Eosinophilic cholangitis coexisted with idiopathic thrombocytopenic purpura: Report of a case

Eosinophilic cholangitis is a rare disease of which only 31 cases have been reported. Eosinophilic infiltration causes stricture of the bile duct diffusely or locally, and the imaging of eosinophilic cholangitis resembles primary sclerosing cholangitis or cancer of the bile tract. For eosinophilic cholangitis, treatment with steroid is effective and the prognosis is good. Therefore, its accurate diagnosis is very important. Here, we describe a patient with eosinophilic cholangitis who was also diagnosed with idiopathic thrombocytopenic purpura (ITP). He was treated for ITP using prednisolone, the unexpected sudden interruption of which caused severe deterioration of eosinophilic cholangitis and acute cholecystitis. Cholecystectomy and choledochojejunostomy were performed, and the addition of treatment by prednisolone resulted in a good clinical course. This is the first report on eosinophilic cholangitis coexisting with ITP.     

Prosaposin: threshold rescue and analysis of the "neuritogenic" region in transgenic mice

Prosaposin is the precursor of four glycoprotein activators (saposins) for lysosomal hydrolases. Intact prosaposin also has lipid transfer properties in vitro as well as neuritogenic effects ex vivo and in vivo. Such "neuritogenic" effects of saposin C were evaluated in vivo using transgenic mice with prosaposin cDNAs having normal (PS-N) or mutated neuritogenic region. The mutant prosaposin cDNA (PS-CBC) encoded a chimeric saposin C that contained the non-neuritogenic sequence of saposin B, but retained acid beta-glucosidase (GCase) activation effects. When driven by the PGK (3-phosphoglycerate kinase) promoter, transgene expression was highest in the cerebrum for any of the transgenes (range from 15% to 42% of wild-type). Low levels were in visceral tissues. Prosaposin knock-out (PS-/-) mice expressing N or CBC transgenes, even at low levels, had delayed onset of neurologic signs and neuropathology, and significant lengthening of life span (from 1.7- to 7-fold) with age dependent partial correction of GlcCer and LacCer accumulation in the brain. Neuropathologic progression and neuronal glycosphingolipid storage were related directly to the transgene expression levels in the brain. Purkinje cell loss was age dependent. Gross brain and neuronal organizations were indistinguishable in PS-/- mice with or without the various transgenes, albeit the phenotype appeared later in the mice with transgenes. These studies show the degree of neuropathologic manifestations in each transgenic line depended on expression level rather than on the nature of the transgene. These studies also show in vivo localization of the GCase activation region to the carboxy terminal half of saposin C and the lack of a significant gross trophic effect of saposin C on CNS organization in vivo.     

Anterior cingulate pathology and social cognition in schizophrenia: a study of gray matter, white matter and sulcal morphometry

The anterior cingulate gyrus (ACG) is a critical structure for social cognitive processing; the pathology of this structure might be a major source of social dysfunction in schizophrenia. Multiple structural abnormalities of the ACG have been demonstrated in schizophrenia including changes in gray matter volume, white matter microstructures and macroscopic sulcal morphology. However, the interrelationships among these different abnormalities have not been investigated. Thus, the relationship between structural abnormalities in the ACG and social cognition in schizophrenia remains to be elucidated. Magnetic resonance imaging data were acquired at 3.0 T from 26 schizophrenic patients and 20 healthy participants. We performed anterior cingulate cortex (ACC) volumetry, evaluated diffusion tensor imaging of the anterior cingulum, analyzed paracingulate/cingulate sulcus (PCS/CS) morphology and investigated the interrelationships among these measures. We also investigated the association between ACG structural abnormalities and psychopathology, and the social cognition ability of schizophrenic patients as estimated by emotion attribution tasks. Compared with healthy subjects, schizophrenic patients exhibited reduced ACC volume, decreased fractional anisotropy in the anterior cingulum bilaterally and a poorly developed PCS/CS in the left hemisphere. No interrelationship was identified among these measures in the schizophrenic group. Schizophrenic patients performed poorly on emotion attribution tasks. Importantly, clinical symptoms and performance on emotion attribution subtasks were associated with ACC volumes and left PCS/CS variation in different ways. These results suggested that pathology of the ACC, anterior cingulum and PCS/CS is, at least partially, independent and has differential impacts on psychopathology and social cognitive impairment in schizophrenia.     

Serum Hyaluronate Level for Predicting Subclinical Liver Dysfunction after Hepatectomy

The serum hyaluronate (HA) level reflects sinusoidal endothelial cell function correlated with liver function. We have reviewed multiple liver function indicators from 37 patients who underwent hepatectomy for various liver diseases. The serum HA level was well correlated with the indocyanine green retention rate at 15 minutes (ICGR₁₅), lectin-cholesterol (LCAT), hepatocyte growth factor (HGF), liver uptake ratio of technetium-99m galactosyl human serum albumin (^99mTc-GSA) at 15 minutes (HH15), prealbumin, and hepatic uptake ratio of ^99mTc-GSA at 15 minutes (LHL15). In addition, the model for end-stage liver disease (MELD) score at 7 days after operation was well correlated with serum HA, ICGR₁₅, HH15, and LHL15. In patients who showed serum an HA level of = 100 ng/ml before hepatectomy, the MELD score had significantly deteriorated by 7 days after hepatectomy. Of the 20 patients who showed a serum HA level < 100 ng/ml before hepatectomy, 11 had high serum HA after hepatectomy. The bilirubin level 7 days after operation in this group was much higher than that for patients who maintained a serum HA level < 100 ng/ml after hepatectomy. In addition, the serum HGF level before hepatectomy in this group was significantly lower. We concluded that the serum HA level is a reliable indicator when evaluating liver function and predicting liver dysfunction after hepatectomy. Furthermore, patients with a significantly low HGF level who have a normal HA level are susceptible to liver dysfunction after hepatectomy.     

Receptor activator of NF-κB ligand-dependent expression of caveolin-1 in osteoclast precursors, and high dependency of osteoclastogenesis on exogenous lipoprotein

Although extensive studies have done much to clarify the molecular mechanisms of osteoclastogenesis during the last ten years, there may still be unknown molecules associated with osteoclast differentiation. Thus, we used fluorescent differential display to screen for genes whose expression is induced by receptor activator of NF-κB ligand (RANKL), a crucial molecule for osteoclast formation. We identified caveolin-1 (Cav-1) as a RANKL-induced gene. Cav-1 is a major structural protein of caveolae and lipid rafts, cholesterol-enriched microdomains in the plasma membrane (PM). The RANKL-induced Cav-1 was immediately conveyed to lipid rafts. Conversely, expression of flotillin-1 (Flot-1), another scaffolding protein of lipid rafts, was reduced during osteoclastogenesis, indicating conversion of Flot-1-predominant rafts into Cav-1-enriched rafts. However, in vitro osteoclastogenesis of precursor cells from Cav-1-null mice was comparable to that of wild-type mice, while Cav-2 expression in the knockout osteoclasts was maintained. Conversely, Cav-2 gene silencing in Cav-1-null osteoclast precursors using siRNA for Cav-2 increased osteoclast formation, suggesting that the Cav-1/Cav-2 complex may act as a negative regulator for osteoclastogenesis. On the other hand, destruction of lipid rafts by removal of cholesterol from the PM by methyl-ß-cyclodextrin (MCD) treatment caused disordered signal transductions for osteoclastogenesis, such as hyperactivation of Erk1/2 and insensitivity of Akt to RANKL stimulus. The abnormal signaling was reproduced by deleting exogenous lipoproteins from the culture medium, which also resulted in reduced osteoclast formation. In addition, the deletion caused delayed expression of nuclear factor of activated T cells c1 (NFATc1), and depressed its activation in the cytosol and inhibited its translocation into nuclei. Simultaneously, the deletion reduced the level of FcRγ, a trigger protein for initiating the calcium signaling needed to activate NFATc1, and decreased Cav-1 in lipid rafts. These findings indicate that the molecular mechanisms of osteoclastogenesis are highly dependent on extracellular lipoprotein and the integrity of lipid rafts, and suggest possible involvement of cholesterol.     

Long-term prognosis of Kawasaki disease patients with coronary artery obstruction

Summary The prognosis of coronary artery obstruction was studied in patients with Kawasaki disease. Between May 1973 and December 1987, coronary artery obstruction was diagnosed by coronary angiography in 30 patients (21 males, 9 females), of whom, only 8 (26.7%) had clinical symptoms. One patient died after 9 years of illness. Two complained of frequent chest pain, which disappeared after bypass surgery in one case and spontaneously in the other. Five had symptomatic myocardial infarction. Myocardial ischemia was diagnosed in 31.8% by treadmill stress testing, but was well demonstrated in 85.7% by thallium-201 myocardial tomography. Frequent ventricular premature beats, Wenckebachtype atrioventricular block, and ST-segment depression accompanied by chest pain were recognized by 24-h Holter monitoring. In the past, the methods used to determine the prognosis of Kawasaki disease patients with coronary artery obstruction were not adequate. However, the examinations used in this study revealed an improved ability to determine the prognosis in this disease. Myocardial tomography, in particular, provided a more accurate evaluation of myocardial damage. Ventricular arrhythmias seem to be a serious problem in these patients. Therefore, careful observation using these tests, especially myocardial tomography and Holter monitoring, should be done even if the patients are free of symptoms.     

Transient increases in anti-aquaporin-4 antibody titers following rituximab treatment in neuromyelitis optica, in association with elevated serum BAFF levels

Rituximab is increasingly used for prevention of relapses of neuromyelitis optica (NMO), a condition that is highly associated with serum anti-aquaporin-4 (AQP4) antibodies. However, B-cell depletion also induces systemic B-cell activating factor (BAFF), which may promote antibody production. We collected serial serum samples from a total of seven patients with NMO prior to, and following, treatment with rituximab. The samples were analyzed for anti-AQP4 antibody titer using a cell-based assay and serum BAFF levels were measured on available samples by standard enzyme-linked immunosorbent assay. Anti-AQP4 antibody levels decreased after 4 weeks to 12 weeks from the first injection of rituximab, but they increased transiently in several patients at 2 weeks after the first injection, in association with a parallel increase in serum BAFF levels. Although anti-AQP4 antibodies appear to decrease overall following rituximab treatment, our findings raise concern over the potential for an early BAFF-mediated worsening of patients with NMO receiving rituximab.     

Expression of a peroxisome proliferator-activated receptor gamma 1 splice variant that was identified in human lung cancers suppresses cell death induced by cisplatin and oxidative stress.

PURPOSE: The activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) has been implicated in the inhibition of tumor progression in lung cancers through the induction of differentiation and apoptosis. Recently, we identified a novel splice variant of human PPAR gamma1 (hPPAR gamma1) that exhibits dominant-negative activity in human tumor-derived cell lines. This study aimed to examine the expression and pathophysiologic roles of a truncated splice variant of hPPAR gamma1 (hPPAR gamma1(tr)) in primary human lung cancer tissues. EXPERIMENTAL DESIGN: The expression and localization of hPPAR gamma1(tr) was surveyed in human primary lung cancer tissues using immunohistochemistry and Western blot analysis. Using transfectants stably expressing wild-type hPPAR gamma1 (hPPAR gamma1(wt)) and hPPAR gamma1(tr), we also analyzed the pathophysiologic roles of hPPAR gamma1(tr). RESULTS: We showed that PPAR gamma is expressed predominantly in the nucleus of nontumorous tissues, whereas it is present in both the nucleus and the cytoplasm of tumorous tissues in squamous cell carcinoma (SCC) of the lung. Western blot analysis confirmed the presence of PPAR gamma1(tr) in primary lung SCC tissue but not in nontumorous tissue. Expression of PPAR gamma1(tr) in Chinese hamster ovary cells attenuated their susceptibility to cell death induced by oxidative stress or cisplatin, whereas their susceptibility was completely recovered by down-regulation of PPAR gamma1(tr) with small interfering RNA. CONCLUSIONS: hPPAR gamma1(tr) is expressed strongly in tumorous tissues of primary human lung SCC and its overexpression renders transfected cells more resistant to chemotherapeutic drug- and chemical-induced cell death. These data suggest that the decreased drug sensitivity of PPAR gamma1(tr)-expressing cells may be associated with increased tumor aggressiveness and poor clinical prognosis of patients.