Factors modifying the prognosis of Wilson's disease in childhood

The prognosis of Wilson's disease was investigated in 96 patients, in whom the disease had presented before 15 years of age and had begun between 1965 and 1983 (when D-penicillamine was widely available in Japan). In the activities of daily living, the prognosis was poor in those patients presenting with neurological symptoms. Interruption of D-penicillamine treatment was seen in one third of the patients, and it worsened the prognosis. Toxic side effects were seen in about half of the patients, being more frequent in the patients with initial neurological symptoms. A disappointing 17% of patients with slight or no side effects discontinued the drug. Death occurred in eight patients of whom seven had had initial hepatic symptoms. Not only early diagnosis and treatment before the appearance of hepatic failure or neurological symptoms, but also treatment throughout life without interruption is important for improving the prognosis of Wilson's disease.     

IgG Anti-GM1 antibody is associated with reversible conduction failure and axonal degeneration in guillain-barré syndrome

To investigate the pathophysiological role of anti-GM1 antibody in Gullain-Barre syndrome (GBS), we reviewed sequential nerve conduction studies of 345 nerves in 34 GBS patients. Statistically significant correlation between IgG anti-GM1 antibodies and electrodiagnoses was found. Sixteen IgG anti-GM1-positive patients were classified as having acute motor sensory axonal neuropathy (AMAN or AMSAN) (12 patients), as having acute inflammatory demyelinating polyneuropathy (AIDP) (3 patientsrpar;, or as undetermined (1 patient) by electrodiagnostic criteria. Besides axonal features, there was rapid resolution of conduction slowing and block. In 3 patients initially diagnosed as having AIDP, conduction slowing was resolved within days, and 1 of them and 3 AMAN patients showed markedly rapid increases in amplitudes of distal compound muscle action potentials that were not accompanied by prolonged duration and polyphasia. The time courses of conduction abnormalities were distinct from those in IgG anti-GM1-negative AIDP patients. Rapid resolution of conduction slowing and block, and the absence of remyelinating slow components, suggest that conduction failure may be caused by impaired physiological conduction at the nodes of Ranvier. Reversible conduction failure as well as axonal degeneration constitutes the pathopsiological mechanisms in IgG anti-GM1)positive GBS. In both cases, immune-mediated attack probably occurs on the axolemma of motor fibers.     

Direct Inhibitory Mechanisms of Halothane on Human Platelet Aggregation

Background: Although halothane directly inhibits platelet aggregation, the mechanisms of this effect are still unknown. The current study aimed to clarify the inhibitory mechanisms of halothane on thrombin-induced human platelet aggregation by measuring (1) platelet-surface glycoprotein Ib expression, (2) the concentration of intracellular free Calcium2+ ([Calcium2+]i) measured simultaneously with aggregation, (3) the concentration of intracellular inositol 1,4,5-triphosphate, and (4) the concentration of intracellular cyclic 3',5'-adenosine monophosphate ([cAMP]i).

Methods: Washed platelet suspensions, obtained from healthy volunteers, were preincubated with halothane (0-2 mM) for 2 min and then exposed to 0.02 units/ml thrombin for 3 min. The glycoprotein Ib bound to fluorescein-labeled antibody was measured by fluorescence flow cytometry. [Calcium2+]i was measured, simultaneously with aggregation, in Fura-2 (Calcium2+ indicator)-loaded platelets by use of a fluorometer. Inositol 1,4,5-triphosphate and [cAMP]i were measured by radioimmunoassay.

Results: Halothane had no effect on glycoprotein Ib expression with or without thrombin. Halothane decreased the thrombin stimulated [Calcium sup 2+]i transient and inhibited platelet aggregation in a dose-dependent manner, both in the presence and in the absence of external Calcium2+. Isoflurane had no apparent effect on either platelet aggregation or [Calcium2+]i in the absence of external Calcium sup 2+. Halothane inhibited the increase in inositol 1,4,5-triphosphate induced by thrombin. Halothane moderately but significantly increased [cAMP]i, but the adenylate cyclase activator forskolin (which has the same inhibitory ability on aggregation as halothane) increased [cAMP]i to a much greater extent than did halothane.     

Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation

Objective: The present study was conducted to identify in vitro the cytochrome P450(CYP) isoform involved in the metabolic conversion of reduced haloperidol to haloperidol using microsomes derived from human AHH-1 TK +/− cells expressing human cytochrome P450s. The inhibitory and/or stimulatory effects of reduced haloperidol or haloperidol on CYP2D6-catalyzed carteolol 8-hydroxylase activity were also investigated. Results: The CYP isoform involved in the oxidation of reduced haloperidol to haloperidol was CYP3A4. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 were not involved in the oxidation. The k_M value for the CYP3A4 expressed in the cells was 69.7 μmol · l⁻¹, and the V_max was 4.87 pmol · min⁻¹ · pmol⁻¹ P450. Troleandomycin, a relatively selective probe for CYP3A enzymes, inhibited the CYP3A4-mediated oxidation of reduced haloperidol in a dose-dependent manner. Quinidine and sparteine competitively inhibited the oxidative reaction with a k_i value of 24.9 and 1390 μmol · l⁻¹, respectively. Carteolol 8-hydroxylase activity, which is a selective reaction probe for CYP2D6 activity, was inhibited by reduced haloperidol with a k_i value of 4.3 μmol · l⁻¹. Haloperidol stimulated the CYP2D6-mediated carteolol 8-hydroxylase activity with an optimum concentration of 1 μmol · l⁻¹, whereas higher concentrations of the compound (>10 μmol · l⁻¹) inhibited the hydroxylase activity. Conclusion: It was concluded that CYP3A4, not CYP2D6, is the principal isoform of cytochrome P450 involved in the metabolic conversion of reduced haloperidol to haloperidol. It was further found that reduced haloperidol is a substrate of CYP3A4 and an inhibitor of CYP2D6, and that haloperidol has both stimulatory and inhibitory effects on CYP2D6 activity. Received: 10 April 1997 / Accepted in revised form: 16 December 1997     

Influence of acute-phase proteins on the activity of natural killer cells

The effects of ₁-antitrypsin ( ₁,-AT), ₁,-acid glycoprotein ( ₁AGP), and haptoglobin (Hp), the main constituents of-globulin and which belong to acute phase proteins, on NK activity were examined using K562 cells as the NK target cells. Among the three proteins, ₁,-AT and ₁AGP had inhibitory effects on NK activity for fast target K562 cells. The,-AT preparations having the same protein concentration and a different trypsin inhibitory capacity (TIC) had an equal effect. Although ₁AT and ₁,-AGP equally reduced the NK activity, the mechanism involved in the reduction differed, in that the effect of ₁,-AT directed toward NK cells reduced their binding capacity with the target cells, ₁,-AGP probably interacts with a cytotoxic factor secreted from NK cells following effector-target interaction. These studies suggest that each of the acute-phase proteins, which increase following inflammation, inhibits NK cell function by two distinct mechanisms.     

Analysis of wild-type and e antigen-defective hepatitis B viruses during the course of a short-term corticosteroid therapy in chronic hepatitis B

Hepatitis B virus (HBV), with a G-to-A point mutation at nucleotide 83 in the precore region (mutant HBV83), accounts for most cases of hepatitis B e antigen (HBeAg)-defective HBV. However, it is still not clear how mutant HBV83 is associated with HBe seroconversion. Twenty-six HBeAgpositive patients with chronic hepatitis B who received oral prednisolone (30 mg/day) for 3 weeks were studied to clarify the prevalence of mutant HBV83 during the treatment using polymerase chain reaction with a restriction fragment length polymorphism assay. Twelve (46%) patients seroconverted to anti-HBe 1 year after treatment, whereas 14 (54%) did not. The proportion of mutant HBV83 to whole HBV remained unchanged in both groups during an acute exacerbation induced by withdrawal of corticosteroids. Among 12 anti-HBe-0seroconverted patients, five (56%) of nine patients with only wild-type HBV at baseline developed detectable levels of mutant HBV83 while all three patients with a mixed viral population of wild-type HBV and mu tant HBV83 at baseline developed a higher pro portion of mutant HBV83 one year after treat ment. In contrast, these changes were observed in only one (14%) of seven who failed to seroconvert. The results indicate that a flare-up of hepa titis precedes emergence or selection of mutant HBV83, followed by HBe seroconversion in patients with chronic hepatitis B. © 1995 WiIey-Liss, Inc.     

Mesenteric lymphadenitis of swine caused by Rhodococcus sputi.

Rhodococcus sputi caused tuberculosislike lymphadenitis of mesenteric lymph nodes in swine. This is the first study reporting that R. sputi can be a pathogen in swine.     

Can Mycobacterium tuberculosis infection prevent asthma and other allergic disorders?

It is generally considered that tuberculosis (TB) is a disease which upregulates Th1 cell function. There is a hypothesis that infection of Mycobacterium tuberculosis may prevent allergic disorders such as bronchial asthma. However, our clinical experience of patients with TB somewhat conflicts this hypothesis. Hence, we investigated Th1/Th2 balance in the peripheral blood of patients with active TB by measuring serum levels of IgE antibody and by intracellular cytokine assay. We found that serum levels of IgE in the patients with active TB were significantly higher than in those with lung cancer or with COPD. In the TB patients, titers of IgE tended to correlate with disease severity. Intracellular cytokine assay demonstrated that IFN-gamma-positive cells were significantly decreased in the patients with active TB compared to normal controls. The ratio of IFN-gamma-positive (Th1-like)/IL-4-positive (Th2-like) cells was remarkably reduced in the TB patients (p < 0.0001). This ratio showed a significant negative correlation with erythrocyte sedimentation rate and with C-reactive protein. Therapy against TB for 2-3 months did not result in significant changes of the Th1/Th2 ratio. These findings suggest that infection of M. tuberculosis does not systematically upregulate Th1 cells in some patients, and is unlikely to prevent allergic disorders like asthma.     

Isoflurane increases norepinephrine release in the rat preoptic area and the posterior hypothalamus in vivo and in vitro: Relevance to thermoregulation during anesthesia

General anesthetics modulate autonomic nervous system function including thermoregulatory control, which resides in the preoptic area of the anterior hypothalamus. However, the mechanism by which anesthetics modulate hypothalamic function remains unknown. We hypothesized that isoflurane increases norepinephrine release in the preoptic area and in the posterior hypothalamus causing hypothermia during anesthesia. To test this hypothesis, we performed a series of in vivo and in vitro studies in rats. In vivo studies: 1) Norepinephrine release was measured by microdialysis in the preoptic area or the posterior hypothalamus (n=9 each) before, during (30 min), and after (50 min) rats were anesthetized with 2% isoflurane. 2) In five rats, blood gases and arterial pressure were measured. 3) Body temperature changes (n=6 each) were measured after prazosin (0, 0.05, 0.5 microg), norepinephrine (0, 0.1, 1.0 microg), or 0.5 microg prazosin with 1.0 microg norepinephrine injection into the preoptic area. In vitro study: Norepinephrine release was measured from anterior or posterior hypothalamic slices (n=10 each) incubated with 0, 1, 2, or 4% isoflurane in Ca2+-containing buffer or with 4% isoflurane (n=10) in Ca2+-free buffer. Data were analyzed with repeated measures or factorial ANOVA and Student-Newman-Keuls tests. P<0.05 was significant. During anesthesia, norepinephrine release in the preoptic area was increased approximately 270%, whereas the release in the posterior hypothalamus remained unchanged. During emergence, posterior hypothalamic norepinephrine release increased by approximately 250% (P<0.05). Rectal temperature changes correlated with norepinephrine release from the preoptic area. Norepinephrine in the preoptic area enhanced isoflurane-induced hypothermia, while prazosin reversed it. Norepinephrine release from anterior hypothalamic slices increased at all isoflurane concentrations, but only at the highest concentration in posterior hypothalamic slices. Under Ca2+-free conditions, 4% isoflurane increased norepinephrine from both regions. These results suggest that augmentation of norepinephrine release in the preoptic area is responsible for hypothermia during general anesthesia.