Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3

The pathogenesis of hepatitis C virus (HCV)-associated insulin resistance remains unclear. Therefore, we investigated mechanisms for HCV-associated insulin resistance. Homeostasis model assessment for insulin resistance was increased in patients with HCV infection. An increase in fasting insulin levels was associated with the presence of serum HCV core, the severity of hepatic fibrosis and a decrease in expression of insulin receptor substrate (IRS) 1 and IRS2, central molecules of the insulin-signaling cascade, in patients with HCV infection. Down-regulation of IRS1 and IRS2 was also seen in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells. Carbobenzoxy-l-leucyl-l-leucyl-l-leucinal, a potent proteosomal proteolysis inhibitor, blocked down-regulation of IRS1 and IRS2 in HCV core-transfected hepatoma cells. In human hepatoma cells, HCV core up-regulated suppressor of cytokine signaling (SOCS) 3 and caused ubiquitination of IRS1 and IRS2. HCV core-induced down-regulation of IRS1 and IRS2 was not seen in SOCS3(-/-) mouse embryonic fibroblast cells. Furthermore, HCV core suppressed insulin-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase and Akt, activation of 6-phosphofructo-2-kinase, and glucose uptake. In conclusion, HCV infection changes a subset of hepatic molecules regulating glucose metabolism. A possible mechanism is that HCV core-induced SOCS3 promotes proteosomal degradation of IRS1 and IRS2 through ubiquitination.     

Defects in regulation of apoptosis in caspase-2-deficient mice

During embryonic development, a large number of cells die naturally to shape the new organism. Members of the caspase family of proteases are essential intracellular death effectors. Herein, we generated caspase-2-deficient mice to evaluate the requirement for this enzyme in various paradigms of apoptosis. Excess numbers of germ cells were endowed in ovaries of mutant mice and the oocytes were found to be resistant to cell death following exposure to chemotherapeutic drugs. Apoptosis mediated by granzyme B and perforin was defective in caspase-2-deficient B lymphoblasts. In contrast, cell death of motor neurons during development was accelerated in caspase-2-deficient mice. In addition, caspase-2-deficient sympathetic neurons underwent apoptosis more effectively than wild-type neurons when deprived of NGF. Thus, caspase-2 acts both as a positive and negative cell death effector, depending upon cell lineage and stage of development.     

Evaluation of time-resolved fluorometric immunoassay of CA 50

Serum CA 50 was determined by a time resolved fluorometric immunoassay (TR-FIA) with CANAG CA-50 DELFIA kit. Evaluation of the assay system gave satisfactory results in its sensitivity, accuracy, reproducibility, dynamic range and easy handling. No prozone phenomenon was observed up to 347,000 U/ml. From a histogram of 134 normal sera, the cut off point was determined at 34 U/ml. CA 50 in 202 patients' sera was determined with this assay. Nineteen of 20 patients pancreatic cancer, 6 of 21 gastric cancer, 14 of 25 hepatoma gave positive values. In comparison with CA 19-9, higher values and higher rates of positive CA 50 were observed in benign and malignant liver diseases, suggesting its non-cancerous origin in the liver. A high correlation was observed between the level of CA 50 and CA 19-9 of 157 patients' sera. Serum CA 50 was completely correlated with CA 19-9 in the clinical course of patients with pancreatic cancer, but not in patients with hepatoma. Thus we conclude that the CANAG CA-50 DELFIA System is useful for the diagnosis and monitoring cancer patients but must be used with care because of its elevation in benign liver diseases.     

FLUORESCENCE AND ELECTRON MICROSCOPIC STUDIES ON THE PERIVASCULAR MESENCHYMAL CELLS AND FIBROBLASTS AFTER VITAMIN A ADMINISTRATION

Findings of perivascular mesenchymal cells and fibroblasts in mice receiving large doses of vitamin A were described. Liver, lung, intestine and skin were investigated by fluorescence and electron microscopy. Marked increase of fluorescence of vitamin A was observed in the sinusoidal wall of the liver, in the alveolar septa of the lungs, in the propria mucosa, submucosa and muscular layer of the intestine and in the dermis of the abdominal skin. Increased fluorescence of these organs corresponded, ultrastructually, to the appearance of numerous fat droplets in Ito cells of the liver, septal cells of the lung and fibroblasts of the intestine and of the skin. All of these cells showed the same morphological features and the same distribution in the tissue, namely in the interstitial connective tissue space. These findings indicate that vitamin A storing cells are distributed widely in the connective tissue of various organs and that perivascular vitamin A storing mesenchymal cells and interstitial fibroblasts are probably of common fibroblastic cell line.     

TWO CASES OF ACQUIRED TOXOPLASMIC LYMPHADENITIS. Light and Electron Microscopic and Immunohistochemical Studies

We report two cases of acquired toxoplasmic lymphadenitis, one with toxoplasmic cysts and the organisms of Toxoplasma gondii and the other with the organisms only. These cysts and organisms were observed in paraffin-embedded sections, touch smears and ultrathin sections for electron microscopy. Touch smears were especially valuable for the quick and accurate diagnosis of toxoplasmic lymphadenitis. We also studied immature sinus histiocytosis (ISH) in these cases. The predominant cells of ISH were confirmed to be B lymphocytes immunohistochemically, the majority being positive for polyclonal surface IgM. ISH was observed in the perifollicular and paracortical areas surrounding post-capillary venules (PCV), whereas the sinuses were only partially involved.     

Immunohistochemical studies of endocrine cells in heterotopic pancreas

Summary Twenty-one specimens of heterotopic pancreas were investigated using the indirect immunoperoxidase method for insulin, somatostatin, glucagon, pancreatic polypeptide (PP) and gastrin. Ten specimens showed ducts, acini and islets, seven showed ducts and acini, and four showed a ductal component alone. Pyloric gland-like mucous glands were occasionally identified in association with the ductal component. In eight of ten lesions containing islets, the islets were round and had a clearly defined outline with many glucagon cells and either none or a modest number of PP cells (dorsal type). In the remaining two lesions, the islets showed varying sizes and irregular outline with many PP cells and a few or no glucagon cells (ventral type). In either type of islets, insulin and somatostatin were detected, but gastrin cells were absent. Some isolated endocrine cells were also present among the acinar and ductal components. Their occurrence in ducts was more frequent in lesions or areas mainly composed of the ductal compoment than in those with less prominent ductal tissue. In eight lesions a few gastrin cells were found in the ductal component which showed goblet cell metaplasia and pyloric gland metaplasia. An intimate relationship between goblet cell metaplasia and appearance of G cells is noteworthy.     

Bovine serum albumin (BSA) nephritis in rats II. Histological findings and complement activation by immune complex in SHR rats.

We introduced a mesangiopathic form of glomerulonephritis in spontaneously hypertensive (SHR) rats. Bovine serum albumin (BSA) was given i.v. to primed rats for 3 weeks and they were unilaterally nephrectomized (Nx). Then, they received rabbit anti-BSA- (Group A) or normal serum (Group B) for seven days, and half the rats were killed to obtain another kidney (Ex-1). The remainder were killed two weeks later and their kidneys were examined (Ex-2). In Nx kidneys, the glomerular lesions were characterized by leucocyte accumulation in the capillary lumina and by deposition of rat IgG, rat C3 and BSA both in the mesangial area and along the capillary walls. Glomeruli of Ex-1 kidneys manifested varying degrees of hypercellularity in the mesangium; a few leucocyte accumulations in the capillary lumina were noted and the immune deposits had decreased in the mesangium but not on the capillary walls. In Ex-2 kidneys, mesangial hypercellularity was conspicuous. There were no remarkable histological differences between Group A and B rats; in Ex-1 and Ex-2 kidneys of Group A, rabbit IgG was closely associated with rat IgG or C3. Serological evaluation revealed that the amount of circulating rat anti-BSA antibody was relatively small and that C3 was consumed by newly formed circulating immune complexes during BSA administration. Polymorphonuclear leucocyte (PMN) binding assay revealed that complement fixation to the immune deposits occurred in vitro and that this activity was highest in tissue from Nx kidneys.     

Protection of mice against virulent virus infection by a temperature-sensitive mutant derived from an HVJ (Sendai virus) carrier culture

Summary Experimental infection with HVJ (haemagglutinating virus of Japan—the Sendai strain of parainfluenza 1 virus) in mice was studied. Aerosol infection of newborn mice with the wild-type virus (HVJ-W) retarded the development of body weight and killed the animals within a few weeks. Large amounts of virus were isolated from both the lungs and the nasal turbinates of infected mice. In contrast, newborn mice exposed by inhalation to a temperature-sensitive(ts) mutant (HVJ-pB) derived from an HVJ carrier culture showed no clinical signs and grew equally well as mock-infected animals. No infectious virus could be recovered from the lungs although thets mutant grew to moderate titre in the nasal turbinates.The prior inoculation of newborn mice with thets mutant virus induced a state of significant resistance to subsequent challenge with the virulent wild-type virus.No replication of challenge virus in both lungs and nasal turbinates could be detected and the animals were protected a lethal infection. It is suggested that an avirulent temperature-sensitive mutant which has lost the capacity to replicate in the lower respiratory tract but is still capable of multiplying in the nasal turbinates may be a promising candidate for use in live vaccines especially against the infectious disease of the lower respiratory tract.With 2 Figures     

A case of mixed connective tissue disease developed into overlap syndrome of progressive systemic sclerosis, systemic lupus erythematosus, polymyositis and Sj?gren's syndrome

We encountered a patient who developed an overlap syndrome of progressive systemic sclerosis (PSS), systemic lupus erythematosus (SLE), polymyositis (PM) and Sj?gren's syndrome (SjS) while we were treating her for mixed connective tissue disease (MCTD). This 42-year-old woman had been photosensitive since 18 years of age. In 1986, Raynaud's phenomenon, swollen hands and arthralgia appeared; therefore, we started to treat this patient based on a diagnosis of MCTD. At that time, her anti-RNP antibody titer was 82,920, but she was negative to anti-Sm antibody. In 1988, she was admitted to our hospital with chief complaints of aggravation of polyarthralgia and myalgia. On physical examination, she showed difficulty in opening her mouth, systemic dermal sclerosis, a decrease in muscular strength and rales. In laboratory tests, her myogenic enzyme level was increased, and she was found to be positive to LE cells, antinuclear antibody, anti-DNA antibody, anti-ENA antibody and anti-SSA antibody. Furthermore, histological features clearly corresponding to those of PSS were found by skin biopsy, myogenic changes by electromyography, evidence of chronic inflammation of the salivary glands by lip biopsy, and proliferative changes in the mesangium were detected by renal biopsy. The concept of MCTD, especially the differences from overlap syndrome, is vague. Therefore we need further study about many cases. Since there have been no reports on cases having sufficient evidence of the development of the overlap syndrome of PSS, SLE, PM and SjS during a course of MCTD, our patient would provide very useful data contributing to the study of MCTD.     

Leiomyosarcoma of the spermatic cord. A case report and a brief review of literature

A case of leiomyosarcoma of the spermatic cord, occurring in a 79-year-old male patient, is reported. The tumor was resected with high inguinal ligation and orchiectomy. It was located at the scrotal part of the spermatic cord on the left side and was shown to have originated from the spermatic duct using the dissecting method. Histologically, it was identical to leiomyosarcoma showing a typical morphological appearance of smooth muscle cell tumor in the conventional histochemical preparations as well as a focal positive reaction to antidesmin antibody, a marked nuclear pleomorphism, and abundant mitotic figures. The patient had been untroubled for six months after the resection of the tumor. Leiomyosarcoma arising in spermatic cord is quite rare.