Biomedical subjects
Publications and source records attributed to A Kennedy.
We report the discovery of four HLA-DRB1 alleles during routine sequencing based typing (SBT). These alleles--DRB1*03052, DRB1*04032, DRB1*1139 and DRB1*1346--differ from previously identified DRB1 alleles by known nucleotide polymorphisms.
Two new HLA-DRB1 alleles have been identified by sequencing based typing (SBT). HLA-DRB1*1138 and DRB1*1344 were discovered after following up ambiguous results involving unusual alleles after DRB1 generic typing.
We report the discovery of four HLA-DRB3 alleles during routine sequencing based typing (SBT); DRB3*02023, DRB3*0212, DRB3*0213 and DRB3*03012. These alleles differ from other HLA-DRB3 alleles by previously undescribed single nucleotide polymorphisms.
This paper describes six new alleles; A*0240, A*2614, B*3924, B*4425, Cw*0807 and Cw*12023, which were discovered during routine genotyping with sequence specific oligonucleotides (SSO's). Five of the new alleles have changes in residues which belong to the antigen binding site of the HLA protein. These new variants may have altered antigen binding properties and may cause differential immunological responses that could affect transplantation outcome1.
Disease relapse occurs in 50% or more of patients who are autografted for relapsed or refractory lymphoma (NHL) or Hodgkin's disease (HD). The administration of non-cross-resistant therapies during the post-transplant phase could possibly control residual disease and delay or prevent its progression. To test this approach, 55 patients with relapsed/refractory or high-risk NHL or relapsed/refractory HD were enrolled in the following protocol: stem cell mobilization: cyclophosphamide (4.5 g/m(2)) + etoposide (2.0 g/m(2)) followed by GM-CSF or G-CSF; high-dose therapy: gemcitabine (1.0 g/m(2)) on day -5, BCNU (300 mg/m(2)) + gemcitabine (1.0 g/m(2)) on day -2, melphalan (140 mg/m(2)) on day -1, blood stem cell infusion on day 0; post-transplant immunotherapy (B cell NHL): rituxan (375 mg/m(2)) weekly for 4 weeks + GM-CSF (250 microg thrice weekly) (weeks 4-8); post-transplant involved-field radiotherapy (HD): 30-40 Gy to pre-transplant areas of disease (weeks 4-8); post-transplant consolidation chemotherapy (all patients): dexamethasone (40 mg daily)/cyclophosphamide (300 mg/m(2)/day)/etoposide (30 mg/m(2)/day)/cisplatin (15 mg/m(2)/day) by continuous intravenous infusion for 4 days + gemcitabine (1.0 g/m(2), day 3) (months 3 + 9) alternating with dexamethasone/paclitaxel (135 mg/m(2))/cisplatin (75 mg/m(2)) (months 6 + 12). Of the 33 patients with B cell lymphoma, 14 had primary refractory disease (42%), 12 had relapsed disease (36%) and seven had high-risk disease in first CR (21%). For the entire group, the 2-year Kaplan-Meier event-free survival (EFS) and overall survival (OS) were 30% and 35%, respectively, while six of 33 patients (18%) died before day 100 from transplant-related complications. The rituxan/GM-CSF phase was well-tolerated by the 26 patients who were treated and led to radiographic responses in seven patients; an eighth patient with a blastic variant of mantle-cell lymphoma had clearance of marrow involvement after rituxan/GM-CSF. Of the 22 patients with relapsed/refractory HD (21 patients) or high-risk T cell lymphoblastic lymphoma (one patient), the 2-year Kaplan-Meier EFS and OS were 70% and 85%, respectively, while two of 22 patients (9%) died before day 100 from transplant-related complications. Eight patients received involved field radiation and seven had radiographic responses within the treatment fields. A total of 72 courses of post-transplant consolidation chemotherapy were administered to 26 of the 55 total patients. Transient grade 3-4 myelosuppression was common and one patient died from neutropenic sepsis, but no patients required an infusion of backup stem cells. After adjustment for known prognostic factors, the EFS for the cohort of HD patients was significantly better than the EFS for an historical cohort of HD patients autografted after BEAC (BCNU/etoposide/cytarabine/cyclophosphamide) without consolidation chemotherapy (P = 0.015). In conclusion, post-transplant consolidation therapy is feasible and well-tolerated for patients autografted for aggressive NHL and HD and may be associated with improved progression-free survival particularly for patients with HD.
Acute poisoning in children is still a major public health problem, and represents a frequent cause of admission in emergency departments. We carried out an epidemiological study of poisonings leading to admission to a paediatric emergency care unit (PECU). We analysed data from 2988 children who were admitted to the PECU of Bordeaux, France with acute poisoning from 1989 through 1995. During the 7-year period, the poison exposure numbers decreased slightly from 490 to 382 (6% vs. 3% of total medical emergencies). This represented a mean annual incidence of 1.4 poison exposures per 1000 children younger than 18 years of age and living in Bordeaux and its surroundings. Characteristics of the study population, circumstances of poisoning and substances involved were similar to those previously described. Eighty per cent of children were younger than 5 years of age, presented with a benign course. Forty per cent were not treated and 75% were discharged home either immediately or within 24 hours of admission. Only 1.5% of cases, mainly adolescent girls who attempted suicide, were admitted to a paediatric intensive care unit. Overall mortality rate was 0.33/1000. In children, most cases of acute poisoning are accidental, benign, and mainly attributed to the ingestion of a non-toxic substance. This points to the need for better information of the population on availability of poison control centre calling facilities, in order to decrease the number of admissions to the PECU. Patients suspected of having ingested a potentially dangerous substance can be managed in short-stay observation units, thus avoiding unnecessarily prolonged hospitalization. Acute poisoning in children remains a frequent problem, highlighting the need to develop an education programme on primary prevention in our region.
OBJECTIVES: To develop a decision analysis based and computerised clinical guidance programme (CGP) that provides patient specific guidance on the decision whether or not to undergo a prophylactic oophorectomy to reduce the risk of subsequent ovarian cancer and to undertake a preliminary pilot and evaluation. SUBJECTS: Women who had already agreed to have a hysterectomy who otherwise had no ovarian pathology. SETTING: Oophorectomy decision consultation at the outpatient or pre-admission clinic. METHODS: A CGP was developed with advice from gynaecologists and patient groups, incorporating a set of Markov models within a decision analytical framework to evaluate the benefits of undergoing a prophylactic oophorectomy or not on the basis of quality adjusted life expectancy, life expectancy, and for varying durations of hormone replacement therapy. Sensitivity analysis and preliminary testing of the CGP were undertaken to compare its overall performance with established guidelines and practice. A small convenience sample of women invited to use the CGP were interviewed, the interviews were taped and transcribed, and a thematic analysis was undertaken. RESULTS: The run time of the programme was 20 minutes, depending on the use of opt outs to default values. The CGP functioned well in preliminary testing. Women were able to use the programme and expressed overall satisfaction with it. Some had reservations about the computerised formal and some were surprised at the specificity of the guidance given. CONCLUSIONS: A CGP can be developed for a complex healthcare decision. It can give evidence-based health guidance which can be adjusted to account for individual risk factors and reflects a patient's own values and preferences concerning health outcomes. Future decision aids and support systems need to be developed and evaluated in a way which takes account of the variation in patients' preferences for inclusion in the decision making process.
PURPOSE: Standard chemotherapy for advanced ovarian cancer currently includes a platinum agent (usually carboplatin) and paclitaxel. Because docetaxel is an active agent in platinum-resistant ovarian cancer, it is relevant to evaluate both the toxicity and efficacy of the combination of carboplatin and docetaxel in this clinical setting. PATIENTS AND METHODS: The Gynecologic Oncology Program of the Cleveland Clinic Taussig Cancer Center conducted a phase II trial of carboplatin (area under the concentration-versus-time curve of 6) and docetaxel (60 mg/m(2)), delivered every 3 weeks for six courses, in patients with ovarian and fallopian tube cancers and primary carcinoma of the peritoneum who had either received no prior chemotherapy or had experienced a treatment-free interval of greater than 2 years before developing disease recurrence. RESULTS: Fifty patients (median age, 57 years; range, 44 to 81 years) entered the trial (47 had had no prior chemotherapy). Our toxicity findings included the following: grade 4 neutropenia (64% of patients); hypersensitivity reactions (34%, none requiring discontinuation of therapy); peripheral neuropathy (6%). We had objective responses for 32 of 42 (81%) assessable patients. CONCLUSION: The combination of carboplatin and docetaxel is highly active in ovarian cancer, with the major toxicity being bone marrow suppression. Hypersensitivity reactions are frequent but do not prevent continuation of treatment. With the dose and schedule employed in this trial, neurotoxicity is uncommon. Defining a role for this regimen in routine clinical practice will require the conduct of randomized controlled clinical trials.
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Lysophospholipids (lyso-PLs), including various glycerol-based and sphingosine-based lysophospholipids, play important roles in many biochemical, physiological, and pathological processes. The classical methods to analyze these lipids involve gas chromatography and/or high-performance liquid chromatography, which are time-consuming, cumbersome, and sometimes inaccurate due to the incomplete separation of closely related lipid species. We now describe the quantitative analysis of lyso-PLs in ascites samples from patients with ovarian cancer using electrospray ionization spectrometry. Three new classes of lyso-PL molecules are detected: alkyl-LPA, alkenyl-LPA, and methylated lysophosphatidylethanolamine. Importantly, the following lysophospholipid species are significantly increased in ascites from patients with ovarian cancer, compared to patients with nonmalignant diseases (e.g., liver failure): LPA (including acyl-, alkyl-, and alkenyl-LPA species), lysophosphatidylinositol, and sphingosylphosphorylcholine. Lysophosphorylcholine contents are also significantly different among ascitic fluids from the two groups of patients. However, the total phosphate content in ascites samples from patients with ovarian cancer is not significantly different compared to that from patients with nonmalignant disease.
BACKGROUND: Despite the demonstrated clinical utility of the serum CA-125 antigen level in ovarian cancer, controversy exists regarding interpretation of "discordant" results between changes in this tumor marker and measurable disease masses. CASE: A patient with ovarian cancer cared for in the Gynecologic Cancer Program of the Cleveland Clinic Foundation receiving second-line single-agent carboplatin for recurrent disease demonstrated a major response in serum CA-125, but minimal shrinkage of a large painful abdominal mass. A laparotomy was performed both to define the nature of this mass and to attempt to relieve symptoms. The mass was found to be a large "inflamed pseudotumor with central necrosis." No viable tumors cells were found. CONCLUSION: This case represents an excellent example of the remarkably complex biology of malignant disease and suggests how evaluation of changes in CA-125 in women with ovarian cancer may be utilized in individual patients to develop optimal management plans.
AIMS/HYPOTHESIS: A strong positive correlation has been found between lipid peroxidation product and vascular endothelial growth factor concentrations in the vitreous of patients with proliferative diabetic retinopathy. To establish a causal relation between diabetes-associated enhanced oxidative stress and vascular endothelial growth factor production, we evaluated two antioxidants, DL-alpha-lipoic acid and taurine, on retinal vascular endothelial growth factor protein and mRNA expression and on parameters of oxidative stress in streptozotocin-diabetic rats. METHODS: Our experiments were on control rats and streptozotocin-diabetic rats with a 6-week duration of diabetes, treated with or without DL-alpha-lipoic acid (100 mg x kg(-1) x d(-1), i.p.) or taurine (1% in the diet) starting from induction of diabetes. Vascular endothelial growth factor protein in retinal homogenates was assessed by sandwich ELISA with an affinity-purified polyclonal antibody and vascular endothelial growth factor mRNA by ribonuclease protection assay. Retinal lipid peroxidation products i.e. malondialdehyde plus 4-hydroxyalkenals were quantified with N-methyl-2-phenylindole. Retinal reduced and oxidized glutathione, ascorbate, dehydroascorbate, and sorbitol pathway intermediates were measured spectrofluorometrically, and taurine by reverse-phase HPLC. RESULTS: Vascular endothelial growth factor protein concentration (means +/- SD) was increased in diabetic rats compared with control rats (33+/-7 vs 19+/-5 pg/mg total protein, p < 0.01) This increase was attenuated by taurine (26+/-8, p < 0.05) and prevented by DL-alpha-lipoic acid (21+/-4, p < 0.01). Vascular endothelial growth factor mRNA abundance was reduced by 1.4-fold in diabetic rats compared with control rats and this decrease was attenuated but not completely prevented by both antioxidants. Malondialdehyde plus 4-hydroxyalkenal concentration was increased in diabetic rats compared with control rats, and both antioxidants arrested accumulation of lipid peroxidation products. Taurine, reduced glutathione, oxidized glutathione, ascorbate, dehydroascorbate and sorbitol pathway intermediate concentrations as well as oxidized glutathione/reduced glutathione and dehydroascorbate/ascorbate ratios were similar in control and diabetic rats treated with or without taurine. CONCLUSION/INTERPRETATION: Oxidative stress is directly involved in up regulation of vascular endothelial growth factor protein in the retina during early diabetes.
While the combination chemotherapy regimen of carboplatin (AUC 5-6) and paclitaxel (175 mg/m2 over 3 h) is widely employed in the treatment of ovarian cancer, there are limited data available in the oncologic literature regarding the neurotoxic potential of the program. We retrospectively reviewed the clinical course of 87 patients treated in the Gynecologic Cancer Program of the Cleveland Clinic Taussig Cancer Center to address this important clinical issue. The overall incidence of peripheral neuropathy in this population was 25%, with 13% of women experiencing symptoms > or = grade 2 in severity. We conclude that while neurotoxicity is common following the use of this regimen, significant neurological dysfunction (> or = grade 2) is relatively infrequent.
Several novel targets are currently being evaluated both preclinically and clinically for the prevention of prostate cancer. Four divergent and novel approaches were discussed at the National Cancer Institute-sponsored workshop entitled, "New Clinical Strategies in Prostate Cancer Prevention." These interventions are further categorized into soy protein-based serine-protease inhibitors that reduce superoxide-induced DNA damage, and molecularly targeted approaches that are directed toward endothelin-1 expression/overexpression, peroxisome proliferator-activated receptor ligands, and insulinlike growth factors. Understanding each of these approaches has offered insights into the process of malignant transformation of prostatic epithelium, and further illustrates the difficulties of developing new agents in the treatment and prevention of prostate cancer. Close scrutiny of the clinical data emerging with these approaches, including validation of biologic endpoints, is required before large-scale prevention studies with these novel agents and targets can be considered.
It is difficult to resolve all heterozygous combinations of the HLA-DRB1*03, *08, *11, *12, *13 and *14 allele group in a one-step generic HLA-DRB1 typing system. Therefore, it is common to employ a secondary technique utilizing group-specific primers to amplify this group of alleles separately from the other HLA-DRB1, -DRB3, -DRB4 and -DRB5 alleles. This paper describes a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for broad typing of the HLA-DRB1*03, *08, *11, *12, *13 and *14 alleles which, as well as being time-efficient and cost-effective, has so far allowed the detection of 10 new alleles. The new alleles were identified after following up unusual or novel PCR-RFLP patterns. Of the 10 novel alleles found so far with this method, seven have been described previously while three, DRB1*13022, DRB1*1336 and DRB1*1435, are presented here.
The regulatory-targeting subunit (RGL), also called GM) of the muscle-specific glycogen-associated protein phosphatase PP1G targets the enzyme to glycogen where it modulates the activity of glycogen-metabolizing enzymes. PP1G/RGL has been postulated to play a central role in epinephrine and insulin control of glycogen metabolism via phosphorylation of RGL. To investigate the function of the phosphatase, RGL knockout mice were generated. Animals lacking RGL show no obvious defects. The RGL protein is absent from the skeletal and cardiac muscle of null mutants and present at approximately 50% of the wild-type level in heterozygotes. Both the level and activity of C1 protein are also decreased by approximately 50% in the RGL-deficient mice. In skeletal muscle, the glycogen synthase (GS) activity ratio in the absence and presence of glucose-6-phosphate is reduced from 0.3 in the wild type to 0.1 in the null mutant RGL mice, whereas the phosphorylase activity ratio in the absence and presence of AMP is increased from 0.4 to 0.7. Glycogen accumulation is decreased by approximately 90%. Despite impaired glycogen accumulation in muscle, the animals remain normoglycemic. Glucose tolerance and insulin responsiveness are identical in wild-type and knockout mice, as are basal and insulin-stimulated glucose uptakes in skeletal muscle. Most importantly, insulin activated GS in both wild-type and RGL null mutant mice and stimulated a GS-specific protein phosphatase in both groups. These results demonstrate that RGL is genetically linked to glycogen metabolism, since its loss decreases PP1 and basal GS activities and glycogen accumulation. However, PP1G/RGL is not required for insulin activation of GS in skeletal muscle, and rather another GS-specific phosphatase appears to be involved.
Chronic alcohol abuse is a major risk factor for osteoporosis but the effects of moderate drinking on bone metabolism are largely uninvestigated. Here, we studied the long-term dose-response (0, 3, 6, 13, and 35% caloric intake) effects of alcohol on cancellous bone in the proximal tibia of 8-month-old female rats. After 4 months of treatment, all alcohol-consuming groups of rats had decreased bone turnover. The inhibitory effects of alcohol on bone formation were dose dependent. A reduction in osteoclast number occurred at the lowest level of consumption but there were no further reductions with higher levels of consumption. An imbalance between bone formation and bone resorption at higher levels of consumption of alcohol resulted in trabecular thinning. Our observations in rats raise the concern that moderate consumption of alcoholic beverages in humans may reduce bone turnover and potentially have detrimental effects on the skeleton.
Retinopathy, a severely disabling complication of diabetes mellitus, is today the leading cause of acquired blindness among young adults in developed countries. Good glycaemic control can attenuate the development of diabetic retinopathy but such metabolic control is often difficult to achieve and maintain and additional therapies need to be identified by which retinopathy can be prevented or arrested. Hyperglycaemia plays a critical role in the development and progression of retinopathy, but the mechanism by which hyperglycaemia results in the development of retinopathy is not clear. Oxidative stress is increased in the retina in diabetes. The possible sources of increased oxidative stress might include increased generation of free radicals or impaired anti-oxidant defence system. Dietary supplementation with anti-oxidants in animal models of diabetic retinopathy inhibits retinal metabolic abnormalities and retinal histopathology, suggesting that oxidative stress is associated with the development of retinopathy. The mechanism by which anti-oxidants inhibit retinopathy in diabetes warrants further investigation, but animal studies show that increasing the diversity of anti-oxidants provides significantly more protection than using any single anti-oxidant. Thus, supplementation with anti-oxidants represents an achievable adjunct therapy to help preserve vision in diabetic patients.