The aminothiol WR-1065 protects T lymphocytes from ionizing radiation-induced deletions of the HPRT gene

Aminothiols, such as WR-2721 and its active free thiol, WR-1065, reduce mutations from ionizing radiation in exponentially growing cells. In this study, human noncycling G0 T lymphocytes were exposed in vitro to gamma-irradiation in the presence or absence of WR-1065. The five treatment groups were: (a) control; (b) treatment with 4 mM WR-1065; (c) treatment with 3 Gy of gamma-radiation, from a 137Cs source; and (d) and (e) treatment with WR-1065 30 min prior to or 3 h after 3 Gy of gamma-irradiaiton, respectively. A total of 224 cloned HPRT mutants representing 179 independent mutations were analyzed for genetic alterations using multiplex PCR. Ionizing radiation alone significantly increased the percentage of mutations with gross structural alterations compared to controls (P = 0.02). Although the frequency of such large structural mutations was not different from control cells treated with WR-1065 alone, this aminothiol significantly reduced their frequency among irradiated mutants (P = 0.01) when the radioprotector was present during the irradiation. Addition of WR-1065 3 h postirradiation also greatly reduced the percentage of gross structural alterations; however, due to small numbers, this was not statistically significant. This is the first demonstration that the antimutagenicity of WR-1065 in human cells specifically protects against these kinds of large-scale DNA alterations induced by ionizing radiation. WR-1065 and similar aminothiol compounds may afford protection against radiation-induced mutations through polyamine-like processes, e.g., stabilization of chromatin structure, inhibition of cell proliferation, and influences on DNA repair systems.     

Enzymatic preparation of heparin oligosaccharides containing antithrombin III binding sites

Two new oligosaccharides were prepared from heparin by its partial depolymerization using heparin lyase I (EC 4.2.2.7) in an attempt to prepare oligosaccharides having intact antithrombin III binding sites. The oligosaccharides were purified by chromatography on the basis of both size and charge and demonstrated a high level of purity by capillary electrophoresis. One- and two-dimensional 1H NMR spectroscopy at 500 MHz revealed the structure of each oligosaccharide. The octasaccharide and decasaccharide are DeltaUAp2S(1-->4)-alpha-DGlcNpS6S(1-->4)-alpha-L-IdoAp (1-->4)-alpha-D -GlcNpAc6S(1-->4)-betaD-GlcAp(1-->4)-alpha-D-GlcNpS 3S6S(1-->4)-alpha- L-IdoAp2S(1-->4)alpha-D-GlcNpS6S (where DeltaUAp is 4-deoxy-alpha-L-threo-hex-enopyranosyluronic acid, GlcNp is 2-amino-2-deoxy-glucopyranose, GlcAp is glucopyranosyluronic acid, S is sulfate and Ac is acetate) and DeltaUAp2S(1-->4)-alpha-D-GlcNpS6S(1-->4)-alpha-L-IdoAp++ +(1-->4)-alpha- D-GlcNpAc6S (1-->4)-beta-D-GlcAp(1-->4)-alpha-D-GlcNpS3S6S(1-->4)-alpha- L-IdoAp2S (1-->4)-alpha-D-GlcNpS6S(1-->4)-alpha-L-IdoAp2S(1-->4)-alpha -D-GlcNpS 6S, respectively. A hexasaccharide containing a similar structural motif to that found in the antithrombin III binding site and having greatly reduced anticoagulant activity was also isolated. The structure of the hexasaccharide is DeltaUAp2S(1-->4)-alpha-D-GlcNpAc6S(1-->4)-beta-D-GlcAp++ +(1-->4)-alpha- D-GlcNpS3S6S(1-->4)-alpha-L-IdoAp(1-->4)-alpha-D-GlcNpS6S . The octasaccharide and decasaccharide correspond to the predominant structural motif found in porcine intestinal mucosal heparin. Sufficient quantities of the decasaccharide were obtained to examine its interaction with antithrombin III using microtitration calorimetry. This decasaccharide bound to antithrombin III with similar avidity as heparin and showed comparable anticoagulant activity, as determined using an antithrombin III dependent anti-factor Xa assay. Interestingly, while both decasaccharide and heparin bound to antithrombin with nanomolar affinity, very little heat of binding was observed.     

Hereditary motor and sensory neuropathies. Clinical and molecular genetic aspects

Hereditary motor sensory neuropathies are a heterogeneous group of inherited diseases of the peripheral nerves. In this review the clinical and genetic differences between the sub-groups of this disease will be discussed. Since the discovery of a 1.5 mb duplication on chromosome 17 p11.2-12 in most patients with a hereditary motor sensory neuropathy and a variety of different mutations on chromosomes 1 and X in other patients with a similar disease profile, Dycks' clinical classification needs to be re-evaluated. In this review Dycks' taxonomy of heridihary neuropathies will be compared to a new genetic classification and a relevant diagnostic procedure proposed when a hereditary neuropathy is suspected.     

The interaction of dexamethasone with ondansetron on drug-induced emesis in the ferret

The characteristics of the five Korean isolates of Japanese encephalitis (JE) virus were compared with those of the already reported JE virus strains from Japan and China using the hemagglutination test and polymerase chain reaction direct sequencing of the JE virus genomes (capsid/premembrane, envelope region). The hemagglutination patterns of all the isolates were distinctly different from the Nakayama-NIH strain. The optimal pH of hemagglutination of all the Korean isolates was 6.6-7.0 and the reaction range was broader than that of the Nakayama-NIH strain. The 198 nucleotide sequences in the capsid/premembrane gene region of the five Korean strains indicated that they were classified into the third genotype group, the JE strains from the countries in the temperate zone including the Nakayama-NIH, JaOArS982, and Beijing-1 strains. Four of the five Korean isolates formed a unique phylogenetic tree within the third genotype group, although the last one was genetically highly related to the Nakayama-NIH strain. The 251 nucleotide sequences in the envelope region of the five isolates were more divergent than the capsid/premembrane region. Four of the five isolates showed a large nucleotide divergency as compared with the JaOArS982 strain (< or = 12.4%), but the last one was similar to the JaOArS982 strain (98% of nucleotide homology). These results suggest the evolutionary divergence of the JE viruses isolated in Korea from the Japanese and Chinese strains and that there may exist at least two antigenically different JE virus strains in Korea.     

Intraperitoneal rupture of ectopic varices--a rare complication of portal hypertension

A 50 year old man presented with sudden abdominal pain, abdominal distension and shock. At emergency laparotomy a large amount of blood was found in the peritoneal cavity. There was micronodular cirrhosis of the liver and the spleen was enlarged. The bleeding was traced to distended veins in the right paracolic gutter which were oversewn and the abdomen closed. A coagulopathy was diagnosed and treatment including high dose aprotinin commenced. However, he continued to bleed and at a second laparotomy the area of previous haemorrhage was packed. Further deterioration continued until death 12 hours later. Intraperitoneal haemorrhage from ectopic varices is a rare occurrence. There is a high mortality rate usually due to an advanced coagulopathy. This is the first report of aprotinin being used in an attempt to treat this. On the basis of this report aprotinin would not seem to be of benefit for this condition.     

Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B

BACKGROUND: About 65 percent of previously untreated adults with primary acute myeloid leukemia (AML) enter complete remission when treated with cytarabine and an anthracycline. However, such responses are rarely durable when conventional postremission therapy is administered. Uncontrolled trials have suggested that intensive postremission therapy may prolong these complete remissions. METHODS: We treated 1088 adults with newly diagnosed AML with three days of daunorubicin and seven days of cytarabine and randomly assigned patients who had a complete remission to receive four courses of cytarabine at one of three doses: 100 mg per square meter of body-surface area per day for five days by continuous infusion, 400 mg per square meter per day for five days by continuous infusion, or 3 g per square meter in a 3-hour infusion every 12 hours (twice daily) on days 1, 3, and 5. All patients then received four courses of monthly maintenance treatment. RESULTS: Of the 693 patients who had a complete remission, 596 were randomly assigned to receive postremission cytarabine. After a median follow-up of 52 months, the disease-free survival rates in the three treatment groups were significantly different (P = 0.003). Relative to the 100-mg group, the hazard ratios were 0.67 for the 3-g group (95 percent confidence interval, 0.53 to 0.86) and 0.75 for the 400-mg group (95 percent confidence interval, 0.60 to 0.94). The probability of remaining in continuous complete remission after four years for patients 60 years of age or younger was 24 percent in the 100-mg group, 29 percent in the 400-mg group, and 44 percent in the 3-g group (P = 0.002). In contrast, for patients older than 60, the probability of remaining disease-free after four years was 16 percent or less in each of the three postremission cytarabine groups. CONCLUSIONS: These data support the concept of a dose-response effect for cytarabine in patients with AML who are 60 years of age or younger. The results with the high-dose schedule in this age group are comparable to those reported in similar patients who have undergone allogeneic bone marrow transplantation during a first remission.