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Biomedical subjects

F Sam

Publications and source records attributed to F Sam.

10 recordsLinked to original sources
PubMed2002

5HT1Dbeta Receptor gene implicated in the pathogenesis of Obsessive-Compulsive Disorder: further evidence from a family-based association study.

Obsessive-Compulsive Disorder (OCD) is a psychiatric condition with strong evidence for a genetic component and for the involvement of genes of the serotonin system. In a recent family-based association study we reported an association between the G allele of the G861C polymorphism of the 5HT1Dbeta receptor gene and OCD. The aim of the present study was to further investigate for the presence of linkage disequilibrium between each of two polymorphisms of the 5HT1Dbeta receptor gene and OCD in a larger sample of OCD families. In a total of 121 families the G861C and the T371G polymorphisms of the 5HT1Dbeta receptor gene were genotyped using standard protocols. The genotyping data were analyzed with a new extension of the Transmission Disequilibrium Test (FBAT). The phenotypes considered in the analyses were the diagnosis of OCD and two quantitative phenotypes related to the diagnosis and clinically relevant, ie, the age at onset and the severity of OCD symptoms. We confirmed the previously found preferential transmission of the G861 allele to the affected subjects (z = 2.262, P = 0.02). No significant association was found between the polymorphism and the quantitative phenotypes considered. These results represent a confirmation of our previous published study and thus, could have important implications for the role of the 5HT1Dbeta receptor gene in the pathogenesis and treatment of OCD. Further genetic investigations on this marker considering additional polymorphisms and other quantitative phenotypes related to OCD are warranted.

Family Health↗
PubMed2001

Mice lacking inducible nitric oxide synthase have improved left ventricular contractile function and reduced apoptotic cell death late after myocardial infarction.

Nitric oxide produced by inducible nitric oxide synthase (NOS2) has been implicated in the pathophysiology of chronic myocardial remodeling and failure. We tested the role of NOS2 in left ventricular (LV) remodeling early (1 month) and late (4 months) after myocardial infarction (MI) in mice lacking NOS2. MI size measured 7 days, 1 month, and 4 months after MI was the same in NOS2 knockout (KO) and wild-type (WT) mice. The LV end-diastolic pressure-volume relationship measured by the isovolumic Langendorff technique showed a progressive rightward shift from 1 to 4 months after MI in WT mice. LV developed pressure measured over a range of LV volumes was reduced at 1 and 4 months after MI in WT mice (P<0.05 and P<0.01 versus shams, respectively). In KO mice, the rightward shift was similar to that in WT mice at 1 and 4 months after MI, as was peak LV developed pressure at 1 month after MI. In contrast, at 4 months after MI, peak LV developed pressure in KO mice was higher than in WT mice (P<0.05 versus WT) and similar to that in sham-operated mice. At 1 month after MI, the frequency of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive myocytes in the remote myocardium was increased to a similar extent in WT and KO mice. At 4 months after MI, the frequency of apoptotic myocytes was increased in WT mice but not in KO mice (P<0.05 versus WT). Improved contractile function and reduced apoptosis were associated with reduced mortality rate in KO mice at 4 months after MI. Thus, NOS2 does not play an important role in determining infarct size or early LV remodeling during the first month after MI. In contrast, during late (ie, 4 months after MI) remodeling, NOS2 in remote myocardium contributes to decreased contractile function, increased myocyte apoptosis in remote myocardium, and reduced survival.

Animals↗
PubMed2001

Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin.

Osteopontin (OPN), an extracellular matrix protein, is expressed in the myocardium with hypertrophy and failure. We tested the hypothesis that OPN plays a role in left ventricular (LV) remodeling after myocardial infarction (MI). Accordingly, OPN expression and LV structural and functional remodeling were determined in wild-type (WT) and OPN knockout (KO) mice 4 weeks after MI. Northern analysis showed increased OPN expression in the infarcted region, peaking 3 days after MI and gradually decreasing over the next 28 days. In the remote LV, OPN expression was biphasic, with peaks at 3 and 28 days. In situ hybridization and immunohistochemical analyses showed increased OPN mRNA and protein primarily in the interstitium. Infarct size, heart weight, and survival were similar in KO and WT mice after MI (P=NS), whereas the lung wet weight/dry weight ratio was increased in the KO mice (P<0.005 versus sham-operated mice). Peak LV developed pressure was reduced to a similar degree after MI in the KO and WT mice. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive myocytes was similar in KO and WT mice after MI. In contrast, post-MI LV chamber dilation was approximately twice as great in KO versus WT mice (P<0.001). Myocyte length increased after MI in WT mice (P<0.001) but not in KO mice. Electron microscopy showed increased collagen content in WT mice after MI but not in KO mice after MI. Type I collagen content was increased approximately 3-fold and approximately 7-fold in remote and infarcted regions, respectively, of WT hearts after MI but not in KO hearts (P<0.01 versus WT hearts). Likewise, Northern analyses showed increased collagen I(alpha(1)) mRNA after MI in remote regions of WT hearts but not in KO hearts. Thus, increased OPN expression plays an important role in regulating post-MI LV remodeling, at least in part, by promoting collagen synthesis and accumulation.

Animals↗
PubMed2001

ET(A)-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat.

Endothelin (ET) A (ET(A)) receptors activate matrix metalloproteinases (MMP). Since endothelin-1 (ET) is increased in myocardium late postmyocardial infarction (MI), we hypothesized that stimulation of ET(A) receptors contributes to activation of myocardial MMPs late post-MI. Three days post-MI, rats were randomized to treatment with the ET(A)-selective receptor antagonist sitaxsentan (n = 12) or a control group (n = 12). Six weeks later, there were rightward shifts of the left ventricular (LV) end-diastolic and end-systolic pressure-volume relationships, as measured ex vivo by the isovolumic Langendorff technique. Both shifts were markedly attenuated by sitaxsentan. In LV myocardium remote from the infarct, the activities of MMP-1, MMP-2, and MMP-9 were increased in the post-MI group, and the increases were prevented by sitaxsentan treatment. Expression of tissue inhibitor of MMP-1 was decreased post-MI, and the decrease was prevented by sitaxsentan treatment. Chronic post-MI remodeling is associated with activation of MMPs in myocardium remote from the infarct. Inhibition of ET(A) receptors prevents MMP activation and LV dilation, suggesting that ET, acting via the ET(A) receptor, contributes to chronic post-MI remodeling by its effects on MMP activity.

Animals↗
PubMed2000

Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart.

We tested the hypothesis that left ventricular (LV) remodeling late after myocardial infarction (MI) is associated with myocyte apoptosis in myocardium remote from the infarcted area and is related temporally to LV dilation and contractile dysfunction. One, four, and six months after MI caused by coronary artery ligation, LV volume and contractile function were determined using an isovolumic balloon-in-LV Langendorff technique. Apoptosis and nuclear morphology were determined by terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) and Hoechst 33258 staining. Progressive LV dilation 1-6 mo post-MI was associated with reduced peak LV developed pressure (LVDP). In myocardium remote from the infarct, there was increased wall thickness and expression of atrial natriuretic peptide mRNA consistent with reactive hypertrophy. There was a progressive increase in the number of TUNEL-positive myocytes from 1 to 6 mo post-MI (2.9-fold increase at 6 mo; P < 0. 001 vs. sham). Thus LV remodeling late post-MI is associated with increased apoptosis in myocardium remote from the area of ischemic injury. The frequency of apoptosis is related to the severity of LV dysfunction.

Animals↗
PubMed2000

Is the 5-HT(1Dbeta) receptor gene implicated in the pathogenesis of obsessive-compulsive disorder?

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a psychiatric condition for which strong evidence of a genetic component and serotonergic system involvement exists. Recent studies have shown that sumatriptan, a selective ligand of the serotonin (5-HT)(1Dbeta) autoreceptor, modifies OCD symptoms. The aim of this study was to investigate the presence of linkage disequilibrium between the 5-HT(1Dbeta) receptor gene, which has a variant caused by a silent G to C substitution at nucleotide 861 of the coding region, and OCD. METHOD: DNA was collected from 67 probands who met DSM-IV criteria for OCD and from their living parents or siblings. Transmission Disequilibrium Test/sib-Transmission Disequilibrium Test analyses were then conducted with the DNA data. RESULTS: Thirty-two families were informative for the analysis, which showed a preferential transmission of the G allele to the affected subjects. CONCLUSIONS: If the results are confirmed, there may be important implications for the 5-HT(1Dbeta) receptor gene in the pathogenesis and treatment of OCD.

Adult↗
PubMed1998

Left-ventricular structural and functional remodeling in the mouse after myocardial infarction: assessment with the isovolumetrically-contracting Langendorff heart.

The goal of this study was to determine whether the isovolumically-contracting Langendorff heart could be used to assess changes in left-ventricular volume and contractile reserve in the mouse heart after myocardial infarction. Myocardial infarction (40 +/- 3% of the left ventricle by weight) was induced in CD-1 mice by ligation of the left-anterior descending coronary artery. Two weeks after infarction there was compensatory hypertrophy of the non-infarcted ventricle as indicated by increases in heart-to-body weight ratio (5.5 +/- 0.2 v 4.9 +/- 0.2 mg/g; P < 0.05; n = 12) and the expression of atrial natriuretic peptide mRNA (4.4 +/- 1.4-fold; P < 0.001; n = 4). Left-ventricular pressure-volume relationships were assessed in vitro in isovolumically-contracting hearts perfused with red cell-supplemented buffer (hematrocrit = 40%). Myocardial infarction caused left-ventricular dilation with a rightward-shift of the diastolic pressure-volume relationship. This was associated with reduced left-ventricular contractile function, as evidenced by a decrease in developed pressure over a range of left-ventricular volumes. Thus, it is feasible to use the isovolumically-contracting Langendorff preparation to assess the structural and functional consequences of left-ventricular remodeling in the mouse after a myocardial infarction.

Animals↗
PubMed1998

Investigation of dopamine system genes in obsessive-compulsive disorder.

Evidence from anatomical, pharmacological, and animal studies on the involvement of the dopamine system in obsessive-compulsive disorder (OCD) is mounting. This, along with evidence for a genetic diathesis provided by family and twin studies, prompted us to conduct genetic association studies of dopamine system genes in OCD. We genotyped OCD patients (n > 100) and matched controls for four loci: (1) a 40-base-pair repeat in the dopamine transporter gene; (2) the TaqIA polymorphism and the serine/cysteine variation in the D2 dopamine receptor gene; (3) an MscI polymorphism in the D3 dopamine receptor gene; and (4) a 48-base-pair repeat in the D4 dopamine receptor gene. Significant differences in allele frequencies were found between patients and controls for the D4 receptor gene, although replication is required with family-based controls before any conclusions can be entertained. This study represents the first comprehensive assessment of the roles of dopamine system genes in OCD.

Age of Onset↗
PubMedDate not supplied

Role of endothelin-1 in myocardial failure.

Endothelin-1 (ET-1) is a potent molecule produced throughout the cardiovascular system; it can exert important effects on both the structure and function of vascular smooth muscle cells and cardiac myocytes. ET-1 appears to play a central role in the physiological regulation of cardiovascular function, particularly in the vasculature. The known actions of ET-1 and the demonstration that plasma ET-1 is elevated in patients with heart failure has raised the possibility that this molecule could play a role in the pathophysiology of heart failure. This thesis has been supported and furthered by studies in animal models of heart failure that demonstrate the salutary, short-term effects of ET-1 receptor antagonists on hemodynamic function, as well as improved ventricular remodeling and survival with long-term administration. Early clinical trials with these ET receptor blockers have demonstrated systemic vasodilation. Long-term trials to determine the effects of ET-1 blockade on symptoms and survival are under way.

Animals↗