A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects

Mitochondrial DNA (mtDNA) coding region polymorphisms, as well as the 150T polymorphism in the noncoding region, have been associated with longevity. We have studied here the association of 150T with longevity further and assessed differences in this association between various mtDNA haplogroups. We analysed a sample of 321 very old subjects and 489 middle-aged controls from Finland and Japan. 150T was more frequent among the very old than among the controls in both the Finnish and Japanese subjects. Interestingly, the association was not similar in all haplogroups, and a stratified analysis revealed that two additional common polymorphisms, 489C and 10398G, modified the association between 150T and longevity. These findings suggest that longevity is partly determined by epistatic interactions involving these three mtDNA loci.     

Carotid plaque mast cells associate with atherogenic serum lipids, high grade carotid stenosis and symptomatic carotid artery disease. Results from the helsinki carotid endarterectomy study

OBJECTIVE: Increased numbers of mast cells (MCs) are present in ruptured coronary plaques, suggesting to play a role in acute coronary syndromes. We evaluated the distribution densities of MCs, macrophages and T cells in carotid plaques and correlated these findings to stroke risk factors as well as history of stroke or TIA. METHODS AND RESULTS: Seventy-eight carotid samples from 75 patients (16 plaques from asymptomatic patients and 62 from patients with recent ischemic symptoms) undergoing carotid endarterectomy with an internal carotid stenosis >70% that were immunostained and quantified for MCs, macrophages and T cells. The MC distribution density showed positive correlation with the degree of carotid stenosis (p = 0.012), serum levels of total cholesterol (p = 0.021), LDL cholesterol (p = 0.013) and triglycerides (p = 0.005), and an inverse correlation with serum HDL cholesterol levels (p = 0.001). The average MC density (p = 0.023), but not the macrophage (p = 0.58) or T cell (p = 0.74) density, was higher in the symptomatic than in the asymptomatic patients. In a comparison of plaques ipsilateral and contralateral to the thromboembolic event, the densities of the three types of inflammatory cells were similar. CONCLUSIONS: Increased MC distribution density is associated with an atherogenic serum lipid profile, high-grade carotid artery stenosis and symptomatic carotid artery disease. These findings suggest a potential involvement of MCs in the pathophysiology of carotid artery stenosis.     

Matrilysins-1 and -2 (MMP-7 and -26) and metalloelastase (MMP-12), unlike MMP-19, are up-regulated in necrotizing enterocolitis

OBJECTIVES: Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants characterized histologically by extensive tissue injury and inflammation. Matrix metalloproteinases (MMP) are involved in tissue remodeling and cell migration, both being important aspects of inflammatory disease. The aim of this study was to investigate whether MMPs play a role in the pathogenesis of NEC. METHODS: Expression of MMP-1, -7, -9, -10, -12, -19 and -26 was studied using in situ hybridization/immunohistochemistry in samples intestinal tissue removed from 15 patients with NEC; in 7 of them control samples were obtained at closure of stomas. Six intestinal samples from patients with intestinal atresia and four samples of necrosis were also included in the material examined. Laminin-5 was immunostained to find migrating enterocytes and cytokeratin to delineate mucosal epithelium. RESULTS: MMP-7 protein was upregulated in the epithelium of 12/18 NEC samples. MMP-26 was induced in stromal cells of 12/17 NEC specimens. Stromal expression was found for MMP-1 and -12 mRNAs in 7/18 samples. MMP-1 was also detected in the epithelium of regenerating areas. Both NEC and stoma samples expressed MMP-9 in inflammatory cells. Epithelial MMP-19 was downregulated in NEC. CONCLUSIONS: Our results suggest that several MMPs may be major factors in tissue destruction and remodeling in NEC. Targeted inhibition of matrilysins, using synthetic MMP inhibitors or blockers of their signal transduction pathways, may represent a novel therapeutic option for the treatment of intestinal inflammation associated with NEC.     

Hyaluronate receptor (CD44) and integrin alpha4 (CD49d) are up-regulated on T cells during MS relapses

A longitudinal study of peripheral blood T cell adhesion molecule expression was performed in 24 relapsing-remitting MS patients. There were 15 relapses in 11 patients during 15 months of observation. In comparison with remission, expression of hyaluronate receptor (CD44) was highly significant, and expression of integrin alpha4 (CD49d, VLA-4) significantly up-regulated during relapses. CD44 and CD49d are putative activity markers and CD44 a potential novel therapeutic target in MS.     

Downregulation of VLA-4 on T cells as a marker of long term treatment response to interferon beta-1a in MS

We determined longitudinally the expression of a panel of adhesion molecules on T cells and soluble ICAM-1, VCAM-1 and tumor necrosis factor apoptosis inducing ligand (TRAIL) in serum during first year of the PRISMS Study with IFNbeta1a in MS. Clinical data and quantitative MRI data were available for 4 years. VLA-4 was down-regulated on T cells and VCAM-1 was up-regulated in serum during the first 3 to 6 months of therapy in patients with favorable long-term treatment response (EDSS progression 相似文献   

Visual assessment of medial temporal atrophy on MR films in Alzheimer's disease: comparison with volumetry

BACKGROUND AND AIMS: To test the agreement of a visual rating scale of medial temporal lobe atrophy (MTA) with linear and volumetric assessments, and to test its accuracy in discriminating between Alzheimer's disease (AD) patients and controls. METHODS: Participants were 28 patients with AD and 29 healthy controls. MTA was evaluated according to Scheltens' five-point scale. Its accuracy in distinguishing AD patients from controls was evaluated as a stand-alone measure and in association with linear [width of the temporal horn (WTH)] and volumetric [hippocampal volume (HV)] measures. RESULTS: The agreement of this visual rating scale with the other MTA measures was statistically significant (vs WTH and vs HV, p for trend < 0.00005). The visual rating scale showed a good accuracy in distinguishing AD patients from controls [area under the curve (AUC) 0.89, 95% confidence interval (CI) 0.79-0.98]. Although the accuracy of the visual rating scale improved in association with linear WTH (AUC 0.91, 95% CI 0.82-0.99) and in association with HV (AUC 0.93, 95% CI 0.86-1.00), the improvement was not significant. CONCLUSIONS: The visual rating scale of MTA, easily applicable in clinical practice, shows good agreement with more demanding quantitative methods, and can discriminate AD patients from controls with good accuracy.     

Alcoholic liver disease: from pathophysiology to therapy

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, in October 2004. A salient feature of this symposium was to demonstrate how the striking advances made in our understanding of the pathophysiology of alcoholic liver disease are now raising prospects for better treatment as well. Genetic factors are now being elucidated, and F. Stickel (Germany) has summarized his own studies as well as those of others. M. Salaspuro (Finland) updated the possible role of gut bacteria in the pathogenesis of alcoholic liver disease, bringing us closer to antibacterial therapy as part of the treatment of alcoholic liver disease. Specifically, the gut bacterial flora may be important via the in situ production of acetaldehyde and the associated intestinal injury, which may favor the translocation of toxins from the gut lumen to the systemic circulation and the liver. The analytical progress in the assessment of alterations of phospholipid composition in liver membranes described by H. P. Schlemmer (Germany) may eventually give us an objective method to recognize patients in whom phospholipid therapy might be indicated. Other novel treatment modalities for severe alcoholic hepatitis were described by Y. Horie and H. Ishii (Japan), including plasma exchange. Finally, the pros and cons of nutraceutical therapy were analyzed by C. S. Lieber, with a demonstration that although some nutraceuticals may have toxicity exacerbated by alcohol and must be administered very carefully within a narrow therapeutic window, others are actually beneficial as demonstrated under controlled conditions.     

Interactions between light-induced currents, voltage-gated currents, and input signal properties in Drosophila photoreceptors

Voltage-gated K(+) channels are important in neuronal signaling, but little is known of their interactions with receptor currents or their behavior during natural stimulation. We used nonparametric and parametric nonlinear modeling of experimental responses, combined with Hodgkin-Huxley style simulation, to examine the roles of K(+) channels in forming the responses of wild-type (WT) and Shaker mutant (Sh(14)) Drosophila photoreceptors to naturalistic stimulus sequences. Naturalistic stimuli gave results different from those of similar experiments with white noise stimuli. Sh(14) responses were larger and faster than WT. Simulation indicated that, in addition to eliminating the Shaker current, the mutation changed the current flowing through light-dependent channels [light-induced current (LIC)] and increased the delayed rectifier current. Part of the change in LIC could be attributed to direct feedback from the voltage-sensitive ion channels to the light-sensitive channels by the membrane potential. However, we argue that other changes occur in the light detecting machinery of Sh(14) mutants, possibly during photoreceptor development.     

No evidence of Mycoplasma pneumoniae in acute myringitis

Our aim was to discover Mycoplasma pneumoniae in bullous and hemorrhagic myringitis in children <2 years of age. Middle ear fluid samples (n = 37) and samples taken from the blisters of the tympanic membranes (n = 12) studied by polymerase chain reaction for M. pneumoniae were negative. This study does not support an important role for M. pneumoniae as an etiologic agent in acute myringitis.     

Epidemiology of choriocarcinoma in Finland, 1953 to 1999

OBJECTIVE: Choriocarcinoma is a rare tumor with remarkable differences in the incidence in various parts of the world. The available data do not elucidate recent time trends in the incidence of the disease in Western countries. We studied the epidemiology of choriocarcinoma in Finland over a period of 47 years. METHODS: Incidence rates for choriocarcinoma from 1953 to 1999, according to the population-based Finnish Cancer Registry, were calculated per number of deliveries, obtained from the National Research and Development Center for Welfare and Health. Standardized incidence ratios (SIRs) for the years 1971 through 1995 for women born between 1906 and 1945 were calculated by occupation taken from the 1970 Population Census. RESULTS: The incidence of choriocarcinoma was 40/10(6) deliveries for the study period 1953-1999 as a whole. The respective incidence rate calculated per female population and adjusted for age to the world standard population was 1.3/10(6). The incidence, per number of deliveries, was remarkably higher in women above 40 years as compared to younger women. There was a decline in the incidence of the disease in women between 25 and 39 years of age from 53/10(6) deliveries in 1953-1984 to 26/10(6) deliveries in 1985-1999. High occupation-specific risks were observed for nurses (SIR 7.8; 95% confidence interval 2.1-20) and agricultural workers (SIR 11; 95% confidence interval 1.4-40). CONCLUSION: The incidence of choriocarcinoma in Finland is similar to that reported earlier for other Western countries. The recent decline in the incidence of the disease, the enormous increase in the risk among old fertile women, and clustering of cases to certain occupations should be targets of future studies.