Role of growth hormone, insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 in development of non-alcoholic fatty liver disease

Background and aims Pituitary dysfunction including growth hormone (GH) deficiency may be associated with non-alcoholic fatty liver disease (NAFLD). Since the relationships among GH, IGF-1, IGFBP-3, and development of NAFLD without hypopituitarism are unclear, we examined the role of these hormones in the development of NAFLD based on clinical, laboratory and liver histology data. Patients and methods A total of 55 consecutive patients (20 males and 35 females) with NAFLD. Results Aspartate amino transferase (AST), AST/ALT, platelet count and IGF-1, levels were significantly associated with differences in fibrosis, since these variables differed between stage 0–1 and stage 2–3 NAFLD. In multivariate analysis, platelet count (P = 0.0223, relative risk (RR), 5.899; 95% confidence interval (CI), 1.288–27.017), and IGF-1 (P = 0.0363, RR, 4.568; 95% CI, 1.101–18.945) showed significant associations with stage 2–3 NAFLD. Additionally, hyaluronic acid levels had a negative relationship with IGF-1 and the IGF-1/IGFBP-3 ratio. There was no relationship of fibrosis with GH level, but decreased GH (P = 0.0414, RR, 0.199; 95% CI, 0.042–0.989) was significantly associated with steatosis of stage 2–3. Low GH/IGF-1 and GH/IGFBP-3 ratios were found in advanced steatosis. Conclusion GH, IGF-1 and IGFBP-3 are associated with hepatic fibrosis and steatosis in NAFLD. Low levels of IGF-1 might be associated with fibrosis while low level of GH with hepatic steatosis.     

Experimental studies on gastric ulcer. (4). Sequential observation and evaluation of gastric ulcers by endoscope in the rat

In the present study, a sequential observation of the gastric lesions or ulcers in rats weighing from 100 g was made with an endoscope. It was found that bleeding, edema, hyperemia, fur of ulcer and convergences of the mucosal folds in the stomach could be observed in rats with a SES-1717S (phi = 1.7 mm) or SES-2217S (phi = 2.2 mm) endoscope. Furthermore, we have devised a method which we named the "sohmen method" for measuring ulcer-sizes with an endoscope. The ulcer-size was compared with 5 mm lengths of sohmen (Japanease vermicelli) which were inserted through the sheath of the endoscope into the stomach. Therefore, the ulcer-size could be accurately measured by this method. By this observation method, it is possible to observe repeatedly over a long term the changes in gastric lesions or ulcers, to measure changes in ulcer-sizes and to evaluate the relapse or recurrence of ulcers in the same rats.     

Inflow Jet Patterns of Unruptured Cerebral Aneurysms Based on the Flow Velocity in the Parent Artery: Evaluation Using 4D Flow MRI

BACKGROUND AND PURPOSE:Inflow jet characteristics may be related to aneurysmal bleb formation and rupture. We investigated the visualization threshold on the basis of the flow velocity in the parent artery to classify the inflow jet patterns observed on 4D flow MR imaging.MATERIALS AND METHODS:Fifty-seven unruptured aneurysms (24 bifurcation and 33 sidewall aneurysms) were subjected to 4D flow MR imaging to visualize inflow streamline bundles whose velocity exceeded visualization thresholds corresponding to 60%, 75%, and 90% of the maximum flow velocity in the parent artery. The shape of the streamline bundle was determined visually, and the inflow jet patterns were classified as concentrated, diffuse, neck-limited, and unvisualized.RESULTS:At the 75% threshold, bifurcation aneurysms exhibited a concentrated inflow jet pattern at the highest rate. At this threshold, the inflow jets were concentrated in 13 aneurysms (group C, 22.8%), diffuse in 18 (group D, 31.6%), neck-limited in 11 (group N, 19.3%), and unvisualized in 15 (group U, 26.3%). In 16 (28.1%) of the 57 aneurysms, the inflow jet pattern was different at various thresholds. Most inflow parameters, including the maximum inflow velocity and rate, the inflow velocity ratio, and the inflow rate ratio, were significantly higher in groups C and D than in groups N and U.CONCLUSIONS:The inflow jet pattern may depend on the threshold applied to visualize the inflow streamlines on 4D flow MR imaging. For the classification of the inflow jet patterns on 4D flow MR imaging, the 75% threshold may be optimal among the 3 thresholds corresponding to 60%, 75%, and 90% of the maximum flow velocity in the parent artery.

The inflow jets of cerebral aneurysms have been characterized as flow structures composed of strongly directed inflow with higher speeds than in other parts of the aneurysm.^1,2 Computational fluid dynamics analyses by using human cerebral aneurysm models suggested that inflow jets may be related to bleb formation and aneurysmal rupture.^3–5 Cebral et al³ reported that most blebs formed at sites where the inflow jet impacted the aneurysmal wall, and they qualitatively classified the inflow jets of ruptured and unruptured cerebral aneurysms into concentrated and diffuse inflow jets.^3–5 They found that most ruptured aneurysms featured concentrated inflow jets, while diffuse inflow jets tended to be seen in unruptured aneurysms.^4,5 This finding suggests that bleb formation and aneurysm rupture may be attributable to a degenerative change in the aneurysm wall exposed to the increased hemodynamic stress exerted by the inflow jet. Therefore, the assessment of inflow jet patterns and quantitative estimation of the inflow hemodynamics may contribute to a more precise prediction of the risk for bleb formation and aneurysm rupture.Computational fluid dynamics analysis uses human aneurysm models based on a number of assumptions and approximations regarding blood properties, vessel wall compliance, and flow conditions.^3–8 For the quantitative evaluation of the hemodynamics in real human cerebral aneurysms, 4D flow MR imaging, which is based on time-resolved 3D cine phase-contrast MR imaging techniques, has been used.^9–20 In this study, we investigated the visualization threshold on the basis of the flow velocity in the parent artery to classify the inflow jet patterns of unruptured cerebral aneurysms on 4D flow MR imaging. We applied different thresholds to visualize the inflow streamlines, evaluated the inflow jet patterns, and examined the relationship between the inflow jet pattern and the inflow hemodynamics.     

Increased number of mitochondria in capillaries distributed in stroke‐like lesions of two patients with MELAS

We investigated two autopsy cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) using immunohistochemical staining with an anti‐mitochondrial antibody against translocase of the outer membrane 20 (TOMM20). In case 1, the patient was a 42‐year‐old man with a disease duration of 53 days, and in case 2, the patient was a 62‐year‐old woman with a disease duration of 27 months. In both the cases autopsy revealed moderate atrophy of the cerebrum and cerebellum and multifocal necrotizing lesions, irrespective of the vascular territory. Case 1 showed multiple areas with total necrosis in the cortex, accompanied by increases in number of protoplasmic astrocytes and acidophilic neurons as well as axonal swelling, suggestive of acute or subacute stage stroke‐like lesions (SLLs). In case 2, most of the SLLs displayed laminar spongy change in a rarefied cortex, and were considered to be at the chronic stage. In both the cases, capillary proliferation was noted within the SLLs, particularly in the acute phase. Endothelial cells of proliferating capillaries were strongly positive for TOMM20. In the cortex outside the SLLs, microvessels displayed only a fine granular immunoreactivity, as is seen in the controls. Although smooth muscle cells and endothelial cells in pial arteries and arterioles were also strongly positive for TOMM20, the territories of the affected pial arteries and arterioles did not correlate with the distribution of the SLLs. Although MELAS is characterized by recurrent stroke‐like episodes (SLEs), the pathogenetic relationship between SLEs and mitochondrial angiopathy remains unknown. An aberrant increase of mitochondria in the capillary endothelial cells of SLLs may disturb endothelial function, thus playing a role in the formation or development of SLLs.     

Initial culprit-only versus initial multivessel percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction: results from the Ibaraki Cardiovascular Assessment Study registry

We investigated clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (CAD) treated for initial culprit-only or by initial simultaneous treatment of nonculprit lesion with culprit lesion. Optimal management of multivessel disease in STEMI patients treated by primary percutaneous coronary intervention (PCI) is still unclear in the drug-eluting stent era. We compared clinical outcomes of 274 STEMI patients (69.3 ± 11.8 years, 77 % men) in the Ibaraki Cardiovascular Assessment Study registry who underwent initial culprit-only (OCL, n = 220) or initial multivessel PCI of nonculprit lesion with culprit lesion (NCL, n = 54) from April 2007 to August 2010. Major adverse cardiac and cerebrovascular events (MACCE) included all-cause death, myocardial infarction (MI), target-vessel revascularization (TVR), and cerebrovascular accident (CVA). Patients in the NCL group were older and had higher Killip class and lower estimated glomerular filtration rate than those in the OCL group. MI, TVR, CVA, and stent thrombosis were not significantly different between the two groups. Incidences of all-cause death and MACCE were lower in the OCL than in the NCL group (all-cause death: 10.9 % vs 31.5 %, P < 0.05; MACCE: 27.7 % vs 46.2 %, P < 0.05). After adjusting for patient characteristics, NCL remained at significantly higher risk compared with OCL for in-hospital and all-cause death (P = 0.001, respectively), and MACCE were not significantly different (odds ratio 1.95, 95 % confidence interval 0.94–4.08; P = 0.07) between groups. Initial multivessel PCI was associated with significantly increased risk of in-hospital death, all-cause death, and MACCE, which was somewhat attenuated in a multivariable model, but the numerically excessive risk with NCL still persisted.     

Fukutin is required for maintenance of muscle integrity,cortical histiogenesis and normal eye development

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal-recessive disorders in Japan, is characterized by congenital muscular dystrophy associated with brain malformation due to a defect during neuronal migration. Through positional cloning, we previously identified the gene for FCMD, which encodes the fukutin protein. Here we report that chimeric mice generated using embryonic stem cells targeted for both fukutin alleles develop severe muscular dystrophy, with the selective deficiency of alpha-dystroglycan and its laminin-binding activity. In addition, these mice showed laminar disorganization of the cortical structures in the brain with impaired laminin assembly, focal interhemispheric fusion, and hippocampal and cerebellar dysgenesis. Further, chimeric mice showed anomaly of the lens, loss of laminar structure in the retina, and retinal detachment. These results indicate that fukutin is necessary for the maintenance of muscle integrity, cortical histiogenesis, and normal ocular development and suggest the functional linkage between fukutin and alpha-dystroglycan.     

Generation of peptide-specific CD8+ T cells by phytohemagglutinin-stimulated antigen-mRNA-transduced CD4+ T cells

Functional analysis of antigen-specific CD8(+) T cells is important for understanding the immune response in various immunological disorders. To analyze CD8(+) T cell responses to a variety of antigens with no readily defined peptides available, we developed a system using CD4(+) phytohemagglutinin (PHA) blasts transduced with mRNA for antigen molecules. CD4(+) PHA blasts express MHC class I and II, and also CD80 and CD86 and are thus expected to serve as potent antigen presenting cells. EGFP mRNA could be transduced into and the protein expressed by more than 90% of either LCL or CD4(+) PHA blasts. Its expression stably persisted for more than 2 weeks after transduction. In experiments with HLA-A*2402 restricted CD8(+) CTL clones for either EBNA3A or a cancer-testis antigen, SAGE, mRNA-transduced lymphoid cells were appropriate target cells in ELISPOT assays or (51)Cr releasing assays. Finally, using CD4(+) PHA blasts transduced with mRNA of a cancer-testis antigen MAGE-A4, we successfully generated specific CTL clones that recognized a novel HLA-B*4002 restricted epitope, MAGE-A4(223-231). Messenger RNA-transduced CD4(+) PHA blasts are thus useful antigen presenting cells for analysis of CD8(+) T cell responses and induction of specific T cells for potential immunotherapy.     

Trajectories of depressive symptoms and stressful life events among male and female adolescents in divorced and nondivorced families

This 11-year longitudinal study models the trajectories of depressive symptoms among approximately 550 females and males raised in divorced and nondivorced families in the rural Midwest. Using multilevel analyses, we demonstrate that, first, depressive symptoms changed according to a curvilinear pattern, especially for females; they increased during early to midadolescence and then declined in late adolescence to young adulthood. Second, compared with males, females experienced a greater number of depressive symptoms in adolescence and early adulthood. Third, children who experienced parental divorce by age 15 manifested a sharper increase in depressive symptoms compared to those from nondivorced families. Fourth, stressful life events children experienced shortly after parental divorce mediated the effect of parental divorce on depressive symptoms. Fifth and finally, time-varying stressful life events, particularly those related to relationship and personal loss, were significantly associated with the trajectories of depressive symptoms.     

Metaphyseal anadysplasia: Evidence of genetic heterogeneity

We report on two unrelated children, a girl and a boy, with regressive metaphyseal dysplasia. Both children had bow legs and a transient growth decline in early childhood. Metaphyseal modifications of the long bones in the children were most conspicuous at an early age and then subsided by age 2 to 3 years. The father of the boy may have had the same disorder, because he was shorter than his sibs and showed mild modifications of the vertebral end plates with mild narrowing of the interpediculate distance of the lumbar spine. The evolution of the metaphyseal dysplasia in the children closely resembled that of metaphyseal anadysplasia (MAD), which is X-linked recessive in inheritance. By contrast, the occurrence of an isolated, affected girl and possible father-to-son transmission reported here were consistent with autosomal dominant transmission, suggesting heterogeneity of MAD. Molecular studies of the type X collagen gene in the boy did not demonstrate any disease-causing mutation. Am. J. Med. Genet. 82:43–48, 1999. © 1999 Wiley-Liss, Inc.     

Th1-derived cytokine IFN-gamma is a potent inhibitor of eotaxin synthesis in vitro.

Eotaxin potentially plays an integral role in tissue eosinophilia. Inasmuch as Th2-derived cytokine IL-4 has been shown to stimulate eotaxin generation, we investigated here the effect of Th1-derived cytokine IFN-gamma on human eotaxin production. IFN-gamma but not -alpha or -beta potently inhibited tumor necrosis factor (TNF)-alpha-induced eotaxin generation by dermal fibroblasts. The inhibitory effect was unique to eotaxin, because production of IL-8 or monocyte chemoattractant protein (MCP)-1 protein was not affected by the treatment with IFN-gamma. Furthermore, the suppressive effect of IFN-gamma was not cell-type or stimulus specific. The level of eotaxin mRNA increased within 2 h after activation with TNF-alpha and continued to increase up to 72 h. IFN-gamma did not inhibit, but rather augmented the TNF-alpha-induced accumulation of mRNA in the early phase ( approximately 6 h). However, in the later phase, IFN-gamma completely prevented the subsequent elevation of eotaxin mRNA and sustained it at low levels. Although the protective effect of IFN-gamma against allergic inflammation has been assumed to result from its sole regulation of the proliferation of Th2-type T lymphocytes, these results imply that IFN-gamma can also directly act on stromal cells to inhibit eotaxin production and consequently intervene in eosinophil recruitment.