The effect of HLA alleles on response to interferon therapy in patients with chronic hepatitis C.

OBJECTIVE: To compare HLA alleles in the patients with chronic hepatitis C treated with interferon-alpha (IFN-alpha) between patients with response to IFN treatment and nonresponse. METHOD: Sixty-seven Japanese patients with chronic hepatitis C were treated with daily intramuscular administration of IFN-alpha (6 million units) for 2 weeks followed by three times per week for 22 weeks. Viral loads of hepatitis virus C (HCV), HCV genotypes and HLA antigens were determined just before IFN-alpha treatment. Responders to IFN-alpha were defined as normalization of alanine aminotransferase at the end of treatment and during a follow-up period at least longer than 6 months. The patients who could not reach the above response criteria were defined as nonresponders. RESULTS: There were 20 responders and 47 nonresponders to IFN treatment. The low viral load with less than 1 x 10(6) copy/ml (P< 0.05), and type 2a genotype (P< 0.05) were significantly increased in responders. Other clinical and biochemical parameters were not significant. There was no difference in HLA-A and C antigens between responders and nonresponders. In contrast, HLA-B54,DR4 and A24-B54-DR4 haplotype of nonresponders increased compared with responders or controls (Pc < 0.0001, Pc < 0.001, Pc < 0.0001, respectively). At multivariate analysis, viral loads, HLA-B54 and HLA-A24-B54-DR4 haplotype were significant (P=0.0002, P=0.0258, P=0.0378, respectively). CONCLUSION: The low viral load is a good predictor. HLA-B54 and HLA-A24-B54-DR4 haplotype should be predictors for poor response to IFN therapy in patients with chronic hepatitis C.

Hypothalamic neuronal histamine regulates feeding circadian rhythm in rats.

To clarify involvement of hypothalamic neuronal histamine in feeding circadian rhythm, we analyzed rat behavioral patterns using chemical probes which affect endogenous histaminergic activity. Sustained infusion of alpha-fluoromethylhistidine (FMH), a specific suicide inhibitor of a histamine-synthesizing enzyme, into the rat third cerebral ventricle disrupted light-dark cycles of feeding, drinking, and ambulatory behavior. Food and water intake and ambulatory activity during the 12-h light period increased, and those during the 12-h dark period decreased after the infusion. The ratio of the light period to the 24-h total period (L/T ratio) increased in all behavioral parameters. Assessed by 3-h cumulative analysis, amplitudes of circadian rhythmicity decreased in all behavioral parameters, whereas only the acrophase of ambulatory activity shifted forward after FMH infusion. Chlorpheniramine, an H1-antagonist, selectively increased food intake during the light and decreased it during the dark period. Consequently, the antagonist increased the L/T ratio in food intake, but did not affect the ratio in water intake or ambulatory activity. Famotidine, an H2-antagonist, did not affect the ratio in any parameter. Thioperamide, an antagonist of auto-inhibitory effects on histamine synthesis and release at presynaptic H3-receptor sites, decreased food intake during the dark, but did not affect the L/T ratio in any parameter. These findings indicate that neuronal histamine may regulate feeding circadian rhythm through the hypothalamic histamine H1-receptor in rats.

Neuronal histamine in the hypothalamus suppresses food intake in rats.

Using probes to manipulate hypothalamic neuronal histamine, we report here that changes in neuronal histamine modulate physiological feeding behavior in rats. Infusion of alpha-fluoromethylhistidine (FMH), a "suicide" inhibitor of histidine decarboxylase (HDC), into the third cerebroventricle induced feeding in the early light phase when the histamine synthesis was most accelerated. FMH at an optimum 2.24 mumol dose elicited feeding in 100% of rats. Treatment of FMH specifically and selectively decreased concentration of histamine without affecting concentrations of catecholamines in the hypothalamus. Immediately before the dark phase, when the histamine synthesis was normally lower, FMH infusion did not affect feeding-related parameters such as meal size, meal duration or latency to eat. Conversely, thioperamide, which facilitates both synthesis and release of neuronal histamine by blocking presynaptic autoinhibitory H3 receptors, significantly decreased food intake after infusion of a 100-nmol dose into the third cerebroventricle. The effect of thioperamide was abolished with i.p. injection of 26 mumol/kg chlorpheniramine, an H1antagonist. FMH at 224 nmol was microinfused bilaterally into the feeding-related nuclei in the hypothalamus. The ventromedial nucleus (VMH) and the paraventricular nucleus (PVN), but not the lateral hypothalamus, the dorsomedial hypothalamus or the preoptic anterior hypothalamus were identified as the active sites for the modulation. Neuronal histamine may convey suppressive signals of food intake through H1 receptors in the VMH and the PVN with diurnal fluctuation.

Abnormalities in obese Zuckers: defective control of histaminergic functions.

Histaminergic functions in the hypothalamus of Zucker obese rats were investigated. Blockade of postsynaptic H1-receptor after infusion of chlorpheniramine into the third cerebroventricle (ICV) failed to affect feeding in obese Zuckers, although feeding was potently elicited in Wistar King A control rats. Presynaptic increase in histamine by an H3-receptor antagonist, thioperamide, suppressed feeding in Wistar controls, but not in obese Zuckers. Under high ambient temperature, Wistar controls decreased food intake and maintained their rectal temperature normally. However, obese Zuckers and histamine depleted rats due to alpha-fluoromethyl-histidine (FMH), a specific "suicide" inhibitor of a histamine synthesizing decarboxylase enzyme (HDC), failed to show this decrease in food intake as adaptive behavior. Their rectal temperature concomitantly elevated in response to heated circumstance. ICV infusion of thioperamide increased the blood glucose level in Wistar controls, but not in obese Zuckers. The defect in all these regulatory functions found in obese Zuckers may be derived from an excessive decrease in hypothalamic histamine content due to inactivity of HDC. The histamine-depleted model sufficiently mimicked the abnormalities in obese Zuckers.

Effect of intravenous administration of apolipoprotein A-IV on patterns of feeding, drinking and ambulatory activity of rats.

To characterize the anorectic effect of apolipoprotein A-IV (apo A-IV), we examined the effect of apo A-IV on the patterns of feeding, drinking and ambulation of rats fed ad libitum. A single dose of 200, 135 or 60 micrograms was infused intravenously through a chronically indwelling right atrial catheter just before the dark period. Apo A-IV suppressed food intake by decreasing meal size, but did not affect the interval between meals, the speed of eating, or the latency to eat the first meal after infusion. The anorectic effect of apo A-IV was dose-dependent and was effective for about 3 h after the infusion. The anorectic effect of apo A-IV is specific because inactivation of apo A-IV abolishes its anorectic effect. The anorectic effect of apo A-IV is not shared by apo A-I. Apo A-IV had no effect on drinking behavior or ambulatory activity. The results seem to indicate that apo A-IV specifically decreases the meal size, which supports our hypothesis that apo A-IV may act as a physiological signal for satiation after the ingestion of a lipid meal.

Ginsenoside Rg1 prevents histaminergic modulation of rat adaptive behavior from elevation of ambient temperature.

Effects of ginsenoside Rg1 (Rg1) on histaminergic modulation of both adaptive behavior and thermoregulation were investigated at high ambient temperature. Continuous infusion of Rg1 using an osmotic minipump into the rat third cerebroventricle attenuated anorexia induced by elevation of ambient temperature from 21 degrees C to 31 degrees C. Intraperitoneal injection of alpha-fluoromethylhistidine (FMH), a specific suicide inhibitor of a histamine synthesizing decarboxylase enzyme, also prevented the anorexia induced by elevated temperature. The ratio of water intake to food intake, which showed no change on the first day after elevation of room temperature, was not influenced by treatment of either FMH or Rg1. Rectal temperature, which was normally maintained at a constant level even after shifting ambient temperature from 21 degrees C to 31 degrees C, elevated after FMH treatment. The Rg1 infusion, however, maintained rectal temperature normally at 31 degrees C. Hypothalamic histamine content increased in response to elevation of ambient temperature. The Rg1 infusion maintained constant histamine level against elevation of environmental temperature. Under the heated condition FMH reduced hypothalamic histamine. These findings suggest that Rg1 may modulate rat adaptive behavior by blockade of temperature-related information into the hypothalamic histamine neurons.

Zucker obese rats: defect in brain histamine control of feeding.

Manipulation of hypothalamic histamine produced different effects on feeding between the Zucker obese (fa/fa) and their lean littermate rats (Fa/-). Infusion of a histamine H1-receptor antagonist into the third cerebroventricle elicited feeding in the lean and Wistar King A rats, but it did not affect feeding in the obese rats. To enhance hypothalamic neuronal histamine, thioperamide, and H3-receptor antagonist, was similarly infused. The lean and Wistar rats decreased their food intake after the infusion, but thioperamide produced no significant effect on feeding in the obese rats. Infusion of histamine into the third cerebroventricle mimicked the effects of thioperamide on feeding: reduction of food intake in the lean and Wistar rats, but no significant change in the obese rats. Hypothalamic histamine of the obese rats (0.430 nmol/g) was significantly lower than the lean (1.209 nmol/g) and Wistar rats (4.838 nmol/g). The histamine concentration of the cerebral cortex in the obese rats was also lower than the non-obese animals. The results indicate that the feeding abnormality of Zucker obese rats may be at least due to disturbance of histamine suppressive signals both at presynaptic and postsynaptic levels.

Acceleration of tail pinch-induced feeding in rats by analgesic effect of neurotropin.

Mechanisms of tail pinch-induced feeding and effects of neurotropin (NSP), an extract from the inflamed skin of rabbit inoculated with vaccinia virus, on behavioral responses were investigated in rats. Treatment of a 5-min tail pinch (tail pinch I) induced feeding response. An intensified 15-min tail pinch (tail pinch II) provoked emotional reactions besides feeding behavior. The rate of food intake (food intake/tail pinch duration) during tail pinch II was less than that at tail pinch I. Intraperitoneal administration of NSP (100 mg/kg/day) by itself produced no remarkable change in feeding or emotional behavior. However, NSP-treated rats increased eating size and prolonged eating duration during tail pinch I. Pretreatment of NSP increased feeding behavior more potently at tail pinch II than at tail pinch I and decreased the incidence of emotional reactions at tail pinch II. The results suggest that NSP, by its analgesic action, may modulate behavioral responses during tail pinch treatment through selective blockade of the nociceptive and feeding-inhibitory information, but not through the nonnociceptive and feeding-excitatory signals.

2,5-Anhydro-D-mannitol: its unique central action on food intake and blood glucose in rats.

Peripheral administration of D-fructose has been reported to decrease food intake, and its 2-deoxy analogue, 2,5-anhydro-D-mannitol (2,5-AM), increased food intake and decreased blood glucose in rats. In the present study, 2,5-AM was selected for comparison with well-known 2-deoxy analogues of glucose. Infusion of 2,5-AM into the rat third cerebroventricle at 11.00 h induced feeding dose dependently (Y = 0.63 logX-1.20, r = 0.95, P less than 0.05). Rats treated with 2,5-AM at a maximal effective dose of 24 mumol/rat ate meals most persistently (P less than 0.05). No periprandial drinking was observed. Ambulatory activity increased concomitantly with feeding, but did not exceed the activity normally associated with a meal. Infusion of 24 mumol 2,5-AM into the third cerebroventricle induced no substantial change in plasma glucose or insulin in any 60-min experimental period. Unilateral microinfusion of 1.2 mumol 2,5-AM induced feeding in all 6 rats (P less than 0.01) when a cannula tip was located in the ventromedial hypothalamic nucleus (VMH), but not in the lateral hypothalamic area (LHA). These findings indicate that feeding elicitation may be due to disinhibition by 2,5-AM through the VMH. This is quite unique compared to the action mechanisms of hexose, pentose and their analogues, except 2,5-AM.

[Liver abscesses successfully treated by intraportal administration of amphotericin B in a case of acute myeloblastic leukemia (M2)].

A 46-year-old male was admitted to our hospital because of relapse of acute myeloblastic leukemia (M2). Remission was successfully reinduced after reinduction chemotherapy consisting of daunorubicin, cytosine arabinoside, etoposide and vincristine, but was complicated by neutropenia. After the therapy, the patient had persistent fever of about 38 degrees C despite broad-spectrum antibiotics therapy and the patient developed pain in the right quadrant of the abdomen. The white blood cell count rose to 23000/mm3. Liver function tests showed abnormal findings mainly consisting of an elevated serum alkaline phosphatase level. Ultrasonography showed multiple hypoechoic lesions in the liver and CT scans also revealed multiple low density areas. Therefore he was suspected of having a complication of liver abscesses. Amphotericin B was administered 75 mg/day intravenously every other day. A percutaneous liver biopsy was performed, but was not diagnostic. Blood cultures were negative for pathogens. Amphotericin B was administered up to a cumulative dosage of 2.3 g, but the patient remained febrile. Then he had an exploratory laparotomy and an open liver biopsy. The liver biopsy samples showed fungal elements proved by PAS staining. A catheter was inserted into the portal vein. Administration of Amphotericin B was started 20 mg daily through the catheter. The temperature fell to normal after institution of this therapy. The abnormal findings in CT scans almost disappeared and the inflammatory findings became negative after he had received intraportal administration of Amphotericin B over three months. Through the analysis of this case study, we confirmed that the intraportal administration of Amphotericin B was effective to the intractable liver abscesses due to fungi.

Attenuation of anorexia induced by heat or surgery during sustained administration of ginsenoside Rg1 into rat third ventricle.

Effects of ginsenoside Rg1 (Rg1), a major component of panax ginseng, on modulation of ingestive behavior were investigated. No direct effect was observed on food intake after 10 microliters infusion of 1.0, 2.0, 4.0 or 8.0 mM Rg1 into the rat third ventricle for 10 min. Continuous osmotic infusion of 4.0 mM Rg1 at a rate of 0.966 microliter/h into the third ventricle prevented feeding suppression caused by surgical procedure to implant an osmotic minipump. Continuous infusion of Rg1 attenuated anorexia, increased water intake, and decreased ambulation, that were produced by elevation of environmental temperature from 21 degrees C to 30 degrees C. Consequently, rats maintained body weight and rectal temperature unchanged. The results indicate that sustained central administration of Rg1 may relieve anorexia caused by implantation surgery or by a heated environment.