Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy

The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.     

Fullerene Reactivity in an Oxygen Plasma

Fullerene reactivity in an oxygen plasma was measured and compared with those determined under the same conditions for a comprehensive set of 50 carbon materials. The possible reasons for the high plasma reactivity of the fullerene sample in an oxygen plasma are discussed.     

Stroke in teenagers

Between 3.7% and 8.5% of all strokes occur before the age of 45 years old. In the population under 15 years of age, the annual incidence of strokes is 2.7 per 100,000 children, with ischaemic strokes making up 1.2 and haemorrhagic strokes 1.5 of this total. The main characteristic of ischaemic strokes in childhood is the wide variety of diagnoses involved. Some of these, such as congenital cardiopathy, are rare in adults, as are dissections and arterial dysplasias, arteritis, hereditary connective tissue disorders and disorders of metabolism. Similarly, the aetiology of haemorrhagic stroke is also very varied, with bursting of a vascular malformation or aneurysm being the commonest. Other aetiologies are disorders of haemostasis, arteritis, migraine, retarded post-traumatic phenomena and the use of drugs and sympathomimetic agents. The personal, family and social repercussions are considerable, since both ischaemic and haemorrhagic strokes have an appreciable mortality and morbidity.     

Mitochondrial DNA haplotype frequencies in natural and experimental populations of Drosophila subobscura

The evolution of Drosophila subobscura mitochondrial DNA has been studied in experimental populations, founded with flies from a natural population from Esporles (Majorca, Balearic Islands, Spain). This population, like other European ones, is characterized by the presence of two very common (>96%) mitochondrial haplotypes (called I and II) and rare and endemic haplotypes that appear at very low frequencies. There is no statistical evidence of positive Darwinian selection acting on the mitochondrial DNA variants according to Tajima's neutrality test. Two experimental populations, with one replicate each, were established with flies having a heterogeneous nuclear genetic background, which was representative of the composition of the natural population. Both populations were started with the two most frequent mitochondrial haplotypes, but at different initial frequencies. After 13 to 16 generations, haplotype II reached fixation in three cages and its frequency was 0.89 by generation 25 in the fourth cage. Random drift can be rejected as the force responsible for the observed changes in haplotype frequencies. There is not only statistical evidence of a linear trend favoring a mtDNA (haploid) fitness effect, but also of a significant nonlinear deviation that could be due to a nuclear component.     

Perturbation in the 240Pu/239Pu global fallout ratio in local sediments following the nuclear accidents at Thule (Greenland) and Palomares (Spain)

Diabetes complicates 2-3% of all pregnancies and is associated with an increase in both perinatal morbidity and mortality, though reasons for these adverse outcomes are unknown. Estrogen biosynthesis is a critical factor during pregnancy and is carried out in the placenta via aromatase (cytochrome P450 19A1), which catalyzes the conversion of C-19 androgens to C-18 estrogens. Previous studies have shown that hormones such as insulin-like growth factors and insulin regulate aromatase activity when studied in vitro. Interestingly, levels of these hormones are altered in patients with diabetes. Thus, we hypothesized that the presence of maternal diabetes may alter placental aromatase activity and thus estrogen biosynthesis, possibly serving as one factor in the adverse outcomes of babies born to mothers with diabetes. To this end, we measured the production of 19-hydroxyandrostenedione, 19-oxoadrostenedione and estrone in 30 placental tissues from diabetic patients, using [7-3H]androst-4-ene-3,17-dione as a model substrate for aromatase (P450 19A1). A statistical difference was detected in the percentage of 19-oxoandrostenedione formed between the overt and control groups (P < 0.05). Additionally, NADPH P450-reductase levels were measured in these same tissues to determine whether alterations in this enzyme necessary for aromatase activity could be affected by diabetes. No differences in reductase levels were detected among the patient groups. However, a statistical correlation was found between NADPH P450-reductase activity and the formation velocities of all three estrogen products (P < 0.05). Thus, it appears that the presence of diabetes does not affect placental aromatase activity.     

Fibrinolytic variables and cardiovascular prognosis in patients with stable angina pectoris treated with verapamil or metoprolol. Results from the Angina Prognosis study in Stockholm

BACKGROUND: Disturbed fibrinolytic function may influence the progression of coronary atherosclerosis and contribute to thrombotic cardiovascular (CV) events. METHODS AND RESULTS: In the Angina Prognosis Study in Stockholm (APSIS), patients with stable angina pectoris were studied prospectively during double-blind treatment with metoprolol or verapamil. Various measures of fibrinolytic function were studied in 631 (of 809) patients. During a median follow-up time of 3.2 years (2132 patient-years), 32 patients suffered a CV death, 21 had a nonfatal myocardial infarction (MI), and 77 underwent revascularization. Plasma levels of tissue plasminogen activator (TPA) activity and antigen (ag), plasminogen activator inhibitor (PAI-1) activity at test, and TPA responses to exercise were determined at baseline and after 1 month's treatment and were related to subsequent fatal and nonfatal CV events. Univariate Cox regression analysis revealed that elevated levels of TPA-ag at rest (P < .05), high PAI-1 activity (P < .05), and low TPA-ag responses to exercise (P < .05) were associated with increased risk of subsequent CV death. After adjustment for baseline risk factors, TPA-ag independently predicted CV death or MI. In addition, PAI-1 activity independently predicted CV death or MI in male patients. Verapamil treatment was associated with a 10% decrease of TPA-ag levels and metoprolol treatment with a 2% increase (P < .001 for treatment difference). CONCLUSIONS: Plasma TPA-ag levels at rest, and among male patients PAI-1 activity as well, independently predict subsequent CV death or MI in patients with stable angina pectoris.     

Diversity of pituitary cells in primary cell culture. An immunocytochemical study

A bioassay system for rapid detection of carcinogenic agents has been developed using male Fischer 344 rats to bridge the gap between long-term carcinogenicity tests and short-term screening assays. The system, called the medium-term liver bioassay, is fundamentally based on the 2-stage hypothesis of tumor production, employing initiation by diethylnitrosamine (200 mg/kg, i.p.) in the first stage and test chemical administration during the second, in combination with two-thirds partial hepatectomy. It requires only 8 wk for animal experimentation and a further few weeks for quantitative analysis of immunohistochemically demonstrated glutathione S-transferase placental form positive hepatic foci. A total of 291 chemicals/substances have already been analyzed in our laboratory. Among 63 chemicals that were proved to be carcinogenic in the liver of rat and/or mouse, 57 (90%) gave positive results irrespective of their mutagenicity. Negative compounds include peroxisome proliferators and tamoxifen. Even nonhepatocarcinogens were positive at a rate of 24%. Eighty-six percent (12/14) of mouse liver carcinogens were also positive. On the other hand, only 2 out of 45 noncarcinogens showed very weak positivity. Thus, the efficacy of the system for hepatocarcinogens has been well established. This bioassay is increasingly regarded as an appropriate alternative test for carcinogenicity risk assessment and is practically used for a rapid evaluation of hepatocarcinogenicity of chemicals.     

Infrequent association: massive inguinoscrotal bladder hernia, multiple scrotal lithiasis, and bilateral obstructive uropathy]

BACKGROUND AND AIMS OF THE STUDY: Surgical treatment of functional tricuspid regurgitation associated with advanced valvular disease remains controversial, mainly due to the difficulty in choosing between valve replacement or reconstructive surgery. Failure to correct tricuspid regurgitation during valvular surgery carries a poor prognosis, as reoperation may represent a significant risk to the patient. Thus correct tricuspid valve surgery is vital to achieve improved early and long-term clinical results. METHODS: A total of 142 patients underwent concomitant tricuspid annuloplasty with mitral valve replacement and their clinical outcome was assessed. RESULTS: Overall hospital mortality rate was 11.3%. Seven patients died during follow up. The overall actuarial survival rate for 10 years was 74.1 +/- 14.2%. Postoperatively, 75.8% of the patients had no residual tricuspid insufficiency, while 24.2% had first- or second-degree tricuspid insufficiency and were treated medically. All patients were in NHYA functional class I or II postoperatively. CONCLUSION: Clinically, it is important to assess the severity of functional tricuspid insufficiency before and/or during the operation. Bicuspidalization annuloplasty for functional tricuspid insufficiency has provided good results, with a low incidence of reoperation and significant clinical improvement. The technique could be used in most patients with functional tricuspid regurgitation.     

Determination of dissociation constants of loop diuretics in acetonitrile-water mixtures

The dissociation pK values of the representative loop diuretics furosemide, bumetanide and ethacrynic acid in 10, 30, 40, 50 and 70% (w/w) acetonitrile-water mixtures at 298.15 K were determined, according to the rules and procedures endorsed by IUPAC. The variation in pK values over the whole composition range studied can be explained by tacking into account the preferential solvation of ionizable substances in acetonitrile-water mixtures. With a view to determining the pK values of the loop diuretics studied in any of the binary solvent acetonitrile-water mixtures, correlations of pK values and different bulk properties of the solvent were examined, and the linear solvation energy relationships method, LSER, has been applied. The pK values were then correlated with the pi*, alpha and beta solvatochromic parameters of acetonitrile-water mixtures. The resulting equations allowed us to calculate pK values for the loop diuretics in any acetonitrile-water mixture up to 70% (w/w) acetonitrile.