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Biomedical subjects

S A Lewis

Publications and source records attributed to S A Lewis.

At least 73 records · Page 4Linked to original sources
PubMed1997

Contemporary use of antibiotics in 1089 adults presenting with acute lower respiratory tract illness in general practice in the U.K.: implications for developing management guidelines.

Respiratory symptoms are the most common cause of general practitioner (GP) consultation, and hospital-based specialists are often called on to provide management guidelines, particularly in the area of antibiotic prescribing. The present authors have assessed factors associated with antibiotic use by 115 GPs when managing 1089 adults with an acute lower respiratory tract illness, including cough. They prescribed antibiotics to three-quarters of patients, but felt antibiotics to be definitely indicated in less than one-third of these cases and not needed in one-fifth. Univariate analysis revealed that antibiotics were prescribed more frequently by older GPs for older patients in the presence of underlying disease, discoloured sputum, shortness of breath, wheeze, fever, signs on chest examination, and 'other factors'. Multivariate logistic regression confirmed an independent effect for all these findings except for the presence of underlying disease, shortness of breath and wheeze. 'Other factors' included patient 'pressure' and social factors, and GP work pressure or prior experience with the patient. These factors were an important influence on prescribing, especially if the GP felt an antibiotic was not indicated. Amoxycillin was the first choice (58% of total) except where the patient had recently received antibiotics for the same illness. Broader spectrum antibiotics were used more commonly in patients with chronic lung disease, discoloured sputum, chest signs on examination and where the GP felt antibiotics were indicated. However, these antibiotics were also prescribed to 14% of previously well patients. General practitioners used a wide variety of terms to describe the illness with little consistency or structure. The decision concerning the use and choice of antibiotics and the confidence with which the GP makes that decision is a complex interaction between patient, doctor and disease, being affected not only by clinical features but also by the social and psychological elements of the presenting problem. Such issues need to be appreciated by hospital specialists when called on to advise on developing relevant guidelines for primary care.

Acute Disease↗
PubMed1997

Cross sectional investigation of the effects of inhaled corticosteroids on bone density and bone metabolism in patients with asthma.

BACKGROUND: Bone mineral density has been reduced in patients with asthma taking inhaled corticosteroids in some cross sectional studies and this could be important if treatment is continued for several decades. The possibility of confounding by age, menopausal status, physical activity and, especially, past oral steroid use has not been excluded in most studies. The present study was designed to assess the magnitude of any reduction in bone mineral density in relation to inhaled steroid use after adjusting for these factors. METHODS: Bone mineral density (BMD), vertebral fractures, and markers of bone metabolism (serum osteocalcin, procollagen peptide I, bone-specific alkaline phosphatase, and urinary deoxypyridinoline cross links) were measured in 81 patients with asthma age 20-40 years; 34 patients (19 men) who had never had inhaled or systemic steroids and 47 (19 men) who had taken inhaled steroids for at least five years with limited exposure to systemic steroids in the past. Data relating to past medication use, physical activity, smoking, and other confounding factors were collected by questionnaire. The relation between inhaled steroid dose and duration and BMD was assessed by linear regression analysis, accounting for potential confounders including weight, exercise, and oral steroid use. RESULTS: The 47 patients taking an inhaled steroid had a mean current dose of 620 micrograms/day (range 100-3000 micrograms), a mean duration of use of 7.8 years, and had had a mean of 0.85 courses of prednisolone in the past. There was no significant difference in mean BMD values between those who were and those who were not on inhaled steroids in men or women. However, on multivariate analysis, cumulative inhaled steroid dose was associated with a reduction in posterior-anterior (P-A) and lateral lumbar spine bone mineral density in women, equivalent to a 0.11 standard deviation reduction in bone density per 1000 micrograms/day inhaled steroid per year after adjustment for potential confounding factors (95% CI for P-A spine 0.01 to 0.22; for lateral spine 0.02 to 0.21). Previous oral steroid use was not an important confounding factor in these patients. Inhaled steroid use was not related to BMD at the wrist or hip in women or at any skeletal site in men. Women taking an inhaled steroid had lower levels of serum osteocalcin than those not taking them, although this was not dose related. Inhaled steroid use was not associated with differences in other markers of bone metabolism in men or women or with the presence of vertebral fractures. CONCLUSIONS: Although an effect of confounding factors cannot be excluded entirely in a cross sectional study, our findings are in keeping with an effect of inhaled steroid therapy in reducing bone density in the spine in women and provide an estimate of the magnitude of this effect.

Administration, Topical↗
PubMed1997

Histone-induced damage of a mammalian epithelium: the role of protein and membrane structure.

In a previous report [T. J. Kleine, A. Gladfelter, P. N. Lewis, and S. A. Lewis, Am. J. Physiol. 268 (Cell Physiol. 37): C1114-C1125, 1995], we found that the cationic DNA-binding proteins histones H4, H1, and H5 caused a voltage-dependent increase in the transepithelial conductance in rabbit urinary bladder epithelium. In this study, results from lipid bilayer experiments suggest that histones H5-H1 and H4 form variably sized conductive units. Purified fragments of histones H4 and H5 were used to determine the role of histone tertiary structure in inducing conductance. Isolated COOH- and NH2-terminal tails of histone H4, which are random coils, were inactive, whereas the central alpha-helical domain induced a conductance increase. Although the activities of the central fragment and intact histone H4 were in many ways similar, the dose-response relationships suggest that the isolated central domain was much less potent than intact histone H4. This suggests than the NH2- and COOH-terminal tails are also important for histone H4 activity. For histone H5, the isolated globular central domain was inactive. Thus the random-coil NH2- and COOH-terminal tails are important for H5 activity as well. These results indicate that histone molecules interact directly with membrane phospholipids to form a channel and that protein tertiary structure and the degree of positive charge play an important role in this activity.

Amino Acid Sequence↗
PubMed1996

Effects of polymyxin B on mammalian urinary bladder.

Previous reports have demonstrated that large cationic polypeptides (of molecular mass 5,000 daltons or greater) cause an increase in the apical membrane conductance of the rabbit urinary bladder epithelium. This report investigates the effects of the small cationic molecule polymyxin B (PX: a 1,400 dalton antibiotic) on the permeability of the rabbit urinary bladder. The addition of micromolar concentrations of polymyxin B to the luminal solution of the rabbit urinary bladder resulted in an increase in the transepithelial conductance of the bladder. The magnitude of the increase in the conductance was dependent upon the concentration of PX, and the polarity and magnitude of the apical membrane potential. As the apical membrane potential was made more cell interior negative, the larger was the increase in the membrane conductance. This voltage-dependent increase in conductance was an exponential function of the applied voltage, with a negligible increase in conductance occurring when the membrane potential was cell interior positive. Upon changing the membrane voltage from cell interior positive to negative, there was a delay before there was a measurable change in the membrane conductance. The longer the apical membrane was exposed to PX, the more poorly reversible was its effect on the transepithelial conductance, suggesting a toxic effect of PX on this epithelium.

Animals↗
PubMed1996

Permeability properties of the intact mammalian bladder epithelium.

Because the mammalian bladder must store urine of composition which differs markedly from that of plasma for prolonged periods, the bladder permeability barrier must maintain extremely low permeabilities to substances which normally cross membranes relatively rapidly, such as water, protons, and small nonelectrolytes like urea and ammonia. In the present studies, permeabilities of the apical membrane of dissected rabbit bladder epithelium to water, urea, ammonia, and protons were measured in Ussing chambers and averaged (in cm/s) for water, 5.15 +/- 0.43 x 10(-5); for urea, 4.51 +/- 0.67 x 10(-6); for ammonia, 5.14 +/- 0.62 x 10(-4); and for protons, 2.98 +/- 1.87 x 10(-3), respectively. These permeability values are exceptionally low and are expected to result in minimal to no leakage of these normally permeable substances across the epithelium. Water permeabilities in intact whole rabbit bladders were indistinguishable from those obtained in the dissected epithelial preparation. Moreover, addition of nystatin to the apical solution of dissected epithelia rapidly increased water permeability in conjunction with loss of epithelial resistance. These results confirm that the apical membrane of the bladder epithelial cells represents the bladder permeability barrier. In addition, they establish a model system that will permit examination of how membrane structure reduces permeability and how epithelial injury compromises barrier function.

Ammonia↗
PubMed1996

Health care seeking by heartburn sufferers is associated with psychosocial factors.

AIM: To determine whether individuals who consult a doctor because of gastroesophageal reflux disease have psychological characteristics and social support patterns that distinguish them from those who remain within the community. METHODS: Comparison of 138 consecutive patients presenting to a gastrointestinal clinic for the first time because of heartburn with 39 heartburn sufferers who had never sought medical help for their reflux disease and 40 healthy individuals with no heartburn. Instruments used were the State-Trait Anxiety Index, the Crown-Crisp Experiential Index, the Hassles Scale, and the Interview Schedule for Social Interaction. RESULTS: Heartburn sufferers who remained within the community in no way differed from healthy controls. Patients who sought medical attention were older and their heartburn was more severe than community heartburn sufferers. When these variables were controlled for in the analysis, patients experienced greater phobia, obsessionality, and somatization, more hassles but of significantly lower intensity, and had less-adequate close social support than those who did not seek medical help. CONCLUSION: Psychological and social factors are associated with individuals with gastroesophageal reflux disease who seek medical help.

Adult↗
PubMed1995

Quasi-native chaperonin-bound intermediates in facilitated protein folding.

Chaperonins are known to facilitate protein folding, but their mechanism of action is not well understood. The fact that target proteins are released from and rebind to different chaperonin molecules ("cycling") during a folding reaction suggests that chaperonins function by unfolding aberrantly folded molecules, allowing them multiple opportunities to reach the native state in bulk solution. Here we show that the cycling of alpha-tubulin by cytosolic chaperonin (c-cpn) can be uncoupled from the action of cofactors required to complete the folding reaction. This results in the accumulation of folding intermediates which are chaperonin-bound, stable, and quasi-native in that they bind GTP nonexchangeably. We present evidence that these intermediates can be generated without the target protein leaving c-cpn. These data show that, in contrast to prevailing models, target proteins can maintain, and possibly acquire, significant native-like structure while chaperonin-bound.

Animals↗
PubMed1995

Specificity in chaperonin-mediated protein folding.

Chaperonins are ubiquitous multisubunit toroidal complexes that aid protein folding in an ATP-dependent manner. Current models of folding by the bacterial chaperonin GroEL depict its role as unfolding and releasing molecules that have misfolded, so that they can return to a potentially productive folding pathway in solution. Accordingly, a given target polypeptide might require several cycles of binding and ATP-driven release from different chaperonin complexes before reaching the native state. Surprisingly, cycling of a target protein does not guarantee its folding, and we report here that unfolded beta-actin or alpha-tubulin both form tight complexes when presented to either GroEL or its mitochondrial homologue, and both undergo cycles of release and rebinding upon incubation with ATP, but no native protein is produced. We conclude that different chaperonins produce distinctive spectra of folding intermediates.

Actins↗
PubMed1995

Cell division does not increase transepithelial permeability of LLC-PK1 cell sheets.

The transepithelial electrical resistance (TER) across LLC-PK1 cell sheets is unstable for several days postseeding, even when the cells are trypsinized from a previously confluent culture and replated at confluent density. We therefore followed the TER of LLC-PK1 cells plated at confluent density to elucidate characteristics of the TER fluctuations after plating of the cells. Control cultures reached a maximum TER of 1800 omega.cm2 approximately 24 h after plating. TER then declined sharply, reaching generally stable values (approximately 175 omega.cm2) only after 4 days. Cell cycle activity ([3H]-thymidine incorporation) peaked approximately 22 h after plating, prior to the peak in TER values, and then followed a decline similar to that of the TER. Treatment of cells with EGF at 24 h after plating caused the TER values reached at 3-4 days postseeding to exceed time matched controls by approximately 100%. This EGF-treated group showed a concomitant increase in [3H]thymidine incorporation and cell density compared to control. Transepithelial fluxes of [14C]D-mannitol across control vs EGF-treated cell sheets were not, however, significantly different at the 4-day time point, indicating that a change in tight junction sieving on the basis of size had not occurred. Diffusion and bi-ionic potential studies indicated that the change in TER in EGF-treated cells was instead due to altered charge selectivity at the tight junction and/or intercellular space. We conclude: (1) TER across LLC-PK1 cell sheets does not stabilize until 4 days after seeding at confluent density and (2) cell division and resultant increased cell density in LLC-PK1 cell sheets can correlate with elevated TER values, due to altered ion permeability of the paracellular pathway. Permeability to both Na+ and Cl- decreased as a result of EGF treatment but the decline in chloride permeability was significantly greater. Not only was there a decrease in the permeabilities of all halide anions after exposure of cell sheets to EGF, but the permeability sequence changed after EGF exposure.

Animals↗
PubMed1995

Stress, personality and social support in gastro-oesophageal reflux disease.

BACKGROUND AND AIM: In 40% of patients presenting to medical clinics with heartburn, no objective evidence of gastro-oesophageal reflux disease can be demonstrated. Little research has been performed regarding the psychological characteristics of these patients. The aim of this study was to assess the psycho-social profiles of patients presenting with heartburn in an attempt to discriminate between those with pathological reflux and those with functional disease. METHODS: One hundred and thirty-eight patients presenting with heartburn underwent endoscopy and oesophageal pH monitoring. They were divided into those with oesophagitis or abnormal degrees of acid reflux into the oesophagus and those with normal endoscopy and normal pH profile. The psychological questionnaires used were the Hassles Scale, the State-Trait Anxiety Index, the Crown-Crisp Experiential Index and the Interview Schedule for Social Interaction. RESULTS: Patients with functional heartburn did not report any increase in daily hassles nor did they have higher levels of anxiety, depression or other psychological characteristics than those with objective reflux disease. In terms of their available social support, the two groups were similar. CONCLUSION: Differences in psychological characteristics and social support structures do not offer an explanation for the heartburn experienced by patients in the absence of objective evidence of reflux disease. Other explanations, including visceral hypersensitivity, should be sought in these patients.

Adult↗
PubMed1995

Histone-induced damage of a mammalian epithelium: the conductive effect.

Human semen has been reported to be cytotoxic to rat descending colon by a mechanism involving polyamines (cationic molecules) and collagenase. In this study, we report that histones, cationic proteins found in human semen, can contribute to semen's cytotoxicity. Histones H1, H4, and H5, when added to the mucosal side of rabbit urinary bladder epithelium, were found to alter the transepithelial conductance (Gt) in a voltage-sensitive manner. When the cell interior was negative, the conductance rapidly increased and plateaued. When the cell interior was positive, the induced conductance decreased to control values. Histone increased the Gt by increasing the apical membrane conductance rather than the tight junction conductance. The magnitude of the Gt increase was dose dependent, and the histone-induced conductance was nonselective for Na+, K+, and Cl-. The induced conductance could be reversed by either increasing mucosal Ca2+ concentration or by removal of histone from the mucosal solution. Prolonged exposure of the epithelium to histone was toxic as determined by the irreversible loss of transepithelial resistance. These results indicate that histone increases membrane ionic permeability, is cytotoxic, and thus may contribute to human semen's toxic effect on colonic epithelium.

Animals↗
PubMed1995

Modulation of epithelial permeability by extracellular macromolecules.

Epithelia are sheets of cells joined together by tight junctions. This geometry allows an epithelium to act as a barrier, i.e., restrict the movement of substances between two compartments that it separates (typically 1 compartment is the blood) and also to actively and selectively transport substances between the two compartments. It has been known for a number of years that both the barrier and transport functions of epithelia can be regulated by hormones and neurotransmitters, and this regulation is a central component of plasma electrolyte and nonelectrolyte homeostasis. Less appreciated is that these epithelial functions can be modified by macromolecules other than neurotransmitters and hormones. These macromolecules have been divided into the following categories: proteases, cytokines, cellular constituents, nonbacterial xenobiotics, and bacterial xenobiotics. Such macromolecules can alter epithelial transport and barrier function by a number of different mechanisms. These include proteolysis of epithelial ion channels and tight junctional complexes, conversion of an ion pump into a nonselective cation channel, increase in epithelial membrane permeability resulting in cell swelling and lysis, and up- or downregulation of cellular second messenger systems that can alter ion transport capabilities or prove cytotoxic to the cells. Finally, these modifications can be either transient or chronic in nature and in many circumstances result in a perturbation of the electrolyte and nonelectrolyte status of the host organism.

Animals↗
PubMed1995

Dietary antioxidant vitamin intake and lung function in the general population.

We have investigated the relation between lung function and dietary intake of the antioxidant vitamins C and E in the general population in a cross-sectional survey of a random sample of adults from the electoral register of an administrative area of Nottingham. In 2,633 subjects 18 to 70 yr of age, we measured FEV1 and FVC, allergen skin sensitivity to grass pollen, cat fur, and Dermatophagoides pteronyssinus, pack-years smoking exposure by personal recall, and usual dietary intake of vitamins C and E by semiquantitative food frequency questionnaire. After adjustment for the effects of age, sex, height, mean allergen skin wheal diameter, and pack-years smoking history, both FEV1 and FVC were significantly and independently related to mean daily intake of vitamin C, such that a standard deviation (40 mg/d) higher vitamin C intake was associated with a 25.0 (95% CI, 5.2 to 44.8; p = 0.01) ml higher FEV1 and a 23.3 (0.94 to 45.7, p = 0.04) ml higher FVC. There was also an association between vitamin E intake and lung function, such that a standard deviation (2.2 mg) higher intake of vitamin E was associated with a 20.1 (1.3 to 40.4, p = 0.04) ml higher FEV1 and a 23.1 (1.0 to 45, p = 0.04) ml higher FVC. However, vitamin C and vitamin E intakes were significantly correlated (r = 0.29, p < 0.001), and after allowing for the effects of vitamin C there was no additional independent effect of vitamin E on either FEV1 or FVC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Acid perception in gastro-oesophageal reflux disease is dependent on psychosocial factors.

BACKGROUND: Our aim was to contrast the psychosocial profiles of patients with gastro-oesophageal reflux disease whose symptoms correlate well with acid reflux against those whose symptoms do not. METHODS: One hundred and one patients presenting with heartburn for the first time underwent oesophageal pH monitoring, and 82 (81%) experienced symptoms during the recording. On the basis of how well their symptoms correlated with acid reflux, patients were divided into symptom-positive and symptom-negative groups. These two groups were then compared on the basis of four questionnaires looking at different psychosocial factors. RESULTS: Symptom-negative patients displayed significantly higher levels of trait anxiety (44.5 versus 38.7; p < 0.05) and hysteria (5.6 versus 4.1; p < 0.05). The adequacy of their social support structures was significantly lower (6.2 versus 7.3; p < 0.05). No difference in daily hassles or uplifts was found. CONCLUSION: Significant psychosocial differences are noted in patients with poor symptom-reflux correlation. These differences may help explain the aetiology of such patients' symptoms.

Anxiety↗