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Biomedical subjects

J D Roberts

Publications and source records attributed to J D Roberts.

At least 73 records · Page 4Linked to original sources
PubMed1995

In vivo gene therapy for hyperlipidemia: phenotypic correction in Watanabe rabbits by hepatic delivery of the rabbit LDL receptor gene.

Elevations of plasma total or LDL cholesterol are major risk factors for cardiovascular disease. Efforts directed at preventing and treating cardiovascular disease have often focused on reducing the levels of these substances in the blood. The Watanabe Heritable Hyperlipidemic Rabbit, which has exceedingly high plasma cholesterol levels resulting from an LDL receptor deficiency, provides an excellent animal model for testing new treatments. A recombinant adenoviral vector containing the rabbit LDL receptor cDNA was administered to Watanabe rabbits. Plasma total cholesterol levels in the treated animals were reduced from 825.5 +/- 69.8 (mean +/- SD) to 247.3 +/- 61.5 mg/dl 6 d after infusion. These animals also demonstrated a 300-400% increase in plasma levels of HDL cholesterol and apo AI 10 d after treatment. As a result, the LDL:HDL ratio exhibited a dramatic decrease. Because only the rabbit LDL receptor gene was used for treatment, the results strongly suggest that the elevations of plasma HDL cholesterol and apo AI were secondary to a reduction in plasma total cholesterol in the treated animals. These results suggest an inverse relationship between plasma LDL and HDL cholesterol levels and imply that reduction of LDL cholesterol levels may have a beneficial effect on plasma HDL cholesterol.

Animals↗
PubMed1995

Relative densities of synaptic and extrasynaptic GABAA receptors on cerebellar granule cells as determined by a quantitative immunogold method.

Ion channels gated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) are thought to be located in synaptic junctions, but they have also been found throughout the somatodendritic membrane of neurons independent of synapses. To test whether synaptic junctions are enriched in GABAA receptors, and to determine the relative densities of synaptic and extrasynaptic receptors, the alpha 1 and beta 2/3 subunits of the GABAA receptor were localized on cerebellar granule cells using a postembedding immunogold method in cats. Immunoparticle density for the alpha 1 and beta 2/3 subunits was approximately 230 and 180 times more concentrated, respectively, in the synaptic junction made by GABAergic Golgi cell terminals with granule cell dendrites than on the extrasynaptic somatic membrane. Quantification of immunoreactivity revealed one synapse population for the beta 2/3, but appeared to show two populations for the alpha 1 subunit immunoreactivity. The concentration of these subunits on somatic membrane was significantly lower than on the extrasynaptic dendritic membrane. Synaptic junctions with glutamatergic mossy fiber terminals were immunonegative. The results demonstrate that granule cells receiving GABAergic synapses at a restricted location on their distal dendrites exhibit a highly compartmentalized distribution of GABAA receptor in their plasma membrane.

Animals↗
PubMed1995

Activation of resident tissue-specific macrophages by swainsonine.

The induction of macrophage tumoricidal activity by swainsonine (8a beta-indolizidine-1 alpha, 2 alpha, 8 beta-triol), an indolizidine alkaloid, has been implicated as possibly an important immune effector mechanism involved in the suppression of tumor growth and metastasis in vital organs such as the lung, liver and spleen (Olden, K. et al. The potential importance of swainsonine in therapy for cancers and immunology. Pharmacol. Ther. 50:285-290; 1991). The present study further explores this possibility by determining whether resident tissue-specific macrophages of several mouse strains can be rendered tumoricidal by systemic administration of swainsonine. We found that systemically administered swainsonine could increase the tumoricidal activity of both alveolar (lung) and splenic macrophages. The activity was enhanced as much as 3- to 4-fold over that obtained with macrophages from organs of control animals and was both dose- and time-dependent. The level and extent of activation by swainsonine was comparable to that achieved with traditional macrophage-activating agents, such as lipopolysaccharide and interferon-gamma. The fact that swainsonine activated highly purified (> 95%) cultures of macrophages from the various sources suggests a direct mechanism of activation. Furthermore, the in vivo activation of macrophages in immune-compromised animals (SCID and nude) lends credence to this suggestion. These findings provide a plausible explanation for the observations that systemically administered swainsonine inhibits organ colonization of metastatic cells and growth of SC tumor xenografts, whereas the growth of tumor cells is not inhibited by swainsonine in culture.

Adjuvants, Immunologic↗
PubMed1994

Mispair-, site-, and strand-specific error rates during simian virus 40 origin-dependent replication in vitro with excess deoxythymidine triphosphate.

We have measured the fidelity of leading and lagging strand DNA replication in HeLa cell extracts. Providing an excess of one dNTP in reactions induces replication errors consistent with misincorporation of that dNTP. With excess dTTP, both substitutions and single-nucleotide frameshifts are induced. Error distribution is nonrandom; reproducible hot spots for a substitution and a frameshift error are observed. Measurements with two vectors having the origin of replication on opposite sides of the mutational target demonstrate that error rates for G.dTTP and C.dTTP mispairs depend on whether the strand is replicated as the leading or lagging strand. Also, the two hot spots are only observed in one origin-target orientation. Replication reactions reconstituted from two fractions derived from extracts are 3-fold less accurate, but the error specificity with excess dTTP is similar to that with extracts. This suggests that the processes responsible for the nonrandom error rates are not lost as a result of fractionation. Furthermore, the reconstituted system is devoid of mismatch repair activity. Thus, mismatch repair is not responsible for the mispair-, site-, and strand-specific differences observed.

Base Sequence↗
PubMed1994

The measurement of nurse performance and its differentiation by course of preparation.

This paper addresses the concept of nurse performance, its measurement and its differentiation by programme of preparation. It is evident from the research conducted to date that a variety of methodologies have been used to explore and compare nurse performance. The process of direct observation, however, has been selected to a lesser degree, and it is argued that its potential has yet to be realized. Further, in recognition of the methodological challenges inherent within research of this nature it is suggested that nurse performance should be explored from a variety of perspectives, using a multi-method research design. Significantly, educational preparation as a potential discriminator of performance has been explored only to a limited extent and studies carried out in the United States predominate. In view of recent nurse education changes in the United Kingdom and the introduction of Project 2000, empirical work comparing outcomes of the different courses of pre-registration preparation is urgently required. The authors are currently engaged in a comparative study of outcomes of pre-registration nurse education programmes funded by the English National Board for Nursing, Midwifery and Health Visiting. This paper draws upon the literature reviewed to date.

Clinical Competence↗
PubMed1994

Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome. Effects on pulmonary hemodynamics and oxygenation.

BACKGROUND: Nitric oxide (NO) inhalation selectively decreases pulmonary artery hypertension and improves arterial oxygenation in patients with the adult respiratory distress syndrome (ARDS). In this study of patients with severe ARDS, we sought to determine the effect of inhaled NO dose and time on pulmonary artery pressure and oxygen exchange and to determine which patients with ARDS are most likely to show this response. METHODS: Thirteen patients with severe ARDS (hospital mortality 67%) inhaled 0-40 parts per million (ppm) NO. Seven of these patients continued to breathe 2-20 ppm NO for 2-27 days. RESULTS: Inhaling 5-40 ppm NO decreased mean pulmonary artery pressure in a dose-related fashion (from 34 +/- 7 to 30 +/- 7 mmHg at 20 ppm NO). Systemic arterial pressure did not change. The ratio of arterial oxygen tension to inspired oxygen fraction increased (from 126 +/- 36 to 149 +/- 38 mmHg) and the venous admixture decreased (from 31.2 +/- 5.5 to 28.2 +/- 5.2%) without a clear dose-response effect. During prolonged NO inhalation, 2-20 ppm NO effectively reduced mean pulmonary artery pressure (38 +/- 7 vs. 31 +/- 6 mmHg) and increased arterial oxygen tension (79 +/- 10 vs. 114 +/- 27 mmHg) without evidence of tachyphylaxis. The decrease of pulmonary vascular resistance during NO inhalation correlated with the level of pulmonary vascular resistance without NO (r = -0.72). The reduction of venous admixture correlated with the level of venous admixture without NO (r = -0.78). CONCLUSIONS: Long-term NO inhalation at low concentrations selectively decreases mean pulmonary artery pressure and improves arterial oxygen tension in patients with ARDS. The selective pulmonary vasodilation effect is most pronounced in ARDS patients with the greatest degree of pulmonary vasoconstriction.

Administration, Inhalation↗
PubMed1994

Increased systemic, but not regional, neopterin production following intraperitoneal administration of interleukin-2 and lack of effect of pterins upon the lymphokine-activated killer cell phenomenon.

Circulating neopterin is derived from monocytes and/or macrophages that produce it upon stimulation by interferon-gamma released from activated T cells. Neopterin production has been proposed as a marker of biological response in the clinical administration of a number of cytokines. Changes in neopterin production as indicated by urinary neopterin excretion were studied in four patients with ovarian carcinoma receiving intraperitoneal interleukin-2 and lymphokine-activated killer cells. Neopterin production increased approximately threefold during treatment with interleukin-2 at doses which represent or exceed the maximum tolerated dose by this route of administration. Increased neopterin apparently was derived from systemic, not regional, tissues. The physiologic role(s) of pterins in immune responses is uncertain. In an in vitro system, the presence of neopterin or tetrahydrobiopterin or the pterin synthesis inhibitor, N-acetyl serotonin, did not modulate cytotoxic effects of lymphokine-activated killer cells.

Biopterins↗
PubMed1994

Monitoring childhood immunizations: a Canadian approach.

In Manitoba, Canada, a centralized, computerized childhood immunization monitoring system serves a population with insured medical coverage; each individual has a unique identification number. All physicians bill a single payer, and specific billing codes are used to identify immunizations given by physicians and by public health nurses. Together with dates of service, this information is used to construct immunizations-to-date and age-at-immunization profiles for individuals and groups. Reminders seeking missing information are built into the system and executed at strategic ages. The quality of input data has been assessed as high. The approach could be used readily by health maintenance organizations in the United States.

Child↗
PubMed1993

Frameshift fidelity during replication of double-stranded DNA in HeLa cell extracts.

The processes by which minus-one frameshifts arise during replication of double-stranded DNA by a human replication apparatus were examined. Using M13mp2 DNA containing the simian virus 40 (SV40) origin of replication and a plus-one frameshift mutation in the lacZ alpha reporter gene, we performed replication reactions using a HeLa cell extract and the SV40 large T antigen. Frameshifts that restore the reading frame to give a blue-plaque phenotype include the loss of one of five consecutive A.T base pairs or any one of 36 non-reiterated base pairs. Although both types of deletions were generated at rates substantially above the background mutant frequency of unreplicated DNA, the rate was highest at the A.T run, suggesting the involvement of a misaligned replication intermediate at this homopolymeric sequence. The error rate for both types of deletions increased as the concentration of dNTPs was increased. A small increase in error rate at the run of A.T base pairs was also observed when a dNMP was added to the replication reaction. These results are consistent with the correction of frameshift intermediates during replication by exonucleolytic proofreading. To examine frameshift error rates on the leading and lagging strands, we compared reversion frequencies for two vectors containing the origin of replication close to, but on opposite sides of, the mutational target. To generate strand-specific errors, nucleotide substrate imbalances were used in replication reactions with these vectors. The results suggest that there is less than a 2-fold difference in the fidelity of leading- and lagging-strand synthesis for deletions at the run of A.T base pairs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine↗
PubMed1993

The metabotropic glutamate receptor (mGluR1 alpha) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction.

An antiserum to mGluR1 alpha labeled a 160 kd protein in immunoblots of membranes derived from rat brain or cells transfected with mGluR1 alpha. Immunoreactivity for mGluR1 alpha was present in discrete subpopulations of neurons. The GABAergic neurons of the cerebellar cortex were strongly immunoreactive; only some Golgi cells were immunonegative. Somatostatin/GABA-immunopositive cells in the neocortex and hippocampus were enriched in mGluR1 alpha. The hippocampal cells had spiny dendrites that were precisely codistributed with the local axon collaterals of pyramidal and granule cells. Electron microscopic immunometal detection of mGluR1 alpha showed a preferential localization at the periphery of the extensive postsynaptic densities of type 1 synapses in both the cerebellum and the hippocampus. The receptor was also present at sites in the dendritic and somatic membrane where synapses were not located.

Amino Acid Sequence↗
PubMed1993

Effect of nitric oxide on the survival rate and incidence of lung injury in newborn lambs with persistent pulmonary hypertension.

We previously showed that inhaling nitric oxide (NO) for up to 30 minutes selectively dilates the pulmonary circulation and improves oxygenation in newborn lambs with persistent pulmonary hypertension. In the current study we determined whether inhaling NO for 23 hours increased the survival rate of newborn lambs with persistent pulmonary hypertension, oxidized hemoglobin to methemoglobin, or damaged the lungs. Persistent pulmonary hypertension was created in newborn lambs by ligating the ductus arteriosus 13 days before delivery. Six lambs were randomly selected to breathe NO at 80 parts per million for 23 hours, and 7 control lambs were untreated. Each lamb was delivered at 135 days of gestation (term is 146 days), and the lungs were ventilated at a fraction of inspired oxygen of 0.92. Each of the control lambs died before the end of the study, whereas only one of the NO-treated lambs died (p < or = 0.05). Arterial oxygen tension was greater in the NO-treated lambs by 15 minutes after delivery (63 +/- 17 vs 14 +/- 4 mm Hg). Oxygen tension increased with time in the NO-treated lambs. Inhaled NO increased the concentration of methemoglobin, but this concentration reached a plateau at 3.0% +/- 0.4%. There was evidence of early airway damage in both groups of lambs but no difference between the groups. We conclude that inhaled NO increased survival rates without increasing the incidence of acute lung injury in newborn lambs with persistent pulmonary hypertension.

Animals↗
PubMed1993

Advances in the treatment of persistent pulmonary hypertension of the newborn.

Despite an association with meconium and blood aspiration, pneumonia, sepsis, pneumothorax, prematurity, and congenital diaphragmatic hernia, no cause for persistent pulmonary hypertension of the newborn can be found in many cases. This article discusses the advances in current therapies including the promising new therapy of inhaled nitric oxide.

Animals↗
PubMed1993

Problem solving in nursing practice: application, process, skill acquisition and measurement.

This paper analyses the role of problem solving in nursing practice including the process, acquisition and measurement of problem-solving skills. It is argued that while problem-solving ability is acknowledged as critical if today's nurse practitioner is to maintain effective clinical practice, to date it retains a marginal place in nurse education curricula. Further, it has attracted limited empirical study. Such an omission, it is argued, requires urgent redress if the nursing profession is to meet effectively the challenges of the next decade and beyond.

Education, Nursing↗
PubMed1993

The relationship between nursing and higher education.

The paper explores the relationship between nursing and higher education with particular reference to the development of nursing degree programmes in the United Kingdom. The literature reveals that the contribution of nurse graduates to the profession has been examined to a limited extent: however, this has predominantly taken the form of follow-up studies, the majority of which were conducted in the 1980s. No empirically based work could be found which explores graduates' practice of nursing, the absence of which is significant in view of the more recent change in the conventional training programme, Project 2000, and the introduction of a number of 3-year nursing degree courses.

Attitude of Health Personnel↗