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Biomedical subjects

S Leonard

Publications and source records attributed to S Leonard.

At least 73 records · Page 4Linked to original sources
PubMed1999

Decreased bombesin peptide response to cigarette smoking in schizophrenia.

Schizophrenic patients are extremely heavy tobacco smokers. However, a lower incidence of lung cancer in schizophrenic patients has been observed in comparison to other heavy smokers. Nicotine increases the proliferation of pulmonary neuroendocrine tissue, causing the release of a bombesin-like peptide. Thus, bombesin-like peptide levels in urine may be an indicator of precancerous, cigarette-induced lung damage. Bombesin-like peptide levels of 10 schizophrenic smokers and 11 schizophrenic nonsmokers were compared to those of nonschizophrenic subjects matched for age and pack-years of smoking. The nonschizophrenic smokers showed the expected increase in urinary bombesin-like peptide levels, as compared to nonschizophrenic nonsmokers. Schizophrenic patients had lower bombesin-like peptide levels independent of smoking effects. The mechanism of the difference in bombesin-like peptide levels between schizophrenic patients and nonschizophrenic subjects is unknown, but one possibility involves alteration in the alpha 7-nicotinic acetylcholine receptor, which mediates the growth of some neuroendocrine cell lines in vitro.

Analysis of Variance↗
PubMed1999

A population-based approach to the investigation of osteopenia in Rett syndrome.

This study compares bone mass in a national sample of girls with Rett syndrome (RS) with a sample of control children. The Australian RS Database was the source of cases for this population-based study. Hand radiographs were available from 101 of 137 subjects (74% of the known Australian population of girls with RS aged < or = 20 years). Control radiographs matched for age, sex, and laterality were obtained from hospital radiology departments. A measure of cortical thickness was made from the difference between the outer diameter and the medullary space in the second metacarpal bone. A mean z-score value for cortical thickness and percentage cortical area for each individual was calculated. The mean cortical thickness (z score) for girls with RS was -1.94 compared with -0.38 for control children (P<0.001). In girls with RS, the mean cortical thickness decreased with age (P<0.001). In girls who were taking epilepsy medication it was -2.21 compared with -1.23 in those not taking epilepsy medication (P<0.001). There was no evidence of a beneficial effect of increased calcium intake on cortical thickness. A similar pattern was obtained when percentage cortical area was estimated. In multivariate analysis, increasing age and use of anticonvulsant medication were associated with decreased cortical thickness and only use of anticonvulsant medication with decreased percentage cortical area. Fractures had occurred in one-third of cases and it was estimated that just over 40% of girls would sustain a fracture by the age of 15 years. Girls with RS may be at increased risk of fractures and their bone quality compromised as determined by cortical thickness and percentage cortical area measurements from the second metacarpal.

Aging↗
PubMed1999

Medical aspects of school-aged children with Down syndrome.

Current and comprehensive information about the medical issues affecting children with Down syndrome (DS) is of value in counselling parents who are considering prenatal diagnosis and in planning services for people with DS as they age, especially given the continued improvements in their survival. Parents of school-aged children (mean age 11.37 years, 57.3% male, 42.7% female) with DS were identified by linking registers from the Disability Services Commission and the Birth Defects Registry. Less than half the children had cardiac and bowel conditions. More than half had ear conditions and more than three quarters had eye conditions. Ear, nose, and throat professionals were the specialists seen most often and the rate of tympanostomy tube insertion was nearly 17 times that of the general childhood population. Children with DS were over five times more likely to wear glasses than other children. These findings suggest that chronic, non life-threatening conditions impose a burden on families but do not threaten quality of life.

Child↗
PubMed1999

Patterns of pregnancy loss, perinatal mortality, and postneonatal childhood deaths in families of girls with Rett syndrome.

Rett syndrome is a neurodevelopmental disorder that occurs predominantly in girls and results in severe physical and intellectual handicap. A popular genetic mechanism is an X-linked dominant disorder, lethal in males. A case control study design was used to investigate fetal wastage as indicated by reported miscarriage and stillbirth prevalence, and the prevalence and cause of reported neonatal and other childhood deaths. There was no disturbance in the sibling sex ratio when case and control families were compared. In the parental generation and in the proband generation miscarriages were reported in similar proportions in case and control families. The reported stillbirth rates in case families was almost double that in control families and reported perinatal loss was more common on the maternal side in case families than in control families. Stillbirths and neonatal deaths affected slightly more boys in the parental and proband generations of case families (19 of 30) than in control families (10 of 21). Childhood deaths also occurred a little more commonly in Rett syndrome families. Sudden infant death syndrome was reported in three siblings of Rett syndrome probands but in no control siblings. Confirmation of this pattern of perinatal loss and infant mortality could indicate an alternative expression of the Rett syndrome gene.

Abortion, Spontaneous↗
PubMed1999

Redox-dependent regulation of interleukin-8 by tumor necrosis factor-alpha in lung epithelial cells.

Increasing evidence supports a major role for interleukin-8 (IL-8), a potent neutrophil chemoattractant, in the chronic progression of inflammatory lung diseases. The present studies were designed to characterize the molecular events involved in IL-8 induction in pulmonary epithelial cells in response to tumor necrosis factor-alpha (TNF-alpha). IL-8 induction by TNF-alpha was redox sensitive, as indicated by electron spin resonance analysis and inhibition with membrane permeable hydroxyl scavengers. Furthermore using cell transfection and mobility shift assays, it was found that transcriptional activation of the IL-8 gene required TNF-alpha-induced activation and binding of nuclear factor-kappaB (NF-kappaB)- and NF-IL-6, nuclear transcription factors to regulatory elements in the IL-8 promoter. Activation of the IL-8 promoter by these transcription factors was also redox-sensitive. This response was mediated through the TNF-R1 receptor (p55), and not the TNF-R2 (p75) receptor, although both receptors can be found on pulmonary epithelial cells. Taken together these studies indicate that TNF-alpha-induced redox changes in lung epithelial cells are responsible for the transcriptional activation of IL-8 and that coordinate activation of NF-kappaB and NF-IL-6 mediate the response.

Antigens, CD↗
PubMed1999

Effects of pirfenidone on the generation of reactive oxygen species in vitro.

Pirfenidone is a newly developed antifibrotic drug that has been reported to retard the progression of pulmonary fibrosis induced by bleomycin and cyclophosphamide in animal models of lung fibrosis. The present in vitro studies using noncellular and cellular systems evaluated the antioxidant and cytotoxic properties of this drug. The Fenton reaction [Fe(II) + H2O2 --> Fe(III) + *OH + OH-] and the xanthine/xanthine oxidase system were used as sources of hydroxyl (*OH) and superoxide anion (O2*-) radicals, respectively. Electron spin resonance spin trapping was used for free radical detection and measurement. The reaction rate of pirfenidone with *OH was found to be 1.63 x 10(10) M(-1) s(-1), which is comparable to several well-established antioxidants, such as ascorbate, glutathione, cysteine, azide, and lipoic acid. Compared to *OH radicals, the O2*- scavenging was less efficient 42.36 M(-1) s(-1) with pirfenidone. Pirfenidone was also effective in inhibiting zymosan-stimulated chemiluminescence. In a noncellular model of lipid peroxidation, pirfenidone inhibited crystalline silica-induced lipid peroxidation. The inhibition of crystalline silica-induced cytotoxic reactions and lipid peroxidation combined with the efficient antioxidant properties of pirfenidone indicate that this agent may express its antifibrotic effects partly through its ability to scavenge reactive oxygen species.

Animals↗
PubMed1998

Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7).

The human alpha7 neuronal nicotinic acetylcholine receptor gene (HGMW-approved symbol CHRNA7) has been characterized from genomic clones. The gene is similar in structure to the chick alpha7 gene with 10 exons and conserved splice junction positions. The size of the human gene is estimated to be larger than 75 kb. A putative promoter 5' of the translation start in exon 1 has been cloned and sequenced. The promoter region lacks a TATA box and has a high GC content (77%). Consensus Sp1, AP-2, Egr-1, and CREB transcription factor binding sites appear to be conserved between bovine and human genes. The alpha7 nAChR gene was found to be partially duplicated, with both loci mapping to the chromosome 15q13 region. A yeast artificial chromosome contig was constructed over a genetic distance of 5 cM that includes both alpha7 loci and the region between them. Four novel exons are described, located in genomic clones containing the partially duplicated gene. The duplicated sequences, including the novel exons, are expressed in human brain.

Base Sequence↗
PubMed1998

Further investigation of a chromosome 15 locus in schizophrenia: analysis of affected sibpairs from the NIMH Genetics Initiative.

Linkage of a neurophysiological deficit associated with schizophrenia, i.e., the failure to inhibit the auditory P50 response, was previously reported at chromosome 15q14. The marker with the highest pairwise lod score, D15S1360, was isolated from a yeast artificial chromosome containing a candidate gene, the alpha7-nicotinic acetylcholine receptor gene. In the present study, this linkage was further investigated in a subset of the NIMH Genetics Initiative schizophrenia families. These families have not been studied neurophysiologically, as were the families in the original report. Therefore, the DSMIII-R diagnosis of schizophrenia was used as the affected phenotype. Twenty families fulfilled the criteria of at least one sibpair concordant for schizophrenia, along with their two parents or another affected relative outside the nuclear family, available for genotyping. Sibpair analysis showed a significant proportion of D15S1360 alleles shared identical-by-descent (0.58; P < 0.0024). The results further support the involvement of this chromosomal locus in the genetic transmission of schizophrenia.

Chromosomes, Human, Pair 15↗
PubMed1998

Antioxidant activity of lazaroid (U-75412E) and its protective effects against crystalline silica-induced cytotoxicity.

Lazaroids (21-amino steroids) are believed to be powerful scavengers of reactive oxygen species (ROS) and inhibitors of lipid peroxidation. Crystalline silica, a potent cytotoxic agent, causes pulmonary fibrosis in experimental animals and humans. ROS have been previously shown to be involved in crystalline silica-induced pulmonary injury and inflammation. In the present study, the reaction rate of lazaroid (U-75412E) with hydroxyl radical (.OH) generated by Fenton reaction (Fe(II) + H2O2 --> Fe(III) + OH- + .OH) was investigated using ESR spin-trapping competition reactions. The reaction rate constant was found to be 1.0 x 10(10) M(-1)s(-1), which was comparable with those of other efficient .OH radical scavengers. As indicators of crystalline silica-induced cytotoxicity and its protection by this antioxidant lazaroid (U-75412E) we measured lactate dehydrogenase, N-acetyl-beta-glucosaminidase, superoxide dismutase, glutathione peroxidase, and hydrogen peroxide released from rat alveolar macrophages. Lipid peroxidation, a prominent manifestation of .OH radical-induced cell injury, was also measured to evaluate the protective value of lazaroid. Alveolar macrophages treated with lazaroid (U-75412E) before crystalline silica exposure were protected against cell injury and lipid peroxidation as demonstrated by those indicators. Lazaroid (U-75412E) scavenges .OH radicals generated by crystalline silica-mediated reaction from H2O2 and inhibits lipid peroxidation in macrophages induced by these particles.

Animals↗
PubMed1998

Acetylcholine activates an alpha-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells.

The effects of acetylcholine on both pyramidal neurons and interneurons in the area CA1 of the rat hippocampus were examined, using intracellular recording techniques in an in vitro slice preparation. In current-clamp mode, fast local application of acetylcholine (ACh) to the soma of inhibitory interneurons in stratum radiatum resulted in depolarization and rapid firing of action potentials. Under voltage-clamp, ACh produced fast, rapidly desensitizing inward currents that were insensitive to atropine but that were blocked by nanomolar concentrations of the nicotinic alpha7 receptor-selective antagonists alpha-bungarotoxin (alphaBgTx) and methyllycaconitine. Nicotinic receptor antagonists that are not selective for alpha7-containing receptors had little (mecamylamine) or no effect (dihydro-beta-erythroidine) on the ACh-induced currents. Glutamate receptor antagonists had no effect on the ACh-evoked response, indicating that the current was not mediated by presynaptic facilitation of glutamate release. However, the current could be desensitized almost completely by bath superfusion with 100 nM nicotine. In contrast to those actions on interneurons, application of ACh to the soma of CA1 pyramidal cells did not produce a detectable current. Radioligand-binding experiments with [125I]-alphaBgTx demonstrated that stratum radiatum interneurons express alpha7-containing nAChRs, and in situ hybridization revealed significant amounts of alpha7 mRNA. CA1 pyramidal cells did not show specific binding of [125I]-alphaBgTx and only low levels of alpha7 mRNA. These results suggest that, in addition to their proposed presynaptic role in modulating transmitter release, alpha7-containing nAChRs also may play a postsynaptic role in the excitation of hippocampal interneurons. By desensitizing these receptors, nicotine may disrupt this action and indirectly excite pyramidal neurons by reducing GABAergic inhibition.

Acetylcholine↗
PubMed1998

Cobalt-mediated generation of reactive oxygen species and its possible mechanism.

Electron spin resonance spin trapping was utilized to investigate free radical generation from cobalt (Co) mediated reactions using 5,5-dimethyl-1-pyrroline (DMPO) as a spin trap. A mixture of Co with water in the presence of DMPO generated 5,5-dimethylpyrroline-(2)-oxy(1) DMPOX, indicating the production of strong oxidants. Addition of superoxide dismutase (SOD) to the mixture produced hydroxyl radical (.OH). Catalase eliminated the generation of this radical and metal chelators, such as desferoxamine, diethylenetriaminepentaacetic acid or 1,10-phenanthroline, decreased it. Addition of Fe(II) resulted in a several fold increase in the .OH generation. UV and O2 consumption measurements showed that the reaction of Co with water consumed molecular oxygen and generated Co(II). Since reaction of Co(II) with H2O2 did not generate any significant amount of .OH radicals, a Co(I) mediated Fenton-like reaction [Co(I) + H2O2-->Co(II) + .OH + OH-] seems responsible for .OH generation. H2O2 is produced from O2.- via dismutation, O2.- is produced by one-electron reduction of molecular oxygen catalyzed by Co. Chelation of Co(II) by biological chelators, such as glutathione or beta-ananyl-3-methyl-L-histidine alters, its oxidation-reduction potential and makes Co(II) capable of generating .OH via a Co(II)-mediated Fenton-like reaction [Co(II) + H2O2-->Co(III) + .OH + OH-]. Thus, the reaction of Co with water, especially in the presence of biological chelators, glutathione, glycylglycylhistidine and beta-ananyl-3-methyl-L-histidine, is capable of generating a whole spectrum of reactive oxygen species, which may be responsible for Co-induced cell injury.

Catalase↗
PubMed1998

Adenovirus-mediated expression of melanoma antigen gp75 as immunotherapy for metastatic melanoma.

Melanocyte differentiation antigens, such as the brown locus protein gp75, are potential biological targets for immunotherapy. We investigated whether expression of the murine gp75 cDNA mediated by an adenovirus (Ad) vector could induce melanoma rejection using this model self antigen that usually induces tolerance, and whether Ad vector-directed production of interleukin-2 (IL2) might augment this response. To evaluate this approach, Ad vectors were constructed containing the murine gp75 cDNA (Ad.gp75) and the human IL2 cDNA (Ad.IL2). Efficacy was evaluated in C57BI/6 mice challenged i.v. with 10(5) B16 cells, using the number of lung metastases as the efficacy parameter. Naive control mice developed 175 +/- 12 metastases by day 14. Controls receiving intranasal Ad.IL2 1 day after B16 cell injection, intraperitoneal (i.p.) mitomycin-C-treated B16 cells +/- i.p. Ad.IL2 before B16 cell challenge and Ad.beta gal-treated mice had similar numbers of metastases as controls (P > 0.1). In marked contrast, preimmunization with intradermal Ad.gp75 provided dramatic reduction in the number of lung metastases (52 +/- 7, 29% of control). Addition of regional (intranasal delivery to the lung) Ad.IL2 to intradermal Ad.gp75 preimmunization 1 day following tumor challenge provided further protection (18 +/- 6, 10% of control). Depletion of CD4+ and CD8+ T-cell subsets effectively blocked the protective effect seen following immunization. Adoptive transfer of macrophage-depleted splenocytes from Ad.gp75-immunized mice similarly afforded significant protection against B16 tumor cell challenge. Further, serum obtained 21 days following Ad.gp75 immunization showed no detectable anti-gp75 antibody by immunoprecipitation. These results suggest that immunization with Ad.gp75 induces cellular immune responses that are capable of rejecting B16 melanoma in a host that is usually tolerant to gp75 antigen.

Adenoviridae↗
PubMed1998

Schizophrenia, sensory gating, and nicotinic receptors.

A series of human and animal investigations has suggested that altered expression and function of the alpha7-nicotinic cholinergic receptor may be responsible for the auditory sensory gating deficit characterized in schizophrenia patients and their relatives as diminished suppression of an auditory-evoked response (P50) to repeated stimuli. This finding, in conjunction with evidence for familial transmission of this sensory gating deficit, suggests a pathogenic role of the gene for the alpha7-nicotinic receptor in schizophrenia. This article considers the possible effects of this dysfunction in a broader context. Not only is this dysfunction consistent with difficulties in sensory gating, but it might also predispose patients to problems with learning efficiency and accuracy. Such learning problems could underlie schizophrenia patients' delusional thinking, hallucinations, and social dysfunction. In addition, heavy smoking in many schizophrenia patients is consistent with the high concentration of nicotine necessary to activate the receptor and with the receptor's extremely rapid desensitization. Finally, the receptor's possible role in cell growth and differentiation should be considered in connection with developmental deficits and other cellular abnormalities in schizophrenia.

Animals↗
PubMed1998

Diagnosis of Rett syndrome: can a radiograph help?

Rett syndrome (RS), a neurodevelopmental disorder almost exclusively affecting girls, is associated with severe intellectual and motor disability. In the absence of biological markers, diagnosis is determined by a set of clinical criteria. In a previous study in Scotland, shortening of the fourth metatarsal was reported clinically in 20% of classical RS cases aged 5 years or older. The Australian Rett Syndrome Study database has facilitated a population-based radiological study of the hands and feet of girls with RS. Straight radiographs of hands and feet were available from 94 cases, representing 70.1% of the known RS population in Australia. Control radiographs were matched for age, sex, and laterality. Relative shortening of the fourth metacarpal/metatarsal was assessed using the sign method. A short ulna (negative ulna variance) was defined as the distal articular surface of the ulna being at least 5mm proximal to the distal articular surface of the radius. A positive metacarpal sign was twice as common in verified cases of RS than in controls in the right but not the left hand. A short ulna was more common in subjects with RS than in controls. A short fourth metatarsal was also more common among subjects with RS. More than half (56.6%) the girls with RS over the age of 4 years had a negative ulnar variance in either wrist or a metatarsal sign in either foot. These findings will assist with the diagnosis of RS and may help direct research towards the location of the molecular defect.

Adolescent↗