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PubMed1992

Peptide-presenting similarities among functionally distant HLA-B27 subtypes revealed by alloreactive T lymphocytes of unusual specificity.

Functional dissection of HLA-B27 subtypes using alloreactive or B27-restricted CTL has shown that the structurally related B*2704 and B*2706 are the most distant subtypes relative to the prototype B*2705. In particular, previous studies have failed to find anti-B*2705 CTL cross-reacting with B*2704 or B*2706. Such failure can be accounted for by the drastic effect on T cell recognition of the change at residue 152 in both subtypes relative to B*2705, as established with site-directed mutants. B*2704 and B*2706 are also related in ethnic distribution, as they are restricted to Orientals, jointly being the predominant HLA-B27 subtypes in this population. As far as it is known, there are no differences relative to B*2705 in their linkage to ankylosing spondylitis. In our study, 5 of 13 examined anti-B*2705 limiting dilution CTL lines from a particular HLA-B27- individual were shown to crossreact with B*2704, B*2706 or both. The monoclonal nature of this cross-reaction was established by cold target competition analysis. This result demonstrates that the apparent differences in T cell antigenicity among anti-B27 subtypes are strongly influenced by the responder individual, as the spectrum of clonal specificities in anti-B27 responses may show significant differences among unrelated responders. Fine specificity differences among the cross-reactive CTL allowed unambiguous functional distinction between B*2704 and B*2706. The molecular basis of such cross-reactivity was examined by correlating CTL reaction patterns with the structure of both subtypes, which differ only by two residues located in the beta-pleated sheet bottom of the peptide binding site, and with site-directed mutants mimicking HLA-B27 subtype polymorphism. The results suggest that: 1) distinct peptides are involved in the allospecific epitopes recognized by the various crossreactive CTL, and 2) B*2704, B*2706, and B*2705 differ in their peptide-presenting specificity, but can present some identical or structurally similar peptides.

Clone Cells↗

PubMed1992

Quantitative autoradiography of muscarinic cholinergic receptor binding in the rat brain: distinction of receptor subtypes in antagonist competition assays.

Prior studies have suggested the presence of muscarinic acetylcholine receptor (MAChR) subtypes within the mammalian central nervous system on the bases of functional ligand binding or molecular biologic evidence. Autoradiographic differentiation of MAChR subtypes in ligand binding assays has previously relied on the use of agonists, results of homogenate binding assays to determine relative subtype binding affinities or both. In the present study, the binding of [3H]scopolamine to intact slide-mounted tissue sections is characterized. The rapid binding kinetics of the ligand permit autoradiographic saturation experiments. Autoradiographic competition assays utilizing [3H]scopolamine and the unlabeled subtype-selective ligands pirenzepine, 11-((2-[(diethylamino)methyl]-1-piperidinyl)acetyl)-5,11,-dihydro-6H-pyr ido (2,3-b)(1,4)benzodiazepin-6-on (AF-DX 116) and 4-diphenylacetoxy-N-methylpiperidine methiodide reveal evidence for the presence of multiple MAChR subtypes distributed heterogeneously throughout the brain. High-affinity pirenzepine MAChR (putative M1 subtype) predominate in the telencephalon. High-affinity AF-DX 116 MAChR (putative M2 subtype) are widely distributed, but are quantitatively minor populations, with the exception of motor cranial nerve nuclei and the basal pons, where they represent the dominant MAChR fractions. Evidence for relative enrichment of M3 receptors was obtained in the thalamus, the superficial layer of the superior colliculus, the periqueductal region, the substantia nigra pars reticulata and the pons. The autoradiographic assays developed in this work may assist in defining altered receptor populations arising in pathologic conditions or resulting from drug therapy.

Animals↗

PubMed2004

Antiretroviral drug resistance in non-subtype B HIV-1, HIV-2 and SIV.

Patients infected with HIV-1 of subtype other than B ('non-subtype B') or with HIV-2 are being treated with antiretroviral drugs in increasing numbers. In addition, healthcare providers and laboratory workers working with clinical specimens or animals infected with HIV, SIV or SHIV are at risk of being exposed to the virus and might require post-exposure prophylactic treatment. Thus, it is important to understand the inherent antiviral susceptibility of non-subtype B HIV-1, HIV-2 and SIV to currently available antiretroviral drugs, which have been developed with subtype B HIV-1-infected patients as the primary target population. In addition, knowledge about the consequences of treatment failure in non-subtype B HIV-1- and HIV-2-infected patients, with respect to the development of drug resistance, is crucial for designing optimal treatment strategies. This review summarizes the current state of knowledge in these areas. Non-subtype B group M HIV-1 appears to be susceptible to available agents, but follows several unique pathways to resistance to some drugs that have important clinical implications. Group O HIV-1 is naturally resistant to the non-nucleoside reverse transcriptase inhibitors (NNRTIs). HIV-2 and SIVsm are also naturally resistant to the NNRTIs as well as the protease inhibitor amprenavir. More research into the clinical responses to existing drugs and interpretation of genotypic information is needed, as well as development of diagnostic assays specific for non-subtype B HIV-1 and HIV-2.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Lipids in ischemic stroke subtypes.

In secondary prevention, reduction of the risk of recurrent ischemic stroke might be expected with statins if a correlation can be established between hyperlipidemia and ischemic stroke or some specific ischemic stroke/TIA subtypes. However, such correlation remains controversial, and more particularly with the etiologic stroke/TIA subtypes. Few studies have evaluated the plasma lipid profile in different ischemic stroke subtypes, and notably in lacunar infarctions and cardioembolic strokes. The objectives of this case-control study was to determine (1) which cholesterol fractions is associated with large vessel disease (LVD), small vessel disease (SVD), and cardioembolic disease (CED); (2) whether hypertriglyceridemia is related more to any particular stroke subtype; and (3) whether the lipid profile is different between LVD and SVD which are both responsible for atherothrombotic cerebral ischemia. From a cohort of 485 patients, were selected 240 consecutive cases with ischemic stroke (n = 182) or transient ischemic attack (n = 58) due to a single etiology. The levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), and triglycerides (TG) were measured in 61 patients with LVD, in 65 with SVD, and in 114 with CED, and compared with age- and sex-matched control subjects. Additional analysis was performed to compare the lipid profile between LVD and SVD after adjustment for other risk factors. Compared to controls, the total-C level was significantly higher in patients with SVD (p = 0.005) and LVD (p = 0.018). A significant increase in the LDL-C level (p < 0.004) and a significant decrease in the HDL-C level (p = 0.001) were only observed in the LVD patients. The three stroke subtypes showed higher TG levels than the controls (CED, p = 0.037; SVD, p < 0.001; LVD, p = 0.014). The plasma lipid profile was similar in the SVD and LVD subtypes except for HDL-C, which was significantly lower in LVD than in SVD (p = 0.047). Logistic regression adjusted for confounders showed that decreased HDL-C (p = 0.020), and smoking (p = 0.019) were significant discriminative factors for LVD vs. SVD. In conclusion, this controlled study shows that hypertriglyceridemia is commonly found in patients with ischemic cerebrovascular disease whatever the etiologic subtype, whereas hypercholesterolemia is related more to SVD and LVD. In addition to hypertension and diabetes, hypercholesterolemia may also be involved in the etiology of SVD and differs from LVD by a lower decrease in HDL-C.

Adolescent↗

PubMed2004

[The mRNA expression of alpha1-adrenergic receptor subtypes in the outer lung tissues of hypoxia pulmonary hypertension rats].

OBJECTIVE: During the development of hypoxic pulmonary hypertension, the quantity of the protein and mRNA of alpha1-adrenergic receptor (alpha1-adrenergic receptor,alpha1-AR) in the lung tissue increased, while no particular reports were found about the change of the alpha1-AR subtypes during that course. The study aimed to understand the quantity and location of alpha1-AR subtypes mRNA expression in control and hypoxia rats,and the effect of phentolamine in hypoxic pulmonary hypertension. METHODS: Fifty-five male Wistar rats were divided randomly into 5 groups: control group (n = 10), hypoxia 2 weeks (n = 13), hypoxia 4 weeks (n = 10), saline control group (n = 10) and hypoxia 4 weeks plus phentolamine group (n = 12). Semi-quantitative reverse transcription and polymerase chain reaction (RT-PCR) were used to examine the mRNA expression of alpha1-AR subtypes in each group. In situ hybridization was also used to detect the location of the alpha1-AR in lungs of normal rats. RESULTS: (1) The pulmonary artery pressure increased with the extension of hypoxia. (2) The results of RT-PCR showed that the mRNA expression of alpha1A-AR was the most,alpha1B-AR the second and alphaZD-AR was the least in all of the groups. (3) The expression of alpha1A-AR and alpha1B-AR mRNA increased with the extension of hypoxia, and the expressions among groups showed difference. (4) The expression of alpha1D-AR also increased with the extension of hypoxia but no difference was found among groups. (5) No difference was found in mRNA quantity of all three subtypes between phentolamine group and hypoxia saline group. (6) In situ hybridization showed that mRNA of the three alpha1-AR subtypes located mainly in the artery and venous smooth muscle cells and endothelial cells. CONCLUSIONS: This study suggested that alpha1-AR subtypes worked in the development of hypoxia pulmonary hypertension. More research on alpha1-AR subtypes may help the clinical treatment of pulmonary hypertension.

Adrenergic alpha-Antagonists↗

PubMed1998

Galanin receptor subtypes.

The potential for drug development in several therapeutic areas has made galanin receptors a popular target for the pharmaceutical industry in recent years. Galanin is present in brain tissue, as well as in peripheral tissues including the gastrointestinal tract, pancreas, bladder and genital tract. In general agreement with the results of immunohistochemical studies of galanin localization, galanin binding sites are found in many regions of the brain. The galanin receptor, a glycoprotein with a molecular mass of 54-60 kDa, was initially identified and characterized by radioligand binding studies with membranes prepared from tissues and cell lines. Several lines of evidence supported the existence of multiple galanin receptors, and at least four subtypes could be discriminated based on pharmacological data. Three galanin receptor subtypes, denoted GalR1, GalR2 and GalR3 (or GALR1, GALR2 and GALR3), have been cloned. Use of these cloned subtypes will allow compound screening, which will likely lead to the identification of compounds with high potency and selectivity for specific subtypes, providing powerful tools in studies of function, structure and regulation of galanin and its receptor subtypes. The next stage of the research in the galanin area will be to establish associations of therapeutic targets such as obesity, nociception and mnemonic processes with specific GalR subtypes. In addition, the generation of novel GalR antagonists/agonists that are bioavailable and subtype-selective will greatly accelerate the research efforts in this important field.

Journal Article↗

PubMed1997

[Subtype and sequence analysis of the C2-V3 region of gp120 genes among human immunodeficiency virus infected IDUs in Ruili epidemic area of Yunnan Province of China].

DNA fragments of HIV-1 env gene were amplified by nested-PCR from 17 uncultured peripheral blood mononuclear cells (PBMCs) obtained from HIV-1 seropositive intravenous drug users (IDUs) in Ruili city of Yunnan Province. The C2-V3 region (about 450 bp) of them were sequenced. Sequence analysis showed that there exists two HIV-1 subtypes, B and C, with 5.8% and 2.2% gene divergence inside each subtype. The 12 subtype B strains, were closely related to those found in Thailand, Myanma and Ruili city of Yunnan, and the nucleotide sequence divergence between them ranged from 4.4% to 4.9%; meanwhile, the 5 subtype C strains were most close to those found in India as well as Ruili city, all with a genetic distance of 1.9%. The small divergence among Ruili HIV-1 subtype C strains suggests a recent epidemic. The analysis of V3 loop amino sequence of 12 subtype B HIV-1 reveals that V3-tip motif of 6 samples (50%) is GPGQ and that of 3 samples (25%) is GPGR. In addition, the codon of arginine (R) of all the strains is CGA instead of AGA. This result is in accordance with our previous hypothesis that there is a drift in vivo from GPGR to GPGQ motif on the tipof V3-loop of HIV-1 subtype B strain in this arm with the elapse of time.

Amino Acid Sequence↗

PubMed2005

Frequency of HIV-1 dual subtype infections, including intersubtype superinfections, among injection drug users in Bangkok, Thailand.

OBJECTIVES: To estimate the frequency and incidence of dual HIV-1 subtype infections, including superinfections, among recent seroconvertors from a cohort of injection drug users (IDUs). METHODS: A total of 1209 HIV-negative IDUs were followed in a prospective cohort study at 15 methadone clinics in Bangkok, Thailand. After 2308 person-years (PY) of follow-up, 133 seroconverted to HIV-1, of which approximately 20% were subtype B and 80% were CRF01_AE (formerly called subtype E). Specimens from 126 individuals were available at time of first seropositive test and specimens from 80 of these 126 individuals were also available more than 12 months later. For each infected participant, we calculated the amount of time to superinfection, loss to follow-up, or to the closest visit more than 12 months after the time of initial seropositivity. RESULTS: Of all 126 seroconverters seen at the time of the first seropositive test result, there was no apparent case of concurrent dual subtype infection detected despite 2301 PY of observation. Overall, the incidence of superinfection was 2.2 per 100 PY [95% confidence interval (CI), 0.3-7.8]. The 1-year incidence of CRF01_AE superinfection following subtype B primary infection was 3.9 per 100 PY (95% CI, 0.1-21.9) and the incidence of subtype B superinfection following CRF01_AE primary infection was 1.5 per 100 PY (95% CI, 0.04-8.3). CONCLUSIONS: Determination of the frequency and incidence of dual HIV-1 subtype infection demonstrates that HIV-1 superinfection is not uncommon in a population with high HIV-1 incidence with more than one circulating strain.

Follow-Up Studies↗

PubMed2005

[The neuropsychological phenotype of attention deficit hyperactivity disorder: are there differences among subtypes?].

INTRODUCTION: Recent studies suggest that the ADHD subtypes would be best conceptualized as separate clinical entities, based on their epidemiology, central and associate symptomatology. OBJECTIVES: To determine the differences and similarities between subtypes in its associate symptomatology, specifically in the neuropsychological phenotype of executive dysfunction. PATIENTS AND METHODS: A group of children between 6 and 14 years of age with a diagnosis of ADHD-innattentive subtype (DESAT, n = 20) and another with ADHD-combined subtype (COMB, n = 39). RESULTS: Overall, the COMB subject sample displayed lower performance than DESAT group. Statistically significant differences were found in Kaufman-ABC-hands movement subtest, Wisconsin Card Sorting Test (WCST)-total error and WCST-conceptual level. CONCLUSIONS: The subtypes differ significantly in measures or non verbal working memory, hindsight, foresight, and motor control. Both groups share a deficit in response output speed and verbal working memory. We hypothesized areas of cognitive superiority for each subtype: spatial memory for the inattentive and gestaltic composition for the combined. Results provide evidence to support quantitative and qualitative differences in the neuropsychological profile between the ADHD-innatentive and combined subtypes.

Attention Deficit Disorder with Hyperactivity↗

PubMedDate not supplied

HIV-1 subtyping using gag/env heteroduplex mobility assay and peptide enzyme-linked immunosorbent assay.

Two HIV-1 subtypes have accounted for virtually all infections in Thailand: subtype B', found mainly in injection drug users (IDUs), and CRF01_AE (initially subtype E), found in over 90% of sexually infected persons and increasingly in IDUs in recent years. During 1997-1998, 227 blood samples were collected from HIV-1 infected individuals consisting of 92 mothers, 35 children and 100 IDUs. The blood samples were subtyped by heteroduplex mobility assay (HMA) and peptide enzyme-linked immunosorbent assay (PEIA). Using gag and env HMA, CRF01_AE and subtype B' accounted for 96-97% and 3-4% of both the mothers and the children, respectively. In the IDU group, 10% of the plasma samples could only be performed by gag HMA and gave the result as CRF01_AE. CRF01_AE and subtype B' using PEIA accounted for 67% and 33% of the IDUs. There was 100% concordance of the results between gag HMA and env HMA. Ninety-five percentages of concordant results were observed between HMA and PEIA. Of the 6/134 (5%) subjects with discordant results, nucleotide sequencing, used as a gold standard, confirmed the HMA result. In this study, HIV-1 was successfully genotyped by HMA and PEIA. However, a comparison of the subtyping results between HMA and PEIA revealed that HMA was slightly more accurate than PEIA.

DNA, Viral↗

PubMed1991

Interaction of subtype-selective antagonists with alpha 1-adrenergic receptor binding sites in rat tissues.

(+)-Niguldipine inhibited specific 125I-BE 2254 binding more potently in membrane preparations from rat tissues enriched in the alpha 1A subtype (hippocampus and vas deferens) than those with the alpha 1B subtype (liver and spleen). Inhibition curves for (+)-niguldipine were better fit by a two-site model in most tissues, although Kl values for each site varied markedly between tissues. The potency of this lipophilic drug was highly dependent on tissue concentration, probably accounting for most of this variability. Pretreatment of membranes with chloroethylclonidine (CEC) to inactivate the alpha 1B subtype did not completely eliminate the low affinity sites for (+)-niguldipine, particularly in heart. Saturation analysis showed that (+)-niguldipine competitively inhibited both alpha 1A and alpha 1B subtypes. However, substantial non-competitive inhibition was also observed in several tissues. Analysis of inhibition curves for 5-methylurapidil gave similar proportions of alpha 1A and alpha 1B receptor sites as were calculated for (+)-niguldipine in various tissues. Although (+)-niguldipine and 5-methylurapidil revealed variable proportions of low affinity sites in CEC-pretreated hippocampus and heart, this was not observed with inhibition curves for WB 4101 and phentolamine. These results are generally consistent with the previously defined alpha 1A and alpha 1B subtypes. 5-Methylurapidil currently appears to be the best antagonist for discriminating these subtypes; (+)-niguldipine shows similar selectivity but is complicated by a high lipophilicity. However, the persistence of low affinity sites for 5-methylurapidil and (+)-niguldipine after CEC pretreatment and the noncompetitive effects of (+)-niguldipine in some tissues raise the possibility of an additional subtype(s) of alpha 1-adrenergic receptors in rat tissues.

Adrenergic alpha-Antagonists↗

PubMed1990

Common and subtypic determinants of hepatitis B surface antigen particles: susceptibility to reduction and/or alkylation evaluated with monoclonal antibodies.

The specificity of five monoclonal antibodies, three raised against hepatitis B surface antigen (HBsAg) particles and two against envelope polypeptides, was tested for on a panel of 366 sera containing HBsAg of various subtypes (131 adw, 146 adr, 39 ayw and 50 ayr). Three monoclonals bound to HBsAg irrespective of subtypes, and therefore, were directed to the common antigenic determinants of HBsAg. Of these, two raised against particles (No. 824 and No. 7922) did not bind with reduced HBsAg particles. The other raised against peptides (No. 5124) bound to reduced HBsAg particles. It did not, however, bind to reduced and alkylated HBsAg particles, thereby indicating that it was directed to an epitope involving cysteine residues not contributing to the conformation. The remaining two monoclonals were directed to subtypic determinants not identical to any of d, y, w and r determinants. The subtypic determinant detectable by one of them (No. 4403), raised against HBsAg polypeptides, markedly increased after reduction of HBsAg particles with or without alkylation. In contrast, the subtypic determinant, detectable by the other monoclonal (No. 2155) raised against particles, substantially decreased after reduction. Non-identity of common or subtypic determinants detectable by the five monoclonals were established by blocking tests in which labeled antibody was competed by non-labeled antibody, of a homologous or heterologous specificity, for the binding with HBsAg. These monoclonals would be useful in studies for immunochemical configuration of HBsAg particles and epidemiology of novel subtypic determinants.

Alkylation↗

PubMed1991

Abortifacient property of bovine herpesvirus type 1 isolates that represent three subtypes determined by restriction endonuclease analysis of viral DNA.

Bovine herpesvirus type 1 (BHV-1) isolates are classified into 3 subtypes by use of restriction endonuclease analysis. Isolates from aborted fetuses have been either subtype 1 or 2a, whereas subtype 2b viruses have not been associated with abortion. We assessed the abortifacient property of isolates representing each of the 3 BHV-1 subtypes by IV inoculation of heifers with the virus 25 to 27 weeks after breeding. Three heifers were given Cooper (subtype 1) isolate, 3 heifers were given FI (subtype 2a) isolate, and 5 heifers were given K22 (subtype 2b) isolate. All heifers developed fever and viremia 2 to 5 days after inoculation. Heifers given Cooper or FI isolate aborted between 17 and 85 days after inoculation. The 5 heifers given K22 isolate delivered full-term calves. Placenta was obtained from 4 of the 5 heifers, and K22 virus was isolated from each placenta. Four calves had BHV-1 neutralizing antibody in precolostral serum, with titer ranging from 1:4 to 1:512.

Abortion, Veterinary↗

PubMedDate not supplied

P1- and P2-purinoceptor subtypes--an update.

It is suggested that neither the P1- nor the P2-purinoceptor forms a homogeneous group and that each can be separated into at least two subtypes. Biochemical, ligand binding and pharmacological studies clearly indicate that the P1-purinoceptor can be subdivided into the A1- and A2-subtypes. The recent development of antagonists, selective for the A1-subtype, supports this conclusion. Evidence for an A3-receptor also exists. On the basis of the rank order of potency of structural analogues of ATP and on the activity of antagonists, it is suggested that the P2-purinoceptor may be divided into the P2x- and P2y-subtypes. beta,gamma-methylene-L-ATP is a specific agonist at the P2x-subtype and ADP-beta-F a specific agonist at the P2y-subtype. Suramin acts as an antagonist at both subtypes, but reactive blue 2 appears to display selectivity for the P2y-purinoceptor. There is also evidence for P2t- and P2z-purinoceptors.

Animals↗

PubMed1990

[Prognostic relevance of histopathologic subtyping of nodular-sclerotic types of Hodgkin's disease].

The paper analyzes the histopathologic pattern of 30 bioptically assessed cases of nodular-sclerotic (NS) type of Hodgkin's disease diagnosed before onset of therapy. The ratio of lymphocytes and tumor cells, as well signs of atypia, pleomorphism and blastic proliferation of tumor cells were evaluated in each case. On the basis of this analysis, the NS type was divided into the subtype NS 1 (14 cases) and subtype NS 2 (16 cases). In the subtype NS 1 lymphocytes were predominant in the tumor nodes and there were only few Sternberg-Reed cells, which were either isolated or in small clusters. Fibrosis in the tumor nodes was mild. In the subtype NS 2 the ratio of lymphocytes was lower, Sternberg-Reed cells were numerous and were found to be in groups and clusters. Pleomorphism and atypia of the tumor cells was remarkable. Pronounced fibrosis was seen in the nodes. The ratio of reactive cells and necroses exhibited individual variation in both subtypes. Statistical evaluation of survival time showed significant differences between the patients with subtype NS 1 and NS 2. Differentiation between NS 1 and NS 2 subtypes of the nodular-sclerotic type of Hodgkin's disease can thus ben considered to be prognostically relevant.

Hodgkin Disease↗

PubMed1987

Genetic restriction of cytolysis during equid herpesvirus 1 subtype 2 infection.

Six Welsh Mountain pony foals were experimentally infected with a subtype 2 isolate of Equid Herpesvirus 1 (EHV-1) and subsequently examined for T cell mediated cytotoxicity against both subtypes. Cytotoxicity was not observed at 3 or 7 days after primary exposure but virus-specific, and genetically restricted, cytotoxicity of EHV-1-labelled autologous skin fibroblasts could be demonstrated 7 and 21 days after the animals were given a second exposure to live virus. Killing of subtype 2 antigen-labelled targets was more efficient than subtype 1 coated cells. This finding was paralleled by the observation that virus-neutralizing and complement-fixing antibody levels were subtype specific after the primary infection but after secondary exposure were directed against both subtypes. During primary infection the lymphocyte proliferative response to EHV-1 subtype 2 was not evident at 7 days post infection (dpi) but by 18 dpi was present in all animals. The second exposure produced an earlier (3 dpi) and larger proliferative response which was specific to the infecting isolate. The non-specific proliferative response to Concanavalin A mitogen indicated that virus infection induced a state of activation in circulating lymphocytes.

Animals↗

PubMed1988

Beta adrenoceptor subtype binding activity in plasma and beta blockade by propranolol and beta-1 selective bisoprolol in humans. Evaluation with Schild-plots.

In the present study we investigated whether the beta adrenoceptor subtype binding activity in plasma samples can predict selective and nonselective beta blockade in humans. From the right shifts of isoprenaline dose-response curves 0 to 84 hr after administration of propranolol and the beta-1 selective bisoprolol, in vivo beta blockade was assessed. In an in vitro radioreceptor assay with membrane preparations of beta-1 or beta-2 adrenoceptors, plasma samples were assayed for subtype selective blocking activity. After propranolol administration, in vitro beta-1 and beta-2 adrenoceptor occupancy declined from initially 97% to less than 10% within 48 hr. An isoprenaline dose ratio (DR)-1 of 1 coincided with a 50% occupancy of the beta-1 or the beta-2 subtype in vitro. In Schild-plots using plasma concentrations (radioreceptor assay) and the isoprenaline DR-1 for heart rate, diastolic blood pressure and inotropy (QS2C), slopes of unity were observed. After bisoprolol administration, in vitro beta-1 occupancy shifted from initially 95% to less than 10% within 72 hr. For the beta-2 subtype, an occupancy of greater than 10% was detectable only within the first 12 hr. An isoprenaline DR-1 of 1 coincided with a 50% occupancy of beta-1 adrenoceptors. The bisoprolol Schild-plots yielded a slope of unity for inotropy, but less than unity for the heart rate and diastolic blood pressure. From an extended analysis of subtype selective antagonism in Schild-plots, the fractions of the beta-2 adrenoceptor subtype participating in the isoprenaline response were calculated: heart rate 0.45 +/- 0.12 and diastolic blood pressure 0.23 +/- 0.13. It is concluded that in vitro receptor occupancy can predict beta blockade in humans for propranolol. Beta adrenoceptor subtype-mediated effects in humans can be evaluated with a selective antagonist and a refined analysis of Schild-plot data.

Adult↗

PubMed1988

Acute anterior uveitis and HLA-B27 subtypes.

The tissue antigen HLA-B27 is found in 50% of Dutch acute anterior uveitis (AAU) patients. The prevalence of HLA-B27 in the normal population is only 8%. However, only approximately 1% of HLA-B27+ individuals will develop AAU. Therefore, it is possible that the disease is associated with a particular B27 subtype. We typed lymphocytes of 36 B27+ AAU patients, of which 20 also had ankylosing spondylitis, for three serologically defined B27 subtypes (B27 W, B27 K and B27 non W/non K). These subtypes were normally associated with AAU. The subtype frequencies in the patients suffering from both AAU and AS also showed no preference for a certain subtype. Subtype-specific characteristics of the primary structure of the various B27 subtype molecules therefore cannot be responsible for the disease association.

Acute Disease↗