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PubMed1990

Expression of three alpha 2-adrenergic receptor subtypes in rat tissues: implications for alpha 2 receptor classification.

Based on biochemical and ligand binding studies in various tissues and species, evidence for several alpha 2-adrenergic receptor subtypes has accumulated. The current alpha 2-adrenergic receptor classification (alpha 2A, alpha 2B, alpha 2C) is based exclusively on pharmacological criteria. The molecular cloning of three distinct genes for human alpha 2-adrenergic receptors has confirmed the existence of multiple alpha 2-adrenergic receptor subtypes. According to their localization on different human chromosomes, the receptor genes were termed alpha 2-C10, alpha 2-C4, and alpha 2-C2. The relationship, however, between the pharmacologically characterized alpha 2-adrenergic receptors and the isolated genes has yet to be clarified. Using Northern blot hybridization, we analyzed the expression of the three cloned alpha 2-adrenergic receptor genes in 13 rat tissues, as well as in cell lines previously described as model systems for the pharmacologically defined alpha 2-adrenergic receptor subtypes. The alpha 2-C10 receptor corresponds to the alpha 2A subtype and is expressed in rat brainstem, cerebral cortex, hippocampus, pituitary gland, cerebellum, kidney, aorta, skeletal muscle, spleen, and lung. Messenger RNA coding for the alpha 2-C4 receptor was detected only in brain regions, not in peripheral tissues, whereas the alpha 2-C2 message was found only in liver and kidney. Hybridization experiments with RNA derived from tissues and cells from which the pharmacological alpha 2-receptor classification has been developed lead to the conclusion that the alpha 2B subtype represents two distinct receptor molecules, the alpha 2-C4 and a subtype previously undetected by classical ligand binding approaches. Furthermore, our results suggest that the alpha 2C subtype characterized in opossum kidney cells is an interspecies variation of alpha 2-C4 rather than a separate subtype. Finally, the cloned alpha 2-C2 receptor was found to be "alpha 2B-like" and not covered by the current pharmacological classification.

Animals↗

PubMed1981

[Neuraminidase-Inhibiting Antibodies to Avian Influenza Virus Subtypes in Human Sera (author's transl)].

400 human sera were tested both in hemagglutination inhibition (HI) and neuraminidase inhibition (NI) tests for antibodies to avian and animal influenza virus subtypes. In the H1 test we only found antibodies to the avian subtype Hav 7 and the animal subtypes Hsw 1 and Heq 2 whereby the latter was mainly demonstrated in elderly persons 60 to 100 years old. The findings of Hav 7 are due to H 3 antibodies and reflect the relationship between both antigens. In the NI test we obtained positive results in 21.8% of the human sera with the neuraminidase subtype N 3 (Nav 2/3) with a peak in persons who were 60 to 70 years old. 11.0% of the sera contained antibodies to the neuraminidase subtype N 8 (Neq 2) and were found exclusively in people 60 to 100 years old, and 9.3% of sera showed positive reactions with the subtype N5 (Nav 5). Until now an immunological relationship between the neuraminidase subtypes N 1, N 2, and N 3 is not known, and could'nt be found in our own studies. Contaminations of antigens can also be excluded. The possible origin of these antibodies to avian neuraminidase subtypes is discussed.

Adolescent↗

PubMed1993

Binding and functional characterization of alpha-2 adrenergic receptor subtypes on pig vascular endothelium.

Alpha-2 adrenergic receptor subtypes were characterized in membranes of pig vascular endothelium using [3H]rauwolscine. Alpha-2 adrenergic receptor subtypes that mediate endothelium-dependent vascular relaxation were studied in vitro by using ring segments of pig epicardial coronary arteries. Specific [3H]rauwolscine binding in endothelial membranes was saturable and to a single class of high-affinity sites with a mean KD of 0.217 +/- 0.05 nM and Bmax of 156 +/- 28 fmol/mg of protein. Nonlinear regression analysis indicated that competition binding curves for drugs that distinguish the alpha-2A adrenergic receptor subtype from the alpha-2C adrenergic receptor subtype fit best to two-site binding models. Kl values for drugs in binding to endothelial alpha-2 adrenergic receptors correlated well with their Kl values for alpha-2A (r = .98) and alpha-2C (r = .97) adrenergic receptor subtypes identified in other tissues. Vascular endothelium contained 23% alpha-2A and 77% alpha-2C adrenergic receptors. In the presence of indomethacin, the rank order of potency for agonists that cause endothelium-dependent vascular relaxation was p-iodoclonidine > clonidine > UK-14,304 > guanabenz > epinephrine > norepinephrine. KB values for antagonist inhibition of epinephrine-induced, endothelium-dependent vascular relaxation correlated best with Kl values for antagonist binding at the alpha-2A adrenergic receptor subtype. These results suggest that the alpha-2A and alpha-2C adrenergic receptor subtypes are present on pig vascular endothelium and that the alpha-2A adrenergic receptor subtype mediates indomethacin-insensitive, endothelium-dependent relaxation of pig epicardial coronary arteries.

Adrenergic alpha-Antagonists↗

PubMed1995

The expression of alpha 1 adrenoceptor subtypes changes with age in the rat aorta.

Previous studies showed that alpha 1 adrenoceptor-mediated contractile responses change with age in the rat aorta, becoming more sensitive to Ca++ channel blockers and less sensitive to chlorethylclonidine (CEC), suggesting a change in the alpha 1 adrenoceptor subtypes that are present. In this study, alpha 1 adrenoceptor density and alpha 1 adrenoceptor subtypes were measured in the Fischer 344 rat aorta during aging. Aortic alpha 1 adrenoceptor densities, determined by saturation binding of 2-[beta-(4-hydroxy-3-[125I]iodophenyl)ethylaminomethyl] tetralone ([125I]-HEAT), were 47, 41 and 45 fmol/mg protein in 1-,6- and 24-month-old rats, respectively. The noncompetitive antagonist CEC completely blocked [125I]-HEAT binding in aortas from 1-month-old rats but inhibited binding only partially in aortas from older rats. Two binding sites were detected for norepinephrine and for WB4101 in all ages. The low-affinity constants for WB4101 (31-51 nM) were consistent with those for the alpha 1b adrenoceptor subtype, and this binding site decreased with age. The high-affinity constant for WB4101 (1.4 nM) in 1-month-old aorta was consistent with that for alpha 1d adrenoceptor subtype, whereas the high-affinity constants (0.03 nM) in 6- and 24-month-old aortas were consistent with those for the alpha 1a adrenoceptor subtype. At least three alpha 1 adrenoceptor subtypes appear to be colocalized in the rat aorta, so the binding affinities may reflect binding to more than one subtype. This makes it difficult to identify denfinitively the subtypes based on their radioligand binding characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1996

The quaternary transformation products of N-(3-chloropropyl)-4-piperidinyl diphenylacetate and N-(2-chloroethyl)-4-piperidinyl diphenylacetate (4-DAMP mustard) have differential affinity for subtypes of the muscarinic receptor.

A 3-chloropropylamine derivative (N-(3-chloropropyl)-4-piperidinyl diphenylactate) of the selective muscarinic antagonist N,N-dimethyl-4-piperidinyl diphenylacetate was synthesized and its conversion to a stable azetidinium ion and interaction with muscarinic receptors was investigated. When dissolved in aqueous solution at pH 7.4, N-(3-chloropropyl)-4-piperidinyl diphenylactate formed a stable azetidinium ion with a half-time of approximately 3.6 hr. The selectivity of the azetidinium ion for native M1, M2 and M3 subtypes of the muscarinic receptors was investigated in competitive binding experiments on the hippocampus, heart and submaxillary gland of rats, respectively, using N-[3H]methylscopolamine as the radioligand. The azetidinium ion exhibited equivalent high affinities for the M1 and M3 mucarinic receptor subtypes (KD = approximately 5 nM), but 10-fold lower affinity for the M2 muscarinic receptor subtype (KD = 44 nM). Similar competitive binding experiments were carried out on Chinese hamster ovary cells transfected with the M1 through M5 subtypes of the muscarinic receptor. In these experiments, the azetidinium ion exhibited similar high affinities for the M1, M3, M4 and M5 muscarinic receptor subtypes (KD = approximately 2.4 nM), but approximately 14-fold lower affinity for the M2 muscarinic receptor subtype (KD = 34 nM). In contrast to the azetidinium ion, the parent N-(3-chloropropyl)-4-piperidinyl diphenylactate compound was 130-fold less potent. An analogous series of experiments were carried out with the aziridinium ion derived from the muscarinic receptor alkylating agent, N-(2-chloroethyl)-4-piperidinyl diphenylactate. For these binding experiments, the incubations were carried out at 0 degrees C to prevent the aziridinium ion from alkylating muscarinic receptors. The aziridinium ion was found to have equivalent high affinities for the M1, M3, M4 and M5 subtypes of the muscarinic receptor (KD = approximately 6.6 nM), but about 11-fold lower affinity for the M2 muscarinic receptor subtype (KD = 72 nM). Our results suggest that 3-haloalkylamine derivatives of 4-piperidinyl diphenylactate may be candidate prodrugs that may penetrate into brain and form azetidinium ions that have a long-lasting central anticholinergic effect.

Animals↗

PubMed1995

Expression of functional muscarinic acetylcholine receptor subtypes in human corpus cavernosum and in cultured smooth muscle cells.

Relaxation of the trabecular smooth muscle, which is necessary for penile erection, is controlled locally by neurotransmitters and vasoactive agents. The goal of this study was to identify and characterize muscarinic acetylcholine receptor (mAChR) subtypes expressed in cultured human corpus cavernosum smooth muscle cells (HCC SMC). Binding analysis with L-[benzilic-4,4'-3H(N)]quinuclidinyl benzilate ([3H]QNB) demonstrated the expression of specific muscarinic receptor binding sites in HCC SMC. Analysis of total RNA isolated from whole corpus cavernosum tissue and smooth muscle cells, by RNase protection assays, demonstrated the expression of mRNA transcripts for m1, m2, m3, and m4 mAChR subtypes in whole tissue and m2 and m4 subtypes in cultured cells. In situ hybridization with specific m2 and m4 probes further confirmed the expression of m2 and m4 mRNA transcripts in cultured cells. Carbachol (CCh), a nonselective cholinergic agonist, inhibited cAMP synthesis at low concentrations (0.1-1 microM) and stimulated cAMP synthesis at high concentrations (100 microM), in cultured HCC SMC. CCh (100 microM) further augmented forskolin (FSK), isoproterenol (ISO), and prostaglandin E1 (PGE1)-induced cAMP synthesis. These observations suggest that, in vivo, in HCC, ACh may activate m3 mAChR subtypes on endothelial cells or m2 and m4 subtypes on the SMC. Although m2 and m4 are thought to inhibit adenylate cyclase (AC), the augmentation of cAMP synthesis by high concentrations of CCh in SMC suggests an alternative mechanism of coupling to G-proteins that stimulates AC activity. These studies show that HCC tissue expresses different subtypes of mAChR (m1, m2, m3, and m4), whereas cultured HCC SMC express m2 and m4 subtypes. It is suggested that m2 and m4 receptor subtypes may play an important role in maintaining trabecular smooth muscle tone in vivo. The augmentation of FSK-, ISO, and PGE1-induced cAMP synthesis by CCh suggests possible development of a multidrug therapeutic approach to treatment of erectile dysfunction.

Adenylyl Cyclases↗

PubMedDate not supplied

[Identification by typological analysis of distinct groups of schizophrenic patients. Applicability of a disorganized schizophrenia subtype].

Since Crow, Andreasen et al. have described schizophrenia in terms of negative and positive symptoms, the dichotomic approach has been well established. As a matter of fact, factor analyses, especially principal components analyses, led with symptomatic specific scales, have proved their validity. But they have shown their limits too : some authors think that the dichotomic model fails to explain all of the schizophrenic psychopathology and that a third dimension including formal thought disorders, most of the time called "disorganization", should systematically be taken into account. In this study, the authors have hypothesized that a categorial approach could describe this "disorganization". Using a cluster analysis they investigated the existence of subtypes in a population including 136 schizophrenic patients assessed with the PANSS (Positive and Negative Syndrome Scale, Kayet al., 1987). The results suggested at least five subtypes: a pure positive subtype, characterized by high scores on items delusions, hallucinatory behavior, suspiciousness/persecution, and by a low score on conceptual disorganization item; a disorganized positive subtype, characterized by high scores on positive items, including conceptual disorganization item, and also high scores on unusual thought content and autistic preoccupation items; a negative subtype, characterized by high scores on negative items and low scores on positive items, including conceptual disorganization item; a mixed subtype, characterized by high scores on the most positive, negative and general psychopathological items; a residual subtype, characterized by low scores on all the positive, negative and general psychopathological items. The good validity of this analysis was showed since differences on a number of clinical characteristics were observed between the five clusters. These results demonstrated the oversimplication of the positive-negative dichotomy and the relevance of a disorganized subtype.

Adult↗

PubMed1996

Coupling efficiencies of human alpha 1-adrenergic receptor subtypes: titration of receptor density and responsiveness with inducible and repressible expression vectors.

We compared the efficiencies with which human alpha 1-adrenergic receptor (AR) subtypes activate inositol phosphate (InsP) formation and increase intracellular Ca2+ in transfected cell lines. Expression of human alpha 1a-, alpha 1b-, and alpha 1d-AR cDNAs under the repressible control of anhydrotetracycline in human embryonic kidney (HEK) 293 cells, which normally express no alpha 1-ARs, was used to compare responses to norepinephrine (NE) at different receptor densities. Maximal NE-stimulated InsP formation was found to increase with increasing density of each subtype, whereas basal levels and responses to sodium fluoride did not change. A comparison of multiple subclones over equivalent ranges of receptor expression showed that activation of each subtype resulted in different maximal responses (alpha 1a > alpha 1b > alpha 1d) in HEK 293 cells. Analogous studies were carried out in human SK-N-MC cells, which normally express low levels of all three alpha 1-AR subtypes, using an isopropyl-beta-D-thiogalactoside-inducible expression system. Induction with isopropyl-beta-D-thiogalactoside increased the density of individual alpha 1-AR subtypes by 4-6-fold over the level of endogenous expression. Increased expression of each of these subtypes in SK-N-MC cells did not alter the EC50 value for NE in stimulating InsP formation or releasing [Ca2+]i but did increase maximal responses to NE. Similar to our findings in HEK 293 cells, a comparison of responses at similar expression levels in SK-N-MC cells showed different maximal responses stimulated by each subtype, for both InsP (alpha 1a > alpha 1b > or = alpha 1d) and [Ca2+]i (alpha 1a > alpha 1b > alpha 1d) responses. These studies show that agonist-occupied human alpha 1-AR subtypes have different efficiencies in activating phospholipase C in human cell lines. In both HEK 293 and SK-N-MC cells, alpha 1a-ARs couple most efficiently, whereas alpha 1d-ARs couple very poorly.

Adrenergic alpha-Agonists↗

PubMed1998

[Survival and disability in stroke by stroke subtype based on computed tomographic findings in three rural Japanese communities].

PURPOSE: We conducted an epidemiological study of survival and disability in stroke in three Japanese communities to seek community strategies for improvement in survival and disability. METHODS: A total of 297 first-ever strokes were identified between 1988 and 1992 in three rural communities (total population = 47,000) located in Akita and Ibaraki. We analyzed survival rates and activity of daily living by sex, age-group and stroke subtypes. Successful review of computed tomography (CT) for 84 percent of the strokes (249 out of 297) was possible and the data were used for subtype analyses. RESULTS: For all strokes (n = 297) survival rates were 85% for 30 day, 70% for one year, 62% for three year. The rates tended to be lower in women than in men. The rates were lowest in ages less than 60 at thirty day, and in ages 80 and older at the end of the first and third year. Intracerebral hemorrhage with ventricular rupture, subarachnoid hemorrhage and cortical cerebral infarction had lower survival rates than intracerebral hemorrhage without ventricular rupture and lacunar infarction. Based on Cox's proportional hazard model, risk ratio for death was 2.07 in ages 70-79, and 3.80 in ages 80 and older compared with ages 60-69. The risk ratio was 3.46 for intracerebral hemorrhage with ventricular rupture, 3.38 for subarachnoid hemorrhage and 2.46 for cortical cerebral infarction compared with lacunar infarction. The proportion of stroke survivors who need assistance from others in the first and third years tended to be higher in women than in men. The proportion was higher in older patients than in the younger, and higher for intracerebral hemorrhage with ventricular rupture and cortical cerebral infarction than in other subtypes of stroke. From logistic regression analysis, the odds ratio for disability in the first year was 6.55 for ages 80 and older compared with ages 60-69. The odds ratio was 5.61 for intracerebral hemorrhage with ventricular rupture, 4.53 for cortical cerebral infarction compared with lacunar infarction. In the third year the odds ratio was significant for ages 70-79, and decreased for intracerebral hemorrhage with ventricular rupture (odds ratio = 2.98), and increased for cortical cerebral infarction (odds ratio = 6.06). CONCLUSIONS: Survival and disability in stroke depended on age and stroke subtypes. Even after age adjustment, stroke subtypes with large cerebral involvement had worse prognosis than stroke subtypes. Community-based hypertension control programs are important to prevent any subtypes of stroke. Stroke subtypes as well as age should be taken into account to develop effective care and medical treatments for strokes.

Activities of Daily Living↗

PubMed2006

A multiplex RT-PCR for detection of type A influenza virus and differentiation of avian H5, H7, and H9 hemagglutinin subtypes.

A multiplex reverse transcriptase-polymerase chain reaction (mRT-PCR) was developed and optimized for the detection of type A influenza virus; the assay simultaneously differentiates avian H5, H7 and H9 hemagglutinin subtypes. Four sets of specific oligonucleotide primers were used in this test for type A influenza virus, H5, H7 and H9 heamagglutinin subtypes. The mRT-PCR DNA products were visualized by gel electrophoresis and consisted of fragments of 860 bp for H5, 634 bp for H7, 488 bp for H9 hemagglutinin subtypes, and 244 bp for type A influenza virus. The common set primers for type A influenza virus were able to amplify a 244 bp DNA band for any of the other subtypes of AIV. The mRT-PCR assay developed in this study was found to be sensitive and specific. Detection limit for PCR-amplified DNA products was 100 pg for the subtypes H5, H7, and H9 and 10 pg for type A influenza virus in all subtypes. No specific amplification bands of the same sizes (860, 634 and 488 bp) could be amplified for RNA of other influenza hemagglutinin subtypes, nor specific amplification bands of type A influenza (244 bp) for other viral or bacterial pathogens.

Animals↗

PubMed1985

Cross-subtype protection in humans during sequential, overlapping, and/or concurrent epidemics caused by H3N2 and H1N1 influenza viruses.

A total of 663 pupils at four schools were studied serologically and clinically during a period of large sequential and/or mixed epidemics of infection with two subtypes of influenza A virus, H3N2 and H1N1. Of 91 middle-school pupils infected with H3N2 virus shortly before and 82 pupils not previously infected with this subtype, 59% and 91% became infected with H1N1 virus, respectively; this difference was significant. Similar results were obtained at the two primary schools studied. At a high school where epidemics due to the H3N2 and H1N1 subtypes occurred concurrently, the rate of infection of individual pupils with both viruses (2%) was significantly lower than those at the other three schools (21%, 23%, and 31%, respectively), where an epidemic caused by the H3N2 subtype appeared first and was then partially overlapped and succeeded by an epidemic caused by the H1N1 subtype. These findings suggest the existence of cross-subtype protection in humans during sequential and/or concurrent epidemics caused by two viral subtypes.

Adolescent↗

PubMed2026

Proteomics-driven discovery of intervention windows and risk subtypes in osteoporosis: A prospective cohort study.

Given the limited feasibility of population-wide bone mineral density screening and the infrequency of long-term monitoring in healthy individuals, identifying the window for early intervention and the populations to be prioritized for screening is critical. This study aimed to identify intervention windows for osteoporosis and to determine potential high-risk subtypes within the healthy population. Based on proteomic data from 41,408 healthy adults, we conducted the DE-SWAN method to identify change peaks in plasma protein during the pre-diagnostic osteoporosis phase, and employed finite Gaussian mixture model-based clustering to delineate high-risk subtypes of osteoporosis. We identified 122 protein biomarkers significantly associated with osteoporosis risk throughout the follow-up period. Importantly, we identified two critical peaks occurring approximately 10 and 6 years before diagnosis, with the former enriched in immune-related pathways and the latter prominently involving responses to retinoic acid and glucocorticoids. Furthermore, one high-risk subtype for osteoporosis was identified in both males and females, termed the Frailty and Obesity Subtype. This subtype is characterized by a high degree of frailty and obesity, accompanied by a significantly elevated risk of both osteoporosis and fractures. Finally, we developed a predictive model comprising 10 proteins for identifying high-risk subtypes of osteoporosis, which demonstrated better performance than the traditional risk factor model (AUC: 0.743 vs. 0.680). Our findings demonstrate that proteomic profiling can reveal early molecular changes and identify high-risk subtypes years before clinical onset, providing a foundation for screening and precision prevention of osteoporosis.

Proteomics↗

PubMed2005

Divergent genetic evolution of hemagglutinin in influenza A H1N1 and A H1N2 subtypes isolated in the south-France since the winter of 2001-2002.

BACKGROUND: Influenza A viruses are divided into subtypes based on their hemagglutinin (H1 to H15) and neuraminidase (N1 to N9) glycoproteins. Of these, three A subtypes H1N1, H3N2 and H1N2 circulate in the human population. Influenza A viruses display a high antigenic variability called "antigenic drift" which allows the virus to escape antibody neutralization. OBJECTIVES: Evaluate the mutations apparition that might predict a divergent antigenic evolution of hemagglutinin in influenza A H1N1 and A H1N2 viruses. STUDY DESIGN: During the three winters of 2001-2002 to 2003-2004, 58 A H1N1 and 23 A H1N2 subtypes have been isolated from patients with influenza-like illness in the south of France. The HA1 region was analyzed by RT-PCR and subsequently sequenced to compare the HA1 genetic evolution of influenza A H1N1 and A H1N2 subtypes. RESULTS: Our results showed that 28 amino acid substitutions have accumulated in the HA1 region since the circulation of A/New Caledonia/20/99-like viruses in France. Of these, fifteen were located in four antigenic sites (B, C, D and E). Six of them were observed only in the A H1N2 isolates, six only in the A H1N1 isolates and three in both subtypes. Furthermore, nine of twenty two A H1N2 isolates from the winter of 2002-2003 shared a T90A amino acid change which has not been observed in any A H1N1 isolate; resulting in the introduction of a new glycosylation site close to the antigenic site E. This might mask some antigenic E determinants and therefore, modify the A H1N2 antigenicity. CONCLUSIONS: The divergent genetic evolution of hemagglutinin may ultimately lead to a significant different antigenicity between A H1N1 and A H1N2 subtypes that would require the introduction of a new subtype in the vaccine batches.

Animals↗

PubMed1999

Identification of a novel GB type C virus/hepatitis G virus subtype in patients with hematologic malignancies.

The existence of four GB C virus/hepatitis G virus (GBV-C/HGV) subtypes has been reported. The subtype was determined in 16 multitransfused GBV-C/HGV infected patients prior to bone marrow transplantation by comparing the 5' untranslated region (5' UTR) sequence with 39 available sequences. Phylogenetic and bootstrap analyses were carried out with PHYLIP package 3.5c. In the samples with undefined subtype, the whole 5' UTR was cloned and sequenced. Comparison of distances showed that the isolates from 12/16 and 4/16 patients belonged theoretically to subtypes 2a and 2b, respectively. The phylogenetic tree and bootstrap analyses confirmed this result in only 11/16 samples. Analysis of the entire 5' UTR from the remaining five samples with undefined GBV-C/HGV subtype revealed genomic variability within the isolates from each patient and between the isolates of different patients. Evolutionary distances, phylogenetic tree, and bootstrap showed that the isolates from these samples were grouped in a separate branch, different from the published subtypes. In conclusion, a novel GBV-C/HGV subtype was found in a group of multitransfused patients with GBV-C/HGV infection.

5' Untranslated Regions↗

PubMed1997

Alpha-1 adrenoceptor subtypes (high, low) in human benign prostatic hypertrophy tissue according to the affinities for prazosin.

BACKGROUND: A novel classification of alpha-1 adrenoceptor subtypes (High, Low) was applied to human benign prostatic hypertrophy (BPH) tissue. METHODS: Human BPH specimens were examined by a radioligand binding assay method using 3H-prazosin, and those data were compared with preoperative therapies. RESULTS: (1) Scatchard analysis showed a high-affinity site (Kd:27.18 +/- 6.41 pM; Bmax:9.29 +/- 0.98 fM/mg protein; mean +/- SE) as alpha 1H, and a low-affinity site (Kd: 4088.0 +/- 744.34 pM, Bmax: 140.81 +/- 19.98 fM/mg protein) as alpha 1L subtype, for prazosin. (2) The Kd and Bmax were not different in the nontreated group (n = 5), alpha 1 blocker group (n = 5), and antiandrogen group (n = 5), in either alpha 1-high affinity or alpha 1-low affinity subtype. (3) Phenoxybenzamine had different pKi values for the above two adrenoceptor subtypes. Scatchard analysis showed that alpha 1-high affinity binding site disappeared in the presence of 1 microM of phenoxybenzamine, and the Kd and Bmax values in the presence of 1 microM of phenoxybenzamine were almost identical to the alpha 1-low affinity site of the two subtypes. CONCLUSIONS: Human BPH tissue possesses both alpha 1H- and alpha 1L-adrenoceptor subtypes according to the affinities for prazosin, and only the alpha 1H subtype can be completely inhibited by some concentration of phenoxybenzamine. Treatment by alpha 1 blocker may not change the conditions of alpha 1-adrenoceptors in prostatic tissue.

Adrenergic alpha-Antagonists↗

PubMed1993

Interobserver variability in histopathologic subtyping and grading of pulmonary adenocarcinoma.

BACKGROUND: The classification of lung tumors by the World Health Organization (WHO 1981) describes subtyping of adenocarcinoma of the lung (ACL) into acinar adenocarcinoma and papillary adenocarcinoma, bronchioloalveolar carcinoma, and solid carcinoma with mucus formation. Acinar and papillary adenocarcinoma may be graded as well-, moderately, or poorly differentiated. This study evaluated the interobserver variability in the subtyping and grading of ACL according to the WHO classification. METHODS: Histologic specimens from 211 patients with disease of Stages IIIa-IV were classified in a blind manner by three panelists. All available paraffin-embedded tissue blocks, including metastatic tumors, were sampled, and new slides were made for the study. RESULTS: Twenty-two ACL tumors could not be assigned a subtype by Panelist 1, which left 189 tumors as the basis for additional evaluation. Overall agreement for the three panelists regarding subtypes was 41%. Nonchance agreement was evaluated by kappa statistics, which may vary between -1 in the event of agreement that is less than that expected by chance and /1 in the event of full agreement. The kappa value regarding subtypes was 0.18 (95% confidence limits, 0.14-0.23). Overall observed agreement regarding degree of differentiation was 43%, with a kappa value of 0.12 (95% confidence limits, 0.06-0.17). Histologic material was obtained by thoracotomy in a subgroup of 53 patients, and in this patient group unanimity among two or more panelists was 88% for subtyping and 100% for degree of differentiation. CONCLUSIONS: The degree of agreement in subtying and grading of ACL in Stages IIIa-IV is low, suggesting that more objective criteria is needed before a prognostic impact of such variables can be assessed. The quality and quantity of material available for subtyping obviously influence the results, which is reflected in a better agreement when histologic material is obtained by thoracotomy.

Adenocarcinoma↗

PubMed2003

Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity. Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor.

BACKGROUND: In primary central high-grade osteosarcoma, a number of distinct subtypes have been identified, but little is known about the response to chemotherapy. METHODS: The authors investigated whether the subtypes correlated with histologic response to chemotherapy in 1058 patients with osteosarcoma of the extremities who were treated with neoadjuvant chemotherapy over the last 20 years. The tumors were classified as osteoblastic (70%), chondroblastic (13%), fibroblastic (9%), and telangiectatic (6%). At diagnosis, 911 patients had localized disease and 147 had resectable lung metastases. RESULTS: The response to preoperative chemotherapy was good (90% or more tumor necrosis) in 59% of patients and poor (< 90% tumor necrosis) in 41% of patients. The rate of good responses was significantly higher (P = 0.0001) in the fibroblastic (83%) and telangiectatic (80%) tumors and significantly lower in chondroblastic tumors (43%). Prognosis was significantly correlated with the histologic subtypes. The 5-year overall survival rate was significantly higher (P = 0.0001) in fibroblastic (83%) and telangiectatic (75%) tumors than in osteoblastic (62%) and chondroblastic (60%) tumors. In all subtypes, except for the chondroblastic subtype, the 5-year overall survival rate was significantly higher (P = 0.0001) in good responders P = 0.0001 (68%) than in poor responders (52%). CONCLUSIONS: The authors concluded that the histologic subtype of primary central high-grade osteosarcoma of the extremity was strictly correlated with histologic response to chemotherapy and probably, as a consequence, also with prognosis. Further studies are needed to establish whether these results justify a specific therapeutic approach based on the histologic subtype of the tumor.

Adolescent↗

PubMed1992

Mapping of angiotensin II receptor subtype heterogeneity in rat brain.

Angiotensin II (Ang II) exerts a number of central actions on fluid and electrolyte homeostasis, autonomic activity, and neuroendocrine regulation. In order to evaluate likely sites where these actions are mediated, Ang II receptor binding was localized in rat brain by in vitro autoradiography with the aid of the antagonist analogue 125I-[Sar1, Ile8]Ang II. Two subtypes of Ang II receptor have been identified using recently developed peptide and nonpeptide antagonists. In the periphery, the receptor subtypes differ in distribution, second messenger coupling, and function. Brain Ang II receptor subtypes were therefore differentiated into AT-1 (type I) and AT-2 (type II) subtypes by using unlabelled nonpeptide antagonists specific for the two Ang II subtypes. AT-1 binding was determined to be that inhibited by Dup 753 (10 microM) and AT-2 binding to be that inhibited by PD 123177 (10 microM). The reducing agent dithiothreitol (DTT) decreased binding to AT-1 receptors and enhanced binding to AT-2 receptors. Many brain structures, such as the vascular organ of the lamina terminalis, subfornical organ, median preoptic nucleus, area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus, which are known to be related to the central actions of Ang II, contain exclusively AT-1 Ang II receptors. By contrast, the locus coeruleus, ventral and dorsal parts of lateral septum, superior colliculus and subthalamic nucleus, many nuclei of the thalamus, and nuclei of the inferior olive contain predominantly AT-2 Ang II receptors. The detailed binding characteristics of each subtype were determined by competition studies with a series of analogues of angiotensin and antagonists. The pharmacological specificity obtained in rat superior colliculus and the nucleus of the solitary tract agreed well with published data on AT-1 and AT-2 receptors, respectively. There was a high degree of correlation between the distribution of Ang II binding sites with published data on Ang II-immunoreactive fields and on the sites of Ang II-responsive neurons. The present study also reveals pharmacological heterogeneity of brain Ang II receptors. The subtype-specific receptor mapping described here is relevant to understanding the role of angiotensin peptides in the central nervous system and newly discovered central actions of nonpeptide Ang II receptor antagonists.

1-Sarcosine-8-Isoleucine Angiotensin II↗