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Biomedical subjects

P Young

Publications and source records attributed to P Young.

At least 91 records · Page 5Linked to original sources
PubMed2000

Predictive value of pharmacological activity for the relative efficacy of antidepressant drugs. Meta-regression analysis.

BACKGROUND: There is uncertainty about the contribution of specific pharmacological properties to the efficacy of antidepressants. AIMS: To assess whether specific pharmacological characteristics of alternative antidepressants resulted in altered efficacy compared to that of selective serotonin reuptake inhibitors in the treatment of major depression. METHOD: Meta-regression analysis of randomised trials that compare treatment with a selective serotonin reuptake inhibitor and an alternative antidepressant. RESULTS: One-hundred-and-five randomised trials were included. None of the factors identified a priori predicted a statistically significant improvement in outcome across the trials. CONCLUSIONS: This analysis does not provide evidence that antidepressants acting at more than one pharmacological site differ in efficacy from drugs selective for serotonin reuptake in the treatment of major depression.

Adrenergic Uptake Inhibitors↗
PubMed2000

A comparison of the reliability of self-reported drug use and sexual behaviors using computer-assisted versus face-to-face interviewing.

The purpose of this study was to assess the reliability of responses to HIV risk behavior questions obtained using a voice-enhanced, computer-administered self-interview (audio-CASI) system with touch-screen response compared with those obtained via face-to-face interviews administered by trained and experienced interviewers. Additionally, the study assessed bias that may be attributable to an audio-CASI data collection format. The design of the study was a four-group crossover design with random assignment to one of four study conditions: (a) audio-CASI interview at both intake and retest, (b) face-to-face interview at both intake and retest, (c) audio-CASI interview at intake and face-to-face interview at retest, and (d) face-to-face interview at intake and audio-CASI interview at retest. The study was conducted with a sample of drug users at risk for HIV infection interviewed in nonclinical settings. Data were collected at intake and 48 hours after intake. Analyses show that data obtained using voice-enhanced computer interviewing with touch-screen response are reliable and are comparable to data obtained using interviewer administered face-to-face interviews. However, bias was found to be associated with data collection format and may be partially attributable to the complexity of the questionnaire.

Adult↗
PubMed2000

[Hemophagocytic syndrome and metastatic melanoma: 3 cases].

BACKGROUND: Macrophage activation syndrome was initially described during viral infections in immunocompromised patients. Since the original report, many diseases have been found to be associated with macrophage activation syndrome. Lymphoproliferative disorders have been more frequently reported to be associated with macrophage activation syndrome than solid tumors. We herein report three cases of macrophage activation syndrome in patients with metastatic malignant melanoma. CASE-REPORTS: Two young 32 and 40 year-old men with a liver metastatic malignant melanoma and a 62 year-old woman with a polymetastatic malignant melanoma presented a sudden deterioration of general health with hyperthermia and biological abnormalities: liver cytolysis, leucocytosis, thrombocytopenia, hypertriglyceridaemia. A fatal clinical outcome occurred rapidly despite corticotherapy and/or chemotherapy. For the first two patients the macrophage activation syndrome diagnosis was delayed because of the similarities of macrophage activation syndrome and metastatic malignant melanoma symptoms. DISCUSSION: The diagnosis of macrophage activation syndrome in patients with metastatic malignant melanoma may be difficult because of the similarities between clinical features of macrophage activation syndrome and those of metastatic malignant melanoma. Hypertriglyceridaemia is present in 60 p. 100 of macrophage activation syndrome and should lead to process a bone marrow aspirate. The search for a triggering infection should be systematically carry out because it is implicated in more than half of macrophage activation syndrome whatever the associated disease may be: neoplasia, autoimmune disease. The pathogenesis of macrophage activation syndromes occurring in patients with metastatic cancer remains unexplained. Treatment of macrophage activation syndrome is not unanimously established and usually consists in the treatment of the associated condition as well as a corticosteroid and/or an immunosuppressive treatment regimens. Prognosis of macrophage activation syndrome is usually poor especially when it is associated with a neoplasia since a fatal outcome occurs in 40 to 60 p. 100 of cases.

Adult↗
PubMed1999

A sequence-ready BAC/PAC contig and partial transcript map of approximately 1.5 Mb in human chromosome 17q25 comprising multiple disease genes.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant recurrent neuropathy mapped to a 4-cM interval on chromosome 17q25 between the short tandem repeat (STR) markers D17S1603 and D17S802. Chromosome 17q25 in general and the 4-cM HNA region in particular are also implicated in the pathogenesis of a number of tumors (tylosis with esophageal cancer, sporadic breast and ovarian tumors) and harbor a psoriasis susceptibility locus. Initial attempts to construct a yeast artificial chromosome contig failed. Therefore, we have now constructed a complete P1 artificial chromosome (PAC) and bacterial artificial chromosome (BAC) contig of the region flanked by the STR markers D17S1603 and D17S802. The contig contains 22 PAC and 64 BAC clones and covers a physical distance of approximately 1. 5 Mb. A total of 83 sequence-tagged site (STS) markers (10 known STSs and STRs, 56 STSs generated from clone end-fragments, 12 expressed sequence tags, and 5 known genes) were mapped on the contig, resulting in an extremely dense physical map with approximately 1 STS per 20 kb. This sequence-ready PAC and BAC contig will be pivotal for the positional cloning of the HNA gene as well as other disease genes mapping to this region.

Bacteriophage P1↗
PubMed1999

Insulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-response element-binding protein.

Insulin-like growth factor-I (IGF-I) is known to prevent apoptosis induced by diverse stimuli. The present study examined the effect of IGF-I on the promoter activity of bcl-2, a gene with antiapoptotic function. A luciferase reporter driven by the promoter region of bcl-2 from -1640 to -1287 base pairs upstream of the translation start site containing a cAMP-response element was used in transient transfection assays. Treatment of PC12 cells with IGF-I enhanced the bcl-2 promoter activity by 2.3-fold, which was inhibited significantly (p < 0.01) by SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK). Cotransfection of the bcl-2 promoter with MAPK kinase 6 and the beta isozyme of p38 MAPK resulted in 2-3-fold increase in the reporter activity. The dominant negative form of MAPKAP-K3, a downstream kinase activated by p38 MAPK, and the dominant negative form of cAMP-response element-binding protein, inhibited the reporter gene activation by IGF-I and p38beta MAPK significantly (p < 0.01). IGF-I increased the activity of p38beta MAPK introduced into the cells by adenoviral infection. Thus, we have characterized a novel signaling pathway (MAPK kinase 6/p38beta MAPK/MAPKAP-K3) that defines a transcriptional mechanism for the induction of the antiapoptotic protein Bcl-2 by IGF-I through the nuclear transcription factor cAMP-response element-binding protein in PC12 cells.

Animals↗
PubMed1999

Structure of the alpha-actinin rod: molecular basis for cross-linking of actin filaments.

We have determined the crystal structure of the two central repeats in the alpha-actinin rod at 2.5 A resolution. The repeats are connected by a helical linker and form a symmetric, antiparallel dimer in which the repeats are aligned rather than staggered. Using this structure, which reveals the structural principle that governs the architecture of alpha-actinin, we have devised a plausible model of the entire alpha-actinin rod. The electrostatic properties explain how the two alpha-actinin subunits assemble in an antiparallel fashion, placing the actin-binding sites at both ends of the rod. This molecular architecture results in a protein that is able to form cross-links between actin filaments.

Actin Cytoskeleton↗
PubMed1999

Systematic review of topical treatments for fungal infections of the skin and nails of the feet.

OBJECTIVE: To identify and synthesise the evidence for efficacy and cost effectiveness of topical treatments for superficial fungal infections of the skin and nails of the feet. DESIGN: Systematic review. INTERVENTIONS: Topical treatments for superficial fungal infections. MAIN OUTCOME MEASURES: Cure confirmed by culture and microscopy for skin and by culture for nails in patients with clinically diagnosed fungal infections. RESULTS: Of 126 trials identified in 121 papers, 72 (57.1%) met the inclusion criteria. Placebo controlled trials yielded pooled relative risks of failure to cure skin infections: allylamines (0.30, 95% confidence interval 0.24 to 0.38); azoles (0.54, 0.42 to 0.68); undecenoic acid (0.28, 0. 11 to 0.74); and tolnaftate (0.46, 0.17 to 1.22). Although meta-analysis of 11 trials comparing allylamines and azoles showed a relative risk of failure to cure of 0.88 (0.78 to 0.99) in favour of allylamines, there was evidence of language bias. Seven reports in English favoured allylamines (0.79, 0.69 to 0.91), but four reports in foreign languages showed no difference between the two drugs (1. 01, 0.90 to 1.13). Neither trial of nail infections showed significant differences between alternative topical treatments. CONCLUSIONS: Allylamines, azoles, and undecenoic acid were efficacious in placebo controlled trials. There are sufficient comparative trials to judge relative efficacy only between allylamines and azoles. Allylamines cure slightly more infections than azoles but are much more expensive than azoles. The most cost effective strategy is first to treat with azoles or undecenoic acid and to use allylamines only if that fails.

Administration, Topical↗
PubMed1999

beta Blockade after myocardial infarction: systematic review and meta regression analysis.

OBJECTIVES: To assess the effectiveness of beta blockers in short term treatment for acute myocardial infarction and in longer term secondary prevention; to examine predictive factors that may influence outcome and therefore choice of drug; and to examine the clinical importance of the results in the light of current treatment. DESIGN: Systematic review of randomised controlled trials. SETTING: Randomised controlled trials. SUBJECTS: Patients with acute or past myocardial infarction. INTERVENTION: beta Blockers compared with control. MAIN OUTCOME MEASURES: All cause mortality and non-fatal reinfarction. RESULTS: Overall, 5477 of 54 234 patients (10.1%) randomised to beta blockers or control died. We identified a 23% reduction in the odds of death in long term trials (95% confidence interval 15% to 31%), but only a 4% reduction in the odds of death in short term trials (-8% to 15%). Meta regression in long term trials did not identify a significant reduction in effectiveness in drugs with cardioselectivity but did identify a near significant trend towards decreased benefit in drugs with intrinsic sympathomimetic activity. Most evidence is available for propranolol, timolol, and metoprolol. In long term trials, the number needed to treat for 2 years to avoid a death is 42, which compares favourably with other treatments for patients with acute or past myocardial infarction. CONCLUSIONS: beta Blockers are effective in long term secondary prevention after myocardial infarction, but they are underused in such cases and lead to avoidable mortality and morbidity.

Adrenergic beta-Antagonists↗
PubMed1999

Roles for Nkx3.1 in prostate development and cancer.

In aging men, the prostate gland becomes hyperproliferative and displays a propensity toward carcinoma. Although this hyperproliferative process has been proposed to represent an inappropriate reactivation of an embryonic differentiation program, the regulatory genes responsible for normal prostate development and function are largely undefined. Here we show that the murine Nkx3.1 homeobox gene is the earliest known marker of prostate epithelium during embryogenesis and is subsequently expressed at all stages of prostate differentiation in vivo as well as in tissue recombinants. A null mutation for Nkx3.1 obtained by targeted gene disruption results in defects in prostate ductal morphogenesis and secretory protein production. Notably, Nkx3.1 mutant mice display prostatic epithelial hyperplasia and dysplasia that increases in severity with age. This epithelial hyperplasia and dysplasia also occurs in heterozygous mice, indicating haploinsufficiency for this phenotype. Because human NKX3.1 is known to map to a prostate cancer hot spot, we propose that NKX3.1 is a prostate-specific tumor suppressor gene and that loss of a single allele may predispose to prostate carcinogenesis. The Nkx3.1 mutant mice provide a unique animal model for examining the relationship between normal prostate differentiation and early stages of prostate carcinogenesis.

Animals↗
PubMed1999

pKa values and the pH dependent stability of the N-terminal domain of L9 as probes of electrostatic interactions in the denatured state. Differentiation between local and nonlocal interactions.

pKa values were measured for the 6 carboxylates in the N-terminal domain of L9 (NTL9) by following NMR chemical shifts as a function of pH. The contribution of each carboxylate to the pH dependent stability of NTL9 was estimated by comparing the pKa values for the native and denatured state of the protein. A set of peptides with sequences derived from NTL9 were used to model the denatured state. In the protein fragments, the pKa values measured for the aspartates varied between 3.8 and 4.1 and the pKa values measured for the glutamates varied between 4.1 and 4.6. These results indicate that the local sequence can significantly influence pKa values in the denatured state and highlight the difficulties in using standard pKa values derived from small compounds. Calculations based on the measured pKa values suggest that the free energy of unfolding of NTL9 should decrease by 4.4 kcal mol-1 when the pH is lowered from 6 to 2. In contrast, urea and thermal denaturation experiments indicate that the stability of the protein decreases by only 2.6 kcal mol-1 when the carboxylates are protonated. This discrepancy indicates that the protein fragments are not a complete representation of the denatured state and that nonlocal sequence effects perturb the pKa's in the denatured state. Increasing the salt concentration from 100 to 750 mM NaCl removes the discrepancy between the stabilities derived from denaturation experiments and the stability changes calculated from the pKa values. At high concentrations of salt there is also less variation of the pKa values measured in the protein fragments. Our results argue that in the denatured state of NTL9 there are electrostatic interactions between groups both local and nonlocal in primary sequence.

Amino Acid Sequence↗
PubMed1999

Nativelike structure and stability in a truncation mutant of a protein minidomain: the peripheral subunit-binding domain.

Despite its small size, the peripheral subunit-binding domain from the dihydrolipoamide acetyltransferase component of the Bacillus stearothermophilus pyruvate dehydrogenase multienzyme complex adopts a unique, compact structure. To determine whether the full 43 residue sequence is required for the domain to adopt a stable, nativelike structure, 3 proteins of different lengths were prepared. Psbd41 corresponds to residues 3-43 of the domain, psbd36 spans residues 6-41, and psbd33 comprises residues 7-39. Psbd41 folds in a cooperative, two-state fashion with a Tm of 53 degrees C and a stability at 25 degrees C of 2.2 kcal mol-1. Psbd36 is nearly as stable with a Tm of 48 degrees C and a stability of 1.8 kcal mol-1. Similar m-values and heat capacities suggest that psbd36 and psbd41 bury approximately the same surface area. Minimal differences in CalphaH and NH chemical shifts between psbd41 and psbd36 show that the two sequences adopt the same tertiary fold. On a per residue basis, DeltaH degrees and DeltaC degrees p fall within the range typical for single-domain globular proteins. Psbd33 is significantly less stable. It is not fully folded at 25 degrees C, and at all temperatures it shows broadened NMR lines. ANS titrations provide evidence that this is due to an equilibrium between nativelike and unfolded molecules rather than formation of a molten globule. The fraction of psbd33 molecules which are folded appear to adopt the same structure as the full-length domain. Thus, although more than the 33 residue core is required to form a fully stable native structure, the entire sequence is not required for folding.

Amino Acid Sequence↗
PubMed1999

A randomized trial of Evidence-based OutReach (EBOR): rationale and design.

There is increasing interest in evaluating the methods used to implement the findings from medical research. This paper describes the Evidence-based OutReach (EBOR) trial, which is the first large randomized study in the United Kingdom that will evaluate the effectiveness and efficiency of educational outreach visits by trained pharmacists who are delivering messages derived from four evidence-based clinical practice guidelines. General practices form the unit of allocation and analysis. The study design addresses important factors that may influence the effectiveness of the intervention, such as the pharmacist who delivers the messages, the health authority in which practices are located, and the size of a practice.

Family Practice↗
PubMed1999

A case-control study of melanomas of the soles and palms (Australia and Scotland).

OBJECTIVES: Because the factors that influence risk of acral melanomas on the soles and palms in White populations are unknown, we investigated these in a multi-center case-control study. METHODS: Cases of melanoma of the feet and hands diagnosed from 1987-93 in persons aged over 18 years were ascertained in eastern Australia and western Scotland. There were 275 cases of melanoma on the soles and palms matched to 496 controls (selected from the electoral roll) in Australia, and 36 cases matched to 72 controls (nominated by general practitioners) in Scotland. RESULTS: Acral melanoma was strongly associated with high total body nevus counts (adjusted relative risk [RR] = 6.3, 95% confidence interval [CI] = 2.5-15.6), and with nevi on the soles (RR = 7.5, CI = 3.0-18.6). There were also significant positive associations with a penetrative injury of the feet or hands (RR = 5.0, CI = 3.0-8.6) and with heavy exposure to agricultural chemicals (RR = 3.6, CI = 1.5-8.3). Sun-sensitive complexions, cumulative sun exposure and a past history of nonmelanoma skin cancer were also associated with increased risk of acral melanoma. Current cigarette smoking was inversely related to acral melanoma (RR = 0.6, CI = 0.4-0.9). CONCLUSIONS: Melanomas of the soles and palms resemble other cutaneous melanomas in their association with sun exposure, but are distinguished from them by their strong positive associations with nevi on the soles, previous penetrative injury, and exposure to agricultural chemicals, and by their inverse association with smoking.

Adolescent↗
PubMed1999

Respiratory rehabilitation in chronic obstructive pulmonary disease: predictors of nonadherence.

Rehabilitation is now an integral part of chronic obstructive pulmonary disease (COPD) management. The objective of the study was to determine predictors of nonadherence to a COPD rehabilitation programme. Patients attending a COPD clinic were invited to participate in a 4 week, hospital-based, outpatient, COPD rehabilitation programme conducted predominantly by respiratory physiotherapists. All potential participants undertook an interviewer administered questionnaire addressing social, economic, psychological and healthcare factors, and underwent baseline physiological measures. Subsequently they were classified as: 1) "adherent" group who completed the total programme (n=55) or 2) "nonadherent" group who refused or began but did not complete the programme (n=36). The nonadherent group compared to the adherent group were more likely to be divorced (22 versus 2%, p<0.005), live alone (39 versus 14%, p<0.02), and to live in rented accommodation (31 versus 6%, p<0.005). There were no differences between the two groups in terms of baseline physiological parameters (forced expiratory volume in one second, forced vital capacity, 6-min walk distance, oxygen saturation, perceived dyspnoea), quality of life domains (Chronic Respiratory Disease Questionnaire), or indices of COPD-related morbidity. The nonadherent group were more likely to be current smokers (28 versus 8%, p<0.02) and less likely to use inhaled corticosteroids (16 versus 42%, p<0.005). The nonadherent group was not significantly likely to be depressed, anxious, prone to hyperventilation or to have had previous emotional counselling and was more likely to be dissatisfied with disease-specific social support (51 versus 2%, p<0.001). In conclusion, a substantial proportion of eligible subjects who did not participate in a chronic obstructive pulmonary disease rehabilitation programme were not more physiologically impaired, but were more likely to be: socially isolated, lack chronic obstructive pulmonary disease-related social support, still be smoking and be less compliant with other healthcare activities. Identification of one or more of these factors reliably allows prediction for nonadherence to a rehabilitation programme.

Aged↗