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Biomedical subjects

M Brown

Publications and source records attributed to M Brown.

At least 343 records · Page 19Linked to original sources
PubMed1995

Quinazoline-based thymidylate synthase inhibitors: relationship between structural modifications and polyglutamation.

Quinazoline-based analogues of folic acid are a group of thymidylate synthase (TS) inhibitors that display a wide spectrum of activity for cultured tumour cells, partly due to their differential ability to form polyglutamate metabolites that are (i) more potent TS inhibitors and (ii) not readily effluxed from cells. The rate of cell membrane transport and folylpolyglutamate synthetase substrate activity influence compound polyglutamation. A series of intact-cell assays has been used to determine how specific modifications of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolate (ICI 198583) affect compound polyglutamation. Those containing the 'classical' glutamate structure were usually, but not always, well polyglutamated intracellularly. Replacement of N10 propargyl with smaller aliphatic substituents, particularly when combined with replacement of the benzene ring with thiophene or thiazole heterocycles, was beneficial for antitumour activity through polyglutamate formation. Fluorination of the benzene, particularly if a F was adjacent to the 'bridge region' (3'F or 2',5'diF), also gave compounds with a high dependence on polyglutamation for activity. Those analogues with 2-CH2OH or NH2 substituents were poor substrates for the reduced-folate cell membrane carrier which can account for their reduced polyglutamation rate and hence growth-inhibitory activity. A large decrease or prevention of polyglutamation was achieved by the introduction of CH3, CH2CH3, Br or C1 on C7. The concomitant enhancement in TS inhibition by these modifications gave compounds active under continuous-exposure cell culture conditions. Some ICI 198583 analogues had the glutamate moiety replaced with unnatural amino acids or dipeptides. Only the L-gamma-L-glu analogue (a polyglutamate metabolite of ICI 198583) gave activity entirely attributable to polyglutamate formation.

Animals↗
PubMed1995

A new in-vitro model to investigate antibiotic penetration of the intervertebral disc.

We have studied the ability of a range of antibiotics to penetrate intervertebral disc tissue in vitro, using a mouse disc model. Equilibrium concentrations of antibiotics incorporated into the entire disc were determined by bioassay using a microbial growth-inhibition method. Uptake was significantly higher with positively-charged aminoglycosides compared with negatively-charged penicillins and cephalosporins. Uncharged ciprofloxacin showed an intermediate degree of uptake. Our results support the hypothesis that electrostatic interaction between charged antibiotics and negatively-charged glycosaminoglycans in the disc is an important factor in antibiotic penetration, and may explain their differential uptake.

Animals↗
PubMed1995

Epilepsy and children's social and psychological adjustment.

This research investigates the effects of epilepsy on the social and psychological adjustment of the children studied in the National Health Interview Survey of 1988. Analyses examine the effect of epilepsy on four measures of adjustment--home behavior problems, school behavior problems, depressed mood, and impulsiveness. For each outcome, we address five questions: (1) Do children with currently active epilepsy have poorer adjustment than children with inactive epilepsy? (2) Do children with epilepsy fare worse than other children? (3) Do demographic background and family structure moderate the apparent effects of epilepsy? (4) Do family processes mediate the apparent effects of epilepsy? and (5) Do cooccurring conditions produce the apparent effects of epilepsy? Generally, we find that: (1) Children with active and inactive epilepsy fare about equally; (2) Children with any history of epilepsy fare worse than children without epilepsy; (3) Demographic and family background moderate only a small part of epilepsy's effect; and (4) A combination of family processes and cooccurring conditions appears to produce epilepsy's apparent effects.

Adaptation, Psychological↗
PubMed1995

The older athlete with tennis elbow. Rehabilitation considerations.

Athletic injury in the older adult community is likely to have more serious repercussions than a similar injury in a young adult because of age-related change. A balance between adequate rest and restoration of movement and strength must be established. Recovery from an athletic injury should be expected, but older tissues take more time to heal. Rest, cold application, avoidance of stressful movements, and compression are known to be highly effective for alleviating symptoms, but other modalities may further enhance recovery. To avoid reinjury and further complications, strength and ROM must be fully restored in the older adult athlete. A careful evaluation of causative factors, treatment efficacy, and the recovery phase is imperative.

Athletic Injuries↗
PubMed1995

Lack of association between angiotensinogen polymorphism (M235T) and cerebrovascular disease and carotid atheroma.

Genetic influences in cerebrovascular disease (CVD) may act either independently or by predisposing to, or modulating, the effect of risk factors such as hypertension. Factors involved in the pathogenesis of atherosclerosis, thrombosis and vasoconstriction are important in CVD. The angiotensinogen gene has recently been linked with essential hypertension in affected sibships and a particular polymorphism in exon 2 of the angiotensinogen gene, a threonine to methionine substitution at position 235 (M235T), has been associated with pre-eclampsia and hypertension. In this study we examined the relation of M235T polymorphism to cerebrovascular disease and carotid atheroma in 100 consecutive Caucasian patients with internal carotid artery territory ischaemia (TIA or stroke), presenting to a carotid ultrasound service. Forty five age-matched controls (mostly patients' spouses) were also studied. Hypertension was defined as current treatment with anti-hypertensive agents, or SBP > 160 mm Hg or DBP > 95 mm Hg. Twelve of 100 cases (12%) and eight of 45 controls (12%) were homozygous for the T235 allele. T:M allele ratios were 0.34:0.66 in cases and 0.34:0.66 in controls. There was no relation between the polymorphism and either internal carotid stenosis or common carotid artery intima-media thickness. In the cases, mean percentage internal carotid artery stenosis was TT 18.3 (SD 18.7)%, MT 38.0 (27.1)% and MM 36.8 (30.2)%. Mean intima-media thickness was TT 0.87 (0.18) mm, MT 0.95 (0.34) mm and MM 0.88 (0.23) mm. There was no relation between the polymorphism and hypertension (TT 11 of 100 cases, six of 45 controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Prognostic significance of a fixed thallium defect one to six months after onset of acute myocardial infarction or unstable angina. Multicenter Myocardial Ischemia Research Group.

In a large prospective study of myocardial ischemia, exercise thallium studies were performed in 896 patients 1 to 6 months after an acute coronary event (acute myocardial infarction, 70%; unstable angina, 30%). Thallium images were analyzed quantitatively and classified as normal or demonstrating either a reversible defect after 2 to 4 hours or having only a fixed defect. The effect of the thallium findings on the time to end point (cardiac death, nonfatal infarction, or unstable angina) were examined by Kaplan-Meier curves and compared using the log-rank statistic. Follow-up averaged 23 months. The likelihood of cardiac death, nonfatal infarction, and unstable angina was similar in patients who had a normal exercise thallium test result or showed only a fixed defect. Moreover, cardiac events were not related to the size of a fixed defect. In contrast, both cardiac death and nonfatal infarction were increased in patients with the largest areas of reversible defects, although the sensitivity for nonfatal myocardial infarction was suboptimal. The presence of a fixed defect on exercise thallium in patients who are stable an average of 2.6 months after an acute cardiac event is associated with a prognosis similar to that of a normal exercise thallium test.

Angina, Unstable↗
PubMed1994

Effect of cysteine substitutions on the mitogenic activity and stability of recombinant human keratinocyte growth factor.

Human Keratinocyte growth factor (hKGF), a member of the FGF family of growth factors, contains five cysteines at amino acid positions 1, 15, 40, 102, and 106. We expressed five cysteine mutants of hKGF in which the cysteines were cumulatively replaced with alanine or serine, starting with cysteine-1. Recombinant hKGF has an inherently higher mitogenic activity and stability to heat and acid than reported for glycosylated hKGF. Mitogenic activity is increased an additional 2.6 fold by substitution of cysteine-1 with alanine. Mutants with the conserved cysteine substituted at position 40 were more susceptible to heat inactivation than rhKGF, but showed no significant difference in acid inactivation. Cysteine-free rhKGF is mitogenic, demonstrating that neither cysteines nor disulfide bonds are required for mitogenic activity. However, cysteine-free rhKGF does not bind Heparin-Sepharose and is unstable to heat and acid compared to rhKGF, suggesting that the cysteines have a role in maintaining KGF's structure. This information will useful in the development of a more stable and more potent wound healing agent from hKGF.

Animals↗
PubMed1994

Stochastic context-free grammars for tRNA modeling.

Stochastic context-free grammars (SCFGs) are applied to the problems of folding, aligning and modeling families of tRNA sequences. SCFGs capture the sequences' common primary and secondary structure and generalize the hidden Markov models (HMMs) used in related work on protein and DNA. Results show that after having been trained on as few as 20 tRNA sequences from only two tRNA subfamilies (mitochondrial and cytoplasmic), the model can discern general tRNA from similar-length RNA sequences of other kinds, can find secondary structure of new tRNA sequences, and can produce multiple alignments of large sets of tRNA sequences. Our results suggest potential improvements in the alignments of the D- and T-domains in some mitochondrial tRNAs that cannot be fit into the canonical secondary structure.

Algorithms↗
PubMed1994

Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription.

The estrogen receptor is a transcription factor which, when bound to estradiol, binds DNA and regulates expression of estrogen-responsive genes. A 160-kilodalton estrogen receptor-associated protein, ERAP160, was identified that exhibits estradiol-dependent binding to the receptor. Mutational analysis of the receptor shows that its ability to activate transcription parallels its ability to bind ERAP160. Antiestrogens are unable to promote ERAP160 binding and can block the estrogen-dependent interaction of the receptor and ERAP160 in a dose-dependent manner. This evidence suggests that ERAP160 may mediate estradiol-dependent transcriptional activation by the estrogen receptor. Furthermore, the ability of antiestrogens to block estrogen receptor-ERAP160 complex formation could account for their therapeutic effects in breast cancer.

Base Sequence↗
PubMed1994

Hidden Markov models in computational biology. Applications to protein modeling.

Hidden Markov Models (HMMs) are applied to the problems of statistical modeling, database searching and multiple sequence alignment of protein families and protein domains. These methods are demonstrated on the globin family, the protein kinase catalytic domain, and the EF-hand calcium binding motif. In each case the parameters of an HMM are estimated from a training set of unaligned sequences. After the HMM is built, it is used to obtain a multiple alignment of all the training sequences. It is also used to search the SWISS-PROT 22 database for other sequences that are members of the given protein family, or contain the given domain. The HMM produces multiple alignments of good quality that agree closely with the alignments produced by programs that incorporate three-dimensional structural information. When employed in discrimination tests (by examining how closely the sequences in a database fit the globin, kinase and EF-hand HMMs), the HMM is able to distinguish members of these families from non-members with a high degree of accuracy. Both the HMM and PROFILESEARCH (a technique used to search for relationships between a protein sequence and multiply aligned sequences) perform better in these tests than PROSITE (a dictionary of sites and patterns in proteins). The HMM appears to have a slight advantage over PROFILESEARCH in terms of lower rates of false negatives and false positives, even though the HMM is trained using only unaligned sequences, whereas PROFILESEARCH requires aligned training sequences. Our results suggest the presence of an EF-hand calcium binding motif in a highly conserved and evolutionary preserved putative intracellular region of 155 residues in the alpha-1 subunit of L-type calcium channels which play an important role in excitation-contraction coupling. This region has been suggested to contain the functional domains that are typical or essential for all L-type calcium channels regardless of whether they couple to ryanodine receptors, conduct ions or both.

Algorithms↗
PubMed1994

Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity.

BACKGROUND: Prostate adenocarcinoma is a significant cause of morbidity and mortality in older men. However, the histologic prevalence far exceeds clinically manifest disease. Increased screening has resulted in the detection of a large number of carcinomas of unknown malignant potential. The authors investigated tumor angiogenesis to predict pathologic stage in prostatic tumors. Angiogenesis in prostatic intraepithelial neoplasia (PIN), a putative premalignant lesion, also was investigated. METHODS: Immunohistochemistry was used to highlight the tumor vasculature. Vessels were quantified using computerized image analysis. A minimum of five randomly selected microscopic fields were measured from each tumor. To investigate PIN, the authors measured vessels per millimeter of gland perimeter, compared with benign glands in the same patient. RESULTS: Vessel density (vessels per millimeter squared [vv/mm2]) correlated with pathologic stage. The mean vessel density of organ-confined tumors was 80.2 vv/mm2 (95% confidence interval [CI], 71.4-91.0), compared with 110.4 vv/mm2 (95% CI, 97.9-122.8) for tumors with capsular penetration or positive lymph nodes. Logistic regression analysis and modeling showed vessel density superior to histologic grade and preoperative prostate-specific antigen (PSA) level in distinguishing organ-confined tumors from those having extracapsular extension or pelvic lymph node metastasis. PIN in acini and ductules had increased microvascularity relative to benign epithelium in 18 of 25 tumors (P < 0.05). CONCLUSIONS: Neovascularity has been demonstrated to be a prerequisite for tumor progression. These data demonstrate that microvessel density in prostatic carcinoma is an independent predictor of pathologic stage and, presumably, malignant potential. Quantification of tumor angiogenesis may allow stratification of patients to type of treatment and may allow selection of expectant management for men with low tumor microvessel density.

Adenocarcinoma↗
PubMed1994

Prediction of atherosclerotic cardiovascular death in men using a prognostic score.

Treadmill and clinical data were gathered prospectively on consecutive patients who underwent exercise testing for evaluation for coronary artery disease in a 1,200 bed Veterans Affairs Medical Center. From 3,609 men referred for exercise testing from 1984 to 1990, 3,134 patients remained after excluding those with significant valvular heart disease and those with prior coronary artery bypass surgery. Of these, 588 were selected for clinical reasons to undergo cardiac catheterization within 3 months of evaluation leaving 2,546 who were not selected. Over 3 years, there were 158 cardiovascular deaths, 99 nonfatal myocardial infarcts and 183 patients who underwent coronary artery bypass surgery. In the total population, the Cox proportional-hazards model demonstrated the following characteristics to be statistically significant independent predictors of time until cardiovascular death: a history of congestive heart failure and/or taking digoxin, exercise-induced ST depression, the change in systolic blood pressure during exercise, and exercise capacity in METs. Using the Cox model coefficients to weight the variables, a simple score (the Veterans Affairs Prognostic Score) was constructed based on these items. Average annual cardiovascular mortality was plotted against the score enabling its estimation for any given patient. In the subgroup selected for cardiac catheterization (n = 588), the mean score was greater, consistent with a poorer prognosis, compared with the total population; 53% (n = 312) had a score < -2 associated with an annual mortality < 2%. Thus, in over half of the patients selected for catheterization, the catheterization was unnecessary if performed to lessen their chance of cardiovascular death, since no intervention could improve their prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Hypopyon uveitis in patients with acquired immunodeficiency syndrome treated for systemic Mycobacterium avium complex infection with rifabutin.

OBJECTIVE: Iridocyclitis has been identified as a dosage-dependent side effect in patients with the acquired immunodeficiency syndrome (AIDS) who are treated for Mycobacterium avium complex (MAC) infection with systemic rifabutin. We reviewed cases of acute hypopyon uveitis occurring in patients with AIDS to establish whether there was an association. DESIGN: Retrospective case series. SETTING: Outpatient clinic and inpatient hospital-based ophthalmology referral practice and infectious disease specialty service. PATIENTS: Seven patients with AIDS, aged 10 to 40 years, presenting with acute unilateral hypopyon mimicking infectious endophthalmitis. MAIN OUTCOME MEASURES: Findings from complete ophthalmological evaluation and ancillary laboratory testing. RESULTS: At the time of presentation, all seven patients were receiving treatment for MAC infection with rifabutin (dosage range, 300 to 600 mg/d) and clarithromycin. Results of microbiological investigations in five patients were negative. Iridocyclitis became bilateral in all seven patients, and hypopyon developed in the contralateral eye in five of seven patients. Hypopyon resolved rapidly with intensive topical corticosteroid therapy. Residual inflammation responded to topical corticosteroids with or without reduction of the rifabutin dosage. CONCLUSIONS: Concomitant use of rifabutin, clarithromycin, and fluconazole may precipitate hypopyon uveitis in patients with AIDS being treated for MAC infection.

AIDS-Related Opportunistic Infections↗