Administration of exogenous acylated ghrelin or rikkunshito, an endogenous ghrelin enhancer, improves the decrease in postprandial gastric motility in an acute restraint stress mouse model.

BACKGROUND: Physical or psychological stress causes functional disorders in the upper gastrointestinal tract. This study aims to elucidate the ameliorating effect of exogenous acylated ghrelin or rikkunshito, a Kampo medicine which acts as a ghrelin enhancer, on gastric dysfunction during acute restraint stress in mice. METHODS: Fasted and postprandial motor function of the gastric antrum was wirelessly measured using a strain gauge force transducer and solid gastric emptying was detected in mice exposed to restraint stress. Plasma corticosterone and ghrelin levels were also measured. To clarify the role of ghrelin on gastrointestinal dysfunction in mice exposed to stress, exogenous acylated ghrelin or rikkunshito was administered, then the mice were subjected to restraint stress. KEY RESULTS: Mice exposed to restraint stress for 60 min exhibited delayed gastric emptying and increased plasma corticosterone levels. Gastric motility was decreased in mice exposed to restraint stress in both fasting and postprandial states. Restraint stress did not cause any change in plasma acylated ghrelin levels, but it significantly increased the plasma des-acyl ghrelin levels. Administration of acylated ghrelin or rikkunshito improved the restraint stress-induced delayed gastric emptying and decreased antral motility. Ameliorating effects of rikkunshito on stress-induced gastric dysfunction were abolished by simultaneous administration of a ghrelin receptor antagonist. CONCLUSIONS & INFERENCES: Plasma acylated/des-acyl ghrelin imbalance was observed in acute restraint stress. Supplementation of exogenous acylated ghrelin or enhancement of endogenous ghrelin signaling may be useful in the treatment of decreased gastric function caused by stress.

Regression of rectal MALT lymphoma after antibiotic treatment in a patient negative for Helicobacter pylori.

A 53-year-old man was referred to our hospital with bloody stool. Barium enema study and colonoscopy revealed multiple small nodules on the anterior wall of the lower rectum. Biopsy specimens showed proliferation of atypical lymphoid cells forming the nodules. Mucosa-associated lymphoid tissue lymphoma was diagnosed on the basis of histologic and immunohistochemical examinations. No metastasis was detected in lymph nodes or distant organs, indicative of clinical stage I disease. Although the test results were negative for Helicobacter pylori, eradication therapy was performed. The lesion disappeared completely within 9 months after the triple antibiotic therapy. H. pylori eradication therapy may be a useful treatment option regardless of H. pylori status.

Hyperthermia ameliorates 2,4,6-trinitrobenzene sulphonic acid-induced colitis in rats: the role of heat shock proteins.

PURPOSE: Hyperthermia is known to protect against cellular injury through the expression of heat shock proteins. In this study, the therapeutic effects of hyperthermia on experimental colitis in the rat were evaluated. MATERIALS AND METHODS: Male Wistar rats were given a single intracolonic injection of 2,4,6-trinitrobenzene sulphonic acid (TNBS). Hyperthermia was induced in anesthetized rats by placing them in a temperature-controlled water bath. We started the hyperthermic treatment on the day after the enema. The severity of colitis was evaluated pathologically, and the activities of tissue myeloperoxidase were measured 6 days after the induction of colitis. Furthermore, cytokines, and hyperthermia-induced heat shock proteins in colonic mucosa were detected by enzyme-linked immunosorbent assay and Western blotting. We also investigated the effects of geranylgeranylacetone and zinc protoporphyrin IX on the therapeutic effect of hyperthermia. RESULTS: Hyperthermia significantly improved the macroscopic scores of colitis. The TNBS-induced increases in the activities of myeloperoxidase in the colonic tissue were blunted significantly in hyperthermia-treated animals. Furthermore, hyperthermia attenuated increases in cytokine-induced neutrophil chemoattractants-1 and tumor necrosis factor-alpha in the colon. Furthermore, hyperthermia induced the production of heat shock proteins in rat colonic mucosa, and the combination of geranylgeranylacetone with hyperthermia further induced the heat shock protein HSP70, which resulted in further improvement of TNBS-induced colitis. On the other hand, the combination of zinc protoporphyrin IX with hyperthermia attenuated the therapeutic effect of hyperthermia. CONCLUSIONS: Hyperthermia ameliorates TNBS-induced colitis in rats through the expression of HSP70 and HO-1. It is postulated that hyperthermia may be useful for the treatment of inflammatory bowel diseases.

Dietary fat and meat intake and idiopathic pulmonary fibrosis: a case-control study in Japan.

SETTING: There is sparse epidemiologic information regarding the role of dietary factors in the development of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: To examine the relationship between specific types of fatty acids and selected foods high in fat and IPF in Japan. DESIGN: Included were 104 cases aged > or = 40 years who had been diagnosed in the last 2 years in accordance with the most recent criteria. Controls aged > or = 40 years consisted of 56 hospitalised patients diagnosed as having acute bacterial pneumonia and four out-patients with common cold. RESULTS: Intake of saturated fatty acids, mono-unsaturated fatty acids, n-6 polyunsaturated fatty acids and meat was independently associated with an increased risk of IPF. Specifically, the multivariate OR for comparison of the highest with the lowest quartile of intake of saturated fatty acids was 6.26 (95%CI 1.79-24.96, P for trend = 0.01) and for meat it was 7.19 (95%CI 2.15-27.07, P for trend = 0.02). Intake of cholesterol, n-3 polyunsaturated fatty acids, fish, eggs and dairy products was not related to the risk. CONCLUSION: These findings suggest that consumption of saturated fatty acids and meat may increase the risk of IPF.

Heme oxygenase-1 (Hsp32) is involved in the protection of small intestine by whole body mild hyperthermia from ischemia/reperfusion injury in rat.

AIM: The aim of the present study was to explore whether heme oxygenase-1 (HO-1) is involved in the hyperthermia-provided protection of the small intestine from ischemia/reperfusion injury in rats. METHODS: Intestinal damage was induced in male Sprague-Dawley rats by clamping both the superior mesenteric artery and the celiac trunk for 30 min, followed by reperfusion. Whole-body hyperthermia was induced in anesthetized rats by placement in a temperature-controlled water bath. Whole-body hyperthermia to a core temperature of 42-43 degrees C for 15 min was followed by passive cooling. We started the hyperthermic treatment 6 h before the vascular clamping. The severity of the mucosal injury was evaluated by several biochemical markers and histological findings. Hyperthermia-induced heat-shock proteins were detected by Western blotting. We also investigated the effect of zinc protoporphyrin IX (an HO-1 inhibitor) on the protective effect of hyperthermia. RESULTS: The rats, which were killed after ischemia/reperfusion, had severe intestinal inflammation. Hyperthermia significantly induced the production of Hsp70 and HO-1 in intestinal mucosa and significantly reduced ischemia/reperfusion-induced mucosal injury. The combination of zinc protoporphyrin IX with hyperthermia extinguished the protective effects of hyperthermia on ischemia/reperfusion injury. CONCLUSION: Hyperthermia protects against ischemia/reperfusion injury in rat small intestine through the expression of heat-shock proteins, especially HO-1.

The effect of diet on blood vitamin K status and urinary mineral excretion assessed by a food questionnaire.

To assess Vitamin K (VK) status by food questionnaire, healthy young males (32) and females (9) were given a food list of 50 VK rich foods (identified in the 4th edition standard tables of food composition in Japan). After checking the food names and approximate amount eaten for 7 days, early morning blood and urine samples were collected. Prothrombin and hepaplastin was tested and plasma protein induced by VK absence factor II (PIVKA-II), osteocalcin, and calcium, phosphorous and magnesium in plasma and urine were determined. Participants who have a habit of eating natto, a traditional Japanese food very rich in Vitamin K, VK were excluded, and lowest and highest VK consumers were compared (males; lowest 7 vs. highest 7, females; 3 vs. 3). Plasma PIVKA-II levels, and urinary calcium and magnesium excretion of the lowest was significantly higher, but urinary phosphorus was lower, than that of the highest in females. In the natto eaters, daily mean VK intakes and hepaplastin test results of natto eaters were significantly higher, but urinary calcium excretions were lower than that of non natto eaters in males. These results suggest that Daily VK intake estimated from a questionnaire, is well related to real VK status, and also that natto is a good dietary source of vitamin K.

Aromatic L-amino acid decarboxylase- and tyrosine hydroxylase-immunohistochemistry in the adult human hypothalamus.

The distribution of cell bodies immunoreactive for tyrosine hydroxylase and aromatic L-amino acid decarboxylase was studied in the adult human hypothalamus. Many neurons in the posterior (A11) and caudal dorsal hypothalamic areas (A13) as well as in the arcuate (A12) and periventricular (A14) zone were immunoreactive for the two enzymes, suggesting that they were dopaminergic. Numerous tyrosine hydroxylase-immunoreactive neurons, which were not immunoreactive for aromatic L-amino acid decarboxylase, could be seen in the paraventricular, supraoptic and accessory nuclei (A15) as well as in the rostral dorsal hypothalamic area. These were considered to be non-dopaminergic. Conversely, large numbers of small neurons immunoreactive for aromatic L-amino acid decarboxylase but not for tyrosine hydroxylase, were identified in the premammillary nucleus (D8), zona incerta (D10), lateral hypothalamic area (D11), anterior portion of the dorsomedial nucleus (D12), suprachiasmatic nucleus (D13), medial preoptic area and bed nucleus of the stria terminalis (D14). In the human hypothalamus, besides dopaminergic cell bodies, there exists a large number of tyrosine hydroxylase-only and aromatic L-amino acid decarboxylase-only neurons, whose physiological roles remain to be determined.

Mineral concentrations in the blood of male smokers and non-smoking males and females measured with fluoro-X-ray analyzer.

For clarification of the effects of smoking on mineral absorption in red blood cells (RBC) and serum, their concentrations at these sites were examined in ten male smokers and 12 male and 10 female non-smokers by fluoro-X-ray analysis. K in serum was high, and P, Ca and Fe low, compared to RBC. Mg and S in serum and RBC were essentially the same. S, Mg, P and K in RBC of smokers were higher than in male non-smokers, and Ca was lower. S and Ca in serum of smokers were significantly lower than in male non-smokers. P in smokers was higher than in non-smokers. P in RBC may possibly activate the reflux of Mg into RBC and may suppress that of Ca. In smokers, the correlation coefficient (gamma) between Fe and Ca was r = -0.68 in RBC, and r = 0.76 in serum. Also gamma between P and Mg was r = 0.4 in RBC and r = -0.48 in serum. Thus Fe in RBC may suppress the reflux of Ca. Mg and Ca in serum of females were significantly higher than in male non-smokers. Ca in RBC of females was significantly higher than in male non-smokers, and P, K and Fe were significantly lower. The product of Ca and P in RBC of females was lower than in male non-smokers, while in serum it was higher. gamma between P and Ca, and between Fe and Ca in RBC of females were negative, while they were positive in male non-smokers. The correlations in female RBC had the same pattern as in male smokers.

[An anaphylactic shock case after hepatic arterial infusion of zinostatin stimalamer suspension improved by anti-histaminics].

A 47-year-old man with hepatocellular carcinoma (HCC) at anterior and medical segment in the liver was treated with hepatic arterial infusion of Zinostatin Stimalamer-lipiodol suspension (SMANCS). After the 2nd infusion of SMANCS, the accumulation of lipiodol in the tumor was not good (Grade II), so additional administration was undertaken at five-weeks intervals. His systolic blood pressure immediately decreased from 120 to 60 mmHg, and he had numbness of hands, shaking chills, sweating, chest pain and numerous urticaria-like red exanthema. In spite of treatment by anti-shock agents such as steroid and catecholamines, these symptoms did not disappear, but antihistaminics greatly improved them without any serious side effects. Because of the remarkable effects of the antihistaminics and possibility of antibody production (IgE) after repeated infusions of high molecular SMANCS, this patient may have suffered anaphylactic shock caused by massive histamine release from mast cells.

Effects of long-term enalapril treatment on persistent micro-albuminuria in well-controlled hypertensive and normotensive NIDDM patients.

OBJECTIVE: To determine whether long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor has a beneficial effect on the urinary microalbumin excretion and renal function in non-insulin-dependent diabetes mellitus (NIDDM) patients, enalapril (5 mg/day) was administered for 48 months. RESEARCH DESIGN AND METHODS: -Fifty-two patients with NIDDM who had persistent microalbuminuria in the range of 20-300 mg/24 h, serum creatinine < 106.1 microM (1.2 mg/dl), supine systolic blood pressure (BP) < 150 mmHg, supine diastolic BP < 90 mmHg, and HbA1c < 10% were divided into four groups. Twenty-six patients with normotension were divided at random into two groups; one group received enalapril (5 mg/day) (NE group), the other did not receive enalapril (NC group). In the same way, 26 other patients who were already well-controlled with nifedipine (30 mg/day) over a long-term period (4-6 years) were divided at random into two groups; one received enalapril (5 mg/day) (HE group), the other did not receive enalapril (HC group). RESULTS: After 48 months, urinary albumin excretion (UAE) was markedly reduced in group NE from 102.4 x/divided by 1.3 to 55.5 x/divided by 1.3 mg/24 h (P < 0.005), whereas no significant change occurred in group NC. In the well-controlled hypertensive groups, a significant reduction in UAE occurred in group HE (P < 0.05), whereas no significant change occurred in group HC. No changes in creatinine clearance, BP, or blood glucose control were seen during the study. CONCLUSIONS: Treatment with enalapril for 48 months may have a beneficial effect on the decline of microalbumin excretion in NIDDM patients.

The effect of acarbose on blood glucose profiles of type 2 diabetic patients receiving insulin therapy.

Nine patients with Type 2 diabetes receiving insulin therapy were treated with acarbose 100 mg thrice daily for 1 week to investigate the effect of acarbose on blood glucose control. Daily blood glucose profiles contained fewer excursions during acarbose administration and low levels were maintained. The M-value, an indicator of blood glucose fluctuation, decreased significantly from a run-in period value of 37.6 +/- 8.7 (SEM) to 16.7 +/- 4.0 during the acarbose period (p < 0.05) and rose again to 28.9 +/- 6.7 (p > or = 0.05) in the follow-up period. The 24-h urinary glucose excretion similarly decreased during acarbose administration. As expected, no decrease in HbA1C was observed due to the short treatment period. The 24-h urinary C-peptide excretions and serum lipids were not influenced by acarbose therapy. Frequent episodes of clinical hypoglycaemia were experienced while on acarbose therapy, indicating a decrease in insulin requirements. Adverse events such as flatulence and abdominal distention were observed in six out of nine cases. Symptoms were generally mild and well tolerated, only one patient dropped out because of diarrhoea and abdominal pain. We conclude that acarbose could usefully be administered to Type 2 diabetic patients treated with insulin to improve blood glucose control and reduce insulin requirement if the appropriate selection criteria were met.

Long-term effect of acarbose on glycaemic control in non-insulin-dependent diabetes mellitus: a placebo-controlled double-blind study.

The efficacy and safety of acarbose therapy (100 mg tds for 24 weeks) was investigated in a placebo-controlled double-blind study in patients with non-insulin dependent diabetes mellitus who could not achieve satisfactory glycaemic control by diet alone. In the acarbose group, the 2 h postprandial blood glucose and haemoglobin A1 levels decreased significantly from 14.0 mmol l-1 to 11.3 mmol l-1 and from 11.1% to 9.7%, respectively. In the placebo group, the 2 h postprandial blood glucose (14.4 mmol l-1 to 14.2 mmol l-1) and the hemoglobin A1 level (10.3% to 9.9%) showed no significant changes. A 75 g oral glucose tolerance test was performed before and after the study, the difference not being significant in either the acarbose group or the placebo group. The incidence of side-effects (mainly gastrointestinal symptoms such as flatulence and abdominal distension) was high at 78.9% in the acarbose group and 61.1% in the placebo group. However, there was no significant difference between the groups, and side-effects in the acarbose group tapered during the trial, suggesting that some at least were not related to the drug. From these findings, it was concluded that acarbose is an effective new treatment for diet treated non-insulin-dependent diabetic patients.

Activation of GABAA receptors in hypothalamus modulates PGF2 alpha- or PGE2-induced catecholamine secretion in rats.

We previously reported that injection of PGF2 alpha into the third cerebral ventricle produces hyperglycemia and hyperthermia associated with catecholamine secretion in anesthetized rats. We have also studied the potency of catecholamine secretion induced by injecting PGE2 or PGF2 alpha into the third cerebral ventricle and the effect of the GABA-selective agonist, muscimol, on the catecholamine secretion induced by PGE2 or PGF2 alpha. Administration of 50 micrograms of PGE2 into the third cerebral ventricle increased norepinephrine secretion to a greater extent than the same dose of PGF2 alpha, whereas the latter increased epinephrine secretion to a greater degree. These effects paralleled the potencies of the hyperglycemic and hyperthermic effects of PGF2 alpha and PGE2, respectively. Simultaneous injection of 2.5 nmol of muscimol into the third cerebral ventricle with 50 micrograms of PGF2 alpha or PGE2 completely suppressed epinephrine and norepinephrine secretion induced by PGF2 alpha or PGE2. These findings suggest that central PGF2 alpha and PGE2 stimulate epinephrine and norepinephrine secretion with different potencies, and that brain GABAA receptors suppress catecholamine secretion induced by PGF2 alpha or PGE2.

Hyperglycemia induced by hippocampal administration of neostigmine is suppressed by intrahypothalamic atropine.

We investigated the relationship between the hyperglycemia induced by the administration of neostigmine into the hippocampus and the hypothalamus. Prior to the injection of neostigmine (5 x 10(-8) mol) into the hippocampus, 1 microliter each of atropine or hexamethonium (5 x 10(-11)-5 x 10(-8) mol) was injected into the bilateral ventromedial hypothalamus (VMH). Atropine suppressed in a dose-dependent manner the hyperglycemia induced by hippocampal administration of neostigmine, whereas hexamethonium had no significant effect. These observations suggest that the pathway for this experimental hyperglycemia involves, at least in part, the muscarinic cholinergic neurons in the VMH.

Dissociation of hyperthermic and hyperglycemic effects of central prostaglandin F2 alpha.

We previously reported that intraventricular prostaglandins (PGs) produced hyperthermia and hyperglycemia in anesthetized rats. However, the relationship of them is little known. We examined the relationship between hyperthermia and hyperglycemia induced by intraventricular PGF2 alpha using curarized and adrenal demedullated rats. Iv curare completely prevented the PGF2 alpha-induced hyperthermia, but enhanced the hyperglycemic effect of PGF2 alpha. Adrenal demedullation completely prevented the hyperglycemia, but did not affect the hyperthermic effect of PGF2 alpha. To further assess the site of action concerned with PGF2 alpha-induced thermoregulation and glucoregulation in the central nervous system (CNS), we injected saline or PGF2 alpha into the preoptic area of the anterior hypothalamus (POA) in intact rats. After microinjection of PGF2 alpha into the POA, the rectal temperature rose, but the plasma glucose level did not increase significantly, as compared with saline-treated control rats. These results suggest that PGF2 alpha causes the central nervous system to produce hyperthermia via shivering, stimulated the somatic motor system, and to produce hyperglycemia by stimulating central sympathetic outflow to the adrenal medulla, but these operate independently under different neural regulation, and these sensitive sites are organically dissociated in the CNS.

Neurotensin immunoreactive neurons in the human infant diencephalon.

Neurotensin-like immunoreactive (NT-IR) neurons are present in discrete subregions of the anterior, medial and lateral thalamic nuclear groups of the human infant brain. The pulvinar is notably rich in such cells. Smaller numbers of cells are present in the ventral group, centromedian nucleus, reticular nuclei and intralaminar nuclei. Neurotensin immunoreactive axons accumulate dorsally in the thalamus and cross the deep white matter. The cerebral cortex contains a rich network of NT-IR axons. The subthalamic nucleus is rich in NT-IR neurons. Within the hypothalamus NT-IR perikarya are present in parts of the lateral and tuberal regions and in the lateral mammillary area. NT-IR axons are widespread being particularly prominent in parts of the tuberal region and the mammillary body.

A copper-sulfur complex in the liver of a patient with Wilson's disease.

An asymptomatic 16-year-old boy was found to have Wilson's disease without Kayser-Fleischer rings. Liver biopsy showed chronic active hepatitis with 1025 micrograms copper/g dry weight. After 19 months of d-penicillamine therapy, the liver histology became almost normal and the copper content decreased to 238 micrograms/g dry weight. The liver specimens obtained before and after treatment were studied by X-ray probe microanalysis. After treatment, both copper and sulfur decreased in hepatocellular lysosomes. The estimated molar ratio of the decreased copper to the decreased sulfur was 32/100. These figures suggest that lysosomal copper exists in the form of metallothionein.

Inhibitory effects of anti-angiogenic agents on neovascularization and growth of the chorioallantoic membrane (CAM). The possibility of a new CAM assay for angiogenesis inhibition.

Protamine sulfate and combinations of heparin-cortisone acetate known as having anti-angiogenic activities impaired the growth of chorioallantois at the dose inducing no decrease in growth rate of the embryos. This inhibitory effect of the agents is presumed to be mediated by the specific inhibition of the growth of endothelial cells forming chorioallantoic blood vessels based on the following results: significant correlations were found between the length of CAM vessels measured by an automatic image analyzer and the estimated volumes of chorioallantois (correlation coefficient r = 0.94) and these agents specifically inhibited the (3H)-thymidine incorporation into cultured endothelial cells at the dose having no effects on that into cultured chick embryonic cells. On the other hand, all DNA-synthesis inhibitors, mitomycin C, 5-fluorouracil, and paraformaldehyde suppressed the growth of both CAM and embryo and resulted in early embryonic death, which might be due to the nonspecific impairment of DNA synthesis by these agents. These results indicate the possibility that the present CAM assay could screen agents having anti-angiogenic activity.

An association of mercury with selenium in inorganic mercury intoxication.

Energy dispersive X-ray analysis was performed on the renal tubular cells of two patients with inorganic mercury intoxication. Some lysosomes of these cells consisted of unusual matrices of aggregated electron-dense grains which were positive for mercury, selenium and sulphur. Though maps of the specific X-rays of both mercury and selenium coincided exactly with these lysosomes, the molecular ratio of selenium to mercury ranged between zero and 2.9. It is unlikely that the trace element of selenium and exogenous inorganic mercury are deposited in the lysosomes independent of each other, but rather their coexistence in the characteristic lysosomes strongly suggests a compound formed by binding mercury to the SeH residues of selenoprotein.

Central hyperglycaemic effect of adrenaline and carbachol.

The effect of chemical stimulation of the brain on glucoregulation was studied in anaesthetized rats. Adrenaline, noradrenaline, acetylcholine, dopamine and carbachol (5 X 10(-8) mol/microliter saline) were injected directly into the third cerebral ventricle and changes in hepatic venous plasma glucose, immunoreactive glucagon and insulin concentrations were studied. The injection of adrenaline and carbachol into the third cerebral ventricle resulted in a marked hyperglycaemia associated with increased immunoreactive glucagon. Adrenaline-induced hyperglycaemia was not affected by bilateral adrenalectomy, while carbachol-induced hyperglycaemia was completely inhibited by adrenalectomy. The injection of somatostatin (1 X 10(-9) mol) with adrenaline into the third cerebral ventricle did not influence adrenaline-induced hyperglycaemia, while carbachol-induced hyperglycaemia was inhibited by co-administration with somatostatin. These results suggest that adrenergic and cholinergic neurons in the central nervous system may increase hepatic glucose output by different mechanism.