Comparison of Renal Hemodynamic Effect of Ramiprilat to Captopril: Possible Role of Kinins

Sincetheintroductionofthefirstlineofangiotensinconvertingenzyme(ACE)inhibitors,ofwhichcaptoprilistheprototype,morepotentlonger-lastingagentshavebecomeavailable[l].AmongtheseisramipriIat,anonsL1lfhydrylACEinhibitorsimilarchemicallytoenalaprilatbutcontaininginadditionapentanering.Benderetal[2Jdemonstratedinvitrothatramiprilatisatleast23timesmorelipophilicthanenalaprilatwithanaffinityforACE47timesgreatc'rthanthatofcaptopril.ItwaspostulatedthatthemorelipophiIicanACEinhibitor,thebetteraccessi…     

The beta-globin gene on the Chinese delta beta-thalassemia chromosome carries a promoter mutation

A new type of delta beta-thalassemia characterized by decreased expression of the beta-globin gene and increased expression of both G gamma and A gamma globin gene in the absence of a detectable deletion has recently been described in the Chinese population. In this study we characterize the mutant beta-globin gene from this delta beta- thalassemia chromosome. An A to G transversion is identified in the "ATA" sequence of the promoter region that leads to decreased expression of the beta-globin gene in vivo and in vitro. We also demonstrate the presence of this mutation in every individual with a high fetal hemoglobin phenotype in this family and its absence in every individual with a normal hemoglobin phenotype. This same promoter mutation has recently been detected in Chinese beta-thalassemia genes where it is present on chromosomes of the same haplotype as that of the delta beta-thalassemia chromosome we are studying. These data support the hypothesis that an as yet unidentified mutation occurred on the ancestral chromosome carrying the promoter mutation and subsequently gave rise to the delta beta-thalassemia phenotype.     

Platelet refractoriness and alloimmunization in pediatric oncology and bone marrow transplant patients

BACKGROUND: The purposes of this study were to determine the overall incidence of platelet refractoriness and alloimmunization among multiply transfused children on a medical oncology and bone marrow transplant service and to evaluate the effect of routine white cell reduction in blood components on that incidence. STUDY DESIGN AND METHODS : The platelet transfusion records of 128 consecutive children admitted to the hospital and requiring blood component support for the treatment of disease were evaluated retrospectively. Mean corrected count increments (CCIs) for each patient were calculated for all random- donor platelet transfusions given within 7 days of the routine weekly testings of the patient's serum for lymphocytotoxic antibodies (LCTAbs). Mean CCIs for HLA-matched platelet transfusions were calculated separately for the patients receiving them. RESULTS : Thirty- one patients (24%) had or developed persistently positive LCTAbs (patient's serum reacted with > or = 3/10 panel lymphocytes); 22 (71%) of these patients had a mean CCI < 7.5 to random-donor platelet transfusions. In contrast, of the 97 patients with negative or transiently positive LCTAbs, only 25 (26%) had a mean CCI < 7.5. The overall incidence of platelet refractoriness (CCI < 7.5) was 37 percent. Patients with acute myelogenous leukemia had a significantly (p < 0.01) reduced incidence (17%) of low CCIs, with or without positive LCTAbs, as compared to patients with other malignant or nonmalignant disorders (41%). No difference in the incidence of LCTAbs or low CCIs was seen in patients undergoing allogeneic or autologous bone marrow transplant or receiving drug therapy only. Among the 24 patients who received HLA-matched platelets, only those with positive LCTAbs showed a significant improvement in CCIs over that achieved with random-donor platelet transfusions. Routine white cell reduction in red cell and platelet components with third-generation white cell filters was performed prior to transfusion in 73 of the patients. There was no significant difference between the incidence of LCTAbs and/or low CCIs in this group and that in the 55 children receiving unfiltered transfusions. CONCLUSION : Alloimmunization and platelet refractoriness occur in pediatric oncology and bone marrow transplant patients, but the incidence-particularly in children with acute myelogenous leukemia- -appears to be low. The detection of LCTAbs predicts a poor response to random-donor platelet transfusion, but most such patients show improved CCIs with HLA-matched platelets. Routine use of white cell-reduction filters has thus far failed to eliminate alloimmunization in children requiring prolonged blood component support.     

Natural kinds, natural history and the clinician-researcher

Recent medical research has been based on a flawed rationale of clinical innovation (here termed the 'basic-to-mega model') which neglects the human organism as a vital focus of clinical scientific study. The consequent over-concentration upon cellular and population levels of analysis has probably damaged the rate of therapeutic progress. The key role in medical research should be acknowledged to lie with clinician-researchers whose 'experimental animal' is the patient and whose 'end-points' are health and disease. The distinctive strength of the clinician-researcher derives from an ability to combine understanding of the 'natural kinds' (i.e. true biological categories) relevant to human disease, with experience of the 'natural history' of disease (i.e. its longitudinal pattern, including the response to interventions). Such knowledge is explicitly formalized by the activities of clinical science and clinical epidemiology. A sufficient supply of active clinician-researchers is the catalyst of innovation, and an insufficient supply is currently a rate-limiting factor in therapeutic progress.      

Design and validation of DNA probe sets for a comprehensive interphase cytogenetic analysis of acute myeloid leukemia

The objective of this study was to design DNA probe sets that enable the detection of chromosome aberrations in acute myeloid leukemia (AML) by interphase cytogenetics using fluorescence in situ hybridization (FISH) and to compare the results of interphase cytogenetics with those of conventional chromosome banding analysis. One hundred five consecutive patients with adult AML entered on a multicenter treatment trial were studied with a comprehensive set of DNA probes recognizing the most relevant AML-associated structural and numerical chromosome aberrations: translocations t(8;21), t(15;17), and t(11q23); inversion inv(16);chromosomal deletions (5q-, 7q-, 9q-, 12p-, 13q-, 17p-, and 20q- ); and chromosomal aneuploidies. Interphase cytogenetics was particularly sensitive for detecting the AML-specific gene fusions: 3 additional cases of inv(16) and 1 additional case of t(8;21) were identified by FISH that were missed by banding analysis, whereas equal numbers of t(11q23) and t(15;17) were detected. Five additional cases of trisomy 8q, 3 more cases of trisomy 11q, and 2 more cases of trisomies 21q and 22q were shown by FISH. These aberrations were either masked in complex karyo-types or identified in cases in which conventional banding analysis failed. On the other hand, the DNA probes selected were not informative to detect 1 case of 5q-, 9q-, and 20q-. In 5 cases, clonal aberrations were detected on banding analysis for which no FISH probes were selected. In conclusion, interphase cytogenetics proved to be more sensitive for detecting AML-specific chimeric gene fusions and some partial trisomies. Interphase cytogenetics provides a powerful technique complementary and, with further development of diagnostic DNA probes, even an alternative to chromosome banding studies for the cytogenetic analysis of AML.     

Myeloma bone marrow acid phosphatase staining: a correlative study of 38 patients

Acid phosphatase (AP) activity of plasma cells was studied in 38 patients with multiple myeloma (MM). The average activity per cell was strong (mean score = 2.42; maximum score = 4) and the percentage of positive cells was greater than 90% in over 71% of patients. The average AP activity per cell was higher prior to treatment (3.06 +/- 0.53) compared to relapse (2.48 +/- 0.77) and remission (1.81 +/- 1.02 (p less than 0.05 and p less than 0.01, respectively). In correlation of AP activity with clinical features at the time of the study, the only significant difference was between kappa and lambda subtype. Patients with lambda MM had a higher average AP activity per cell in remission (2.71 +/- 0.43) as opposed to kappa MM (1.17 +/- 1.06, p less than 0.05 for difference). AP activity was not significantly correlated with degree of bone involvement. However, activity seemed to be a good marker of disease activity.     

Platelet modulation of polymorphonuclear leukocyte shear induced aggregation

A cone and plate viscometer and Coulter Counter were used to study platelet modulation of polymorphonuclear leukocyte (PMNL) aggregation caused by controlled shear stress. As an index of aggregation, the large-particle percentage (LPP) was calculated. This represents the ratio of aggregated cell count to total cell count. PMNL suspensions in buffer (1.0 X 10(7) cells per milliliter, final concentration) did not show any aggregate formation at shear stresses below 150 dynes/cm2 for one minute exposure time (LPP less than 3%). However, there was PMNL aggregation in mixed PMNL and platelet-rich plasma suspensions in this shear stress range. Supernatant plasma from sheared platelets initiated PMNL aggregation at moderate shear stress (150 dynes/cm2 for one minute; LPP, 20.3% +/- 2.5%). In contrast, platelet release factors, such as adenosine diphosphate (2 mumol/L) and serotonin (2 mumol/L) did not cause PMNL aggregation (LPP, 2.9% +/- 1.2% and 3.3% +/- 0.8%, respectively). The use of a cyclo-oxygenase inhibitor (acetylsalicylic acid, 50 mumol/L) did not suppress the aggregation of PMNLs after shear (LPP, 20.1% +/- 2.4%). However, preincubation with nordihydroguaiaretic acid (10 mumol/L), an inhibitor of C-5 and C-12 lipoxygenase, and 6,9- deepoxy-6,9-(phenylimino)-6,8-prostaglandin I1 (U-60257, 10 mumol/L), an inhibitor of C-5 lipoxygenase in human leukocytes, suppressed this aggregation (LPP, 9.1% +/- 2.5% and 10.4% +/- 3.2%, respectively). Also, the formation of lipoxygenase products (5-HETE, 12-HETE, 15-HETE, and LTB4) activated by shear stress was documented by reversed phase- high-performance liquid chromatography (RP-HPLC). These data support the possibility of a cooperation between platelets and leukocytes in shear-induced PMNL aggregation that is dependent on C-12 or C-5 lipoxygenase activity, or both.