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PubMed1980

Variant von Willebrand's disease: characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets.

We have examined the multimeric composition of factor VIII/von Willebrand factor in plasma and platelet lysates by means of sodium dodecyl sulfate agarose electrophoresis followed by staining with (125)I-labeled affinity-purified antibody. In normal plasma and platelet lysates, factor VIII/von Willebrand factor displayed 10 distinct multimers that ranged in apparent molecular weight from 0.86 to 9.9 x 10(6). The molecular weight difference between adjacent bands was 0.8-1.1 x 10(6). Larger material, not resolved into discrete bands, was also present with an average M(r) of 14.5 x 10(6). Though the dimer (apparent M(r) = 0.48 x 10(6)) and the monomer (apparent M(r) = 0.28 x 10(6)) generated by reduction of disulfide bonds were readily identified in this system, they were not detected in normal plasma or platelets. No differences were observed between fresh plasma prepared without anticoagulant and fresh or frozen plasma anticoagulated with either citrate or heparin. "Variant" (type II) von Willebrand's disease could be divided into two subtypes. In subtype IIA, factor VIII/von Willebrand factor in plasma consisted predominantly of the five smaller multimers with traces of the sixth and seventh (M(r) up to 4.5 x 10(6)). In subtype IIB, all these multimers were easily detected and, in addition, bands of intermediate size (M(r) = 8.5 x 10(6) and smaller) were present. In contrast, the multimeric composition of IIB platelet factor VIII/von Willebrand factor was identical to normal, whereas in subtype IIA the larger multimers were absent from platelets as well as from plasma. In subtype IIB, binding of factor VIII/von Willebrand factor to platelets occurred at lower concentrations of ristocetin than required for normal and multimers of smaller size than in normal bound. On the contrary, in subtype IIA, binding was minimal, as was true of normal factor VIII/von Willebrand factor of equivalent size. Thus, physical as well as functional differences in the two subtypes of variant von Willebrand's disease described suggest that different pathogenetic mechanisms underlie the factor VIII/von Willebrand factor abnormalities in these patients.

Biopolymers↗

PubMedDate not supplied

Stability of arithmetic disability subtypes.

Cross-sectional research has identified subtypes of children with learning disabilities who may have distinctive cognitive ability patterns. This study examined the stability over 19 months of academic subtyping classifications for 80 children ages 9 to 13 representing four subtypes of arithmetic disabilities (AD), using three criteria for learning disability identification. Approximately half of the sample retained AD regardless of identification method. Children with pervasive deficits in arithmetic, reading, and spelling displayed the greatest subtype stability. Only one third of the children with the other subtypes, including those with isolated arithmetic deficits, retained their original subtypes. Thus, drawing conclusions and making recommendations based on academic subtyping at a single point in time may be unwise.

Adolescent↗

PubMed2006

Differential contribution of GABA(A) receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands.

Non-selective benzodiazepines, such as diazepam, interact with equivalent affinity and agonist efficacy at GABA(A) receptors containing either an alpha1, alpha2, alpha3 or alpha5 subunit. However, which of these particular subtypes are responsible for the anticonvulsant effects of diazepam remains uncertain. In the present study, we examined the ability of diazepam to reduce pentylenetetrazoLe (PTZ)-induced and maximal electroshock (MES)-induced seizures in mice containing point mutations in single (alpha1H101R, alpha2H101R or alpha5H105R) or multiple (alpha125H-->R) alpha subunits that render the resulting GABA(A) receptors diazepam-insensitive. Furthermore, the anticonvulsant properties of diazepam, the alpha1- and alpha3-selective compounds zolpidem and TP003, respectively, and the alpha2/alpha3 preferring compound TP13 were studied against PTZ-induced seizures. In the transgenic mice, no single subtype was responsible for the anticonvulsant effects of diazepam in either the PTZ or MES assay and neither the alpha3 nor alpha5 subtypes appeared to confer anticonvulsant activity. Moreover, whereas the alpha1 and alpha2 subtypes played a modest role with respect to the PTZ assay, they had a negligible role in the MES assay. With respect to subtype-selective compounds, zolpidem and TP003 had much reduced anticonvulsant efficacy relative to diazepam in both the PTZ and MES assays whereas TP13 had high anticonvulsant efficacy in the PTZ but not the MES assay. Taken together, these data not only indicate a role for alpha2-containing GABA(A) receptors in mediating PTZ and MES anticonvulsant activity but also suggest that efficacy at more than one subtype is required and that these subtypes act synergistically.

Animals↗

PubMed2006

Genetic variability of the envelope gene of Type D simian retrovirus-2 (SRV-2) subtypes associated with SAIDS-related retroperitoneal fibromatosis in different macaque species.

BACKGROUND: D-type simian retrovirus-2 (SRV-2) causes an AIDS-like immune deficiency syndrome (SAIDS) in various macaque species. SAIDS is often accompanied by retroperitoneal fibromatosis (RF), an aggressive fibroproliferative disorder reminiscent of Kaposi's sarcoma in patients with HIV-induced AIDS. In order to determine the association of SRV-2 subtypes with SAIDS-RF, and study the evolution and transmission of SRV-2 in captive macaque populations, we have molecularly characterized the env gene of a number of SRV-2 isolates from different macaque species with and without RF. RESULTS: We sequenced the env gene from eighteen SRV-2 isolates and performed sequence comparisons and phylogenetic analyses. Our studies revealed the presence of six distinct subtypes of SRV-2, three of which were associated with SAIDS-RF cases. We found no association between SRV-2 subtypes and a particular macaque species. Little sequence variation was detected in SRV-2 isolates from the same individual, even after many years of infection, or from macaques housed together or related by descent from a common infected parent. Seventy-two amino acid changes were identified, most occurring in the larger gp70 surface protein subunit. In contrast to the lentiviruses, none of the amino acid variations involved potential N-linked glycosylation sites. Structural analysis of a domain within the gp22/gp20 transmembrane subunit that was 100% conserved between SRV-2 subtypes, revealed strong similarities to a disulfide-bonded loop that is crucial for virus-cell fusion and is found in retroviruses and filoviruses. CONCLUSION: Our study suggests that separate introductions of at least six parental SRV-2 subtypes into the captive macaque populations in the U.S. have occurred with subsequent horizontal transfer between macaque species and primate centers. No specific association of a single SRV-2 subtype with SAIDS-RF was seen. The minimal genetic variability of the env gene within a subtype over time suggests that a strong degree of adaptation to its primate host has occurred during evolution of the virus.

Amino Acid Sequence↗

PubMed1991

Angiotensin-II receptor subtypes and coupling to signaling systems in cultured fetal fibroblasts.

Angiotensin-II (AII) receptors and their coupling to signaling transduction systems were studied in fetal skin fibroblasts using the receptor subtype-specific antagonists Dup753 (type 1) and PD123177 (type 2). In primary cultures, total binding per cell remained constant from days 2-6 of culture, but after subculture levels were initially decreased, then increased until the cells reached confluence. In freshly isolated cells more than 90% of the receptors were type 2, and only a minor fraction were type 1, findings that are consistent with autoradiographic analyses and membrane binding assays. The proportions tended to reverse during culture, with type 1 receptors accounting for 60-80% and type 2 for 20-40% by day 6 of culture. In secondary culture, subtype 1 was about 50% on day 1 and increased to 70% by day 6. At subsequent passages, the proportion of receptor subtypes remained constant up to 6 days, with 90% being of the type 1 variety and 10% of type 2. Scatchard analysis of binding in the presence of the selective antagonists showed similar binding affinities for both subtypes, and the changes in receptor subtype during culture were due primarily to changes in receptor number. Treatment of primary cultures with actinomycin-D for 24 h prevented the transition from AII receptor type 2 to type 1 by increasing the absolute number of type 2 receptors, suggesting that receptor synthesis is regulated at the posttranscriptional level. Stimulation of the cells with 100 nM AII resulted in increases in inositol phosphate accumulation, an effect that was prevented by the type 1 antagonist, but not by the type 2 antagonist. In contrast with other systems in which AII inhibits adenylate cyclase, in fetal fibroblasts AII stimulate cAMP production. The increases in cAMP were more pronounced in secondary cultures in which type 1 receptor content is higher, and the effect was prevented by the type 1, but not the type 2, antagonists. These findings demonstrate the presence of both AII receptor subtypes in fetal fibroblasts, but only the type 1 receptors are coupled to a known intracellular signalling system. The changes in AII receptor subtypes may be the consequence of alterations in intercellular communication, endocrine, or paracrine factors during culture.

Angiotensin II↗

PubMed1996

Prostaglandin E receptor subtypes in mouse osteoblastic cell line.

PGE2 is one of the key molecules in the osteoblast. It is the major prostanoid in the bone, and its production is under the control of both systemic and local factors. PGE2 has been reported to have multiple actions in the osteoblast, such as growth promotion and cell differentiation. To better understand the action of PGE2 in the osteoblast, we determined the PGE receptor subtypes in MC3T3-E1, an osteoblastic cell line derived from the normal mouse calvaria. Northern blot analysis revealed that EP1 and EP4 subtypes are expressed in MC3T3-E1. In contrast, EP3 subtype was not detected by either Northern blot analysis or RT-PCR. The contribution of each subtype was evaluated by studying the effects of subtype-specific analogs on osteoblastic function at confluency and 5 days after confluency. An EP1 agonist, 17-phenyl-omega-trinor PGE2, increased DNA synthesis and decreased alkaline phosphatase activity. 11-Deoxy-PGE1, and EP2 and EP4 agonist, decreased DNA synthesis and increased alkaline phosphatase activity at both stages. Butaprost, an EP2-selective agonist, showed effects similar to those of 11-deoxy-PGE1 only at confluency. Another and more differentiated osteoblastic marker, osteocalcin production, was detectable and was stimulated by 11-deoxy-PGE1 only 5 days after confluency. The exposure of these cells to EP1 agonist changed the cell shape to a more fibroblastic appearance. These results indicate that EP1, EP4, and probably EP2 are present in MC3T3-E1 cells; EP1 promotes cell growth, and EP2 and EP4 mediate differentiation of the osteoblast. Furthermore, the decreased response to EP2-specific agonist 5 days after confluency suggests that the expression of PGE receptor subtype is dependent on the stage of osteoblastic differentiation. This is the first report to determine PGE receptor subtypes in the bone.

Alprostadil↗

PubMed2005

Comparison of the binding affinity of some newly synthesized phenylethanolamine and phenoxypropanolamine compounds at recombinant human beta- and alpha1-adrenoceptor subtypes.

We evaluated six new compounds, SWR-0065HA ([4-[2-[3-[[(3,4-dihydro-4-oxo-[1,2,4]-triazino(4,5-a)indol)-lyl]oxy]-2-hydroxypropylamino]ethoxy]phenyl]acetic acid methyl ester hydrochloride), SWR-0098NA ((R*R*-UE)-(E)-[4-[3-[(2-phenyl-2-hydroxyethyl)amino]-1-butenyl]phenoxy]acetic acid sodium salt), SWR-0315NA ((E, Z)-[4[[1-[2-[(3-phenoxy-2-hydroxy propyl)]amino]ethyl]-1-propenyl]phenoxy]acetic acid sodium), SWR-0338SA ((E)-[4-[5-[(2-phenyl-2-hydroxyethyl)amino]-2-pentene-3-yl]phenoxy] acetic acid ethanedioic acid), SWR-0342SA ((S)-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino] ethyl]-1-propenyl]phenoxy]acetic acid ethanedioic acid) and SWR-0345HA ((E)-2-methyl-3-[4-[2-(2-phenyl-2-hydroxyethylamino)ethoxy]phenyl]-2-propenoic acid ethyl ester hydrochloride) for their potencies as selective ligands at human beta-adrenoceptors expressed in COS-7 cells and compared the binding affinities for human alpha(1)-adrenoceptors expressed in Chinese hamster ovary (CHO) cells using a radioligand-binding assay. Phenoxypropanolamine derivatives SWR-0315NA and SWR-0342SA showed higher binding affinities for beta-adrenoceptor subtypes; SWR-0065HA, however, showed a higher affinity for only beta-adrenoceptors, accounting for 3-fold and 6-fold selectivity against beta(1)- and beta(3)-adrenoceptors. Compounds SWR-0315NA and SWR-0342SA did not show any binding selectivity for any of the subtypes. However, functionally these two compounds are selective for beta(3)-adrenoceptors. Among the phenylethanolamine derivatives, SWR-0338SA and SWR-0345HA showed 9-fold and 16-fold higher binding selectivity for beta(3)-adrenoceptors against beta(1)-adrenoceptors, respectively, whereas they both showed a 7-fold higher binding selectivity for beta(3)-adrenoceptors against beta(2)-adrenoceptors. SWR-0098NA did not show any significant binding affinity for any of the beta-adrenoceptor subtypes. These compounds, except for SWR-0098NA, were not found to possess any significant binding affinity for alpha(1)-adrenoceptor subtypes over that for beta-adrenoceptor subtypes. However, SWR-0098NA has about a 3-fold to 22-fold higher binding selectivity for alpha(1)-adrenoceptor subtypes against beta-adrenoceptor subtypes, making it difficult for use in a beta-adrenoceptor receptor study. Compounds SWR-0315NA and SWR-0342SA have similar binding potency for alpha(1)-adrenoceptors as adrenaline (epinephrine), proving the finding of this manuscript that this phenoxypropanolamine group of beta-adrenoceptor ligands could also be used as alpha(1)-adrenoceptor ligands. Functional assays have to be performed to confirm their agonistic activity.

Adrenergic beta-Agonists↗

PubMed2005

Distinct clinicopathologic subtypes of cortical dysplasia of Taylor.

BACKGROUND: Two pathologic subtypes based on the presence or absence of balloon cells have been described in cortical dysplasia of Taylor (CDT). OBJECTIVE: To determine whether the pathologic subtype has any distinct clinical or MRI features that are relevant to management. METHODS: The histopathologic, clinical, and MRI features of 34 children with CDT who underwent epilepsy surgery at Miami Children's Hospital from 1990 to 2001 were investigated. RESULTS: Bizarre neuronal cytomegaly was the primary pathologic feature of 15 patients with the dysplasia-only subtype, and 19 cases showed additional characteristics including balloon cells and marked white matter abnormalities. Both groups presented with severe intractable epilepsy of very-early-onset, multiple daily seizures, cognitive disability, and focal neurologic deficits. The dysplasia-only subtype had higher rates of neonatal onset, hemiparesis, and severe mental retardation (p < 0.05). The MRI features of focal cortical thickening with associated cortical T2 signal change showed excellent sensitivity (94%) and reasonable specificity (73%) for the diagnosis of the balloon cell subtype. The overall surgical outcome was 59% seizure freedom at 2 years. CONCLUSIONS: Children with cortical dysplasia of Taylor type have in common a very-early-onset, severe epilepsy with neurologic co-morbidity. Patients with the non-balloon cell pathologic subtype have a more severe phenotype. A trend toward a better outcome in the balloon cell group suggests that preoperative identification of these subtypes may impact surgical planning.

Adolescent↗

PubMed1975

Distinct subtypes of type I fibers of human skeletal muscle.

We have identified two distinct and consistent type I fiber subtypes in histochemically normal biopsies (vastus lateralis or biceps brachialis) from 12 healthy persons, both sexes, ages 15 to 42. The type I fibers were uniformly light with the regular ATPase (9.4) and uniformly dark with the acid-preincubated reverse ATPase reactions. However, the subtype IA fibers were stained darker than subtype IB fibers with the nicotinamide adenine nucleotide dehydrogenase-tetrazolium reductase, Oil red O, reduced nicotinamide adenine dinucleotide phosphate-tetrazolium reductase, nonspecific esterase, succinic-tetrazolium reductase, nicotinamide adenine dinucleotide-linked malic-tetrazolium reductase, and "nicotinamide adenine dinucleotide-linked lactic-tetrazolium reductase," and stained lighter with the phosphorylase, periodic acid-Schiff for glycogen, and menadione-mediated alpha-glycerophosphate-tetrazolium reductase reactions. The IB fibers were not as light (or as dark, depending on the stain) as any of the type II fibers. In one pathologic case, all the "hypotrophic type I muscle fibers with central nuclei" were subtype IB. In case of chronic infantile spinal atrophy the muscle showed some type-grouping and marked type I fiber predominance--the great majority of type I fibers were subtype IB, among which were islands (subtype-groups) of IA fibers. Subtyping of type I fibers may be informative in evaluating the pathologic process of certain human neuromuscular diseases.

Adolescent↗

PubMed2005

The effects of anesthetics and ethanol on alpha2 adrenoceptor subtypes expressed with G protein-coupled inwardly rectifying potassium channels in Xenopus oocytes.

A wide range of physiological effects are mediated by alpha2-adrenoceptors (ARs) through their association with G protein-coupled inwardly rectifying potassium (GIRK) channels. Although alpha2-ARs are divided into three subtypes (alpha2A-C), a pharmacological distinction among the subtypes is difficult to establish because of the lack of a selective agonist and antagonist; therefore, little is known about the effects of anesthetics on the alpha2-AR subtypes. We expressed each subtype together with GIRK1/GIRK2 subunits in Xenopus oocytes and observed alpha2-AR-mediated GIRK1/GIRK2 currents to test the effects of ethanol, halothane, and several IV anesthetics at clinical concentrations. UK 14,304, a selective alpha2-AR agonist, evoked GIRK1/GIRK2 currents in every subtype. None of the IV anesthetics, which included pentobarbital, propofol, ketamine, and alphaxalone, influenced UK 14,304-evoked potassium currents in any of the receptor subtypes. Ethanol enhanced the UK 14,304-evoked potassium currents, whereas halothane inhibited the currents. However, these effects were not significantly different from those on the baseline-GIRK1/GIRK2 current, suggesting that neither ethanol nor halothane acts directly on the alpha2-AR subtypes. Although none of the drugs examined had any effect on the alpha2-ARs, the physiological actions of the alpha2-ARs mediated by the GIRK1/GIRK2 channels may be affected by ethanol and halothane.

Anesthetics↗

PubMed2004

HIV-1 subtype dynamics over 10 years in a rural Ugandan cohort.

Our objective was to monitor changes in the subtypes of HIV-1 infecting a rural Ugandan cohort where the spread of HIV-1 is by unprotected heterosexual contact and subtypes A and D predominate. Should one subtype be better able to spread we would anticipate a rise in incidence of one subtype at the expense of the other over a decade of study. We employed a natural history cohort, which had been established by the Medical Research Council in 1990 and subtyped virus from 90% (139) incident cases by DNA sequencing in two separate genes. We found that viral subtype had no predilection for males, females or age at infection and that between 1990 and 2000 there was no significant change in the relative number of different subtypes. The only significant trend was a reduction in the proportion of viruses classified as recombinant. This may reflect the overall decline in prevalence of HIV-1 in Uganda over this period.

Adolescent↗

PubMed2005

Estimation of prevalence of DSM-IV and latent class-defined ADHD subtypes in a population-based sample of child and adolescent twins.

The goal of this study is to determine the prevalence and age of onset of Diagnostic and Statistical Manual of Mental Disorders and latent class-derived attention deficit/hyperactivity disorder (ADHD) subtypes in a population-based twin sample of boys and girls. Missouri birth records identified families with a twin pair 7 to 18 years of age. Telephone screening interviews for ADHD symptoms were completed for 5007 families. Diagnostic assessments were administered to 564 families with at least one twin meeting screening criteria, plus 183 control families. Prevalence and age of onset for both ADHD nosologies were calculated by sex and zygosity from parent report data. The prevalence of any DSM-IV ADHD was 6.2% overall, 7.4% in boys and 3.9% in girls. The inattentive subtype was most common in boys; the combined subtype was most common in girls. The mean age of onset of symptoms in children with any DSM-IV ADHD was 3.5 years, with no significant differences between boys and girls. Prevalences of latent class defined ADHD subtypes also varied by sex with the severe inattentive and combined classes more common in boys than girls. The age of onset of symptoms did not differ between boys and girls but were higher than in the DSM-IV subtypes. Findings in this twin sample showed that clinically significant ADHD, defined by either DSM-IV or latent class criterion, has an early age of onset and is more common in boys than girls. As clinical samples are most commonly composed of male combined subtypes, the inattentive subtype of both sexes in the general population is an under-treated segment of the general population.

Adolescent↗

PubMed2003

Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue and intratumoral vessels in malignant endocrine pancreatic tumors.

Somatostatin analogs are well established in the treatment of malignant endocrine pancreatic tumors (EPTs). Our goal is to individualize their treatment using receptor-subtype-specific analogs and, therefore, exploring the receptor expression is highly important. We have examined the expression of somatostatin receptor (sst) subtypes 1-5 on tumor cells and in intratumoral vessels in 28 tumor tissues from malignant EPTs with immunohistochemistry using sst-subtype-specific polyclonal antibodies. We found that sst(2) and sst(4) stained positive in 90% and sst(1) in 70% of the tumor tissues, whereas sst(3) and sst(5) stained positive in only 50% of the tumor tissues. Sst expression in intratumoral vessels was high for sst(2) and sst(4) (80%), moderate for sst(1) (40%), and low for sst(3) and sst(5) (10%). The ssts were evenly distributed among the different tumor subtypes. However, tumors belonging to the same subgroup of EPTs showed a variable expression of receptor subtypes. No differences in receptor-subtype expression could be seen between poorly and welldifferentiated tumors, nor between primary tumors and metastases. Prior medical treatment did not influence sst expression pattern. In conclusion, sst(2) and sst(4) were expressed in most tumor tissues and intratumoral vessels from EPTs. However, sst(3) and sst(5) were lacking in half of the tumor tissues and in most of the intratumoral vessels. These differences indicate the importance of determining each tumor s subset of receptors before treatment with receptor-subtype-specific analogs is initiated. The importance of sst expression in intratumoral vessels is not yet known.

Adult↗

PubMed2005

Systemic distribution of somatostatin receptor subtypes in human: an immunohistochemical study.

Somatostatin is well known to inhibit the hormone secretion of various peptides. This action has been considered to be generally mediated via six different specific somatostatin receptors (sstr), sstr1, sstr2A, sstr2B, sstr3, sstr4, and sstr5. It then becomes very important to demonstrate the localization of these sstr subtypes in order to elucidate the possible biological and/or clinical significance of somatostatin actions. These sstr subtypes have been demonstrated to be expressed throughout the human body, including the central nervous system, gastrointestinal tract, pancreas, kidney, and other organs, but its details, especially its systemic distribution and localization in tissue compartments, have yet to be examined thoroughly in human. Therefore, in this study, we examined the systemic localization of all six somatostatin receptors in normal human organs using immunohistochemistry with recently developed specific antibodies against these receptor subtypes. In all of the human tissues examined, various sstr subtypes were detected not only in parenchymal cells but also in various stromal cells such as lymphocytes, fibroblasts, and endothelial cells. Among human tissues in which the presence of sstr has not been previously reported, the parotid gland demonstrated immunoreactivity for sstr2B and sstr5, bronchial gland for sstr1, 2B, 3, 4, 5, parathyroid gland for sstr1, 3, 4, and duodenum for all subtypes immunoreactivity. The great majority of other organs examined demonstrated results consistent with those of previously reported biochemical studies. In pancreatic islet cells, only sstr2A was positive in all the cases but other sstr subtypes were associated with marked intraislet heterogeneity in their distribution. In stomach, all subtypes of receptor were detected in various cell types of the mucosa, but none in ECL cells of fundic gland. These findings demonstrated the broad systemic actions of somatostatin in non-endocrine cells.

Cell Membrane↗

PubMed2003

Vector competence of rural and urban strains of Aedes (Stegomyia) albopictus (Diptera: Culicidae) from São Paulo State, Brazil for IC, ID, and IF subtypes of Venezuelan equine encephalitis virus.

Aedes albopictus (Skuse) is an Asiatic mosquito species that has spread and colonized all continents except Antarctica. It has major public health importance because it is a potential vector of several pathogens. The objectives of our study were to analyze the vector competence of urban and rural strains of Ae. albopictus from São Paulo State (Brazil) for Venezuelan equine encephalitis virus (VEE) subtypes IC, ID, and IF, and to evaluate the effect of infection with subtype IC of VEE on mosquito longevity. Both mosquito strains were susceptible to subtypes IC and ID, but the infection rate for subtype IF was low. Infection and transmission rates of Ae. albopictus for subtype IC were similar to those reported for Ochlerotatus taeniorhynchus (Wiedemann). The high infection, dissemination, and transmission rates for subtype ID reported for Oc. fulvus (Wiedemann) and Culex (Melanoconion) spp. are comparable with those found in this study. We found significant differences in the susceptibility to subtype IC between rural and urban populations of São Paulo. Significant survival rate differences were observed between uninfected and infected mosquitoes, but there were no differences in survival between rural and urban mosquito strains.

Aedes↗

PubMed1999

Somatostatin receptor subtype expression in cells of the rat immune system during adjuvant arthritis.

Somatostatin is a neuropeptide that is widely distributed throughout the body. It acts as a neurohormone and a neurotransmitter and may also have an immunomodulatory role. The genes for five subtypes of somatostatin receptors (sst) have been cloned, suggesting that the diverse effects of the peptide might be mediated by different receptors. We are interested in studying the role of sst ininflammation, using an animal model. Because of the up-regulation of sst expression in inflamed joints in human rheumatoid arthritis, we chose rat adjuvant arthritis as an experimental model. In order to determine which of the sst subtypes might be important in immune modulation, subtype expression in leukocytes isolated from different lymphoid tissues of the rat was studied. Also, the expression levels of the most abundantly expressed sst mRNAs in leukocytes from spleen and blood were compared in rats with adjuvantarthritis and controls, using a semi-quantitative approach. Furthermore, the effect of systemic administration of a long-acting somatostatin analogue, octreotide, which binds selectively to sst subtypes 2 and 5 (sst2 and sst5), on the incidence and the severity of rat adjuvant arthritis, was studied. The main sst expressed in cells of the rat immune system, both resting and activated, were found to be sst3 and sst4. This contrasts with the human and murine situations, in which sst2 appears to be the main subtype expressed in the immune system. No quantitative differences in sst subtype mRNA levels in leukocytes from spleen and blood were found between rats with adjuvant arthritis and controls. Finally, no effect of systemic administration of octreotide on either the incidence or severity of adjuvant arthritis in Lewis rats was found. As octreotide binds selectively to sst2 and sst5, the absence of an immunomodulatory effect of this analogue in rat adjuvant arthritis corroborates our finding that these sst subtypes are not expressed in cells of the rat immune system. In conclusion, cells of the rat immune system appear to express a spectrum of sst (sst3 and sst4) different from that found in human granulomatous and autoimmune disease (mainly sst2). Therefore, the rat adjuvant arthritis model appears to be suitable only for studying the immunomodulatory effects of somatostatin analogues which have a high affinity for sst3 and sst4, but not for studying the immunomodulatory effects of octreotide, which has a high affinity only for sst2 and sst5.

Animals↗

PubMed2001

Regulatory effect of experimental diabetes on the expression of endothelin receptor subtypes and their gene transcripts in the rat adrenal gland.

Endothelins (ETs) mediate paracrine control of vascular tone and secretion of steroids and catecholamines in the adrenal gland through two ET receptor subtypes, ETA and ETB. The differential distribution and function of these subtypes are responsible for the multiplicity of endothelin actions in this tissue. This study examines the regulatory effects of experimental diabetes on the gene expression, subtype specificity and localization of ET receptor subtypes, ET isopeptides, and endothelin-converting enzyme-1 (ECE-1) in the rat adrenal gland. The densities, pharmacological properties and distribution of ET receptor subtypes ETA and ETB in adrenal glands from streptozotocin-induced diabetic, insulin-treated diabetic and age-matched control rats were investigated, using radioligand receptor binding and autoradiographic techniques. The gene expression of ETA and ETB receptors ET-1, ET-3 and ECE-1 was evaluated using relative multiplex reverse transcription/PCR. The induction of diabetes caused a marked reduction in body weight but no significant change in adrenal gland size. The density of ET receptors was significantly increased in the diabetic rat adrenal gland, mainly because of an increase in the expression of ETB receptors. Insulin treatment normalized the diabetes-induced changes in the expression levels of ET receptor subtypes to control levels. The expression level of ET-1 mRNA was up-regulated, whereas ET-3 mRNA was down-regulated in the diabetic adrenal gland compared with the controls. The ECE-1 mRNA level in the adrenal gland was not altered by the induction of diabetes. Autoradiographic studies showed that ETA and ETB are the predominant receptor subtypes in the adrenal medulla and cortex respectively. These results suggest that ETA and ETB receptors are differentially distributed and regulated in the diabetic rat adrenal gland.

Adrenal Glands↗

PubMed2002

Subunit composition, distribution and function of GABA(A) receptor subtypes.

GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain and are the site of action of many clinically important drugs. These receptors are composed of five subunits that can belong to eight different subunit classes. Depending on their subunit composition, these receptors exhibit distinct pharmacological and electrophysiological properties. Recent studies on recombinant and native GABA(A) receptors suggest the existence of far more receptor subtypes than previously assumed. Thus, receptors composed of one, two, three, four, or five different subunits might exist in the brain. Studies on the regional, cellular and subcellular distribution of GABA(A) receptor subunits, and on the co-localization of these subunits at the light and electron microscopic level for the first time provide information on the distribution of GABA(A) receptor subtypes in the brain. These studies will have to be complemented by electrophysiological and pharmacological studies on the respective recombinant and native receptors to finally identify the receptor subtypes present in the brain. The distinct cellular and subcellular location of individual receptor subtypes suggests that they exhibit specific functions in the brain that can be selectively modulated by subtype specific drugs. This conclusion is supported by the recent demonstration that different GABA(A) receptor subtypes mediate different effects of benzodiazepines. Together, these results should cause a revival of GABA(A) receptor research and strongly stimulate the development of drugs with a higher selectivity for alpha2-, alpha3-, or alpha5-subunit-containing receptor subtypes. Such drugs might exhibit quite selective clinical effects.

Animals↗