Biomedical subjects

P Wills

Publications and source records attributed to P Wills.

17 recordsLinked to original sources

PubMed2006

Inhaled hyperosmolar agents for bronchiectasis.

BACKGROUND: Mucus retention in the lungs is a prominent feature of bronchiectasis. The stagnant mucus becomes chronically colonised with bacteria, which elicit a host neutrophilic response. This fails to eliminate the bacteria, and the large concentration of host-derived protease may contribute to the airway damage. The sensation of retained mucus is itself a cause of suffering, and the failure to maintain airway sterility probably contributes to the frequent respiratory infections experienced by many patients. Hypertonic saline inhalation is known to accelerate tracheobronchial clearance in many conditions, probably by inducing a liquid flux into the airway surface, which alters mucus rheology in a way favourable to mucociliary clearance. Inhaled dry powder mannitol has a similar effect. Such agents are an attractive approach to the problem of mucostasis, and deserve further clinical evaluation. OBJECTIVES: To determine whether inhaled hyperosmolar substances are efficacious in the treatment of bronchiectasis SEARCH STRATEGY: The Cochrane Airways Group Specialised Register was searched, and leaders in the field were contacted. Searches were current as of October 2005. Search updates will be run annually. SELECTION CRITERIA: Any trial using hyperosmolar inhalation in patients with bronchiectasis not caused by cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two reviewers assessed studies for suitability. MAIN RESULTS: Two small studies met the inclusion criteria of the review (28 participants). One study reported tracheobronchial clearance of a particulate radio aerosol after inhalation of dry mannitol on a single occasion, with appropriate control. Airway clearance doubled in the central and intermediate regions of the lung, but not in the peripheral region, after mannitol administration. No side effects were observed, but two patients were premedicated with nedocromil to prevent bronchospasm. Findings from one further trial indicated that one domain of a sensitive health status instrument showed a favourable response to mannitol. AUTHORS' CONCLUSIONS: Dry powder mannitol has been shown to improve tracheobronchial clearance in bronchiectasis, as well as cystic fibrosis, asthmatics, and normal subjects. Hypertonic saline has not been specifically tested in bronchiectasis, but improves clearance in these other conditions and in chronic bronchitis. The measurement of health status in one of the studies should be repeated in future longer term randomised controlled studies of mannitol and hypertonic saline. Consideration should also be given to exacerbations and symptom scores, as well as drug-related adverse events.

Bronchiectasis↗

PubMed2001

Inhaled hyperosmolar agents for bronchiectasis.

BACKGROUND: Mucus retention in the lungs is a prominent feature of bronchiectasis. The stagnant mucus becomes chronically colonised with bacteria, which elicit a host neutrophilic response. This fails to eliminate the bacteria, and the large concentration of host-derived protease may contribute to the airway damage. The sensation of retained mucus is itself a cause of suffering, and the failure to maintain airway sterility probably contributes to the frequent respiratory infections experienced by many patients. Hypertonic saline inhalation is known to accelerate tracheobronchial clearance in many conditions, probably by inducing a liquid flux into the airway surface, which alters mucus rheology in a way favourable to mucociliary clearance. Inhaled dry powder mannitol has a similar effect. Such agents are an attractive approach to the problem of mucostasis, and deserve further clinical evaluation. OBJECTIVES: To determine whether inhaled hyperosmolar substances are efficacious in the treatment of bronchiectasis SEARCH STRATEGY: MEDLINE and Cochrane databases were searched, and leaders in the field contacted. SELECTION CRITERIA: Any trial using hyperosmolar inhalation in patients with bronchiectasis not caused by cystic fibrosis. DATA COLLECTION AND ANALYSIS: One reference were identified by the searches conducted. MAIN RESULTS: Only one trial was identified, a crossover study of 11 patients with bronchiectasis. The outcome measure was tracheobronchial clearance of a particulate radioaerosol after inhalation of dry mannitol on a single occasion, with appropriate controls. Airway clearance doubled in the central and intermediate regions of the lung, but not in the peripheral region, after mannitol administration. No side effects were observed, but two patients were premedicated with nedocromil to prevent bronchospasm. REVIEWER'S CONCLUSIONS: Dry powder mannitol has been shown to improve tracheobronchial clearance in bronchiectasis, as well as cystic fibrosis, asthmatics, and normal subjects. It is not yet available for clinical use. Hypertonic saline has not been specifically tested in bronchiectasis, but improve clearance in these other conditions and in chronic bronchitis. Longer term randomised controlled studies of mannitol and hypertonic saline with clinical endpoints are now needed.

Bronchiectasis↗

PubMed2000

Assessing subtle memory impairments in the everyday memory performance of brain injured people: exploring the potential of the extended Rivermead Behavioural Memory Test.

A substantial number of brain injured patients complain of memory deficits, despite achieving scores within the normal range on tests of memory functioning. The Rivermead Behavioural Memory Test is an ecologically valid test used to assess everyday memory problems. This test is effective at detecting moderate to-severe impairments, yet subtle memory deficits may go undetected for some patients who achieve a score within the normal range. The initial development of an extended version of this test (RBMT-E), designed to detect subtle decrements in memory performance, has recently been described. The performance of 16 brain injured patients was assessed on both the RBMT and the KBMT-E. The performance of these patients on the RBMT-E was compared with that of matched controls. Overall, the patients performed significantly worse than the controls, and showed particular difficulty in two subtests involving recalling a route and remembering to deliver a message. Those patients who scored in the 'normal' range on the RBMT could be further differentiated on the basis of their RBMT-E scores into 'good', 'average' and 'poor' performance categories. The patients' performance was not significantly associated with general intellectual ability. These results suggest that the RBMT-E may be a useful clinical tool to aid therapists in the assessment of subtle impairments of everyday memory performance following brain injury.

Adolescent↗

PubMed1998

Cognitive impairment, drug use, and the risk of hip fracture in persons over 75 years old: a community-based prospective study.

The authors examined the effects of cognitive function, as assessed by the Mini-Mental State Examination, and drug use on the incidence of hip fracture in a community-based Swedish population of 1,608 subjects who were aged > or = 75 years on October 1, 1987, and who had not had a hip fracture. During the 7,123.8 person-year follow-up, 134 first hip fractures were identified. The Cox proportional hazards model was used to estimate the relative risk of developing hip fracture, taking into account several potential confounders. Compared with those without cognitive impairment, subjects with mild impairment (Mini-Mental State Examination scores 18-23) had a relative risk of 2.04 (95% confidence interval (CI) 1.29-3.24), and subjects with moderate-severe impairment (Mini-Mental State Examination score < 18) had a relative risk of 2.09 (95% CI 1.17-3.72). Subjects using opioid analgesics (97% took propoxyphene) had a relative risk of 2.01 (95% CI 1.19-3.40). Taking potassium supplements (99% took potassium chloride) was related to a reduced risk of hip fracture (relative risk = 0.55, 95% CI 0.31-0.98), while diuretics did not have an independent impact. In summary, the results show that cognitive impairment and use of propoxyphene are associated with increased risk of hip fracture. The observed protection of potassium chloride merits further attention. The limitation of the study was that the assessment of drug use was made only at baseline.

Aged↗

PubMed1998

Effect of dirithromycin on Haemophilus influenzae infection of the respiratory mucosa.

Macrolides have properties other than their antibiotic action which may benefit patients with airway infections. We have investigated the effect of dirithromycin (0.125 to 8.0 microg/ml) on the interaction of Haemophilus influenzae with respiratory mucosa in vitro using human nasal epithelium, adenoid tissue, and bovine trachea. Dirithromycin did not affect the ciliary beat frequency of the nasal epithelium or the transport of mucus on bovine trachea, but dirithromycin (1 microg/ml) did reduce the slowing of the ciliary beat frequency and the damage to the nasal epithelium caused by H. influenzae broth culture filtrate. Amoxicillin (2 microg/ml) did not reduce the effects of the H. influenzae broth culture filtrate. H. influenzae infection of the organ cultures for 24 h caused mucosal damage and the loss of ciliated cells. Bacteria adhered to damaged epithelium and to a lesser extent to mucus and unciliated cells. Incubation of H. influenzae with dirithromycin at sub-MICs (0.125 and 0.5 microg/ml) prior to infection of the organ cultures did not reduce the mucosal damage caused by bacterial infection. By contrast, incubation of adenoid tissue with dirithromycin (0.125 to 1.0 microg/ml) for 4 h prior to assembling the organ culture reduced the mucosal damage caused by subsequent H. influenzae infection by as much as 50%. The number of bacteria adherent to the mucosa was reduced, although the tissue that had been incubated with dirithromycin (0.125 and 0.5 microg/ml) did not inhibit bacterial growth. This was achieved by a reduction in the amount of damaged epithelium to which H. influenzae adhered and a reduction in the density of bacteria adhering to mucus. We conclude that dirithromycin at concentrations achievable in vivo markedly reduces the mucosal damage caused by H. influenzae infection due to a cytoprotective effect.

Amoxicillin↗

PubMed1997

Drug use by demented and non-demented elderly people.

AIM: to determine the use of drugs by demented and non-demented elderly people in a population, by dementia status and type, age, sex and accommodation type. METHOD: data were obtained from the Kungsholmen project, a longitudinal community study of people over 75 in Stockholm, Sweden. RESULTS: 85% used at least one medicinal drug, and of these 12% were demented. Mean numbers of drugs used were 2.8 for demented and 3.2 for non-demented people. 45% of demented people and 38% of non-demented people used psychotropic agents. Psychotropic use was higher in women and increased with institutionalization. Antipsychotic agents were used more by demented (22%) than by non-demented (3.5%) people: this was largely explained by differences in accommodation type. The odds ratio (OR) for use of antipsychotics by those in institutions compared with those living in their own homes was 9.32. Opioids were commonly prescribed for demented people. The proportions taking opioids in those using analgesics were 42% in demented and 23% in non-demented people (OR 2.07). Laxatives were used by 18% of the demented people in institutions compared with 39% of non-demented people in institutions. CONCLUSION: being in an institution had a stronger association with the use of certain drugs (e.g. psychotropics) than did dementia status. Demented people, especially those in institutions, used a large number of antipsychotics and opioids, but fewer laxatives and minor analgesics. Prescribers and institutional staff should be aware of these factors so they can optimize patient treatment.

Aged↗

PubMed1996

A novel in vitro model system for studying the action of ara-C.

The antimetabolite 1-beta-D-arabinofuranosyl-cytosine (ara-C) has proven to be one of the most effective agents available for the treatment of acute leukemia. While ara-C has been implicated as a potent inhibitor of mammalian cell DNA replication, the specific mechanism by which ara-C kills cells is not known. In this report we describe the development of an in vitro model system to study the molecular mechanism of ara-CMP incorporation into DNA. This model system makes use of a recently described human cell multiprotein DNA replication complex (MRC) that is competent to replicate DNA in vitro. The MRC can successfully incorporate ara-CMP into replicating DNA at internucleotide positions. These results are similar to those described for studies using intact cells. This MRC-driven in vitro replication system may therefore serve as a powerful model for the study of anticancer agents that directly affect human cell DNA synthesis.

Antimetabolites, Antineoplastic↗

PubMed1996

Use of cardiovascular drugs in an older Swedish population.

OBJECTIVE: To describe the use of cardiovascular drugs in an older population with respect to age, sex, housing type, and creatinine clearance. DESIGN: A cross-sectional survey. PARTICIPANTS: All residents of a district of Stockholm (Kungsholmen), Sweden, aged 75 and older, living in institutions or at home. MEASUREMENTS: Cardiovascular drug use, serum creatinine, electrolytes, height, weight, and symptoms. RESULTS: A total of 43 cardiovascular (CV) drugs were used. The most common drugs were digoxin (used by 18.2%), furosemide (16.4%), and glyceryl trinitrate (12.4%). Drugs with an antihypertensive effect accounted for 61% of all CV drugs. CV drug use increased with age for cardiac glycosides and diuretics, but decreased with age for calcium antagonists and beta-blockers. Drug doses tended to be less than the recommended daily dose except for a few drugs, e.g., furosemide. There was a trend toward decreasing dose with increasing age, but this was not significant. Diuretics were the only CV drugs used more often in women. People living in institutional care used the least amount of CV drugs. The dose of drugs taken did not appear to be related to estimated creatinine clearance. Comparisons between drug use and complaint of symptoms showed a strong correlation between the use of cardiac glycosides and anorexia, calcium antagonists and constipation, and nitrates and vertigo. There were weaker correlations with cardiac glycosides and visual disturbances and with potassium sparing diuretics and a high potassium. CONCLUSIONS: CV drugs are used commonly in older people. We suggest that the symptoms correlating with cardiac glycoside use may be signs of unrecognized toxicity, and this may relate to our finding that drug use is often not tailored to renal function as measured by creatinine clearance.

Aged↗

PubMed1995

Further characterization of the human cell multiprotein DNA replication complex.

Evidence for multiprotein complexes playing a role in DNA replication has been growing over the years. We have previously reported on a replication-competent multiprotein form of DNA polymerase isolated from human (HeLa) cell extracts. The proteins that were found at that time to co-purify with the human cell multiprotein form of DNA polymerase included: DNA polymerase alpha, DNA primase, topoisomerase I, RNase H, PCNA, and a DNA-dependent ATPase. The multiprotein form of the human cell DNA polymerase was further purified by Q-Sepharose chromatography followed by glycerol gradient sedimentation and was shown to be fully competent to support origin-specific and large T-antigen dependent simian virus 40 (SV40) DNA replication in vitro [Malkas et al. (1990b): Biochemistry 29:6362-6374]. In this report we describe the further characterization of the human cell replication-competent multiprotein form of DNA polymerase designated MRC. Several additional DNA replication proteins that co-purify with the MRC have been identified. These proteins include: DNA polymerase delta, RF-C, topoisomerase II, DNA ligase I, DNA helicase, and RP-A. The replication requirements, replication initiation kinetics, and the ability of the MRC to utilize minichromosome structures for DNA synthesis have been determined. We also report on the results of experiments to determine whether nucleotide metabolism enzymes co-purify with the human cell MRC. We recently proposed a model to represent the MRC that was isolated from murine cells [Wu et al. (1994): J Cell Biochem 54:32-46]. We can now extend this model to include the human cell MRC based on the fractionation, chromatographic and sedimentation behavior of the human cell DNA replication proteins. A full description of the model is discussed. Our experimental results provide further evidence to suggest that DNA synthesis is mediated by a multiprotein complex in mammalian cells.

Blotting, Western↗

PubMed1994

A 17S multiprotein form of murine cell DNA polymerase mediates polyomavirus DNA replication in vitro.

We have identified and purified a multiprotein form of DNA polymerase from the murine mammary carcinoma cell line (FM3A) using a series of centrifugation, polyethylene glycol precipitation, and ion-exchange chromatography steps. Proteins and enzymatic activities associated with this mouse cell multiprotein form of DNA polymerase include the DNA polymerases alpha and delta, DNA primase, proliferating cell nuclear antigen (PCNA), DNA ligase I, DNA helicase, and DNA topoisomerases I and II. The sedimentation coefficient of the multiprotein form of DNA polymerase is 17S, as determined by sucrose density gradient analysis. The integrity of the murine cell multiprotein form of DNA polymerase is maintained after treatment with detergents, salt, RNase, DNase, and after chromatography on DE52-cellulose, suggesting that the association of the proteins with one another is independent of nonspecific interaction with other cellular macromolecular components. Most importantly, we have demonstrated that this complex of proteins is fully competent to replicate polyomavirus DNA in vitro. This result implies that all of the cellular activities required for large T-antigen dependent in vitro polyomavirus DNA synthesis are present within the isolated 17S multiprotein form of the mouse cell DNA replication activities. A model is proposed to represent the mammalian Multiprotein DNA Replication Complex (MRC) based on the fractionation and chromatographic profiles of the individual proteins found to co-purify with the complex.

Animals↗

PubMed1988