Autoantibodies against the platelet glycoproteins (GP) IIb/IIIa, Ia/IIa, and IV and partial deficiency in GPIV in a patient with a bleeding disorder and a defective platelet collagen interaction

To evaluate the physiologic importance of the different collagen receptors on platelets, we screened 806 patients admitted to the hospital because of hemorrhagic diathesis for eventual laboratory evidence of a pathologic platelet collagen interaction, and found 5 patients with an isolated deficiency in collagen-induced platelet aggregation. Four of these five patients had a partial defect, one had a complete defect. The structural and functional analysis of the platelets from the patient with a complete defect showed a deficiency in glycoprotein (GP) IV and autoantibodies against GPIIb/IIIa, GPIa/IIa, and GPIV. Patient plasma had only a minimal effect on normal control platelets and Naka-negative platelets. The analyses of the defect in the patient and of the data in the literature suggest that a single defect may not result in clinical bleeding (GPIV-deficient patients do not bleed), but may become symptomatic in combination with another defect such as the autoantibodies against GPIa/IIa, GPIV, and/or GPIIb/IIIa, all of which are involved in platelet collagen interactions (three of four of our immune thrombocytopenic purpura patients with anti-GPIV and anti-GPIIb/IIIa autoantibodies had a bleeding disorder). We hypothesize that it is the synergism of two abnormalities that results in the defective function, a mechanism that is in agreement with earlier studies on platelet collagen interaction that suggests that a double defect in platelet collagen interactions is required to become clinically apparent.     

El sobrecrecimiento bacteriano de intestino delgado es una entidad frecuente tras gastrectomía,pero con escasa relevancia en el estado nutricional

Background

Available evidence assessing the impact of small intestinal bacterial overgrowth (SIBO) following gastrectomy is limited.

Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients

Initial studies have shown that recombinant human interleukin-6 (rhIL- 6) induces anemia. Until now, the pathophysiologic mechanism of this induced anemia has been unknown. To unravel the underlying mechanism, we examined 15 cancer patients receiving rhIL-6 as an antitumor immunotherapy in a phase II study. rhIL-6 was administered subcutaneously at 150 micrograms once daily for 6 consecutive weeks. Various hematologic and biochemical parameters were measured weekly during rhIL-6 treatment and 4 weeks after rhIL-6 discontinuation. To determine plasma volume and red blood cell (RBC) volume, radioisotope dilution assays with labeled autologous RBCs and with human serum albumin were performed before rhIL-6 administration and on day 8 of rhIL-6 therapy. Hemoglobin levels decreased (mean change +/- SE) 7% +/- 1.5% within 3 days after the start of rhIL-6 therapy (P < .0001) and 19% +/- 2% at week 4. Levels had normalized at follow-up. The plasma volume increased 18% +/- 5% during the first week of rhIL-6 administration (P < .003), whereas RBC volume remained unaffected. The mean RBC corpuscular volume remained unchanged for 2 weeks and then began to decrease slowly, reaching its nadir at week 6 (5% +/- 1%; P < .01). Serum iron levels decreased 65% +/- 12% at week 4 (P < .002) and then returned to initial baseline values. Erythropoietin levels increased rapidly up to 68% at week 3 (P < .0001) and had normalized 4 weeks after rhIL-6 therapy. Levels of serum albumin, prealbumin, and transferrin decreased (P < .0001, P < .003, and P < .0001, respectively), whereas levels of serum amyloid A (P < .003), C-reactive protein, haptoglobin, and alpha-1-antitrypsin (P < .0001) increased during rhIL-6 treatment. All levels returned to pretreatment values after discontinuation of rhIL-6. No alterations in reticulocyte counts, serum lactic dehydrogenase levels, and bilirubin levels were observed. A 6-week regimen of subcutaneous rhIL-6 results in a rapid dilution anemia, caused by an acute and significant increase in plasma volume and followed by hypoferremia. This anemia is reversible after the cessation of rhIL-6 treatment.     

A murine cytokine fusion toxin specifically targeting the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor on normal committed bone marrow progenitor cells and GM-CSF-dependent tumor cells

A fusion protein was synthesized consisting of the murine granulocyte- macrophage colony-stimulating factor (mGM-CSF) gene spliced to a truncated form of the diphtheria toxin (DT390) gene coding for a molecule that retained full enzymatic activity, but excluded the native binding domain. The DT390-mGM-CSF hybrid gene was cloned into a vector under the control of an inducible promoter and the protein expressed in Escherichia coli. After induction, a protein was purified from inclusion bodies in accord with the deduced molecular weight of DT390 mGM-CSF. Cell-free studies of the adenosine diphosphate-ribosylating activity of DT390 mGM-CSF showed results that were similar to those of native DT. The DT390 mGM-CSF immunotoxin inhibited FDCP2.1d, a murine myelomonocytic tumor line expressing the GM-CSF receptor with an IC50 (concentration inhibiting 50% activity) of 5 x 10(-11) mol/L. The fusion toxin was specifically cytotoxic and directed by the GM-CSF portion of the molecule because addition of a monoclonal antibody directed against GM-CSF inhibited its ability to kill the cell line. Cell lines that do not express GM-CSF receptor were not inhibited by the fusion toxin. DT390 mGM-CSF was also able to specifically inhibit normal committed bone marrow (BM) progenitor cells as measured in clonal colony-forming unit granulocyte-macrophage assays. Together, these findings indicate that DT390 mGM-CSF may be useful as a novel tool for purging BM of contaminating leukemia cells or in vivo for eliminating residual leukemia cells. Also, it can be used to determine whether committed and/or noncommitted BM progenitor cells express the GM-CSF receptor.     

The change with age in biogenic amines and their metabolites in the striatum of the rat

The changes in the content of the biogenic amines and their metabolites in the striatum of the rat during the aging period (3-30 months) have been studied. The maximum levels of dopamine (DA) have been found at 6 months of age and this concentration is maintained until 24 months. Between 24 to 30 months there is a decrease in the concentration of this compound. At that time, there is a slight increase in 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) concentration, the main metabolites of DA, which suggests a slight increase in DA metabolism. The 3-methoxytyramine (3-MT) concentration also increases at this time. The maximum concentration of noradrenaline (NA) was also found at 6 months of age. Tryptophan has the maximum concentration after DA and this is maintained over the life-span of the rat. The concentration of serotonin (5-HT) is high and does not change during this period. However, the concentration of 5-HT, as occurred with DA, decreased between 24 and 30 months. Also the DA/5-HT ratio does not change during the period studied.     

大鼠心肌梗死后的原癌基因表达

目的本实验旨在探讨心肌梗死后左心室重构的分子生物学机制。方法用地高辛标记的原位杂交方法观察了大面积心肌梗死后存活心肌细胞的原癌基因c-myc。c-fos及c-jun的mRNA水平的动态变化，并用巯甲丙脯酸进行干涉。大鼠随机分为三组：（1）单纯心肌梗死组；（2）梗塞给药组；（3）假手术组。梗塞给药组于手术前3d开始饲以巯甲丙脯酸（2g／L）。结果左室非梗塞区心肌的c-myc，c-fos及c-jun的mRNA水平手术后24h达峰值，c-myc于手术后10d，c-jun于手术后7d恢复到假手术组水平，但c-fos于术后持续高表达。在梗塞给药组，c-myc，c-fos于手术后7d、10d，c-jun于手术后各时间点其mRNA水平达假手术组程度。结论上述基因在非梗塞区心肌均有过量表达，持续时间较长，转换酶抑制剂对其有所抑制。     

Adult bone marrow-derived pluripotent hematopoietic stem cells are engraftable when transferred in utero into moderately anemic fetal recipients

We have used W41/W41 (C57BL/6-Ly 5.1, Gpi-1b) anemic mice and a newly developed double congenic donor strain (C57BL/6-Ly 5.2, Gpi-1a) to determine if adult bone marrow (BM) injected in utero could provide stem cell engraftment. Of 38 fetuses injected intraperitoneally on day 13/14 of gestation with donor BM cells, 17 (47%) were live-born. On day 6, 12% had erythroid engraftment. On day 59, in 50% (8/16) of mice, 50% to 75% of erythroid cells, 42% of T cells, 5% of B cells, and 26% of granulocytes in the peripheral blood (PB) were derived from the in utero-injected donor BM. At 141 days, thymic, splenic, lymph node, BM, and PB chimerism studies showed that 57% to 80% of T cells, 10% to 15% of B cells, and 27% to 43% of granulocytes were of donor origin. At this time, BM was injected into irradiated secondary recipients. On day 104 posttransfer, a mean 23% of T cells, 8% of B cells, and 40% of granulocytes were derived from the in utero donor BM. These data indicate that adult BM has hierarchical engraftment capabilities in W41/W41 mice and prove that stem cells are engraftable in utero.     

Effect of metoclopramide in chronic gastric retention after gastric surgery.

The effect of metoclopramide, a stimulant of gastric motility, on gastric emptying was tested in 6 patients with chronic gastric retention after vagotomy and gastric resection, unexplained by mechanical obstruction or stomal ulceration. Gastric emptying was measured using a gamma camera technique and a solid meal labeled with 99mtechnetium-labeled diethylenetriaminepentaacetic acid. Metoclopramide produced a 2.6-fold increase in gastric emptying in the first 90 min after eating the meal, compared to placebo (P less than 0.01). Metoclopramide did not alter gastric emptying in 8 normal volunteers. These data indicate that metoclopramide may be useful in treatment of patients with chronically impaired gastric emptying after gastric surgery.     

Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years

Hematopoietic stem cell transplantation from unrelated donors is an effective treatment for myeloid malignancies, but its use is usually restricted to young patients without comorbidities. The development of reduced-intensity preparative regimens has allowed the extension of this form of treatment to older and medically infirm patients. We assessed the outcomes of patients older than 54 years who received unrelated donor transplants for the treatment of myeloid malignancies in our institution. There were 29 patients (median age, 59 years) with advanced acute myeloid leukemia (n = 13), myelodysplastic syndrome (n = 7), and chronic myeloid leukemia (n = 9) included. With a median follow-up of 27 months, the probability of overall and event-free survival, and nonrelapse mortality at one year were 44%, 37%, and 55%, respectively. Grades II to IV acute graft-versus-host disease (GVHD) occurred in 41% of patients and chronic GVHD developed in 63% of patients surviving more than 100 days. Of the 11 survivors, 9 were interviewed and reported good quality of life after transplantation using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) questionnaire, with high scores in all dimensions. Unrelated donor transplantation is a treatment option for older patients with myeloid malignancies. The results in this cohort of patients are comparable with those reported in younger patients with similarly advanced disease.