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Biomedical subjects

M A Silverman

Publications and source records attributed to M A Silverman.

At least 19 recordsLinked to original sources
PubMed2005

Motifs that mediate dendritic targeting in hippocampal neurons: a comparison with basolateral targeting signals.

One model for dendritic protein sorting in neurons is based on parallels with basolateral targeting in Madin-Darby Canine Kidney (MDCK) epithelial cells. The goal of this study was to further evaluate this model by analyzing the neuronal targeting of several proteins that contain well-defined basolateral sorting motifs. When we expressed FcRgammaII-B2 and CD44, two basolateral markers whose sorting depends on dihydrophobic motifs, they were unpolarized in hippocampal neurons. We also assessed the localization of the Epidermal Growth Factor Receptor (EGFR), a basolateral protein whose sorting signal contains a proline-rich motif and two dihydrophobic motifs. EGFR was restricted to the dendrites in neurons and relied on the same sorting signal for proper targeting. These results show that the dendritic sorting machinery in neurons does not recognize dihydrophobic-based basolateral sorting signals. In contrast, the sorting signal present in EGFR directs both basolateral and dendritic targeting and defines a novel dendritic targeting motif.

Amino Acid Motifs↗
PubMed2002

Regulation of peptidergic vesicle mobility by secretagogues.

Neuropeptides are released into the extracellular space from large secretory granules. In order to reach their release sites, these granules are translocated on microtubules and thought to interact with filamentous actin as they approach the cell membrane. We have used a green fluorescent protein-tagged neuropeptide prohormone (prepro-orphanin FQ) to visualize vesicle trafficking dynamics in NS20Y cells and cultures of primary hippocampal neurons. We found that the majority of secretory granules were mobile and accumulated at both the tips of neurites as well as other apparently specialized cellular sites. We also used live-cell imaging to test the notion that peptidergic vesicle mobility was regulated by secretagogues. We show that treatment with forskolin appeared to increase vesicle rates of speed, while depolarization with high K+ had no effect, even though both treatments stimulated neuropeptide secretion. In cultured hippocampal neurons the green fluorescent protein-tagged secretory vesicles were routed to both dendrites and axons, indicating that peptidergic vesicle transport was not polarized. Basal peptidergic vesicle mobility rates in hippocampal neurons were the same as those in NS20Y cells. Taken together, these studies suggest that secretory vesicle mobility is regulated by specific classes of secretagogues and that neuropeptide containing secretory vesicles may be released from dendritic structures.

Animals↗
PubMed2001

Sorting and directed transport of membrane proteins during development of hippocampal neurons in culture.

Hippocampal neurons in culture develop morphological polarity in a sequential pattern; axons form before dendrites. Molecular differences, particularly those of membrane proteins, underlie the functional polarity of these domains, yet little is known about the temporal relationship between membrane protein polarization and morphological polarization. We took advantage of viral expression systems to determine when during development the polarization of membrane proteins arises. All markers were unpolarized in neurons before axonogenesis. In neurons with a morphologically distinguishable axon, even on the first day in culture, both axonal and dendritic proteins were polarized. The degree of polarization at these early stages was somewhat less than in mature cells and varied from cell to cell. The cellular mechanism responsible for the polarization of the dendritic marker protein transferrin receptor (TfR) in mature cells centers on directed transport to the dendritic domain. To examine the relationship between cell surface polarization and transport, we assessed the selectivity of transport by live cell imaging. TfR-green fluorescent protein-containing vesicles were already preferentially transported into dendrites at 2 days, the earliest time point we could measure. The selectivity of transport also varied somewhat among cells, and the amount of TfR-green fluorescent protein fluorescence on intracellular structures within the axon correlated with the amount of cell surface expression. This observation implies that selective microtubule-based transport is the primary mechanism that underlies the polarization of TfR on the cell surface. By 5 days in culture, the extent of polarization on the cell surface and the selectivity of transport reached mature levels.

Animals↗
PubMed2001

An association study of DRD5 with smoking initiation and progression to nicotine dependence.

A large body of genetic epidemiological data strongly implicate genetic factors in the etiology of smoking behavior. Polymorphisms of genes in the dopaminergic system are plausible functional candidate genes and a linkage and an association study suggested that the type 5 dopamine receptor gene (DRD5) may be etiologically involved. We investigated the association of four DRD5 polymorphisms with smoking initiation and progression to nicotine dependence in a population-based sample of over 900 subjects. For smoking initiation, there was no significant association with the four DRD5 markers we studied; however, maximum likelihood analyses suggested the presence of a haplotype protective against smoking initiation. For progression to nicotine dependence, there were no strongly significant associations with the four DRD5 markers or for the estimated haplotypes. These data are not consistent with a strong etiological role for DRD5 in the etiology of these complex smoking behaviors.

Adolescent↗
PubMed2000

Haplotypes of four novel single nucleotide polymorphisms in the nicotinic acetylcholine receptor beta2-subunit (CHRNB2) gene show no association with smoking initiation or nicotine dependence.

Several types of evidence, including experiments with mice that lack the nicotinic acetylcholine receptor beta2-subunit gene (CHRNB2), have suggested that a beta2-containing nicotinic receptor is necessary for at least some of the reinforcing properties of nicotine. However, sequence variations in CHRNB2 have not been reported, and its role in influencing human smoking behavior and nicotine dependence is not known. We screened most of the introns and exons and found five novel single nucleotide polymorphisms (SNPs). We tested four of these SNPs in three large, carefully selected samples: nonsmokers (n = 317) and regular smokers low levels of nicotine dependence (ND, n = 238), or smokers with high-ND (n = 317). None of the four polymorphisms we tested, nor their estimated haplotypes, were associated with smoking initiation or progression to nicotine dependence.

DNA↗
PubMed2000

Cancer screening in the elderly population.

This article reviews the current state of knowledge regarding cancer screening in the geriatric population. Care of the elderly requires knowledge of underlying physiologic changes, comorbidities, quality-of-life factors, and life expectancies. There is always the danger that ageism may prevent elderly cancer patients from receiving the proper treatment. On the other hand, overzealous treatment can lead to adverse results if elderly patients are not properly targeted based on current evidence of the benefits and risks of specific screening practices.

Age Factors↗
PubMed2000

The role of selective transport in neuronal protein sorting.

To assess whether selective microtubule-based vesicle transport underlies the polarized distribution of neuronal proteins, we expressed green fluorescent protein- (GFP-) tagged chimeras of representative axonal and dendritic membrane proteins in cultured hippocampal neurons and visualized the transport of carrier vesicles containing these proteins in living cells. Vesicles containing a dendritic protein, transferrin receptor (TfR), were preferentially transported into dendrites and excluded from axons. In contrast, vesicles containing the axonal protein NgCAM (neuron-glia cell adhesion molecule) were transported into both dendrites and axons. These data demonstrate that neurons utilize two distinct mechanisms for the targeting of polarized membrane proteins, one (for dendritic proteins) based on selective transport, the other (for axonal proteins) based on a selectivity "filter" that occurs downstream of transport.

Animals↗
PubMed2000

The frequency of blood pressure measurements in children in four EDs.

The study's objective was to assess the frequency of triage blood pressure measurements in pediatric patients and the recognition of an elevated blood pressure. The design was retrospective and included chart review. The setting consisted of four emergency departments associated with one medical school, including one level I academic center, two level II Community departments, and a regional children's hospital. A convenience sample of 437 patients, aged 1 month to 18 years, was selected. The frequency of triage blood pressure measurements was recorded. The number of patients whose blood pressure was higher than the 90th percentile for age and sex as established by the Second Task Force on Blood Pressure Control in Children was also recorded. The frequency of a second blood pressure measurement in patients with an elevated initial blood pressure was recorded. All frequency data were stratified by hospital and by age group. The results showed 294/437 (66%) of children had blood pressures measured at triage. Of these measurements, 153/294 (52%) reflected blood pressures greater than the 90th percentile for age and sex, but only 58/153 (38%) of patients with such blood pressures had a second blood pressure measured. Hospitals varied in their frequency of blood pressure measurement. Adolescents had their blood pressure measured more frequently, 981105 (93%) than two to 12-year-olds, 144/185 (78%) or 1-month to 2-year-olds, 52/147 (35%). Frequency of triage blood pressure measurements in children varied by institution and increased in frequency with age.

Adolescent↗
PubMed2000

Defining patterns of benzodiazepine use in older adults.

Benzodiazepines are disproportionately prescribed to older adults. Elderly adults with comorbid medical and psychiatric conditions, elderly adults taking multiple medications, and elderly women are the most likely adults to continuously use benzodiazepines. These are also the groups of elderly who are likely to experience adverse effects, including falls, accidents, and motor vehicle crashes. Despite recommendations for short-term treatment and the potential risks of long-term use, some patients continue to receive benefit for extended time periods, occasionally years. Future research needs to be directed at improved identification of which patients will benefit from intermittent versus continuous treatment while minimizing risk for adverse side effects. In order to advance the study of the risks and benefits of benzodiazepine use, we have proposed a set of definitions for classification of use. These definitions can be used to develop clinical guidelines based on empirically derived clinical research models.

Aged↗
PubMed1999

CPG16, a novel protein serine/threonine kinase downstream of cAMP-dependent protein kinase.

Gene expression is necessary for the formation and consolidation of long term memory in both invertebrates and vertebrates. Here, we describe the expression and characterization of candidate plasticity gene 16 (cpg16), a protein serine/threonine kinase that was previously isolated from rat hippocampus as a plasticity-related gene. CPG16, when expressed in and purified from bacteria and COS7 cells, was only capable of autophosphorylation and phosphorylation of myelin basic protein but failed to phosphorylate many other peptides and proteins in in vitro phosphorylation assays. Recombinant CPG16, when overexpressed and purified from COS7 cells, had a relatively low level of autophosphorylation activity. This activity was significantly stimulated when cAMP-elevating agents (forskolin, 8-bromo-cAMP) were added to the cells but not by any other extracellular stimuli tested, e.g. serum, phorbol esters, and a calcium ionophore. Although the stimulation of CPG16 activity was inhibited by the cAMP-dependent protein kinase inhibitor H-89, it did not serve as a direct substrate for this kinase. This suggests that CPG16 may be activated by a cAMP-stimulated protein kinase cascade. Immunolocalization studies in COS7 and NIH-3T3 cells showed mostly cytoplasmic localization of CPG16 that turned partially nuclear upon stimulation with 8-bromo-cAMP. Moreover, overexpression of CPG16 seems to partially inhibit cAMP-stimulated activity of the transcription factor CREB (cAMP response element-binding protein), suggesting its involvement in the down-regulation of cAMP-induced transcription. Thus, CPG16 is a protein serine/threonine kinase that may be involved in a novel signaling pathway downstream of cAMP-dependent protein kinase.

3T3 Cells↗
PubMed1999

Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study.

Cigarette smoking is associated with considerable morbidity, mortality, and public health costs. Genetic factors influence both smoking initiation and nicotine dependence, but none of the genes involved have been identified. A genome scan using 451 markers was conducted to identify chromosomal regions linked to nicotine dependence in a collection of 130 families containing 343 genotyped individuals (308 nicotine-dependent) from Christchurch, New Zealand. By pairwise analysis, the best result was with marker D2S1326 which gave a lod score under heterogeneity (H-LOD) of 2.63 (P=0.0012) and a nonparametric linkage (NPL, Zall) score of 2.65 (P=0.0011). To identify regions that warranted further study, rather than comparing the pairwise scores from the scan to theoretical thresholds, we compared them to an empirical baseline, found here to be H-LOD scores of 0.5 and Zall scores of 1.0. We also found a number of large (31-88 cM) regions where many (8-16) consecutive markers yielded small but positive Zall scores. Selected regions of chromosomes 2, 4, 10, 16, 17 and 18 were investigated further by additional genotyping of the Christchurch sample and an independent sample from Richmond, Virginia (91 families with 264 genotyped individuals, 211 nicotine-dependent). Multipoint nonparametric analysis showed the following maximums for the Christchurch sample: Chr. 2 (Zlr=2.61, P=0.005), Chr. 4 (Zlr=1.36, P=0.09), Chr. 10 (Zlr=2.43, P=0.008), Chr. 16 (Zlr=0.85, P=0.19), Chr. 17 (Zlr=1.64, P=0.05), Chr. 18 (Zlr=1.54, P=0.06). Analysis of the Richmond sample showed the following maximums: Chr. 2 (Zlr=1.00, P=0.15), Chr. 4 (Zlr=0.39, P=0.34), Chr. 10 (Zlr=1.21, P=0.11), Chr. 16 (Zlr=1.11, P=0.13), Chr. 17 (Zlr=1.60, P=0.05), Chr. 18 (Zlr=1.33, P=0.09). It is probable that the small samples used here provided only limited power to detect linkage. It may have been difficult therefore to detect genes of small effect, or those that are influencing risk in only a small proportion of the families. When simply judged against the usual standards of linkage significance, none of the individual regions yielded strong evidence in either sample. Some or all of the most positive results in the genome scan of the Christchurch sample, therefore, could be due to chance. However, the presence in the Christchurch scan of multiple large regions containing many consecutive positive markers, coupled with the relatively positive results in these same regions in the Richmond sample, suggests that some of these regions may contain genes influencing nicotine dependence and therefore deserve further study.

Adult↗
PubMed1999

University of Miami division of clinical pharmacology therapeutic rounds: issues in prescribing for geriatric patients and emerging practice guidelines.

The geriatric population accounts for over 12% of the United States population and consumes over 25% of all prescription medications. Polypharmacy and patient noncompliance are often encountered in caring for these patients. These issues along with a variety of age-related physiologic changes and the presence of multiple medical illnesses place the elderly at an increased risk for adverse drug reactions. Especially worrisome is the use of long-acting benzodiazepines and anticholinergic medications in this population. The problem of adverse drug reactions is a common clinical problem that is of great public concern as the number of older persons in the United States continues to grow. In response, a variety of proactive measures have been developed. These measures include the development of consensus criteria for inappropriate medications, federal government regulation, expansion of the role of clinical pharmacists, and computer-assisted prescribing protocols.

Aged↗
PubMed1999

Inappropriate medication prescribing in homebound older adults.

OBJECTIVES: Little is known about the prescribing of medications in the growing population of homebound older adults. We report on the prevalence and pattern of inappropriate medications in a nursing home-eligible, homebound population. DESIGN: A cross-sectional design. SETTING: A managed care plan for individuals meeting nursing home eligibility. PARTICIPANTS: 2193 homebound people older than age 60. MEASUREMENTS: We reviewed the pharmacy profiles of all older homebound enrollees. We identified the average number of medications per patient and the most commonly prescribed classes of drugs. The medication profiles were also analyzed in the context of the 26 drugs/groups listed as inappropriate by the explicit criteria of Beers [Arch Intern Med 1997; 157:1531-1536]. RESULTS: A total of 2193 people aged 60 to 106 (mean 82.8 +/- 8.8) were taking an average of 5.3 +/- 2.9 drugs (range 0-22). Cardiac drugs and benzodiazepines were the medications most commonly prescribed. We found 1152 of the total 11,689 prescriptions (9.9%) to be inappropriate. Eight hundred seventy-one (39.7%) of these 2193 residents had at least one inappropriate prescription, and 230 (10.4%) had two or more. Of particular concern were 285 people prescribed excessive doses of temazepam and zoldipem, 211 people taking first-generation antihistamines, 115 taking doxepin or amitriptyline, 106 taking an ergoloid, 98 taking dipyridamole, and 85 prescribed a long-acting benzodiazepine. CONCLUSIONS: Our study revealed a high prevalence of psychotropic medications and inappropriate drug use among older homebound residents, a group that is at the highest risk for adverse drug reactions. Because this group is not subject to oversight by regulatory agencies, further interventional studies and provider education will be important.

Aged↗
PubMed1999

Community formation and community roles among persons with Alzheimer's disease: a comparative study of experiences in a residential Alzheimer's facility and a traditional nursing home.

Based on an ethnographic study in a residential Alzheimer's facility and a traditional nursing home, this article discusses the process of community formation and the maintenance of community roles among individuals suffering from dementia in institutional settings. These include: therapeutic programming that promotes resident independence and choice; flexible and person-centered staff roles; and a physical environment that facilitates social interaction, autonomy, and participation in the activities of daily living. In contrast, institutional programs that are regimented, that follow a medical rather than a social model of care, and that take place in physical environments that have limited options may discourage resident interaction and social bonding, thus inhibiting community formation. Although Alzheimer's disease and other forms of dementia may create difficulties for the realization of community and community roles among institutionalized people, more significant are the environmental conditions in which such individuals live and the programs designed for their care.

Aged↗
PubMed1998

Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms.

Long-term plasticity of the central nervous system (CNS) involves induction of a set of genes whose identity is incompletely characterized. To identify candidate plasticity-related genes (CPGs), we conducted an exhaustive screen for genes that undergo induction or downregulation in the hippocampus dentate gyrus (DG) following animal treatment with the potent glutamate analog, kainate. The screen yielded 362 upregulated CPGs and 41 downregulated transcripts (dCPGs). Of these, 66 CPGs and 5 dCPGs are known genes that encode for a variety of signal transduction proteins, transcription factors, and structural proteins. Seven novel CPGs predict the following putative functions: cpg2--a dystrophin-like cytoskeletal protein; cpg4--a heat-shock protein: cpg16--a protein kinase; cpg20--a transcription factor; cpg21--a dual-specificity MAP-kinase phosphatase; and cpg30 and cpg38--two new seven-transmembrane domain receptors. Experiments performed in vitro and with cultured hippocampal cells confirmed the ability of the cpg-21 product to inactivate the MAP-kinase. To test relevance to neural plasticity, 66 CPGs were tested for induction by stimuli producing long-term potentiation (LTP). Approximately one-fourth of the genes examined were upregulated by LTP. These results indicate that an extensive genetic response is induced in mammalian brain after glutamate receptor activation, and imply that a significant proportion of this activity is coinduced by LTP. Based on the identified CPGs, it is conceivable that multiple cellular mechanisms underlie long-term plasticity of the nervous system.

Amino Acid Sequence↗
PubMed1998

Use of antipsychotic drugs in nursing homes: current compliance with OBRA regulations.

OBJECTIVE: To examine the degree and patterns of compliance with the Omnibus Budget Reconciliation Act (OBRA) regulations regarding the use of antipsychotic drugs in nursing homes. DESIGN: Retrospective chart review of all resident records. PARTICIPANTS: Eight nursing homes: five community, two county-owned, and one university-affiliated Veterans Administration facility. MEASUREMENTS: A structured assessment instrument to track compliance with each aspect of the OBRA regulations regarding antipsychotic drug use. RESULTS: A total of 1573 nursing home residents' pharmacy records were reviewed between August 1994 and March 1996. Two hundred seventy-nine residents were actively taking antipsychotic medications (prevalence = 17.7%). Mean compliance greater than 70% was found for (1) appropriate diagnostic indication (mean = 70.9%), (2) dosage within recommended limits (mean = 90.1%), and 3) documented appropriate target symptoms (mean = 90.4%). Dosages were more likely to exceed limits in those patients with histories of major mental illness, particularly schizophrenia. CONCLUSIONS: Nursing homes were better able to comply with those guidelines that are most specific. Educational interventions now need to focus on behavioral interventions, monitoring of adverse effects, and efficacy. These data are useful in establishing threshold levels of performance and can be used by nursing homes for continuous quality improvement. OBRA continues to impact neuroleptic drug prescribing practices in nursing homes significantly.

Aged↗