Search PubMed⌕ Search

Biomedical subjects

D M Smith

Publications and source records attributed to D M Smith.

At least 181 records · Page 10Linked to original sources
PubMed1996

An intervention on discharge polypharmacy.

OBJECTIVE: To determine if providing a way to cancel pre-admission prescriptions would reduce the number of active drug prescriptions (RXs) at discharge. DESIGN: A randomized non-blinded clinical trial. SETTING: Inpatient acute medical service of a university affiliated Veterans Administration medical center. PARTICIPANTS: Twelve medicine ward teams were randomized to control and intervention groups. Patients controlled had been discharged from these teams during 12 weeks and were receiving outpatient medications from this facility at hospital admission; control = 180, intervention = 168. INTERVENTION: At discharge, intervention teams used a computer-generated drug list to cancel or renew previous outpatient RXs or to prescribe new medications. Control teams could not cancel outpatient drugs and wrote all medications on individual prescriptions. MEASUREMENTS: The difference between admission and discharge RXs. RESULTS: There were no significant differences in patients' age, sex, race, Charlson Index (CI), or LOS between patient groups at discharge. The intervention group had fewer RXs on admission (5.4 vs 6.2, P < .05) and at discharge was not significantly different (2.9 vs 2.9, P = .87) from the control group. CONCLUSIONS: Providing a method for canceling pre-admission medications did not reduce the number of RXs at discharge. Further research is needed to evaluate the appropriateness of the large increase in RXs from admission to discharge for patients in acute hospital settings.

Analysis of Variance↗
PubMed1996

NYVAC-Pf7: a poxvirus-vectored, multiantigen, multistage vaccine candidate for Plasmodium falciparum malaria.

The highly attenuated NYVAC vaccinia virus strain has been utilized to develop a multiantigen, multistage vaccine candidate for malaria, a disease that remains a serious global health problem and for which no highly effective vaccine exists. Genes encoding seven Plasmodium falciparum antigens derived from the sporozoite (circumsporozoite protein and sporozoite surface protein 2), liver (liver stage antigen 1), blood (merozoite surface protein 1, serine repeat antigen, and apical membrane antigen 1), and sexual (25-kDa sexual-stage antigen) stages of the parasite life cycle were inserted into a single NYVAC genome to generate NYVAC-Pf7. Each of the seven antigens was expressed in NYVAC-Pf7-infected culture cells, and the genotypic and phenotypic stability of the recombinant virus was demonstrated. When inoculated into rhesus monkeys, NYVAC-Pf7 was safe and well tolerated. Antibodies that recognize sporozoites, liver, blood, and sexual stages of P. falciparum were elicited. Specific antibody responses against four of the P.falciparum antigens (circumsporozoite protein, sporozoite surface protein 2, merozoite surface protein 1, and 25-kDa sexual-stage antigen) were characterized. The results demonstrate that NYVAC-Pf7 is an appropriate candidate vaccine for further evaluation in human clinical trials.

Amino Acid Sequence↗
PubMed1996

Adrenomedullin activity in chronically hypoxic rat lungs.

Adrenomedullin (AM) is a novel vasodilator with structural similarities to calcitonin gene-related peptide (CGRP). This study investigated AM activity in the rat lung during hypoxia-induced pulmonary hypertension. Both rat AM (0.2-10 nmol) and alpha-CGRP (0.2-2 nmol) produced dose-related reductions in pulmonary artery pressure in the isolated perfused lung ventilated with 2% O2. Pretreatment with alpha-CGRP, which demonstrated tachyphylaxis, or its antagonist, CGRP-(8-37), reduced the hypotensive response to AM, suggesting that part of the response to AM is mediated by CGRP receptors. 125I-labeled AM and 125I-labeled CGRP binding was significantly increased in lung membranes from 7-day hypoxic animals (AM from 1.94 +/- 0.3 to 3.36 +/- 0.4 and CGRP from 0.06 +/- 0.01 to 0.12 +/- 0.02 pmol/mg protein), with no change in dissociation constant. Moreover, the hypotensive response to both peptides was increased in the lungs of 7-day hypoxic rats. There was no significant change in lung immunoreactive AM concentrations (hypoxic 5.04 +/- 0.48 vs. control 6.28 +/- 0.76 pmol/g wet wt of tissue) or steady-state AM mRNA levels in 7-day hypoxic rats. Nonetheless, AM may be useful for the acute pharmacological manipulation of pulmonary artery pressure in hypoxia-induced pulmonary hypertension.

Adrenomedullin↗
PubMed1996

Glucagon-like peptide-1 (GLP-1) releases thyrotropin (TSH): characterization of binding sites for GLP-1 on alpha-TSH cells.

We have demonstrated specific binding sites for [125I]glucagon-like peptide 1 (GLP-1) on membranes from the rodent thyrotrope cell line, alpha-TSH. Specific [125I]GLP-1 binding was saturable and time dependent. Equilibrium saturation binding analysis was consistent with the presence of a single class of binding site (binding capacity, 85 +/- 7 fmol/mg protein) with a dissociation constant (Kd) of 28 +/- 13 pM. The specific GLP-1 receptor agonists, exendin-4 and exendin-3, and the antagonist, exendin-(9-39), bound to the receptor sites with high affinity (Ki = 190 +/- 70 pM; 130 +/- 50 and 1200 +/- 470 pM, respectively). Chemical cross-linking of [125I]GLP-1-receptor complexes revealed a single band of 64,300 +/- 100 Mr in alpha-TSH membranes. In addition, specific PCR studies demonstrated the presence of GLP-1 receptor messenger RNA. Binding of the peptide to alpha-TSH cell membranes resulted in increased intracellular cAMP concentrations (10 nM GLP-1, 1010 +/- 83 pmol/10(6) cells.h; control, 175 +/- 60 pmol/10(6) cells.h; P < 0.002), indicating that the receptor is linked to stimulation of adenylyl cyclase. GLP-1-mediated increases in cAMP were inhibited by exendin-(9-39) in a dose-dependent manner. Furthermore, GLP-1 stimulates basal TSH release from dispersed anterior pituitary cells in a concentration-dependent manner (100 nM GLP-1, 63 +/- 3 fmol/10(6) cells.h; control, 35 +/- 1 fmol/10(6) cells.h; P < 0.0005), but had no effect on basal PRL, GH, or LH release.

Animals↗
PubMed1996

Adrenomedullin inhibits feeding in the rat by a mechanism involving calcitonin gene-related peptide receptors.

The central effect of adrenomedullin on feeding was investigated in fasted rats. After intracerebroventricular administration, adrenomedullin decreased 2-h food intake in a dose-dependent manner. A dose of 1.7 nmol adrenomedullin decreased 2-h food intake by 57%. Adrenomedullin shares sequence homology with calcitonin gene-related peptide (CGRP), a central anorectic agent, and binding sites for both are present in the hypothalamus. Adrenomedullin competed for [125I]adrenomedullin- and [125I]CGRP-binding sites in hypothalamic membranes. The Kd for the [125I]adrenomedullin-binding site was 0.54 +/- 0.07 nM, with a binding capacity of 214 +/- 27 fmol/mg membrane protein (n = 3). CGRP and the CGRP receptor antagonist CGRP-(8-37) at concentrations up to 1 microM did not compete at these sites. The Kd for the CGRP-binding site was 0.10 +/- 0.02 nM, with a binding capacity of 250 +/- 31 fmol/mg, and the Ki values for adrenomedullin and CGRP-(8-37) were 4.6 +/- 2.1 and 4.0 +/- 1.6 nM, respectively (n = 3). Thus, adrenomedullin showed high affinity binding at both adrenomedullin- and CGRP-binding sites. To establish whether adrenomedullin reduces feeding via CGRP receptors, we coadministered adrenomedullin (1.7 nmol) and CGRP-(8-37) (30 nmol). The reduction in 2-h food intake induced by adrenomedullin was 50% inhibited by CGRP-(8-37). These results show that adrenomedullin decreases food intake in the rat, and this effect is mediated at least in part via CGRP receptors.

Adrenomedullin↗
PubMed1996

Investigation of the effects of antisense oligodeoxynucleotides to islet amyloid polypeptide mRNA on insulin release, content and expression.

We have investigated the effects of antisense oligodeoxynucleotides (oligos) to islet amyloid polypeptide (IAPP) mRNA on the expression and secretion of IAPP and insulin, in the clonal beta-cell line HIT-T15. Phosphorothioate-modified oligos were cytotoxic compared with phosphodiester (D)-oligos. Of the nine oligos tested using a lipofection reagent, O3, a 30-mer D-oligo complementary to a sequence downstream of the IAPP initiation codon, showed a significant dose-dependent suppression of IAPP mRNA, with a 42% decrease at 7.5 microM, compared with a scrambled (MSO3) control oligo (n = 3, P < 0.01). A subsequent 89% suppression of IAPP release was observed in the 4-h period following antisense treatment (1.78 +/- 0.13 (MSO3) vs 0.19 +/- 0.14 (O3) pmol/10(6) cells per 240 min, n = 7, P < 0.01). A significant increase in insulin mRNA (100 +/- 10% (MSO3) vs 124 +/- 8% (O3), n = 3, P < 0.05) and insulin content (13.0 +/- 0.9 (MSO3) vs 17.4 +/- 1.4 (O3) pmol/10(6) cells, n = 7, P = 0.028) was observed following treatment with O3 at 7.5 microM. O8, a 20-mer D-oligo directed to a region of IAPP mRNA further downstream than O3, also showed a decrease in IAPP mRNA and peptide release and an increase in insulin content. No significant changes were observed in the expression and release of the unrelated beta-cell peptide, neuropeptide Y. We thus show a suppression of synthesis and release of IAPP in HIT-T15 cells using antisense oligos. The associated increase in insulin mRNA and content in these cells after treatment with IAPP antisense oligos is in accord with an inhibitor action of IAPP on insulin availability.

Amyloid↗
PubMed1996

Metaplastic breast carcinoma.

Metaplastic breast carcinoma, a rare entity, accounts for only about 0.02% of all breast carcinomas. It involves the transformation of mammary neoplasms into osteoid and chondroid substances. Because of the relatively small patient population and the limited number of controlled studies, there is confusion regarding its classification and staging. Its histogenesis is unknown. The authors describe a 65-year-old woman with findings consistent with metaplastic breast carcinoma. Theories as to etiology and prognosis as well as treatment are discussed.

Aged↗
PubMed1995

Pressure ulcers in the nursing home.

OBJECTIVE: To review the literature on the causes, epidemiology, prevention, and treatment of pressure ulcers in nursing homes and to summarize this information for clinicians caring for nursing home residents. DATA SOURCES: A MEDLINE search of English-language articles published between 1980 and October 1994 using the terms decubitus ulcer and elderly. References from identified articles were also examined. STUDY SELECTION: Articles were excluded if the title indicated that patients were not nursing home residents (unless data from nursing homes were limited or unavailable), that patients were not elderly, or that the ulcers were related to peripheral vascular disease or neuropathy. DATA EXTRACTION: Selected studies either contained original data or were meta-analyses. Prevalence studies were required to have an identifiable denominator; risk factor and incidence studies were required to have an identifiable cohort and a specified duration of follow-up. Preference was given to risk factors identified through multivariate analyses. Studies of preventive and therapeutic interventions were required to have an identifiable control group; preference was given to randomized controlled trials. DATA SYNTHESIS: Seventeen percent to 35% of patients have pressure ulcers at the time of admission to a nursing home, and the prevalence of pressure ulcers among nursing home residents ranges from 7% to 23%. Among high-risk patients, the incidence of pressure ulcers is estimated to be 14/1000 patient-days. Residents at higher risk for developing ulcers are those who have limited ability to reposition themselves, cannot sense the need to reposition, have fecal incontinence, or cannot feed themselves. Occlusive dressings are as effective and less costly than traditional wet-to-dry saline dressings for treating earlier stages of pressure ulcers. There is no consensus on the use of specialized beds in the nursing home for promoting the healing of advanced-stage ulcers or for reducing the incidence of ulcers in high-risk patients. Specific interventions should not detract from careful, total assessment and management of the patient. CONCLUSIONS: Pressure ulcers in the nursing home are common problems associated with significant morbidity and mortality. Because resident characteristics can identify residents likely to develop ulcers, preventive measures can be implemented early. Therapy for advanced stages of pressure ulcers is expensive and prolonged. Involvement of the physician with the multidisciplinary nursing home team is essential for prevention and therapy.

Aged↗
PubMed1995

Prognostic factors for local and distant recurrence in stage I and II cervical carcinoma.

PURPOSE: The effects of tumor size, parametrial involvement, and other variables on treatment outcome for patients with Federation Internationale de Gynecologie et d'Obstetrique (FIGO) Stage I or II cervical carcinoma, as well as treatment complications, were analyzed retrospectively. METHODS AND MATERIALS: Records of 125 patients with FIGO Stage I or II carcinoma of the uterine cervix selected for curative radiotherapy between January 1980 and December 1990 were reviewed. Twelve patients (9.9%) underwent adjuvant extrafascial hysterectomy and 8 patients (6.4%) received chemotherapy. Median age was 55 years. Median follow-up time was 40 months, and minimum follow-up time was 24 months. The data were analyzed for site of first relapse, survival, overall incidence of complications, and incidence of grade 4 complications. RESULTS: The overall 5-year survival was: Stage IA: 100%, Stage IB: 72%, Stage IIA: 90%, and Stage IIB: 72%. The 5-year survival with no evidence of disease (NED) was: Stage IA: 100%, Stage IB: 67%, Stage IIA: 90%, and Stage IIB: 50%. Patients with bulky (> 5 cm) tumors had a shorter overall and NED survival than patients with nonbulky tumors (53% vs. 83%; p = 0.0008 and 44% vs. 78%; p = 0.0001, respectively). Thirty-nine tumor recurrences (39 out of 125 = 31%) occurred and were scored as local (23 out of 125 = 18.3%), if initial failure had a local component, or distant (16 out of 125 = 12.7%), if initial failure was distant only. Patients with bulky (more than 5 cm) tumors (32 out of 125) were more likely to experience a recurrence (18 out of 32 = 56%) than patients with nonbulky tumors (21 out of 93 = 22%; p = 0.0004). The initial site of recurrence was more likely to be local for bulky tumors (14 out of 18 = 78%) than for nonbulky tumors (9 out of 21 = 43%; p = 0.03). The probability of a recurrence increased with the number of involved parametria (none: 20 out of 78 = 25%; one: 12 out of 34 = 35%; two: 7 out of 13 = 54%; p = 0.04 for linear trend), as did the probability that the initial failure was distant rather than local (none: 4 out of 20 = 20%; one: 7 out of 12 = 58%; two: 5 out of 7 = 71%; p = 0.01 for linear trend). Positive lymph nodes, vessel invasion, and low hemoglobin level all correlated with an increased risk of a recurrence (RR 2.41, p = 0.004; RR 2.20, p = 0.01; OR 2.02, p = 0.01, respectively). There were 46 complications among 37 (29%) patients. The incidence of grade 4 complications was 8.8% (11 out of 125). History of pelvic surgery and bulky tumor were significant predictors of a grade 4 complication (p < 0.0001 and 0.021, respectively). Also, a dose rate to point A of > 0.6 Gy/h increased the chance of a grade 4 complication (p = 0.007). CONCLUSION: For patients with FIGO Stage I or II cervical carcinoma, tumor size was more predictive of local recurrence than was overall stage, and the extent of parametrial involvement was strongly predictive of distant recurrence, as was the stage. These findings suggest that tumor size and extent of parametrial involvement should be incorporated into the staging system. Patients with bulky tumors had a shorter survival and were more likely to experience a grade 4 toxicity of therapy. Dose rate to point A of > 0.6 Gy/h was associated with the increased risk of grade 4 complications.

Adenocarcinoma↗
PubMed1995

Rapid mass spectrometric peptide sequencing and mass matching for characterization of human melanoma proteins isolated by two-dimensional PAGE.

We report a general mass spectrometric approach for the rapid identification and characterization of proteins isolated by preparative two-dimensional polyacrylamide gel electrophoresis. This method possesses the inherent power to detect and structurally characterize covalent modifications. Absolute sensitivities of matrix-assisted laser desorption ionization and high-energy collision-induced dissociation tandem mass spectrometry are exploited to determine the mass and sequence of subpicomole sample quantities of tryptic peptides. These data permit mass matching and sequence homology searching of computerized peptide mass and protein sequence data bases for known proteins and design of oligonucleotide probes for cloning unknown proteins. We have identified 11 proteins in lysates of human A375 melanoma cells, including: alpha-enolase, cytokeratin, stathmin, protein disulfide isomerase, tropomyosin, Cu/Zn superoxide dismutase, nucleoside diphosphate kinase A, galaptin, and triosephosphate isomerase. We have characterized several posttranslational modifications and chemical modifications that may result from electrophoresis or subsequent sample processing steps. Detection of comigrating and covalently modified proteins illustrates the necessity of peptide sequencing and the advantages of tandem mass spectrometry to reliably and unambiguously establish the identity of each protein. This technology paves the way for studies of cell-type dependent gene expression and studies of large suites of cellular proteins with unprecedented speed and rigor to provide information complementary to the ongoing Human Genome Project.

Amino Acid Sequence↗
PubMed1995

Microheterogeneity of erythropoietin carbohydrate structure.

The microheterogeneity of the carbohydrate structures on recombinant human erythropoietin (rHuEPO) expressed in Chinese hamster ovary cells has been evaluated by electrospray ionization (ESI) mass spectrometry (MS) of glycopeptide fragments. The microheterogeneity is largely associated with the presence or absence of terminal N-acetylneuraminic acid (Neu5Ac) residues, varying amounts of O-acetylation of the Neu5Ac residues, and the presence or absence of N-acetyllactosamine extensions. The N-linked carbohydrate structures were structurally diverse; 52 different N-linked oligosaccharide structures were identified. Consistent structural assignments could be made from data obtained using different proteolytic digests, ESI solvent systems (aqueous/methanol systems with acetic or formic acid), and on-line or off-line LC/MS analysis. All glycosylation sites exhibited some level of O-acetylation of Neu5Ac residues. Interestingly, glycosylation site asparagine-83 exhibits mono-O-acetyl and di-O-acetyl Neu5Ac residues, while the other sites, asparagine-24, asparagine-38, and serine-126, exhibit mainly mono-O-acetyl Neu5Ac derivatization. This difference in O-acetylation may be site specific or due to sample handling of labile structures. However, mild base treatment of rHuEPO with NaOH on ice removed the O-acetyl groups associated with a given carbohydrate structure, without adversely affecting the underlying oligosaccharide structure, resulting in a simplified mass spectra. Nuclear magnetic resonance spectroscopy of Neu5Ac residues released by neuraminidase treatment of total rHuEPO indicated that Neu5,9Ac2 residues were present. Additional resonances were also observed that were consistent with other Neu5Ac O-acetyl linkages; these O-acetyl resonances could be removed by mild base hydrolysis of rHuEPO.

Amino Acid Sequence↗
PubMed1995

Primary care physician productivity: the physician factor.

OBJECTIVES: To model physician productivity as a function of clinic (support system) characteristics and physician characteristics and to model the time a physician spends with the patient as a function of patient characteristics. DESIGN: Observational study. SETTING: A general medicine clinic of a university-affiliated Veterans Affairs medical center. PATIENTS: A cohort of 2,520 patients having 2,721 consecutive outpatient visits to 56 physicians. MAIN OUTCOME MEASURES: Physician productivity defined as patients seen/physician/hour and time (minutes) spent with the patient. RESULTS: Physicians saw a mean (+/- SD) of 1.62 +/- 0.68 patients/hour. Clinic characteristics explained 8.2% of the variability of session-specific physician productivity. Controlling for clinic characteristics, a factor representing the physician explained an additional 55.4%. A model for overall physician productivity, using physician characteristics, explained 84.9% of the variance, and time spent with the patient was an important predictor. Modeling physician time with patients, patient characteristics accounted for only 7% of the variability. Controlling for patient characteristics, the individual physician again provided the greatest explanatory power, an additional 22.8% of the variability. CONCLUSIONS: Physicians' practice patterns, rather than clinic or patient characteristics, may account for most of the variation in physician productivity. Given the magnitude of the influence of individual practice patterns, interventions to increase productivity need to consider methods to affect physician behavior.

Appointments and Schedules↗
PubMed1995

Myoblast transplantation in the porcine model: a potential technique for myocardial repair.

The use of transgenic cells transplanted in syngeneic rodents has shown modest success, but allogeneic and xenogeneic transplants have not been uniformly successful. To assess the feasibility of xenogeneic and allogeneic myoblast transplantation, we subjected seven adult swine to transplantation of murine atrial tumor cells (xenogeneic), neonatal porcine myocytes (allogeneic), and human fetal cardiomyocytes into the left ventricular wall. After general anesthesia, isolated cells were injected along the anterior and posterior walls of the porcine left ventricle. All the animals were immuno-suppressed and observed for 1 month after injection, at which time they were killed and analyzed. This report will present results primarily concerned with the success of human cell transfers. In all injected sites examined, the transplanted cells thrived within the host myocardium with no significant rejection. Transplant cells formed close associations with host myocytes that resembled nascent intercalated disks on electron microscopy. These cells also contained myofibrils and other cell architecture resembling the transplanted cell lines. Additionally, these cells appeared to produce an angiogenic influence resulting in the proliferation of the surrounding microvasculature. We believe that these findings indicate successful xenogeneic and allogeneic myoblast cell transplantation in a large animal model. These experiments set the stage for future studies to assess the ability of these cells to form a syncytium, contract, and potentially repair failed myocardium.

Animals↗
PubMed1995

Aminothiadiazole in the treatment of advanced leiomyosarcoma of the uterine corpus. A Gynecologic Oncology Group study.

Aminothiadiazole was used to treat 21 patients with metastatic or recurrent leiomyosarcoma of the uterus. All patients received a starting dose of aminothiadiazole of 125 mg/m2 intravenously (30-to-45-minute infusion), which was repeated at weekly intervals. All patients also took allopurinol 300 mg per day orally to prevent hyperuricemia, a side effect of aminothiadiazole. Five patients (25%) had stable disease but there were no objective responses. Toxicity was generally mild with this regimen. There was no life-threatening toxicity and only three episodes of severe toxicity. One patient experienced both grade 3 leukopenia and thrombocytopenia, while another patient had grade 3 nausea and vomiting. Further studies in this disease are not planned.

Adult↗
PubMed1995

A phase II study of fazarabine (NSC 281272) in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study.

Promising preclinical data and reasonable toxicity in Phase I trials encouraged the Gynecologic Oncology Group to study Fazarabine (FZB) in patients with recurrent squamous cell cancer of the cervix. Twenty-three patients with histologically proven recurrent cervical cancer with measurable disease received FZB at a dosage of 30 mg/m2 per day for 5 days; cycles repeated every 28 days. In the absence of grade 3 or 4 toxicity, dose escalation was planned to a maximum dose of 40 mg/m2 per day for 5 days. All patients were evaluable for toxicity. Seven patients developed neutropenia; in two instances, it was considered life-threatening. The only other serious adverse effect was seen in one patient who developed grade 4 nephrotoxicity. Nineteen women who had failed prior chemotherapy were evaluable for response. There were no complete or partial responses; and seven had stable disease. Fazarabine exhibits no demonstrable activity in this patient population at the dose and schedule tested and further clinical trials as second-line chemotherapy are not warranted.

Adult↗