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Biomedical subjects

R A Smith

Publications and source records attributed to R A Smith.

At least 145 records · Page 8Linked to original sources
PubMed1997

Is epinephrine contraindicated during cardiopulmonary resuscitation?

BACKGROUND: Why pulmonary gas exchange deteriorates after administration of epinephrine during cardiopulmonary resuscitation (CPR) is unclear. METHODS AND RESULTS: Forty-four anesthetized swine received an infusion of six inert gases. Animals underwent ventricular fibrillation with CPR and intravenous administration of saline (control), epinephrine (15 microg/kg), or methoxamine (150 microg/kg). Cardiac output, aortic blood pressure, pH, and arterial oxygen saturation were recorded. Distributions of VA and Q were determined by the multiple inert gas elimination technique. Ventricular fibrillation and CPR caused significant decreases in cardiac output, aortic blood pressure, and arterial pH. With epinephrine (versus saline), diastolic blood pressure was significantly higher (23+/-7 versus 8+/-4 mm Hg), but the increase in shunt (from 7+/-4% to 29+/-17%) and the reduction in SaO2 (from 99.7% to 76.8%) were significantly larger. Also, the increase in dead space was greater and elimination of CO2 less. There were no differences between animals given methoxamine or saline, except for increased diastolic blood pressure. CONCLUSIONS: During experimental ventricular fibrillation and CPR, epinephrine increased intrapulmonary shunt approximately 300% more than saline or methoxamine and significantly reduced arterial oxygen saturation. We suspect that the beta-adrenergic receptor activity of epinephrine attenuated hypoxic pulmonary vasoconstriction. Methoxamine is as effective a pressor as epinephrine for CPR and devoid of beta-adrenergic activity. We recommend that such an agent be considered, instead of epinephrine, for CPR.

Adrenergic alpha-Agonists↗
PubMed1997

The role of putative fibrinogen Aalpha-, Bbeta-, and GammaA-chain integrin binding sites in endothelial cell-mediated clot retraction.

In this study, endothelial cell-mediated clot retraction was supported by fibrin generated from several purified fractions of plasma fibrinogen, purified proteolytic fragments of plasma fibrinogen, recombinant normal fibrinogen, and recombinant variant fibrinogen. These results were surprising because some of these fibrinogens lack domains that are known binding sites for the integrin receptors that support clot retraction. Specifically, fibrinogens lacking Aalpha-chain RGD residues at 572-574 or lacking the gamma-chain residues AGDV 408-411 supported endothelial cell-mediated clot retraction as well as intact fibrinogen. Thus, clot retraction mediated by endothelial cells is not dependent on either of these sites. A variety of monoclonal antibodies against the integrin alphavbeta3 partially inhibited the endothelial cell-mediated retraction of clots formed from plasma fibrinogen. As expected, an antibody to the platelet integrin alphaIIbbeta3 did not inhibit endothelial cell-mediated clot retraction. These results indicate that this retraction is mediated at least in part by alphavbeta3. These results support the conclusion that (a) neither of the two fibrinogen cell binding sites described above is required to support clot retraction or that (b) either site alone or in conjunction with other fibrin(ogen) region(s) can support clot retraction. Thus, endothelial cell-mediated clot retraction appears to be dependent on fibrinogen cell binding sites other than those required to support adhesion of resting platelets to immobilized fibrinogen and platelet aggregation.

Binding Sites↗
PubMed1997

Results of a phase I clinical trial of a T-cell receptor peptide vaccine in patients with multiple sclerosis. I. Analysis of T-cell receptor utilization in CSF cell populations.

To identify a panel of multiple sclerosis patients (MS) for a phase I clinical trial of a T-cell receptor (TCR) peptide vaccine we characterized the T-cell populations present in the cerebrospinal fluids (CSF) of a large group of patients with respect to surface phenotype and state of activation, TCR beta chain utilization, features of the CDR3 junctional region, the extent of clonality and persistence of selected clonotypes over time. These CSF cell populations consist of approximately 60% CD4+ T-cells, half of which bear IL-2 receptors, indicating these activated T-cells may be part of the pathogenic process in MS. When these activated CD4+ T-cells were selectively expanded in IL-2/IL-4 supplemented cultures, an over-representation of several TCRV beta families was noted in 39/47 patients, the most frequent being V beta 6.5, V beta 6.7, V beta 2, V beta 5 and V beta 4. Biased expression of various members of the V beta 6 family was seen in 21 of this group of 39 patients. Clonal analysis of TCR beta 6 CDR3 sequences, revealed two notable features: clonal dominance and clonal persistence. CSF cells from two-thirds of MS patients contained a dominant clone comprising 50% or more of sequences and the same patient-specific clone could be shown to persist for up to 18 months. This clonal prevalence and over representation of V beta 6+TCR raises the possibility that immunization with a V beta 6 peptide vaccine may produce a regulatory immune response leading to a clinical benefit.

Adult↗
PubMed1997

Results of a phase I clinical trial of a T-cell receptor vaccine in patients with multiple sclerosis. II. Comparative analysis of TCR utilization in CSF T-cell populations before and after vaccination with a TCRV beta 6 CDR2 peptide.

We report here the results of a phase I trial of a T-cell receptor (TCR) V beta 6 CDR2 region peptide vaccine in 10 patients with multiple sclerosis who showed biased over-representations of V beta 6 mRNA among T-cells in their cerebrospinal fluids (CSF). One group of 5 patients was immunized twice during a four week period with 100 micrograms of the TCRV beta 6 peptide 39-LGQGPEF LTYFQNEAQLEKS-58 emulsified in incomplete Freund's adjuvant (IFA); the second group of 5 MS patients received 300 micrograms of the same peptide in IFA over a similar time period. Patients were monitored for adverse events, immunogenicity of the peptide and changes in their CSF T-cell populations. The results indicate that this peptide was immunogenic (T-cell proliferation assays and recall DTH responses) in some of the patients, although none of the immunized patients produced detectable anti-peptide antibodies. More importantly, we show that the 5 patients treated with higher doses of the vaccine displayed a slight decrease in CSF cellularity, a lack of growth of CSF cells in cytokine supplemented expansion cultures that implies a significant absence of a subset of activated CD4 T-cells and a marked diminution in V beta 6 mRNA levels among T-cells in these cultures. By comparison, in 5 patients receiving the lower dosage of the vaccine, CSF cellularity was the same or slightly increased over pre-vaccination levels, CSF cells from 1 patient failed to grow in expansion cultures and cultured CSF cells from 2 patients underwent a change from an oligoclonal V beta 6 pattern to one that was more polyclonal. These results justify a more through exploration of the use of TCR peptide vaccines as a possible therapeutic treatment for MS.

Adult↗
PubMed1997

Immunohistochemical and genetic evidence of myeloperoxidase involvement in multiple sclerosis.

The myeloperoxidase enzyme (MPO) is expressed specifically in myeloid cells and catalyzes the formation of hypochlorous acid and other cytotoxic oxidants. We previously reported that two alleles of MPO exist which differ in promoter strength due to a base difference in an Alu-encoded hormone response element. The present study shows that the higher expressing MPO genotype is overrepresented in early onset multiple sclerosis in females, implicating MPO in this demyelinating disease. Contrary to the general conception that macrophages lack MPO, immunohistochemical analysis shows that MPO is present in microglia/macrophages in and around MS lesions as shown by colocalization with major histocompatibility antigens HLA-DR and phagocytized myelin. Also, MPO mRNA sequences are detected in cDNA derived from isolated human adult microglia. This is the first evidence that MPO is present in microglia/macrophages at MS lesions, that MPO gene expression occurs in microglia and that MPO plays a role in MS pathogenesis as shown by the allelic disequilibrium in early onset disease.

Adult↗
PubMed1997

Does significant arterial hypoxemia alter vital signs?

STUDY OBJECTIVE: To determine the cardiovascular and respiratory effects of arterial hypoxemia in adult volunteers. DESIGN: Prospective, subject-controlled. SETTING: University-affiliated hospital. SUBJECTS: 16 awake, unsedated, unanesthetized adult volunteers. INTERVENTIONS: Inspired oxygen concentration (FIO2) was decreased in decrements to reduce pulse oximeter values to a range of 95% to 90%, 89% to 85%, 84% to 80%, and 79% to 70%. MEASUREMENTS AND MAIN RESULTS: Heart rate (HR), blood pressure (BP), respiratory rate (RR), arterial blood pH, gas tensions, and oxyhemoglobin saturation were determined during normoxia and each level of oxyhemoglobin desaturation. FIO2 was reduced from 21% to 10%. Arterial blood oxyhemoglobin saturation and oxygen tension ranged from 100% to 71% and 103 to 35 mmHg, respectively. There were no significant changes in RR, BP, or HR during the study. CONCLUSIONS: HR, BP, and RR are not reliable indicators of arterial hypoxemia in awake volunteers. If this finding is also true for sedated or anesthetized patients, then continuous monitoring with pulse oximetry should be used whenever patients are at risk for arterial hypoxemia. Stable HR, BP, and RR may not eliminate the possibility of significant arterial hypoxemia and impending catastrophic events.

Adult↗
PubMed1997

Health and fertility outcomes among women surgically treated for endometriosis.

STUDY OBJECTIVE: To assess health and fertility status among women after surgical treatment of endometriosis. DESIGN: Prospective study. SETTING: Community-based gynecologic specialty practice. PATIENTS: Two hundred ninety women with newly diagnosed endometriosis. MEASUREMENTS AND MAIN RESULTS: Medical records of all women were abstracted at baseline; self-administered questionnaires were used to collect follow-up data. Most women (68-79%) reported some or great improvement in symptomology after surgical treatment. One hundred twenty-four (53%) of 232 women reported one or more pregnancies, two-thirds of which resulted in live births. Secondary sex ratios were below 1 (range 0.92-0.50), reflecting a female excess. Logistic regression analysis identified previous live birth as the only significant predictor of pregnancy after surgery; advancing maternal age significantly decreased the likelihood of a live birth. CONCLUSIONS: Overall, these women reported improvement in symptoms at follow-up. Operative and clinical findings were not significant predictors of pregnancy likelihood. Prior live birth conferred more than a twofold increase in pregnancy likelihood, whereas advancing age decreased the likelihood. Reasons for reversed sex ratios are unknown but warrant further study.

Adult↗
PubMed1997

An intranet database for pacemaker patients.

A database system, incorporating smartcard technologies, was designed to hold the personal and pacing details of pacemaker patients, who attended a clinic at the Royal Sussex County Hospital (RSCH), Brighton, UK. Following an initial period of a 12 month clinical trial, with the database running on a standalone personal computer, the Pacemaker Patient Database has been redesigned and implemented as an intranet-based system. This paper describes the issues relating to the development of the new prototype system and identifies the design principles for intranet-based electronic health care (EHCR) record database systems.

Computer Communication Networks↗
PubMed1997

Screening fundamentals.

While researchers have established the value of screening for breast cancer with mammography, with and without clinical breast examination, age-specific analyses have led to differing opinions regarding the ages and the intervals that breast cancer screening should begin. This article, therefore, provides a detailed, age-specific evaluation of mammography screening by assessing the severity of breast cancer, the effectiveness of earlier versus later treatment, and the accuracy and reliability of mammography. Data from previous randomized trials and other sources are used to evaluate these criteria. The results indicate that screening programs must have high levels of participation, achieve acceptable sensitivity (85%) and specificity (90%), adopt age-specific screening intervals, and consider how disease stage influences diagnosis. In addition, as others have noted, the following benchmarks can be used to evaluate screening programs: (1) more than 50% of screen-detected cancers should be smaller than 15 mm; (2) 30% or more of grade 3 cancers detected on screening should be less than 15 mm; and (3) more than 70% of cancers detected on screening should be node negative.

Adult↗
PubMed1997

Benefit of screening mammography in women aged 40-49: a new meta-analysis of randomized controlled trials.

Eight randomized controlled trials (RCTs) of screening mammography have been conducted involving women aged 40-49 at entry. Current data are now available from these trials at 10.5 to 18 years of follow-up (average follow-up time: 12.7 years). Meta-analysis has been performed using a Mantel-Haenszel estimator method to combine current follow-up data from the eight RCTs of mammography that included women aged 40-49 at entry, including new follow-up data presented at the NIH Consensus Development Conference held January 21-23, 1997. Combining the most recent follow-up data on women aged 40-49 at entry into all eight RCTs yields a statistically significant 18% mortality reduction among women invited to screening mammography (relative risk: 0.82; 95% confidence interval: 0.71-0.95). Combining all current follow-up data on women aged 40-49 at entry into the five Swedish RCTs yields a statistically significantly 29% mortality reduction among women invited to screening (relative risk: 0.71; 95% confidence interval: 0.57-0.89). Meta-analysis including the most recent follow-up data from all eight RCTs involving women aged 40-49 at entry demonstrates for the first time a statistically significant mortality reduction due to regular screening mammography in women of this age group.

Adult↗
PubMed1997

Is there an optimal electrode pad size to maximize intracardiac current in transthoracic defibrillation?

Achieving defibrillation depends on adequate intracardiac current. The purpose of this study was to determine, in advance of administering shocks which parameters of body habitus can be used to select the electrode size that maximizes intracardiac current in transthoracic defibrillation. We administered direct current shocks to 18 mongrel dogs over a wide range of weight and size (weight 10-30 kg with chest circumferences 44-77 cm) using a damped sine wave defibrillator and self-adhesive electrode pairs of various diameters (4 cm, 5.8 cm, 8 cm and 10 cm), placed on the right and left lateral chest walls. The energy levels used were 50, 100, and 150 J. Intracardiac voltage gradient, a parameter of intracardiac current, was determined in three orthogonal planes using an intramyocardial electrode array placed in the interventricular septum. The relation between intracardiac voltage gradient magnitude magnitude of VG and various parameters (body weight, chest, circumference, chest volume, chest radius, and heart weight divided by chest radius) was determined. The correlation (r) with the smallest P value was between magnitude of VG and the heart weight divided by chest radius (HW/R) (r = 0.71). Intracardiac current was highest at intermediate pad sizes. The electrode pads that maximized magnitude of VG tended to be large for the larger HW/R dogs, and smaller HW/R dogs. In none of the HW/R groups did the largest electrode pads yield the highest intracardiac voltage gradient. We conclude that there is no simple way to determine in advance an electrode pad size that maximizes intracardiac current. The HW/R ratio influences but does not determine intracardiac intracardiac current.

Animals↗
PubMed1997

Direct demonstration of retroviral recombination in a rhesus monkey.

Recombination may be an important mechanism for increasing variation in retroviral populations. Retroviral recombination has been demonstrated in tissue culture systems by artificially creating doubly infected cells. Evidence for retroviral recombination in vivo is indirect and is based principally on the identification of apparently mosaic human immunodeficiency virus type 1 genomes from phylogenetic analyses of viral sequences. We infected a rhesus monkey with two different molecularly cloned strains of simian immunodeficiency virus. One strain of virus had a deletion in vpx and vpr, and the other strain had a deletion in nef. Each strain on its own induced low virus loads and was nonpathogenic in rhesus monkeys. When injected simultaneously into separate legs of the same monkey, persistent high virus loads and declines in CD4+ lymphocyte concentrations were observed. Analysis of proviral DNA isolated directly from peripheral blood mononuclear cells showed that full-length, nondeleted SIVmac239 predominated by 2 weeks after infection. These results provide direct experimental evidence for genetic recombination between two different retroviral strains in an infected host. The results illustrate the ease and rapidity with which recombination can occur in an infected animal and the selection that can occur for variants generated by genetic recombination.

Animals↗
PubMed1997

A novel Met-to-Thr mutation in the YMDD motif of reverse transcriptase from feline immunodeficiency virus confers resistance to oxathiolane nucleosides.

Variants of feline immunodeficiency virus (FIV) that possess a unique methionine-to-threonine mutation within the YMDD motif of reverse transcriptase (RT) were selected by culturing virus in the presence of inhibitory concentrations of (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC]. The mutants were resistant to (-)-FTC and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) and additionally exhibited low-level resistance to 2',3'-dideoxycytidine (ddC). DNA sequence analysis of the RT-encoding region of the pol gene amplified from resistant viruses consistently identified a Met-to-Thr mutation in the YMDD motif. Purified RT from the mutants was also resistant to the 5'-triphosphate forms of 3TC, (-)-FTC, and ddC. Site-directed mutants of FIV were engineered which contain either the novel Met-to-Thr mutation or the Met-to-Val mutation seen in oxathiolane nucleoside-resistant HIV-1. Both site-directed mutants displayed resistance to 3TC, thus confirming the role of these mutations in the resistance of FIV to beta-L-3'-thianucleosides.

Animals↗
PubMed1997

Hypercalcaemia in osteogenesis imperfecta treated with pamidronate.

The response to the bisphosphonate, pamidronate, is reported in a child with osteogenesis imperfecta who had recurrent symptomatic hypercalcaemia after immobilisation following fractures. Oral clodronate was effective in the prevention of immobilisation hypercalcaemia in the same child. The bisphosphonates may have other roles in osteogenesis imperfecta by decreasing bone turnover.

Adolescent↗
PubMed1997

Planning for the future: the experience of implementing a children's day assessment unit in a district general hospital.

A paediatric day assessment unit was opened in May 1995. An audit of the first year's activity showed that, despite an increase in emergency admissions of 8.4%, the number of children admitted as an emergency overnight was reduced by 3% in paediatrics and 7.2% in surgery. In the first year, 1731 children were assessed as an emergency of whom 658 did not require admission to the inpatient ward. Midnight occupancy fell 17.7% in paediatrics and 25.4% in surgery. The nurse staffing costs fell over Pounds 32,000 in the first year. No adverse events occurred during the first year of operation; this type of facility could lead to a more efficient use of resources in any children's unit.

Bed Occupancy↗
PubMed1997

A self report measure of affective lability.

OBJECTIVES: The development and validation of the Center for Neurologic Study-Lability Scale (CNS-LS), the first self report measure of affective lability in patients with amyotrophic lateral sclerosis (ALS). METHODS: Potential questionnaire items were identified through interviews with patients and families and expert review. Potential items, as well as measures of affect intensity, affective lability in psychopathology, and depression were administered to 99 patients with ALS for item selection and the examination of factor structure and construct validity. Test-retest reliability was examined using an additional sample of 31 patients with ALS, and criterion related validity was examined by comparing CNS-LS scores with physicians' diagnoses of affective lability in a sample of 77 patients with ALS. RESULTS: A seven item questionnaire emerged, composed of two subscales measuring labile laughter (four items) and labile tearfulness (three items). The CNS-LS showed a pattern of associations with affect intensity, affective lability in psychopathology, and depression consistent with a scale measuring affective lability. The CNS-LS also showed good test-retest reliability and internal consistency, and successfully predicted physicians' diagnoses of affective lability. An auxiliary subscale measuring labile frustration, anger, and impatience also emerged. CONCLUSIONS: The CNS-LS is a short, easily administered, and psychometrically sound measure of affective lability for use with patients with ALS. It has potential applications as both a clinical screening device and a research tool. The need for future research into the relation of depression as well as labile frustration, anger, and impatience to the syndrome of affective lability in neurological disorders is discussed.

Affect↗