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Biomedical subjects

R Freedman

Publications and source records attributed to R Freedman.

At least 55 records · Page 3Linked 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

Intravascular extraction of problematic or infected permanent pacemaker leads: 1994-1996. U.S. Extraction Database, MED Institute.

Of the 400,000-500,000 permanent pacemaker leads implanted worldwide each year, around 10% may eventually fail or become infected, becoming potential candidates for removal. Intravascular techniques for removing problematic or infected leads evolved over a 5-year period (1989-1993). This article analyzes results from January 1994 through April 1996, a period during which techniques were fairly stable. Extraction of 3,540 leads from 2,338 patients was attempted at 226 centers. Indications were: infection (27%), nonfunctional or incompatible leads (25%), Accufix or Encore leads (46%), or other causes (2%). Patients were 64+/-17 years of age (range 5-96); 59% were men, 41% women. Leads were implanted 47+/-41 months (maximum 26 years), in the atrium (53%), ventricle (46%), or SVC (1%). Extraction was attempted via the implant vein using locking stylets and dilator sheaths, and/or transfemorally using snares, retrieval baskets, and sheaths. Complete removal was achieved for 93% of leads, partial for 5%, and 2% were not removed. Risk of incomplete or failed extraction increased with implant duration (P<0.0001), less experienced physicians (P<0.0001), ventricular leads (P<0.005), noninfected patients (P<0.0005), and younger patients (P<0.0001). Major complications were reported for 1.4% of patients (<1% at centers with >300 cases), minor for 1.7%. Risk of complications increased with number of leads removed (P<0.005) and with less experienced physicians (P<0.005); risk of major complications was higher for women (P<0.01). Given physician experience, appropriate precautions, and appropriate patient selection, contemporary lead removal techniques allow success with low complication rates.

Adolescent↗
PubMed1998

Monomeric monocyte chemoattractant protein-1 (MCP-1) binds and activates the MCP-1 receptor CCR2B.

To address the role of dimerization in the function of the monocyte chemoattractant protein-1, MCP-1, we mutated residues that comprise the core of the dimerization interface and characterized the ability of these mutants to dimerize and to bind and activate the MCP-1 receptor, CCR2b. One mutant, P8A*, does not dimerize. However, it has wild type binding affinity, stimulates chemotaxis, inhibits adenylate cyclase, and stimulates calcium influx with wild type potency and efficacy. These data suggest that MCP-1 binds and activates its receptor as a monomer. In contrast, Y13A*, another monomeric mutant, has a 100-fold weaker binding affinity, is a much less potent inhibitor of adenylate cyclase and stimulator of calcium influx, and is unable to stimulate chemotaxis. Thus Tyr13 may make important contacts with the receptor that are required for high affinity binding and signal transduction. We also explored whether a mutant, [1+9-76]MCP-1 (MCP-1 lacking residues 2-8), antagonizes wild type MCP-1 by competitive inhibition, or by a dominant negative mechanism wherein heterodimers of MCP-1 and [1+9-76]MCP-1 bind to the receptor but are signaling incompetent. Consistent with the finding that MCP-1 can bind and activate the receptor as a monomer, we demonstrate that binding of MCP-1 in the presence of [1+9-76]MCP-1 over a range of concentrations of both ligands fits well to a simple model in which monomeric [1+9-76]MCP-1 functions as a competitive inhibitor of monomeric MCP-1. These results are crucial for elucidating the molecular details of receptor binding and activation, for interpreting mutagenesis data, for understanding how antagonistic chemokine variants function, and for the design of receptor antagonists.

Chemokine CCL2↗
PubMed1998

Anticipatory saccades during smooth pursuit eye movements and familial transmission of schizophrenia.

BACKGROUND: Smooth pursuit eye movement (SPEM) abnormalities are a putative marker of genetic risk for schizophrenia. Accurate SPEM performance requires the subject to activate neural systems responsible for smooth pursuit tracking, while simultaneously suppressing activity of neurons responsible for saccadic movements that would move the eye ahead of the target. This study examined whether specific aspects of SPEM dysfunction cosegregate with genetic risk in parents of schizophrenic probands. METHODS: Eighteen probands and their parents had SPEM recorded. Parents with an ancestral history of schizophrenia were hypothesized to be more likely than their spouses without such a history to carry a genetic risk for schizophrenia. RESULTS: Ten families had a single parent with a positive ancestral history for schizophrenia. The frequency of anticipatory saccades, which were mostly small, and the fraction of total eye movement that they represented were the only measures that differentiated the more likely genetic carrier parents in these families from their spouses and age-matched normals. CONCLUSIONS: Failure to suppress saccadic anticipation of target motion during smooth pursuit appears an aspect of SPEM dysfunction related to presumed genetic risk for schizophrenia.

Adult↗
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

Nicotinic receptor desensitization and sensory gating deficits in schizophrenia.

BACKGROUND: Nicotinic receptor dysfunction is a possible mechanism of the abnormal sensory gating observed in schizophrenia with the P50 auditory event-related potential. Although nicotinic receptors normally desensitize after activation by acetylcholine or nicotine, pathologically increased desensitization might cause receptor dysfunction in schizophrenia. To examine this possibility, central cholinergic neuronal activity was diminished by allowing schizophrenic patients to sleep briefly, after which they experienced a transient period of normal P50 gating, consistent with receptor resensitization during the absence of cholinergic stimulation. A critical test of the mechanism is whether this resensitization is blocked by concurrent administration of nicotine, which would provide continuous receptor stimulation. METHODS: Six schizophrenic patients repeated the sleep experiment during nicotine exposure from a dermal patch, in a double-blind, placebo-controlled design. RESULTS: The normalization of P50 gating immediately postsleep was replicated in the placebo arm, but this effect was decreased in all six patients during exposure to nicotine. CONCLUSIONS: The results suggest that nicotinic receptor desensitization is responsible for the loss of P50 gating in schizophrenia.

Acoustic Stimulation↗
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

Familial transmission of two independent saccadic abnormalities in schizophrenia.

Difficulties with inhibiting inappropriate responses, i.e. disinhibition, and problems with spatial memory are both presumed to be a part of the phenotypic expression of the genetic risk for schizophrenia. Schizophrenic probands are impaired on saccadic eye movement tasks which require (a) response inhibition to prepotent stimuli and (b) generation of an accurate response to a remembered or calculated spatial location, but it is unknown how these deficits are inherited. Sixteen schizophrenic probands, their 32 parents, and two normal control groups completed a delayed oculomotor response and an antisaccade task. The parents with a positive ancestral family history for chronic psychosis (n = 8) were presumed to be more likely than their family history-negative spouses to be genetic carriers for schizophrenia. Probands and their positive family history parents had more failures of response inhibition than did normal control groups. However, it was the probands and their negative family history spouses who demonstrated impaired accuracy of the remembered- or antisaccades. Disinhibition may be closely tied to a specific genetic risk for schizophrenia. However, a second familial factor related to the maintenance or manipulation of spatial information may also contribute to the genetic risk of the full clinical disorder.

Adult↗
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

Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice.

Abnormal sensory inhibition is a measurable indicator of a sensory processing deficit which is observed in schizophrenia, and other disorders, and which may be heritable. This deficit has also been observed in certain inbred mouse strains where the intensity of the deficit has been correlated with reduction in the number of hippocampal alpha-bungarotoxin-sensitive nicotinic receptors. Nicotine and certain nicotinic agonists produce brief periods of normal sensory inhibition in these mice. Similarly, nicotine also transiently normalizes sensory inhibition in schizophrenics. The present study assessed the effects of a novel nicotinic partial agonist (GTS-21), selective for the alpha-bungarotoxin site, on sensory inhibition in DBA mice, a strain with no sensory inhibition under routine experimental conditions. GTS-21 produced a dose-dependent normalization of sensory inhibition which was blocked by alpha-bungarotoxin but not mecamylamine. In contrast to other nicotinic agonists, normalization of sensory inhibition by GTS-21 and two related anabaseine compounds, DMAB-anabaseine and DMAC-anabaseine, was observed when administered a second time to the animal, after a 40-min delay. Our results indicated that the anabaseine compounds increase sensory inhibition through alpha7 nicotinic receptors, and that their ability to act repeatedly on these receptors may be less affected by desensitization.

Anabasine↗
PubMed1998

Improvement in smooth pursuit eye movements after cigarette smoking in schizophrenic patients.

This study examined whether schizophrenics' cigarette smoking normalized smooth pursuit eye movement abnormalities. Fifteen schizophrenic and 15 nonschizophrenic subjects abstained from their usual cigarette smoking for an average of 10 h. Their baseline performance during a constant velocity smooth pursuit task was then assessed. The subjects smoked as much as they desired in a 10-min period and then were retested immediately postsmoking, and 10 and 20 min later. Smooth pursuit gain and the percentage of total eye movement due to various saccadic subtypes were computed using infrared oculography and computerized pattern recognition software. After smoking, smooth pursuit gain increased and the percentage of total eye movements due to leading saccades decreased significantly in the schizophrenic patients. There were no changes in the gain or leading saccades of nonschizophrenic subjects after smoking. Nicotinic receptor dysfunction may be a candidate mechanism for smooth pursuit eye movement abnormalities in schizophrenia.

Adult↗
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

Nicotinic receptors, smoking and schizophrenia.

Neuronal nicotinic acetylcholine receptor expression was examined in schizophrenia. The incidence of smoking in schizophrenia is remarkably high and nicotine has been found to normalize an auditory evoked potential deficit seen in most subjects who suffer from this disease. Antagonists and agonists of a specific subset of this receptor family, the alpha7 nicotinic receptor, were found to regulate the gating of filtering of auditory information in both humans and in an animal model. The alpha7 gene has been cloned and a polymorphic dinucleotide repeat near the gene was used for linkage analysis, showing the alpha7 locus to be linked to the P50 deficit. Expression of the alpha7 receptor, which binds nicotine with low affinity, is reduced in the hippocampus of schizophrenics. [3H]-nicotine binding, a measure of the high affinity nicotinic receptors, was also decreased in schizophrenics and does not increase in response to tobacco use, as is seen in control subjects. The results of these studies suggest the presence of abnormal expression and function of the neuronal nicotinic receptor gene family in schizophrenia.

Journal Article↗
PubMed1998

Electronic surveillance of disease states: a preliminary study in electronic detection of respiratory diseases in a primary care setting.

The present project is a step by step description of the creation of a computerized surveillance system using historical information derived from automated expert system acquisition. Since historical information is in many cases not sufficient for establishing an individual's medical diagnosis, the accuracy of surveillance is measured against the "gold standard" diagnosis provided by a panel of physicians. It was possible to survey within acceptable limits of accuracy in the conditions of the project. The results reveal a high level of sensitivity by computer surveillance as well as an accurate ability of electronic tracking of disease incidence over a period of time. However, further investigation into the accuracy of electronic surveillance and selection of symptoms used to define a disease should be studied. The feasibility of employing electronic historical medical information to survey disease has potential in providing real-time epidemiological data.

Expert Systems↗
PubMed1997

Nicotinic antagonist alpha-bungarotoxin binding to rat hippocampal neurons containing nitric oxide synthase.

The hippocampus is a major target of alpha-bungarotoxin (alpha-BTX) binding. This ligand binds to the alpha 7 nicotinic, cholinergic receptor, which has been implicated in hippocampal habituation to repetitive auditory stimulation, a phenomenon thought to involve inhibitory neurons. This study examined whether alpha-BTX binds to neurons containing nitric oxide synthase (NOS), a marker of one subgroup of inhibitory hippocampal neurons. Rat hippocampal sections were processed for NOS immunohistochemistry, photographed and then processed for [125I]alpha-BTX autoradiography. Comparison between the distribution of neurons immunoreactive for NOS and those positive for alpha-BTX binding in the same regions of the hippocampal formation revealed a variable degree of colocalization of NOS and alpha-BTX. Of the cells labeled with alpha-BTX, 2% in the dentate gyrus and 40% in the hippocampus proper were also immunoreactive for NOS. These NOS/alpha-BTX neurons were most prevalent in CA1 stratum oriens. The results suggest a possible role for NOS-containing neurons in alpha 7-mediated inhibition to repetitive auditory stimulation in rat hippocampus.

Animals↗