Alcoholic foamy degeneration in Spain. Prevalence and clinico-pathological features

Among 389 consecutive chronic alcoholics in whom a liver biopsy was performed for diagnostic purposes, nine patients (2.3%) had histological changes of "alcoholic foamy degeneration" (AFD), characterized by numerous small fat droplets in the swollen hepatocytes of the centrilobular area. In five cases, there were non-specific clinical features, while the other four cases presented acute hepatic decompensation with jaundice and a reduced prothrombin activity. Seven patients had high serum lipid concentrations including hypertriglyceridemia and hypercholesterolemia, which improved after withdrawal of alcohol intake. In conclusion, AFD has a broad clinicopathological spectrum including asymptomatic patients and other cases with severe liver decompensation manifested by jaundice and reduced prothrombin activity. AFD is usually associated with hyperlipemia.     

Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease

Collapsin response mediating protein-2 (CRMP2) has been identified as an intracellular protein mediating Semaphorin3A (Sema3A), a repulsive guidance molecule. In this study, we demonstrate that cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3beta (GSK3beta) plays a critical role in Sema3A signalling. In In vitro kinase assay, Cdk5 phosphorylated CRMP2 at Ser522, while GSK3beta did not induce any phosphorylation of CRMP2. Phosphorylation by GSK3beta was exclusively observed in Cdk5-phosphorylated CRMP2, but barely in CRMP2T509A. These results indicate that Cdk5 primarily phosphorylates CRMP2 at Ser522 and GSK3beta secondarily phosphorylates at Thr509. The dual-phosphorylated CRMP2, but not non-phosphorylated or single-phosphorylated CRMP2, is recognized with the antibody 3F4, which is highly reactive with the neurofibrillary tangles of Alzheimer's disease. 3F4 recognized the CRMP2 in the wild-type but not cdk5-/- mouse embryonic brain lysates. The phosphorylation of CRMP2 at Ser522 caused reduction of its affinity to tubulin. In dorsal root ganglion neurones, Sema3A stimulation enhanced the levels of the phosphorylated form of CRMP2 detected by 3F4. Over-expression of CRMP2 mutant substituting either Ser522 or Thr509 to Ala attenuates Sema3A-induced growth cone collapse response. These results suggest that the sequential phosphorylation of CRMP is an important process of Sema3A signalling and the same mechanism may have some relevance to the pathological aggregation of the microtubule-associated proteins.     

Investigation of initial changes in the mouse olfactory epithelium following a single intravenous injection of vincristine sulphate

To investigate initial changes in the olfactory epithelium, vincristine sulphate (VCR) was administered intravenously once to male BALB/c mice on day 1 in comparison with unilateral bulbectomy (UBT). The light and electron microscopy of the olfactory epithelium, nerve and/or bulb with BrdU-morphometry was performed sequentially. Further, whole-body radioluminography was conducted at 1 and 24 hours postdose. Apoptosis and an increased number of mitotic cells with a tendency toward decreasing BrdU-positive olfactory epithelial cell counts were observed in olfactory epithelial cells at 6 hours postdose of VCR and became more pronounced at 24 hours postdose. These changes disappeared on days 4 or 15, but minimal axonal degeneration was seen in the olfactory nerve from day 4 onward. Semiquantitative measurement of VCR levels in the ethmoturbinals elicited high drug retention even 24 hours after administration. In contrast, UBT showed no effect on mitosis and BrdU-positive cell counts at 6 hours postdose, but severe lesions in the olfactory epithelium and nerve were seen on days 2, 4, and/or 15. The above results suggest that the initial event of VCR-induced apoptosis in the mouse olfactory epithelium would be mitotic arrest with high drug retention, unlike that evoked by UBT.     

Immunogenetic analysis of gastric MALT lymphoma-like lesions induced by Helicobacter pylori infection in neonatally thymectomized mice

Most gastric mucosa-associated lymphoid tissue (MALT) lymphomas are caused by Helicobacter pylori (H. pylori) infection. We previously reported that acquired lymphoid follicles with germinal centers were induced by H. pylori infection in neonatally thymectomized (nTx) mice. In the present study, we developed gastric MALT lymphoma-like lesions in nTx mice by long-term H. pylori infection, and performed immunogenetic analyses. BALB/c mice were thymectomized on the 3rd day after birth. At 6 weeks of age, mice were orally infected with 10(8) H. pylori and serially killed 2, 4, 6, and 12 months later. Normal BALB/c and noninfected nTx mice served as controls. Follicle formation occurred after 2 months of H. pylori infection in the nTx mice. Follicle formation and infiltration of intraepithelial lymphocytes progressed in a time-dependent manner. Lymphoepithelial lesions, a characteristic feature of MALT lymphoma, also occurred in a time-dependent manner (100% at 12 months). Serum immunoelectrophoresis revealed a monoclonal band (M-protein) in 30% (3/10) of mice 6 months after infection. M-protein-positive mice had amplification of one or two IgM and/or IgG heavy-chain genes in the gastric B lymphocytes, as determined with polymerase chain reaction, suggesting mono- or oligoclonality. Overexpression of Bcl-X(L) protein was immunohistologically observed in the infiltrating B lymphocytes and in some follicular B lymphocytes in 80% (8/10) of the cases at 12 months. Thus, H. pylori infection is involved in the development of gastric MALT lymphoma-like lesions in nTx mice. Our mouse model is useful for clarifying the pathogenetic mechanism of gastric MALT lymphoma by H. pylori infection.     

Polymers containing stable free radicals, 6. Reactions of 2,4,6-triphenyl-3,4-dihydro-s-tetrazin-1 (2H)-yl (1,3,5-triphenylverdazyl) with organometallic compounds

2,4,6-Triphenyl-3,4-dihydro-s-tetrazin-1(2H)-yl ( 1 ) (1,3,5-triphenylverdazyl) was allowed to react with ethyl- and butyllithium, ethyl-, isopropyl-, and butylmagnesium bromide, as well as benzylmagnesium chloride to give the coupling products 2a–d . These results indicate that structures corresponding to 2 are present in the polymers resulting from vinyl monomers containing the verdazyl structure, if they are initiated with alkyllithium or a Grignard reagent. A reaction mechanism is discussed.     

Influence of acute-phase proteins on the activity of natural killer cells

The effects of ₁-antitrypsin ( ₁,-AT), ₁,-acid glycoprotein ( ₁AGP), and haptoglobin (Hp), the main constituents of-globulin and which belong to acute phase proteins, on NK activity were examined using K562 cells as the NK target cells. Among the three proteins, ₁,-AT and ₁AGP had inhibitory effects on NK activity for fast target K562 cells. The,-AT preparations having the same protein concentration and a different trypsin inhibitory capacity (TIC) had an equal effect. Although ₁AT and ₁,-AGP equally reduced the NK activity, the mechanism involved in the reduction differed, in that the effect of ₁,-AT directed toward NK cells reduced their binding capacity with the target cells, ₁,-AGP probably interacts with a cytotoxic factor secreted from NK cells following effector-target interaction. These studies suggest that each of the acute-phase proteins, which increase following inflammation, inhibits NK cell function by two distinct mechanisms.     

A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia

Genetic contributions to the etiology of substance abuse and dependence are topics of major interest. Acute and chronic cannabis use can produce drug-induced psychosis resembling schizophrenia and worsen positive symptoms of schizophrenia. The endocannabinoid system is one of the most important neural signaling pathways implicated in substance abuse and dependence. The fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme of endocannabinoids. To clarify a possible involvement of FAAH in the etiology of methamphetamine dependence/psychosis or schizophrenia, we examined the genetic association of a nonsynonymous polymorphism of the FAAH gene (Pro129Thr) by a case-control study. We found no significant association in allele and genotype frequencies of the polymorphism with either disorder. Because the Pro129Thr polymorphism reduces enzyme instability, it is unlikely that dysfunction of FAAH and enhanced endocannabinoid system induce susceptibility to either methamphetamine dependence/psychosis or schizophrenia.     

Etiology of IgA nephropathy syndrome

Since Berger's original paper on mesangial IgA-IgG deposition with hematuria, there have been a number of clinical and pathological studies regarding IgA immune complexes, the mechanisms of glomerular IgA deposition leading to glomerular injury and animal models of IgA nephropathy. During the last quarter of this century, glomerular changes such as IgA nephropathy have also been observed in cases associated with other diseases, such as systemic lupus erythematosus, Schoenlein-Henoch purpura, liver cirrhosis and chronic inflammatory diseases of the lung. This evidence supports the idea of an IgA nephropathy syndrome. On the other hand, IgA is thought to be an important humoral factor at the mucosal immune system and appears to have an antibody function against various etiologic candidates of extrinsic or intrinsic substances at the mucosal and systemic immune system. Glomerular IgA deposition in IgA nephropathy syndrome is thought to result from elevated levels of circulating immune complexes or aggregated IgA due to an overproduction of polymeric IgA as antibodies in the serum and due to the clearance impairment of IgA immune complexes in the hepatic and splenic phagocytic system. The glomerular IgA subclass is not one-sided, but should be evaluated in comparison with the age of patients at renal biopsy; this indicates the approximate age of onset. Cirrhotic IgA glomerulonephritis is not related to Hepatitis B or C virus infection, but to the pathophysiologic condition of liver cirrhosis. Various etiologic candidates such as viral, microbial, dietary antigens or auto-antigens have been listed and experimental models of IgA nephropathy syndrome have provided some clues in understanding the etiology of primary IgA nephropathy. However much still remains to be clarified and some specific epitopes common among these etiologic candidates will have to be identified.     

Establishment of dental epithelial cell line (HAT-7) and the cell differentiation dependent on Notch signaling pathway

Rat incisors grow continuously throughout life. Producing a variety of dental epithelial cells is performed by stem cells located in the cervical loop of the incisor apex. To study the mechanisms for cell differentiation, we established a dental epithelial cell line (HAT-7) originating from a cervical loop epithelium of a rat incisor. Immunochemical studies showed that HAT-7 produced the cells expressing amelogenin, ameloblastin, or alkaline phosphatase (ALP). To illustrate a role of Notch signaling in the determinant of the cell fate, we examined expression patterns of Notch1 and Jagged1 in HAT-7 density dependently. At lower cell density, Notch1- or Jagged1-expressing cells were not seen. However, when they were fully confluent, cells began to express Notch1 or Jagged1 strongly. Some ALP-positive cells were almost consistent with Notch1-expressing cells but not Jagged1-expressing cells. These results suggested that the determinant of direction of differentiation was associated with Notch signaling pathway.