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PubMed2006

Mouse cerebellar nicotinic-cholinergic receptor modulation of Delta9-THC ataxia: role of the alpha4beta2 subtype.

In spite of widespread association of nicotine and cannabinoids in humans, very few studies in which nicotine and cannabinoids are co-administered have been reported. Previously, we have reported that intracerebellar (ICB) Delta(9)-tetrahydrocannabinol (Delta(9)-THC) produces dose-dependent cerebellar ataxia. The present study investigated the functional consequences of ICB microinfusion of nicotine on ICB Delta(9)-THC ataxia in CD-1 male mice. Nicotine (0.625, 1.25, 2.5, 5 ng; ICB) markedly attenuated Delta(9)-THC ataxia dose dependently, which was abolished by ICB hexamethonium (5 microg), thus suggesting that the attenuation by nicotine occurred via the nicotinic acetylcholine receptor (nAChR). To further investigate which specific nAChR subtype was involved, ICB microinfusion of RJR-2403 (250, 375, 500, 750 ng), a alpha(4)beta(2) selective nAChR agonist, markedly attenuated Delta(9)-THC ataxia. DHbetaE (500 ng), a alpha(4)beta(2) selective nAChR antagonist, virtually abolished RJR-2403-induced attenuation of Delta(9)-THC ataxia. ICB microinfusion of MLA, a alpha(7) selective nAChR antagonist (1, 5 microg) failed to antagonize nicotine or RJR-2403-induced attenuation of Delta(9)-THC ataxia. This suggested a lack of a role of the alpha(7) subtype and further reinforced the significance of alpha(4)beta(2). Additionally, ICB treatment with DHbetaE virtually abolished nicotine-induced attenuation of Delta(9)-THC ataxia that suggested alpha(4)beta(2) as the primary cerebellar nAChR subtype. Lack of effect of ICB DHbetaE or MLA alone on Delta(9)-THC ataxia ruled out a tonic effect of the alpha(4)beta(2) subtype. The results of the present investigation, therefore, strongly support involvement of the cerebellar alpha(4)beta(2), but not alpha(7), nicotinic receptor subtype in the mediation via nicotine and RJR-2403 on attenuation of Delta(9)-THC ataxia.

Animals↗
PubMed2004

Inositol 1,4,5-trisphosphate receptor subtypes are differentially distributed between smooth muscle and endothelial layers of rat arteries.

In blood vessels, the ability to control vascular tone depends on extracellular calcium entry and the release of calcium from inositol 1,4,5-trisphosphate receptor (IP3R)-gated stores located in both the endothelial and smooth muscle cells of the vascular wall. Therefore, we examined mRNA expression and protein distribution of IP3R subtypes in intact aorta, basilar and mesenteric arteries of the rat. IP3R1 mRNA was predominantly expressed in all three arteries. Immunohistochemistry showed that IP3R1 was present in both the muscle and endothelial cell layers, while IP3R2 and IP3R3 were largely restricted to the endothelium. Weak expression of IP3R2 was observed in the smooth muscle of the basilar artery. Co-localisation studies of IP3R subtypes with known cellular elements showed no association of any of the three subtypes with the endothelial cell plasma membrane, but a close association between the subtypes and actin filaments was observed in all cell layers. IP3R2 was found to be present near the endothelial cell nucleus. We are the first to demonstrate differential IP3R subtype distribution between the cell layers of the intact vascular wall and hypothesise that this may underlie the diversity of IP3R-dependent responses, such as vasoconstriction, vasodilation and vasomotion, displayed by arteries.

Animals↗
PubMed2006

Association between the methicillin resistance of clinical isolates of Staphylococcus aureus, their staphylococcal cassette chromosome mec (SCCmec) subtype classification, and their toxin gene profiles.

Virulence and antimicrobial resistance are important determinators of the clinical manifestations and of the treatments of bacterial infections. Here, we studied the associations between the methicillin resistance of clinical Staphylococcus aureus isolates, their classifications as particular staphylococcal cassette chromosome mec (SCCmec) subtypes, and their toxin gene profiles. In total, 252 S. aureus isolates were collected from 13 healthcare facilities in 6 Korean provinces. The overall prevalence of methicillin-resistant S. aureus (MRSA) was 63%. SCCmec typing and toxin gene analysis were performed by multiplex polymerase chain reaction. One or more staphylococcal toxin genes were found in 190 (75.4%) strains. Methicillin-resistant S. aureus strains carried toxin genes more frequently than methicillin-susceptible S. aureus strains (85.5% versus 53.8%). SCCmec subtypes differed in terms of their frequencies of toxin gene carriage (95.9% in SCCmec II, 74.4% in SCCmec III, and 68.8% in SCCmec IV). Specific SCCmec subtypes frequently harbored particular toxin gene combinations: 77.3% of SCCmec II strains carried sec and tst genes, 48.8% of SCCmec III strains carried sea and see genes, and 46.9% of SCCmec IV carried sea and seb genes. Indeed, the most prevalent combination in MRSA strains, that of sec and tst, was only observed in SCCmec II strains, and these strains failed to show the coexistence of sea and see or sea and seb genes. Thus, the SCCmec subtypes of S. aureus revealed specific staphylococcal toxin profiles. We revealed that certain staphylococcal toxin gene profiles are associated not only with the methicillin resistance of S. aureus but also with their SCCmec subtypes.

Bacterial Toxins↗
PubMed2026

Whole genome sequencing of unusual Hepatitis C virus subtypes and drug resistance analysis during direct-acting antiviral therapy in India.

INTRODUCTION AND OBJECTIVES: Pangenotypic direct-acting antivirals (DAA) are effective against highly prevalent Hepatitis C virus (HCV) subtypes, but have been clinically validated almost exclusively in high-income countries. Unusual HCV subtypes may carry natural polymorphisms, potentially impacting DAA susceptibility. We conducted full-genome characterization and resistance analysis of unusual HCV subtypes in patients receiving DAA treatment. PATIENTS AND METHODS: In this prospective hospital-based study, eligible patients were screened for anti-HCV antibodies and active infection was confirmed by diagnostic 5'NCR-based HCV RNA detection. Genotyping was performed by core region sequencing, and viral load quantified by real-time PCR. For whole genome sequencing, multiplex primers were designed using alignments of global reference sequences. Sequencing was carried out using the Oxford Nanopore Technology platform. Phylogenetic analysis used multiple sequence alignment and the HCV-GLUE resource for resistance-associated substitution (RAS) analysis. RESULTS: Predominant genotype was genotype 3 in 64.3% (n = 45); genotype 6 in 21.4% (n = 15); and genotype 1 in 14.2% (n = 10). Unusual HCV subtype 6xa was detected in two patients and showed no NS5A resistance mutations. One genotype 3b patient relapsed at 24 weeks post-DAA treatment completion and carried NS5A resistance-associated substitutions 30 K and 31 M both at baseline and at relapse, conferring high-level resistance to NS5A inhibitors. CONCLUSION: This is the first report from India of whole genome sequencing of HCV subtype 6xa. The identification of NS5A resistance mutations in the 3b relapse case underscores challenges for global HCV elimination strategies.

Humans↗
PubMed2004

Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype.

Which of the three alpha2-adrenoceptor subtypes of alpha2A, alpha2B, or alpha2C mediates the neuroprotective effect of dexmedetomidine was examined in cell culture as well as in an in vivo model of neonatal asphyxia. Dexmedetomidine dose-dependently attenuated neuronal injury (IC50=83+/-1 nM) in neuronal-glial co-cultures derived from wild-type mice; contrastingly, dexmedetomidine did not exert neuroprotection in injured cells from transgenic mice (D79N) expressing dysfunctional alpha2A-adrenoceptors. An alpha2A-adrenoceptor subtype-preferring antagonist 2-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408) completely reversed dexmedetomidine-induced neuroprotection, while other subtype-preferring antagonists 2-[2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239) (alpha2B) and rauwolscine (alpha2C) had no significant effect on the neuroprotective effect of dexmedetomidine in neuronal-glial co-cultures. Dexmedetomidine also protected against exogenous glutamate induced cell death in pure cortical neuron cultures assessed by flow cytometry and reduced both apoptotic and necrotic types of cell death. Likewise this neuroprotective effect was antagonised by BRL44408 but not ARC239 or rauwolscine. Dexmedetomidine exhibited dose-dependent protection against brain matter loss in vivo (IC50=40.3+/-6.1 microg/kg) and improved the neurologic functional deficit induced by the hypoxic-ischemic insult. Protection by dexmedetomidine against hypoxic-ischemic-induced brain matter loss was reversed by the alpha2A-adrenoceptor subtype-preferring antagonist BRL44408; neither ARC239 nor rauwolscine reversed the neuroprotective effect of dexmedetomidine in vivo. Our data suggest that the neuroprotective effect of dexmedetomidine is mediated by activation of the alpha2A adrenergic receptor subtype.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2006

Epidemiology of specific phobia subtypes: findings from the Dresden Mental Health Study.

This study determined the prevalence, age of onset, comorbidity, and impairment associated with specific phobia subtypes in the community. Data were drawn from the Dresden Mental Health Study (N=2064), a representative community-based sample of young women in Dresden, Germany. The lifetime prevalence of any specific phobia was 12.8%, with subtypes ranging in prevalence between 0.2% (vomiting, infections) and 5.0% (animals). There were significant differences in the mean age of onset of specific phobias. Significant differences in comorbidity patterns also emerged between subtypes. No significant differences were found in level of impairment associated with the subtypes. The findings suggest that specific phobias are common among young women and that they differ in prevalence, associated comorbidity, and mean age of onset. These data suggest significant differences in the phenomenology and clinical significance of specific phobia subtypes.

Adolescent↗
PubMed2004

Age-related changes of muscarinic cholinergic receptor subtypes in the striatum of Fisher 344 rats.

Striatum expresses a cholinergic system involved in the regulation of its activity and changes in striatal cholinergic receptors may be related to cognitive impairment. This study has investigated muscarinic cholinergic M1-M5 receptor subtype expression in striatum of Fischer 344 rats aged 6 (young), 15 (adult) and 22 months (senescent) to assess the contribution of different muscarinic cholinergic receptor subtypes in age-related changes of striatal cholinergic neurotransmission. Western blot analysis revealed the expression of the M1-M5 muscarinic receptor subtytpes in the striatum of rats of the three age groups investigated. Both radioligand binding assay and light microscope autoradiography showed in young rats a M4>M1>M2>M3>M5 rank order of receptor density. With the exception of M1 receptor, the density of which is similar in the dorsal (motor) and ventral (limbic) striatum, other receptor subtypes were more abundant in ventral than in dorsal striatum. M1 receptor expression was unchanged between young and adult rats and decreased in senescent animals both in dorsal and ventral striatum. In dorsal striatum M2 and M5 receptor expression did not show age-related changes, whereas in ventral striatum it was slightly decreased in adult rats compared to young or senescent cohorts. M3 receptor expression did not show age-related modifications, whereas a progressive age-related decrease of M4 receptor was found, both in dorsal and ventral striatum. These data indicate a heterogeneous response to age of different muscarinic receptor subtypes. Striatal cholinergic markers are thought to correlate with cognitive impairment in aged rats. In view of this, the identification of age-related changes of striatal muscarinic receptor subtypes may contribute to develop cholinergic strategies to counter cholinergic neurotransmission changes occurring with aging.

Aging↗
PubMed2005

Divergent activities of interferon-alpha subtypes against intracellular hepatitis C virus replication.

BACKGROUNDS: Interferon (IFN)-alpha is represented by several structurally related subtypes that show different antiviral and anti-tumor effects. Here, we analyzed differential effects of IFN-alpha subtypes on intracellular hepatitis C virus (HCV) replication using HCV subgenomic replicon system as a model. METHODS: Huh7 and HeLa cells supporting expression of HCV replicon were treated with various concentrations of five recombinant human IFN-alpha subtypes 1, 2, 5, 8, and 10, and with IFN-alpha con1. The effects of IFNs on various cell-signaling pathways were assayed by using ISRE-, GAS-, AP1-, NF-kappa B-, CRE-, and SRE-luciferase reporter plasmids. RESULTS: Each IFN-alpha subtype suppressed HCV replication in a dose-dependent manner. Among them, IFN-alpha8 was the most effective, while IFN-alpha1 was the least effective with 50% inhibitory concentrations of 0.123IU/ml versus 0.375IU/ml, respectively. These differential effects against HCV replication did not correlate with levels of the IFN-responsive ISRE or GAS reporter activities, nor they did activate the other reporters, AP1, NF-kappa B, CRE and SRE. CONCLUSION: There were divergent effects of IFN-alpha subtypes against HCV replication that may be through JAK-STAT-independent pathways. Exploring further mechanisms of action may elucidate IFN-mediated cellular antiviral mechanisms.

Journal Article↗
PubMed2005

Genetic variability of principal neutralizing determinants on HIV-1 gp41 and its correlation with subtypes.

Several neutralizing determinants have been identified on HIV-1 envelope glycoprotein gp41: LGIWGCSGKLIC (HXB2: aa593-604), ELDKWA (aa662-667), NWFDIT (aa671-676), and ERDRDR (aa739-744). Restricted mutations were observed on these epitopes. In this study, the genetic variability of these neutralizing determinants in 3799 isolates from different M-group subtypes (A, B, C, D, F, G, H, CRF01_AE and CRF02_AG) and O group was analyzed. Many variants were found to be closely correlated with certain subtypes. These subtype-related variants could be recruited into the subtype identification and subtype-specific vaccine development.

Amino Acid Motifs↗
PubMed2006

Effects of estrogen receptor subtype-selective agonists on immune functions in ovariectomized mice.

Estrogens have multiple influences on immune functions. Estrogen receptors (ERs) have two distinct subtypes - alpha and beta. To explore the specific roles of each ER subtype in estrogen-mediated immunomodulation, we investigated the effects of ER subtype-selective agonists on immune functions in ovariectomized Balb/c mice. Treatment with ERalpha-selective agonist propyl pyrazole triol (PPT) caused thymic atrophy and significant changes in thymic CD4/CD8 phenotypic profile. In contrast, ERbeta-selective agonist diarylpropionitrile (DPN) alone had no effect on thymic weight, cellularity or CD4/CD8 phenotype expression. When coadministered with PPT, DPN partially antagonized PPT-evoked decrease in thymic cellularity and also partially attenuated PPT-induced shifts in thymic T-cell phenotype. These results indicate that ERalpha plays a predominant role in estrogen-induced thymic atrophy and ERbeta activation may partially down-regulate ERalpha-mediated effects on thymic cellularity and T-cell phenotype expression. In addition, PPT administration induced a reduction in the percentage of mature B cells in the spleen, and enhanced IFN-gamma production but suppressed IL-6 production from in vitro Con A-stimulated splenocytes as estradiol (E(2)) did, whereas DPN treatment had no effects either alone or with PPT, suggesting ERalpha mediates these estrogen actions. Treatment with PPT or DPN did not augment anti-DNP antibody production after DNP-KLH immunization as E(2) did, implying that not merely one ER signaling pathway is involved in mediating estrogen's effects on specific humoral immune responses. Our study further indicates ER subtype-selective agonists provide a novel approach to explore each ER subtype-mediated immunomodulation.

Animals↗
PubMed2004

Identification of granulocyte subtype-selective receptors and ion channels by using a high-density oligonucleotide probe array.

BACKGROUND: During inflammation, neutrophils, basophils, and eosinophils release cell type-specific mediators and proteases through signaling molecules, such as G protein-coupled receptors and ion channels. As such, ion channels and receptors, including G protein-coupled receptors, are common drug targets. OBJECTIVE: We sought to identify, for the first time, ion channels and receptors preferentially expressed by each granulocyte subtype. METHODS: Using GeneChip, we compared approximately 20,000 transcripts present in 7 leukocyte types, platelets, mast cells, and fibroblasts to identify granulocyte subtype-selective transcripts for receptors and ion channels. Granulocyte subtype-selective transcripts were chosen on the basis of several conditions, such as the transcript having a 5-fold or greater expression level compared with the maximum level of other leukocytes. RESULTS: Fifty-one transcripts were chosen to be preferentially expressed by each granulocyte subtype. Seventeen of the 51 transcripts have not been previously reported as granulocyte subtype selective. Among the 17 receptors and ion channels, 6 were basophil selective, eosinophil selective, or both and were not highly expressed by other organs, indicating that they might be potential targets for antiallergy drugs. CONCLUSION: Use of this database of potential cell type-selective drug targets should minimize the efforts required for pharmaceutical development.

Basophils↗
PubMed2005

Ductal carcinoma in situ of the breast and heparanase-1 expression: a molecular explanation for more aggressive subtypes.

BACKGROUND: Ductal carcinoma in situ of the breast (DCIS) forms a heterogeneous group of lesions with varying invasive potential. This study tested whether heparanase-1 (HPR1), an endoglycosidase that specifically degrades the heparan sulfate (HS) proteoglycans in the breast extracellular matrix, was associated with the most aggressive DCIS subtypes. STUDY DESIGN: Fifty-seven DCIS specimens and 10 normal breast specimens were examined for HPR1 expression using immunohistochemical staining. Twenty-seven arbitrarily selected specimens were also examined for HS deposition by immunofluorescence staining, confirming HPR1 activity. Patient medical records were obtained to explore a possible association between biologic potential using Van Nuys Prognostic Index (VNPI) and HPR1 expression. RESULTS: Twenty-one (75%) of 28 comedo and microinvasive DCIS specimens stained HPR1 positive; 4 (14%) of 29 other subtypes (papillary, cribriform, and solid subtypes) stained HPR1 positive on immunohistochemistry (p = 0.003). Among 27 DCIS stained for HS, we found that 8 (67%) of 12 HPR1-negative DCIS had intact HS deposition in the extracellular basement membrane; none of the 15 HPR1-positive DCIS stained HS positive. Six (86%) of seven DCIS with VNPI scores 8 to 9 and 14 (50%) of 28 DCIS with VNPI scores 5 to 7 were HPR1 positive; only 3 (17%) of 18 DCIS with VNPI scores 3 to 4 were HPR1 positive. Median VNPI score in patients with HPR1-positive DCIS was 7 (range 3 to 9), compared with 4.5 (range 3 to 7) in patients with HPR1-negative DCIS (p < 0.001). CONCLUSIONS: HPR1 was expressed at a significantly higher frequency in the invasive comedo and DCIS with microinvasion subtypes than in the noninvasive subtypes. HPR1 expression was inversely associated with HS deposition in the extracellular basement membrane of the DCIS. HPR1 expression was associated with a higher VNPI score. These observations suggest that HPR1 expression in DCIS can play an important role in development of DCIS into an invasive breast cancer.

Antibodies, Monoclonal↗
PubMed2006

Susceptibility of HIV-1 non-B subtypes and recombinant variants to Enfuvirtide.

BACKGROUND: Data on susceptibility of HIV-1 non-B subtypes to Enfuvirtide (ENF) is rather limited. OBJECTIVE: To determine if ENF could be active in vitro against HIV-1 non-B subtypes and how the gp41 genetic variability across variants may influence ENF susceptibility. METHODS: Using PHENOSCRIPT Env, a recombinant envelope virus assay, ENF susceptibility was investigated in isolates from 19 drug-naive HIV-1-infected individuals harboring non-B subtypes. RESULTS: Using phylogenetic analyses of the gp41 gene, distinct HIV-1 subtypes were recognized: A (2), C (5), D (1), F (2), G (1), J (1), CRF02_AG (6) and CRF06 (1). Susceptibility to ENF and IC(50) values in vitro could be obtained in only 13 (68.4%) specimens, most likely due to the high genetic variability in HR1 and HR2 regions in the remaining cases. A wide range of IC(50) values with a median of 0.013 microg/ml was observed (range, 0.005-0.180 microg/ml). Natural polymorphisms, but not classical ENF resistance associated mutations within HR1 (residues 36-45) were identified in most non-B viruses. CONCLUSION: This study provides information about the baseline susceptibility to ENF in antiretroviral-naive subjects infected with different HIV-1 non-B subtypes. Susceptibility to ENF seems to be preserved despite high genetic variability in HR1 and HR2 regions.

Adult↗
PubMed2004

Differential expression of somatostatin receptor subtypes in hepatocellular carcinomas.

BACKGROUND/AIMS: Somatostatin analogues inhibit cell proliferation by stimulation of distinct somatostatin receptor (SSTR) subtypes. In recent years, these compounds have been introduced into the therapy of advanced hepatocellular carcinoma (HCC). The efficacy of this treatment is under debate due to the controversial results of clinical trials. Despite the widespread clinical use of somatostatin analogues in HCC, little is known about the expression of each of the five SSTRs in these tumors. METHODS: We analyzed the expression of SSTR subtypes in 56 HCCs by immunohistochemistry using subtype-specific antibodies. Six of the samples were also investigated by RT-PCR using subtype-specific oligonucleotide primers. RESULTS: HCCs display differential, individual expression patterns as well as variable expression levels for SSTRs. The overall expression rate of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 is 46, 41, 64, 0, and 75%, respectively. No significant correlation was observed between SSTR expression and tumor stage, differentiation, histological tumor type, or underlying liver disease. CONCLUSIONS: Individual patterns and levels of SSTR expression might determine the response to treatment with somatostatin analogues in HCC. Selective treatment of these tumors based on the analysis of SSTR subtype expression might lead to an increase in response rates.

Adolescent↗
PubMed2005

A monoclonal antibody-based ELISA allows discrimination between responses induced by bovine herpesvirus subtypes 1 (BoHV-1.1) and 2 (BoHV-1.2).

Bovine herpesvirus type 1 (BoHV-1) has distinct subtypes according to genomic characterization. Immune responses induced by BoHV-1 subtype 1 (BoHV-1.1) are not distinguishable from those induced by BoHV-1 subtype 2 (BoHV-1.2) through conventional serological methods. In the present report, an enzyme linked immunosorbent assay is described that allows discrimination between immune responses in cattle immunized with either subtype, based on a monoclonal antibody that recognizes specifically the amino-terminal region of glycoprotein C (gC) on BoHV-1.1 strains, thus not reacting with BoHV-1.2a. The test displayed a sensitivity of 92%, specificity of 90% and a good correlation with serum neutralization tests on samples from BoHV-1.1-immunized calves (kappa = 0.799). The test may be useful to provide new insights into the roles played by each of these two subtypes in the epidemiology of BoHV-1 infections.

Animals↗
PubMed2005

Muscarinic cholinergic receptor subtypes in cerebral cortex of Fisher 344 rats: a light microscope autoradiography study of age-related changes.

The density and localization of muscarinic cholinergic M1-M5 receptor subtypes was investigated in frontal and occipital cortex of male Fisher 344 rats aged 6 months (young-adult), 15 months (mature) and 22 months (senescent) by combined kinetic and equilibrium binding and light microscope autoradiography. In 6-month-old rats, the rank order density of muscarinic cholinergic receptor subtypes was M1>M2>M4>M3>M5 both in frontal and occipital cortex. A not homogeneous distribution of different receptor subtypes throughout cerebrocortical layers of frontal or occipital cortex was found. In frontal cortex silver grains corresponding to the M1 and M2 receptor subtypes were decreased in 15- and 22-month-old groups. The M3 receptor density was remarkably and moderately decreased in layers II/III and V, respectively, of rats aged 15 and 22 months. A reduced M4 receptor density was observed in layer I and to a lesser extent in layer V of mature and senescent rats, whereas no age-related changes of M5 receptor were found. In occipital cortex a diminution of M1 receptor was observed in layers II/III and V of mature and senescent rats. The M2 receptor expression decreased in layer I of 15- and 22-month-old senescent rats, whereas M3-M5 receptors were unchanged with exception of a slight decrease of the M4 receptor in layer IV and of M5 receptor in layers II/III. These findings indicate a different sensitivity to aging of muscarinic receptor subtypes located in various cerebrocortical layers. This may account for the difficulty in obtaining relevant results in manipulating cholinoceptors to counter age-related impairment of cholinergic system.

Aging↗
PubMed2006

Automated segmentation of multiple sclerosis lesion subtypes with multichannel MRI.

PURPOSE: To automatically segment multiple sclerosis (MS) lesions into three subtypes (i.e., enhancing lesions, T1 "black holes", T2 hyperintense lesions). MATERIALS AND METHODS: Proton density-, T2- and contrast-enhanced T1-weighted brain images of 12 MR scans were pre-processed through intracranial cavity (IC) extraction, inhomogeneity correction and intensity normalization. Intensity-based statistical k-nearest neighbor (k-NN) classification was combined with template-driven segmentation and partial volume artifact correction (TDS+) for segmentation of MS lesions subtypes and brain tissue compartments. Operator-supervised tissue sampling and parameter calibration were performed on 2 randomly selected scans and were applied automatically to the remaining 10 scans. Results from this three-channel TDS+ (3ch-TDS+) were compared to those from a previously validated two-channel TDS+ (2ch-TDS+) method. The results of both the 3ch-TDS+ and 2ch-TDS+ were also compared to manual segmentation performed by experts. RESULTS: Intra-class correlation coefficients (ICC) of 3ch-TDS+ for all three subtypes of lesions were higher (ICC between 0.95 and 0.96) than that of 2ch-TDS+ for T2 lesions (ICC = 0.82). The 3ch-TDS+ also identified the three lesion subtypes with high specificity (98.7-99.9%) and accuracy (98.5-99.9%). Sensitivity of 3ch-TDS+ for T2 lesions was 16% higher than with 2ch-TDS+. Enhancing lesions were segmented with the best sensitivity (81.9%). "Black holes" were segmented with the least sensitivity (62.3%). CONCLUSION: 3ch-TDS+ is a promising method for automated segmentation of MS lesion subtypes.

Adult↗
PubMed2005

Expression of somatostatin receptor subtypes (SSTR1-5) in Alzheimer's disease brain: an immunohistochemical analysis.

Somatostatin, widely distributed in human cortical brain regions, acts through specific high affinity somatostatin receptors (SSTR1-5) to exert profound effects on motor, sensory, behavioral, cognitive and autonomic functions. Somatostatin levels are consistently decreased in the cortex of Alzheimer's disease (AD) brain and in cerebrospinal fluid, and have become reproducible markers of this disease. In the present study, the distributional pattern of SSTR1-5 antigens in the frontal cortex of AD and age-matched control brains was studied using antipeptide polyclonal rabbit antibodies directed against the five human somatostatin receptor subtypes. All five SSTRs were differentially expressed as membrane and cytoplasmic proteins in cortical neurons with significant variations in control vs. AD brain. In AD cortical brain region, somatostatin and neuropeptide-Y-positive neurons decreased (>70%), and glial fibrillary acidic protein-positive astrocytes significantly increased (>130%) in comparison to control brain. SSTR2 and 4 were the predominant subtypes followed by SSTR1, 3 and 5. AD cortex showed a marked reduction in neuronal expression of SSTR4 and 5 and a modest decrease in SSTR2-like immunoreactivity without any changes in SSTR1 immunoreactive neurons. In contrast, SSTR3 was the only receptor subtype that increased in AD cortex. In AD cortex, SSTR1-, 3- and 4-like immunoreactivities were strongly expressed in glial cells but not SSTR2 and 5. These findings suggest the differential loss of immunoreactivity of SSTR2, 4 and 5 but not SSTR1, and increased SSTR3 in frontal cortex of AD brain as well as subtype-selective glial expression in AD brain. In summary, subtype-selective changes in the expression of SSTRs at protein levels in AD cortical regions suggest that somatostatin and SSTR-containing neurons are pathologically involved in AD and could possibly be used as markers of this disease.

Aged↗