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Biomedical subjects

David M Smith

Publications and source records attributed to David M Smith.

47 records · Page 3Linked to original sources
PubMed2002

Effects of cognitive training interventions with older adults: a randomized controlled trial.

CONTEXT: Cognitive function in older adults is related to independent living and need for care. However, few studies have addressed whether improving cognitive functions might have short- or long-term effects on activities related to living independently. OBJECTIVE: To evaluate whether 3 cognitive training interventions improve mental abilities and daily functioning in older, independent-living adults. DESIGN: Randomized, controlled, single-blind trial with recruitment conducted from March 1998 to October 1999 and 2-year follow-up through December 2001. SETTING AND PARTICIPANTS: Volunteer sample of 2832 persons aged 65 to 94 years recruited from senior housing, community centers, and hospital/clinics in 6 metropolitan areas in the United States. INTERVENTIONS: Participants were randomly assigned to 1 of 4 groups: 10-session group training for memory (verbal episodic memory; n = 711), or reasoning (ability to solve problems that follow a serial pattern; n = 705), or speed of processing (visual search and identification; n = 712); or a no-contact control group (n = 704). For the 3 treatment groups, 4-session booster training was offered to a 60% random sample 11 months later. MAIN OUTCOME MEASURES: Cognitive function and cognitively demanding everyday functioning. RESULTS: Thirty participants were incorrectly randomized and were excluded from the analysis. Each intervention improved the targeted cognitive ability compared with baseline, durable to 2 years (P<.001 for all). Eighty-seven percent of speed-, 74% of reasoning-, and 26% of memory-trained participants demonstrated reliable cognitive improvement immediately after the intervention period. Booster training enhanced training gains in speed (P<.001) and reasoning (P<.001) interventions (speed booster, 92%; no booster, 68%; reasoning booster, 72%; no booster, 49%), which were maintained at 2-year follow-up (P<.001 for both). No training effects on everyday functioning were detected at 2 years. CONCLUSIONS: Results support the effectiveness and durability of the cognitive training interventions in improving targeted cognitive abilities. Training effects were of a magnitude equivalent to the amount of decline expected in elderly persons without dementia over 7- to 14-year intervals. Because of minimal functional decline across all groups, longer follow-up is likely required to observe training effects on everyday function.

Activities of Daily Living↗
PubMed2002

Limbic thalamic lesions, appetitively motivated discrimination learning, and training-induced neuronal activity in rabbits.

A substantial literature implicates the anterior and mediodorsal (limbic) thalamic nuclei and the reciprocally interconnected areas of cingulate cortex in learning, memory, and attentional processes. Previous studies have shown that limbic thalamic lesions severely impair discriminative avoidance learning and that they block development of training-induced neuronal activity in the cingulate cortex. The present study investigated the possibility that the limbic thalamus and cingulate cortex are involved in reward-based discriminative approach learning, wherein head-extension responses yielding oral contact with a drinking spout that was inserted into the conditioning chamber after a positive conditional stimulus (CS+) were reinforced with a water reward but responses to the spout after a negative conditional stimulus (CS-) were not reinforced. In this task, the rabbits learned primarily to omit their prepotent responses to the spout on CS- trials. Acquisition was severely impaired in rabbits given limbic thalamic lesions before training. As during avoidance learning, posterior cingulate cortical neurons of control rabbits developed learning-related neuronal responses to task-relevant stimuli, but this activity was severely attenuated in rabbits with lesions. These results support a general involvement of the cingulothalamic circuitry in instrumental approach and avoidance learning. The fact that learning consisted of response omission indicated that the cingulothalamic role is not limited to acquisition or production of active behavioral responses, such as locomotion. It is proposed that cingulothalamic neurons mediate associative attention, wherein enhanced neuronal responses to stimuli associated with reinforcement facilitate the selection and production of task-relevant responses.

Acoustic Stimulation↗
PubMed2002

A controlled trial of inpatient and outpatient geriatric evaluation and management.

BACKGROUND: Over the past 20 years, both inpatient units and outpatient clinics have developed programs for geriatric evaluation and management. However, the effects of these interventions on survival and functional status remain uncertain. METHODS: We conducted a randomized trial involving frail patients 65 years of age or older who were hospitalized at 11 Veterans Affairs medical centers. After their condition had been stabilized, patients were randomly assigned, according to a two-by-two factorial design, to receive either care in an inpatient geriatric unit or usual inpatient care, followed by either care at an outpatient geriatric clinic or usual outpatient care. The interventions involved teams that provided geriatric assessment and management according to Veterans Affairs standards and published guidelines. The primary outcomes were survival and health-related quality of life, measured with the use of the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36), one year after randomization. Secondary outcomes were the ability to perform activities of daily living, physical performance, utilization of health services, and costs. RESULTS: A total of 1388 patients were enrolled and followed. Neither the inpatient nor the outpatient intervention had a significant effect on mortality (21 percent at one year overall), nor were there any synergistic effects between the two interventions. At discharge, patients assigned to the inpatient geriatric units had significantly greater improvements in the scores for four of the eight SF-36 subscales, activities of daily living, and physical performance than did those assigned to usual inpatient care. At one year, patients assigned to the outpatient geriatric clinics had better scores on the SF-36 mental health subscale, even after adjustment for the score at discharge, than those assigned to usual outpatient care. Total costs at one year were similar for the intervention and usual-care groups. CONCLUSIONS: In this controlled trial, care provided in inpatient geriatric units and outpatient geriatric clinics had no significant effects on survival. There were significant reductions in functional decline with inpatient geriatric evaluation and management and improvements in mental health with outpatient geriatric evaluation and management, with no increase in costs.

Activities of Daily Living↗
PubMed2002

Sustained orexigenic effect of Agouti related protein may be not mediated by the melanocortin 4 receptor.

Intracerebroventricular (ICV) injection of Agouti related protein (AgRP), an endogenous melanocortin 3 and 4 receptor (MC3/4-R) antagonist, produces a prolonged increase in food intake. To clarify the roles of the MC3-R and MC4-R in AgRP-induced hyperphagia, the feeding effect of AgRP (83-132) was compared with that of the selective MC4-R antagonist, JKC-363 (cyclic [Mpr11, D-Nal14, Cys18, Asp22-NH2]-beta-MSH11-22). Single ICV administration of AgRP (83-132) increased food intake for 48 h whilst ICV JKC-363 increased food intake for 8h. An increase in body weight at 24 and 48 h was observed following AgRP (83-132) but not JKC-363 treatment. These data suggest that the sustained orexigenic action of AgRP (83-132) may not be through MC4-R antagonism.

Agouti-Related Protein↗
PubMed2002

Comparison of the expression of calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) with CGRP and adrenomedullin binding in cell lines.

1. The calcitonin receptor-like receptor (CRLR) and specific receptor activity modifying proteins (RAMPs) together form receptors for calcitonin gene-related peptide (CGRP) and/or adrenomedullin in transfected cells. 2. There is less evidence that innate CGRP and adrenomedullin receptors are formed by CRLR/RAMP combinations. We therefore examined whether CGRP and/or adrenomedullin binding correlated with CRLR and RAMP mRNA expression in human and rat cell lines known to express these receptors. Specific human or rat CRLR antibodies were used to examine the presence of CRLR in these cells. 3. We confirmed CGRP subtype 1 receptor (CGRP(1)) pharmacology in SK-N-MC neuroblastoma cells. L6 myoblast cells expressed both CGRP(1) and adrenomedullin receptors whereas Rat-2 fibroblasts expressed only adrenomedullin receptors. In contrast we could not confirm CGRP(2) receptor pharmacology for Col-29 colonic epithelial cells, which, instead were CGRP(1)-like in this study. 4. L6, SK-N-MC and Col-29 cells expressed mRNA for RAMP1 and RAMP2 but Rat-2 fibroblasts had only RAMP2. No cell line had detectable RAMP3 mRNA. 5. SK-N-MC, Col-29 and Rat-2 fibroblast cells expressed CRLR mRNA. By contrast, CRLR mRNA was undetectable by Northern analysis in one source of L6 cells. Conversely, a different source of L6 cells had mRNA for CRLR. All of the cell lines expressed CRLR protein. Thus, circumstances where CRLR mRNA is apparently absent by Northern analysis do not exclude the presence of this receptor. 6. These data strongly support CRLR, together with appropriate RAMPs as binding sites for CGRP and adrenomedullin in cultured cells.

Adrenomedullin↗
PubMed2002

A novel beta-lactam antibiotic activates tumor cell apoptotic program by inducing DNA damage.

Many of the anticancer drugs in current use are toxic and thus limited in their efficacy. It therefore becomes essential to develop novel chemotherapeutic agents with lower levels of toxicity. The beta-lactam antibiotics have been used for many years to treat bacterial infections with limited or no toxicity. Until now, it has never been shown that beta-lactams could kill tumor cells. Here, for the first time, we have discovered and characterized the apoptosis-inducing properties of a family of novel beta-lactam antibiotics against human leukemia, breast, prostate, and head-and-neck cancer cells. We found that one particular lead compound (lactam 1) with an N-methylthio group was able to induce DNA damage and inhibit DNA replication in Jurkat T cells within a 2-h treatment. This was followed by p38 mitogen-activated protein kinase activation, S phase arrest, and apoptotic cell death. p38 was found to be a central player in beta-lactam-induced apoptosis and resided downstream of DNA damage but upstream of caspase activation. Accompanying caspase-8 activation was cleavage of the pro-apoptotic Bcl-2 family protein Bid, and release of the mitochondrial cytochrome c. This was also associated with activation of caspase-9 and -3. Analogs of lactam 1 in which the N-methylthio group was replaced with other organothio chains exhibited progressive decreased potencies to induce DNA damage, p38 kinase activation, S phase arrest, and apoptosis, demonstrating requirement of the N-methylthio group. Because of the ease of synthesis and structural manipulation, we believe these beta-lactams may have the potential to be developed into anticancer agents.

Anti-Bacterial Agents↗
PubMed2002

Inhibition of bcl-x(l) phosphorylation by tea polyphenols or epigallocatechin-3-gallate is associated with prostate cancer cell apoptosis.

Prostate cancer cells demonstrate slow growth kinetics and chemoresistance. Tea polyphenols have been shown to exert prostate cancer-preventative effects. Here we report that growth-arrested prostate cancer cells expressed high levels of a hyperphosphorylated Bcl-X(L) in mitochondria. Treatment with tea polyphenols or the major tea component epigallocatechin-3-gallate blocked expression of the hyper-, but not hypophosphorylated Bcl-X(L) in mitochondria, accompanied by cytochrome c release, caspase activation, and apoptosis. Studies using specific inhibitors suggest that tea inhibits p38 mitogen-activated protein kinase and the proteasome activities, leading to inhibition of Bcl-X(L) phosphorylation and induction of prostate cancer cell death.

Apoptosis↗
PubMed2002

International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors.

The calcitonin family of peptides comprises calcitonin, amylin, two calcitonin gene-related peptides (CGRPs), and adrenomedullin. The first calcitonin receptor was cloned in 1991. Its pharmacology is complicated by the existence of several splice variants. The receptors for the other members the family are made up of subunits. The calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor. RAMP2 and -3 enable the same CL receptor to behave as an adrenomedullin receptor. Although the calcitonin receptor does not require RAMP to bind and respond to calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP. This review aims to reconcile what is observed when the receptors are reconstituted in vitro with the properties they show in native cells and tissues. Experimental conditions must be rigorously controlled because different degrees of protein expression may markedly modify pharmacology in such a complex situation. Recommendations, which follow International Union of Pharmacology guidelines, are made for the nomenclature of these multimeric receptors.

Animals↗
PubMed2002

Synthetic analogs of green tea polyphenols as proteasome inhibitors.

BACKGROUND: Animal, epidemiological and clinical studies have demonstrated the anti-tumor activity of pharmacological proteasome inhibitors and the cancer-preventive effects of green tea consumption. Previously, one of our laboratories reported that natural ester bond-containing green tea polyphenols (GTPs), such as (-)-epigallocatechin-3-gallate [(-)-EGCG] and (-)-gallocatechin-3-gallate [(-)-GCG], are potent and specific proteasome inhibitors. Another of our groups, for the first time, was able to enantioselectively synthesize (-)-EGCG as well as other analogs of this natural GTP. Our interest in designing and developing novel synthetic GTPs as proteasome inhibitors and potential cancer-preventive agents prompted our current study. MATERIALS AND METHODS: GTP analogs, (+)-EGCG, (+)-GCG, and a fully benzyl-protected (+)-EGCG [Bn-(+)-EGCG], were prepared by enantioselective synthesis. Inhibition of the proteasome or calpain (as a control) activities under cell-free conditions were measured by fluorogenic substrate assay. Inhibition of intact tumor cell proteasome activity was measured by accumulation of some proteasome target proteins (p27, I kappa B-alpha and Bax) using Western blot analysis. Inhibition of tumor cell proliferation and induction of apoptosis by synthetic GTPs were determined by G(1) arrest and caspase activation, respectively. Finally, inhibition of the transforming activity of human prostate cancer cells by synthetic GTPs was measured by a colony formation assay. RESULTS: (+)-EGCG and (+)-GCG potently and specifically inhibit the chymotrypsin-like activity of purified 20S proteasome and the 26S proteasome in tumor cell lysates, while Bn-(+)-EGCG does not. Treatment of leukemic Jurkat T or prostate cancer LNCaP cells with either (+)-EGCG or (+)-GCG accumulated p27 and IkappaB-alpha proteins, associated with an increased G(1) population. (+)-EGCG treatment also accumulated the pro-apoptotic Bax protein and induced apoptosis in LNCaP cells expressing high basal levels of Bax, but not prostate cancer DU-145 cells with low Bax expression. Finally, synthetic GTPs significantly inhibited colony formation by LNCaP cancer cells. CONCLUSIONS: Enantiomeric analogs of natural GTPs, (+)-EGCG and (+)-GCG, are able to potently and specifically inhibit the proteasome both, in vitro and in vivo, while protection of the hydroxyl groups on (+)-EGCG renders the compound completely inactive.

Adenocarcinoma↗
PubMedDate not supplied

Potential molecular targets of tea polyphenols in human tumor cells: significance in cancer prevention.

Next to water, tea is the most popular beverage in the world, and the cancer-preventive effects of this beverage have been suggested. Epidemiological studies have shown decreased cancer occurrence in those individuals who drink green tea regularly. A wealth of research suggests numerous mechanisms of action to explain these observations. The most abundant and popular compound studied in tea research is (-)-epigallocatechin-3-gallate (EGCG), which acts as a powerful antioxidant and can inhibit a number of tumor cell proliferation- and survival-related proteins. Tea polyphenols are known to inhibit the large multi-catalytic protease (the proteasome) and metaloproteionases, involved in tumor survival and metastasis, respectively. Additionally, tea polyphenols inhibit the activities of many tumor-associated protein kinases, including epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, mitogen-activated protein kinase, and IkB kinase. Tea polyphenols have also been found to inhibit some cancer-related proteins that regulate DNA replication and transformation. At present, it is not known which of these activities of tea polyphenols are required for its cancer-preventive effects. However, by understanding the in vivo concentrations of tea polyphenols required to inhibit each of these activities, we may start to sort out in the future the mechanisms responsible for the cancer-preventive effects of tea.

Animals↗