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J A Dunn

Publications and source records attributed to J A Dunn.

At least 37 records · Page 2Linked to original sources
PubMed1998

MRC trial of alpha2b-interferon maintenance therapy in first plateau phase of multiple myeloma. MRC Working Party on Leukaemia in Adults.

Plateau phase has been achieved in 64% of all newly diagnosed patients with multiple myeloma treated with the ABCM (adriamycin, BiCNU, cyclophosphamide and melphalan) regimen in the Medical Research Council (MRC) trials; this stable clinical stage of the disease is associated with no more than minimal symptoms. Several studies have found that alpha-interferon (alpha-IFN) maintenance therapy increases the duration of plateau phase, but it is less clear if this translates into prolonged survival. We report the effect of alpha-IFN on the duration of plateau phase and overall survival in a trial with 284 patients who were randomized to receive alpha2b-IFN (Intron-A) or no maintenance therapy during first plateau phase. The minimum follow-up after randomization was 21 months. There was no significant difference in the overall survival between the two treatment groups (X2=0.32, P=0.57). There was a trend towards longer relapse-free survival in the patients allocated alpha-IFN, but this trend to longer plateau phase was not statistically significant (X2 = 1.62, P = 0.2). Disease progression at relapse on alpha-IFN appears to be more severe with greater elevations from plateau levels of serum paraprotein (P = 0.06) and beta2-microglobulin (P= 0.03) levels. Physicians tended to start chemotherapy sooner after diagnosis of relapse when patients had received alpha-IFN (P = 0.16). Although, in common with most other studies, there is a trend for patients treated with alpha-IFN to have a longer plateau phase, this is counteracted by morbidity attributable to the treatment and a somewhat shortened survival post relapse. Meta-analysis of interferon trials is required to assess whether the minor trend for longer survival in patients maintained on alpha-IFN found in some studies is significant and, if so, the extent of this advantage.

Adult↗
PubMed1997

Immunoglobulin molecules are present in early-generated neuronal populations in the rat cerebral cortex and retina.

Immunoglobulin-like antigens have been identified in neuronal subsets restricted to deeper layers of the developing mammalian cerebral cortex. The pattern is suggestive of selective uptake of immunoglobulin (Ig) from serum or synthesis of Ig or a molecule with Ig-like motifs. To distinguish between these alternatives, biochemical, immunocytochemical, and birthdating analyses were conducted. In neonatal rat cerebral cortex, immunoglobulin-like immunoreactivity was chiefly in subplate neurons, marginal zone neuropil, and processes spanning the cortical plate. Isolated staining was also observed within the ventricular zone. Although most staining in the cortical plate was absent several days after birth, subplate neuron staining persisted until the end of the second postnatal week. Quantitative immunoassays showed that the antigen concentration dropped from 130 ng/mg in cortical cytosol at birth to approximately 80 ng/mg by postnatal day 7 (P7) and remained low thereafter. Two Ig-immunoreactive polypeptides with mobilities similar to heavy and light chains of serum IgG, were identified by Western blotting. The larger band was purified, partially sequenced by Edman degradation, and found to match rat IgG heavy chain. Bromodeoxyuridine birthdating and anti-IgG double-labeling studies showed that most of the Ig-containing cells were early-generated neurons. Outside of the cortex, transient IgG staining was also detected in neurons of the retina and cerebellum. These studies suggest that subplate and other early-generated neurons selectively take up Ig from serum. The IgG may then either be degraded or lost from the central nervous system (CNS) during developmentally regulated cell death.

Amino Acid Sequence↗
PubMed1997

Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers.

Bupropion is an antidepressant agent that is also effective as an aid to quit cigarette smoking. A single 150-mg tablet of sustained-release bupropion hydrochloride was administered to two groups of volunteers, cigarette smokers and nonsmokers, who were matched for race, gender, body frame, age, and weight. Pharmacokinetic parameters were calculated for bupropion, and three major metabolites (hydroxybupropion and the aminoalcohol isomers, threohydrobupropion and erythrohydrobupropion, expressed as a composite total). Mean (+/-SD) values of area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity), maximum concentration (Cmax), time to reach Cmax (tmax), and half-life (t1/2) of bupropion in smokers and nonsmokers, respectively, were 1,164 +/- 220 ng.hr/mL and 1,161 +/- 292 ng.hr/mL; 144 +/- 28 ng/mL and 143 +/- 39 ng/mL; 3.00 +/- 0.50 hours and 2.88 +/- 0.49 hours; and 19 +/- 5 hours and 18 +/- 3 hours. No clinically significant differences between smokers and nonsmokers or between male and female volunteers were observed for the pharmacokinetics of bupropion or its metabolites. The absence of pharmacokinetic differences indicates that dosage adjustments are not necessary when bupropion is prescribed to male and female cigarette smokers.

Adolescent↗
PubMed1997

Randomised trial of immediate versus deferred treatment strategies for the management of minor cervical cytological abnormalities.

OBJECTIVE: To compare immediate and deferred treatment in women with cervical smears showing borderline nuclear abnormalities or mild dyskaryosis. DESIGN: Prospective randomised trial. SETTING: Colposcopy clinics at Birmingham and Midland Hospital for Women and the City Hospital NHS Trust, Dudley Road, Birmingham. PARTICIPANTS: Four hundred and thirty-five women with minor cytological abnormality younger than 35 years of age, of whom 353 were randomised to immediate treatment or deferred treatment. MAIN OUTCOME MEASURES: Comparison of histologies in the subsequent two years in the immediate and deferred treatment groups. RESULTS: Thirty-six women (21%) defaulted from follow up. The percentage of high grade abnormalities (CIN II and III) in the deferred treatment arm at two years is similar to that in the immediate treated arm at first colposcopy (25% vs 24%). Cytology failed to pick up two cases of CIN III and there was one case of early invasive carcinoma at the six month follow up. If treatment is deferred, the proportion with CIN I is almost halved (25% vs 13%); the proportion with koilocytic atypia is slightly reduced (51% vs 42%) and the proportion with no abnormality is substantially increased (0.6% vs 20%). CONCLUSION: Immediate referral and a select-and-treat management strategy of all women with any degree of dyskaryosis is recommended based on the case of invasive cervical cancer, high default rate and the failure of cytology to pick up two cases of CIN III.

Adolescent↗
PubMed1997

Therapeutic modification of nuclear factor kappa B binding activity and tumor necrosis factor-alpha gene expression during acute biliary pancreatitis.

The role of cytokines has been well documented in the pathogenesis of acute pancreatitis. Antibodies against specific cytokines have been used to treat pancreatitis, with mixed results. The transcription factor nuclear factor (NF)-kappa B is a pleiotropic regulator of many genes involved in stress and inflammatory responses. The aim of this study was to prevent the NF-kappa B binding activity and tumor necrosis factor (TNF)-alpha gene overexpression as a possible therapeutic intervention for acute pancreatitis. Reversible acute biliary pancreatitis was induced in male Sprague Dawley rats as established in this laboratory. The animals were sacrificed at 0, 5, 15, 30 min and 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after the induction of pancreatitis. NF-kappa B binding activity was determined by electrophoretic mobility shift assay, and TNF-alpha gene expression was assayed by reverse transcription-PCR. NF-kappa B binding activity was markedly higher around 4 hours and persisted up to 24 hours after pancreatitis induction in animals with acute pancreatitis, whereas TNF-alpha mRNA levels peaked at 24 hours. When amobarbital (to block NF-kappa B activation) was given (60 mg/kg body weight, I.P.) 3 hours before induction of pancreatitis, the activation of NF-kappa B and the overexpression of TNF-alpha gene was prevented, with significantly decreased severity of pancreatitis as assessed by amylase and clinical recovery. We conclude that 1) preventing the activation of NF-kappa B eliminates the induced overexpression of inflammatory cytokines (TNF-alpha) in acute pancreatitis, 2) such intervention correlates with clinical improvement in pancreatitis, and 3) this genetic modification offers a possible therapeutic intervention in acute pancreatitis.

Acute Disease↗
PubMed1996

Validation of a high-performance liquid chromatographic-mass spectrometric method for the measurement of 5-chloro-2',3'-dideoxy-3' -fluorouridine (935U83) in human plasma.

An isocratic reversed-phase LC-MS method for measuring concentrations of 5-chloro-2',3'-dideoxy-3'-fluorouridine (935U83; I) directly and its 5'-glucuronide metabolite (5-chloro-2',3'-dideoxy-5'-O-beta-D-glucopyranuronosyl-3'-fluorour idine) indirectly in human plasma was developed, validated, and applied to a Phase I clinical study. The pyrimidine nucleoside, I, was extracted from human plasma by using anionic solid-phase extraction. The concentration of the glucuronide conjugate was determined from the difference between the molar concentration of I in a sample hydrolyzed with beta-glucuronidase and the nonhydrolyzed sample. Recovery of I from human plasma averaged 90%. The bias of the assay for I ranged from -5.5 to 7.1% during the validation and from -6.0 to 1.4% during application of the assay to the Phase I single-dose escalation study. The intra- and inter-day precision was less than 8% for I and its glucuronide conjugate. The lower and upper limits of quantitation for a 50-microliters sample were 4 ng/ml and 3000 ng/ml, respectively. No significant endogenous interferences were noted in human plasma obtained from drug-free volunteers nor from predose samples of HIV-infected patients.

Antiviral Agents↗
PubMed1996

In vitro characterization of a novel series of platelet-derived growth factor receptor tyrosine kinase inhibitors.

In this report, we describe the discovery and characterization of a novel biarylhydrazone series of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors typified by the prototype WIN 41662 (3-phenyl-N1-[1-(4-pytidyl)pyrimidine]hydrazone). WIN 41662 inhibited PDGF-stimulated autophosphorylation of PDGF receptors from human vascular smooth muscle cells (hVSMC) with an IC50 value of 60 nM. The inhibitor appeared to be competitive with respect to substrate (Mn(2+)-ATP), having a calculated Ki of 15 +/- 5 nM. WIN 41662 was approximately 500-fold more potent in inhibiting the PDGF receptor tyrosine kinase than the p56lck tyrosine kinase. It was inactive against other serine/threonine and tyrosine kinases tested. WIN 41662 produced concentration-dependent inhibition of PDGF-stimulated receptor autophosphorylation in intact hVSMC with an IC50 < 100 nM. Intracellular Ca2+ mobilization and cell proliferation were events that occurred in hVSMC subsequent to PDGF receptor activation. WIN 41662 inhibited PDGF-stimulated Ca2+ mobilization and cell proliferation ([3H]TdR incorporation) with IC50 values of 430 nM and 2.3 microM, respectively. These effects appeared to be specifically related to PDGF receptor tyrosine kinase inhibition since WIN 41662 was not cytotoxic (in vitro) and since WIN 72039, a close structural analog that does not inhibit PDGF receptor tyrosine kinase, also did not inhibit PDGF-stimulated receptor autophosphorylation, Ca2+ mobilization, or hVSMC proliferation. Thus, WIN 41662 is representative of a novel class of selective PDGF receptor tyrosine kinase inhibitors that inhibit PDGF-regulated secondary events in intact cells.

Adenosine Triphosphate↗
PubMed1996

Safety and pharmacokinetics of 5-chloro-2',3'-dideoxy-3'-fluorouridine (935U83) following oral administration of escalating single doses in human immunodeficiency virus-infected adults.

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a nucleoside analog reverse transcriptase inhibitor that has demonstrated selective anti-human immunodeficiency virus (HIV) activity in vitro and favorable safety profiles in monkeys and mice. A phase I study was conducted to evaluate the safety and pharmacokinetics of six escalating single oral doses of 935U83 in 12 HIV-infected adults. The effect of a high-fat meal on the oral bioavailability of 935U83 was also assessed. The volunteers enrolled had CD4+ cell counts ranging from < 50 to 753 cells per mm3 (median, 198). In the dose range of 100 to 1,500 mg 935U83 was well tolerated by all subjects with no drug-related adverse events reported. No significant clinical or laboratory abnormalities were observed throughout the study. 935U83 was rapidly and well absorbed following oral administration with peak plasma concentrations (Cmax) occurring at 0.8 to 1.3 h postdosing. Mean Cmax and AUC0-infinity values of 935U83 were nearly dose proportional in the 100- to 1,500-mg dose range (from 2.4 to 30 micrograms/ml and from 3.4 to 59 h.micrograms/ml, respectively). Elimination of 935U83 from the plasma was rapid, with an apparent half-life of 1.3 to 1.7 h which was independent of the dose level. Administration of 935U83 with a high-fat meal decreased the rate of 935U83 absorption (mean Cmax decreased by approximately 50% and mean time to Cmax increased by approximately 1 h) but did not affect the extent of oral bioavailability (AUC0-infinity) of 935U83. The 5'-O-glucuronide conjugate was the principal metabolite of 935U83 and was present in the plasma of all volunteers at concentrations lower than 935U83. The molar AUC0-infinity ratio (935U83 glucuronide to the parent compound) was similar across all dose levels (mean, 21 to 27%). At least 60% of the 935U83 dose was absorbed, and approximately an equal percentage of the dose (approximately 30%) was excreted as unchanged 935U83 and as 935U83 glucuronide. Systemic exposure to 935U83 at levels exceeding its average in vitro antiretroviral 50% inhibitory concentration (approximately 0.5 microgram/ml or 1.8 microM) can be achieved after a single oral dose.

Administration, Oral↗
PubMed1996

Occult ascending aortic rupture in the presence of an air bag.

A patient presented to the emergency department after a high-speed decelerating-type motor vehicle accident. Due to activation of his air bag device, the patient was without significant obvious injury. Upon evaluation in the emergency department he was also without any radiographic or physical signs of serious injury. In the ensuing 24 hours, severe chest pain developed, and subsequent aortography demonstrated a tear of his ascending aorta just distal to the root. Although occult injury to the aorta and great vessels does occur in a small percentage of patients, it is quite rare. However, with the advent of air bags, in the absence of associated injuries, signs, and symptoms, a high index of suspicion must be entertained in decelerating-type accidents to diagnose occult injury to the aorta and great vessels.

Accidents, Traffic↗
PubMed1995

Pathological prognostic factors in the second British Stomach Cancer Group trial of adjuvant therapy in resectable gastric cancer.

The second British Stomach Cancer Group trial was a prospective randomised controlled trial of adjuvant radiotherapy or cytotoxic chemotherapy after gastrectomy for adenocarcinoma. It recruited between 1981 and 1986. No survival advantage has been demonstrated for the patients receiving either type of adjuvant therapy compared with those undergoing surgery alone. We report on 436 patients randomised into the trial together with 203 patients, who did not fulfil the trial criteria, referred to the trial. A univariate (log-rank) analysis of pathological factors obtained from the local referring centres showed that tumour size, macroscopic type, number os sites involved, depth of invasion, involvement of resection lines and lymph nodes and histological grade were significant determinants of survival. Histological review by two experienced histopathologists found that the Lauren classification and histological grade, but not the Ming classification, were significant prognostic factors. The degree of lymphocytic and eosinophilic infiltration and presence of dysplasia assessed by one of the pathologists showed a significant correlation with survival. However, inter-observer correlation for these histological parameters and grade was poor. Multivariate analysis identified only depth of invasion, resection line and nodal involvement as significant independent pathological variables influencing survival. This study confirms the need for expert preparation of the resected specimen to obtain the important information on depth of invasion and nodal status and also reveals some variation in histological assessment, particularly grading, in gastric carcinoma.

Adenocarcinoma↗
PubMed1994

Cigarette smoking and pancreas cancer: a case-control study based on direct interviews.

BACKGROUND: Cigarette smoking is the most consistently reported risk factor for pancreas cancer, yet the dose-response relationship in many pancreas cancer studies is weak. Because of the poor prognosis for pancreas cancer, many case-control studies have been based largely on interviews with proxy respondents, who are known to report less reliable information on detailed smoking habits than original subjects. PURPOSE: Our purpose was to evaluate cigarette smoking as a risk factor for pancreas cancer based on data obtained only from direct interviews and to estimate the effects of quitting smoking and of switching from nonfiltered to filtered cigarettes on risk. Our objective also was to estimate the contribution of cigarette smoking toward explaining the higher pancreas cancer incidence experienced by black Americans compared with white Americans. METHODS: A population-based, case-control study of pancreas cancer was conducted during 1986-1989 in Atlanta, Ga., Detroit, Mich., and 10 counties in New Jersey. Direct interviews were successfully completed with 526 case patients and 2153 control subjects aged 30-79 years, making this the largest population-based, case-control study of pancreas cancer to date based only on direct interviews. RESULTS: Cigarette smokers had a significant, 70% increased risk of pancreas cancer compared with the risk in nonsmokers. A significant, positive trend in risk with increasing duration smoked was apparent (P < .0001), with long-term (> or = 40 years) smokers experiencing a modest 2.1-fold risk. We also observed a negative trend in risk with increasing years quit smoking. Smokers who quit for more than 10 years experienced about a 30% reduction in risk relative to current smokers; quitters of 10 years or less experienced no risk reduction. Switching from nonfiltered to filtered cigarettes did not appear to decrease risk. Compared with nonsmokers, subjects who smoked only filtered cigarettes had a 50% elevated risk and those who smoked only nonfiltered cigarettes had a 40% elevated risk. The proportion of pancreas cancer attributable to cigarette smoking was 29% in blacks and 26% in whites. CONCLUSIONS: The relationship between cigarette smoking and pancreas cancer risk is likely to be causal, despite the weakness of the dose-response data. Long-term smoking cessation clearly reduces risk, whereas switching from nonfiltered to filtered cigarettes may not be beneficial. Cigarette smoking appears to explain little of the excess pancreas cancer risk experienced by blacks. IMPLICATIONS: Elimination of cigarette smoking would eventually prevent approximately 27% of pancreas cancer, saving 6750 lives in the United States annually.

Adult↗
PubMed1994

The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up.

The overall survival in patients with gastric cancer is low, even among those undergoing resection. It has been hoped that the development of adjuvant therapy might improve survival in patients following surgery when tumour burden was minimal and both chemotherapy and radiotherapy have been proposed as suitable for use in gastric cancer. Their value has been evaluated by the British Stomach Cancer Group Second adjuvant therapy trial. 436 patients entered a prospective, randomised, controlled trial of adjuvant radiotherapy or cytotoxic chemotherapy with mitomycin, doxorubicin, and fluorouracil after gastrectomy for adenocarcinoma. After at least 5 years, there have been 372 deaths of which 7 were due to surgical complications and 327 from recurrent cancer. Following stratified randomisation, 145 patients were allocated to surgery alone, 153 to receive adjuvant radiotherapy, and 138 to adjuvant combination chemotherapy. The overall 2-year and 5-year survival were 33% (95% confidence interval 31-35%) and 17% (13-21%). No survival advantage has been shown for those patients receiving either adjuvant therapy compared to those undergoing surgery alone. The 5-year survival for surgery alone was 20%, for surgery plus radiotherapy 12%, and for surgery plus chemotherapy 19%. Surgery, therefore, remains the standard treatment for this condition and the use of adjuvant treatments should be restricted to controlled trials.

Adolescent↗
PubMed1994

Steroid receptors, pS2 and cathepsin D in early clinically node-negative breast cancer.

Four oestrogen-regulated proteins of reported prognostic value, oestrogen receptor (ER), progesterone receptor (PR), pS2 and cathepsin D (Cat D), have been quantified by immunoassays, and the latter studied by immunohistochemistry (IHC) in primary tumours from clinically node-negative early breast cancer patients, entered into a trial of breast conservation therapy in which all the patients received adjuvant tamoxifen. ER, PR and pS2 significantly co-correlated but none correlated with Cat D. ER, PR and pS2, but not Cat D, were significantly associated with tumour size and grade, although Cat D tended to show an inverse relationship with the latter. Cat D (radioimmunoassay) in pmol/mg significantly correlated with the IHC score for Cat D in carcinoma cells as well as the number of Cat D-expressing macrophages. At a median follow-up of only 16 months, recurrence was significantly more common in patients with tumours having negative status for ER, PR and pS2 but was not associated with Cat D status.

Biomarkers, Tumor↗
PubMed1994

Repeat testing for haematuria and underlying urological pathology.

OBJECTIVE: To assess the incidence of urological pathology in a group of patients referred for the investigation of haematuria and whose symptoms had resolved at the time of investigation. PATIENTS AND METHODS: The results from examination of 395 patients attending for investigation of haematuria were analysed. The group comprised 198 men and 197 women with a mean age of 51 years (range 19-73). RESULTS: In 220 patients (56%) no evidence of haematuria was detected despite its diagnosis in all patients at the time of referral. One-hundred and thirteen patients (51%) without detectable haematuria had urological pathology and 16 of these (14%) had an underlying malignancy in the urinary tract. CONCLUSION: Repeat urine analysis to determine whether haematuria persists has been considered as a way to define a high risk group which requires urgent investigation. Our results clearly indicate that the finding of haematuria, even in one urine specimen, warrants full urological assessment.

Adult↗
PubMed1994

Rapid diagnostic service for patients with haematuria.

OBJECTIVE: To assess the feasibility of a clinic for the investigation of haematuria, with open access to general practitioners. PATIENTS AND METHODS: A total of 395 patients (198 men and 197 women), with mean age 51 years (range 19-73), were referred from 13 general practitioner clinics. All investigations were performed at the patient's first visit at which time either a provisional or a definitive diagnosis was made. RESULTS: Urinary tract infection was the most common diagnosis. Of all the patients, 43 (11%) had a malignancy of whom nine presented with microscopic haematuria. Fifty-nine per cent of patients were discharged after their first visit and 26% were placed on the waiting list for in-patient procedures. CONCLUSION: An open access clinic such as this is efficient and easily run. The high incidence of pathological abnormalities makes it a worthwhile facility.

Adult↗
PubMed1994

Digital imaging colposcopy, image analysis and quantification of the colposcopic image.

OBJECTIVE: To investigate the use of a digital imaging system for colposcopy, its use for image analysis and quantification of the colposcopic features that may predict histological outcome as defined by large loop excision of transformation zone. DESIGN: Prospective programme study of all patients undergoing colposcopy for cytological abnormalities. SETTING: Dudley Road Hospital, Birmingham. SUBJECTS: Fifty consecutive patients having cytological and colposcopic abnormality treated with large loop excision of transformation zone formed the study group. MAIN OUTCOME MEASURES: Pretreatment and colposcopic features correlated with histological diagnosis of excised transformation zone. RESULTS: Index cytology and current smoking status are the most important variables for prediction of histological diagnosis. Other important variables are focality of lesion, surface pattern, intercapillary distance and degree of acetowhiteness. CONCLUSION: Digital imaging colposcopy allows image capture, processing and objective analysis. This methodology holds advantages for basic and clinical research, teaching, diagnostics and clinical audit. The system can act as a quality control tool for colposcopy units. This system should prove invaluable for further quantitative studies, for natural history studies and for those patients with deferred treatment of their cytological and colposcopic abnormalities. The statistical models described may be incorporated into the system and can aid the colposcopist in management of the woman with abnormal cervical cytology and colposcopic abnormality.

Adolescent↗
PubMed1994

Pathogenesis of gall stones in Crohn's disease: an alternative explanation.

The increased prevalence of gall stones in Crohn's disease is thought to be related to depletion of the bile salt pool due either to terminal ileal disease or after ileal resection. This study was designed to examine whether this hypothesis is correct and explore alternative explanations. Two hundred and fifty one randomly selected patients (156 females, 95 males, mean age 45 years) were interviewed and screened by ultrasonography to determine the prevalence of gall stones in a large population of patients with Crohn's disease. Sixty nine (28%) patients had gall stones proved by ultrasonography (n = 42), or had had cholecystectomy for gall stone disease (n = 27). The risk factors for the development of gall stones including sex, age, site, and duration of disease, and previous intestinal resection were examined by multivariate analysis. Age and duration of disease were positive risk factors for gall stones and were covariables. The site of disease and of previous intestinal resection did not predispose to gall stones. Previous surgery was an independent risk factor for the development of gall stones, the risk increasing with number of laparotomies. It is suggested that mechanisms other than ileal dysfunction may predispose to gall stones. Postoperative gall bladder hypomotility with biliary sludge formation may be precursors of gall stone formation in patients with Crohn's disease.

Adolescent↗