Biomedical subjects
J Barrett
Publications and source records attributed to J Barrett.
Loss of KAI1 messenger RNA expression in both high-grade and invasive human bladder cancers.
The molecular mechanisms responsible for metastasis are not fully understood. Recently, expression of the KAI1 gene on human chromosome 11p11.2 was found to be down-regulated in metastatic prostate cancer cell lines compared with normal human prostate, suggesting that KAI1 may be a metastasis suppressor gene. The aim of this study was to investigate whether there is reduced expression of KAI1 in late-stage bladder cancer. Sixty-six paraffin-embedded bladder tissue sections were analyzed for KAI1 mRNA by in situ hybridization. Nineteen of these were from patients with no histological evidence of bladder cancer, and 47 were from papillary transitional cell carcinomas (TCCs); of these, 16 were highly invasive. KAI1 mRNA was highly expressed in the specimens of normal bladder (11 of 11; 100%), inflammatory bladder (5 of 8; 63%), and noninvasive papillary TCCs of grades 1 and 2 (15 of 24; 63%), compared to grade 3 papillary TCCs (1 of 7; 14%) or invasive TCCs (1 of 16; 6%). The differences in expression between local and invasive disease were statistically significant (P </= 0.01, chi2 test). Our results suggest that down-regulation of KAI1 mRNA is significantly associated with invasive bladder cancer and that KAI1 may represent an invasion/metastasis suppressor gene in bladder cancer.
CD34+ cell dose predicts survival, posttransplant morbidity, and rate of hematologic recovery after allogeneic marrow transplants for hematologic malignancies.
After autologous or allogeneic transplants of peripheral blood stem cells (PBSC), an adequate dose of CD34+ cells is necessary to ensure early and sustained hematopoietic engraftment and favorable clinical outcome. There are no comparable data on the relationship between CD34+ cell dose and recovery after allogeneic bone marrow transplants (BMT). Twenty-eight patients with hematologic malignancies received a BMT from an HLA-identical sibling, using T-cell depletion and cyclosporin for graft-versus-host disease prophylaxis and delayed donor lymphocyte transfusions in an attempt to prevent leukemia relapse. The treatment-related mortality (TRM), primarily due to infections and cytopenias, was significantly higher for 13 patients receiving less than 1 x 10(6) CD34+ cells/kg (64.9% +/- 12.8% v 6.9% +/- 6.4%, P = .003). Survival at a median follow-up of 1 year was also lower in the group receiving less than 1 x 10(6) CD34+ cells/kg (30.8% +/- 12.8 v 74.3% +/- 13.7%, P = .005). The CD34+ cell dose was the only variable significantly associated with TRM. The dose of CD34+ cells also correlated with speed of hematopoistic recovery. Patients receiving more than 2 x 10(6) CD34+ cells/kg showed significantly earlier recovery of monocytes and a trend for earlier recovery of lymphocytes. They achieved platelet and red blood cell transfusion independence earlier, required less granulocyte colony-stimulating factor support during ganciclovir treatment, and spent fewer days in the hospital after transplantation. These results suggest that, for allogeneic T-cell-depleted BMT, the higher CD34+ cell doses may improve outcome in engrafting patients.
A link between c-Myc-mediated transcriptional repression and neoplastic transformation.
Recent studies indicate that the transcription factor c-Myc contributes to oncogenesis by altering the expression of genes involved in cell proliferation, but its precise function in neoplasia remains ambiguous. The ability of c-Myc to bind the sequence CAC(G/A)TG and transactivate appears to be linked to its transforming activity; however, c-Myc also represses transcription in vitro through a pyrimidine-rich cis element termed the initiator (Inr). In transfection experiments using the adenoviral major late (adML) promoter, which contains two Myc binding sites and an Inr, we determined that c-Myc represses transcription through the initiator in vivo. This activity requires the dimerization domain and amino acids 106 to 143, which are located within the transactivation domain and are necessary for neoplastic transformation. We studied a lymphoma-derived c-Myc substitution mutation at 115-Phe, which is within the region required for transcriptional suppression, and found the mutant more effective than wild-type c-Myc in transforming rodent fibroblasts and in suppressing the adML promoter. Our studies of both loss-of-function and gain-of-function c-Myc mutations suggest a link between c-Myc-mediated neoplastic transformation and transcriptional repression through the Inr.
Diffuse choroidal melanoma. Clinical features predictive of metastasis.
OBJECTIVE: To assess the clinical features that predict metastasis of diffuse choroidal melanoma. DESIGN: A review of patients who had been diagnosed clinically as having diffuse choroidal melanoma evaluated on the Oncology Service at Wills Eye Hospital, Philadelphia, Pa. MAIN OUTCOME MEASURE: Effect on metastasis of clinical features of the tumor. RESULTS: Of 3500 consecutive patients with choroidal melanoma, 111 (3%) had diffuse choroidal melanoma. Of these 111 tumors, the mean tumor base was 14.7 mm and the mean overall tumor thickness was 2.1 mm. The thickness-to-base percentage averaged 14.8%. The tumor had poorly defined margins in 39 patients (35%), orange pigment on its surface in 49 (44%), and a secondary serous retinal detachment in 76 (68%). Optic nerve invasion was clinically suspected in 2 patients (2%) and transcleral extension in 3 (3%). Initial management was enucleation in 36 patients (32%), plaque radiotherapy in 60 (54%), laser photocoagulation in 3 (3%), and observation in 12 (11%). During a mean follow-up of 5.3 years (median, 3.9 years), metastasis developed in 29 patients (26%). Using Kaplan-Meier survival estimates, the probability of metastasis developing was 16% at 3 years, 24% at 5 years, and 36% at 10 years. The clinical factors predictive of metastasis by univariate analysis included tumor basal dimension 18 mm or more (P = .002), poorly defined tumor margins (P = .03), transcleral extension (P = .003), and optic nerve invasion (P = .03). The clinical factors predictive of metastasis by multivariate analysis included basal dimension of 18 mm or more (P = .01), optic nerve invasion (P = .03), and poorly defined tumor margins (P = .05). CONCLUSIONS: Despite its relative flatness, diffuse choroidal melanoma carries a metastatic potential of 24% at 5 years. The risks for metastasis are greatest with increasing tumor base and poorly defined margins. Recognition of the clinical features of this tumor in the earliest stage and prompt treatment are encouraged.
Polarization and chemokinesis of ovine and human neutrophils in response to Fasciola hepatica excretory-secretory products.
The effect of Fasciola hepatica excretory-secretory products (ES products) on the polarization and chemokinesis of sheep and human neutrophils was investigated. Flukes were cultured overnight in RPMI-1640 medium, and the resulting ES products concentrated by dialysis (cut-off 1.2 kDa) before use. At the concentrations used toxicity tests showed no effect on neutrophil viability, but ES products were capable of causing morphological changes and chemokinesis in both sheep and human neutrophils. The polarizing effect of the ES products was found to be greater in the case of sheep neutrophils with 81% of cells polarizing at 80 micrograms total ES protein/ml as opposed to 36% of human neutrophils. Chemokinesis in response to 80 micrograms total ES protein/ml was significant (P < 0.01) in both species with sheep producing the stronger response. Delipidation of the ES products with Lipidex caused no loss of polarizing activity, nor did the purified lipid fraction show any polarizing effect. ES products lost polarizing activity after heat treatment or trypsin digestion. Preliminary fractionation on an S-300 Sephacryl column suggested the presence of at least four fractions capable of causing polarization in sheep neutrophils.
A novel cystathionine beta-synthase from Panagrellus redivivus (Nematoda).
The free-living nematode Panagrellus redivivus can be used as a biochemical model for parasitic nematodes in the search for new chemotherapeutic agents. A novel cystathionine beta-synthase has been purified 3600-fold from the cytosol of P. redivivus. The enzyme catalyses the synthesis of cystathionine from homocysteine plus serine or cysteine. The enzyme, native M(r) 71.7 kDa, pI 4.7, is a dimer and also catalyses the replacement of the beta-SH group of cysteine with 2-mercaptoethanol to yield a thioether, S-(2-hydroxyethyl) cysteine and H2S. This reaction proceeds much faster than cystathionine synthesis and L-cysteine cannot be replaced by D-cysteine, L-cystine, N-acetyl L-cysteine, cysteamine of D,L-homocysteine. 2-Mercaptoethanol in the assay can be replaced by monothiolglycerol and to a lesser extent by cysteamine. The absolute K(m) values for L-cysteine and 2-mercaptoethanol were 0.13 +/- 0.05 mM and 1.72 +/- 0.24 mM, respectively, the absolute V(max) was 55 +/- 4.9 mumol.min(-1).mg protein(-1). The enzyme had a pH optimum of approx. 8.5 and did not require metal ions for activity. The enzyme was inhibited by a series of substrate analogues, anthelmintics and plant phenols. The P. redivivus enzyme differs markedly from its mammalian equivalent and suggests distinctive differences in sulphur amino acid metabolism in nematodes.
Methionine and cysteine metabolism in Fasciola hepatica.
Radiolabel from the methyl groups of serine and methyltetrahydrofolate was readily incorporated into methionine in adult Fasciola hepatica, and a substantial proportion of the label from [35S]methionine appeared in cysteine. The data suggest that methionine synthesis is via methyltetrahydrofolate-homocysteine methyltransferase and that there is cysteine synthesis from methionine. Cystathionine-beta-synthase and gamma-cystathionase activities were demonstrated in homogenates.
The graft-versus-leukemia effect.
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Basic epidemiology of fractures of the upper and lower limb among Americans over 65 years of age.
Current knowledge regarding the basic epidemiology of fractures is largely limited to a few fracture sites, notably those of the hip and distal forearm. To clarify the patterns of incidence of limb fractures in the elderly, we used data from a 5% sample of the U.S. Medicare population over age 65 years during the years 1986-1990. We identified incident fractures of the proximal humerus, other parts of the humerus, proximal radius/ ulna, shaft of the radius/ulna, distal radius/ulna, pelvis, hip, other parts of the femur, patella, ankle, and other parts of the tibia/fibula from diagnoses and procedures coded on claims for inpatient services, outpatient facility use, and physician services. We used Poisson regression to investigate the relation between demographic factors and fracture risk at these sites. Fractures at the hip were the most common, accounting for 38% of the fractures identified. The proximal humerus, distal radius/ulna, and ankle also were common fracture sites. A pattern of rapidly rising rates with age was seen for fractures of the pelvis, hip, and other parts of the femur among women. Fractures distal to the elbow or knee, however, had, at most, modest increases in incidence with age over 65 years. For each of the fractures studied, women had higher rates than men of the same race, and whites generally had higher rates than blacks of the same gender. Gender-related differences in risk were larger among whites than among blacks, and racial differences in risk were more marked among women than among men.
The graft-versus-leukemia effect.
Although the graft-versus-leukemia effect was predicted from animal experiments almost 40 years ago, only recently has its role in clinical bone marrow transplantation become better defined. The graft-versus-leukemia effect was initially considered to be a minor component of the graft-versus-host reaction. However, more recent analyses of clinical bone marrow transplants and the successful treatment of relapsed leukemia with donor lymphocyte transfusions indicate that the graft-versus-leukemia effect can be very powerful and to some degree independent of graft-versus-host disease. Results of donor lymphocyte transfusions draw attention to wide variability in response according to the nature of the relapsed leukemia and also to additional therapies that may enhance the efficacy of donor lymphocyte transfusions. Although natural killer lymphocytes may play a role in the graft-versus-leukemia effect, attention is focusing increasingly on T lymphocytes as potent mediators of the effect. Both CD4+ and CD8+ cells, together with the cytokines they produce, can interact with leukemia cells to deliver a cytotoxic hit on the malignant clone. Although leukemia cells undoubtedly share common antigens with other tissues of the recipient resulting in nonspecific graft-versus-host and graft-versus-leukemia reactions, there is also the possibility that distinct antigens are presented to T cells by the leukemia cells, providing a basis for separating the graft-versus-leukemia from graft-versus-host reactions. The current clinical challenge is to devise strategies for separating the graft-versus-leukemia response from graft-versus-host disease.
Computed tomography screens stable patients at risk for penetrating cardiac injury.
OBJECTIVE: To determine the accuracy of CT of the chest in diagnosing the presence of cardiac injury in stable patients with penetrating chest injuries. METHODS: A retrospective chart review of a convenience sample of stable patients with penetrating thoracic wounds evaluated for hemopericardium using chest CT at an urban level I trauma center. RESULTS: 60 stable patients with penetrating wounds in proximity to the heart underwent CT. Three patients had radiographic evidence of pericardial fluid, and 1 had an equivocal study. These 4 patients underwent subxiphoid pericardial window exploration: 2 had only clear fluid present, the other 2 had hemopericardium. The latter patients had a total of 3 cardiac and 1 diaphragmatic injuries, which were repaired at subsequent sternotomy. None of the 56 patients who had negative CTs had further clinical evidence of cardiac injury. The sensitivity, specificity, and accuracy of CT in this setting for hemopericardium are 100% (95% CI 18-100%), 96.6% (95% CI 88-100%), and 96.7% (95% CI 89-100%), respectively. CONCLUSION: Chest CT may be a useful test for diagnosing the presence of hemopericardium in the setting of penetrating thoracic injury. With the caveat that the patient must be removed from a closely monitored environment, the authors the use of CT in stable patients with penetrating chest wounds whenever echocardiography is unavailable.
SSRI and sympathominetic interaction.
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Phytoestrogens. Friends or foes?
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Total hip arthroplasty: use and select complications in the US Medicare population.
Use and outcomes of primary total hip arthroplasty among US Medicare recipients more than 65 years of age were investigated by means of physician and hospital claims for a 5% random sample during 1986 through 1989. Cases involving hip fracture or evidence of existing orthopedic devices in the hip were omitted. Use rates were higher for women than for men and were substantially lower for Blacks than Whites. Major complications (death, further hip surgery, infection pulmonary embolism) were uncommon. These data document the frequent use of total hip arthroplasty, and confirm the rarity of serious adverse outcomes. Further studies should investigate the lower use of total hip arthroplasty among Blacks.
Experience with three prosthetic materials in temporary abdominal wall closure.
There are circumstances that make abdominal wall closure unsafe and technically impossible after laparotomy for trauma. In these difficult cases, prosthetic materials may be necessary to temporarily close the abdominal wall. To determine the optimal prosthetic in these instances, a retrospective chart review was conducted in our urban Level I trauma center. Twenty-five patients received 31 abdominal wall prostheses over a 4-year period. There were 7, 8, and 10 patients with 7 Marlex, 9 Dexon, and 15 Goretex prostheses, respectively. Each patient had only one type of prosthesis placed. The average age was 30.7 +/- 12.0 years, injury severity score was 20.3 +/- 7.4, and abdominal trauma index was 35.9 +/- 18.0; there was no significant difference in these values between groups. Eight patients died soon after the prosthesis was placed (average, 12.9 days) secondary to ongoing shock or multiple organ failure. Three of the seven surviving Goretex patients (43%) were intentionally left with small hernias. Three of the six Dexon patients (50%) were left with hernias; one of these eviscerated on day 150 and subsequently died, and the others have disabling gigantic hernias. Three of the four Marlex patients (75%) developed fistulae as a result of erosion into the small bowel or colon. One Marlex patient suffered with a chronically draining abdominal wound for 398 days prior to definitive closure. Goretex appears to be the best prosthetic for temporary abdominal wall closure because it causes less inflammatory reaction because of its smooth surface. It is therefore easier to retrieve at the time of definitive closure and carries less risk of fistula formation than other prostheses. Our Dexon patients suffered with gigantic hernias and one died because of complications of evisceration. We have abandoned the use of Marlex in abdominal wall closure because of the high incidence of fistula formation. We advocate the use of Goretex in temporary abdominal wall closure in this challenging group of patients.
Immunomodulation of sheep and human lymphocytes by Fasciola hepatica excretory-secretory products.
Fasciola hepatica excretory-secretory (ES) products (30 micrograms ml-1 total ES protein upwards) significantly decreased tritiated thymidine (3HTh) uptake in phytolectin-stimulated sheep lymphocytes. Lower doses of ES products, however, caused an increase in 3HTh uptake in sheep cells stimulated with phytohaemagglutinin (PHA) and Concanavalin A (Con A) and, indeed, ES products were mitogenic on their own. In contrast, 3HTh uptake by human lymphocyte cultures in the presence of phytolectins was progressively inhibited by increasing doses of ES products, and ES products were not mitogenic on their own. The observed inhibitory effects on 3HTh incorporation were not due to toxicity of ES products.
A novel lipid-binding protein from the cestode Moniezia expansa.
A lipid-binding protein (LBP) has been purified from the cytosol of the cestode Moniezia expansa. The native LBP was found to be an oligomer of approx. 250 kDa, consisting of 11 kDa monomers. The LBP bound saturated and unsaturated fatty acids, but not their CoA derivatives, with KD values in the range 0.68-7.8 microM. Cholesterol, dihydroergosterol, bilirubin and retinoids were also bound, but alpha-tocopherol, bile acids, alk-2-enals and alka-2,4-dienals were not. Evidence suggests that there are two binding sites per subunit, each with different specificities. The fluorescent fatty acid 11-[(5-dimethylaminonaphthalene-1-sulphonyl)amino]undecanoic acid (DAUDA) and retinol both showed an additional high-affinity binding site with a density of approximately 0.1 per subunit, suggesting specific binding to the oligomer. The amino acid composition of Moniezia LBP was distinct from that of previously characterized fatty acid-binding proteins (FABPs). The protein was not N-terminally blocked and yielded a unique amino acid sequence, unrelated to that of any known FABP; there was also evidence of microheterogeneity. Polyclonal antibodies raised to the Moniezia protein did not cross-react with mammalian, nematode or digenean FABP. The Gibbs free energy for protein folding (13.02 kJ/mol; 3.1 kcal/mol), determined by urea denaturation, was identical for both the native and ligand-bound Moniezia LBP. CD spectra showed that the Moniezia protein contained 36% alpha-helix and that the secondary structure underwent only minor changes on ligand binding. Moniezia LBP binds a range of anthelmintics, with KD values again in the range 0.66-7.3 microM. It is possible that, in helminths, binding proteins may play a role in determining the specificity and site of action of anthelmintics.