Monozygotic twins with suspected hereditary sensory and autonomic neuropathy (HSAN) type V

We report a pair of 1-year-5-month-old female monozygotic twins with generalized loss of pain sensation, but without impairment of other sensory modalities and the diaphoretic function. Routine electrophysiological investigations revealed no abnormalities. Morphometric analysis of biopsied sural nerve showed that the number of small myelinated fibers was reduced and that of unmyelinated fibers was normal or mildly reduced. On the basis of these findings, we suspected a diagnosis of a rare disorder, HSAN type V, which has not previously been reported in Japan.     

New method of bladder biopsy using combined aspiration and snare

A method of multiple random biopsy combined with bladder wall aspiration and snare in bladder cancer is presented. Our method was used on 23 patients with clinically superficial bladder cancer and was found to have advantages in obtaining an adequate amount of tissue with minimal thermal degeneration.     

Successful treatment of acute renal failure in a patient with essential mixed cryoglobulinemia using prednisolone and cryofiltration

We report a case of acute renal failure associated with cryoglobulinemic glomerulonephritis. The patient, a 49-year-old woman, was referred to our hospital because of acute nephritic syndrome. After admission, she developed oliguria, and hemodialysis was instituted. Renal biopsy was performed and the specimens showed moderate endocapillary proliferation, large deposits filling the capillary lumen ("intraluminal thrombi"), and a double-contoured appearance, which are typical morphologic features of cryoglobulinemic glomerulonephritis. Immunoelectrophoresis showed a monoclonal increase of IgM kappa. On the basis of these findings, we diagnosed type II essential mixed cryoglobulinemia. Cryofiltration was performed with oral administration of prednisolone. Following the start of therapy, the patient's renal function gradually improved. Because of severe hypoproteinemia, cryofiltration was discontinued after three sessions. However, renal function recovered and was maintained with prednisolone only. This case shows that acute oliguric renal failure caused by cryoglobulinemic glomerulonephritis can be reversible if immunosuppressive therapy, together with plasmapheresis in more severe cases, is instituted promptly.     

Human erythrocyte band 3 (EPB3) polymorphism: Analysis of blood and bloodstains by an immunodetection method and frequency of the EPB3* Memphis variant

Summary The erythrocyte band 3 (EPB3) variant, band 3 Memphis (EPB3*Memphis), was detected by immunoblotting with a monoclonal antibody to the 41 kDa cytoplasmic N-terminal domain of band 3 without protease treatment of erythrocytes. EPB3*Memphis was also detected by immunoblotting from 3-month-old bloodstains subjected to -chymotrypsin treatment. A population genetic study using this method indicated that the EPB3 variant would be useful for forensic work in Japan, since the frequency of this variant in Japanese (Wakayama prefecture) is relatively high (0.159).     

Metabolism-based inactivation of neuronal nitric-oxide synthase by components of cigarette and cigarette smoke.

It has been shown that administration of cigarette smoke to rats leads to loss of neuronal nitric-oxide synthase (nNOS) activity and nNOS protein in penile tissue. The exact mechanism for this loss of activity and protein is not known. In the current study, we investigated whether extracts prepared from cigarette smoke or from the cigarette itself could directly inhibit nNOS activity. We discovered that the cigarette smoke extract and the cigarette extract cause a time-, concentration-, and calmodulin-dependent inactivation of nNOS in an in vitro system containing the purified enzyme. L-Arginine, but not D-arginine, protects nNOS from this time-dependent inactivation, suggesting an active site directed event. The kinetics of inactivation are consistent with the metabolism-based or suicide inactivation of nNOS. Based on studies with other metabolism-based inactivators, this cigarette-mediated inactivation may render nNOS more susceptible to proteasomal degradation and thereby may explain the loss of nNOS protein in vivo. The component(s) responsible for nNOS inactivation is not volatile, is not retained by a 3,000 molecular weight cut-off membrane, binds to activated charcoal, and is highly water-soluble under both acidic and basic conditions. The discovery of a direct inactivation of nNOS by an organic, cationic compound(s) present in tobacco and tobacco smoke provides a basis for further study of not only the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of nNOS.     

Time-dependent inhibition and tetrahydrobiopterin depletion of endothelial nitric-oxide synthase caused by cigarettes.

Smoking causes a dysfunction in endothelial nitric-oxide synthase (eNOS), which is ameliorated, in part, by administration of tetrahydrobiopterin (BH(4)). The exact mechanism by which the nitric oxide deficit occurs is unknown. We have previously shown that aqueous extracts of chemicals in cigarettes (CE) cause the suicide inactivation of neuronal NO synthase (nNOS) by interacting at the substrate-binding site. In the current study, we have found that CE directly inactivates eNOS by a process that is not affected by the natural substrate l-arginine and is distinct from the mechanism of inactivation of nNOS. We discovered that CE causes a time-, concentration-, and NADPH-dependent inactivation of eNOS in an in vitro system containing the purified enzyme, indicating a metabolic component to the inactivation. The CE-treated eNOS but not nNOS was nearly fully reactivated upon incubation with excess BH(4), suggesting that BH(4) depletion is a potential mechanism of inactivation. Moreover, in the presence of CE, eNOS catalyzed the oxidation of BH(4) to dihydrobiopterin and biopterin by a process attenuated by high concentrations of superoxide dismutase but not catalase. We speculate that a redox active component in CE, perhaps a quinone compound, causes oxidative uncoupling of eNOS to form superoxide, which in turn oxidizes BH(4). The discovery of a direct inactivation of eNOS by a compound(s) present in tobacco provides a basis not only for further study of the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of eNOS.     

Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase.

Constitutively active internal tandem duplication (ITD) in the juxtamembrane domain of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase, is the most common molecular defect associated with acute myeloid leukemia. Its presence confers a poor outcome in patients with acute myeloid leukemia who receive conventional chemotherapy. FLT3-ITD has therefore been considered to be an attractive molecular target for a novel therapeutic modality. We describe here the identification and characterization of Ki23819 as a novel FLT3 inhibitor. Ki23819 suppressed proliferation and induced apoptosis of FLT3-ITD-expressing human leukemia cell lines. The growth-inhibitory effect of Ki23819 on MV4-11 cells was superior to that of SU11248, another FLT3 inhibitor (IC(50)<1 vs 3-10 nM). Ki23819 inhibited the autophosphorylation of FLT3-ITD more efficiently than that of wild-type FLT3. FLT3-ITD-dependent activation of the downstream signaling proteins ERK and STAT5 was also inhibited within similar concentration ranges. Thus, Ki23819 is a potent in vitro inhibitor of FLT3.     

ANTITHROMBIN III SUPPLEMENTATION IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH L-ASPARAGINASE

The change of plasma antithrombin III (AT) levels after supplementation of AT concentrates was examined in ALL children with acquired AT deficiency following L-asparaginase (ASP) administration. The patients received AT concentrates of 34.5 &#45 7.6 U/kg. The increase of plasma AT activity and antigen was 2.07 &#45 0.62% and 0.70 &#45 0.16 mg/dL per unit AT infused per kilogram of body weight, respectively. The activity decreased to 62.0 &#45 7.7% of the peak values by 48 hours after supplementation. The administration of AT concentrates constantly increased the plasma AT activity in ALL children treated with ASP, which may minimize the acquired prothrombotic state.