A case report: Severe bone marrow suppression caused by 6-mercaptopurin in Crohn's disease patient]

A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/microl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.     

Effect of oxitropium bromide (Ba253) on isolated respiratory smooth muscle and release of chemical mediators from passively sensitized lung fragments

The effect of oxitropium bromide (Ba253), a quaternary scopolamine derivative, on the resting tonus and agonist-induced contraction of isolated guinea pig airway smooth muscle and on the anaphylactic release of histamine and immunoreactive leukotrienes (i-LTs) from lung fragments were investigated and compared with those of Sch1000, atropine and isoproterenol. Ba253 dose-dependently inhibited the acetylcholine (ACh)-induced contraction of the isolated trachea and lung parenchyma. The degree of inhibitory potency was similar to that of Sch1000 and 10 times higher than that of atropine. Ba253 minimally influenced the resting tonus or contractions induced by other agonists including histamine, serotonin and LTD4. Sch1000 and atropine had similar or slightly stronger inhibitory effects on the tonus and contractions than Ba253. On the other hand, low concentrations of isoproterenol solely relaxed the resting tonus and inhibited the the agonist-induced contractions of both preparations. Neither Ba253 nor Sch1000 inhibited the anaphylactic release of histamine and LTs from both guinea pig and human lung fragments, but both mediator releases from either species were slightly inhibited with dose-dependency by atropine and potently inhibited by isoproterenol. From these results, it is suggested that Ba253 is a relatively specific antagonist to cholinergic receptors and might be possibly effective as an inhalant for asthma.     

Purkinje cell abnormalities and synaptogenesis in genetically jaundiced rats (Gunn rats)

The course of cytological abnormalities and synaptogenesis of Purkinje cells were investigated in the culmen of cerebella from homozygous Gunn rats with hereditary hyperbilirubinemia from postnatal day 7 to adulthood (5-10 months old). The affected Purkinje cells were abundant at day 7. A large number of Purkinje cells reached the fully advanced stage of degeneration during the ensuring 16 days and disappeared between days 12 and 30. The Purkinje cells remaining at day 30 were less affected and recovered by the adult stage. Various abnormalities in Purkinje cell synaptogenesis with the parallel fibers, climbing fibers, and basket and stellate cell axons were observed. Primitive junctions between parallel fibers and Purkinje dendritic shafts were often found in adulthood. The parallel fiber boutons lacking postsynaptic partners and facing astrocytic processes were often noted from day 18 to adulthood. The persistence of such presynaptic elements suggests some mechanisms for stabilizing the synaptic elements once they have been formed. Many of the parallel fiber synaptic boutons with or without their postsynaptic partners were enlarged and were assumed to be transsynaptically affected by Purkinje cell damage. A number of climbing fiber synapses with perisomatic process of Purkinje cells, which are transient in normal synaptogenesis, were present at day 30 and a few of them were still found even in adulthood. Basket and stellate cell synapses were often found in abundance on the remaining Purkinje cells in adulthood, though they were not frequently encountered during the development period.     

Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.

BACKGROUND: Gitelman's syndrome (GS) is an autosomal recessive disorder resulting from inactivating mutations in the thiazide-sensitive Na-Cl co-transporter (NCCT) gene. To date, almost 90 mutations have been identified. It is possible that there is a population-specific distribution of mutations. In this study, we analysed mutations in the NCCT gene of seven Japanese patients with GS. METHODS: Peripheral blood mononuclear cells were isolated from patients with GS, their family members and healthy control subjects. A mutation analysis of the NCCT gene was performed completely by direct automated sequencing of polymerase chain reaction-amplified DNA products. In patients with a deletion or splice site mutation, we undertook cDNA sequence analysis. RESULTS: We identified nine mutations. Five of them [c.185C>T (Thr60Met), c.1712C>T (Ala569Val), c.1930C>T (Arg642Cys), c.2552T>A (Leu849His) and c.1932delC] have been reported in Japanese patients, but not in GS patients from other ethnic groups. The remaining four mutations [c.7A>T (Met1Leu), c.1181_1186+20del26, c.1811_1812delAT and IVS16+1G>A] were novel. In cDNA derived from a patient with c.1181_1186+20del26, a deletion of exon 9 and a frameshift at the start of exon 10 were observed. In cDNA derived from patients with IVS16+1G>A, an additional 96 bp insertion between exons 16 and 17 was observed. Six out of seven patients were compound heterozygotes, and the remaining one carried a single heterozygous mutation. CONCLUSIONS: We found four novel mutations in the NCCT gene in seven Japanese patients with GS. Moreover, our study suggests that the distribution of mutations in the NCCT gene in Japanese GS patients potentially differs from that in other populations.     

Comparative pharmacokinetics of pipecuronium bromide, pancuronium bromide and vecuronium bromide in anesthetized man

The pharmacokinetics of pipecuronium bromide was studied in 9 male patients (ASA class 1-2, 20-65 years of age). Following a single intravenous dose of pipecuronium 0.08 mg.kg-1, plasma levels were measured by capillary gas chromatography. Plasma concentration-time curves were evaluated by fitting the data to a bi-exponential equation. The pharmacokinetic parameters of pipecuronium were compared with those of pancuronium (0.08 mg.kg-1) and vecuronium (0.08 mg.kg-1) previously obtained under the same anesthesia (66% N2O, 33% O2 and 1% halothane). With pipecuronium, following pharmacokinetic parameters were obtained; distribution half-life; T1/2 alpha = 3.9 +/- 0.7 min (mean +/- SEM), elimination half-life; T1/2 beta = 102 +/- 12 min, volume of the central compartment; V1 = 95 +/- 13 ml.kg-1, volume of distribution at steady state; Vdss = 264 +/- 41 ml.kg-1, clearance; Cl = 1.8 +/- 0.2 ml.min-1.kg-1. Microconstants of two-compartment open models (k12, k21, k10) were also calculated. Using Mann-Whitney's U-test, these parameters of pipecuronium were compared with those of pancuronium (n = 3) and vecuronium (n = 4). V1 and Vdss of pipecuronium were significantly larger than those of pancuronium (V1; 38 +/- 12 ml.kg-1 and Vdss; 120 +/- 4 ml.kg-1) (both P less than 0.10). Reflecting the larger central volume of pipecuronium, pipecuronium tended to have a larger clearance than that of pancuroniumu (Cl; 1.1 +/- 0.2 ml.min-1.kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Synaptic mechanisms of excitatory amino acids and NMDA receptor mediated brain excitability

L-Glutamate and related excitatory amino acids (EAA) are firmly established as major excitatory synaptic transmitter substances in the vertebrate central nervous system. Questions which have been addressed include: How many receptors are there for the EAAs?; What ion channels and/or 'second-messenger' systems are regulated by these receptors?; What are the roles of EAAs in higher neural functions?; Are they involved in neurological disorders? EAA receptors appear not only to mediate normal synaptic transmission along excitatory pathways but also to participate in the modification of synaptic connections during development. However, overaction of receptors can also mediate neuronal degeneration and even cell death. NMDA receptor antagonists markedly attenuate neuronal necrosis. Therefore, it appears that ischemia- and hypoglycemia-associated brain damage results not from a lack of energy substrates but rather via the mediation of NMDA receptors and 'excitotoxic' mechanisms. The action of ketamine anesthesia is closely associated with a block of the NMDA receptor. Ketamine binds to a site within the lumen of the NMDA-activated channel and can become trapped there when the channel closes. Current evidence indicated that NMDA receptor antagonists will be of value for the treatment of delayed neuronal death. NMDA receptor will lead to understanding the mechanisms underlying learning and memory, the control of neuronal excitability and neuronal death.