was used as the standard for comparison. The diagnostic yield (proportion of biopsies with correct subtype diagnosis) of percutaneous biopsy for identifying all subtypes of liposarcoma was 81% (64% for fine needles and 73% for large needles alone). There was a significant association between pathologic subtype and the probability of a correct diagnosis (P=0.05). Accurate diagnostic subset classification of liposarcoma by percutaneous biopsy is feasible, although both fine and large needles should be used. Although these data cannot be extrapolated to primary diagnosis of liposarcoma, they are important for screening and subtyping of possible recurrence.

Adult↗
PubMed2006

Genotype and subtype analyses of Cryptosporidium isolates from dairy calves and humans in Ontario.

To assess the importance of dairy cattle as a source of human Cryptosporidium infections in Ontario, Canada, 44 Cryptosporidium isolates from neonatal dairy calves and 11 from sporadic human cases of cryptosporidiosis in the province were genotyped by PCR-RFLP analyses of the Cryptosporidium oocyst wall protein (COWP) and 18S rRNA genes. Isolates were also subtyped by sequence analysis of the 60-kDa glycoprotein (GP60) gene. All bovine isolates successfully subtyped belonged to Cryptosporidium parvum subtype family (allele) IIa. Seven subtypes of this family were identified among the bovine isolates. Four human isolates were Cryptosporidium hominis, of alleles Ia, Id, and Ie. Of the remaining seven human specimens, four were C. parvum allele IIa, two were C. parvum of an undetermined subtype, and one was identified as Cryptosporidium cervine genotype. Three of the C. parvum isolates from humans were the same subtypes as isolates from the calves. These findings suggest that cattle and other ruminants may be a source of sporadic human infections in Ontario. This is the first published description of Cryptosporidium genotypes and subtypes in Ontario, and is the second published report of human infection with Cryptosporidium cervine genotype.

Animals↗
PubMed2006

Genotypes and subtypes of Cryptosporidium spp. in neonatal calves in Northern Ireland.

Cryptosporidium spp. in diarrheic calves less than 30 days old from farms across Northern Ireland were examined over a year period by microscopic, genotyping, and subtyping techniques to characterize the transmission dynamics. Cryptosporidium oocysts were detected in 291 of 779 (37.4%) animals. The prevalence rates of rotavirus, coronavirus, and Escherichia coli K99+ were lower as seen in 242 of 806 (30.0%), 46/806 (5.7%), and 16/421 (3.8%) of animals, respectively. Of the 224 Cryptosporidium-positive specimens available for molecular analysis, Cryptosporidium parvum was identified in 213 (95.1%) specimens, Cryptosporidium bovis in eight (3.6%), and Cryptosporidium deer-like genotype in three (1.3%). Sequence analysis of the 60-kDa glycoprotein gene identified 16 IIa subtypes and a new subtype family, with 120 of the 216 (55.6%) positive specimens having the subtype IIaA18G3R1. Eight of the IIa subtypes were previously seen in humans in Northern Ireland. Several subtypes were temporally or geographically unique. The genetic diversity in calves in Northern Ireland was much greater than that reported from other areas. This work demonstrates the utility of genotyping and subtyping tools in characterizing the transmission of Cryptosporidium spp. in calves and humans.

Animals↗
PubMed1988

Tissue distribution and selective inhibition of subtypes of high affinity cAMP phosphodiesterase.

High affinity cAMP phosphodiesterase (PDE), also referred to as PDE III, or low Km PDE occurs as two subtypes. One subtype is sensitive to inhibition by cGMP while the other is relatively insensitive. To be consistent with previously recommended nomenclature, these subtypes were designated Types IV and V PDEs respectively. Tissue distribution of these subtypes of high affinity cAMP PDE was investigated using comparative potencies of specific inhibitors. Of the tissues examined, dog heart contained the highest proportion of the cGMP inhibitable form (Type IV PDE), whereas dog kidney cortex and brain were composed almost entirely of the cGMP non-inhibitable form (Type V PDE). Enoximone and other new cardiotonic drugs that inhibit high affinity cAMP PDE were shown to be specific for the cGMP inhibitable form, whereas rolipram was specific for the cGMP non-inhibitable form. The apparently partially competitive kinetics shown by one of these drugs, enoximone, was due to the presence of both subtypes of the enzyme. When the activity of the cGMP non-inhibitable form was suppressed by rolipram, competitive inhibition of the cGMP inhibitable subtype by enoximone was observed. Rat heart high affinity cAMP PDE activity contained a higher proportion of the cGMP non-inhibitable subtype than did the enzyme from dog heart. It is suggested that this may account for the relative insensitivity of rats to the cardiotonic PDE inhibitors.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

Heterologous expression of the cloned guinea pig alpha 2A, alpha 2B, and alpha 2C adrenoceptor subtypes. Radioligand binding and functional coupling to a CAMP-responsive reporter gene.

Functional studies have shown that 6-chloro-9-[(3-methyl-2-butenyl)oxy]-3-methyl-1H-2,3,4,5-tetrahydro-3- benzazepine (SKF 104078) has very low affinity for prejunctional alpha 2-adrenoceptors (alpha 2-AR) in the guinea pig atrium. In this study, we have cloned guinea pig homologues of the human alpha 2-C10, alpha 2-C4 AR subtypes and have studied them in isolation by heterologous expression in cultured mammalian cells. Oligonucleotide primers, designed from conserved areas of the human alpha 2-ARs were used in a polymerase chain reaction (PCR) with template cDNA synthesized from guinea pig atrial mRNA. Three PCR products were obtained that shared identity with the three human alpha 2-AR subtypes. A guinea pig (gp) genomic library was screened with a cDNA clone encoding a portion of the gp-alpha 2A, and genes containing the complete coding sequences of the guinea pig alpha 2A, alpha 2B, and alpha 2C AR subtypes were obtained. These guinea pig genes were subcloned into a eukaryotic expression plasmid and were expressed transiently in COS-7 cells. The binding of the alpha 2-selective antagonist [3H]MK-912 to membranes prepared from these cells was specific and of high affinity with Kd values of 810 pM for gp-alpha 2A, 2700 pM for gp-alpha 2B and 110 pM for gp-alpha 2C. Competition for the binding of [3H]MK-912 by SKF 104078 indicated that it was of moderately high affinity (approximately 100 nM) but that it was not selective for any of the guinea pig alpha 2-AR subtypes. Co-expression of guinea pig alpha 2-AR subtypes with a cyclicAMP-responsive chloramphenicol acetyltransferase (CAT) reporter gene resulted in agonist-dependent modulation of CAT activity. For the gp-alpha 2 A, a biphasic response was obtained with low concentrations of noradrenaline (NE) decreasing forskolin-stimulated CAT activity and high concentrations causing a reversal. For the gp-alpha 2B, NE produced mostly potentiation of forskolin-stimulated activity, and for the gp-alpha 2C, NE caused mainly inhibition. Overall, the pharmacology of the cloned guinea pig alpha 2-AR subtypes was in agreement with data obtained for the native guinea pig receptors and was functionally similar to that of the cloned human alpha 2-AR subtypes.

Adrenergic alpha-Antagonists↗
PubMed1986

Alpha-2 adrenergic receptor subtypes indicated by [3H]yohimbine binding in human brain.

Pharmacologic characterization of mammalian alpha-2 adrenergic receptors in various tissues and species has provided evidence for the existence of two alpha-2 adrenergic receptor subtypes. Prazosin and oxymetazoline have been shown to differentiate between the receptor subtypes as defined in rat tissues. In order to determine the relative proportions of these two receptor subtypes in human brain, the inhibition of the binding of the alpha-2 adrenergic antagonist [3H]yohimbine by oxymetazoline and prazosin was studied in membranes from three brain regions. Inhibition curves in membranes from the cerebral cortex and cerebellum were consistent with a single class of receptor binding sites suggesting that these two brain regions contain only one of the two subtypes. This subtype has the pharmacologic characteristics of the alpha-2A adrenergic subtype (yohimbine greater than oxymetazoline much greater than prazosin). In contrast, inhibition curves for both ligands in the human caudate nucleus were consistent with a model of two classes of binding sites in approximately equal proportions, suggesting that this tissue contains approximately equal densities of the alpha-2A and alpha-2B adrenergic receptor subtypes.

Binding, Competitive↗
PubMed1994

Identification of alpha 1-adrenoceptor subtypes present in the human prostate.

alpha 1-Adrenoceptors (ARs) play an important role in mediating human prostatic smooth muscle contraction. In the present study cDNA fragments covering different domains of 3 alpha 1-AR subtypes (alpha 1b, alpha 1c and alpha 1d) were generated from human prostate by reverse transcription coupled to the polymerase chain reaction (RT-PCR). The reconstituted partial sequence (349 amino acids) of the human prostatic alpha 1c-AR PCR products showed 94% identity at the amino acid level with that of the corresponding region of the cloned bovine brain alpha 1c-AR. Using human alpha 1-AR subtype selective cDNA probes in Northern blot analysis, the co-expression of mRNA transcripts corresponding to alpha 1b-, alpha 1c- and alpha 1d-AR subtypes was detected in 4 different regions (apex, base, periurethra and lateral lobe) of the human prostate. Competitive inhibition experiments of [3H]-prazosin binding to membrane preparations of human prostate revealed that the non-selective alpha 1-subtype antagonist, alfuzosin, produced a monophasic inhibition curve, whereas oxymetazoline produced a 2-component inhibition curve with pKi values of 8.54 and 5.46. The high-affinity alpha 1-AR component of the oxymetazoline inhibition curve was predominant (57%-66%) and showed an affinity for oxymetazoline comparable to that of the alpha 1c-AR subtype. As such our results illustrate the expression of different alpha 1-AR subtypes in human prostate and importantly that alpha 1c represents the predominant alpha 1-AR subtype present in this tissue.

Adenoma↗
PubMed1990

Identification of muscarinic receptor subtypes present in cerebellar granule cells: prevention of [3H]propylbenzilyl choline mustard binding with specific antagonists.

Subtypes of muscarinic receptors (possible m1 to m5) can be identified by their molecular size, specific effector systems and antagonist specificity. In membranes prepared from primary cultures of cerebellar granule cells, [3H]propylbenzilylcholine mustard [( 3H]PBCM) irreversibly binds to muscarinic receptive proteins, having two major molecular sizes, 92 and 66 kDa. With relatively short periods of incubation (approx. 30 min, 30 degrees C) of [3H]PBCM with atropine, a nonspecific competitive receptor antagonist, the irreversible labeling of these muscarinic proteins by [3H]PBCM could be prevented. Methoctramine, a specific competitive antagonist at muscarinic receptors coupled to inhibition of adenylate cyclase, protected most of the muscarinic receptors having a molecular size of 66 kDa from binding of [3H]PBCM. These 66 kDa receptive proteins are suggested to be muscarinic m2 and m4 subtypes. (-)Quinuclidinyl xanthene-9-carboxylate [(-)QNX], a somewhat specific competitive antagonist at muscarinic receptors coupled to hydrolysis of phosphatidylinositol, prevented the binding of [3H]PBCM to 92 kDa muscarinic receptive proteins and some 66 kDa muscarinic receptive proteins. The 92 kDa receptive proteins are suggested to be the muscarinic m3 subtype and the 66 kDa proteins could be either the m2 or m4 receptor subtype. Lastly, pirenzepine, a nonspecific antagonist at muscarinic receptors mediating inhibition of adenylate cyclase and hydrolysis of PI in these cultures, resembled (-)QNX in preventing binding of [3H]PBCM to the 92 kDa receptive proteins and some 66 kDa receptive proteins. The suggested subtypes of muscarinic receptors, specifically bound by pirenzepine should be the m3 (92 kDa) and the m4 (66 kDa) subtypes, since pirenzepine reportedly exhibits a low affinity for the muscarinic m2 subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗
PubMed1996

Expression of alpha 1 adrenergic receptor subtype mRNAs in the rat cardiovascular system with aging.

Alpha 1 adrenoreceptors mediate inotropic and chronotropic responses in the heart and vaso-constriction in blood vessels. Pharmacological studies using selective antagonists for subtypes of alpha 1 receptor suggest that different receptor subtypes may mediate different physiological effects. Prior studies have demonstrated that alpha 1-mediated cardiac responses are altered in aging and that alpha 1 receptor number declines with age in the rat heart. The distribution of alpha 1 receptor subtypes in cardiac tissue and subtype-specific changes with aging, however, have not been established. Using R Nase protection assays and in situ hybridization techniques, we have detected message for alpha 1B, alpha 1A, and alpha 1D in all four chambers of the rat heart and in multiple blood vessels. We found no significant changes in alpha 1 receptor subtype mRNA levels in hearts from young (4 months) and old (25 months) Sprague-Dawley rats. Also, there was expression of these three subtypes in all blood vessels assayed. We conclude that transcriptional regulation of alpha 1 adrenoreceptor subtypes does not account for age-related changes in cardiac alpha-adrenergic responsiveness.

Aging↗
PubMed1996

Muscarinic receptor subtypes in subpopulations of human blood mononuclear cells as analyzed by RT-PCR technique.

In this study we have analysed the expression of mRNA encoding the m1-m5 mAChR subtypes in human blood mononuclear cells and subpopulations of lymphocytes using reverse transcriptase-polymerase chain reaction (RT-PCR) technique. Total RNA was extracted from human blood mononuclear cells. T cells, monocytes. EB virus transformed B cells and from two leukemic cell lines and analysed by RT-PCR. Our results indicate that mRNAs for the m3, m4 and m5 muscarinic subtypes are expressed in mononuclear cells and purified T cells while m1 and m2 mRNAs were not detected in these cells. No m1-m5 subtype mRNA was detected in B cells and monocytes, indicating absence of muscarinic receptors in these cells. The expression of muscarinic subtypes in the leukemic T cell line. Peer, and the promyelocytic leukemic cell line HL-60 was different from peripheral mononuclear cells. Both m3 and m5 subtypes were expressed in Peer cells but not the m4 subtype, whereas the m4 and m5 subtypes detected in HL-60 cells.

B-Lymphocytes↗
PubMed1993

Ligand binding, internalization, degradation and regulation by guanine nucleotides of bombesin receptor subtypes: a comparative study.

Recent cloning studies confirm two subtypes of Bn receptors exist, a neuromedin B-preferring receptor (NMB-R) and a gastrin-releasing peptide-preferring receptor (GRP-R). Both subtypes occur widely in GI tract and the CNS; however, in contrast to the GRP-R subtype little is known about the ligand-receptor interactions for the NMB-R. Therefore, in the present study we explored the ligand-receptor interactions including kinetics, stoichiometry, internalization, degradation and regulation by guanine nucleotide binding proteins with the NMB-R and compared it to the GRP-R. The rat glioblastoma C-6 cell line which possess functional NMB-R and 3T3 cells which possess functional GRP-R were used. 125I-[D-Tyr0]NMB and 125I-[Tyr4]Bn were prepared using Iodogen and purified on HPLC. At 37 degrees C binding of 125I-[D-Tyr0]NMB to NMB-R or 125I-[Tyr4]Bn to GRP-R was maximal by 5-15 min and decreased to 60-70% after 60 min. HPLC analysis of the 60 min supernatant showed that > 80% of each tracer was degraded. Addition of proteinase inhibitors had a varied inhibitory effect on degradation with the relative order of potency in C-6 cells being leupeptin > bacitracin < chymostatin > phosphoramidon >> bestatin and amastatin and 3T3 cells being bacitracin = phosphoramidon > leupeptin = bestatin > chymostatin > amastatin in 3T3 cells. By HPLC analysis addition of bacitracin prevented the degradation in both cell types. With both receptor subtypes dissociation of bound radioligands was slow, with 70-80% of either 125I-[D-Tyr0]NMB or 125I-[Tyr4]Bn remained cell-associated after 60 min suggesting possible peptide internalization. With an acid wash procedure to remove surface bound radioligands, 60% of the C-6 cell-associated 125I-[D-Tyr0]NMB and 52% of the 3T3 cell-associated 125I-[Tyr4]Bn were internalized after 30 min at 37 degrees C. With membranes from cells possessing either receptor subtype, the stable guanine nucleotide GPP(NH)P inhibited in a dose-dependent fashion binding of ligands. Computer analysis demonstrated that GPP(NH)P decreased receptor affinity for ligands to both receptor subtypes. These results demonstrated that NMB receptors, similar to GRP receptors and rapidly internalize bound agonists and rapidly degrade agonists. The ligand-receptor interaction is regulated by a guanine nucleotide binding protein for both Bn receptor subtypes.

Animals↗
PubMed1995

Localization of mRNAs of voltage-dependent Ca(2+)-channels: four subtypes of alpha 1- and beta-subunits in developing and mature rat brain.

The heterogeneous gene expression for four subtypes of alpha 1 (A,B,C,D)- and beta (beta 1,beta 2,beta 3,beta 4)-subunits of voltage-dependent calcium channels was demonstrated in developing and adult rat brain by in situ hybridization histochemistry. In the adult rat brain the gene expression for A- and B-subtypes was predominant in the cerebellar cortex and hippocampal neuronal layers, with the A-subtype expressed most intensely in the Purkinje cells, while the expression for C- and D-subtypes was predominant in the olfactory mitral and granule cells and the dentate granule cells. The expression of beta 1-mRNA was prominent in the olfactory mitral cells and dentate granule cells whereas that of beta 2-mRNA was evident in the hippocampal neuronal layers and cerebellar Purkinje cells. The expression of beta 3-mRNA was prominent in the olfactory mitral and internal granule cells and medial habenula, whereas that of beta 4-mRNA in the olfactory mitral cells and cerebellar Purkinje and granule cells. Comparison between the expression patterns for individual alpha- and beta-subunits suggests that the beta 4-subunit contributes to P-type channel, whereas the beta 1- and beta 3-subunits contribute respectively to D- and C-subtypes of L-type channels, although dissociation in the expression patterns were also noted in several brain regions. In addition to neuronal populations, the gene expression for the C-subtype of L-type channel was detected at substantial level in glial cells. In developing brains, the genes for the all subtypes of alpha 1- and beta-subunits were expressed in the mantle zones, but not the ventricular zones, of the entire neuraxis and the expression was more or less attenuated during early postnatal periods in most of the brain regions except for the olfactory bulb, hippocampus and cerebellar cortex, suggesting that the Ca(2+)-channels are intimately involved in the neuronal differentiation.

Age Factors↗
PubMed1994

Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain.

alpha 2-Adrenergic receptors in brain are important presynaptic modulators of central noradrenergic function (autoreceptors) and postsynaptic mediators of many of the widespread effects of catecholamines and related drugs. alpha 2-Adrenergic agonists are currently used as antihypertensives and preanesthetic agents, but new subtype-selective alpha 2-adrenoceptor agonists and antagonists have additional therapeutic application potential. Three genes encoding specific alpha 2-adrenoceptor subtypes (alpha 2A, alpha 2B, and alpha 2C) have been isolated and characterized. RNA blotting indicates that all three are expressed in rat brain. This study used in situ hybridization with 35S-labeled RNA probes to map the distribution of alpha 2-adrenoceptor subtype gene expression in rat brain. alpha 2A mRNA was most abundant in the locus coeruleus, but was also widely distributed in the brain stem, cerebral cortex, septum, hypothalamus, hippocampus and amygdala. alpha 2B mRNA was observed only in the thalamus. alpha 2C mRNA was mainly localized to the basal ganglia, olfactory tubercle, hippocampus, and cerebral cortex. These mRNA distributions largely agree with previous findings on the alpha 2-adrenoceptor distributions in the rat brain, but suggest that the localization patterns for each receptor subtype are unique. The expression of alpha 2A mRNA in noradrenergic neurons indicates that this subtype mediates presynaptic autoreceptor functions. Furthermore, the localization of alpha 2A mRNA in noradrenergic projection areas suggests that this receptor may also have an important role in mediating postsynaptic effects. The precise physiological and pharmacological roles of the alpha 2-adrenoceptor subtypes are still largely unknown, but it is expected that in situ hybridization coupled to various methods to identify the transmitter phenotypes of the subtype-expressing neurons will help to clarify these important issues in the near future.

Animals↗
PubMed1994

HLA-B35-subtype mismatches in ABDR serologically matched unrelated donor-recipient pairs.

We have characterized HLA incompatibilities in a group of 17 B35-positive patients who were ABDR matched (AB serology and oligotyping for DR1-14) with their 28 (unrelated) potential bone marrow donors. High-resolution oligotyping for DR subtypes disclosed that nine combinations were in fact DR mismatched. Cytotoxic T-lymphocyte (CTL) activity was detected in nine combinations (32%). In the group matched for DR subtypes, three (16%) of 19 combinations were CTL positive. Patient-specific cytotoxic activity appeared to be directed against HLA C (two cases) or against a subtype of B35. In the group of DR-subtype-mismatched combinations, CTL activity was found in six (67%) of nine pairs. In all four cases that were studied in detail, however, CTL reactivity appeared to be directed against a variant subtype of B35. We have studied the B35 incompatibilities recognized in five different combinations by specificity analysis of the B35-specific CTLs and by partially sequencing of relevant segments of B35 exon 3. Preliminary data show that, within this relatively small Caucasoid group, at least five B35-variant subtypes could be distinguished. This would make B35 an antigen that will be frequently subtype mismatched, in particular when DR matching is done with low resolution (DR1-14) only.

HLA-A Antigens↗