Clinical challenge for gastroenterologists–Gastrointestinal manifestations of systemic mastocytosis: A comprehensive review

Mastocytosis is a rare and heterogeneous disease characterized by various clinical and biological features that affect different prognoses and treatments. The disease is usually divided into 2 principal categories: cutaneous and systemic disease (SM). Clinical features can be related to mast cell (MC) mediator release or pathological MC infiltration. SM is a disease often hard to identify, and the diagnosis is based on clinical, biological, histological, and molecular criteria with different specialists involved in the patient’s clinical work-up. Among all manifestations of the disease, gastrointestinal (GI) symptoms are common, being present in 14%-85% of patients, and can significantly impair the quality of life. Here we review the data regarding GI involvement in SM, in terms of clinical presentations, histological and endoscopic features, the pathogenesis of GI symptoms, and their treatment.     

Clinical implications of local impedance measurement using the IntellaNav MiFi OI ablation catheter: an ex vivo study

Journal of Interventional Cardiac Electrophysiology - Clinical implication of local impedance (LI) for radiofrequency (RF) ablation has not been fully established. This study aimed to investigate...     

Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin

Since a variety of cell intrinsic and extrinsic molecular abnormalities cooperatively promote tumor formation in multiple myeloma (MM), therapeutic approaches that concomitantly target more than one molecule are increasingly attractive. We herein demonstrate the anti-myeloma effect of a cephalotaxus alkaloid, homoharringtonine (HHT), an inhibitor of protein synthesis, through the induction of apoptosis. HHT significantly reduced Mcl-1, a crucial protein involved in myeloma cell survival, in all three myeloma cell lines examined, whereas certain BH3-only proteins, such as Bim, Bik, and Puma, remained unchanged following HHT treatment, and their expression levels depended on the cell type. HHT also reduced the levels of c-FLIP(L/S), activated caspase-8, and induced active truncated-Bid. Thus, HHT-induced apoptosis appears to be mediated via both intrinsic and extrinsic apoptosis pathways, and the resultant imbalance between BH3-only proteins and Mcl-1 may be pivotal for apoptosis by HHT. In addition, HHT treatment resulted in reduced levels of beta-catenin and XIAP proteins, which also contribute to disease progression and resistance to chemotherapy in MM. In combination, HHT enhanced the effects of melphalan, bortezomib, and ABT-737. These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules.     

Fibrolamellar hepatocellular carcinoma: report of a case

We report a case of fibrolamellar hepatocellular carcinoma, which occurred in a 58-year-old man with normal liver function. Preoperative ultrasonography, computed tomography and magnetic resonance imaging depicted a large tumor in the left lateral segment, which was compatible with the typical radiological features of fibrolamellar hepatocellular carcinoma. He underwent left lobectomy and no lymphadenopathy or distant metastasis was demonstrated. Macroscopic findings of the resected liver demonstrated a well-defined whitish-yellow tumor with a central scar. Microscopic findings of the tumor showed cords of tumor cells, which were surrounded by abundant collagenous fibrous tissue arranged in a lamellar distribution. He has been doing well for approximately one year since the surgery without any signs of recurrence. In addition, we discuss the clinicopathological features of fibrolamellar hepatocellular carcinoma based on a review of 22 Japanese patients who have been previously reported.     

Kir6.2 is required for adaptation to stress

Reaction to stress requires feedback adaptation of cellular functions to secure a response without distress, but the molecular order of this process is only partially understood. Here, we report a previously unrecognized regulatory element in the general adaptation syndrome. Kir6.2, the ion-conducting subunit of the metabolically responsive ATP-sensitive potassium (K(ATP)) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted K(ATP) channel-dependent adjustment of membrane excitability and calcium handling, compromising the enhancement of cardiac performance driven by sympathetic stimulation, a key mediator of the adaptation response. In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade. Thus, this vital function identifies a physiological role for K(ATP) channels in the heart.     

Expression cloning of a human dual-specificity phosphatase.

Using an expression cloning strategy, we isolated a cDNA encoding a human protein-tyrosine-phosphatase. Bacteria expressing the kinase domain of the keratinocyte growth factor receptor (bek/fibroblast growth factor receptor 2) were infected with a fibroblast cDNA library in a phagemid prokaryotic expression vector and screened with a monoclonal anti-phosphotyrosine antibody. Among several clones showing decreased anti-phosphotyrosine recognition, one displayed phosphatase activity toward the kinase in vitro. The 4.1-kilobase cDNA encoded a deduced protein of 185 amino acids with limited sequence similarity to the vaccinia virus phosphatase VH1. The purified recombinant protein dephosphorylated several activated growth factor receptors, as well as serine-phosphorylated casein, in vitro. Both serine and tyrosine phosphatase activities were completely abolished by mutagenesis of a single cysteine residue conserved in VH1 and the VH1-related (VHR) human protein. These properties suggest that VHR is capable of regulating intracellular events mediated by both tyrosine and serine phosphorylation.     

Pathological characteristics of the thyroid gland in patients with triiodothyronine-predominant Graves' disease

Pathology of the thyroid gland tissue was characterized in patients with Triiodothyronine (T3)-predominant Graves' disease who had normal levels of serum T4 but increased levels of serum T3 during antithyroid drug therapy. In order to compare this group of patients with an usual type of Graves' patients, age, sex, dietary intake of iodide, duration of antithyroid therapy and the dose of thionamide drugs were matched between the two groups of patients. Thyroid tissue was obtained from subtotal thyroidectomy. In examining the histology of the thyroid gland, integration eye piece plate II with regularly arranged 100 lattice points was set on eye lens of a microscope. The number of crossing points which were projected on each 4 histological elements was counted in randomly selected 10 fields of vision in each patient's thyroid. Assuming that the every histological element is arranged in a random manner, errors of each visual field by this method would be less than 12%. In consequence, the significant difference was demonstrated in the weight of subtotally resected thyroid and the ratio of each histological element except interstitial tissue occupied in the total thyroid tissue between T3-predominant Graves' disease and control Graves' disease. The volume composition of the epithelial cells and vacuoles in patients with T3-predominant Graves' disease was significantly greater than that of patients with control Graves' disease (24.7 +/- 10.6 vs 14.4 +/- 6.5%, 5.9 +/- 3.9 vs 2.0 +/- 1.0%, Mean +/- SD, respectively, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Detection of c-Ki- ras point mutation from pancreatic juice

Summary Cytological diagnosis of pancreatic carcinoma sometimes poses difficulties in distinguishing malignant from benign cells. Recent molecular study of pancreatic carcinoma has revealed a very high incidence of a point mutation of the c-Ki-ras oncogene at codon 12 in this neoplasm. To take advantage of this technique for the diagnosis of pancreatic carcinoma, we attempted to amplify the c-Ki-ras gene from endoscopically obtained pancreatic juice by isolation of DNA and polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). PCR was possible in approx 70% of the cases. A point mutation was nonradioisotopically detected in 4 of 6 pancreatic carcinomas and in one intraductal papillary neoplasm, whereas no mutation was detected in other cases. Thus, this method was thought to be useful for the diagnosis of pancreatic carcinoma.