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Biomedical subjects

S Harper

Publications and source records attributed to S Harper.

52 records · Page 3Linked to original sources
PubMed1993

The effect of increasing doses of beta-agonists on airflow in patients with chronic airflow limitation.

OBJECTIVE: To determine the increase in FEV1 associated with increasing doses of inhaled terbutaline and salbutamol, the reproducibility of the increase in FEV1, and the reproducibility of the associated optimal bronchodilator dose, in patients with chronic airflow limitation (CAL). DESIGN: Double-blind, randomized, controlled trial examining spirometric response to cumulative doses of bronchodilators. PATIENTS AND SETTING: Patients with clinical diagnosis of CAL, FEV1 below 70% predicted, and FEV1 to FVC ratio less than 0.7 after administration of bronchodilator recruited from secondary care respirology practices. MEASURES OF OUTCOME: The estimates of maximum and optimal bronchodilation, as well as the associated drug dosages, were established in each patient on three occasions (twice on terbutaline and once on salbutamol). The 'optimal' drug dose was defined as the lowest dose associated with an FEV1 not exceeded by 50 ml on any other dose. MAIN RESULTS: Thirty-five patients completed the trial. FEV1 improved from 0.93 to a maximum of 1.191 with terbutaline (average of the two administrations) and from 0.951 to 1.141 with inhaled salbutamol (difference in increase in FEV1 between terbutaline and salbutamol P = 0.006). In less than 50% of cases administration of more than four puffs of bronchodilator resulted in FEV1 increase by more than 50 ml. The average dose of salbutamol and terbutaline associated with optimal bronchodilation were 430 micrograms and 1160 micrograms respectively. Patients varied widely in the optimal dose. Estimates of optimal dose were not reproducible (intraclass correlation coefficient < 0.5). CONCLUSION: Substantial incremental increase in FEV1 in response to increasing doses of beta-agonists beyond those commonly used in clinical practice is restricted to a minority of patients. Lack of reproducibility limits the clinical usefulness of establishing the optimal dose of beta-agonist for a given patient.

Administration, Inhalation↗
PubMed1992

Interaction of Epstein-Barr virus nuclear antigen 1 with the viral latent origin of replication.

The Epstein-Barr virus latent origin of replication (oriP) requires only one viral protein, the Epstein-Barr virus nuclear antigen 1 (EBNA-1), for activity. oriP consists of two spatially separated, essential sequence elements, regions I and II, both of which contain multiple EBNA-1-binding sites. Region II contains, or is close to, the site at which DNA synthesis initiates. The role of region I, a transcriptional enhancer in cells that express EBNA-1, in replication is not understood. To determine how the binding of EBNA-1 to sites in region II leads to the initiation of DNA synthesis and to investigate the role of region I, EBNA-1 has been overproduced in insect cells by using a baculovirus vector and purified to homogeneity, and the interaction of EBNA-1 with oriP has been examined. Footprinting experiments demonstrated that EBNA-1 binds to oriP in a sequence-specific manner and bends or untwists the DNA at two symmetry-related sites in region II. Distortion of region I by EBNA-1 was not detected, suggesting that differences in the spacing of binding sites in regions I and II and resulting protein-protein interactions underlie differences in their biological properties. KMnO4 footprinting experiments did not reveal significant single-stranded structures in region II, suggesting that cellular proteins may recognize the EBNA--region II complex and unwind the DNA duplex. Region I did not quantitatively or qualitatively alter the interaction of EBNA-1 with region II. The contribution of an A + T-rich sequence in region II to replication was investigated by a mutational analysis. The results indicated that the overall A + T-rich nature of this sequence is not essential for replication of oriP-bearing plasmids. Nuclease protection experiments performed with these mutagenized plasmids provided additional evidence for protein-protein interactions in region II.

Animals↗
PubMed1990

NGF mRNA expression in developing cutaneous epithelium related to innervation density.

To determine if the initial level of NGF mRNA in developing cutaneous epithelium is correlated with its final innervation density, we measured the concentration of NGF mRNA in the epithelia of the maxillary, mandibular and ophthalmic territories of trigeminal ganglion in the embryonic mouse. At the onset of neuronal death in the ganglion there were marked differences in the concentration of NGF mRNA in these epithelia: the level was highest in the epithelium of the densely innervated maxillary territory, it was lower in the epithelium of the moderately innervated mandibular territory and was lowest in the epithelium of the sparsely innervated ophthalmic territory. These regional differences in the level of NGF mRNA during the early stages of target field innervation suggest that the level of NGF production in target field cells, rather than regional differences in the access of innervating neurons to NGF, governs the number of neurons that survive. Because the same percentage cell death occurs in each of the subsets of trigeminal neurons that innervate the maxillary, mandibular and ophthalmic territories, regional differences in NGF synthesis are not responsible for establishing differences in innervation density, rather they maintain differences that arise earlier in development.

Animals↗
PubMed1990

Wives, husbands, and daughters caring for institutionalized and noninstitutionalized dementia patients: toward a model of caregiver burden.

The primary purposes of this article are to clarify some of the inconsistencies in the previous research studies done on factors associated with caregiver burden; to identify specific sets of variables that best explain the differential burden levels among caregivers; and to provide a substantial foundation for developing a model of caregiver burden useful for both research and clinical interventions. The caregiver's gender, relationship to the patient, and the residential location of the patient (same house, community, or institution) are major considerations in our analyses. This study is also unique, because it uses a relatively large national sample of caregivers, which is necessary to accomplish the study's objectives. Mailed questionnaires were completed by 409 caregivers identified by fifty local support groups in sixteen different states in the United States. Generally, the primary correlates of burden were factors related to the levels and types of impairment in patient functioning, caregiver life satisfaction, and social support. Each category of caregiver circumstances had a unique set of three to five correlates with the total amount of variance explained in burden ranging from 25 percent (husbands living with the patients) to 68 percent (husbands with spouses in nursing homes). Implications for future research and interventions are discussed.

Alzheimer Disease↗
PubMed1983

Failure of bovine complement levels measured by radial hemolysis to correlate with tube titration.

Hemolytic complement levels in 30 duplicate samples of normal bovine sera were determined by a tube titration method (CH50) and by a radial hemolysis in gel assay. Significant correlation was not observed between the values obtained by the 2 tests. This lack of correlation could be a result of considerable error observed in values obtained for duplicate samples in the CH50 method or to the relative insensitivity of the hemolysis in gel test. The hemolytic reaction in gel was found to depend on Mg2+, thus raising questions (i) about its validity in determining total hemolytic complement or (ii) about bovine C1q depending on Mg2+ rather than Ca2+ for binding to immune complexes.

Animals↗
PubMed1982

Evidence for a separate meal-associated oscillator in the rat.

Three experiments were conducted to explore the relationship between food availability and the wheel running activity rhythms of intact rats. In two experiments re-entrainment when meal times were changed was studied. The rats showed an increase in activity immediately prior to a regular feeding time and this increase was more rapid when rats had been fed at that time in an earlier condition. Some evidence of transients at a former meal time was observed when the meal time was shifted to later in the day, but not when the meal time was shifted to earlier in the day. This led to the hypothesis that ad lib feeding masks rather than abolishes meal-entrained activity. In a third experiment, therefore, rats were entrained to a daily meal under a light-dark (LD) cycle, then placed in constant dark (DD) on ad lib food with occasional periods of deprivation. A burst of activity associated with the former meal time occurred during the deprivation period, but not during ad lib periods; it returned during subsequent deprivation. It is concluded that meal feeding entrains a separate oscillator with a period different from the oscillator entrained by the LD cycle.

Animals↗
PubMed1981

Comparison of Marion's anaerobic culture/set-A and the Baltimore Biological Laboratory Gaspak anaerobic system in the cultivation and recovery of bacteria from human dental plaque.

Marion's anerobic culture/set-A (Bio-Bag A) and the Baltimore Biological Laboratory (BBL) Gaspak anaerobic system were evaluated for their efficiency in the cultivation and recovery of anaerobes and capnophilic organisms from human dental plaque samples. Both culture systems were relatively efficient in supporting the growth of pure culture of various bacterial species recently isolated from the human dental plaques. When the dental plaque samples were cultured the organisms commonly found were cultivatable in both culture systems. However, the counts and proportions of Fusobacterium nucleatum from the samples were significantly higher in Marion's culture system, whereas the proportions of black-pigmented Bacteroides sp. were significantly higher in the BBL anaerobic system.

Actinomyces↗
PubMedDate not supplied

Preclinical pharmacokinetics and metabolism of a potent non-nucleoside inhibitor of the hepatitis C virus NS5B polymerase.

The disposition of compound A, a potent inhibitor of the hepatitis C virus (HCV) NS5B polymerase, was characterized in animals in support of its selection for further development. Compound A exhibited marked species differences in pharmacokinetics. Plasma clearance was 44 ml min-1 kg-1 in rats, 9 ml min-1 kg-1 in dogs and 16 ml min-1 kg-1 in rhesus monkeys. Oral bioavailability was low in rats (10%) but significantly higher in dogs (52%) and monkeys (26%). Compound A was eliminated primarily by metabolism in rats, with biliary excretion accounting for 30% of its clearance. Metabolism was mainly mediated by cyclohexyl hydroxylation, with N-deethylation and acyl glucuronide formation constituting minor metabolic pathways. Qualitatively, the same metabolites were identified using in vitro systems from all species studied, including humans. The low oral bioavailability of compound A in rats was mostly due to poor intestinal absorption. This conclusion was borne out by the findings that hepatic extraction in the rat was only 30%, intraperitoneal bioavailability was good, and compound A was poorly absorbed from the rat isolated intestinal loop, with no detectable intestinal metabolism. Compound A was not an inhibitor of major human cytochrome P450 enzymes, indicating minimal potential for clinical drug-drug interactions. The metabolic clearance of compound A in rat, dog and monkey hepatocytes correlated with the systemic clearance observed in these species. Since compound A was very stable in human hepatocytes, the results suggest that it will be a low clearance drug in humans.

Animals↗
PubMedDate not supplied

Colorectal carcinogenesis: sequential steps in the in vitro immortalization and transformation of human colonic epithelial cells (review).

The development of colorectal cancer is an excellent example of the complex multistage nature of carcinogenesis and most colorectal cancers are thought to develop from adenomas. In this paper we have reviewed in vitro models developed in our laboratory for the study of human colorectal carcinogenesis. For these studies epithelial cell lines have been isolated from hereditary and sporadic colorectal adenomas representing different stages in tumour progression. Karyotypic analysis has shown specific abnormalities of chromosomes 1, 7, 14, 17, 18 and 22 to occur in these premalignant adenoma cell lines. The majority of cell cultures derived from small adenomas (less than 1 cm in diameter) senesced whereas the larger adenomas (greater than 2 cm in diameter) were more likely to give rise to immortal cell lines indicating that the acquisition of in vitro immortality occurs at a relatively late stage of colorectal carcinogenesis. Abnormalities of chromosome I have been implicated in tumour progression and in the in vitro immortalization of colorectal adenomas. Furthermore, several stages have been described in the transformation of an adenoma cell line PC/AA to a tumorigenic phenotype. Sodium butyrate and the potent carcinogen N-methyl-N-nitro-nitrosoguanidine (MNNG) were used in this transformation. Sodium butyrate is proposed to act as a possible promoter of colorectal carcinogenesis, and MNNG to cause the further genetic changes required for the conversion of the premalignant cells to a carcinoma. Markers to study the progression of an adenoma cell line to a tumorigenic phenotype in vitro include in vitro immortalization, aneuploidy, clonogenicity, resistance to the inhibitory effects of sodium butyrate, anchorage independent growth, ras gene activation, production of active proteinases and tumorigenicity in athymic nude mice. A role for a constitutively produced tumour promoter in colorectal carcinogenesis is discussed together with the possibility that different events are involved in the development of sporadic versus hereditary tumours due to the importance of the microenvironment in hereditary cancer. Our in vitro progression provides the first experimental evidence for the adenoma to carcinoma sequence and the cytogenetic evidence suggests that it is relevant to in vivo carcinogenesis.

Adenoma↗