X-ray absorption near edge structure and first-principles spectral investigations of cationic disorder in MgAl2O4 induced by swift heavy ions.

Cationic disorder in the MgAl2O4 spinel induced by swift heavy ions was investigated using the X-ray absorption near edge structure. With changes in the irradiation fluences of 200 MeV Xe ions, the Mg K-edge and Al K-edge spectra were synchronously changed. The calculated spectra based on density function theory indicate that the change in the experimental spectra was due to cationic disorder between Mg in tetrahedral sites and Al in octahedral sites. These results suggest a high inversion degree to an extent that the completely random configuration is achieved in MgAl2O4 induced by the high density electronic excitation under swift heavy ion irradiation.

Ecological niche and potential geographic distribution of the invasive fruit fly Bactrocera invadens (Diptera, Tephritidae).

Two correlative approaches to the challenge of ecological niche modeling (genetic algorithm, maximum entropy) were used to estimate the potential global distribution of the invasive fruit fly, Bactrocera invadens, based on associations between known occurrence records and a set of environmental predictor variables. The two models yielded similar estimates, largely corresponding to Equatorial climate classes with high levels of precipitation. The maximum entropy approach was somewhat more conservative in its evaluation of suitability, depending on thresholds for presence/absence that are selected, largely excluding areas with distinct dry seasons; the genetic algorithm models, in contrast, indicate that climate class as partly suitable. Predictive tests based on independent distributional data indicate that model predictions are quite robust. Field observations in Benin and Tanzania confirm relationships between seasonal occurrences of this species and humidity and temperature.

Pharmacokinetics of recombinant human soluble thrombomodulin, thrombomodulin alfa in the rat.

1. The study aimed to investigate the pharmacokinetics of thrombomodulin alpha (TM-alpha), human-soluble thrombomodulin in rats. 2. Intravenously administered TM-alpha was eliminated in two phases (T(1/2 alpha) = 0.2-0.3 h and T(1/2 beta) = 6-8 h), and the elimination curve was linear in a dose range of 10-250 microg kg(-1). Based on the results of tissue concentration studies after reaching the steady-state, the highest concentration of TM-alpha was seen in the plasma, suggesting the low levels of transfer to tissues (< or = 22% of plasma levels). 3. In vivo metabolism of TM-alpha was also analysed using high-performance liquid chromatography. The main peak observed in the plasma was TM-alpha, and even 72 h after the last dose of repeated administrations, 80% or more was unchanged form. Approximately half of the radioactivity excreted in the urine was recovered as a peak corresponding to TM-alpha. 4. The results reveal that although plasma clearance was lower in the renally impaired rats, the decrease was not large, with a difference of only about 20%. As a result, although the cause remains unclear, it is considered unlikely that the plasma concentrations of TM-alpha will vary considerably in patients with renal impairment.

Can MRCP replace ERCP for the diagnosis of autoimmune pancreatitis?

BACKGROUND: It is of utmost importance that autoimmune pancreatitis (AIP) be differentiated from pancreatic cancer. Irregular narrowing of the main pancreatic duct is a characteristic finding in AIP; it is useful for differentiating AIP from pancreatic cancer stenosis. This study evaluated the usefulness of magnetic resonance cholangiopancreatography (MRCP) for the diagnosis of AIP and assessed whether MRCP could replace endoscopic retrograde cholangiopancreatography (ERCP) for diagnosing AIP. METHODS: The MRCP and ERCP findings of 20 AIP patients were compared. RESULTS: On MRCP, the narrowed portion of the main pancreatic duct was not visualized, while the noninvolved segments of the pancreatic duct were visualized. The degree of upstream dilatation of the proximal main pancreatic duct was milder in AIP than in pancreatic cancer patients. In the skipped type, only skipped narrowed lesions were not visualized. After steroid therapy for AIP, the nonvisualized main pancreatic duct became visualized. CONCLUSIONS: MRCP cannot replace ERCP for the diagnosis of AIP, since narrowing of the main pancreatic duct in AIP was not visualized on MRCP. MRCP findings of segmental or skipped nonvisualized main pancreatic duct accompanied by a less dilated upstream main pancreatic duct may suggest the presence of AIP. MRCP is useful for following AIP patients.

The presence of a common channel and associated pancreaticobiliary diseases: a prospective ERCP study.

BACKGROUND: There are few endoscopic retrograde cholangiographic studies dealing with the relationship between the presence of a common channel and associated pancreaticobiliary diseases. AIMS: To endoscopically determine the incidence of common channels and assess whether the anatomy of the pancreaticobiliary ductal drainage into the duodenum has any bearing on pancreaticobiliary diseases. PATIENTS AND METHODS: We prospectively examined a common channel formation in 354 endoscopic retrograde cholangiographic cases. Cases with a common channel were divided into three groups: pancreaticobiliary maljunction, high confluence of pancreaticobiliary ducts with a common channel > or =6 mm in which the communication was occluded with the sphincter contraction, and common channel < or =5 mm in length. RESULTS: A common channel was observed in 131 cases (37.0%) including 11 with pancreaticobiliary maljunction and 13 with high confluence of pancreaticobiliary ducts. In cases with a common channel, the incidences of associated gallbladder carcinoma and acute pancreatitis were both 11.5%, which were significantly higher than 1.8% and 4.9% seen in cases without a common channel. In pancreaticobiliary maljunction cases, incidence of associated gallbladder carcinoma was 72.7%. CONCLUSION: The presence of an obvious common channel was observed in 37.0%. A close relationship is suggested between the presence of a common channel and development of gallbladder carcinoma and acute pancreatitis.

Evaluation of immunomodulatory effect of recombinant human granulocyte-macrophage colony-stimulating factor on polymorphonuclear cell from dogs with cancer in vitro.

The objective of this in vitro study was to evaluate the immunomodulatory effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on polymorphonuclear cell (PMN) function in dogs with cancer. PMNs were harvested from dogs with naturally developing cancer as a pre-clinical model to evaluate the immunomodulatory effects of rhGM-CSF on PMN phagocytic and cytotoxic functions, cytokine production and receptor expression. Some aspects of cancer-related PMN dysfunction in dogs with cancer were restored following incubation with rhGM-CSF including PMN phagocytosis, respiratory burst and LPS-induced TNF-α production. In addition, rhGM-CSF increased surface HLA-DR expression on the PMNs of dogs with cancer. These data suggests that dysfunction of innate immune response in dogs with cancer may be improved by rhGM-CSF. The results of this study provided a pathophysiologic rationale for the initiation of clinical trials to continue evaluating rhGM-CSF as an immunomodulatory therapy in dogs with cancer.

The mouse L-histidine decarboxylase gene: structure and transcriptional regulation by CpG methylation in the promoter region.

To investigate the regulation of mouse L-histidine decarboxylase (HDC) gene expression, we isolated genomic DNA clones encoding HDC. Structural analysis revealed that the mouse HDC gene was composed of 12 exons, spanning approximately 24 kb. Northern blotting analysis indicated that, among the cell lines examined, a high level of HDC gene expression was restricted to mature mast cell lines and an erythroblastic cell line. The gene was induced strongly in the mouse immature mast cell line P815 after incubation in the peritoneal cavity of BDF1 mice. We observed that the promoter region was demethylated in the HDC-expressing cell lines and in induced P815 cells. Interestingly, forced demethylation by 5-azacytidine (5-azaC) treatment induced high expression of HDC mRNA in P815 cells. The activity of a mouse HDC promoter-reporter construct stably transfected in P815 cells was repressed by in vitro patch-methylation. This low promoter activity of the patch-methylated reporter construct was restored after 5-azaC treatment, which demethylated the patch-methylated promoter. These results indicate that DNA methylation state of the promoter region controls HDC gene expression.

Frequent loss of heterozygosity for loci on chromosome 8p in hepatocellular carcinoma, colorectal cancer, and lung cancer.

Frequent loss of heterozygosity at chromosomal loci in a specific tumor type may indicate the presence of a tumor suppressor gene. We have examined loss of heterozygosity on chromosome 8p in paired tumor and constitutional DNA from 346 patients representing seven different types of human cancer. Frequent allelic losses were observed in hepatocellular carcinoma (22 of 46 cases, 47.8%), in colorectal cancer (12 of 26, 46.2%), and in non-small cell lung cancer (14 of 35, 40.0%), in contrast to low frequencies detected in breast cancer (5 of 56, 8.9%) and renal cell carcinoma (2 of 27, 7.4%). Ovarian cancer and gastric cancer showed intermediate frequencies of 33.3% and 22.2%. Subsequent analysis of 120 hepatocellular carcinomas and 94 colorectal cancers with five polymorphic markers along the short arm of chromosome 8 defined commonly deleted regions within the same chromosomal interval, 8p23. 1-8p21.3, suggesting that one or more tumor suppressor genes for both cancers may be present in that region.

Contactless electrical conductivity measurement of metallic submicron-grain material: Application to the study of aluminum with severe plastic deformation.

We measured the electrical conductivity σ of aluminum specimen consisting of submicron-grains by observing the AC magnetic susceptibility resulting from the eddy current. By using a commercial platform for magnetic measurement, contactless measurement of the relative electrical conductivity σn of a nonmagnetic metal is possible over a wide temperature (T) range. By referring to σ at room temperature, obtained by the four-terminal method, σn(T) was transformed into σ(T). This approach is useful for cylinder specimens, in which the estimation of the radius and/or volume is difficult. An experiment in which aluminum underwent accumulative roll bonding, which is a severe plastic deformation process, validated this method of evaluating σ as a function of the fraction of high-angle grain boundaries.

Gastrointestinal findings in patients with autoimmune pancreatitis.

BACKGROUND AND STUDY AIMS: Autoimmune pancreatitis (AIP) is a condition that has been proposed as a clinical entity only fairly recently. Its pathogenesis involves autoimmune mechanisms. Although the radiological findings in patients with AIP have been well evaluated, few studies have focused on the gastrointestinal findings in these patients. The aim of this study was to explore the endoscopic and histological findings in the gastrointestinal tract in patients with autoimmune pancreatitis. PATIENTS AND METHODS: The endoscopic findings in the stomach (n = 10), the duodenum (n = 18), the major duodenal papilla (n = 18), and the colon (n = 5) in 24 patients with AIP were reviewed. These were compared with the results of histological examination of gastric mucosa (n = 13), duodenal mucosa (n = 9), the major duodenal papilla (n = 3), and colonic mucosa (n = 3) in these patients. All these specimens were subjected to immunohistochemical study using anti-IgG4 antibody. RESULTS: Foci of slightly pale, thickened mucosa with loss of visible vascular pattern were observed in the stomach in four patients and in the colon in two patients on endoscopy. Slight or moderate swelling of the major duodenal papilla was detected in five patients. Slight to moderate lymphoplasmacytic infiltration was observed in the lamina propria of the gastric and colonic mucosa, and of the major duodenal papilla. Heavy infiltration with IgG4-positive plasma cells (>10 cells per high-power field) was observed in the lamina propria of the stomach in seven patients, of the colon in two patients, and of the major duodenal papilla in three patients; this was not observed in the control patients, who had other diseases. CONCLUSIONS: Although there were no specific endoscopic findings in the stomach or colon in patients with autoimmune pancreatitis, foci of slightly pale, thickened mucosa with loss of visible vascular pattern were observed in some cases. This indistinct change seen on endoscopy appears to be due to heavy infiltration with IgG4-positive plasma cells, associated with CD4- or CD8-positive T lymphocytes, in the lamina propria of the gastric or colonic mucosa.

Origin of the long common channel based on pancreatographic findings in pancreaticobiliary maljunction.

BACKGROUND AND AIMS: The origin of a long common channel in pancreaticobiliary maljunction was suggested to be the ventral pancreatic duct. Pathogenesis of long common channels was investigated by anatomically analysing the arrangement of pancreatic ducts in pancreaticobiliary maljunction. MATERIALS AND METHODS: Cholangiopancreatography was performed for 66 cases of pancreaticobiliary maljunction and 200 controls. The accessory pancreatic duct was classified according to course and shape. In cases with long- or short-type accessory pancreatic duct, lengths of the main pancreatic duct from orifice to first inferior branch and junction with the accessory pancreatic duct, and the common channel were measured. RESULTS: Lengths of the main pancreatic duct from orifice to first inferior branch or junction with the accessory pancreatic duct were significantly longer in cases of pancreaticobiliary maljunction cases with the long- or short-type accessory pancreatic duct than in controls (p<0.01). Lengths of the main pancreatic duct from first inferior branch to junction with the accessory pancreatic duct were roughly equivalent in pancreaticobiliary maljunction and controls. CONCLUSIONS: Long common channels in pancreaticobiliary maljunction might be formed embryologically with adhesion of the right ventral pancreatic duct and the terminal portion of the bile duct.

Concentrations of vascular endothelial growth factor in the sera of normal controls and cancer patients.

Vascular endothelial growth factor (VEGF) is known to play crucial roles in tumor angiogenesis. We have investigated the circulating level of VEGF in sera from cancer patients as well as from healthy normal controls using a sensitive enzymatic immunoassay. Immunoreactive VEGF proteins were detectable in normal sera, and the cutoff level was determined to be 180 pg/ml. In examined patients with all types of cancer, including breast, gastrointestinal, hepatobiliary, and lung cancer, an aberrant increase in the circulating level of VEGF was detected. For example, in 137 primary breast cancer patients, 12 (8.8%) showed an aberrant increase in VEGF levels. This aberrant expression of VEGF in sera was significantly associated with the progression of the disease, and with VEGF protein expression in tumor tissues. In addition, a Western blot analysis confirmed the presence of the VEGF165 form in sera from a patient with recurrent breast cancer. It was concluded that VEGF was detectable in normal sera, and its level was increased in some populations of cancer patients. A positive angiogenesis regulator, VEGF might function as an endocrine growth factor, particularly for solid tumors.

Coordinated action of calcium ion and adenosine 3',5'-monophosphate upon the release of alpha-melanocyte-stimulating hormone from the intermediate lobe of the rat pituitary gland.

Stimulation of the release of alpha MSH from dispersed rat melanotrophs by L-isoproterenol, 8-bromo-cAMP, or cholera toxin requires calcium ion (Ca++) in the incubation medium; the stimulatory effect of each of these agents is attenuated by D-600, a Ca++ antagonist. In contrast, stimulation of the formation of cAMP by L-isoproterenol, isobutyl methylxanthine, or cholera toxin does not require Ca++ in the incubation medium. Ca++ diminishes the amount of cAMP formed by cholera toxin-treated melanotrophs. Ca++ inhibits adenylate cyclase activity and enhances cyclic nucleotide phosphodiesterase activity in cell-free homogenates of intermediate lobe tissue. A23187, a calcium ionophore, increases the accumulation of 45Ca by melanotrophs and enhances the release of alpha MSH. Furthermore, when tested upon cholera toxin-treated melanotrophs, A23187 potentiates the Ca++-induced inhibition of cAMP formation. The results indicate that Ca++ is essential for the release of alpha MSH, and that cAMP in some way enhances the effects of Ca++ upon the release process.

The dopamine receptor in the intermediate lobe of the rat pituitary gland: pharmacological characterization.

The dopamine receptor in the intermediate lobe (IL) of the hypophysis of the rat is characterized on the basis of the ability of dopamine and other dopaminergic agonists to decrease the consequences of activation of the beta-adrenoceptor. Stimulation of the dopamine receptor diminishes the L-isoproterenol-induced accumulation of cAMP and the catecholamine-stimulated enhancement of adenylate cyclase activity. The dopamine receptor in the IL can be assigned to the category of dopamine receptor designated D-2 on the basis of the following criteria: 1) occupancy of the dopamine receptor does not result in enhancement of adenylate cyclase activity or an accumulation of cAMP, 2) the dopaminergic ergots and apomorphine mimic the inhibitory effect of dopamine upon cAMP formation or alpha MSH release, and 3) metoclopramide and sulpiride, substituted benzamides, block the inhibitory effect of dopamine. The sympathetic neurotransmitter, norepinephrine, interacts with the dopamine receptor and the beta-adrenoceptor in the IL.

D-2 dopamine receptor-mediated inhibition of adenylate cyclase activity in the intermediate lobe of the rat pituitary gland requires guanosine 5'-triphosphate.

After treatment with cholera toxin, homogenates of intact intermediate lobe (IL) tissue of rat pituitary gland synthesized more cAMP than did homogenates of untreated IL tissue, and only in the presence of GTP did dopamine or apomorphine diminish the elevated adenylate cyclase activity in homogenates of cholera toxin-treated IL tissue. Furthermore, when tested on cholera toxin-treated IL tissue, 5'-guanylyl imidodiphosphate [Gpp(NH)p] and two other nonhydrolyzable analogs of GTP inhibited adenylate cyclase activity in the absence of either a dopaminergic agonist or GTP; GTP reversed the Gpp(NH)p-induced inhibition of adenylate cyclase activity. Apomorphine, a dopaminergic agonist, abolished the ability of GTP to reverse the inhibition by Gpp(NH)p; this effect of apomorphine was prevented by fluphenazine, a dopaminergic antagonist. Sodium fluoride inhibited adenylate cyclase activity to approximately the same level obtained with GTP and apomorphine. In addition, apomorphine decreased cAMP accumulation and alpha MSH release from dispersed IL cells pretreated with cholera toxin.

Mice lacking histidine decarboxylase exhibit abnormal mast cells.

Histidine decarboxylase (HDC) synthesizes histamine from histidine in mammals. To evaluate the role of histamine, we generated HDC-deficient mice using a gene targeting method. The mice showed a histamine deficiency and lacked histamine-synthesizing activity from histidine. These HDC-deficient mice are viable and fertile but exhibit a decrease in the numbers of mast cells while the remaining mast cells show an altered morphology and reduced granular content. The amounts of mast cell granular proteases were tremendously reduced. The HDC-deficient mice provide a unique and promising model for studying the role of histamine in a broad range of normal and disease processes.

A new family with Joseph disease in Japan. Homovanillic acid, magnetic resonance, and sleep apnea studies.

Four male patients and one female patient of a new family with Joseph disease are reported. Their disease was characterized by autosomal dominant inheritance, bulging eyes, rigidity and spasticity of the lower extremities, dystonia, and bradykinesia. Cerebrospinal fluid homovanillic acid level was markedly reduced. Levodopa improved dystonia. Magnetic resonance imaging revealed mild atrophy of the frontal lobe and the cerebellum and marked atrophy of the lenticular nucleus and the brain stem. Polysomnographic studies revealed non-rapid eye movement stage central type sleep apnea syndrome. This is the first report using magnetic resonance imaging and sleep apnea studies of Joseph disease.

Phase I study of a novel recombinant human soluble thrombomodulin, ART-123.

BACKGROUND: Anticoagulants are often given for extended periods of time to patients at high risk for venous thromboembolism, such as after orthopedic surgery. Daily subcutaneous (sc) injections can be inconvenient to the patient. A long-acting anticoagulant requiring less frequent dosing could make treatment more acceptable. Thrombomodulin is a natural anticoagulant that activates protein C, which leads to inactivation of factor (F)Va and FVIIIa and decreased thrombin formation. Recombinant human thrombomodulin is a novel anticoagulant with a long half-life in animal models. METHODS AND RESULTS: This phase I study examined pharmacokinetics, pharmacodynamics, and safety of recombinant human soluble thrombomodulin (ART-123) after administration of doses between 0.02 and 0.06 mg kg(-1) body weight intravenously (iv), and between 0.02 and 0.45 mg kg(-1) sc in 55 healthy volunteers. The plasma half-life was 2-3 days after sc injection of various single doses. Plasma ART-123 levels estimated to be needed for prevention of thrombus formation in humans were maintained for at least 6 days after single sc injection of 0.30 and 0.45 mg kg(-1) ART-123. Antithrombotic activity with these doses was demonstrated by achieving prothrombinase inhibition of more than 80% for more than 6 days after administration. No major bleeding occurred. Pharmacodynamic modeling revealed that adequate antithrombotic ART-123 levels can be achieved for 6 days with one dose of 0.45 mg kg(-1) ART-123, and for 12 days with 2 doses of 0.30 mg kg(-1), given 5 days apart. CONCLUSIONS: Recombinant human soluble thrombomodulin (ART-123) has a long half-life after sc injection and is well tolerated, making it a suitable agent to be tested in clinical thromboprophylaxis trials.

Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas.

Pancreatic involvement in primary sclerosing cholangitis (PSC) is an extremely rare condition, and its pathologic features are poorly documented. We report two cases of an unusual lymphoplasmacytic sclerosing inflammatory disease involving the total pancreas, common bile duct, gallbladder, and, in one patient, the lip. Two elderly men presented with waxing and waning obstructive jaundice, and exhibited radiologic and ultrasonographic findings highly suggestive of pancreatic carcinoma. Gross appearance of the pancreas showed firm and mass-like enlargement with regional lymph node swelling. Histologic findings were characterized by diffuse lymphoplasmacytic infiltration with marked interstitial fibrosis and acinar atrophy, obliterated phlebitis of the pancreatic veins, and involvement of the portal vein. Similar inflammatory processes involved the bile duct and the gallbladder. Lymphoplasmacytic sclerosing pancreatitis with cholangitis is thought to be a more appropriate term for this condition, of which a similar lesion has been previously noted in a single case of "PSC involving pancreas". Differences in age, radiologic appearance, and the negative history of ulcerative colitis exist, but the two cases in this study could be considered as a variant of PSC extensively involving pancreas, which can readily be mistaken for pancreatic carcinoma.

Regression of an unresectable pancreatic tumor following nonmyeloablative allogeneic peripheral-blood stem-cell transplantation.

A 59-year-old female with an unresectable, large pancreatic tumor (10.0 x 8.0 cm(2) on CT scan) underwent nonmyeloablative allogeneic peripheral-blood stem-cell transplantation from her HLA-identical sibling. Pronounced tumor regression and relief from pain without acute graft-versus-host disease (GVHD) were observed following transplantation. The patient is surviving (more than 300 days) after transplantation, with extensive chronic GVHD, and has tumor regression with an 80% reduction in tumor size. The observed clinical course may suggest a graft-versus-tumor effect on the pancreatic tumor following allogeneic stem-cell transplantation.