Familial occurrence of cutaneous T cell lymphoma: a case report of monozygotic twin sisters.
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Female↗
Biomedical subjects
M E Williams
Publications and source records attributed to M E Williams.
The interdisciplinary geriatric team evaluation project. A new approach to the delivery of geriatric medicine in geographically remote locations.
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Aged↗
Immunohistochemical staining and Southern blot hybridization for glutathione S-transferase pi in mammary infiltrating ductal carcinoma.
Glutathione S-transferase pi, a drug-detoxifying isoenzyme of potential prognostic value for subsets of patients with mammary cancer, was studied by immunohistochemistry and Southern blot analysis in 58 infiltrating ductal carcinomas. The results were compared with the findings of six important clinicopathologic parameters. Cytoplasmic immunoreactivity for glutathione S-transferase pi was absent in 40%, 1+ in 26%, 2+ in 15%, and 3+ in 19% of the cases. There were no significant correlations between the level of immunostaining and patient age, tumor size, axillary lymph node status, nuclear pleomorphism, or tubule formation, but there was a trend with mitotic count (P = 0.06). Immunoreactivity was associated with histologic grade (P = 0.02) and inversely correlated with estrogen (P = 0.006) and progesterone (P = 0.02) receptor content. Ten percent of the cases showed modest levels of glutathione S-transferase pi gene amplification, but no significant correlations were observed between glutathione S-transferase pi amplification and any of the clinicopathologic parameters or level of immunostaining. The results indicate that increased immunohistochemical staining for glutathione S-transferase pi occurs in high-grade, estrogen and progesterone receptor-negative neoplasms. As glutathione S-transferase pi gene amplification appears unassociated with immunopositivity, other mechanisms are responsible for the production of this isoenzyme in infiltrating ductal carcinomas.
Blotting, Southern↗
Structure and functional characterization of neuronal alpha 1E calcium channel subtypes.
We have cloned overlapping cDNAs encoding alpha 1E Ca2+ channel subunits from mouse and human brain. We observed that these alpha 1E transcripts were widely distributed in the central nervous system. We also demonstrated the existence of two variants of the human alpha 1E subunit. Comparison of the sequence of these alpha 1E subunits to those from other species suggests that at least four alternatively spliced variants of alpha 1E exist. Expression of human alpha 1E in HEK293 cells and Xenopus oocytes produced high voltage-activated Ca2+ currents that inactivated rapidly (tau approximately 20 ms at 0 mV). The size of the currents obtained were enhanced approximately 40-fold by co-expression with human neuronal alpha 2 and beta Ca2+ channel subunits. alpha 1E currents were insensitive to the drugs and toxins previously used to define other classes of voltage-activated Ca2+ channels. Thus, alpha 1E-mediated Ca2+ channels appear to be a pharmacologically distinct class of voltage-activated Ca2+ channels.
Alternative Splicing↗
Anti-IL-4 treatment of Schistosoma mansoni-infected mice inhibits development of T cells and non-B, non-T cells expressing Th2 cytokines while decreasing egg-induced hepatic fibrosis.
Increasing evidence suggests that schistosome egg granulomas are primarily Th2 cellular reactions. Mice infected with Schistosoma mansoni were treated with a neutralizing mAb against IL-4 to evaluate the role of this cytokine in the generation of parasite egg-induced cell-mediated responses and hepatic pathology. Animals treated with anti-IL-4 before egg deposition showed decreased IL-4, IL-5, and IL-10 production in response to in vitro antigenic stimulations and decreased IL-5 and IL-13 mRNA levels in the liver. As observed previously, non-B, non-T cells were a major source of IL-4 in infected mice treated with control mAb, and the diminished IL-4 response in anti-IL-4-treated animals was shown to be caused at least in part by a reduction in the number of these cells, as well as by decreased secretion of IL-4 per cell. In contrast, production of the Th1 cytokines IL-2 and IFN-gamma was elevated in anti-IL-4-treated infected mice in vitro, and the corresponding mRNAs in the liver were increased. Anti-IL-4 treatment did not consistently reduce the size of hepatic granulomas around S. mansoni eggs, but markedly inhibited granuloma formation in the lungs of the same animals after i.v. egg injection. Nevertheless, anti-IL-4-treated infected mice showed consistent and marked reductions in hepatic collagen deposition. These findings indicate that IL-4 plays a major role in the development of the Th2 response in S. mansoni-infected mice and contributes to the pathogenesis of hepatic fibrosis.
Animals↗
RARA and PML gene rearrangements in acute promyelocytic leukemia with complex translocations and atypical features.
The translocation t(15;17) associated with acute promyelocytic leukemia (APL) results in fusion of the retinoic acid receptor alpha (RARA) gene on chromosome 17 with the putative transcription factor gene, PML, on chromosome 15. We report three cases of APL with complex cytogenetic translocations and five cases with atypical phenotypic features with rearrangements within or adjacent to the second intron of the RARA gene. Two patients demonstrated three-way translocations involving chromosomes 3, 15, and 17, but with differing breakpoints on the short arm of chromosome 3. A third patient developed a complex karyotype at the time of third relapse, but with no change in RARA and PML gene rearrangement pattern. Three patients had normal karyotypes; however, only small numbers of cells could be analyzed. One patient's leukemic cells expressed the T-cell-associated antigen CD2 and revealed T-cell receptor beta and gamma gene rearrangements. The localization of breakpoints to the second intron of the RARA gene in cytogenetically and phenotypically atypical cases provides additional support for a requisite role of the PML/RARA fusion gene in the pathogenesis of APL.
Adolescent↗
Oxidant-sensitive protein phosphorylation in endothelial cells.
Reactive oxygen is an important regulator of vascular cell biology; however, the mechanisms involved in transducing signals from oxidants in endothelial cells are poorly defined. Because protein phosphorylation is a major mechanism for signal transduction, cultured aortic endothelial cells were exposed to nonlethal concentrations of H2O2 to examine oxidant-sensitive changes in phosphorylation state. Addition of H2O2 increases the phosphorylation of the heat shock protein 27 (HSP27) within 2 min. This response is maximal by 20 min and remains constant for more than 45 min. Levels of intracellular free Ca2+ in endothelial cells did not change following addition of 100 microM H2O2, nor did the ability of the cells to respond to bradykinin. H2O2-induced phosphorylations were either not affected or were slightly increased in cells pretreated with PKC inhibitors (H-8, staurosporin, or calphostin c). Two-dimensional analysis of phosphoproteins from homogenates of 32P-labeled cells revealed that phorbol myristate acetate (PMA) did not cause the same degree of HSP27 phosphorylation as H2O2. Simultaneous addition of 10 eta M PMA and 50 microM H2O2 decreased the oxidant-stimulated phosphorylation of the most acidic HSP27 isoform. These data suggest that signal transduction for H2O2-sensitive endothelial cell responses are not only independent of PKC, but may also be suppressed by the action of the kinase.
Analysis of Variance↗
Life-long bleeding diathesis: effect of orthotopic liver transplantation.
Proper regulation of the fibrinolytic system is critical to the prevention of both thrombosis and hemorrhage. Patients with inherited or acquired excess fibrinolysis may have a bleeding tendency, usually characterized by delayed and posttrauma or postoperative bleeding. The liver plays many roles in this regulation, including the synthesis of plasminogen, alpha 2-antiplasmin (alpha 2-AP) and plasminogen activator inhibitor-1 (PAI-1), and the clearance of tissue-plasminogen activator (t-PA). Inherited deficiencies of alpha 2AP, PAI-1 and inherited excess t-PA associated with clinically significant bleeding have been reported. The authors describe a patient with a life-long bleeding diathesis who demonstrated evidence of excess t-PA. One of two daughters also had a bleeding tendency and demonstrated excess t-PA. The patient developed cirrhosis and underwent orthotopic liver transplantation. Following transplantation, all fibrinolytic parameters returned to normal, and the bleeding diathesis appeared to no longer exist. The effect of liver transplantation on this patient's fibrinolytic abnormalities and the effect of cirrhosis on this patient's laboratory evaluation are discussed.
Aminocaproic Acid↗
Cyclin D1 overexpression in non-Hodgkin's lymphoma with chromosome 11 bcl-1 rearrangement.
BACKGROUND: Approximately 70% of centrocytic (mantle-cell) lymphomas have the chromosomal translocation t(11;14) (q13; q32) and associated rearrangements at the bcl-1 breakpoint locus and at the cyclin D1 (PRAD1, CCND1) gene, thus implicating this gene in the pathogenesis of centrocytic lymphoma. In order to determine cyclin D1 expression in hematopoietic neoplasms with and without bcl-1 or cyclin D1 rearrangements, northern blot analysis was performed. METHODS: Total RNA was isolated from peripheral blood cells of patients with hematopoietic neoplasms in leukemic phase, including three patients with B-cell lymphoma containing chromosome 11q13 bcl-1 rearrangements. Northern blots were hybridized with a cyclin D1 cDNA probe and the degree of mRNA expression determined. RESULTS: Each of the bcl-1-rearranged cases showed high levels of cyclin D1 expression, whereas no expression was detected in RNA from samples of B-cell CLL, T-cell prolymphocytic leukemia, or acute nonlymphocytic leukemia which lacked bcl-1 or cyclin D1 rearrangement. CONCLUSIONS: Overexpression of cyclin D1, a G1 cyclin implicated in cell-cycle regulation, may play a critical role in the pathogenesis of t(11; 14)-positive lymphomas.
Blotting, Northern↗
Leukocytes of patients with Schistosoma mansoni respond with a Th2 pattern of cytokine production to mitogen or egg antigens but with a Th0 pattern to worm antigens.
Cytokine responses of peripheral blood mononuclear cells from humans infected with Schistosoma mansoni were assessed. By ELISA and ELISPOT, persons with acute and hepatosplenic infections produced higher levels of interleukin (IL)-4 and IL-5 and higher frequencies of IL-4-producing cells in response to mitogen than did uninfected persons. In contrast, mitogen-induced production of the Th1 cytokine interferon-gamma (IFN-gamma) did not differ from that of uninfected controls. Upon stimulation with egg antigens, many patients responded with elevated IL-4 mRNA levels but displayed no appreciable increases in Th1 (i.e., IFN-gamma and IL-2) cytokine transcripts. Nevertheless, in cells stimulated with adult worm antigen, a more mixed Th0-type response was observed with production of both Th1 and Th2 cytokines. These results support previous findings in laboratory mice that schistosome infection results in increased production of Th2 cytokines. Unlike mice, infected humans do not display a generalized down-modulation in Th1 responses but instead show a selective deficiency in IFN-gamma and usually IL-2 responses to egg antigens.
Adolescent↗
Cognitive/neuropsychological studies of children with a schizophrenic disorder.
This article summarizes a series of cognitive/neuropsychological studies of children with schizophrenia. One set of studies, which surveyed a broad range of neuropsychological functions, revealed no evidence that children with schizophrenia are consistently impaired in sensory, perceptual, or language functions. Rather, the studies showed that children with schizophrenia performed poorly on tasks requiring sensory, perceptual, and language processing that made extensive demands on information-processing capacity. A second series of studies, which examined visual information processing by manipulating the processing demands of span of apprehension tasks, yielded similar findings. The key characteristic of tasks that elicit impaired performance in children with schizophrenia is that the task makes extensive demands on processing resources. This suggests that these children have limited information-processing capacity. Three hypotheses are proposed concerning the cognitive processes that are impaired in children with schizophrenia: (1) the cognitive processes that seem to be impaired in these children are part of a more general, hierarchically organized attention system; (2) the component processes of the system are subserved by different brain structures; and (3) the structures are part of a network that includes the frontal lobe and thalamus in interaction with the reticular activating system.
Adolescent↗
A brief history of the development of geriatric medicine.
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Aged↗
The Timed Manual Performance test as a predictor of hospitalization and death in a community-based elderly population.
OBJECTIVE: To determine the usefulness of timed manual performance measurements (TMP) as predictors of health outcomes, hospitalization, and mortality in a large, heterogeneous sample of elderly people living in the community. DESIGN: Prospective cohort study. SETTING: Central North Carolina. PARTICIPANTS: 1,286 community-dwelling older people. MEASUREMENTS: Demographic background, health problems, number of prescribed medications, perceived health, quality of life, and the TMP, a 27-item test that has been shown to predict functional dependency and need of health-care services in older people. RESULTS: During the 2-year follow-up period, 127 people died and 200 were hospitalized. Scores for those who were able to complete the original TMP, as well as scores for two shorter versions of the TMP, predicted mortality and, to a lesser extent, hospitalization within 2 years. For both original and shorter versions of the TMP, relative risk of death was approximately 2.5 times greater for those in the poorest performance quartile, as compared with the best performing quartile, when adjusted for age, gender, race, and number of prescribed medications. TMP tests and an index of IADL were independent predictors of death. CONCLUSIONS: TMP scores may be useful in the clinical setting as a vital sign of functioning, providing a means of targeting those individuals at increased risk of mortality.
Activities of Daily Living↗
Reducing hospital costs for the geriatric patient admitted from the emergency department: a randomized trial.
OBJECTIVE: To test the impact of a geriatric evaluation and management model on the costs of acute hospital management of emergently admitted older adults. DESIGN: Randomized controlled trial. Patients were followed in the acute hospital from admission through discharge. Results based on both univariate and multiple regression analyses. SETTING: Private, nonprofit, academic medical center in a densely populated urban area. PATIENTS: Adults 70 years of age and older admitted from the Emergency Department to the medicine service (non-ICU admission) who did not have an internist on staff at the admitting hospital. Of 141 randomized patients, 111 (78.7%) met eligibility criteria. INTERVENTION: Assignment of a geriatrician and a social worker as the primary managing team during the hospital stay. MAIN OUTCOME MEASURES: Length of stay, total cost of acute hospital care, cost of laboratory, pharmacy, and rehabilitation services. RESULTS: Patients in the intervention group had 2.1 fewer days of hospitalization, but this shorter length of stay was not statistically significant (P = 0.108). There were no differences in mortality or discharge disposition. In risk-adjusted, multiple regression analysis the intervention group had a statistically significant lower predicted total cost per patient than the usual care group (-$2,544, P = 0.029); assignment to the intervention group was associated with a lower predicted cost per patient for laboratory (including cardiology graphics) services (P = 0.007) and pharmacy costs (P = 0.047). CONCLUSIONS: When controlled for important predictors of expected resource use, care provided by a geriatric management team resulted in a significant reduction in the cost of hospitalization. A reduction in the cost of laboratory, cardiographic, and pharmacy services is consistent with the team's philosophy of defining the services needed based on goals related to functional outcomes.
Academic Medical Centers↗
Cytokeratin in anaplastic large cell lymphoma.
A B-cell anaplastic large cell lymphoma, confirmed by immunohistochemistry and Southern blot immunoglobulin gene rearrangement analysis, contained neoplastic cells that were immunoreactive for cytokeratin using antibodies CAM 5.2, M20, MAK 6, and KS-B17.2. Bands corresponding to cytokeratin 18 and cytokeratins 18 and 8 were seen on Western blot immunoanalysis using antibodies KS-B17.2 and CAM 5.2. The lymph node also contained cytokeratin-positive extrafollicular fibroblastic reticulum cells. Although it is possible that the presence of cytokeratin in the cells of anaplastic large cell lymphoma represented phagocytosed filaments from the reticulum cells, it is more likely that the cytokeratins were synthesized by the malignant cells. The finding of cytokeratin in anaplastic large cell lymphoma, although infrequent, adds to the confusion in the diagnosis of this pleomorphic neoplasm.
Aged↗
Lymphoproliferative disorder of granular lymphocytes: nine cases including one with features of CD56 (NKH1)-positive aggressive natural killer cell lymphoma.
Twelve cases of large granular lymphocytosis were examined by flow cytometry and Southern blot analysis to correlate immunophenotypic and molecular genetic markers with clinical features. Nine cases fulfilled clinical criteria for the lymphoproliferative disorder of granular lymphocytes, and eight of these demonstrated the molecular features of T-cell-type lymphoproliferative disorder of granular lymphocytes including surface expression of CD3, expression of one or more natural killer (NK)-cell antigens (CD11b, CD16, or CD57), and clonal rearrangement of both the T-cell receptor beta- and gamma-chain-joining genes. One of these cases demonstrated coexisting clonal rearrangement of the immunoglobulin heavy-chain-joining genes, but none demonstrated kappa-light-chain-joining gene rearrangement. The eight T-cell lymphoproliferative disorder of granular lymphocytes cases all lacked expression of the NK antigen CD56 (NKH1). In contrast, the other case of lymphoproliferative disorder of granular lymphocytes rapidly evolved into an aggressive NK-cell lymphoma which did not express CD3, did express CD56, had germline T-cell receptor gene configurations, and had multiple clonal chromosomal abnormalities. This case demonstrated nasal cavity and cutaneous tumor infiltrates consistent with previously described CD3-negative, CD56-positive NK-cell lymphoma of the upper aerodigestive tract. Three cases of transient large granular lymphocytosis demonstrated germline T-cell receptor gene configurations. This study demonstrates the usefulness of Southern blot analysis and flow cytometry in characterizing proliferations of large granular lymphocytes. The transformation of a single case into an aggressive NK-cell lymphoma with blastic morphology and tissue infiltration was associated with a fatal outcome.
Aged↗
Transferrin in the central nervous system of the shiverer mouse myelin mutant.
Transferrin, the iron mobilization protein, and its mRNA are normally present in oligodendrocytes. Previous reports using myelin mutants have shown both a decrease in transferrin protein and mRNA when the oligodendrocyte population is compromised. In this study the shiverer mouse mutant in which the oligodendrocyte population is numerically normal, but has both quantitatively diminished and qualitatively abnormal myelin was used. This animal model was chosen to address the question whether expression of the transferrin message and/or protein correlated more closely to the number of oligodendrocytes (normal) or the amount of myelin (abnormally low). A 1/2 to 2/3 decrease in transferrin protein occurred in all brain regions examined except for the spinal cord in the shiverer group compared to both heterozygous littermates and wild type controls. Levels of transferrin transcripts in the brain are not affected by the shiverer mutation. These results taken with previous reports from this laboratory indicate that the presence of oligodendrocytes is a requirement for normal expression of transferrin mRNA in brain but is not sufficient for normal values of the protein. The level of Tf protein correlates more closely with the amount of myelin present than it does with the numbers of oligodendrocytes present. These data are consistent with previous reports from our laboratory that transferrin accumulation by oligodendrocytes is associated with myelin production by these cells. These data further suggest transferrin mRNA may be constitutively expressed by oligodendrocytes and that the protein expression is regulated at the level of translation.
Animals↗
A decision support system using milk progesterone tests to improve fertility in commercial dairy herds.
MOIRA (the Management of Insemination through Routine Analysis) is a computer program that is a module of DAISY, the Dairy Information System. This decision support system uses the results of milk progesterone tests to determine when to inseminate cows. The MOIRA program plans a series of weekly tests for each cow, to check for cyclicity. Subsequently, the program lists cows for alternate day tests to identify the days when they should be served, and if necessary, a cow can be served without being seen in heat. The work which led to the development of MOIRA showed that ovulation detection rates of 98 per cent were achieved; in commercial herds the rate is around 85 per cent. As pregnancy rates were unchanged, the effect of MOIRA was to reduce calving to conception interval from 90 to 85 days and the culling rate for failure to conceive from 13 per cent to 5 per cent in one herd and from 104 to 100 days and 21 per cent to 12 per cent in another herd. The use of the program produced an estimated extra net profit for the farmers of pounds 52/cow in the first herd and pounds 54/cow in the second.
Animal Husbandry↗