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Biomedical subjects

S L Allen

Publications and source records attributed to S L Allen.

At least 55 records · Page 3Linked to original sources
PubMed1994

Upregulation of the POMC gene in rats by a neurotoxicant which targets motoneurones.

Immunocytochemistry and histochemical in situ hybridisation were used to detect POMC-derived peptides (beta-endorphin and alpha-MSH) and POMC mRNA respectively, in the lumbar spinal cord of adult rats. In normal rats the incidence of ventral horn cells which expressed the peptides or mRNA was negligible. However after treatment with IDPN a neurotoxicant which targets the motoneurones the peptides and POMC mRNA were detectable in over 65% of ventral horn motoneurones. After treatment with 1,3 DNB a neurotoxicant which does not target motoneurones immunostaining for the peptides and mRNA was negligible. Thus chemical intoxication of the motoneurones causes upregulation of the POMC gene.

Animals↗
PubMed1993

Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside, tetrahydrouridine, and carboplatin.

Eight patients, of whom four had acute myeloid leukemia (AML) and four had chronic myeloid leukemia (CML) blast crisis, were treated with a combination of cytosine arabinoside (ARA-C: 1,600 mg/m2 in three patients, 1,200 mg/m2 in five patients), tetrahydrouridine (THU: 2,800 mg/m2 in two patients, 2,646 mg/m2 in one patient, 2,100 mg/m2 in five patients), and carboplatin (900 mg/m2 in four patients, 720 mg/m2 in one patient, 450 mg/m2 in three patients). As a result of this treatment, five of the eight patients became aplastic. Two of the four patients with CML blast crisis reverted to the chronic phase and two of the four patients with acute nonlymphocytic leukemia (ANLL) attained a remission (one partial remission and one complete remission). The major toxicities included myelosuppression, unacceptable hepatotoxicity, and diarrhea. Pharmacokinetics studies revealed that the addition of carboplatin did not significantly change the disposition of ARA-C. ARA-C levels were not significantly changed in comparison with those obtained in a prior study of ARA-C with THU (ARA-C plasma levels at 3 h, 2630 +/- 1170 ng/ml).

Acute Disease↗
PubMed1993

A comparison of propofol with other injectable anaesthetics in a rat model for measuring cardiovascular parameters.

Prolonged, stable, non-recovery anaesthesia is required for the assessment of the effects of novel compounds on the cardiovascular system. A comparison of injectable anaesthetic agents and combinations (thiobarbital, fentanyl-fluanisone and midazolam, propofol, fentanyl-fluanisone and propofol, and alphaxalone/alphadolone) was made in laboratory rats and the following parameters assessed over 3 h: blood pressure, heart rate and rhythm, respiration rate and depth, analgesia, ease of induction and maintenance of anaesthesia. It was found that propofol, with fentanyl-fluanisone premedication, provided stress-free induction, easily controlled anaesthesia, good analgesia and muscle relaxation for surgery, for up to 3 h duration. Heart rate, blood pressure and respiration remained stable and within normal limits during this time. The other anaesthetics/combinations assessed did not rate as highly in these respects. Propofol, following fentanyl-fluanisone premedication, would appear to be a useful and safe anaesthetic for use in rodents, which avoids significant effects on heart rate or blood pressure.

Anesthesia, Intravenous↗
PubMed1992

Use of cisplatin for elderly patients.

The ageing of the population has resulted in a greater emphasis on cancer treatment effects in elderly patients. This population has often had arbitrary dose modification of chemotherapy owing to fear of excessive side-effects. A review was undertaken to evaluate cisplatin toxicity in patients of 70 years of age or older. Thirty-four patients were evaluated. Their mean age was 72.8 years and 85.3% were women. Fourteen of 34 (41%) patients completed the planned therapy. Treatment was terminated because of disease progression (35%), renal toxicity (9%) and non-renal toxicity (15%). Our conclusion is that cisplatin can safely be administered to elderly patients. Arbitrary dose modification or elimination of cisplatin from a treatment programme on the grounds of patient age alone is not justified.

Acute Kidney Injury↗
PubMed1992

Clostridium sordellii bacteremia: case report and review.

Clostridium sordellii is a gram-positive, anaerobic bacillus that has rarely been implicated as a human pathogen. It produces several exotoxins, which contribute to the progressive edema and refractory shock frequently seen with human infection. There have been eight prior reports of bacteremic C. sordellii infection and seven prior reports of nonbacteremic infections not due to myonecrosis of skeletal muscle. Mortality was 50% in the bacteremic group and 71% in the nonbacteremic group. Mortality correlated with both shock and leukemoid reaction at presentation. We present a case of C. sordellii sepsis in an asplenic patient with sickle beta thalassemia and inflammatory bowel disease, and we review the literature.

Adult↗
PubMed1991

Phase I/II study of cyclophosphamide, doxorubicin, fluorouracil, and leucovorin for treatment of metastatic adenocarcinoma.

Leucovorin enhances the cytotoxicity of fluorouracil (5-FU) in patients with colorectal cancer and may increase the efficacy of combination chemotherapy regimens containing 5-FU. To determine the maximum tolerated dose of 5-FU with leucovorin for use in combination with cyclophosphamide and doxorubicin, we conducted a phase I/II trial in 20 patients. The doses of leucovorin (200 mg/m2 on days 1-5), cyclophosphamide (500 mg/m2 on day 1), and doxorubicin (40 mg/m2 on day 1) were held constant, while the dose of 5-FU was escalated in cohorts of patients beginning at 150 mg/m2 on days 1-5. Cycles were repeated every 3 weeks. Significant mucositis, diarrhea, and myelosuppression were infrequently observed in patients receiving up to 250 mg/m2 5-FU on days 1-5. In contrast, at a dose of 300 mg/m2 on days 1-5, three of six patients had granulocyte count nadirs of less than 500/microL during the first cycle of therapy, and two of these three had platelet counts of less than 25,000/microL. In addition, two patients treated at this dose had significant mucosal toxic effects, and three had insufficient recovery to permit a second course by day 22. Among 14 patients with assessable breast cancer, there were one complete and nine partial responses (response rate 71%). Leucovorin modulation of 5-FU can be safely incorporated into combination chemotherapy with cyclophosphamide and doxorubicin and provides a highly active regimen for treatment of metastatic breast cancer. Further study will be required to determine whether the addition of leucovorin significantly enhances the activity of this regimen.

Adenocarcinoma↗
PubMed1991

Correlation between molecular and clinical events in the evolution of chronic myelocytic leukemia to blast crisis.

A patient with typical Philadelphia chromosome (Ph1)-positive chronic myelocytic leukemia (CML) was studied during sequential phases of disease: (1) initial chronic phase; (2) myeloid blast crisis; (3) second chronic phase; and (4) accelerated disease. A point mutation in the coding sequence of the p53 gene first appeared concomitantly with the blast crisis and then disappeared with the re-establishment of a second chronic phase. The chromosomal concomitant of the molecular alteration was a deletion of 17p. These observations suggest that abnormalities of the p53 anti-oncogene are temporally related to the clinical progression of some cases of CML and are probably responsible for the development of blast crisis in these cases.

Adult↗
PubMed1991

Prognostic value of lymphocyte surface markers in acute myeloid leukemia.

We studied the expression of cell surface antigens associated with myeloid and lymphoid leukemias on bone marrow-derived blast cells from 339 patients with newly diagnosed de novo acute myeloid leukemia (AML) enrolled on Cancer and Leukemia Group B (CALGB) chemotherapy protocols. Surprisingly, of 211 cases studied for the expression of CD2 (T-cell marker, sheep erythrocyte binding receptor for T lymphocytes) 45 were positive (21%). In addition, of 298 patients studied for CD19 (B-lymphocyte marker), 41 were positive (14%). Overall, of 170 patients studied for both CD2 and CD19, 56 (33%) were positive. Interestingly, central review of the French-American-British (FAB) morphology of the CD2- and CD19-positive cases showed that FAB M3 was twice as frequent, and M4E eight times as frequent compared with the CD2- and CD19-negative cases. Of 22 lymphocyte antigen-positive cases in which cells were available for studies of Ig or T-cell antigen receptor (TCR) gene rearrangement, 20 were germline, one had a rearranged Ig heavy chain gene, and one had rearranged TCR beta and Ig heavy chain genes. The presence of messenger RNA for CD2 was demonstrated in four CD2 surface antigen-positive cases, thus validating the cell surface data. Lymphocyte antigen-positive cases had karyotypes commonly seen in AML; 71% of cases with an abnormal clone had t(8;21)(q22;q22), inversion 16(p13q22), t(15;17)(q22;q12), or t(9;11)(p22;q23). The patients with lymphocyte markers had a significantly higher incidence of these karyotypic abnormalities compared with patients with lymphocyte antigen-negative AML (34% v 15%, P less than .02). When the outcome to therapy of the lymphocyte antigen-positive cases was compared with that for the CD2, CD19-negative cases, we found that the CD2, CD19-positive cases actually had higher complete remission rates (75% v 59%, P = .04), and significantly longer time to failure (P = .02; 32.4% +/- 6.0% v 18.0% +/- 4.1% at 2 years) and overall survival (P = .02; 43.5% +/- 6.3% v 26.0% +/- 4.5% at 2 years). CD2 antigen-positive cases also had a significantly superior survival (P = .02; 43.8% +/- 7.9% v 29.8% +/- 3.8% at 2 years). There were no significant differences (P less than or equal to .05) between the two groups in age, leukocyte count at diagnosis, incidence of extramedullary disease, or FAB classification.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1991

The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia.

DNA from 135 patients with chronic myelogenous leukemia (CML) at various clinical stages and Philadelphia (Ph1) chromosome positive acute lymphoblastic leukemia was investigated for alterations in a variety of proto-oncogenes which have been implicated in the evolution of CML from its chronic phase to blast crisis. The most common genetic change found in the evolution of typical Ph1 chromosome positive CML to blast crisis was an alteration of the p53 gene involving either a rearrangement, a deletion, or a point mutation in the coding sequence of the gene. Alterations of the p53 gene were found in the myeloid and the rare megakaryocytic variant of blast crisis but were absent in the lymphoid leukemic transformants. Gross structural alterations were seen in 11 of 54 (20%) of myeloid or unknown phenotypes of blast crisis and in only 1 of 44 chronic phase cases. Eight examples of mutations in the open reading frame of the p53 gene at codons 49, 53, 60, 140, 202, 204, 238, and 239 were observed in blast crisis patients. Mutations in the N-RAS gene were rare in typical blast crisis (2 of 27 cases) but were found in megakaryocytic and Ph1 negative myeloid blast crisis. We concluded that heterogeneous alterations in the p53 gene and occasionally in the N-RAS genes accompany the evolution of chronic phase CML to blast crisis.

Blotting, Northern↗
PubMed1991

Different patterns of chromosome and molecular breakage in classic Ph1 chronic myelogenous leukemia (CML) and variant Ph1 CML.

Variant translocations involving either chromosome 9, chromosome 22, or both with other chromosomes have been reported in about 8% of chronic myelogenous leukemia (CML) patients. In the 22 Ph+ patients studied in our laboratory, two showed variant translocations: t(9;22;11) (q34;q11;q13), and t(9;11) (q34;q11). We compared the pattern of involvement of different chromosomes (and bands) in secondary structural changes in CMLs carrying the t(9;22) (q34;q11) and in the variant translocations. Analysis showed significant differences in the pattern of involvement of different chromosomes and chromosome sites in the secondary structural changes in classic CMLs. This study, thus identifies nonrandomly involved chromosome sites that may be targeted for detailed molecular analysis to obtain an understanding of their role in disease progression. In the variant translocations chromosomes and chromosome bands were nonrandomly involved. Breakpoint cluster region (bcr) of the BCR gene was found to be rearranged in our two cases. We compared the location of molecular breaks within the bcr in classic and variant translocations. We found that translocation breaks occurred more frequently in the 5' region, and less frequently in the 3' region of bcr in variant translocations as compared with classic translocations. The significance of these findings in the etiology of CML is discussed.

Bone Marrow↗
PubMed1991

Therapy of refractory/relapsed acute leukemia with cytosine arabinoside plus tetrahydrouridine (an inhibitor of cytidine deaminase)--a pilot study.

Thirty two patients with refractory or recurrent acute leukemia or blast crisis of chronic myelocytic leukemia were treated with 1-beta-D-arabinofuranosylcytosine (Ara-C), 100 mg/m2 [group I (n = 15)] or 200 mg/m2 [group II (n = 18)], and tetrahydrouridine (THU) 350 mg/m2, given concurrently as a 3 h continuous intravenous infusion at 12 h interval for eight doses. Two of 13 (15.3%) evaluable patients in group I achieved a complete response, both of whom had acute myelocytic leukemia. In group II, seven of 14 evaluable patients (50%) obtained objective responses--six with complete responses (42.8%) and one with partial response (7%). Myelosuppression was seen in all patients with a median duration of 32.5 days (group I) and 36.3 days (group II), respectively. Non-hematologic toxicity consisted of nausea, vomiting, diarrhea, conjunctivitis, skin rash, hepatocellular toxicity, hemorrhage, and renal toxicity. Pharmacokinetic studies revealed, for group I, mean peak plasma Ara-C levels at 3 h (Cp3h) of 1254 ng/ml, area under the curve (AUC) 4651 ng x h/ml, total body clearance (TBC) 32.65 l/h/m2, renal clearance (RC) 7.04 l/h/m2 with a mean of 12.36% of the injected amount of Ara-C excreted unchanged in urine over the first 24 h. The corresponding mean values for group II are Cp3h 3305 ng/ml, AUC 15080 ng x h/ml, TBC 20.48 l/h/m2, RC 7.02 l/h/m2 and 26.23%. Ara-C 200 mg/m2 combined with THU gave serum Ara-C levels and response rates comparable to those achieved with high dose Ara-C (HiDAC) (greater than or equal to 1 g/m2). Central nervous system toxicity associated with HiDAC was not seen. Pharmacokinetics for uracil arabinoside (Ara-U) in patients treated with Ara-C 200 mg/m2 plus THU, were comparable to values seen with Ara-C for Cp3h, AUC and 24 h urine, amounting to 3160 ng/ml, 21717 ng x h/ml and 23.62% whereas TBC was significantly lower (p less than 0.001) for Ara-U than for Ara-C (3.02 versus 20.48 l/h/m2).

Adult↗
PubMed1990

The effect of acrylamide on the induction of ornithine decarboxylase in the dorsal root ganglion of the rat.

Injury of the rat sciatic nerve is accompanied by an increased activity of the enzyme ornithine decarboxylase (ODC) in dorsal root ganglia. This increase is impaired in streptozotocin-induced diabetes, in which retrograde axonal transport of proteins is reduced. In order to confirm the relationship between altered axonal transport and ODC induction we treated rats with acrylamide i.p. to cumulative doses of 150 and 350 mg/kg. One sciatic nerve was crushed under anaesthesia and 24 h later dorsal root ganglia were removed and assayed for ODC activity by a dual-label radioenzymatic method. The ratio of activity of 2.41 +/- 0.57 (crushed side over control side) was reduced to 1.66 +/- 0.9 and 1.7 +/- 0.65 after acrylamide treatment at 150 and 350 mg/kg, respectively. The results are consistent with the postulated role of retrograde axonal transport in the cell body responses to nerve injury and may explain the effect of acrylamide on nerve regeneration.

Acrylamide↗
PubMed1990

The effect of 2,5-hexanedione on the induction of ornithine decarboxylase in the dorsal root ganglion of the rat.

Rat dorsal root ganglia respond to sciatic nerve injury with an increase in the activity of the enzyme ornithine decarboxylase (ODC). The increase is impaired under certain conditions (e.g. diabetes, Vinca alkaloid treatment) where retrograde axonal transport is reduced. The purpose of the experiments was to determine if the neurotoxin 2,5-hexanedione, also known to interfere with retrograde axonal transport, similarly affected ODC induction. Rats were treated with 2,5-hexanedione i.p. to a cumulative dose of 6 and 8 g/kg. One sciatic nerve was crushed under anaesthesia and 24 h later the dorsal root ganglia were removed and assayed for ODC activity by a radioenzymatic method. The ratio of ODC activity of 1.57 +/- 0.58 (crushed side over control side) was reduced to 1.02 +/- 0.41 1.08 +/- 0.39 after 2,5-hexanedione at 6 g and 8 g/kg, respectively. The enzyme was not inhibited by addition of 2,5-hexanedione in vitro. The results confirm the role of retrograde axonal transport in nerve cell responses to injury and are consistent with the effects of 2,5-hexanedione on nerve regeneration.

Animals↗
PubMed1990

Phase I trial of intravenous vinzolidine (LY 104208) given on a biweekly dosing schedule.

Vinzolidine (VZL) is a semisynthetic vinca alkaloid with broad antitumor activity in animal models of malignancy but had unpredictable toxic effects when given orally to humans. To minimize the toxic effects due to potential erratic gastrointestinal absorption, this drug was restudied in man as an intravenous preparation given as a rapid injection every two weeks. The maximum tolerated dose (MTD) on this schedule was 9.0 mg/m2 with unpredictable leukopenia (usually occurring 5-14 days post treatment but appearing erratically), constipation, paralytic ileus, and inappropriate ADH syndrome as major toxicities. Nonhematologic toxicities were dose-limiting. Repetitive dosing at two week intervals was associated with leukopenia at D 14-15 in some but not all patients treated above 5.0 mg/m2 precluding further treatment on schedule. In contrast, the oral MTD of this agent in our prior studies was 45 mg/m2 with no evidence of delayed leukopenia. Intrapatient variability of toxicity was small; interpatient variability of toxicity was substantial and did not correlate with prior therapy. Because of the presence of delayed hematologic toxicity on repetitive dosing schedules, intravenous VZL should be given on a dosing schedule longer than 14 days. No antitumor activity was seen in this study.

Adult↗
PubMed1990

Mechanism of action of triethyltin on identified leech neurons.

The effects of triethyltin (TET) have been examined using intracellular electrophysiological recording techniques from identified neurons of the leech (Hirudo medicinalis) CNS and from salivary glands of the giant Amazon leech (Haementeria ghilianii). TET, at concentrations as low as 10(-5) M, caused a reversible neuronal membrane depolarisation accompanied by an increase in firing frequency of action potentials (which could lead to conduction block at 10(-4) M) and a concomitant decrease in membrane resistance. TET-induced membrane depolarisation still occurred in saline where Na+, K+ and Ca2+ had been replaced by choline. TET decreased the rate of the depolarising and repolarising phases of the action potential. This also occurred in Haementeria salivary gland cells, in which the only inward cation channel is a calcium channel. The calcium channel blocker, manganese, did not block the effects of TET. TET counteracted the effects on the action potential of the potassium channel blocker, tetraethylammonium chloride (TEA). TET-induced neurotoxicity occurred independently of any resultant toxic effects on the myelin sheath. The action of TET is consistent with our view that it causes an increase of intracellular free Ca2+ probably via release from intracellular stores and inhibition of Ca2+ reuptake. A resulting inhibition of the Na+/K+ and Ca2+ pumps may also occur.

Action Potentials↗
PubMed1990

Aggressive phase multiple myeloma: a terminal anaplastic transformation resembling high-grade lymphoma.

The term "aggressive phase" has been applied in multiple myeloma to the development of rapidly enlarging extramedullary soft tissue masses or of bone marrow transformation with histologic features resembling high-grade or anaplastic lymphomas. One hundred and one patients who fulfilled this definition were identified in a review of the literature. Eighty-six patients had soft tissue or visceral involvement and 15 bone marrow involvement. The mean age at initial diagnosis of myeloma was 53 years, suggesting that the aggressive phase may be more likely to develop in younger patients. A disproportionate percentage of these patients have an IgA gammopathy. Following the onset of the aggressive phase, these patients have a rapidly fatal course, refractory to therapy, with a mean survival of less than 3.5 months. It is hypothesized that this aggressive phase represents part of the natural history of multiple myeloma, analogous to the terminal transformations associated with other relatively indolent myeloproliferative and lymphoproliferative disorders. Studies are reviewed supporting the proposition that the clinical and morphological changes associated with the aggressive phase result from a clonal evolution of the original malignant cell line and do not represent the development of an independent new neoplasm.

Adult↗
PubMed1989

Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia.

CD5-expressing B lymphocytes from patients with selected chronic lymphoproliferative disorders were used to determine whether monoclonal populations of CD5+ human B cells produce autoantibodies. CD5+ B cells from 19 patients with chronic lymphocytic leukemia (CLL) and one with diffuse well-differentiated lymphocytic lymphoma (DWDL) were cultured, with and without mitogenic stimulation, to obtain Ig from these cells. 17 of the 20 samples produced Ig in vitro. mAb from nine of the 17 patients were reactive with either IgG, ssDNA, or dsDNA. In every instance, the autoantibodies displayed monotypic L chain usage that correlated precisely with the L chain expressed on the CD5+ leukemic B cell surface. These monoclonal autoantibodies varied in their degree of antigenic specificity; some were quite specific, reacting with only one antigen, whereas others were polyspecific, reacting with two or all three autoantigens tested. Three features distinguish these autoantibodies from those observed in prior studies of CD5+ B cells. First, they are clearly the products of monoclonal populations of CD5+ cells; second, several react with dsDNA, a specificity not previously reported and often seen in association with significant autoimmune disorders; and third, two of the monoclonal autoantibodies secreted by the CD5+ clones were of the IgG class. Although not all of the Ig-producing, CD5-expressing clones elaborated mAbs reactive with the autoantigens tested, greater than 50% did. It is possible that with a broader autoantigenic panel or with larger quantities of CLL/DWDL-derived Ig, even more autoantibody-producing clones might be identified. These studies may have important implications for the antigenic specificity of subsets of human B lymphocytes as well as for lymphoproliferative and autoimmune disorders in general.

Antibody Specificity↗