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We report a type IIa early gastric cancer associated with xanthoma cell proliferation in a 61-year-old man. The patient was admitted to our hospital because of a gastric polyp detected at a medical checkup. An irregular protruding lesion with xanthoma cell proliferation was detected endoscopically. Histological examination showed a well differentiated tubular adenocarcinoma in the mucosa associated with xanthoma cell proliferation. The distribution of the xanthoma cells in the stroma corresponded closely with that of the cancer cells. Neither atypism nor mitotic figures were recognized in the xanthoma cells. In an immunohistochemical study, almost all the xanthoma cells were stained positive for alpha 1-antitrypsin, while relatively few exhibited positive S-100 protein staining. Specific monocyte chemotactic and activating factor immunoreactivity was present only in the xanthoma cells, and not in the cancer cells. On the basis of these findings, it was speculated that the gastric cancer cells may have caused the xanthoma cell proliferation via an autocrine mechanism i.e., by a chemical mediator acting in a paracrine or juxtacrine manner. [ABSTRACT FROM AUTHOR]

The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv ( 25 ), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis., Competing Interests: The authors declare no competing financial interest.

Objective: To report successful use of low-volume intrathecal (IT) daptomycin and loading strategy for the treatment of ventriculostomy-associated meningitis., Case Summary: A 23-year-old man with a history of multiple ventriculoperitoneal shunt revisions resulting from multidrug-resistant Staphylococcus epidermidis shunt infection presented with meningitis despite suppressive antibiotic therapy. After source control surgery, the patient improved with intravenous daptomycin plus IT vancomycin. Then, 4 days later, significant ventriculostomy output occurred, and the S epidermidis was confirmed to be intermediately sensitive to vancomycin (MIC = 8 µg/mL) and susceptible to daptomycin (MIC = 2 µg/mL). IT vancomycin was changed to IT daptomycin 5 mg in 3 mL normal saline (NS) every 24 hours for 3 days, then every 72 hours for 18 days. The cerebrospinal fluid (CSF) was sterile after 1 day of IT daptomycin and remained so. Creatine kinase remained normal throughout the course of treatment. The patient was discharged on hospital day 50 without antibiotics., Discussion: IT daptomycin has been reported for adult doses ranging from 5 to 10 mg once every 24 to 72 hours in volumes ranging from 5 to 10 mL; drug accumulation has been seen after the third dose of once every 24 hours dosing, and delayed improvement has been seen with once every 72 hours dosing. We planned for rapid load and CSF sterilization and extended the dosing interval once drug accumulation was expected to have occurred., Conclusions: IT daptomycin 5 mg diluted to 3 mL in NS and dosed in a loading strategy was effective and without adverse sequelae., (© The Author(s) 2014.)

Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

We report the design, synthesis, and optimization of the first, selective activators of cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.

A 30-year-old woman was admitted to our hospital because of recurrent ureterolithiasis. She was suspected of having adenine phosphoribosyltransferase (APRT) deficiency based on the presence of 2,8-dihydroxyadenine (DHA) crystals in her urinary sediment, infrared spectrophotometric analysis of the excreted stone, and then the definitive diagnosis by gene analysis. A pedigree study indicated only a slight possibility of this disease in the family. From these results, we consider that urinary sediment and stone analysis should be used for screening while gene analysis should be employed for definitive diagnosis of APRT deficiency, so that the complications of this condition can be prevented.

Anisakiasis is a disease which occurs following eating raw fish infected with anisakis larvae. Many cases have been reported from Japan and from other countries with increasing opportunities of eating raw fish such as "sushi" and "sashimi." We have reviewed 28 patients with acute gastric anisakiasis during the last 10 years from November 1984 to October 1994. This disease has rarely been detected in persons over 60 years of age and in patients with gastric surgery. Therefore it is postulated that gastric acid secretion influences the activities of anisakis larvae. An alkaline gastric pH could interfere with the toxicity of anisakis larvae.

delta-Aminolevulinic acid dehydratase deficiency porphyria (ALAD porphyria, ADP) with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in a 69-year-old woman is reported. The patient was admitted to our hospital complaining of slight cough with low-grade fever, and treated with piperacillin sodium, resulting in complete resolution of the symptoms, following a diagnosis of bronchopneumonia. Thereafter, however, she began to complain of vomiting, abdominal pain, facial numbness and paresis of the extremities with gait disturbance, and became comatose with hyponatremia (serum Na concentration 119 mEq/L) in a few days. Laboratory tests revealed an antidiuretic hormone (ADH) level of 13.5 pg/mL, plasma osmolality 218 mOsm/KgH2O, urinary osmolality 429 mOsm/KgH20, urinary Na concentration > 20 mEq/L, and no abnormalities of thyroid, adrenal or renal function. Neither edema nor dehydration was evident. These data indicated the presence of SIADH. No abnormalities suggestive of malignant or infectious diseases such as lung cancer, pneumonia and Guillain-Barré syndrome were evident from laboratory and roentgenographic findings. As the cause of SIADH, therefore, porphyria was suspected. Metabolites and activities of enzymes in the heme biosynthetic pathway were examined, and very low activity of delta-aminolevulinic acid dehydratase (ALA-D) (0.14 mumol PBG/mL RBC/h) was found. The patient was neither an alcoholic nor a heavy smoker, and she had no past history of heavy metal intoxication, photosensitivity or tyrosinemia. On the basis of these data and clinical features, she was diagnosed as having ADP. We consider this to be the first case of ADP reported in Japan.

Pancreatic exocrine function in rats given synthetic protease inhibitor camostate (200 mg/kg body weight) perorally once daily for 10 days was investigated. Pancreatic wet weight was significantly increased in the camostate-treated rats. The increase in pancreatic weight was associated with pronounced hypertrophy and moderate hyperplasia. Total amylase, trypsin, and lipase contents in the pancreas were also increased in the camostate-treated group compared with the control rats. Secretory patterns of pancreatic juice and amylase in response to caerulein were similar in both groups, whereas the dose-response curve for pancreatic juice secretion in the camostate-treated rats was shifted tenfold toward higher concentrations of caerulein. Basal and caerulein-stimulated flow rates of pancreatic juice were significantly greater in the camostate-treated rats than the control rats, although both groups showed a threefold increase over basal secretion in response to maximal stimulation. Amylase outputs in basal state and in response to submaximal doses of caerulein were significantly lower, whereas those to maximal and supramaximal doses were significantly greater in the camostate-treated animals than that in the control rats. These results indicate that treatment with camostate induces pancreatic hypertrophy and hyperplasia, and that the secretory function of the hypertrophied pancreas is quantitatively but not qualitatively altered.

The mode of inhibition of a new complex oligosaccharide that inhibits the alpha-glucoside hydrolase activity of pancreatic and salivary alpha-amylase was studied. Kinetic analysis revealed a non-competitive type of inhibition with a Ki of 1.47 +/- 0.03 micrograms when tested against human pancreatic alpha-amylase and 3.89 +/- 0.08 micrograms against human salivary alpha-amylase. The inhibitory action of alpha-glucoside hydrolase inhibitor (alpha-GHI) on pancreatic amylase was observed over a wide range of pH (6.0--7.9), whereas the inhibition of salivary amylase was optimal at pH 6.5. Column chromatographic investigations suggested the possible formation of an enzyme-inhibitor complex because the mixture of alpha-GHI and pancreatic alpha-amylase was eluted as a single component through a Sephadex G200 column. However, this enzyme-inhibitor complex was easily separated into each component and the enzyme activity was fully recovered after electrophoresis.

A 48-year-old woman was examined who had a limited form of Wegener's granulomatosis with neurologic manifestations. Despite the relative frequency of neurologic manifestations, we found only two other cases in the literature in which intracerebral granulomas were involved. Moreover, mammary manifestations with necrotizing granulomas developed in this case. Glucocorticoid treatment was effective because the case showed both brain and mammary involvement. This case was uncommon in that the intracerebral and mammary granulomas developed in an area remote from that usually affected by Wegener's granulomatosis.

The acute and chronic effects of hydrocortisone on insulin secretion were examined in the isolated perfused rat pancreas. In the first part of this study, the chronic effects of hydrocortisone on insulin release were examined using isolated perfused pancreas prepared from rats that had been given subcutaneous injections of hydrocortisone at doses of 1.25, 2.5, 5.0, and 10.0 mg/kg body weight once daily for 7 days. Hydrocortisone treatment led to a dose-dependent increase in insulin secretion in response to 8.3 mM glucose. The insulin response to 100 pM cholecystokinin (CCK-8) was also significantly higher in the hydrocortisone-treated rats than in the control group. However, the increment of insulin level over the value before CCK-8 addition in rats treated with hydrocortisone was not significantly different from that in the control rats. In the second part, the acute effects of hydrocortisone on insulin release were studied. Hydrocortisone (17-hydroxycorticosterone) at a concentration of 100 microM caused significant inhibition of the stimulatory effect of CCK-8 on insulin secretion. The inhibition started within 1 min of the beginning of hydrocortisone administration and ceased immediately after the termination of its infusion. We have demonstrated in this study a dual effect of hydrocortisone on insulin release: first, the potentiation of the insulin secretion stimulated by glucose but not by CCK-8 and, second, the inhibition of CCK-8-stimulated insulin secretion.

We studied pancreatic exocrine function in response to cerulein and carbamylcholine in isolated perfused pancreas obtained from control, streptozotocin-induced diabetic, and insulin-treated diabetic rats. The time course of pancreatic juice, protein, amylase, and trypsinogen secretion in response to cerulein or carbamylcholine in diabetic rats was similar to that in control rats. Basal as well as cerulein- or carbamylcholine-stimulated output of amylase from diabetic rat pancreas was significantly reduced, whereas that of trypsinogen was similar to the control. Amylase and trypsinogen outputs in response to 620 pM (1.0 ng/ml) cerulein from insulin-treated diabetic rat pancreas were significantly lower than those from control rat pancreas, although the pancreatic contents of these enzymes were similar to or greater than those in control rats. The dose-response curves of pancreatic juice, protein, amylase, and trypsinogen for cerulein and carbamylcholine were biphasic in both control and diabetic rats. The minimal and the maximal release in response to cerulein occurred with higher concentrations in diabetic rats compared with control rats. In contrast, the maximal responses were obtained with 1 microM carbamylcholine in control rats and with 0.1-1 microM carbamylcholine in diabetic rats. The present study demonstrates that the concentration of cerulein required to elicit maximal response was increased, whereas that to carbamylcholine was reduced in diabetic rat pancreas, and that the protein and enzyme outputs in response to cerulein were significantly reduced in insulin-treated diabetic rat pancreas despite restoration of the pancreatic enzyme contents to control levels.

The acute and chronic effects of hydrocortisone on exocrine pancreatic function were examined in the isolated perfused rat pancreas. In the first part of this study, rats were given subcutaneous injections of hydrocortisone at doses of 1.25, 2.5, 5, and 10 mg/kg body wt once daily for 7 days. Trypsin and lipase secretion in response to 100 pM cholecystokinin-octapeptide was significantly increased in rats with the two highest doses of hydrocortisone compared with controls, irrespective of whether calculated as the total amount of stimulated output of enzymes or related to the secretion of enzyme to the pancreas content. On the other hand, the secretory responsiveness of amylase to 100 pM cholecystokinin-octapeptide was maximal at the 5-mg dose, and decreased with higher doses. In the second part, 100 microM hydrocortisone was superimposed for 20 min on 100 pM cholecystokinin-octapeptide stimulation to examine the acute effects of hydrocortisone on exocrine pancreatic function in the isolated perfused rat pancreas. Addition of hydrocortisone caused a significant inhibition of the secretion of pancreatic juice and amylase. The present study has clearly demonstrated the dual effects of glucocorticoids on the pancreas: inhibition and potentiation. There is a possibility that chronic treatment with large doses of glucocorticoid may sensitize the acinar cells an induce hypersecretion of trypsin and lipase, whereas acute treatment inhibits secretory function of exocrine pancreas.

The electrophoretic and column chromatographic characteristics of an amylase inhibitor of wheat origin were investigated. Further, the clinical usefulness of this inhibitor for determining the ratio of pancreatic to salivary isoamylase activity in serum was evaluated. Amylase inhibitor inhibits the action of salivary alpha-amylase by making an amylase-inhibitor complex, which is easily separated into its individual component during electrophoresis with full recovery of amylase activity. Using the specific inhibitory effect of this inhibitor on salivary alpha-amylase activity, the ratio of pancreatic to salivary isoamylase activity (P/S) in serum was determined. There was a good correlation in P/S ratio in serum between the results obtained with the inhibitor method and those with electrophoretic method. The P/S ratio in sera from patients with acute pancreatitis was over 8.0, whereas that in sera from patients with salivary-type hyperamylasemia such as mumps, pulmonary diseases and following surgery was less than 0.1. However, hyperamylasemia due to macroamylase or renal failure could not be identified by the inhibitor method.

The effect of the alpha-glucosidase inhibitor acarbose on pancreatic exocrine and endocrine function was studied using the isolated perfused pancreata prepared from rats fed a normal (control diet) or an acarbose-containing sucrose- (ACS diet) or glucose-supplemented diet (ACG diet) for 10 days. Pancreatic amylase and insulin contents in rats fed the ACS diet were significantly decreased compared with those in rats with the control diet. Rats fed the ACG diet, however, had normal enzyme and hormone contents. Basal and cerulein-stimulated flow rates of pancreatic juice in rats with the ACS or ACG diet were similar to those in rats fed the control diet, suggesting that the pancreata from rats treated with acarbose have normal sensitivity and responsiveness to cerulein. On the other hand, cerulein-stimulated amylase output was significantly decreased in rats with the ACS diet, but was normal in rats with the ACG diet. Insulin secretion to both glucose and cerulein stimulation in rats fed the ACS diet was reduced by approximately 55% compared with the control rats. On the other hand, rats fed the ACG diet showed normal insulin secretion to glucose stimulation, although the insulin response to cerulein stimulation was reduced by 30%. These results suggest that the addition of acarbose to the sucrose-rich diet decreases the secretory responsiveness of amylase to cerulein stimulation and that of insulin to both glucose and cerulein stimulation. All these alterations, except the sensitivity of B cells to cerulein, can be normalized by replacing sucrose with glucose.

We describe the results of metabolic studies in a 17-year-old woman with diabetes mellitus which was the initial manifestation of idiopathic chronic calcifying pancreatitis (CCP). These studies were done on 2 occasions, 5 months and 5 years after the onset of diabetes, when her diabetes could be managed by glibenclamide and insulin, respectively. Five months after the onset of diabetes, oral glucose produced a small increase in insulin and a paradoxical rise in both glucagon immunoreactivity (GI) and growth hormone (GH). BY contrast, arginine-stimulated responses of the three hormones were normal. No increase in GI and a blunted rise in GH resulted from an insulin-induced decrease in blood glucose. Five years later, when CCP was demonstrated by roentogenologic examinations and tests of pancreatic exocrine function, oral glucose was followed by a flat and depressed response of C-peptide immunoreactivity and a markedly elevated response of gut glucagon-like-immunoreactivity (gut GLI). There were delayed and extremely low responses of pancreatic polypeptide to a test meal, irrespective whether or not her diabetes required treatment with insulin. These results demonstrate that CCP can cause diabetes in adolescents, as it does in adults, and that the adolescent woman described here had impaired responses of PP and gut GLI as well as insulin, GI and GH, especially to changes in blood glucose levels.

The clinical usefulness of serum pancreatic secretory trypsin inhibitor (PSTI) in pancreatic diseases was evaluated. The mean serum PSTI level of 41 healthy normal persons was 9.4 ng/ml (ranging from 5.2 to 16.7 ng/ml). Serum PSTI levels were abnormally raised in all patients with acute pancreatitis ranging from 35.0 to 4500 ng/ml, but were almost within normal range in patients with chronic pancreatitis, pancreatic cyst, acute abdominal emergencies such as perforated ulcer and intestinal obstruction, and macroamylasemia. There was no correlation between serum PSTI levels and total or pancreatic-type isoamylase activity. Patients with acute pancreatitis in whom the elevation of serum PSTI was transient and occurred after that of serum amylase activity had relatively mild symptoms and recovered along with normalization of serum PSTI levels. On the other hand, patients whose serum PSTI values became increased coincidentally with serum amylase activity and remained elevated, had severe clinical symptoms and unfavorable clinical outcome. Of 2 patients who underwent partial pancreatectomy, the serum PSTI level increased markedly in one who developed postoperative pancreatitis but not in the other without pancreatitis. In contrast to patients with acute pancreatitis, the serum response to the secretin stimulation in patients with chronic pancreatitis, was only small and transient, reaching the maximum at 10 min after administration of secretin. These results suggest that measurement of serum PSTI concentration may be useful in the diagnosis of acute pancreatitis and that the degree of rise and the duration of the elevated levels of serum PSTI are closely related to the severity of acute pancreatitis.

5'-DFUR was administered orally to advanced or recurrent cancer patients at a daily dosage of 600-1200 mg divided into 3 or 4 times a day. Out of 13 evaluable cases 2PR, 2MR, 4NC and 5PD were observed, response rate was 15.4%. PR were obtained in one gastric cancer case and one breast cancer case. Side effects were observed in 6 cases out of 14 cases (42.9%) and major adverse reaction was gastro-intestinal toxicities such as anorexia, nausea-vomiting and diarrhea. Two leukocytopenia and one erythrocytopenia were observed. This study indicated that 5'-DFUR would be useful as a new anticancer agent.

(Bu)2cGMP is known to act as a specific competitive inhibitor for gastrin and cholecystokinin (CCK) peptides. We have examined the effects of (Bu)2cGMP on CCK octapeptide (CCK-8) stimulation of insulin release in the isolated perfused pancreas and compared them with those on protein output. Addition of (Bu)2cGMP after a 20-min perfusion with 100 pM CCK-8 resulted in two distinctly different phases of insulin suppression. There was a sharp initial decline in insulin release for 3 min, followed by transient recovery toward the control level for 5 min, and then a small decline until termination of (Bu)2cGMP infusion. (Bu)2cGMP produced a concentration-dependent inhibition of both phases of insulin decrement. (Bu)2cGMP also produced a concentration-dependent inhibition of protein output. Addition of 1 mM (Bu)2cGMP rapidly and completely abolished CCK-8-stimulated protein output. Since CCK is released by meal intake and exogenous CCK stimulates insulin release and augments glucose-induced insulin release, it is possible that endogenous CCK plays an important role in the enteroinsular axis. The present findings of blockade of CCK-8-induced insulin release by selective antagonist of the action of CCK provide evidence for CCK as a mediator in the enteroinsular axis.