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S Leonard

Publications and source records attributed to S Leonard.

At least 37 records · Page 2Linked to original sources
PubMed2001

Evidence for the multigenic inheritance of schizophrenia.

Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these findings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy-seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome-wide significant linkage (Z = 3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the alpha 7-nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z = 2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait-locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci.

Alleles↗
PubMed2001

Iron tetrakis (n-methyl-4'-pyridyl) porphyrinato (FeTMPyP) is a potent scavenging antioxidant and an inhibitor of stimulant-induced NF-kappaB activation of raw 264.7 macrophages.

Metalloporphyrins have been shown to be protective in oxidative stress models. However, the molecular basis for the antioxidative and antiinflammatory activities of iron tetrakis (N-methyl-4'-pyridyl) porphyrinato (FeTMPyP) is not known. The objective of this study was to determine whether FeTMPyP exhibited the ability to (1) scavenge reactive oxygen species (ROS), (2) inhibit the activation of nuclear factor kappa B (NF-kappaB), or (3) block the production of interleukin 1 (IL-1) in RAW 264.7 cultured macrophages. The results indicate that FeTMPyP is a potent scavenger of hydroxyl radicals and superoxide anion radicals, and an effective inhibitor of stimulant-induced NF-kappaB activation and IL-1 production by RAW 264.7 cells. Therefore, FeTMPyP may be a useful tool to investigate the molecular mechanisms involved in stimulant-induced signal pathways, and may possess therapeutic utility in diseases associated with overproduction of ROS.

Animals↗
PubMed2001

Complete genome sequence of Salmonella enterica serovar Typhimurium LT2.

Salmonella enterica subspecies I, serovar Typhimurium (S. typhimurium), is a leading cause of human gastroenteritis, and is used as a mouse model of human typhoid fever. The incidence of non-typhoid salmonellosis is increasing worldwide, causing millions of infections and many deaths in the human population each year. Here we sequenced the 4,857-kilobase (kb) chromosome and 94-kb virulence plasmid of S. typhimurium strain LT2. The distribution of close homologues of S. typhimurium LT2 genes in eight related enterobacteria was determined using previously completed genomes of three related bacteria, sample sequencing of both S. enterica serovar Paratyphi A (S. paratyphi A) and Klebsiella pneumoniae, and hybridization of three unsequenced genomes to a microarray of S. typhimurium LT2 genes. Lateral transfer of genes is frequent, with 11% of the S. typhimurium LT2 genes missing from S. enterica serovar Typhi (S. typhi), and 29% missing from Escherichia coli K12. The 352 gene homologues of S. typhimurium LT2 confined to subspecies I of S. enterica-containing most mammalian and bird pathogens-are useful for studies of epidemiology, host specificity and pathogenesis. Most of these homologues were previously unknown, and 50 may be exported to the periplasm or outer membrane, rendering them accessible as therapeutic or vaccine targets.

Animals↗
PubMed2001

Zinc tetrakis(N-methyl-4'-pyridyl) porphyrinato is an effective inhibitor of stimulant-induced activation of RAW 264.7 cells.

One proposed mechanism for the development of silica-induced fibrosis is prolonged pulmonary inflammation and lung damage resulting from the secretion of reactive mediators from alveolar macrophages. Metalloporphyrins have antioxidative and antiinflammatory activities. However, the molecular basis for the antiinflammatory action of zinc tetrakis(N-methyl-4'-pyridyl) porphyrinato (ZnTMPyP) has not been elucidated. The objective of this study was to determine whether ZnTMPyP exhibited the ability to inhibit the production of reactive oxygen species (ROS), the activation of NF-kappaB, or the secretion of IL-1 in RAW 264.7 cells, and whether such inhibitory activity was related to the ROS-scavenging ability of ZnTMPyP. The results indicate that, although ZnTMPyP is not cytotoxic to RAW 264.7 cells, it is a potent inhibitor in ROS production by RAW 264.7 cells in response to various stimulants, such as silica, zymosan, or phorbol myristate acetate. ZnTMPyP is also effective in reducing stimulant-induced DNA-binding activity of NF-kappaB and silica-induced tyrosine phosphorylation of IkappaB-alpha. ZnTMPyP also inhibits LPS-induced IL-1 production. However, ZnTMPyP exhibits relatively weak ability to directly scavenge hyroxyl or superoxide radicals. On the basis of effective concentrations of ZnTMPyP, these results suggest that ZnTMPyP directly acts as an inhibitor of cellular activation in addition to exhibiting an antioxidant effect. Therefore, it is suggested that further studies concerning the effects of ZnTMPyP using in vivo oxidative stress models or its effects on the cytotoxic process of human diseases associated with lung inflammation and injury are warranted. In addition, ZnTMPyP may be a useful tool to investigate the molecular mechanisms involved in stimulant-induced signal pathways.

Animals↗
PubMed2001

The effect of nicotine and haloperidol co-treatment on nicotinic receptor levels in the rat brain.

Genetic and biological data have suggested a role for the neuronal nicotinic acetylcholine receptors in the neuropathophysiology of schizophrenia. Studies in human postmortem brain demonstrate dose-dependent increases in nicotinic receptor binding in normal smokers. We found this upregulation to be reduced in schizophrenic smokers, many of whom had taken typical neuroleptics during their lifetime. The present study examined the hypothesis that typical antipsychotic drug treatment might modulate nicotinic receptor upregulation in a rat model. Nicotine, administered alone or in combination with haloperidol, increased both high and low affinity neuronal nicotinic receptors in a region specific manner. Haloperidol had no generalized effect on basal levels of nicotinic receptor binding or nicotine induced upregulation of nicotinic receptors. However, haloperidol attenuated high affinity nicotinic receptor upregulation in thalamus and low affinity receptor upregulation in hippocampus. These results suggest that haloperidol is not likely to affect nicotinic receptor regulation by smoking in most brain regions.

Aconitine↗
PubMed2001

Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7).

The transmission/disequilibrium test was used for fine mapping of the linkage of schizophrenia to the chromosome 15q13-14 region, the site of a candidate gene, the alpha7 nicotinic acetylcholine receptor subunit gene (CHRNA7), in parent-child triads from the NIMH Schizophrenia Genetics Initiative families. This candidate gene was identified from neurobiological studies of deficits in schizophrenics of the inhibitory gating of the P50 auditory evoked potential. The neurobiological deficit was also used as a phenotype for subsequent linkage analysis. In the present study, significant genotype-wise disequilibrium (P < 0.007) was found at D15S165, a polymorphic simple sequence marker physically located within 1 megabase of both CHRNA7 and a partially duplicated, expressed sequence that includes exons 5-10 of CHRNA7. Replication of this result was found in an additional set of families. The results support this region as a chromosomal location involved in the genetic transmission of schizophrenia.

Chromosomes, Human, Pair 15↗
PubMed2001

Abundance, diversity, and patterns of distribution of primates on the Tapiche River in Amazonian Peru.

This work presents data on the relative diversity, abundance, and distribution patterns of primates in a 20 km2 area of the Tapiche River in the Peruvian Amazon. Population data were collected while the study area was both inundated and dry (March to September 1997) using conventional line-transect census techniques. Survey results reflected the presence of 11 primate species, but population parameters on only eight of the species will be presented, including saddleback tamarins (Saguinus fuscicollis), Bolivian squirrel monkeys (Saimiri boliviensis), brown capuchins (Cebus apella), white-fronted capuchins (Cebus albifrons), monk sakis (Pithecia monachus), red titi monkeys (Callicebus cupreus), red uakaris (Cacajao calvus), and red howler monkeys (Alouatta seniculus). Woolly monkeys (Lagothrix lagotricha), night monkeys (Aotus nancymaae), and pygmy marmosets (Callithrix pygmaea) were also seen in the area. The data for the smaller-bodied primates is similar to that reported almost 18 years earlier, but the data for the larger-bodied primates reflect a loss in the number of animals present in the area. Pressure from hunters and the timber industry may account for declining numbers of large-bodied primates, while it appears that natural features peculiar to the conservation area contribute to the patchy pattern of distribution.

Animals↗
PubMed2001

Alpha- and gamma-tocotrienols are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine.

Limited information is available regarding metabolism of vitamin E forms, especially the tocotrienols. Carboxyethyl-hydroxychromans (alpha- and gamma-CEHC) are human urinary metabolites of alpha- and gamma-tocopherols, respectively. To evaluate whether tocotrienols are also metabolized and excreted as urinary CEHC, urine was monitored following tocotrienol supplementation. Complete (24 h) urine collections were obtained for 2 d prior to (baseline), the day of, and 2 d after human subjects (n = 6) ingested tocotrienol supplements. The subjects consumed 125 mg gamma-tocotrienyl acetate the first week, then the next week 500 mg; then 125 mg alpha-tocotrienyl acetate was administered the third week, followed by 500 mg the fourth week. Urinary alpha- and gamma-CEHC were measured by high-performance liquid chromatography with electrochemical detection. Urinary gamma-CEHC levels rose about four- to sixfold in response to the two doses of gamma-tocotrienol and then returned to baseline the following day. Significant (P < 0.0001) increases in urinary alpha-CEHC were observed only following ingestion of 500 mg alpha-tocotrienyl acetate. Typically, 1-2% of alpha-tocotrienyl acetates or 4-6% of gamma-tocotrienyl acetates were recovered as their respective urinary CEHC metabolites. A gamma-CEHC excretion time course showed an increase in urinary gamma-CEHC at 6 h and a peak at 9 h following ingestion of 125 mg gamma-tocotrienyl acetate. In summary, tocotrienols, like tocopherols, are metabolized to CEHC; however, the quantities excreted in human urine are small in relation to dose size.

Chromans↗
PubMed2001

Removal of fat from cow's milk decreases the vitamin E contents of the resulting dairy products.

The present study was undertaken to determine whether decreases in fat contents result in lower vitamin E contents. Milk samples of varying fat contents (half and half, whole milk, reduced-fat milk, low-fat milk, and nonfat milk) were obtained from a local dairy on six different occasions. alpha-Tocopherol was the major form of vitamin E (>85%); gamma-tocopherol and alpha-tocotrienol were present to a lesser extent. As the fat contents of milk products decreased from 11 to 0.3%, the vitamin E contents decreased. For example, raw milk as compared to nonfat milk had both higher (-tocopherol contents (45.5 +/- 4.6 vs. 4.5 +/- 0.5 microg/100 g; P < or = 0.0001) and higher total lipids (3.46 +/- 0.49 vs. 0.30 +/- 0.07 g/100 g; P < or = 0.0001). Vitamin E, cholesterol, and total lipids increased as cream was added back to nonfat milk during production. For every 1 mg cholesterol increase, there was an increase of approximately 4 microg of alpha-tocopherol; for every 1 g total lipids increase, the alpha-tocopherol content increased by 17 microg. These data demonstrate that removal of milk fat markedly decreases the vitamin E content of various milk products.

Animals↗
PubMed2001

Smoking and mental illness.

Patients with mental illness have a higher incidence of smoking than the general population and are the major consumers of tobacco products. This population includes subjects with schizophrenia, manic depression, depression, posttraumatic stress disorder (PTSD), attention-deficit disorder (ADD), and several other less common diseases. Smoking cessation treatment in this group of patients is difficult, often leading to profound depression. Several recent findings suggest that increased smoking in the mentally ill may have an underlying biological etiology. The mental illness schizophrenia has been most thoroughly studied in this regard. Nicotine administration normalizes several sensory-processing deficits seen in this disease. Animal models of sensory deficits have been used to identify specific nicotinic receptor subunits that are involved in these brain pathways, indicating that the alpha 7 nicotinic receptor subunit may play a role. Genetic linkage in schizophrenic families also supports a role for the alpha 7 subunit with linkage at the alpha 7 locus on chromosome 15. Bipolar disorder has some phenotypes in common with schizophrenia and also exhibits genetic linkage to the alpha 7 locus, suggesting that these two disorders may share a gene defect. The alpha 7 receptor is decreased in expression in schizophrenia. [(3)H]-Nicotine binding studies in postmortem brain indicate that high-affinity nicotinic receptors may also be affected in schizophrenia.

Animals↗
PubMed2001

Neuronal nicotinic receptors: from structure to function.

Molecular identification of the genes and resulting protein sequences for a large number of nicotinic acetylcholine receptor (nAChR) subunits has stimulated numerous studies highlighting their role in several human behaviors including neurological disorders and nicotine addiction. This receptor gene family is likely to be involved in release of multiple neurotransmitters in both brain and periphery that mediate sensitivity and tolerance to nicotine. Recent findings also suggest that alterations in these receptors may lead to neurological diseases, some associated with increased incidence of smoking. This review addresses current knowledge of nicotinic receptor structure, regulation of expression, and function, in both normal and psychiatric subjects.

Brain↗
PubMed2001

Interleukin-10-mediated inhibition of free radical generation in macrophages.

Interleukin-10 (IL-10) is a pleiotropic cytokine that controls inflammatory processes by suppressing the production of proinflammatory cytokines that are known to be transcriptionally regulated by nuclear factor-kappaB (NF-kappaB). Although still controversial, IL-10 has been shown to inhibit NF-kappaB activation through a process that involves proteolytic degradation of inhibitory subunit IkappaB-alpha. What is not known, however, is the mechanism by which IL-10 exerts its effect on IkappaB-alpha degradation. The present study investigates the possible role of reactive oxygen species (ROS) and their inhibition by IL-10 in NF-kappaB activation and IkappaB-alpha degradation in macrophages. Treatment of the cells with lipopolysaccharide (LPS) caused activation of NF-kappaB and rapid proteolysis of IkappaB-alpha as determined by the electrophoretic mobility shift assay, gene transfection, and Western blot. IL-10 pretreatment inhibited both NF-kappaB activation and IkappaB-alpha degradation. Both of these processes were also inhibited by ROS scavengers, catalase (H(2)O(2) scavenger), and sodium formate (.OH scavenger) but were minimally affected by superoxide dismutase (O scavenger). These results suggests that.OH radicals, formed by an H(2)O(2)-dependent, metal-catalyzed Fenton reaction, play a major role in this process. Electron spin resonance studies confirmed the formation of.OH radicals in LPS-treated cells. Addition of IL-10 inhibited both IkappaB-alpha degradation and generation of.OH radicals in response to LPS stimulation. These results demonstrate, for the first time, direct evidence for the role of IL-10 in ROS-dependent NF-kappaB activation.

Animals↗
PubMed2001

Reactivity of free radicals on hydroxylated quartz surface and its implications for pathogenicity experimental and quantum mechanical study.

We studied the adsorption of hydroxyl radicals and superoxide anion radicals on a hydroxylated alpha-quartz surface using cluster and periodic slab models by means of density functional calculations. Models of two hydroxylated alpha-quartz surfaces--(0001) and (0111)--have been used in the simulations. The hydroxyl radical adsorbs readily on both surfaces. The subsurface Si-O bonds are weakened during the adsorption resulting in surface layer destabilization. This destabilization leads directly to surface disintegration in the case of *OH/(0111) adsorption. The product of the surface disintegration and reconstruction is a surface terminated by silanol groups (Si-OH) and siloxyl radicals (Si-O*). The model calculations suggest that adsorption of *OH on a hydroxylated quartz surface transforms a chemically inert, aged, silanol terminated surface to a very reactive, silicon-based radical terminated surface. The activated surface may then cause oxidative damage to the adsorbed biomaterial. The superoxide anion radical adsorbs on both surfaces, but the adsorption products are only weakly bonded to the surface. The calculated energy barrier for the O2*- activated subsurface Si-O bond dissociation is 10 kcal/mol, which is higher than for the *OH activated process (4 kcal/mol). The calculated weaker bonding to the surface and higher activation energy barrier suggest that the superoxide anion radical will be less efficient in reactivation of an aged, hydroxylated quartz surface than the hydroxyl radical. The importance of the specific geometry of the surface silicon atoms on the surface reactivity and adsorption properties is also discussed. The theoretical predictions are supported experimentally using chemiluminescence to monitor reactivation of the aged silica surface by superoxide anion radicals.

Adsorption↗
PubMed2000

Sequence and analysis of chromosome 5 of the plant Arabidopsis thaliana.

The genome of the model plant Arabidopsis thaliana has been sequenced by an international collaboration, The Arabidopsis Genome Initiative. Here we report the complete sequence of chromosome 5. This chromosome is 26 megabases long; it is the second largest Arabidopsis chromosome and represents 21% of the sequenced regions of the genome. The sequence of chromosomes 2 and 4 have been reported previously and that of chromosomes 1 and 3, together with an analysis of the complete genome sequence, are reported in this issue. Analysis of the sequence of chromosome 5 yields further insights into centromere structure and the sequence determinants of heterochromatin condensation. The 5,874 genes encoded on chromosome 5 reveal several new functions in plants, and the patterns of gene organization provide insights into the mechanisms and extent of genome evolution in plants.

Animals↗
PubMed2000

NURR1 mutations in cases of schizophrenia and manic-depressive disorder.

Transgenic mice lacking the nuclear orphan transcription factor Nur-related receptor 1 (Nurr1) fail to develop mesencephalic dopamine neurons. There is a highly homologous NURR1 gene in humans (formerly known as NOT) which therefore constitutes a good candidate gene for neurologic and psychiatric disorders with an involvement of the dopamine neuron system, such as Parkinson's disease, schizophrenia, and manic-depression. By direct sequencing of genomic DNA, we found two different missense mutations in the third exon of NURR1 in two schizophrenic patients and another missense mutation in the same exon in an individual with manic-depressive disorder. All three mutations caused a similar reduction of in vitro transcriptional activity of NURR1 dimers of about 30-40%. Neither of these amino acid changes, nor any sequence changes whatsoever, were found in patients with Parkinson's disease or control DNA material of normal populations. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:808-813, 2000.

Alleles↗
PubMed2000

Induction of activator protein-1 through reactive oxygen species by crystalline silica in JB6 cells.

We reported previously that freshly fractured silica (FFSi) induces activator protein-1 (AP-1) activation through extracellular signal-regulated protein kinases (ERKs) and p38 kinase pathways. In the present study, the biologic activities of FFSi and aged silica (ASi) were compared by measuring their effects on the AP-1 activation and phosphorylation of ERKs and p38 kinase. The roles of reactive oxygen species (ROS) in this silica-induced AP-1 activation were also investigated. We found that FFSi-induced AP-1 activation was four times higher than that of ASi in JB6 cells. FFSi also caused greater phosphorylation of ERKs and p38 kinase than ASi. FFSi generated more ROS than ASi when incubated with the cells as measured by electron spin resonance (ESR). Studies using ROS-sensitive dyes and oxygen consumption support the conclusion that ROS are generated by silica-treated cells. N-Acetylcysteine (an antioxidant) and polyvinyl pyridine-N-oxide (an agent that binds to Si-OH groups on silica surfaces) decreased AP-1 activation and phosphorylation of ERKs and p38 kinase. Catalase inhibited phosphorylation of ERKs and p38 kinase, as well as AP-1 activation induced by FFSi, suggesting the involvement of H(2)O(2) in the mechanism of silica-induced AP-1 activation. Sodium formate (an ( small middle dot)OH scavenger) had no influence on silica-induced MAPKs or AP-1 activation. Superoxide dismutase enhanced both AP-1 and MAPKs activation, indicating that H(2)O(2), but not O(2), may play a critical role in silica-induced AP-1 activation. These studies indicate that freshly ground silica is more biologically active than aged silica and that ROS, in particular H(2)O(2), play a significant role in silica-induced AP-1 activation.

Animals↗
PubMed2000

Capillary electrophoresis analysis of gentamicin sulphate with UV detection after pre-capillary derivatization with 1,2-phthalic dicarboxaldehyde and mercaptoacetic acid.

A selective, sensitive, and rapid pre-capillary derivatization method for determination of the multicomponent aminoglycoside antibiotic gentamicin is described. The derivatization reagents 1,2-phthalic dicarboxaldehyde and mercaptoacetic acid were used and the thioisoindole derivative was UV detected at 330 nm. A central composite experimental design was performed to optimize selectivity and derivatization conditions. Baseline separation of gentamicin C1, C1a, C2, C2a, C2b, sisomicin and several minor components was achieved with a background electrolyte containing 30 mM sodium tetraborate, 7.5 mM beta-cyclodextrin and 12.5% (v/v) methanol at pH 10. Quantitative analysis was performed and illustrated the potential use of capillary electrophoresis for the identification and quantitation of gentamicin as an alternative to methods prescribed in the United States Pharmacopeia and European Pharmacopoeia.

Electrophoresis, Capillary↗