Effect of a bovine hemoglobin preparation on the response of the FSaIIC fibrosarcoma to chemotherapeutic alkylating agents

Summary Polymerized bovine hemoglobin solutions (PBHS) are being actively investigated as blood substitutes. In studies analogous to those we conducted with perfluorochemical emulsions/carbogen, we have examined the effect of PBHS ± carbogen (95% O₂, 5% CO₂) breathing on the antitumor efficacy of melphalan, cyclophosphamide,N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU) andcis-diamminedichloroplatinum(II) (cisplatin). The tumor growth delay of the FSaIIC fibrosarcoma treated with melphalan (10 mg/kg), cyclophosphamide (150 mg/kg), cisplatin (10 mg/kg) and BCNU (15 mg/kg) was increased about 2.2-fold, about 2.1-fold, about 1.2-fold and about 1.5-fold, respectively, when PBHS (12 mg/kg) was administered i.v. before each drug was injected i.p. The tumor growth delay produced by each drug was further increased when carbogen breathing for 6 h was allowed after administration of the drug and PBHS. In tumor cell survival experiments 24 h following drug treatment, the addition of PBHS increased the tumor cell killing of both melphalan and cyclophosphamide by about a factor of 10 at the lowest doses of each drug tested (10 mg/kg for melphalan and 100 mg/kg for cyclophosphamide) compared to the drug alone. However, at higher drug doses this effect was lost. The toxicity of each antitumor agent toward bone marrow (granulocyte/macrophage-colony-forming units) was increased 2- to 3-fold by the combined treatment. These results suggest that use of PBHS ± carbogen breathing may add significantly to the efficacy of antitumor alkylating agents, however, the in vivo/in vitro data suggest that there will be increased bone marrow toxicity with this approach. This needs to be taken into account in the design of clinical trials.Abbreviations PBHS polymerized bovine hemoglobin solution - BCNU N,N-bis(2-chloroethyl)-N-nitrosourea This work was supported by NIH grant PO1-19589 and a gift from Biopure Inc., Boston, Mass.     

Interactions among prions and prion "strains" in yeast

Prions are "infectious" proteins. When Sup35, a yeast translation termination factor, is aggregated in its [PSI(+)] prion form its function is compromised. When Rnq1 is aggregated in its [PIN(+)] prion form, it promotes the de novo appearance of [PSI(+)]. Heritable variants (strains) of [PSI(+)] with distinct phenotypes have been isolated and are analogous to mammalian prion strains with different pathologies. Here, we describe heritable variants of the [PIN(+)] prion that are distinguished by the efficiency with which they enhance the de novo appearance of [PSI(+)]. Unlike [PSI(+)] variants, where the strength of translation termination corresponds to the level of soluble Sup35, the phenotypes of these [PIN(+)] variants do not correspond to levels of soluble Rnq1. However, diploids and meiotic progeny from crosses between either different [PSI(+)], or different [PIN(+)] variants, always have the phenotype of the parental variant with the least soluble Sup35 or Rnq1, respectively. Apparently faster growing prion variants cure cells of slower growing or less stable variants of the same prion. We also find that YDJ1 overexpression eliminates some but not other [PIN(+)] variants and that prions are destabilized by meiosis. Finally, we show that, like its affect on [PSI(+)] appearance, [PIN(+)] enhances the de novo appearance of [URE3]. Surprisingly, [PSI(+)] inhibited [URE3] appearance. These results reinforce earlier reports that heterologous prions interact, but suggest that such interactions can not only positively, but also negatively, influence the de novo generation of prions.     

Origin of all three coronary arteries from separate ostia in the right sinus of Valsalva: a rarely reported coronary artery anomaly.

Anomalous origin of the circumflex and left anterior descending coronary arteries from separate ostia in the right sinus of Valsalva is a rarely reported phenomenon. Few clinical details concerning patients with this anomaly are available in the literature. Angiographic and clinical data in an adult patient with this finding are reported here.     

Characterization of deletions of chromosome 7 short arm occurring as primary karyotypic anomaly in acute myeloid leukaemia

Three patients with an acute myeloid leukaemia (AML) showed a deletion of the short arm of chromosome 7 with loss of the deleted material. The 7p- anomaly originated from either a terminal or an interstitial deletion and it represented the only karyotypic aberration in all the three cases. According to the clinical, morphological and immunological features of this series of patients, a 7p- chromosome appears to be associated with a group of AML with myelodysplastic features in the bone marrow, including secondary disorders in patients treated for a previous malignancy.     

Effects of vitamin K and oral anticoagulants on urinary calcium excretion

Summary In a subgroup of postmenopausal women vitamin K induced a decrease of the urnary calcium loss. This effect was significant ( P < 0.0001) in the so-called fast losers of calcium (calcium/creatinine ratio > 0.5). To find out whether vitamin K antagonists would have an opposite effect, a study was started among 141 persons on long-term oral anticoagulant therapy. In this population the number of fast losers was recorded, and compared to that in a group of age- and sex-matched non-treated controls. Notably in young men the fraction of fast losers was significantly higher in the anticoagulant-treated group than in the control group (25 v 0%, P < 0.02). Differences between treated and non-treated groups may also be found in other markers for calcium and bone metabolism, notably in serum osteocalcin concentration and in urinary hydroxyproline excretion. The conclusion of our study is that oral anticoagulant treatment must be regarded as a potential risk factor for a high loss of urinary calcium.     

Baseline characteristics of patients in the national heart, lung, and blood institute percutaneous transluminal coronary angioplasty registry

The efficacy of PTCA was evaluated in several subgroups of patients. Of special clinical interest were the comparisons between subgroups of patients with multivessel disease vs 1-vessel disease, unstable angina vs stable angina, older age vs younger age, and female sex vs male sex. As a prerequisite for such comparisons, baseline characteristics of patients in the subgroups were examined. Compared with the subgroup with 1-vessel CAD, the subgroup with multivessel CAD had more elderly patients (age 65 years and older) and more of these patients had previous MI or CABG. PTCA was more often unsuccessful in patients with multivessel CAD because of inability to pass the catheter across the lesion. The subgroup of women tended to be older than men, and more women had severe and unstable angina, although fewer had multivessel CAD, previous MI or previous CABG. The PTCA success rate was 5% lower in women because of a greater frequency of inability to pass the lesion. Compared with younger patients, older patients had a higher prevalence of severe angina, multivessel CAD and lesions with larger diameters. The older patients had a 5% lower PTCA success rate, once again because of a greater frequency of inability to pass the lesion. The learning experience with PTCA was measured by the overall success rate as well as by the rate of ability to pass the lesion and the rate of dilating it once it was passed. These rates improved significantly by the investigators' case accumulations and independently by calendar year. Multivariate prediction of crossing the lesion and of overall success showed that favorable lesion characteristics and increasing physician experience were more important than the patient characteristics just discussed, although both female sex and multivessel CAD remained significant independent risk factors.     

Gut inflammation and spondyloarthropathies

Spondyloarthropathies (SpA) are a group of related disorders with common clinical and genetic characteristics. The prototype disease in this group is ankylosing spondylitis; other entities include reactive arthritis, psoriatic arthritis, and arthritis in patients with inflammatory bowel disease. Over recent years, there has been a special interest in the relation between spondylitis/ synovitis and gut inflammation in patients with SpA. Two thirds of patients with undifferentiated SpA show histologic signs of gut inflammation, and a fraction of these patients go on to develop clinically overt Crohn’s disease. In this review, the authors will focus on 1) the growing evidence that has been provided that gut inflammation in SpA is immunologically related to Crohn’s disease, based on the molecular characterization of the inflammation (lymphocyte homing markers and ligands, T cell cytokines, macrophage markers, and serology); and 2) on the therapeutic implications resulting from this concept. The recent introduction and positioning of anti-tumor necrosis factoralpha therapy in patients with ankylosing spondylitis and other types of SpA is, in large part, based on this concept.