Fluoxetine and ventricular torsade--is there a link?
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Aged↗
Biomedical subjects
B Clarke
Publications and source records attributed to B Clarke.
Flexible sigmoidoscopy plus air-contrast barium enema versus colonoscopy for evaluation of symptomatic patients without evidence of bleeding.
One hundred forty-nine patients aged 40 years or more with symptoms suggestive of colonic disease but without evidence of gastrointestinal bleeding (absence of hematochezia, normal serum levels of hemoglobin, and at least one test negative for fecal occult blood) were randomized to undergo either initial colonoscopy or initial flexible sigmoidoscopy plus air-contrast barium enema. Patients with incomplete initial colonoscopy and certain patients with polyps seen on flexible sigmoidoscopy plus barium enema underwent the alternative procedure (barium enema or colonoscopy). The main results were as follows: First, the overall prevalence of cancer in the study was very low (0.67%). Second, initial flexible sigmoidoscopy plus barium enema detected more patients with diverticulosis than did initial colonoscopy (46% versus 31%; p = .01). Initial colonoscopy detected more persons with adenomas (p = .06) than did initial flexible sigmoidoscopy plus barium enema. Patients undergoing initial flexible sigmoidoscopy plus barium enema require the alternative procedure (24%) than were patients undergoing initial colonoscopy (6%; p = .002). Third, sensitivity analyses suggested that for most areas in the United States, initial colonoscopy would be more cost-effective for the outcomes of detection of adenomas and detection of large adenomas, although very few patients in the study had large adenomas. We conclude that the prevalence of colorectal cancer in persons with colonic symptoms but no evidence of bleeding is low and is comparable with the prevalence in an asymptomatic population. Cost-effective selection of imaging strategies in this population can be based on demographic factors such as age and sex, which are better predictors of the presence of adenomas than are symptoms.
Adenoma↗
Large-volume leukapheresis using regional citrate anticoagulation to collect peripheral blood progenitor cells.
The use of peripheral blood progenitor cells (PBPC) for hematopoietic rescue after high-dose chemotherapy is limited by the number of leukaphereses required to collect an adequate number of hematopoietic progenitors. To optimize the collection of PBPC, we evaluated a single large-volume leukapheresis protocol with citrate anticoagulation. A group of 23 patients received cyclophosphamide (4 g/m2) and GM-CSF (5 micrograms/kg/day for 15 days) as PBPC mobilization, with a single outpatient 6 h leukapheresis performed on the COBE Spectra 15 days later. Citrate (0.190 mmol/ml) was infused at 1.2 ml/L of blood/minute with a whole blood to citrate ratio between 17:1 and 25:1. Calcium chloride (50 mM) was administered at a citrate to calcium molar ratio between 10:1 and 5:1 to prevent hypocalcemia. A median 36.6 L (range 24.4-46.4) blood was processed using 338 mM citrate (269-473) and 50 mM calcium (25-75). A median 5 x 10(6) CD34+ cells/kg (< 0.3-24) and 6.2 x 10(5) CFU-GM/kg (< 0.001-29) were collected, representing 5.6 and 5.9 more PBPC, respectively, than were in circulation at the initiation of leukapheresis. We conclude that a 6 h large-volume leukapheresis following cyclophosphamide and GM-CSF mobilization is safe, can recruit hematopoietic progenitors into the circulatory compartment, and allows the collection of high numbers of PBPC in a single procedure.
Adolescent↗
Familial focal glomerulosclerosis: a genetic linkage to the HLA locus?
The aetiology and pathogenesis of focal glomerulosclerosis is poorly understood and many conflicting reports suggest HLA locus associations in both familial and non-familial glomerulosclerosis. We report a family in which 4 of 5 sisters developed proteinuria, 2 with hypertension and 1 progressing to end-stage renal failure (index case). Three underwent renal biopsy which displayed characteristic features of focal glomerulosclerosis and all shared the HLA alleles HLA-A1, B8, DR3, DR7. The index case received two cadaveric renal transplants from HLA-A1, B8, DR3 donors and developed chronic rejection with no histological evidence of recurrent glomerulonephritis in either kidney. The frequency of this haplotype in the Australian dialysis and transplant population with focal glomerulosclerosis was compared to that seen in the general Australian Caucasian population and was not significantly different suggesting that the presence of the HLA alleles HLA-A1, B8, DR3, DR7 may increase the predisposition to familial glomerulosclerosis but additional factors are required for disease development and progression.
Adolescent↗
Predictive factors for peripheral-blood progenitor-cell collections using a single large-volume leukapheresis after cyclophosphamide and granulocyte-macrophage colony-stimulating factor mobilization.
PURPOSE: (1) To study the ability of mobilized peripheral-blood progenitor cells (PBPC) collected in a single large-volume leukapheresis performed on a predetermined date to accelerate engraftment after high-dose cyclophosphamide and thiotepa; (2) to establish the minimum dose of PBPC associated with early engraftment; and (3) to identify parameters predictive of collection of large numbers of PBPC. PATIENTS AND METHODS: Twenty-three patients with breast cancer received cyclophosphamide (4 g/m2) and granulocyte-macrophage colony-stimulating factor ([GM-CSF] 5 micrograms/kg/d x 15 days) for PBPC mobilization. A single leukapheresis was performed 15 days after cyclophosphamide administration. Then, patients received high-dose cyclophosphamide and thiotepa followed by reinfusion of PBPC and 4-hydroperoxycyclophosphamide (4HC)-purged bone marrow. PBPC concentration was measured in serial peripheral-blood samples and in the leukapheresis product. Correlation analysis between PBPC dose and engraftment and between leukapheresis yield and patient characteristics was attempted. RESULTS: A single leukapheresis processed a median 36 L (range, 24 to 46) blood and collected 5 x 10(6) CD34+ cells/kg (< 0.3 to 24) and 6.2 x 10(5) colony-forming units granulocyte-macrophage (CFU-GM)/kg (< 0.001 to 29). All sixteen patients (70%) reinfused with > or = 2.9 x 10(6) CD34+ cells/kg reached a level of greater than 1,000 leukocytes/microL by day 13 and greater than 50,000 platelets/microL by day 15. All of these patients had a percentage of peripheral-blood CD34+ cells > or = 0.5%, and all but one, a level of greater than 100,000 platelets/microL, on the day of leukapheresis. The bone marrow CD34+ cell percentage at study entry predicted the number of CD34+ cells collected after PBPC mobilization (R2 = .42, P = .002). All patients with > or = 2.5% bone marrow CD34+ cells experienced early engraftment. CONCLUSION: Reinfusion of PBPC collected in a single leukapheresis accelerates engraftment in the majority of patients. Pretreatment bone marrow CD34+ cell content determines PBPC mobilization capacity and may help select hematopoietic rescue strategies.
Adult↗
Severe factor VII deficiency caused by mutations abolishing the cleavage site for activation and altering binding to tissue factor.
Factor VII (F.VII) is a vitamin-K-dependent serine protease required in the early stages of blood coagulation. We describe here a patient with severe F.VII deficiency, with a normal plasma F.VII antigen level (452 ng/mL) and F.VII activity less than 1%, who is homozygous for two defects: a G-->A transition at nucleotide 6055 in exon 4, which results in an Arg-->Gln change at amino acid 79 (R79Q); and a G-->A transition at nucleotide 8961 in exon 6, which results in an Arg-->Gln substitution at amino acid 152 (R152Q). The R79Q mutation occurs in the first epidermal growth factor (EGF)-like domain, which has previously been implicated in binding to tissue factor. The R152Q mutation occurs at a site (Arg 152-Ile 153) that is normally cleaved to generate activated F.VII (F.VIIa). Analysis of purified F.VII from patient plasma shows that the material cannot be activated by F.Xa and cofactors. In addition, in an in vitro binding assay using relipidated recombinant tissue factor, patient plasma showed markedly reduced binding to tissue factor at all concentrations tested. In an effort to separate the contributions of the two mutations, three recombinant variants, wild-type, R79Q, and R152Q, were prepared and analyzed. The R152Q variant had markedly reduced activity in a clotting assay, whereas R79Q showed a milder, concentration-dependent reduction. The R152Q variant exhibited nearly normal binding in the tissue factor binding assay, whereas the R79Q variant had markedly reduced binding. The time course of activation of the R79Q variant was slowed compared with wild-type. Our results suggest that the first EGF-like domain is required for binding to tissue factor and that the F.VII zymogen lacks activity and requires activation for expression of biologic activity.
Adult↗
Bone marrow micrometastases in chemotherapy-responsive advanced breast cancer: effect of ex vivo purging with 4-hydroperoxycyclophosphamide.
Tumor contamination of hematopoietic stem cell grafts may influence the outcome of breast cancer patients treated with high-dose chemotherapy. The goals of this study were: (a) to evaluate the prevalence of tumor contamination of bone marrow (BM) harvests in patients responding to systemic chemotherapy; (b) to evaluate reduction of BM tumor contamination by ex vivo purging with 4-hydroperoxycyclophosphamide (4HC); and (c) to compare the tumor contamination of peripheral blood progenitor cell collections and BM in advanced-stage breast cancer patients designated for peripheral blood progenitor cell infusion. We evaluated pre- and post-4HC purge BM specimens from 20 patients for tumor contamination using immunocytochemistry and for in vitro growth potential of tumor cells using a tumor cell clonogenic assay. Pre-4HC purge BM specimens from 15 of 20 (75%) patients were immunocytochemistry and tumor cell clonogenic assay negative. The remaining 5 BM specimens were immunocytochemistry positive, but only 3 of 5 specimens were tumor cell clonogenic assay positive. In vitro tumor colony growth was not observed in any post-4HC purge BM specimens. We also evaluated nine patients with bone or BM metastases from the start of induction chemotherapy. We found less tumor involvement of peripheral blood progenitor cell collections than of simultaneously obtained bone marrow aspirates. We conclude that bone marrow micrometastases occur with low frequency in women with chemotherapy-sensitive breast cancer and that ex vivo purging with 4HC may render tumor cells nonviable.
Adult↗
Congenital hypertrophy of the retinal pigment epithelium and mandibular osteomata as markers in familial colorectal cancer.
Congenital hypertrophy of the retinal pigment epithelium (CHRPE) and multiple mandibular osteomata are markers of familial adenomatous polyposis (FAP). We have assessed their prevalence in non-polyposis familial colorectal neoplasia. Multiple mandibular osteomata were present in 1/29 (3%) patients with familial colorectal neoplasia. CHRPE was present in 11/33 (33%) patients with familial colorectal neoplasia compared with 3/36 (8%) with sporadic disease (P = 0.01) and 4/32 (12.5%) control subjects (P = 0.04). Seven patients with familial colorectal neoplasia had multiple areas of CHRPE compared with one with sporadic disease (P = 0.02) and one control subject (P = 0.02). There was no obvious correlation between calculated familial colorectal cancer risk and the presence of multiple areas of CHRPE. A proportion of patients with familial colorectal cancer have a marker found in FAP and may therefore have a constitutional genetic defect, at least in part responsible for their cancer, making them an interesting group for genetic study. Ophthalmoscopy may contribute to risk assessment in familial colorectal cancer.
Adult↗
Bicoronary-pulmonary fistulae with coexistent mitral valve prolapse: a case report and literature review of coronary-pulmonary fistula.
Bicoronary-pulmonary artery fistulae are rare congenital coronary artery fistulae. We report the case of a 57-year-old man who presented with biventricular failure and angina pectoris. At angiography the coronary arteries were normal, but bicoronary-pulmonary fistulae were noted; severe mitral regurgitation secondary to mitral valve prolapse was also present. At right heart catheterization the calculated left to right shunt was 2.1. Fistula ligation and repair of both mitral and tricuspid valves was undertaken. The literature regarding coronary-pulmonary fistula is also reviewed.
Arterio-Arterial Fistula↗
Disseminated Mycobacterium avium-intracellulare infection in an HIV-negative male.
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Adult↗
Diagnosis in Prader-Willi syndrome.
Thirty one patients with the putative diagnosis of Prader-Willi syndrome were reassessed clinically and by DNA analysis. Eleven patients were judged not to have Prader-Willi syndrome and 20 to have the condition. This was confirmed by DNA analysis in all but one case. The diagnosis of Prader-Willi syndrome, especially in early infancy, should be made with caution unless confirmed by molecular genetic studies.
Adolescent↗
A model for the evolution of networks of genes.
An organism persists through the activity of structural genes, which is co-ordinated by clusters of coupled regulatory genes. During evolution, changes of coupling within a cluster can increase the reliability with which its structural genes perform a task. To study the evolution of coupling, we have simulated and analyzed a stochastic model for a simple problem. The assumptions of the model are these: A network of regulatory genes co-ordinates the synthesis of four structural proteins, which associate in distinct heterodimers that form a heterotetramer. Mutation in cis-regulatory regions produces transitions among 64 types of network. In a population, each network reproduces in proportion to its fitness, which depends on its probability (reliability) of synthesizing the tetramer. Fitness-dependent attrition keeps the size of the population constant. Regulatory genes occur in a sequence of levels; each level is associated with a different family of transcription factors. The following results emerge: Because different messengers within a family can give networks with the same connectivity, the 64 types of networks cluster into eight equivalence classes. During evolution with a low mutation rate, high-fitness classes can be approached through various paths on a fitness landscape. With a higher mutation rate, networks remain more uniformly distributed among the 64 types, and lower-fitness networks remain preponderant. An initially homogeneous population becomes more heterogeneous through mutation, but selection according to fitness later reduces its diversity. During this process the dispersion of the population over the possible networks increases, then decreases as the population approaches a unique steady state.
Animals↗
Protective effects of ranolazine in guinea-pig hearts during low-flow ischaemia and their association with increases in active pyruvate dehydrogenase.
1. In isolated Langendorff-perfused, electrically-paced, hearts of guinea-pigs, global low-flow-ischaemia (LFI; at 0.7 ml min-1) resulted in marked increases in the rates of release of lactate, lactate dehydrogenase (LDH) and creatine kinase (CK) over a 30 min period. At the end of the LFI period, tissue ATP content was significantly reduced from a control value of 11.8 +/- 0.8 (5) to 5.6 +/- 0.8 (5) mumol g-1 dry weight. 2. The presence of ranolazine [(+/-)-N-(2,6-dimethyl-phenyl)-4[2-hydroxy-3-(2-methoxy-phenoxyl)- propyl] - l-piperazine acetamide dihydro-chloride; RS-43285-193] at 10 microM, from 20 min prior to and during LFI, resulted in significant reductions in the release of lactate, LDH and CK during the ischaemic period and a significant preservation of tissue ATP (9.0 +/- 1.1 (6) mumol g-1 dry wt.). Ranolazine did not prevent the reductions in creatine phosphate or glycogen observed in LFI, nor did it have any significant effects on any contractile parameters before or during the LFI period. 3. Neither ranolazine nor LFI affected the total amounts of tissue pyruvate dehydrogenase (PDH) activity; however, the significant reduction in the amount of active, non-phosphorylated PDH caused by LFI (from 88.2 +/- 5.5 to 44.2 +/- 3.2% of total activity) was partially but significantly prevented by ranolazine (67.2 +/- 6.8%). This effect of ranolazine on PDH may be part of the mechanism whereby the compound reduces lactate release and preserves tissue ATP during ischaemia.
Acetanilides↗
Managing risk: a priority in the health service.
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Decision Making↗
Targeting deletion (homoeologous chromosome pairing locus) or addition line single copy sequences from cereal genomes.
We describe here a protocol for obtaining clones containing sequences present in low copy-number from genomic DNA where moderately and highly repeated sequences predominate. Specific chromosomal regions can be targeted by using deletion or addition line material. We have used this protocol to identify a sequence which has been deleted in both the tetraploid and hexaploid wheat mutants for the homoeologous chromosome pairing locus.
Chromosome Deletion↗
Stimulation of specific immune responses to simian immunodeficiency virus using chimeric hepatitis B core antigen particles.
Subunit approaches to vaccines against viral diseases have resulted in the development of a number of methods for presentation of defined epitopes to the immune system. We have exploited a highly immunogenic presentation system based on hepatitis B core antigen (HBcAg) particles to produce a number of candidate vaccines against simian immunodeficiency virus (SIV). Recombinant particles have been produced in bacteria which carry multiple copies of defined or predicted neutralizing epitopes of SIV at a number of different sites within the particle. In parallel, a number of synthetic peptide-based SIV vaccines have been produced based on homology to reported neutralizing epitopes in human immunodeficiency virus. Although potent immune responses were elicited against both particulate and peptide forms of the antigen, neutralizing antibodies were not induced as judged by available assays.
Acquired Immunodeficiency Syndrome↗
Urethral instability.
Urethral instability is still evolving as a clinical entity. Using pressure variation of 15 cm water or more at the point of maximum urethral pressure (MUP), urethral pressure profilometry on patients referred for urodynamic assessment for lower urinary tract symptoms revealed urethral instability in 6.4% of 608 patients. The close association between urethral and detrusor instability was noted. Urethral instability appears to be a cause of frequency and urgency of micturition, and its presence increase the risk of urinary incontinence.
Adult↗
Neurophysiological effects of left vagal stimulation in man.
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Adult↗