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Biomedical subjects

J M Lindstrom

Publications and source records attributed to J M Lindstrom.

At least 19 recordsLinked to original sources
PubMed2004

Childhood myopia and parental smoking.

AIM: To examine the relation between exposure to passive parental smoke and myopia in Chinese children in Singapore. METHODS: 1334 Chinese children from three schools in Singapore were recruited, all of whom were participants in the Singapore Cohort study Of the Risk factors for Myopia (SCORM). Information on whether the father or mother smoked, number of years smoked, and the number of cigarettes smoked per day during the child's lifetime were derived. These data were correlated with contemporaneously obtained data available in SCORM. The children's cycloplegic autorefraction, corneal curvature radius, and biometry measures were compared with reported parental smoking history. RESULTS: There were 434 fathers (33.3%) and 23 mothers (1.7%) who smoked during their child's lifetime. There were no significant trends observed between paternal smoking and refractive error or axial length. After controlling for age, sex, school, mother's education, and mother's myopia, children with mothers who had ever smoked during their lifetime had more "positive" refractions (adjusted mean -0.28 D v -1.38 D) compared with children whose mother did not smoke (p = 0.012). CONCLUSIONS: The study found no consistent evidence of association between parental smoking and refractive error. There was a suggestion that children whose mothers smoked cigarettes had more hyperopic refractions, but the absence of a relation with paternal smoking and the small number of mothers who smoked in this sample preclude definite conclusions about a link between passive smoking exposure and myopia.

Child↗
PubMed2001

Spontaneous remission in canine myasthenia gravis: implications for assessing human MG therapies.

The natural course of autoimmune canine MG was determined in 53 dogs with muscular weakness and a positive acetylcholine receptor antibody titer. Dogs were treated with anticholinesterase therapy, without immunosuppression. Spontaneous clinical and immunologic remission occurred in 47 of 53 dogs within an average of 6.4 months. Neoplasia was identified in the six dogs that did not spontaneously remit. This study questions the value of using canine MG in studies designed to assess the effect of immunotherapies.

Animals↗
PubMed2001

Differential localization of acetylcholinesterase in relation to pre- and postsynaptic nicotinic receptors in the chick brain.

Immunofluorescence and confocal microscopy were combined to study the distribution of acetylcholinesterase in relation to the localization of the beta2 subunit of the nicotinic acetylcholine receptors in the chick brain. In several areas where the beta2 subunit is recognizably part of presynaptic receptors, the localization of acetylcholinesterase appeared not to overlap the localization of beta2. On the other hand, acetylcholinesterase and the beta2 subunit exhibited a strictly matching localization in areas where postsynaptic nicotinic receptors are known to be present. These data may represent a morphological substrate for possible differential actions of acetylcholinesterase at presynaptic and postsynaptic nicotinic sites.

Acetylcholinesterase↗
PubMed2001

Nootropic drug modulation of neuronal nicotinic acetylcholine receptors in rat cortical neurons.

Nefiracetam (DM-9384) is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and poststroke vascular-type dementia. Because the cholinergic system plays an important role in cognitive functions and Alzheimer's disease dementia, the present study was conducted to elucidate the mechanism of action of nefiracetam and aniracetam on neuronal nicotinic acetylcholine receptors (nnAChRs). Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell, patch-clamp technique. Two types of currents were evoked by acetylcholine (ACh): alpha-bungarotoxin-sensitive, alpha 7-type currents and alpha-bungarotoxin-insensitive, alpha 4 beta 2-type currents. Although nefiracetam and aniracetam inhibited alpha 7-type currents only weakly, these nootropic agents potentiated alpha 4 beta 2-type currents in a very potent and efficacious manner. Nefiracetam at 1 nM and aniracetam at 0.1 nM reversibly potentiated alpha 4 beta 2-type currents to 200 to 300% of control. Nefiracetam at very high concentrations (approximately 10 microM) also potentiated alpha 4 beta 2-type currents but to a lesser extent, indicative of a bell-shaped dose-response relationship. Nefiracetam markedly increased the saturating responses induced by high concentrations of ACh. However, human alpha 4 beta 2 subunits expressed in human embryonic kidney cells were inhibited rather than potentiated by nefiracetam. The specific protein kinase A inhibitors (H-89, KT5720, and peptide 5-24) and protein kinase C inhibitors (chelerythrine, calphostin C, and peptide 19--63) did not prevent nefiracetam from potentiating alpha 4 beta 2-type currents, indicating that these protein kinases are not involved in nefiracetam action. The nefiracetam potentiating action was not affected by 24-h pretreatment of neurons with pertussis toxin, but was abolished by cholera toxin. Therefore, G(s) proteins, but not G(i)/G(o) proteins, are involved in nefiracetam potentiation. These results indicate that nnAChRs are an important site of action of nefiracetam and G(s) proteins may be its crucial target.

Acetylcholine↗
PubMed2001

Effects of nicotinic antagonists on ocular growth and experimental myopia.

PURPOSE: To learn whether nicotinic cholinergic receptors modulate postnatal eye growth and influence the course of form-deprivation myopia. METHODS: One-week-old White Leghorn chicks wore a unilateral goggle to induce form-deprivation myopia. Other chicks were never goggled. Nicotinic antagonist drugs were administered by intravitreal injection, usually daily or every other day to the goggled eye or to one eye of never-goggled chicks. After 1 week, the eyes were studied by refractometry, A-scan ultrasonography, and caliper measurements. RESULTS: The relatively non-subtype-specific channel-blocking nicotinic antagonists chlorisondamine and mecamylamine each inhibited the development of form-deprivation myopia but with complex multiphasic dose responses. Chlorisondamine was the most effective. Mecamylamine, at the lowest tested doses, tended to stimulate the growth response and myopic refractive shift of goggle wearing. Methyllycaconitine competitively inhibits nicotinic receptors containing the alpha7 and alpha8 subunits, which are highly expressed in chick retina. It showed a less dramatic but still significant inhibitory effect on myopia. The effects of dihydro-beta-erythroidine, a competitive antagonist relatively selective for nicotinic receptors with alpha3 or alpha4 subunits and particularly for alpha3beta2-containing receptors, were the weakest and inhibited primarily axial elongation. Chlorisondamine but not mecamylamine also affected nongoggled eyes, inhibiting growth and shifting refraction toward hyperopia, but chlorisondamine also induced degenerative changes to the retinal pigment epithelium (RPE). CONCLUSIONS: Nicotinic receptors are involved in eye growth control. Nicotinic antagonists affect the development of form-deprivation myopia and perhaps the growth of nongoggled eyes. The differences in drug activity and multiphasic dose-response curves may reflect the complexity of nicotinic receptor subtypes associated with the eye and/or pharmacokinetic differences between the individual drugs. Although another tissue(s) cannot be completely excluded by these data, the site of action of these agents may be neural retina or RPE.

Animals↗
PubMed2000

Effects of cholinergic deafferentation upon the expression of the alpha2 subunit of the nicotinic acetylcholine receptors in the chick lateral spiriform nucleus.

Lesion, immunohistochemical, and immunoblotting methods were used to evaluate the effects of cholinergic deafferentation upon the expression of the alpha2 subunit of the nicotinic acetylcholine receptors in the lateral spiriform nucleus (SpL) of the chick brain. The expression of the alpha2 subunit in the SpL showed biphasic changes after lesion of its cholinergic source (nucleus semilunaris), with an increase after 2 days postlesion and a decrease after 3-7 days. Our results could represent a correlate of the phenomena of nicotinic receptor up- and down-regulation, induced by removal of the cholinergic input.

Animals↗
PubMed2000

Acetylcholine receptors and myasthenia.

Much progress has been made in the 26 years since initial studies of the first purified acetylcholine receptors (AChRs) led to the discovery that an antibody-mediated autoimmune response to AChRs causes the muscular weakness and fatigability characteristic of myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG). Now, the structure of muscle AChRs is much better known. Monoclonal antibodies to muscle AChRs, developed as model autoantibodies for studies of EAMG, were used for initial purifications of neuronal AChRs, and now many homologous subunits of neuronal nicotinic AChRs have been cloned. There is a basic understanding of the pathological mechanisms by which autoantibodies to AChRs impair neuromuscular transmission. Immunodiagnostic assays for MG are used routinely. Nonspecific approaches to immunosuppressive therapy have been refined. However, fundamental mysteries remain regarding what initiates and sustains the autoimmune response to muscle AChRs and how to specifically suppress this autoimmune response using a practical therapy. Many rare congenital myasthenic syndromes have been elegantly shown to result from mutations in muscle AChRs. These studies have provided insights into AChR structure and function as well as into the pathological mechanisms of these diseases. Evidence has been found for autoimmune responses even to some central nervous system neurotransmitter receptors, but only one neuronal AChR has so far been implicated in an autoimmune disease. Thus far, only two neuronal AChR mutations have been found to be associated with a rare form of epilepsy, but many more neuronal AChR mutations will probably be found to be associated with disease in the years ahead.

Animals↗
PubMed1998

Ion channel modulation as the basis for general anesthesia.

(1) Modulation of the function of the GABA(A) and neuronal nicotinic acetylcholine receptor channels caused by general anesthetics and modulation of the GABA(A) receptor-channel by halothane, enflurane, isoflurane, and n-octanol was channel state-dependent. (3) Halothane modulation of the GABA(A) receptor was independent of subunits, but n-octanol modulation was subunit-dependent. (4) Ethanol at 30-100 microM was very potent in accelerating the desensitization of currents induced by acetylcholine. (5) The ethanol modulation was subunit- and state-dependent, occurring in the alpha3beta4 combination but only weakly in the alpha3beta2 combination. (6) In contrast, halothane at 430 microM (approximately 1 MAC) potently suppressed ACh-induced currents in the alpha3beta2 subunit combination.

Anesthesia, General↗
PubMed1998

Distribution of the alpha7 nicotinic acetylcholine receptor subunit in the developing chick cerebellum.

Previous studies of the nicotinic acetylcholine receptor (nAChR) subunits in adult mammalian and avian brains have demonstrated a spatially restricted distribution of these subunits; little, however, is known about the nAChR subunit developmental distribution. The present study demonstrated a transient pattern of distribution of the neuronal nAChR subunit, alpha7, in the developing chick cerebellum by using immunohistochemical techniques. This transient distribution may suggest a critical period for the development of the cholinergic system in the cerebellum.

Animals↗
PubMed1998

Response of CD4+ T cells from myasthenic patients and healthy subjects of biosynthetic and synthetic sequences of the nicotinic acetylcholine receptor.

We investigated the suitability of pools of overlapping synthetic peptides spanning the complete alpha 1 subunit sequence of the human muscle acetylcholine receptor (AChR) (alpha 1 pool) or the extracellular domain (residues 1-218, alpha 11-218 pool), and of biosynthetic alpha 1 constructs from E. coli, as stimulants of human CD4+ cells from myasthenia gravis (MG) patients and healthy subjects. A construct corresponding to residues alpha 11-209 was obtained as solubilized inclusion bodies (ib alpha 11-209), or purified by SDS gel electrophoresis (pur alpha 11-209). A second construct included the extracellular, cytoplasmic and carboxylterminal domains plus histidine residues, and was obtained as inclusion bodies (ib alpha 1NoTrans) or purified by gel permeation and histidine tag affinity chromatography (pur alpha 1NoTrans). A biosynthetic extracellular domain of the neuronal AChR alpha 7 subunit (ib alpha 71-206) isolated from E. coli as inclusion bodies served as control for bacterial contaminants. We used ib alpha 11-209, pur alpha 11-209 and peptide pools to propagate CD4+ lines from two MG patients. The lines obtained using pur alpha 11-209 and the peptide pools recognized the peptide pools and alpha 1 constructs tested well, but ib alpha 71-206 poorly or not at all. These lines recognized peptides known to form CD4+ epitopes in these patients. The ib alpha 11-209 lines recognized ib alpha 11-209 and ib alpha 71-206 strongly, but recognized poorly pur alpha 11-209 and the alpha 11-218 pool. We propagated T-cell lines from a healthy subject using pur alpha 11-209 and ib alpha 11-209. The pur alpha 11-209 line recognized pur alpha 11-209 and the alpha 11-218 pool, but not ib alpha 11-209 or ib alpha 71-206. The ib alpha 11-209 line recognized ib alpha 11-209 and ib alpha 71-206, but not pur alpha 11-209 or the alpha 11-218 pool. We tested blood CD4+ cells from six MG patients and eight healthy subjects with ib alpha 11-209, pur alpha 11-209, the alpha 11-218 pool and--in the healthy subjects--also ib alpha 71-206, ib alpha 1NoTrans and pur alpha 1NoTrans. In both populations, the alpha 11-218 pool elicited low and sporadic responses, while the constructs elicited clear responses that were frequently higher for ib alpha 11-209 than pur alpha 11-209. The responses to ib alpha 71-206 were strong and comparable to those to ib alpha 11-209, ib alpha 1NoTrans, and pur alpha 1NoTrans. These results indicate that even purified constructs from E. coli contain bacterial contaminants recognized by CD4+ cells. They should not be used to test unselected blood CD4+ cells, because they may evoke strong CD4+ responses to the bacterial antigens. Purified recombinant sequences may be suitable for propagation of CD4+ cell lines, if the specificity of the lines can be verified using different antigen preparations. Short synthetic peptide sequences can be safely used for propagation of specific CD4+ cells. Although they are poor stimulants for unselected blood CD4+ cells, the low responses they elicit are probably due to these cells.

Amino Acid Sequence↗
PubMed1998

Evidence that porcine native 5-HT3 receptors do not contain nicotinic acetylcholine receptor subunits.

The present investigation utilised monoclonal antibodies directed against subunits of the nicotinic acetylcholine receptor in immunoblot and immunoprecipitation studies, which failed to demonstrate that the native 5-hydroxytryptamine3 (5-HT3) receptor complex purified from porcine brain contains the alpha1, alpha3, alpha4, alpha5, alpha7 or beta2 subunits of the nicotinic acetylcholine receptor.

Animals↗
PubMed1997

Differential co-localization of nicotinic acetylcholine receptor subunits with calcium-binding proteins in retinal ganglion cells.

Immunohistochemistry was used to examine the co-occurrence of nicotinic acetylcholine receptor subunits with calcium-binding proteins in ganglion cells of the chick retina. The alpha3 subunit was rarely observed in ganglion cells containing calbindin, calretinin, or parvalbumin. On the other hand, the alpha8 subunit was more often co-localized with all calcium-binding proteins studied. These results may be related to the high calcium permeability of nicotinic receptors that contain the alpha8 subunit.

Animals↗
PubMed1997

Distribution of the alpha 2, alpha 3, and alpha 5 nicotinic acetylcholine receptor subunits in the chick brain.

Nicotinic acetylcholine receptors (nAChRs) are ionotropic receptors comprised of alpha and beta subunits. These receptors are widely distributed in the central nervous system, and previous studies have revealed specific patterns of localization for some nAChR subunits in the vertebrate brain. In the present study we used immunohistochemical methods and monoclonal antibodies to localize the alpha 2, alpha 3, alpha 5 nAChR subunits in the chick mesencephalon and diencephalon. We observed a differential distribution of these three subunits in the chick brain, and showed that the somata and neuropil of many central structures contain the alpha 5 nAChR subunit. The alpha 2 and alpha 3 subunits, on the other hand, exhibited a more restricted distribution than alpha 5 and other subunits previously studies, namely alpha 7, alpha 8 and beta 2. The patterns of distribution of the different nAChR subunits suggest that neurons in many brain structures may contain several subtypes of nAChRs and that in a few regions one particular subtype may determine the cholinergic nicotinic responses.

Animals↗
PubMed1997

Society for Research on Nicotine and Tobacco.

The proceedings of the second annual scientific conference of the Society for Research on Nicotine and Tobacco are summarized. The goal of the annual conference was to disseminate information about ongoing nicotine research from biological, behavioral and social perspectives. Data were presented describing our current understanding of the structure and function of neuronal nicotinic acetylcholine receptors, by which nicotine exerts most, if not all, of its effects in the brain. The conformational complexity of receptor subunits expressed in different brain areas contributes significantly to the complexity of responses observed to nicotinic agonists. Nicotine is being developed as a medication that might be used to maintain smoking cessation and to treat various medical diseases. The potential toxicity of nicotine, apart from cigarette smoking, is an important variable in assessing the benefits and risks of such therapeutic applications. The risks of nicotine-containing medications appear to be far less than those associated with tobacco use. Recent data indicate that cigarette smoking is increasing among young in the United States. Adolescent smokers are interested in quitting and make frequent quit attempts, but are usually not successful. Effective methods are needed to manage adolescent smokers before they become heavily addicted. Nicotine replacement as a pharmacological treatment for smoking cessation has made a significant contribution in improving quit rates. New medications have been developed that target specific populations of smokers.

Adolescent↗
PubMed1996

Presumptive presynaptic nicotinic acetylcholine receptors in the chick tectum: effects of lesions of the lateral spiriform nucleus.

There are indications that nicotinic acetylcholine receptor subunits in the superficial layers of the chick tectum (Cajal's layers 1-7) may be transported from the retina. However, nicotinic receptor subunits are detectable by immunohistochemistry in all layers of the optic tectum. In this study, we performed unilateral electrolytic lesions of the lateral spiriform nucleus, which projects to the deep layers of the tectum and contains high amounts of nicotinic receptors in its perikarya. Following lesions of the lateral spiriform nucleus, both the alpha 5 and the beta 2 subunits were markedly depleted in the neuropil of the deep layers of the ipsilateral optic tectum (layers 8-13). No changes were observed in somata that contain either subunit. The present results suggest that most of the nicotinic acetylcholine receptor subunits in the chick optic tectum occur in axonal systems and could then constitute presynaptic receptors.

Animals↗