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Biomedical subjects

R Nitschke

Publications and source records attributed to R Nitschke.

At least 73 records · Page 4Linked to original sources
PubMed1992

Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study.

To account for the superior prognosis of hyperdiploid, B-progenitor acute lymphoblastic leukemia (ALL), we investigated the influence of trisomy in 1021 children greater than or equal to 1 year old by recursive partitioning analysis. The patients were treated according to a stratified, randomized study testing antimetabolite-based therapies. Trisomies of several individual chromosomes were associated with a better prognosis in a univariate statistical analysis. Of greater importance, trisomy of both chromosomes 4 and 10 identified a subgroup of patients (n = 180) with an extremely favorable 4-year event-free survival (EFS). Combined trisomy of chromosomes 4 and 10 retained its prognostic significance after stratification of patients by DNA index, age, and leukocyte count. Among patients with a DNA index greater than 1.16, patients with trisomies of both chromosomes 4 and 10 had a 4-year EFS of 96.6% (n = 161, SE = 3.8%), whereas patients with neither or only one of these trisomies had a 4-year EFS of 70.4% (n = 73, SE = 11.5%). All 19 patients with a DNA index less than or equal to 1.16 but with trisomies of chromosomes 4 and 10 remain in remission, suggesting that favorable chromosome trisomy dominates in a situation in which the cellular DNA content of less than or equal to 1.16 predicts a less favorable outcome. We conclude that combined trisomy of chromosomes 4 and 10 independently predicts EFS among children with B-progenitor ALL. Patients within the B-progenitor group who have this feature (about 20% of those with clonal abnormalities) are likely to be cured with antimetabolite-based chemotherapy--an approach that should produce few significant late effects.

Adolescent↗
PubMed1992

Age-linked prognostic categorization based on a new histologic grading system of neuroblastomas. A clinicopathologic study of 211 cases from the Pediatric Oncology Group.

Histologic sections (minimum of four sections per patient) from 211 patients with neuroblastoma were reviewed. The tumors were resected before therapy, which was standardized according to age and stage. Low mitotic rate (MR) (less than or equal to ten per ten high-power fields) and calcification emerged as the most significant prognostic features after statistical analysis by stepwise log-rank tests (P less than 0.0001 and P = 0.0065, respectively). Histologic Grades 1, 2, and 3 were defined on the basis of the presence of both, any one, or none of these two prognostic features, respectively (Grade 3 had absence of low MR, i.e., these tumors had high MR [greater than ten per ten high-power fields]). Statistically significant differences in survival were observed in the grades after adjusting for age and stage (P less than 0.001). The degree of differentiation, although significant by itself, was no longer significant after adjusting for the grades. Age groups (less than or equal to 1 versus greater than 1 year of age), which also emerged as an independent prognostic feature (P less than 0.001), were linked with the grades to define two risk groups as follows: (1) a low-risk (LR) group consisting of patients in both age groups with Grade 1 tumors and patients 1 year of age or younger with Grade 2 tumors and (2) a high-risk (HR) group consisting of patients older than 1 year of age with Grade 2 tumors and patients in both age groups with Grade 3 tumors. The difference in survival between LR (160 cases) and HR groups (51 cases) was statistically significant (P less than 0.001). Concordance between these LR and HR groups and the Shimada classification was observed in 84% of cases. The new histologic grading system has the following advantages: (1) use of familiar terminology and histologic features in the grading system and (2) relative ease of assessment because the degree of differentiation does not need to be determined. The grading system should be tested on a new data set with an appropriate histologic sample of similar size to confirm these results.

Age Factors↗
PubMed1992

Evaluation of CHIP (iproplatin) in recurrent pediatric malignant solid tumors. A phase II study (Pediatric Oncology Group).

CHIP (325 mg/M2), a second generation cisplatin derivative, was administered intravenously every 3 weeks to 85 pediatric patients with recurrent sarcomas (19), osteosarcomas (20), neuroblastoma (23), germ cell tumors (10), and other malignant tumors (7). Thirty-eight of them had been previously exposed to cisplatin. Partial remissions were only observed in 3 of 23 (13% SE = 7%) patients having neuroblastoma. Severe thrombocytopenia (65%) and neutropenia (35%) were the dose limiting factors.

Adolescent↗
PubMed1992

A study of toxicity and comparative therapeutic efficacy of vindesine-prednisone vs. vincristine-prednisone in children with acute lymphoblastic leukemia in relapse. A Pediatric Oncology Group study.

Vindesine (des-acetyl Vinblastine) is a synthetic derivative of vinblastine, and was produced with the hope that it would have less neurotoxicity and hematopoietic toxicity than other vinca alkaloids. Phase I and II studies also demonstrated significant activity in lymphoid malignancies, especially Acute Lymphoblastic Leukemia (ALL). The present study was designed to compare therapeutic effectiveness of twice weekly vindesine (2 mg/M2/dose) plus Prednisone (60 mg/M2/dose) (Treatment 1) to weekly Vincristine (2 mg/M2/dose) plus Prednisone (60 mg/M2/day) (Treatment 2). All patients were less than 21 years of age, and had documented bone marrow relapse (blast count > 25%). In 39 patients presumed sensitive to vincristine, there were 11 complete responses out of 20 patients (55%) randomized to receive vindesine/prednisone and 7 complete responses out of 19 patients (37%) treated with Vincristine/Prednisone. In 37 patients resistant to vincristine, there were 7 complete responses (19%). Vindesine was more toxic than Vincristine. Major toxicities of vindesine included paraesthesias, peripheral neuropathy and ileus. Vindesine hematological toxicity appeared greater, but such toxicity is hard to assess in patients with bone marrow disease. In this study, vindesine and vincristine had similar efficacy, but vindesine use was associated with more toxicity.

Adolescent↗
PubMed1992

Serum lactate dehydrogenase in childhood neuroblastoma. A Pediatric Oncology Group recursive partitioning study.

On the basis of an extensive recursive partitioning analysis of 668 patients with newly diagnosed neuroblastoma registered on Pediatric Oncology Group (POG) studies between October 1981 and May 1987, four major subsets of patients were created. Important prognostic factors included the patient's stage of disease, age, and level of serum lactate dehydrogenase (LDH). After adjusting for these factors, no other clinical prognostic factors were significant. The implications for protocol design are that (a) fine tuning of current therapy should be sought for the two favorable disease patient subsets, while (b) novel aggressive therapies are needed for the two unfavorable disease patient subsets where the overwhelming majority are dying. This article may serve as a model for others investigating prognostic factors. The data were divided into two subsets: one was used for an exploratory analysis; the other was used to confirm the exploratory findings. Despite spite the large number of statistical tests performed, the likelihood that the findings can be attributed to chance can be dismissed as virtually zero.

Adolescent↗
PubMed1992

Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study.

PURPOSE: Infants less than or equal to 1 year of age with neuroblastoma (NB) have a favorable outlook with minimal to moderate therapy. Patients with complete or partial removal of the primary tumor but positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) have a higher risk for recurrent disease. To determine the importance of distinguishing infants with POG stage C NB from those with POG stage B disease and to assess the efficacy and toxicity of treating POG stage C infants with limited, postoperative chemotherapy, a study was conducted by the POG. PATIENTS AND METHODS: Forty-four eligible POG stage C infants received cyclophosphamide 150 mg/m2 orally on days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR), every 3 weeks for five courses followed by second-look surgery. No continuation therapy was given if surgical and pathologic complete response (CR) was achieved. Secondary therapy with five courses of cisplatin 90 mg/m2 on day 1 followed by teniposide (VM-26) 100 mg/m2 on day 3 (CDP/VM) was given to infants with gross residual tumor after CYC/ADR and second-look surgery. RESULTS: Thirty-four infants achieved CR after CYC/ADR alone, three after CYC/ADR and second-look surgery, two after CYC/ADR, surgery, and maintenance therapy, and two after alternative treatment with CDP/VM (total CR rate, 42 of 44). The 3-year survival and disease-free survival are both 93%. Toxicity was nominal. CONCLUSIONS: Infants with POG stage C NB have a favorable outlook, which is similar to infants with POG stage B NB; the surgical staging procedure for distinguishing these infant subsets may not be necessary. Future studies should focus on the reduction of treatment toxicity and efficacy maintenance, and address methods to identify infants at risk for failure.

Actuarial Analysis↗
PubMed1992

The availability of psychosocial interventions to children with cancer and their families.

Awareness of the need for and efficacy of psychosocial services for pediatric oncology patients and their families has increased greatly in the last decade. However, it is currently unknown to what extent these services are available. Therefore, a national survey of pediatric oncologists was conducted to determine the availability of the following services: psychological/psychiatric and social work consultation, support groups for patients and family members, nonpharmacological pain and anxiety management, and nonpharmacological treatment of anticipatory emesis. Results suggest that most centers offer social work consultation and support groups to parents. Fewer support groups are offered to patients and even fewer nonpharmacological services to assist patients in coping with anticipatory nausea and pain are offered. Results are discussed in terms of the pattern of service delivery and cost-effectiveness.

Cancer Care Facilities↗
PubMed1991

Remission induction and continuation therapy in children with their first relapse of acute lymphoid leukemia. A Pediatric Oncology Group study.

Between January 1979 and April 1983, 113 children undergoing their first relapse of acute lymphoid leukemia (ALL) at any site were registered in Pediatric Oncology Group study 7834; 98 were eligible and evaluable. In addition to radiotherapy administered to sites of local relapse, induction consisted of vincristine, doxorubicin, and prednisone (VAP) chemotherapy. Continuation therapy consisted of triple-drug intrathecal therapy and regimens of 6-thioguanine and cytarabine alternating with vincristine, prednisone, cyclophosphamide, and cytarabine. Randomization in continuation was between VAP pulses or no pulse, regardless of the site of relapse. This report provides long-term follow-up of these patients. Thirty-two of 39 children with bone marrow involvement achieved a complete response (CR). Only one of these is alive in an unmaintained remission, a child who did not have an initial CR. Thirty-four of 36 evaluable children with central nervous system involvement as the site of relapse achieved CR. Of these ten are alive; eight are in continuing CR. Nineteen of 20 boys with testicular relapse achieved CR. Of these, 14 are still alive and not receiving therapy, although only one half received treatment in compliance with the protocol described. These results illustrate the possibility of cure of patients who have relapsed with ALL when it is (1) confined to a meningeal or gonadal site and (2) treated vigorously with radiotherapy and a new regimen of systemic chemotherapy. The results reconfirm the need to prevent an initial relapse at any site.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Antidiuretic hormone acts via V1 receptors on intracellular calcium in the isolated perfused rabbit cortical thick ascending limb.

The effect of antidiuretic hormone [( Arg]vasopressin, ADH) on intracellular calcium activity [Ca2+]i of isolated perfused rabbit cortical thick ascending limb (cTAL) segments was investigated with the calcium fluorescent dye fura-2. The fluorescence emission ratio at 500-530 nm (R) was monitored as a measure of [Ca2+]i after excitation at 335 nm and 380 nm. In addition the transepithelial potential difference (PDte) and transepithelial resistance (Rte) of the tubule were measured simultaneously. After addition of ADH (1-4 nmol/l) to the basolateral side of the cTAL R increased rapidly, but transiently, from 0.84 +/- 0.05 to 1.36 +/- 0.08 (n = 46). Subsequently, within 7-12 min R fell to control values even in the continued presence of ADH. The increase in R evoked by the ADH application corresponded to a rise of [Ca2+]i from a basal level of 155 +/- 23 nmol/l [Ca2+]i up to 429 +/- 53 nmol/l [Ca2+]i at the peak of the transient, as estimated by intra- or extracellular calibration procedures. The electrical parameters (PDte and Rte) of the tubules were not changed by ADH. The ADH-induced Ca2+ transient was dependent on the presence of Ca2+ on the basolateral side, whereas luminal Ca2+ had no effect. d(CH2)5[Tyr(Me)2]2,Arg8vasopressin, a V1 antagonist (Manning compound, 10 nmol/l), blocked the ADH effect on [Ca2+]i completely (n = 5). The V2 agonist 1-desamino-[D-Arg8]vasopressin (10 nmol/l, n = 4), and the cAMP analogues, dibutyryl-cAMP (400 mumol/l, n = 4), 8-(4-chlorophenylthio)-cAMP (100 mumol/l, n = 1) or 8-bromo-cAMP (200 mumol/l, n = 4) had no influence on [Ca2+]i. The ADH-induced [Ca2+]i increase was not sensitive to the calcium-channel blockers nifedipine and verapamil (100 mumol/l, n = 4). We conclude that ADH acts via V1 receptors to increase cytosolic calcium activity transiently in rabbit cortical thick ascending limb segments, possibly by an initial Ca2+ release from intracellular stores and by further Ca2+ influx through Ca2+ channels in the basolateral membrane. These channels are insensitive to L-type Ca2+ channel blockers, e.g. nifedipine and verapamil.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1991

Transient white matter changes on MR images in children undergoing chemotherapy for acute lymphocytic leukemia: correlation with neuropsychologic deficiencies.

The cranial magnetic resonance (MR) images of 25 children with acute lymphocytic leukemia (ALL) who were undergoing chemotherapy were retrospectively studied to determine the frequency of white matter changes and to analyze the significance of these observed changes in predicting subsequent neuropsychologic deficiencies. MR images showed transient white matter abnormalities in 17 of the 25 patients during consolidation therapy. Twelve of 20 children showed neuropsychologic deficits. There was no correlation between white matter changes and neuropsychologic deficits. In the subgroup of children under age 5 years at the time of diagnosis, 10 of 11 showed neuropsychologic deficits, and eight of 11 had white matter changes. Children under age 5 who undergo chemotherapy for ALL are at high risk to develop neuropsychologic deficiencies. Age at diagnosis is a reliable predictor of subsequent neuropsychologic deficits.

Adolescent↗
PubMed1991

Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma.

Children older than 1 year of age who have neuroblastoma with complete or partial removal of the primary tumor and positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) are a small but higher-risk subset of patients. To further evaluate the importance of identifying patients with POG stage C neuroblastoma and to assess the efficacy and toxicity of adding concurrent radiation therapy (RT) to chemotherapy (CT) in these children, a randomized study was conducted. Eligible patients received cyclophosphamide 150 mg/m2 orally days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR) every 3 weeks for five courses with or without RT to primary tumor and regional lymph nodes (24 to 30 Gy/16 to 20 fractions). Second-look surgery was advised to evaluate response and to remove residual disease. Continuation therapy alternated CYC/ADR every 3 weeks with cisplatin 90 mg/m2 day 1 followed by teniposide 100 mg/m2 day 3 (CDP/VM) for two courses each. Secondary CT with CDP/VM alone was available for patients not achieving complete response (CR) following induction treatment and second-look surgery. Of 29 eligible patients randomized to CT alone, 13 achieved CR, and nine are disease-free (NED) 1 to 52 months (median, 35 months) off therapy. Twenty-two of 33 eligible cases treated with CT/RT attained CR, and 19 are NED 1 to 77 months (median, 23 months) off therapy. Local and metastatic relapses occurred in both arms. Differences in CR, event-free survival, and survival rates were significant, P = .013, .009, and .008, respectively. Surgical compliance was excellent and complications uncommon. Therapy was tolerable in both groups but hematopoietic toxicity was more common in the CT/RT arm. We conclude that POG stage C neuroblastoma in children older than 1 year of age is a higher-risk group that should be identified, that CT/RT provides superior initial and long-term disease control compared with CT alone in this patient subset, and that the occurrence of metastatic failures in both treatment groups suggests a need for more aggressive chemotherapy.

Adolescent↗
PubMed1991

Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group study.

The Pediatric Oncology Group (POG) evaluated in a prospective study the hypothesis that patients who had localized, visible residual neuroblastoma without regional lymph node involvement after surgery (POG stage B) have a favorable prognosis when treated with moderate intensive chemotherapy. Eligible patients were initially treated with five courses of Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co., Evansville, IN) and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) followed by surgery (CY/AD +/- surgery). Those patients not achieving a complete remission (CR) crossed over to five courses of cisplatin and teniposide (PL/VM) +/- surgery. Radiation therapy (XRT) was given to selected patients who still were not in CR after the crossover therapy. Of the 61 eligible patients, 38 (62%) patients achieved CR after CY/AD proven by clinical (31) or surgical (seven) evaluation. One (2%) patient in clinical partial remission (PR-C) entered CR without further therapy. Nineteen (31%) patients achieved CR with the following salvage therapies: surgery (five), PL/VM +/- surgery (five) followed by XRT (three) or autologous bone marrow transplant (ABMT) (one) and further courses of CY/AD +/- PL/VM instead of courses of PL/VM (five). The overall CR rate was 95% (58 of 61). Four patients had recurrence of the disease. The probability of being disease-free at 3 years after initial or salvage therapy was estimated at 84% (SE, 5%). The overall prognosis of children older than 1 year and younger than 1 year was similar (P = .26). If, however, the three remission deaths (all younger than 1 year) were censored, there was only one other failure in 32 children younger than one versus seven of 29 children older than 1 year (P = .018). These results confirm the excellent prognosis for patients with POG stage B neuroblastoma and indicate that most patients are curable with CY/AD +/- surgery, and those not achieving CR with this therapy are curable with alternate therapy.

Abdominal Neoplasms↗
PubMed1990

Effects of parathyroid hormone and calcitonin on Na+, Cl-, K+, Mg2+ and Ca2+ transport in cortical and medullary thick ascending limbs of mouse kidney.

The effect of parathyroid hormone (PTH) on transepithelial Na+, Cl-, K+, Ca2+ and Mg2+ transport was investigated in isolated perfused cortical thick ascending limbs (cTAL) and that of human calcitonin (hCT) was tested in both cortical and medullary thick ascending limbs (mTAL) of the mouse nephron. The transepithelial ion net fluxes (Jx) were determined by electron probe analysis of the perfused and collected fluids. Simultaneously, the transepithelial voltage (PDte) and resistance (Rte) were recorded. In cTAL segments, PTH and hCT significantly stimulated the reabsorption of Na+, Cl-, Ca2+ and Mg2+, hCT generated a net K+ secretion towards the lumen and PTH tended to exert the same effect. Neither PDte nor Rte were significantly altered by either PTH or hCT. However, in the post-experimental period a significant decrease in PDte was noted. Time control experiments carried out under similar conditions revealed a significant decrease in PDte with time, which could have masked the hormonal response. In mTAL segments, Mg2+ and Ca2+ transport was close to zero, hCT did not exert any detectable effect on either PDte or Jcl-, JNa+, JK+, JMg2+ and JCa2+ in these segments. In conclusion, our data demonstrate that PTH and hCT stimulate NaCl reabsorption as well as Mg2+ and Ca2+ reabsorption in the cTAL segment of the mouse. These data are in agreement with and extend data obtained in vivo in the rat.

Animals↗
PubMed1989

Granulocyte-macrophage colony-stimulating factor is an endogenous regulator of cell proliferation in juvenile chronic myelogenous leukemia.

Juvenile chronic myelogenous leukemia (JCML) is a rare myeloproliferative disorder of early childhood that is clinically and cytogenically distinct from the well-recognized adult type of chronic myeloid leukemia. Unlike the adult disease, growth of hematopoietic progenitors from peripheral blood (PB) occurs in the absence of exogenous stimulus even at low cell densities. This so-called "spontaneous" growth can be abrogated by adherent cell depletion and appears to depend on production of endogenous growth factors. We studied seven children with JCML to determine the nature of endogenous stimulators. With isolated PB mononuclear cells (PBMNCs) and a 3H-thymidine (3H-TdR) incorporation assay, JCML cells were shown to incorporate high levels of 3H-TdR when cultured in the absence of stimulus even at low cell densities. When neutralizing antisera prepared against each of the four known colony-stimulating factors (CSFs), GM-CSF, G-CSF, M-CSF, and interleukin-3 (IL-3), as well as antisera against interleukin-1 (alpha and beta) and tumor necrosis factor (TNF) were added to these cultures, only the antisera against recombinant human GM-CSF (rhGM-CSF) consistently resulted in significant inhibition of cell proliferation, achieving up to 72% inhibition of 3H-TdR incorporation in one case. Monoclonal antibodies (MoAbs) against rhGM-CSF resulted in a similar and highly significant degree of inhibition. A marked inhibitory effect of rhGM-CSF antiserum on "spontaneous" growth of PB CFU-GM derived colonies in semisolid medium was also demonstrated in four of five patients studied (87% to 90% inhibition). Production of growth factors by highly enriched JCML monocytes was variable. When initially studied in five of the seven patients, the monocytes from three of the patients revealed increased release of IL-1-like activities; two patients had levels similar to those of controls. One patient with normal levels when initially studied was later shown to have markedly increased amounts of IL-1-like activities in a second preparation of monocyte-conditioned medium (MCM). High levels of GM-CSF were detected in the initial MCM from one patient, but this may have indirectly reflected elevated IL-1-like activities present in the MCM. IL-3 and M-CSF levels were either low or undetectable in the patients studied as compared with MCM prepared with normal adult monocytes. These results clearly implicate GM-CSF as the primary endogenous regulator of JCML cell proliferation in culture and suggest that this malignant myeloproliferative disease may in part result from paracrine stimulation of marrow progenitor cells by growth factors/cytokines secreted by the malignant monocytes.

Bone Marrow↗
PubMed1989

Effects of glucagon on Na+, Cl-, K+, Mg2+ and Ca2+ transports in cortical and medullary thick ascending limbs of mouse kidney.

The effects of glucagon on transepithelial Na+, Cl-, K+, Ca2+ and Mg2+ net fluxes were investigated in isolated perfused cortical (cTAL) and medullary (mTAL) thick ascending limbs of Henle's loop of the mouse nephron. Transepithelial ion net fluxes (JNa+, JCl-, JK+, JCa2+, JMg2+) were determined by electron probe analysis of the collected tubular fluid. Simultaneously the transepithelial voltage (PDte) and the transepithelial resistance (Rte) were recorded. In cTAL-segments (n = 8), glucagon (1.2 x 10(-8) mol.1-1) stimulated significantly the reabsorption of Na+, Cl-, Ca2+ and Mg2+: JNa+ increased from 204 +/- 20 to 228 +/- 23 pmol.min-1.mm-1, JCl- from 203 +/- 18 to 234 +/- 21 pmol.min-1.mm-1, JCa2+ from 0.52 +/- 0.13 to 1.34 +/- 0.30 pmol.min-1.mm-1 and JMg2+ from 0.51 +/- 0.08 to 0.84 +/- 0.08 pmol.min-1.mm-1.JK+ remained unchanged: 3.2 +/- 1.3 versus 4.0 +/- 1.9 pmol.min-1.mm-1. Neither PDte (16.3 +/- 1.5 versus 15.9 +/- 1.4 mV) nor Rte (22.5 +/- 3.0 versus 20.3 +/- 2.6 omega cm2) were changed significantly by glucagon. However, in the post-experimental periods a significant decrease in PDte and increase in Rte were noted. In mTAL-segments (n = 9), Mg2+ and Ca2+ transports were close to zero and glucagon elicited no significant effect. The reabsorptions of Na+ and Cl-, however, were strongly stimulated: JNa+ increased from 153 +/- 17 to 226 +/- 30 pmol.min-1.mm-1 and JCl- from 151 +/- 23 to 243 +/- 30 pmol.min-1.mm-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Piretanide-dextran and piretanide-polyethylene glycol interact with high affinity with the Na+ 2 Cl- K+ cotransporter in the thick ascending limb of the loop of Henle.

Piretanide blocks the Na+ 2Cl- K+ cotransporter protein in the thick ascending limb (TAL) of the loop of Henle reversibly. When tested from the luminal side in isolated perfused cTAL segments it leads to a half maximal inhibition (IC50) of the equivalent short circuit current (Isc) at a concentration of 10(-6) mol/l. From the basolateral side it has no effect on Isc up to 10(-4) mol/l. The present study was designed to search for high affinity blockers of the Na+ 2Cl- K+ cotransporter with large molecular weight in an attempt to use these macromolecules for antibody-labelling or affinity separation of this transport-protein. Amino-ethyl-dextran or amino-ethyl-polyethylene glycol (M.W. 5kd) were coupled to isothiocyanato-piretanide (ISO-PIR) at room temperature in DMSO. The resulting compounds dextran-sulfonylurea-piretanide (PIR-DEX) and polyethylene glycol-sulfonylurea-piretanide (PIR-PEG) (M.W. 5.38kd) were purified and tested in isolated perfused cTAL segments. IC50 values for ISO-PIR, PIR-DEX and PIR-PEG were estimated from dose response curves after their addition to the lumen or bath perfusate, respectively. ISO-PIR, PIR-DEX and PIR-PEG acted from the lumen side at 3.10(-6), 6.10(-6) and 2.10(-6) mol/l. The inhibitory effect was easily reversible. From the basolateral side no effect for any compound was seen at up to 10(-4) mol/l. In clearance experiments PIR-DEX was given to female Wistar rats as an i.v. bolus (25 mumol/kg) and the diuretic urine was collected. After dialysis (exclusion limit 2.5kd) the dialysed urine and the dialysate were tested in isolated perfused cTAL segments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Reversible treatment-related leukoencephalopathy.

We present two children with acute lymphocytic leukemia who developed leukoencephalopathy following administration of a combination of intravenous ara = C and methotrexate during the consolidation phase of chemotherapy. Cranial magnetic resonance imaging showed widespread, abnormally high signal intensity in the deep white matter in both patients, though one patient had normal cranial computed tomographic scan. Treatment was modified, symptoms resolved in 1 to 2 weeks, and the white-matter changes resolved over 6 to 12 months. Intravenous cytarabine and methotrexate appear to act synergistically to enhance the potential for central nervous system toxicity. Awareness of this potentially serious complication of chemotherapy can facilitate timely recognition of leukoencephalopathy with the use of magnetic resonance imaging.

Child↗