Successful treatment with mitoxantrone chemotherapy of acute disseminated intravascular coagulation due to metastatic androgen independent prostate cancer.
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Acute Disease↗
Biomedical subjects
M R Smith
Publications and source records attributed to M R Smith.
A mutation that causes ataxia shifts the voltage-dependence of the Scn8a sodium channel.
A mutation of alanine to threonine in the III S4-S5 linker of the mouse Scn8a sodium channel has previously been identified as causing the ataxia in med(jo) mice. The electrophysiological effects of this mutation in Scn8a sodium channels were characterized in Xenopus oocytes. The med(jo) mutation caused a 10 mV positive shift in the voltage dependence of activation, without any significant changes in the kinetics of either inactivation or recovery from inactivation. The shift in the voltage dependence of activation observed for the mutant channel would reduce the spontaneous activity of Purkinje cells and lead to a decrease in output from the cerebellum, which is consistent with the phenotype of cerebellar ataxia observed in med(jo) mice.
Alanine↗
Prediction of cardiovascular risk. Program is not suitable for diabetic patients.
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Adult↗
The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1.
Recently, Salmonella spp. were shown to induce apoptosis in infected macrophages. The mechanism responsible for this process is unknown. In this report, we establish that the Inv-Spa type III secretion apparatus target invasin SipB is necessary and sufficient for the induction of apoptosis. Purified SipB microinjected into macrophages led to cell death. Binding studies show that SipB associates with the proapoptotic protease caspase-1. This interaction results in the activation of caspase-1, as seen in its proteolytic maturation and the processing of its substrate interleukin-1beta. Caspase-1 activity is essential for the cytotoxicity. Functional inhibition of caspase-1 activity by acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone blocks macrophage cytotoxicity, and macrophages lacking caspase-1 are not susceptible to Salmonella-induced apoptosis. Taken together, the data demonstrate that SipB functions as an analog of the Shigella invasin IpaB.
Animals↗
Cell cycle-related differences in susceptibility of NIH/3T3 cells to ribonucleases.
Microinjection of Onconase or RNase A into NIH/3T3 cells was used to study the intracellular actions of these two proteins. Onconase preferentially killed actively growing cells in both microinjection and cell culture experiments. Moreover, agents that increased the number of cells in S phase such as serum or microinjected signal transduction mediators (Ras, protein kinase C, and mitogen-activated protein kinase) enhanced Onconase cytotoxicity. Conversely, agents that decreased these proliferative pathways (dibutyryl cAMP and protein kinase A) correspondingly diminished Onconase cytotoxicity in microinjection experiments. These results were also mimicked in cell culture experiments since log-phase v-ras-transformed NIH/3T3 cells were more sensitive to Onconase (IC50 of 7 microg/ml) than parental NIH/3T3 fibroblasts (IC50 of 40 microg/ml). Based on those data we postulated that Onconase-mediated cell death in NIH/3T3 cells was related to events occurring at two or more points in the cell cycle preferentially associated with late G1/S and S phases. In contrast, quiescent NIH/3T3 cells were more sensitive to microinjected RNase A than log phase cells and positive mediators of proliferative signal transduction did not enhance RNase A-mediated cytotoxicity. Taken together, these results demonstrate that these two RNases use different pathways and/or mechanisms to elicit cytotoxic responses in NIH/3T3 cells. Predictions formulated from these studies can be tested for relevance to RNase actions in different target tumor cells.
3T3 Cells↗
Anomalous origin of the right coronary artery from the pulmonary artery.
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Child↗
Coexisting myelodysplasia and myeloproliferative features in a single clone containing 5q-, Ph and i(17q).
A case with myelodysplasia in which a single clone contained both 5q- and Ph chromosomes at diagnosis is presented. The patient subsequently developed leukocytosis and at that time was found to have acquired an additional chromosomal abnormality, i(17)(q10). This case illustrates the role of three different genetic changes that impart different clinical characteristics, i.e. myelodysplastic as well as myeloproliferative changes, as part of a multistep leukemogenic process.
Aged↗
Thrombotic complications resulting from hypercoagulable states in chronic hemodialysis vascular access.
BACKGROUND: Vascular access-related complications are an important cause of morbidity, and they account for 14% to 17% of dialysis patients' hospitalizations with an annual cost in the United States of approximately $1 billion. Previous studies have related the major predisposing factor of thrombotic complications to stenosis of the graft anastomosis. Several recent reports suggest that antiphospholipid antibodies may cause frequent thrombotic complications. The broad spectrum of diseases that cause hypercoagulable states has not been correlated with frequent PTFE graft thrombosis. STUDY DESIGN: A retrospective case series study was performed to determine the frequency of hypercoagulable states in dialysis patients who had repeated thrombotic complications of their PTFE grafts. Between May 1996 and June 1998, 91 operations were performed on 34 patients with end-stage renal disease. All arteriovenous fistulas were created with PTFE grafts and placed by a single surgeon. All patients were evaluated at operation for anastomotic stenosis, and the majority of patients were studied for hypercoagulable states. Patients with a documented hypercoagulable state were considered for warfarin therapy. RESULTS: Twenty-two individuals (64.7%) developed 67 thrombotic complications. Twelve of the 14 patients tested (85.7%) were shown to have hypercoagulable states of various causes and degrees. Thirteen patients developed multiple thrombotic complications, 11 (81.8%) were tested and proved to be hypercoagulable. Thirty-eight of the thrombotic complications had nonanatomic causes and 28 (41.8%) had hypercoagulability as the only determinable cause. Ten of the 12 hypercoagulable patients (83.3%) were relegated to intermediate to high-intensity warfarin therapy to reduce the incidence of thrombotic events. Hypercoagulable patients not receiving warfarin had a thrombosis rate of 4.0 events per year; patients on warfarin had a rate of 1.2 events per year. Twenty-three thrombotic events occurred in the anticoagulated group all with an International Normalized Ratio (INR) less than 2.7. This incidence of vascular access thrombosis may be prevented when patients are maintained at an optimal INR of 2.7-3.0. CONCLUSIONS: Hypercoagulability has been a major etiologic factor in PTFE graft thrombosis. Hypercoagulable states are often found in patients with multiple graft thromboses and in patients with nonanatomic causes for thrombosis. Antiphospholipid antibodies are prevalent in the patients with PTFE graft thrombosis, as well as abnormalities in the Protein-C, Protein-S, and Antithrombin III systems. PTFE graft thrombosis has been a frequent cause of morbidity in patients on hemodialysis, and diagnostic evaluation should include a hypercoagulability profile. Based on our data, warfarin therapy should be instituted when hypercoagulable states are found, unless otherwise contraindicated, and INR maintained at 2.7-3.0 to decrease morbidity and frequency of graft thrombosis.
Adult↗
Some structural features of an insoluble alpha-D-glucan from a mutant strain of Leuconostoc mesenteroides NRRL B-1355.
Leuconostoc mesenteroides strain NRRL B-1355 produces two soluble extracellular alpha-D-glucans from sucrose: alternan and dextran. An unusual mutant strain derived from NRRL B-1355 has recently been isolated which produces practically no soluble polysaccharide, but significant amounts of an insoluble D-glucan. Methylation analysis shows it contains linear (1-->3) and (1-->6) linkages as well as (1-->2) and (1-->3) branch linkages. The insoluble glucan was partially digestible by endodextranase, giving rise to a series of oligosaccharides, a high-molecular weight soluble fraction and an insoluble residue. Treatment of the soluble dextranase-limit fraction with an alpha(1-->2) debranching enzyme led to further dextranase susceptibility. Methylation, FTIR and NMR analyses of the dextranase-treated fractions indicate a non-uniform structure with domains bearing similarities to L. mesenteroides strain NRRL B-1299 dextran and to insoluble streptococcal D-glucans.
Carbohydrates↗
Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.
PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.
Androgens↗
Therapy and clinical trials.
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Clinical Trials as Topic↗
Genitourinary malignancies.
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Antineoplastic Combined Chemotherapy Protocols↗
Utilization of fine-needle aspiration cytology and flow cytometry in the diagnosis and subclassification of primary and recurrent lymphoma.
BACKGROUND: The primary diagnosis of non-Hodgkin's lymphoma/leukemia (NHL) by fine-needle aspiration (FNA) is controversial. The authors reviewed their experience with FNA and flow cytometry (FC) to determine the usefulness and limitations of these techniques in the diagnosis of NHL. METHODS: Slides and reports from all lymph node and extranodal FNAs performed during the period July 1993 to January 1997 with a diagnosis of lymphoma or benign lymphoid process were reviewed. Clinical and biopsy follow-up data were recorded. Results were tabulated and the usefulness of cytology was analyzed. RESULTS: There were 100 adequate aspirates from 87 patients. These included 72 cases of NHL, 58 (80%) of which were diagnosed by FNA and FC without the need for histologic sampling (69% of the primary lymphomas and 88% of the recurrent lymphomas). There were 22 aspirates suspicious for lymphoma, 12 equivocal results, and 7 benign diagnoses. Eighty-six percent of malignant FNAs (50 of 58) had flow cytometry (FC) as compared with only 15% (5 of 34) of the suspicious or equivocal FNAs. CONCLUSIONS: FNA is a valuable method for diagnosing and subclassifying NHL, although immunophenotyping by FC is often an essential ancillary test. In our experience, correlating the FNA results with the FC results can eliminate the need for a more invasive surgical biopsy in many cases.
Biopsy, Needle↗
Functional analysis of the mouse Scn8a sodium channel.
The mouse Scn8a sodium channel and its ortholog Na6 in the rat are abundantly expressed in the CNS. Mutations in mouse Scn8a result in neurological disorders, including paralysis, ataxia, and dystonia. In addition, Scn8a has been observed to mediate unique persistent and resurgent currents in cerebellar Purkinje cells (Raman et al., 1997). To examine the functional characteristics of this channel, we constructed a full-length cDNA clone encoding the mouse Scn8a sodium channel and expressed it in Xenopus oocytes. The electrophysiological properties of the Scn8a channels were compared with those of the Rat1 and Rat2 sodium channels. Scn8a channels were sensitive to tetrodotoxin at a level comparable to that of Rat1 or Rat2. Scn8a channels inactivated more rapidly and showed differences in their voltage-dependent properties compared with Rat1 and Rat2 when only the alpha subunits were expressed. Coexpression of the beta1 and beta2 subunits modulated the properties of Scn8a channels, but to a lesser extent than for the Rat1 or Rat2 channels. Therefore, all three channels showed similar voltage dependence and inactivation kinetics in the presence of the beta subunits. Scn8a channels coexpressed with the beta subunits exhibited a persistent current that became larger with increasing depolarization, which was not observed for either Rat1 or Rat2 channels. The unique persistent current observed for Scn8a channels is consistent with the hypothesis that this channel is responsible for distinct sodium conductances underlying repetitive firing of action potentials in Purkinje neurons.
Amino Acid Sequence↗
Cardiovascular effects of the beta-carboline FG 7142 in borderline hypertensive rats.
The hypothesis that acute and chronic administration of the benzodiazepine inverse agonist FG 7142 (N-methyl-beta-carboline-3-carboxamide) produces cardiovascular changes similar to those seen during acute and chronic episodes of stress was studied using conscious, unrestrained borderline hypertensive rats (BHR). Chronic intraperitoneal administration of FG 7142 (10 mg/kg; 5 days/week for 8 weeks) failed to alter resting mean arterial pressure or heart rate compared to maturation and vehicle controls. However, chronic administration of FG 7142 prevented the hypertension associated with a high salt diet. Similarly, acute intravenous (i.v.) administration of FG 7142 (10 mg/kg) in BHR rendered hypertensive with a high-salt diet produced a significant reduction in resting mean arterial pressure as well as marked increases in heart rate. Pretreatment with the benzodiazepine receptor antagonist flumazenil (RO 15-1788, 10 mg/kg, i.v.) blocked the tachycardic response but had no effect on the hypotensive effect of FG 7142 administered i.v. in BHR with salt-induced hypertension. Acute administration of FG 7142 (0.1-10 mg/kg, i.v.) in normal BHR produced no significant changes in resting mean arterial pressure and dose-related increases in heart rate. These experiments indicate that, in conscious unrestrained BHR, FG 7142 can elicit changes in heart rate but not the changes in arterial pressure typically associated with stress or anxiety. Therefore, it appears that FG 7142 is of limited use as a pharmacological tool for investigating the cardiovascular effects of acute or chronic stress in BHR.
Animals↗
Adenocarcinoma of the uterine cervix metastatic to lymph nodes.
OBJECTIVE: We set out to evaluate the prognostic factors in cervical adenocarcinoma metastatic to lymph nodes. STUDY DESIGN: We performed a retrospective review of 40 patients with cervical adenocarcinoma and lymph node metastasis from 1976 to 1996. RESULTS: Thirty-four patients had adenocarcinoma, and six had adenosquamous carcinoma. Median survival was 50 months. The median survival for patients with stage I disease was 69 months. Stage at diagnosis, treatment with radical hysterectomy, and receiving adjuvant therapy were associated with prolonged survival. A trend toward improved survival was noted with the use of concurrent radiation and chemotherapy as an adjuvant therapy. CONCLUSIONS: Adenocarcinoma metastatic to the lymph nodes does not have a uniformly poor prognosis, especially with early-stage disease. Improved survival was observed with the use of adjuvant therapy, specifically the use of combined chemotherapy and radiation after radical hysterectomy. The optimal therapy in this setting is yet to be determined.
Adenocarcinoma↗
Dexamethasone plus retinoids decrease IL-6/IL-6 receptor and induce apoptosis in myeloma cells.
Interleukin 6 (IL-6) is the most important known growth factor for multiple myeloma, and IL-6 signalling pathways are potential targets for therapy. We hypothesized that interfering with the IL-6 signalling pathway at more than one level would be more effective than a single block in inhibiting proliferation of myeloma cells. Accumulating data support the concept that glucocorticoids down-regulate IL-6, whereas retinoic acid derivatives (RA) down-regulate IL-6R in myeloma. We found that all-trans RA (ATRA), 13-cis-RA and 9-cis-RA each similarly inhibited growth of RPMI 8226 myeloma cells and that addition of dexamethasone (DEX) added to RA growth inhibition. The major effects of retinoids were to reduce the proliferative fraction and induce apoptosis whereas DEX increased the apoptotic fraction. When combined, apoptosis was enhanced. Effects of RA + DEX were also least able to be overcome by exogenous IL-6. RA decreased IL-6R levels and addition of DEX to RA delayed recovery of IL-6R levels compared with RA alone. Since RPMI 8226 cells have undetectable IL-6, we investigated U266B1 cells and found that RA and DEX decreased both IL-6 secretion and IL-6 RNA levels. Mechanistically, IL-6R down-regulation by RA was enhanced by DEX, whereas IL-6 protein and RNA levels were reduced by DEX and by RA. In summary, combinations of RA + DEX were not only more effective in inhibiting myeloma cells growth by the dual mechanisms of decreasing proliferative fraction and increasing apoptotic fraction, but were also less able to be overcome by IL-6.
Antineoplastic Agents↗
Personal need for structure and attitudes toward homosexuality.
The need of a sample of U.S. students to cognitively structure reality as measured by the Personal Need for Structure (PNS) Scale was examined as a predictor of attitudes toward homosexuality measured by the Attitudes Toward Lesbians and Gay Men (ATLG) Scale. Significant relationships between the two constructs and strong gender differences on the ATLG were found.
Adolescent↗