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Biomedical subjects

M C Wilson

Publications and source records attributed to M C Wilson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Mouse model of hyperkinesis implicates SNAP-25 in behavioral regulation.

Although hyperkinesis is expressed in several neurological disorders, the biological basis of this phenotype is unknown. The mouse mutant coloboma (Cml+) exhibits profound spontaneous locomotor hyperactivity resulting from a deletion mutation. This deletion encompasses several genes including Snap, which encodes SNAP-25, a nerve terminal protein involved in neurotransmitter release. Administration of amphetamine, a drug that acts presynaptically, markedly reduced the locomotor activity in coloboma mice but increased the activity of control mice implicating presynaptic function in the behavioral abnormality. In contrast, the psychostimulant methylphenidate increased locomotor activity in both coloboma and control mice. When a transgene encoding SNAP-25 was bred into the coloboma strain to complement the Snap deletion, the hyperactivity expressed by these mice was rescued, returning these corrected mice to normal levels of locomotor activity. These results demonstrate that the hyperactivity exhibited by these mice is the result of abnormalities in presynaptic function specifically attributable to deficits in SNAP-25 expression.

Amphetamine↗
PubMed1996

Characterization and ontogeny of synapse-associated proteins in the developing facial and hypoglossal motor nuclei of the Brazilian opossum.

The characterization and ontogeny of synapse-associated proteins in the developing facial and hypoglossal motor nuclei were examined in the Brazilian opossum (Monodelphis domestica). Immunohistochemical markers utilized in this study were the synaptic vesicle-associated proteins synaptophysin and synaptotagmin; a synaptic membrane protein, plasma membrane-associated protein of 25 kDa (SNAP-25); a growth cone protein, growth-associated phosphoprotein-43 (GAP-43); and the microtubule-associated proteins axonal marker tau and dendritic marker microtubule-associated protein-2 (MAP-2). In this study, we have found that, during the first 10 postnatal days (1-10 PN), the facial motor nucleus lacked immunoreactivity for synaptophysin, synaptotagmin, GAP-43, tau, and SNAP-25. After 10 PN, immunoreactivity increased in the facial motor nucleus for synaptophysin, synaptotagmin, GAP-43, and tau, whereas immunoreactivity for SNAP-25 was not evident until between 15 and 25 PN. Conversely, immunoreactivity for MAP-2, was present in the facial motor nucleus from the day of birth. In contrast, the hypoglossal motor nucleus displayed immunoreactivity from 1 PN for synaptophysin, synaptotagmin, SNAP-25, GAP-43, tau, and MAP-2. These results suggest that the facial motor nucleus of the opossum may not receive afferent innervation as defined by classical synaptic markers until 15 PN and, further, that characteristic mature synapses are not present until between 15 and 25 PN. These results indicate that there may be a delay in synaptogenesis in the facial motor nucleus compared to synaptogenetic events in the hypoglossal motor nucleus. Because the facial motor nucleus is active prior to completion of synaptogenesis, we suggest that the facial motoneurons are regulated in a novel or distinct manner during this time period.

Animals↗
PubMed1996

Coloboma contiguous gene deletion encompassing Snap alters hippocampal plasticity.

Mice heterozygous for the semidominant mutation coloboma (Cm/+) display several distinct pathologies including head bobbing, ophthalmic deformation, and locomotor hyperactivity. The Cm/+ mutation comprises a contiguous gene defect which encompasses deletion of the gene Snap encoding the presynaptic nerve terminal protein SNAP-25 that is an integral component of the synaptic vesicle docking and fusion complex. Indeed, SNAP-25 is required for axonal growth and for the regulated release of neurotransmitters at the synaptic cleft. As an extension of our studies on the behavioral deficits exhibited by these mutants, including evaluation of the hyperkinesis and dopamine-related behavioral pharmacology that might be related to attention-deficit hyperactivity disorder in humans, we have studied spontaneous electroencephalographic and evoked potential recordings in the dentate gyrus of halothane-anesthetized Cm/+ and normal (+/+) littermates to evaluate potential physiological abnormalities of synaptic function in these mice. While sensory activation elicited by brief (10 sec) tail-pinch produced 1-2 min of theta rhythmic activity in +/+ mice, theta induction was markedly reduced in Cm/+ mice. There were no significant differences in dentate afferent-evoked population excitatory postsynaptic potential (pEPSP) slopes, pEPSP facilitation, or population spike (PS) amplitudes; however, paired-pulse inhibition of dentate PS amplitudes was significantly increased in Cm/+ mice. Furthermore, although brief high-frequency stimulation of the perforant path produced robust long-term potentiation (LTP) of synaptic responses in the dentate gyrus of +/+ mice, LTP was attenuated in Cm /+ mice. It has been previously demonstrated that dopamine (DA) neurotransmission is essential for induction of one type of hippocampal theta rhythm and also may modulate hippocampal LTP, suggesting that alterations in DA synaptic transmission may underlie the behavioral abnormalities, in particular the hyperactivity, associated with Cm/+ mutant mice.

Animals↗
PubMed1996

Practice guidelines. What are internists looking for?

To determine features of the presentation of clinical practice guidelines that may enhance their use by internists, we conducted a cross-sectional survey to which 1,513 (60%) of 2,513 eligible internists responded. Endorsements by respected colleagues and by major organizations were identified as very important by 72% and 69% of respondents, respectively. Respondents preferred short pamphlets and manuals summarizing a number of guidelines and felt that concise recommendations (86%), synopsis of supporting evidence (85%), and quantification of benefit (77%) were important in guideline presentation. We conclude that guideline developers should gain the endorsement of major organizations and present key aspects in brief, easily assimilated formats.

Attitude of Health Personnel↗
PubMed1996

The effects of cocaine and nandrolone co-administration on aggression in male rats.

1. Cocaine and anabolic-androgenic steroids are among the more commonly abused substances in selected populations. These agents, when used alone or in combination, have been reported to cause aggressive tendencies in both laboratory-based animal models and in human clinical situations. This project, using a resident-intruder paradigm, examined the effects of co-administration of cocaine and a typical anabolic-androgenic steroid, nandrolone decanoate, on the development of aggression in male Sprague-Dawley rats. 2. Dose response studies demonstrated that low dose cocaine (1 mg/kg) produced more aggression in a greater percentage of animals than for either the controls or groups receiving higher doses (up to 20 mg/kg). Initially, high intermittent doses of nandrolone (20 mg twice weekly) produced more aggression; however, low daily doses of nandrolone (2 mg) produced greater levels of aggression following 4 weeks of treatment. 3. Optimal doses of cocaine and nandrolone, when administered together, resulted in aggression scores that were not significantly different from controls or either drug singly. However, a greater percentage of animals receiving both drugs exhibited aggression than did rats receiving either drug alone. 4. These results support the interpretation that the drugs interact to produce unique effects in the development of aggression. However, the complexity and extent of the interactions is great and remains to be fully elucidated.

Aggression↗
PubMed1996

Hippocampal-dependent learning and experience-dependent activation of the hippocampus are preferentially disrupted by ethanol.

A classical fear conditioning paradigm was used to examine the effect of acute ethanol on the acquisition of context conditioning, a hippocampal-dependent associative task, and tone conditioning, a hippocampal-independent task. Administration of ethanol before the presentation of seven tone-shock pairings severely disrupted the acquisition of context conditioning, but had only a slight effect on tone conditioning, when conditioned fear was measured 48 h later. This effect was dose dependent: a dose of 0.5 g/kg had no effect on either context or tone conditioning, while doses of 1.0 and 1.5 g/kg disrupted context conditioning by 78-86%, and tone conditioning by 9-17%. Subsequent experiments indicated that ethanol's preferential effect on context conditioning could not be attributed to the fact that context conditioning is weaker than tone conditioning, ethanol-induced changes in motivational state or state-dependent learning. The effect of ethanol on stimulus-induced increases in hippocampal and neocortical expression of c-fos mRNA, a marker for changes in metabolic neuronal activity, was also examined. Ethanol completely blocked the induction of hippocampal c-fos mRNA by exposure to the conditioning context alone or seven tone-shock pairings, but only attenuated neocortical responses to these stimuli. Together, these results suggest that ethanol disrupts hippocampal-dependent learning by preferentially impairing stimulus processing at the level of the hippocampus.

Animals↗
PubMed1996

Long-term follow-up of ocular findings in children with Stickler's syndrome.

PURPOSE: To document the longitudinal changes in eye status of children diagnosed with Stickler's syndrome in the first decade of life. METHOD: All patients with cleft palate were referred for eye examination. Of these, patients with systemic findings of Stickler's syndrome were included in this report. RESULTS: Thirty-four eyes in 17 patients met inclusion criteria, with median best-corrected recognition acuity of 20/30. The mean cycloplegic refraction at presentation was -5.00 diopters, and the mean refraction at last visit was -5.50 diopters. CONCLUSIONS: Refractive errors, cataracts, and vitreoretinal abnormalities can be detected early in life in patients with Stickler's syndrome, and refractive error changed little during the follow-up period.

Cataract↗
PubMed1995

Coloboma hyperactive mutant exhibits delayed neurobehavioral developmental milestones.

The coloboma mutation (Cm) is a neutron-irradiation induced gene deletion located on the distal portion of mouse chromosome 2. This deletion region includes a gene encoding the synaptic vesicle docking fusion protein, synaptosomal-associated protein of 25 kDa (SNAP-25). The resulting mutation is semi-dominant with heterozygote mice exhibiting a triad of phenotypic abnormalities that comprise profound spontaneous hyperactivity, head bobbing and a prominent eye dysmorphology. Because the expression pattern of two SNAP-25 isoforms begins to change during the first postnatal week, neurobehavioral developmental milestones were examined in order to determine if the expression of the coloboma behavioral phenotype could be detected during this period of postnatal development. The early classification of coloboma mutant offspring may help to further describe the penetrance of this mutation as well as the contribution of developmental changes to the adult behavioral phenotype. The coloboma mutation resulted in delays in some tests of complex motor skills including righting reflex and bar holding. In addition, coloboma mutants were characterized by body weight differences (first appearance day 7) and hyperreactivity to touch (day 11) and head bobbing (day 14). These data demonstrate disruptions in the time course of attaining developmental milestones in coloboma mutants and provide further evidence supporting the hypotheses that alterations in Snap gene expression are associated with functional behavioral consequences in developing offspring.

Aging↗
PubMed1995

Regulation of neurite outgrowth and SNAP-25 gene expression by the Brn-3a transcription factor.

SNAP-25 is a presynaptic nerve terminal protein which is also essential for the process of neurite outgrowth in vivo and in vitro. However the processes regulating its expression have not been characterized previously. We show that the gene encoding this protein, SNAP, is strongly activated by the Brn-3a POU (Pit-Oct-Unc) family transcription factor. Expression of both Brn-3a and SNAP-25 increases when ND7 neuronal cells are induced to extend neurite processes by serum removal. Inhibition of Brn-3a expression in these cells inhibits SNAP-25 expression and abolishes the neurite outgrowth that normally occurs in response to serum removal. These results identify Brn-3a as the first transcription factor having a role in process outgrowth in neuronal cells acting, at least in part, via the activation of SNAP-25 gene expression.

Base Sequence↗
PubMed1995

Differential expression of SNAP-25 protein isoforms during divergent vesicle fusion events of neural development.

The presynaptic plasma membrane protein SNAP-25 (synaptosome-associated protein of 25 kDa) has been implicated as one of several neural-specific components that direct constitutive fusion mechanisms to the regulated vesicle trafficking and exocytosis of neurotransmitter release. There exist two alternatively spliced isoforms of SNAP-25, a and b, which differ in a putative membrane-interacting domain. We show that these two isoforms have distinct quantitative and anatomical patterns of expression during brain development, in neurons, and in neuroendocrine cells and that the proteins localize differently in neurites of transfected PC12 pheochromocytoma cells. These findings indicate that alternative isoforms of SNAP-25 may play distinct roles in vesicular fusion events required for membrane addition during axonal outgrowth and for release of neuromodulatory peptides and neurotransmitters.

Adrenal Glands↗
PubMed1995

Immediate upstream promoter regions required for neurospecific expression of SNAP-25.

The promoter structure and regulation of Snap, a gene encoding the presynaptic t-SNARE SNAP-25 implicated in synaptic vesicle docking and fusion, was studied. Transcription start-site analysis revealed two major start sites located 42 nucleotides apart. Nucleotide sequence of a promoter region 2073 nucleotides upstream of the first transcription site contains three AP-1, one CRE sequence, and three Sp1-like sites close to the TATA box. Further upstream of these sites two TG repeats were found. The ability of regions within the 5' upstream sequence to promote basal neural-specific expression in tissue culture cells was evaluated using a series of constructs containing both Snap gene start sites with progressively restricted 5' sequence linked to the chloramphenicol acetyl transferase (CAT) reporter gene. CAT expression was maximal in neuron-like undifferentiated ND7 and PC12 cells transfected with constructs containing Snap sequences up to 127 bp from the start site. In contrast, nonneuronal fibroblast cell lines did not express significant amounts of CAT, suggesting that this short 127-bp sequence is sufficient to drive neural specific expression of SNAP-25. Band shift analysis of oligonucleotides spanning from -127 to -41 bp of the Snap promoter revealed three distinct DNA-protein complexes generated by brain nuclear extracts and one by liver nuclear extracts, indicating that transcription factors that bind to this 86-bp sequence located just upstream of the TATA box are involved in regulation of basal neurospecific expression of this gene.

Animals↗
PubMed1995

Patient-controlled analgesia: a method for the controlled self-administration of opioid pain medications.

The purposes of this article are to introduce the reader to patient-controlled analgesia (PCA) and to summarize its use in several selected pain-related conditions. patient-controlled analgesia is a relatively new technique for managing pain in which patients are able to self-administer small doses of opioid analgesic medications when needed. The authors briefly review some of the problems associated with current and previous opioid delivery strategies and highlight the advantages of PCA over these other methods. They then discuss the components of the PCA system and briefly describe how the system is operated and controlled. In this discussion, the authors indicate an appropriate therapeutic goal and suggest knowledge requirements for the effective use of PCA. The authors close with a brief summary of several reports describing the use of PCA in the management of postoperative pain, cancer pain, and pain associated with labor and delivery. Indications and contraindications for use in these conditions are presented. Because physical therapists often play a major role in pain management, it is important for them to be well informed with regard to recent developments in this rapidly developing area of clinical practice.

Analgesia, Patient-Controlled↗
PubMed1995

Exposure of neonatal rats to alcohol by vapor inhalation demonstrates specificity of microcephaly and Purkinje cell loss but not astrogliosis.

The artificial rearing model (AR) of fetal alcohol syndrome (FAS) has been shown to induce several major pathologies in the early postnatal rat brain development: microcephaly, selective neuronal cell loss, and activation of astroglia in the neocortex. The purpose of this study was to determine whether these pathologies were specific to the action of alcohol or, in contrast, could result from confounds attributed to this model of FAS. For this purpose, the pathological effects of AR were compared with those of a vapor inhalation (VI) model of FAS. Our studies showed that the microcephaly that developed after exposure to periodic blood alcohol levels (BALs) of 300-350 mg% during postnatal days 4-9 could be achieved by both AR and IV models of FAS, and thus is independent of the method of alcohol administration. In contrast, the gliosis measured by glial fibrillary acidic protein (GFAP) mRNA levels in cortex, as well as by immunohistochemical staining for GFAP, was found only in the AR-FAS model, but not in the VI model. However, the lack of gliosis in VI was apparently not due to a less intrusive intervention of alcohol, because VI exposure resulted in a reduction in Purkinje cell number comparable with that found after AR or intragastric intubation of alcohol. Based on these observations, we conclude that the activation of gliosis observed after AR is not a specific effect of alcohol, but rather is caused by an interaction of alcohol with as yet unidentified factors present in AR.

Administration, Inhalation↗
PubMed1995

Alcohol selectively attenuates stress-induced c-fos expression in rat hippocampus.

The ability of ethyl alcohol to modify responses to stress has been well documented (cf. Pohorecky, 1990). However, the structural substrate mediating these effects of alcohol remains undefined. Using immediate early gene (IEG) expression in the brain as a marker of altered neuronal response, we investigated the effect of acute alcohol exposure on the activity of brain regions of rats exposed to 15 min of restraint stress. Immunocytochemical localization c-Fos protein demonstrated that restraint stress led to an induction of c-Fos expression in several brain structures including cingulate and piriform cortex, cortico-amygdaloid and hippocampo-amygdaloid transition zones, hippocampus, hypothalamus, supramammillary nucleus, and centromedial nucleus of thalamus. An intraperitoneal injection of 2 g/kg alcohol prior to stress decreased c-Fos expression in several but not all of these structures. In particular, alcohol strongly attenuated the stress-induced expression of c-Fos in hippocampus and cingulate cortex. Using slot-blot hybridization, significant induction of c-fos mRNA after restraint stress was demonstrated both in hippocampus and cortex, but prior alcohol exposure specifically attenuated c-fos induction only in the hippocampus. The response of c-fos mRNA expression to stress and alcohol differed from the effects on jun-B, c-jun and jun-D mRNA levels. Perhaps surprisingly, acute exposure to alcohol in otherwise unstressed rats did not induce significant changes in expression of IEGs in comparison to control (saline-injected) animals even with doses sufficient to elevate plasma corticosterone. In summary, these studies demonstrate a selective sensitivity of stress-induced activity of neurons of hippocampus and cingulate cortex to acute alcohol exposure.

Animals↗
PubMed1994

Barriers to the provision of complex dental treatment for dentate older people: a comparison of dentists' and patients' views.

The majority of older people live active lives and more are retaining their teeth. These people rely for their dental care on general dental practitioners. However, many find that the service they are offered falls short of their desires, and this study examined this problem from the points of view of the public and the dentists. Qualitative group discussions were conducted among 61 middle-aged and elderly people and 20 dentists, followed by a quantitative study involving 20 dentists and 57 of their patients. The aim was to discover what, if any, differences there may have been between their expectations of dental treatment. There were no significant differences between middle-aged and older peoples' views on barriers to the receipt of dental care. However, dentists assumed that their older patients would have significantly greater negative dental attitudes than their middle-aged patients. Dentists considered that ability to pay would be a significantly greater barrier for their working-class rather than their middle-class patients. However, among the patients themselves there was no significant difference. The comparison of dentists' and patients' views on barriers to treatment showed that dentists significantly overestimated their older patients' reluctance to receive dental treatment.

Aged↗
PubMed1994

Internists' attitudes about clinical practice guidelines.

OBJECTIVE: To assess internists' familiarity with, confidence in, and attitudes about practice guidelines issued by various organizations. DESIGN: Cross-sectional, self-administered survey. PARTICIPANTS: Questionnaires were mailed to a stratified random sample of 2600 members of the American College of Physicians (ACP) in 1992. Of the 2513 internists who met our eligibility criteria, 1513 responded (60%). MEASUREMENTS AND RESULTS: Familiarity with guidelines varied from 11% of responders for the ACP guideline on exercise treadmill testing to 59% of responders for the National Cholesterol Education Program guideline. Confidence was reported in ACP guidelines by 82% of responders but by only 6% for Blue Cross and Blue Shield guidelines. Subspecialists had greatest confidence in guidelines developed by their own subspecialty organizations. It was thought that guidelines would improve the quality of health care by 70% of responders, increase health care costs by 43%, be used to discipline physicians by 68%, and make practice less satisfying by 34%. More favorable attitudes were held by internists who were paid a fixed salary, saw patients for less than 20 hours per week, had recently graduated from medical school, or were not in private practice. CONCLUSIONS: Although most ACP members studied recognized the potential benefits of practice guidelines, many were concerned about possible effects on clinical autonomy, health care costs, and satisfaction with clinical practice.

Attitude of Health Personnel↗