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Biomedical subjects

M Knowles

Publications and source records attributed to M Knowles.

At least 37 records · Page 2Linked to original sources
PubMed1996

Skin testing with Mycobacterium avium sensitin to identify infection with M. avium complex in patients with cystic fibrosis.

We sought to determine if patients with cystic fibrosis and sputum cultures positive for Mycobacterium avium complex (MAC) have delayed-type hypersensitivity to an M. avium sensitin. Seventeen (33%) of 51 selected patients had MAC isolated from at least one sputum culture. Skin tests with purified protein derivative and M. avium sensitin demonstrated that five (10%) of 51 patients were anergic, and anergy was correlated with use of systemic steroids. Sixteen (35%) of 46 nonanergic patients had M. avium-dominant skin test reactions. Twelve (75%) of these 16 patients with cultures positive for MAC had M. avium-dominant skin tests; the specificity of skin testing was 87%. These data suggest that most patients with cystic fibrosis and sputum cultures positive for MAC have infection rather than colonization with MAC. Skin testing with M. avium sensitin is a sensitive and specific method for screening these infections.

Adolescent↗
PubMed1995

A school and community outbreak of influenza A.

In May 1995 a department of public health medicine was informed of an outbreak of respiratory and gastrointestinal illness in a local school. Eighty-three pupils and staff were affected out of a total of 247 people--an attack rate of 34%. The outbreak was investigated, control measures were instigated, and the outbreak subsided. Pupils and staff were surveyed and faecal specimens were collected. Blood specimens from a sample of pupils were examined serologically. No organisms were isolated from faecal specimens. Nine of the 18 blood specimens taken showed raised antibody titres against influenza A. This labour intensive investigation revealed a community outbreak of influenza A. Investigations in schools can be useful in community surveillance.

Antibodies, Viral↗
PubMed1995

The shifting stroke belt. Changes in the geographic pattern of stroke mortality in the United States, 1962 to 1988.

BACKGROUND AND PURPOSE: The factors that contribute to the Stroke Belt--a concentration of high stroke mortality rates in the southeastern United States--remain unidentified. Previous hypotheses that focused on physical properties of the area have not been confirmed. This study describes changes in the locations of areas with the highest rates of stroke mortality and the implications for new hypotheses regarding the Stroke Belt. METHODS: We calculated annual, age-adjusted stroke mortality rates for black women, black men, white women, and white men for the years 1962 to 1988 using a three-piece log-linear regression model. Maps were produced with the state economic area (SEA) as the unit of analysis. The baseline Stroke Belt was defined as the area with the largest concentration of high-quintile SEAs in 1962. RESULTS: The concentration of high-rate SEAs tended to shift away from the Piedmont region of the Southeast and toward the Mississippi River valley. For example, whereas among black women in 1962, 72% of SEAs in the baseline Stroke Belt were in the highest quintile, by 1988 this percentage had dropped to 48%. Similar patterns were observed for the other race/sex groups. CONCLUSIONS: Temporal changes in the location of areas with the highest stroke mortality rates suggest that new hypotheses for understanding the geographic pattern of stroke mortality should consider temporal trends in a variety of medical, socioeconomic, and behavioral factors.

Adult↗
PubMed1995

Evaluation of periodontal treatments using controlled-release tetracycline fibers: clinical response.

The purpose of this investigation was to evaluate the clinical efficacy of controlled-release tetracycline fiber therapy in adult periodontitis patients. One hundred-twenty-two (122) adult patients from 3 dental centers were enrolled at baseline for this study. each patient provided at least one site in each of four quadrants that was > or = 5 mm and bled on probing. One or two such sites were selected as test sites and were randomly assigned to receive one of four treatments: scaling and root planing (S), scaling and root planing plus tetracycline fiber for 10 days (SF), fiber therapy alone for 10 days (F), or two 10-day serial fiber applications (FF). After treatment, no periodontal maintenance or supportive care was provided until the end of this 12-month study. Probing depth (PD), clinical attachment level (CAL), plaque, and bleeding on probing (BOP) were measured at baseline and at 1, 3, 6, 9, and 12 months following treatment. Repeated PD and CAL measurements were taken at three locations within each site and averaged for each site. One hundred-sixteen (116) subjects completed the study. All treatments resulted in similar improvements in clinical parameters compared to baseline and were equally effective in the treatment of periodontitis as measured by probing depth reduction, clinical attachment level gain, and reduction of bleeding on probing. The clinical response, established primarily by 3 months following therapy, was generally sustained in all treatment groups for 12 months without the benefit of supportive maintenance therapy.

Adult↗
PubMed1995

Evaluation of periodontal treatments using controlled-release tetracycline fibers: maintenance response.

The purpose of this investigation was to examine periodontal disease recurrence from 3 to 12 months following various treatments with scaling and root planing and controlled-release tetracycline fibers. One-hundred-twenty-two (122) adult volunteers with at least one bleeding pocket > or = 5 mm in each of four quadrants were enrolled in this study. One or two such sites in each quadrant were selected as test sites. Quadrants were randomly assigned to receive one of four treatments: scaling and root planing (S); scaling and root planing plus tetracycline fiber for 10 days (SF); fiber therapy alone for 10 days (F); or fiber therapy alone for 20 days (FF). After treatment, no supportive care was provided during the 12-month study period. Probing depth (PD), attachment loss (AL), plaque, and bleeding on probing were measured at baseline, and at 1, 3, 6, 9, and 12 months after treatment. PD and AL measures were taken at three locations within each site and averaged for each site. Disease recurrence was defined as > or = 1 mm mean attachment loss at a site during the 3- to 12-month period. One-hundred-sixteen (116) subjects completed the study. Sites treated with SF experienced significantly (P < 0.05) less disease recurrence (4%) than S, F, or FF (9%, 10%, and 12%, respectively). Results of this study suggest that, compared to S, F, or FF, scaling and root planing in conjunction with tetracycline fiber therapy for 10 days can significantly reduce disease recurrence 3 to 12 months following treatment in the absence of supportive care.

Adult↗
PubMed1994

Deconvolution method for assessing the absorption of a drug with reversible metabolic pathways.

A method has been established to determine the input rate for a drug with reversible metabolic processes. This method is based on linear system properties without imposing a compartment model for describing the disposition of the drug and the metabolite and their interconnections. The solution is a deconvolution method in N-dimensional space. A general solution has been obtained for calculating the parameters needed to describe the input function. The specific solution for a staircase input function (point-area deconvolution) is explicitly derived. Using a staircase input function is not a robust method and can give negative input values when applied to simulated data sets with a large amount of variability. This suggests the need for more robust functional forms to describe the input function.

Absorption↗
PubMed1994

Pharmacology of high-threshold calcium currents in GH4C1 pituitary cells and their regulation by activation of human D2 and D4 dopamine receptors.

1. The objective of this study was to characterize the pharmacology of calcium currents in GH4C1 pituitary cells and determine whether activation of heterologously expressed human dopamine receptors can regulate their function. Human D2(short), D3 and D4.2 receptor cDNA's were separately transfected into GH4C1 cells and whole cell calcium currents were recorded by use of nystatin-perforated patch clamp techniques. 2. High-threshold calcium currents were antagonized in a biphasic manner by the dihydropyridine, nisoldipine. The half-maximally effective concentration for each site was 0.2 nM (pIC50 = 9.78 +/- 0.21, n = 4) and 339 nM (pIC50 = 6.47 +/- 0.12, n = 4). The component of current inhibited by 10 nM nisoldipine was also blocked by omega-conotoxin GVIA (30 +/- 9% at 30 nM, n = 6) or by omega-agatoxin IVA (34 +/- 7% at 100 nM, n = 4). 3. Activation of either D2 or D4 receptors by dopamine (10 microM) or quinpirole (0.1 to 10 microM) reduced the peak calcium current by ca. 20% in the majority of cells studied. No inhibition was observed in control or D3 transfected GH4C1 cell lines. 4. The mobilisation of intracellular calcium by thyrotropin releasing hormone in hD4-GH4C1 cells was also studied using Fura-2 AM microspectrofluorimetry. Thyrotropin releasing hormone caused a concentration-dependent increase in calcium mobilisation with an EC50 of 7 nM. D4 receptor activation had no effect upon either basal or hormone-induced [Ca2+]i transients. 5. These results demonstrate that GH4C1 pituitary cells have at least two types of dihydropyridine sensitive high-threshold calcium currents and that like D2 receptors, human D4 receptors can also regulate calcium channel function.

Animals↗
PubMed1993

Immunocytochemical localization of c-erbB-2 protein in transitional cell carcinoma of the urinary bladder.

The level of expression and cellular localization of the c-erbB-2 gene product in transitional cell carcinoma of the urinary tract is controversial. Analysis of the c-erbB-2 gene structure and comparison of its expression in the same cells by Southern, Northern and immunoblotting, and by immunocytochemistry minimize the errors of interpretation inherent in one technique. Such a 'correlative study' has been performed on tumours from 82 patients. c-erbB-2 gene amplification was detected in 14 per cent of initial tumours and was associated with grade (P < 0.001). Raised levels of mRNA were seen in those tumours with increased gene copy number and in 13 per cent of the remainder. Immunoblotting detected the expected 185 kD immunoreactive protein and a 155 kD protein associated with high gene copy number. Immunocytochemistry localized c-erbB-2 immunoreactivity to the cell membrane and cytoplasm, and the latter predominated. Four antibodies to c-erbB-2 (AB-3, 21N, pAb 1, and NCL CB11) were compared on contiguous sections of the same tumour and showed the same pattern of immunoreactivity. Similarly, analyses carried out in three independent laboratories identified the same cellular localization. Membrane and cytoplasmic immunoreactivity was demonstrated in all tumours with gene amplification or increased mRNA levels and in 40 per cent of the remaining tumours. We showed that immunocytochemistry requires careful standardization of techniques and quantitation between different groups. However, despite variations in the intensity of immunoreactivity, the total number of positive cells remained constant. Therefore quantitation must be based on the number of positive cells and, ideally, their immunoreactive content relative to normal and positive tissue controls.

Biomarkers, Tumor↗
PubMed1993

Black-white comparisons of 20-year coronary heart disease mortality in the Evans County Heart Study.

The Evans County Heart Study was initiated to compare the epidemiology of coronary heart disease (CHD) of black and white residents of a southeastern United States community. The study was prompted by a clinical observation that CHD appeared to be less frequent in black than white patients, despite a much higher prevalence and greater severity of hypertension in blacks. A total community-based, closed cohort study was initiated with a prevalence survey in 1960-1962. The 20-year follow-up experience of the Evans County cohort confirmed the importance of the major risk factors of serum cholesterol, smoking and blood pressure for middle age and older, black and white men and women for CHD, cardiovascular disease (CVD) and all-cause mortality. Black men were less likely to die of CHD than white men, and this relative protectiveness increased upon adjusting for risk factors and also increased with age. The relative protectiveness of black men for CHD mortality was also reflected in lower black than white CVD and all-cause mortality in men 65 years of age and older.

Adult↗
PubMed1993

Isobutylmethylxanthine fails to stimulate chloride secretion in cystic fibrosis airway epithelia.

It has been proposed that a combination of an activated adenylyl cyclase and a high concentration of a phosphodiesterase inhibitor (isobutylmethylxanthine [IBMX], 5 mM) stimulates Cl- secretion mediated by the heterologously expressed cystic fibrosis transmembrane regulator protein carrying the most common cystic fibrosis (CF) mutation (delta F508). We tested whether Cl- secretion could be stimulated by this protocol in vitro and in vivo in CF airway epithelia expressing endogenous delta F508 CFTR protein. In cultured airway preparations, forskolin (a direct adenylyl cyclase activator) stimulated Cl- secretion in amiloride-pretreated normal (delta Isc = 7.1 +/- 1.7 microA.cm-2) but not CF tissues (delta Isc = -02 +/- 0.1 microA.cm-2). Unexpectedly, IBMX partially inhibited the forskolin-induced Cl- secretion in normal tissues; IBMX addition had no effect on CF tissues. Direct measurements of cell cAMP concentrations revealed that 0.1 mM IBMX and forskolin produced the maximum levels of cell cAMP levels attainable with this drug combination, and 5 mM IBMX was without further effect. The combination of forskolin (10(-5) M) and isoproterenol, an adenylyl cyclase activator (10(-5) M), produced approximately 3 times higher levels of cAMP than forskolin/IBMX but also did not induce Cl- secretion in CF tissues. Studies of Cl- secretion in vivo, assessed by the transepithelial electric potential difference (PD), showed that isoproterenol (10(-5) M) stimulated Cl- secretion (delta PD = -16.3 +/- 4.3 mV; n = 4) in nasal epithelia of normal subjects but not in CF patients homozygous for the delta F508 mutation (delta PD = -2.6 +/- 1.9 mV; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1991

Effect of food on bioavailability of pseudoephedrine and brompheniramine administered from a gastrointestinal therapeutic system.

The purpose of this study was to determine how a high-fat meal affects the delivery and absorption of pseudoephedrine and brompheniramine maleate when delivered from a gastrointestinal therapeutic system (GITS). This study was a randomized, complete crossover trial with 12 healthy male volunteers who were given single doses of the 24-h GITS under fed and fasted conditions. Pharmacokinetic parameters for both drugs were comparable between fed and fasted treatments, except for a shorter time to maximum concentration of pseudoephedrine for fed subjects (p = 0.002). Bioavailability of pseudoephedrine was 91% for fed relative to fasted treatment; for brompheniramine it was 89%. These results indicate that codelivery of the two drugs from the GITS is reliable and prolonged, and that the resulting absorption of pseudoephedrine and brompheniramine is minimally affected by food.

Adult↗
PubMed1991

Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy. A randomized, placebo-controlled, double-blind study.

To assess the smoking cessation efficacy of transdermal nicotine patches as an adjunct to low-intervention therapy, we conducted a double-blind, placebo-controlled trial in 158 smokers. Participants were randomly assigned to one of the following three study regimens that required daily application of two 15-cm2 patches: (1) 24-hour nicotine delivery, (2) nicotine delivery during wakeful hours only, and (3) placebo. The impact of the three regimens on smoking cessation rates and tobacco withdrawal symptoms was examined. During the last 2 weeks of the trial, 39% of the 24-hour nicotine regimen delivery group, 35% of those on wakeful hour nicotine regimens, and 13.5% of the placebo treatment group achieved abstinence. Self-reported quit rates for the two nicotine patch-wearing regimens, as compared with that for the placebo group, continued to be significantly higher at 6 months. Moreover, compared with placebo, the transdermal nicotine patches significantly reduced tobacco withdrawal symptoms during the first few weeks of quitting. The differences in quit rates and tobacco withdrawal symptoms between the two active groups were not statistically significant. The patches were well tolerated both topically and systemically. We concluded that transdermal nicotine, when used as an adjunct to low-intervention therapy, significantly reduced tobacco withdrawal symptoms and enhanced smoking cessation rates.

Administration, Cutaneous↗
PubMed1990

Oxidation of low-density lipoprotein and macrophage derived foam cells.

Copper-oxidized LDL has many of the characteristics of the modified LDL generated in the artery wall during the initial stages of atherosclerosis. It is not, however, a chemically defined species but shows significant variations in both its chemical composition and behaviour in biological systems depending upon the extent to which the peroxidation reaction has occurred (Fig. 1). Taking care to define the extent of LDL modification we have used this form of oxidized LDL to investigate the effects on the macrophage of this potentially toxic particle. This cell, in contrast to endothelial cells, appears to be particularly well adapted to detoxify lipid peroxidation products since it possesses glutathione peroxidases capable of metabolizing oxidized LDL and responds to oxidized LDL by increasing its GSH content. Acetylated LDL had little or no effect on GSH levels showing that lipid loading per se or recognition by the macrophage scavenger receptor is not sufficient to induce the synthesis of this antioxidant. We have confirmed the observation that oxidized LDL does not activate expression of the gene for TNF and raise the possibility that PGE2 produced by the cells and possibly during the oxidation of LDL may be the mediator suppressing the synthesis of this cytokine. Our results support the hypothesis that the lipid-laden macrophage does not contribute to an inflammatory response in the artery wall and imply a protective role for the macrophage in scavenging oxidized LDL.

Animals↗