START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells

The intracellular trafficking of cholesterol in steroidogenic cells plays an important role in the regulation of hormone synthesis. Recent evidence indicates that a family of proteins related to the steroidogenic acute regulatory protein (StAR) perform critical functions in moving the sterol substrate to the mitochondrial inner membrane where the first committed step in steroid hormone synthesis occurs. StAR, the prototype of the family, is known to promote the translocation of cholesterol from the outer to the inner mitochondrial membrane. Mutations in StAR cause congenital lipoid adrenal hyperplasia, a cholesterol storage disorder in which synthesis of all gonadal and adrenocortical steroid hormones is severely impaired, and the cholesterol that is not efficiently moved into the mitochondria accumulates in cytoplasmic lipid droplets. The StAR-related lipid transfer (START) domain consists of an approximately 210 amino acid residue sequence that forms a compact alpha/beta structure, a helix-grip fold, with a hydrophobic tunnel that can accommodate a sterol molecule. START domains can bind sterol, facilitate the transfer of cholesterol from sterol-rich unilammelar liposomes to acceptor membranes, and stimulate steroidogenesis when expressed in cells co-expressing the cholesterol side-chain cleavage system or when added to isolated steroidogenic mitochondria. Sixteen human START domain proteins have been identified to date. Of these, StAR and MLN64 consist of one subfamily and newly described proteins named StarD4, StarD5, and StarD6 represent a closely related second subfamily. MLN64 is incorporated into the late endosomal compartment and is involved in the movement of cholesterol acquired from endocytosed LDL out of these vesicles. Expression of a dominant negative form of MLN64 causes accumulation of free cholesterol in lysosomes. The roles of StarD4, StarD5, and StarD6 in sterol movement remain to be determined. These genes have tissue-specific patterns of expression that may predict specialized roles.     

A case of early asymptomatic carcinoma of the hepatic hilus.

We describe a 54-year-old asymptomatic male with carcinoma of the hepatic hilus. Elevated serum transaminases were detected during the annual medical examination. The diagnosis was confirmed by ultrasonography (US), computed tomography (CT), percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP). Curative surgery, which included right hepatic lobectomy with total caudate lobectomy, was performed. The resected specimen revealed a localized tumor in the right anterosuperior dorsal intrahepatic bile duct branch. The histological diagnosis was moderately differentiated tubular adenocarcinoma. The patient's postoperative recovery was smooth and he has remained in good health for 15 months after surgery without any signs of recurrence. This case report discusses the early diagnosis and rational surgical treatment for carcinoma of the hepatic hilus.     

Flowcharts for the management of biliary tract and ampullary carcinomas

No strategies for the diagnosis and treatment of biliary tract carcinoma have been clearly described. We developed flowcharts for the diagnosis and treatment of biliary tract carcinoma on the basis of the best clinical evidence. Risk factors for bile duct carcinoma are a dilated type of pancreaticobiliary maljunction (PBM) and primary sclerosing cholangitis. A nondilated type of PBM is a risk factor for gallbladder carcinoma. Symptoms that may indicate biliary tract carcinoma are jaundice and pain in the upper right area of the abdomen. The first step of diagnosis is to carry out blood biochemistry tests and ultrasonography (US) of the abdomen. The second step of diagnosis is to find the local extension of the carcinoma by means of computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), percutaneous transhepatic cholangiography (PTC), and endoscopic retrograde cholangiopancreatography (ERCP). Because resection is the only way to completely cure biliary tract carcinoma, the indications for resection are determined first. In patients with resectable disease, the indications for biliary drainage or portal vein embolization (PVE) are checked. In those with nonresectable disease, biliary stenting, chemotherapy, radiotherapy, and/or best supportive care is selected.     

Functional heterogeneity of colony-stimulating factor-induced human monocyte-derived macrophages

Objectives:   Macrophages (Mφs) have various functions and play a critical role in host defense and the maintenance of homeostasis. Mφs exist in every tissue in the body, but Mφs from different tissues exhibit a wide range of phenotypes with regard to their morphology, cell surface antigen expression and function, and are called by different names. However, the precise mechanism of the generation of macrophage heterogeneity is not known. In the present study, the authors examined the functional heterogeneity of Mφs generated from human monocytes under the influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage-CSF (M-CSF).
Methodology:   CD14 positive human monocytes (Mos) were incubated with M-CSF and GM-CSF for 6–7 days to stimulate the generation of M-CSF-induced monocyte-derived Mφs (M-Mφs) and GM-CSF-induced monocyte-derived Mφs (GM-Mφs), respectively. The expression of cell surface antigens and several functions such as antigen presenting cell activity, susceptibility to oxidant stress, and the susceptibility to HIV-1 and mycobacterium tuberculosis infection were examined.
Results:   GM-Mφs and M-Mφs are distinct in their morphology, cell surface antigen expression, and functions examined. The phenotype of GM-Mφs closely resembles that of human Alveolar-Mφs (A-Mφs), indicating that CSF-induced human monocyte-derived Mφs are useful to clarify the molecular mechanism of heterogeneity of human Mφs, and GM-Mφs will become a model of human A-Mφs.     

Invasive carcinoma derived from intraductal papillary mucinous carcinoma of the pancreas

BACKGROUND/AIMS: Most patients with intraductal papillary mucinous tumors of the pancreas have a favorable prognosis after surgical treatment. However, recurrent disease frequently occurs in patients with invasive carcinoma derived from intraductal papillary mucinous carcinoma. The objective of this study was to clarify the clinicopathological features of invasive carcinoma derived from intraductal papillary mucinous carcinoma. METHODOLOGY: We performed a retrospective review of the 29 patients with intraductal papillary mucinous tumor including 10 patients with invasive carcinoma who underwent pancreatic resection between June 1995 and December 2001 at the National Cancer Center Hospital East. RESULTS: Of 10 patients with invasive carcinoma derived from intraductal papillary mucinous carcinoma, 7 patients had lymph node involvement and 8 patients had retroperitoneal invasion. The overall 1-, 2-, 4-year actuarial survival rate for invasive carcinoma derived from intraductal papillary mucinous carcinoma was 39%, 26%, 13%. Recurrence occurred as liver metastasis in 3 patients, carcinomatous peritonitis in 3, local recurrence in 3, and lung metastasis in 1. All patients with adenoma, non-invasive carcinoma, and minimally invasive carcinoma are alive without recurrent disease after pancreatic resection. CONCLUSIONS: Patients with invasive carcinoma derived from intraductal papillary mucinous carcinoma had a worse prognosis. Margin-negative pancreatic resection is essential for treating this disease.     

A prospective, single-blind trial comparing wireless capsule endoscopy and double-balloon enteroscopy in patients with obscure gastrointestinal bleeding

BACKGROUND: Wireless capsule endoscopy (CE) and double-balloon enteroscopy (DBE) are new methods enabling diagnostic endoscopy of the entire small intestine. However, which of the two is superior is unclear. We therefore prospectively compared the clinical efficacy of CE and DBE. METHODS: We prospectively examined 32 patients with obscure gastrointestinal bleeding. CE preceded DBE by 1-7 days, and all patients underwent DBE twice, by antegrade and retrograde approaches, to evaluate the entire small intestine. Physicians evaluating the results of CE and DBE were blind to the results of the other method. We evaluated diagnosis, diagnostic yield of the two methods, and clinical outcomes. RESULTS: CE revealed abnormal findings in 29 (90.6%) of 32 patients. CE definitively or probably detected the sources of bleeding in 23 (71.9%) of the 32 patients, including angioectasias (eight), erosions (seven), ulcers (five), tumor (one), and hemorrhagic polyps (two). DBE definitely or probably detected the sources of bleeding in 21 (65.6%) of the 32 patients, including angioectasias (seven), erosions (four), ulcers (five), tumor (one), hemorrhagic polyps (two) and diverticula (two). CE yielded more abnormal findings than DBE (CE 90.6%, DBE 65.6%) (P = 0.032), although there were no significant differences in diagnostic yield between the methods. We were able to perform additional treatment or biopsy with DBE in 13 patients, including coagulation therapy (ten), endoscopic mucosal resection (one), biopsy (seven), and extraction of retained CE (two). CONCLUSIONS: Our results demonstrate the superiority of CE in detecting abnormal lesions, and the superiority of DBE in endoscopic management.     

Thyroid hormone regulation of rat pituitary tumor cell growth: a new role for apotransferrin as an autocrine thyromedin.

In the 40 years of transferrin research, no previous role for apotransferrin has been recognized other than to serve as a plasma carrier for dietary and storage iron. Our studies have revealed a new 'autocrine' growth role for this molecule as well as a possible new cell-cell bridge/CAM function. Certainly, these observations have opened many new areas of investigation both with regard to thyroid hormone action and the function of apotransferrin. In addition, there is now accessible the broader question of tissues other than pituitary which might utilize apotransferrin to regulate responsiveness to thyroid hormones.     

Reversible respiratory failure due to rhabdomyolysis associated with cytomegalovirus infection

A 58-year-old woman presented with muscle weakness, whole body myalgia, and dyspnea. On admission, neurological examination showed proximal muscle weakness in the extremities. The weakness gradually extended to the bulbar and respiratory muscles, necessitating an artificial ventilator. Serum CK level was markedly increased (33,774 IU/L; normal <150 IU/L) and myoglobinuria was noted in urinalysis. There was no sign of renal failure. Nerve conduction study was normal, but needle EMG showed myopathic changes in the weak muscles. Serological studies for virus titers showed more than a four-fold increase of cytomegalovirus (CMV) antibody titer during the disease course. The IgM anti-GM2 antibody was also elevated in the acute phase and decreased in the recovery phase. The muscle weakness and respiratory failure gradually improved after intravenous methylprednisolone administration, and the serum CK level was normalized in several days. CMV infection was thought to have played a central role in the rhabdomyolysis, leading to critical but reversible respiratory muscle paralysis.