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Biomedical subjects

D M Watson

Publications and source records attributed to D M Watson.

At least 19 recordsLinked to original sources
PubMed2001

Duration of symptoms prior to diagnosis is related inversely to presenting disease stage in children with medulloblastoma.

BACKGROUND: The authors tested the hypothesis that children with a longer duration of symptoms prior to diagnosis of medulloblastoma have more advanced disease. In addition, they evaluated whether there are correlations between gender, duration of presenting symptoms, and disease stage. METHODS: The study population consisted of 122 patients with medulloblastoma who were evaluated between 1974 and 1999. The data abstracted from each chart included the date of diagnosis, date of birth, gender, race, presenting symptoms, duration of symptoms in weeks, and disease stage. RESULTS: There were 70 males (57%) and 52 females (43%); 105 Caucasians (86%), 16 non-Caucasians (13%), and 1 patient of unknown race. Eighteen percent of the patients were age < or = 3 years, 59% were ages 4-16 years, and 23% were age > or = 17 years. The presenting stage was determined in 108 patients. Thirty-eight patients (35%) had high stage disease (T1-T4 M1-M4), and 70 patients (65%) had low stage disease (T1-T4 M0). The most common presenting symptoms were emesis (68%), headache (66%), nausea (40%), and ataxia (40%). The median symptom durations for patients ages 0-3 years were 4 weeks and 8 weeks for both those ages 4-16 years and those age > or = 17 years, respectively (P > 0.11). The median symptom duration for males (8 weeks) was longer than for females (5 weeks; P = 0.08). Patients with low stage disease had a median duration of symptoms (8 weeks) that was significantly greater compared with patients with high stage disease (4 weeks; P = 0.01). Relating patient age to disease stage, 47% of patients ages 0-3 years had high stage disease; 36% of patients ages 4-16 years had high stage disease; and 24% of patients age > or = 17 years had high stage disease (P = 0.20). Relating disease stage to gender, 40% of males had high stage disease compared with 28% of females (P = 0.20). Of the factors age, gender, race, and duration of symptoms, only the later was correlated significantly with disease stage at the time of presentation in both univariate and multivariate analyses. CONCLUSIONS: Contrary to expectations, the duration of presenting symptoms was correlated inversely with disease state at the time of presentation. This finding has implications for lawsuits alleging that a "delay in diagnosis" leads to more advanced disease. There is weak evidence (P = 0.08) that males have a longer duration of symptoms than females. This may be related to gender-associated behavior expectations.

Adolescent↗
PubMed2001

Integrated pest management of two-spotted mite Tetranychus urticae on greenhouse roses using petroleum spray oil and the predatory mite Phytoseiulus persimilis.

From 1995 to 1999, four experiments were conducted on greenhouse roses to assess the effectiveness of the nC24 petroleum spray oil (PSO), D-C-Tron Plus, against two-spotted mite, Tetranychus urticae Koch (Acarina: Tetranychidae), and to determine how the oil could be most efficiently and effectively used in combination with the predatory mite Phytoseiulus persimilis Athias-Henriot (Acarina: Phytoseiidae) in an integrated pest management program. The results showed that 0.5% PSO applied fortnightly to roses gave excellent protection from T urticae infestation when the mite population was not already established. However, PSO applied after roses were infested with T. urticae above the economic threshold only stabilised populations without reducing them below that threshold. Populations of P. persimilis in the upper and lower canopies were unchanged after two sprays of PSO at 7-day intervals, and application of PSO to the upper canopy was as effective in controlling T. urticae in the presence of P persimilis as spraying the entire plant. Combining PSO with P. persimilis gave better control of T. urticae than using P. persimilis alone. The most cost-effective use of PSO in the presence of P. persimilis is, therefore, to apply spray only to the upper canopy. This will not affect control of powdery mildew with PSO. Comparison of a control program for T urticae based on the monitored use of synthetic miticides with that based on calendar application of PSO revealed that both gave equally effective control. The benefits of combining PSO and P. persimilis in an integrated pest management program for T. urticae on roses over a program based on synthetic fungicides are discussed.

Animals↗
PubMed1998

Evaluation and eligibility of HLA-identical sibling donors for stem cell/bone marrow donation.

Overall, the number of allogeneic transplants performed world-wide has not increased dramatically over the past 5 years. However, the proportion of allogeneic transplants undertaken using peripheral blood progenitor cells (PBPCs) has risen significantly. Currently, as part of an ethically approved trial, potential donors are seen, assessed and consented by physicians not caring directly for the recipients. Thirty-five potential sibling donors were seen and assessed for their willingness and fitness to donate for 28 patients. One donor opted to give bone marrow and the rest selected PBPC donation. Seven of these donors were found to have concurrent medical conditions. Due to poor venous access, one donor was advised to donate bone marrow and two others donated bone marrow due to an underlying condition. Four others were deemed unfit for donation. Donation of stem cells from bone marrow or peripheral blood is not a risk-free procedure; careful preassessment and counselling is mandatory especially when the age of prospective patients and therefore donors is increasing.

Adult↗
PubMed1994

Selective inhibition of mammalian lanosterol 14 alpha-demethylase by RS-21607 in vitro and in vivo.

The discovery of selective lanosterol 14 alpha-demethylase inhibitors may lead to novel hypolipidemic drugs. RS-21607, (2S,4S)-cis-2[1H-imidazol-1-yl)methyl]-2-[2-(4-chlorophenyl)ethyl]-4- [[(4-aminophenyl)thio]methyl]-1,3-dioxolane, was characterized as a tight-binding, competitive inhibitor of lanosterol 14 alpha-demethylase purified from rat liver. The apparent Ki was determined to be 840 pM and found to be similar in hepatic microsomes from human, rat, and hamster. RS-21607, which contains two chiral centers, was a more effective lanosterol 14 alpha-demethylase inhibitor than its three stereoisomers. In vitro, RS-21607 had a greater affinity for lanosterol 14 alpha-demethylase than the other cytochromes P450 evaluated: CYP7, CYP27, CYP11A1, CYP19, CYP17, CYP11B1, CYP21, CYP3A4, CYP4A, CYP2D6, CYP1A2, CYP2C9, and 27-hydroxycholesterol 7 alpha-hydroxylase. The other stereoisomers were not as selective as RS-21607. Doses of 3-30 mg/kg RS-21607 given orally to hamsters caused a dose-dependent decrease in cholesterol biosynthesis with a corresponding accumulation of 24,25-dihydrolanosterol. RS-21607 inhibited the enzyme and cholesterol biosynthesis in hamster liver by 50% at 18 h following a 30 mg/kg oral dose. This was interpreted to indicate that RS-21607 is able to distribute to the site of action in hamsters and inhibit the target enzyme. In the same dose range, the plasma concentrations of testosterone, corticosterone, and progesterone, the endpoints for the cytochromes P450 involved in steroid biosynthesis, were relatively unaffected. These data show RS-21607 to be an effective and selective inhibitor of lanosterol 14 alpha-demethylase, both in vivo and in vitro. RS-21607 interacted with the purified enzyme to produce a type II binding spectrum, consistent with an interaction between the imidazole moiety and the heme. The electrostatic contribution of the imidazole binding was investigated using the desimidazole analog of RS-21607. The apparent Ki for the desimidazole compound (65 microM) was similar to the apparent Km for the substrate DHL (79 microM). Together, these data confirm that the ligand attached to the imidazole in RS-21607 is a good non-sterol substitute for DHL, i.e., binding to the enzyme with similar affinity, and that the coordination of the imidazole to the heme provides a major electrostatic contribution for the inhibition of lanosterol 14 alpha-demethylase by RS-21607. RS-21607 was also observed to increase the accumulation of 3 beta-hydroxy-24,25-dihydrolanost-8-en-32-al, the second intermediate in the multistep oxidation, but not the first intermediate. 24,25-dihydrolanost-8-ene-3 beta,32-diol.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Accumulation of intermediates and isotopically sensitive enolization distinguish between aromatase (cytochrome P450 CYP19) from rat ovary and human placenta.

Aromatase activity in microsomes from human placenta (HPM) and rat ovary (ROM) was compared by measuring the accumulation of 19-oxygenated intermediates, the effect of tritium substitution upon rates, and the distribution of tritium in products. A considerable accumulation of intermediates (19-hydroxyandrogen and 19-al-androgen) and a lag in product formation (estrogen and water) was observed with ROM but not HPM. Addition of purified NADPH-cytochrome P450 reductase to ROM decreased the accumulation of 19-hydroxyandrostenedione and increased the rate of estrone formation. This difference could not be attributed to the microsomal reductase concentration since its concentration was similar in both tissues. Estrogen formation by aromatase from these tissues was not associated with a significant kinetic isotope effect when androstenedione was labeled with tritium at C-1 and C-2. Isotopically sensitive switching (branching) from the 19-al-androstenedione enzyme complex to form free 19-al-androstenedione rather than estrogen was not observed. These data suggest that for aromatase in both tissues, an enzymatic step exists between the 19-al-androstenedione intermediate and hydrogen abstraction or enolization that has a large commitment to catalysis. The distribution of tritium into the products, water and estrogen, was dependent upon substrate, enzyme source, and position of the label. Incubation of 1 beta, 2 beta-[3H]androstenedione and testosterone with ROM and 1 beta,2 beta-[3H]testosterone with HPM resulted in approximately 50% of the label being retained in the estrogen and 50% being lost in water. The majority of the label was lost in water upon incubation of 1 beta-labeled substrates with microsomes from both sources. Unexpectedly, no label was lost to water upon incubation of the specifically 1 alpha,2 alpha-labeled substrates with either enzyme source. Only incubation of 1 beta,2 beta-[3H]androstenedione with HPM resulted in loss of tritium from the 2-position. These data were interpreted to indicate that, for androstenedione metabolism by ROM and testosterone metabolism by both ROM and HPM, enolization occurs nonspecifically in an isotopically sensitive manner following deformylation, but for HPM metabolism of androstenedione enolization occurs in an enzyme-assisted manner. The studies show that aromatase located in ROM differs from that in HPM by its accumulation of intermediates and inability to selectively remove the 2 beta-tritium from androstenedione.

Androgens↗
PubMed1993

Tumour cyclic AMP binding proteins: an independent prognostic factor for disease recurrence and survival in breast cancer.

In two separate cohorts of breast cancer patients presenting without evidence of distant metastatic disease, high levels of tumour cyclic AMP binding proteins (> 8 pmol/mg cytosol protein) have been shown to be associated with poor prognosis in terms of both disease recurrence and overall survival. This association is independent of known established prognostic factors and allows the identification of a small subgroup of patients whose outlook warrants the implementation of aggressive systemic therapy.

Breast Neoplasms↗
PubMed1991

Topical amethocaine in strabismus surgery.

A randomized study was performed to assess the effect of topical 1% amethocaine hydrochloride on postoperative analgesia requirements after strabismus surgery. Forty children scheduled for elective operation were allocated randomly to receive either topical amethocaine or normal saline. Postoperative analgesia was evaluated with the use of a four-point assessment score and analgesic requirements. The topical amethocaine provided significantly better postoperative analgesia (p less than 0.001) as measured by both the assessment score and the postoperative analgesia requirement.

Anesthesia, Local↗
PubMed1991

Milrinone, a bridge to heart transplantation.

We describe the use of a milrinone infusion as a bridge to heart transplantation in the treatment of severe congestive cardiac failure secondary to viral cardiomyopathy. The clinical improvement that occurred when milrinone was commenced made it possible to wean the patient from conventional cardiovascular support with an intra-aortic balloon pump and dobutamine. There was an improvement in organ perfusion.

Cardiomyopathies↗
PubMed1991

Reversal of the relationship between heart rate and blood pressure in phaeochromocytoma: a non-invasive diagnostic approach?

A comparison was made between the relationship of heart rate and blood pressure over 24 hours in three patients with phaeochromocytoma and in 56 patients with untreated essential hypertension. All patients wore a non-invasive ambulatory monitor (Accutracker) for 24 hours. A diurnal rhythm of BP and pulse was seen in essential hypertension [daytime; BP 155 +/- 18/86 +/- 12 mmHg (mean +/- SD), pulse 79 +/- 13. Night-time; 142 +/- 21/73 +/- 14 mmHg, pulse 68 +/- 12, P less than 0.05] and a positive correlation was observed between BP and pulse (r = +0.53). Patients with phaeochromocytoma had no diurnal rhythm of BP and all three had a negative relationship between BP and pulse (r = -0.66, -0.51 and -0.79). This negative relationship was abolished by alpha blockade and became positive (+0.5 and +0.6) in two patients who were cured by surgery. The 'normalisation' of this relationship was associated with an increase in plasma volume of approximately 500 ml and probably reflects an intact baro-reflex system in phaeochromocytoma. The observation of a lack of diurnal rhythm together with a negative correlation between BP and pulse may be a clue to phaeochromocytoma in patients with raised blood pressure.

Adrenal Gland Neoplasms↗
PubMed1990

Pharmacokinetics and toxicity of two schedules of high dose epirubicin.

Epirubicin, a stereoisomer of doxorubicin, is reported to have equal antitumor activity with lower cardiac and systemic toxicity. Recently the maximum tolerated dose of this drug has been revised upwards with reported increased response rates. However, the pharmacokinetics of epirubicin at high doses have never been reported. Accordingly, this study was designed to evaluate the pharmacokinetics of epirubicin when administered as either a 15-min i.v. bolus or a 6-h i.v. infusion in a phase I study at high doses. Nineteen patients with a variety of malignancies were given a total of 52 cycles of epirubicin at doses of 90 to 150 mg/m2 given once every 3 weeks. The maximum tolerated dose was 150 mg/m2 epirubicin given either as a bolus or as an infusion. The major dose-limiting toxicity was neutropenia. Interpatient variation occurred in the pharmacokinetics at each dose level but overall there were dose-dependent pharmacokinetics. This was manifested as a disproportionate increase in plasma levels and areas under the curve as the epirubicin dose was increased from 90 to 150 mg/m2. The pharmacokinetics of epirubicin could best be described by an open two-compartment model. Peak plasma concentrations were attained at a median of 12 min following the bolus injection and concentrations approached the steady state within a median of 55 min following the start of the 6-h infusion. Administration of the 150 mg/m2 dose over the 6 h compared to the bolus administration was associated with a 92% decrease in peak concentration from 3088 +/- 1503 to 234 +/- 126 ng/ml. This was not associated with an appreciable change in hematological or nonhematological toxicities. The median distribution half-life was 10 min and the median elimination half-life was 42.0 h. The cumulative renal excretion of the parent compound accounted for less than 2% of the administered dose. The major metabolites in both plasma and urine samples were 4'-O-beta-D-glucuronyl-4'-epidoxorubicin, 13-S-dihydro-4'-epidoxorubicin, and 4'-O-beta-D-glucuronyl-13-S-dihydro-4'-epidoxorubicin. This study demonstrates that a 135 mg/m2 bolus infusion given on a 3-weekly schedule is an appropriate initial dose for further clinical studies.

Biotransformation↗
PubMed1990

Cyclic AMP binding proteins and prognosis in breast cancer.

Cyclic AMP binding proteins were measured in the primary tumour from 100 patients with non-disseminated breast cancer selected on the basis that sufficient tumour material was available for analysis. These measurements have been related to factors of established prognostic value and to the patients' disease-free interval and survival. There was a wide variation in amounts of binding proteins in different tumours. Values were significantly higher (P less than 0.05) in oestrogen receptor-negative tumours but no statistically significant correlations were apparent between levels and tumour grade or whether the patients had lymph node metastasis or adjuvant treatment. However, levels were significantly higher in patients whose disease recurred within 3 years of primary treatment as compared with those who remained disease-free. Using a retrospectively determined cut off point of 8 pmol mg-1 cytosol protein, it was shown that patients with tumour cyclic AMP binding in excess of this value had a significantly greater chance of developing recurrent disease and poorer survival rates (P less than 0.001 by Cox analysis) than those with lower levels. This remained true when other prognostic factors were taken into account in a multivariate analysis. It is suggested that the level of tumour cyclic AMP binding may be an independent prognostic factor for patients with early breast cancer.

Breast Neoplasms↗
PubMed1990

Use and importance of the NIH noncompeting continuation application.

Each year National Institutes of Health (NIH) grant recipients must submit a noncompeting continuation application before receiving continued federal funding. This paper describes the use and value of the application. Investigators benefit by a yearly self-assessment of the research progress and future plans. The noncompeting continuation application is part of the important communication and interaction that should exist between the investigator and NIH staff. NIH staff members use the application to determine important scientific advances that have resulted from supported grants. Many planning activities and required reports are based on information contained in these applications. NIH staff performs scientific and budgetary review to ensure that research progress is satisfactory and that all budgetary and certification issues are in order. Detailed guidance is provided to help the grantee prepare the application. A separate significance section is suggested as a means to document key findings and their importance.

Financing, Government↗
PubMed1990

Cyclic-AMP binding proteins in the head and neck.

Results are presented of a preliminary study in which cAMP binding activity was measured in 34 specimens from a variety of head and neck sites. A wide range of cAMP binding protein levels was detected in all tissues assessed. There appeared to be a subgroup of parotid adenomas with increased cAMP binding activity. The biological significance of these proteins remains to be determined and their relationship to tumour growth in the head and neck is likely to be complex.

Adenoma↗
PubMed1990

Problems in the measurement of blood pressure.

Several placebo-controlled trials have established the value of drug treatment in even mild hypertension. It is axiomatic, however, that prior to treatment of an individual patient it be known that blood pressure is consistently elevated. In addition, assessment of the value of any particular form of therapy depends upon the accurate measurement of blood pressure. Unfortunately current evidence would suggest that neither of these prerequisites pertain. This paper reviews the evidence for this and discusses ways of improving clinical practice.

Ambulatory Care↗
PubMed1989

Role of corticosteroids in the diurnal rhythm of blood pressure.

Blood pressure, a chronobiological parameter, shows a circadian rhythm which parallels the levels of hormones such as glucocorticoids and catecholamines. This rhythm is lost in excess states like Cushing's syndrome or phaeochromocytoma. We designed a double-blind crossover study to look at the role of physiological doses of glucocorticoids in the circadian rhythm of blood pressure. We found no change in the circadian rhythm when 30 mg hydrocortisone (20 + 10 mg versus 10 + 20 mg, a.m./p.m.) was administered.

Addison Disease↗