Hematoma Size in Deep Intracerebral Hemorrhage and its Correlation with Dot-Like Hemosiderin Spots on Gradient Echo T2*-Weighted MRI

BACKGROUND AND PURPOSE: Dot-like low intensity spots (dot-like hemosiderin spots: dotHSs) on gradient echo T2*-weighted MRI have been histologically diagnosed to represent old cerebral microbleeds associated with microangiopathies. They have also been correlated to the fragility of small vessels and the tendency to bleed. Therefore, a substantial number of dotHSs might be associated with a large-sized, deep intracerebral hematoma (ICH). On the other hand, dotHSs may reflect old microbleeds that did not enlarge to symptomatic size. METHODS: To investigate how dotHSs are related to the size (maximal diameter) of primary deep ICH, we analyzed the diameter and the number of dotHSs in 151 patients with deep ICH not associated with subarachnoid hemorrhage or intraventricular hemorrhage (75 males and 76 females, age ranged from 37 to 90 [65.7 +/- 11.3 years old] who were consecutively admitted to Hakodate Municipal Hospital. The hazard ratio (HR) for a maximal diameter of deep ICH < or =2 cm was estimated, using the number of dotHSs and risk factors for stroke. RESULTS: The number of dotHSs associated with the diameter < or =2 cm was 9.2 +/- 11.5, significantly larger than that with the diameter > or =2 cm (4.7 +/- 7.0, P= .012). Multivariate analysis revealed that a maximal diameter of deep ICH of < or =2 cm was found in patients with dotHS (HR, 3.7; 95% confidence interval [CI], 1.4-10.1; P= .009). CONCLUSION: Though small sample size limited the power of our analyses, these findings suggest that the number of dotHSs may be associated with a small diameter of deep ICH.     

Sex differences of human trabecular bone microstructure in aging are site-dependent.

In this study, we characterize bone microstructure, specifically sex differences, at multiple skeletal sites in 165 subjects >52 yr of age, using microCT technology in vitro. Significant sex differences are observed at the distal radius, femoral neck, and femoral trochanter, but not at the iliac crest, calcaneus, and lumbar vertebral body. Correlations in BV/TV between sites ranged from r = 0.13 to 0.56. INTRODUCTION: The goals of this study were (1) to assess potential sex differences of bone microstructure and their difference between skeletal sites and (2) to explore the relationship of trabecular microstructural properties between relevant skeletal sites. MATERIALS AND METHODS: Trabecular bone microstructural properties were measured in vitro in 165 subjects 52-99 yr of age using microCT. Defined volumes of interest (cylinders with 6 mm diameter and 6 mm length) were scanned at a resolution of 26 microm (isotropic) in six different anatomical sites: distal radius, femoral neck and trochanter, iliac crest, calcaneus, and second lumbar vertebral body. RESULTS: At the radius and femoral neck, trabecular bone displayed a more plate-like structure, thicker trabeculae, smaller separation/higher trabecular number, higher connectivity, and a higher degree of anisotropy in men than in women (p < 0.05). At the trochanter, men displayed more plate-like structure and thicker trabeculae (p < 0.05), but no differences in trabecular separation or other parameters compared with the women. At the calcaneus, iliac crest, and second lumbar vertebra none of the bone parameters displayed significant differences between sexes. The BV/TV at one site explained a range of only 2-32% of the variability at other sites. CONCLUSIONS: These results suggest that trabecular bone microstructural properties are remarkably heterogeneous throughout the skeleton. Significant differences between men and women are observed at some, but not at all, sites. The magnitude of sex differences in trabecular microstructure coincides with that of fracture incidence observed for some of the sites in epidemiological studies.     

Increase of Bone Mass and Mechanical Strength in Rats after Treatment with a Novel Bisphosphonate,YM175, for Two Years

Abstract: We have evaluated the relationship between bone mass and mechanical properties of bone from male and female rats treated with YM175, a novel bisphosphonate, for 104 weeks. YM175 [disodium (cycloheptylamino) methylenediphosphonate monohydrate] was given via the drinking water at a concentration of 0, 0.005, 0.015, 0.05, or 0.15%. Since the mortality in the male 0.15% group exceeded the exclusion criteria (75%) at week 88, this group was omitted from the study. Mean daily intake of YM175 was 2.2-22.1 mg/kg for males and 3.6-104 mg/kg for females. After the treatment, mechanical properties and ash weight of the humerus were determined. In males, 0.015 and 0.05% of YM175 (6.6–22.1 mg/kg) significantly increased failure load of the midshaft. In females, failure load and stiffness of the midshaft tended to be increased by YM175 (up to 104 mg/kg). Furthermore, ultimate compressive load at the humeral metaphysis treated with the highest dose of YM175 was 2- or 3.5-fold greater than that of untreated male or female control. Ash weight of the humerus was increased dose-dependently and was positively correlated with failure load of the midshaft. These findings indicate that treatment for 2 years with YM175 increased bone mass and mechanical strength without blocking bone mineralization.     

Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia

We report here that loss of the Sprouty2 gene (also known as Spry2) in mice resulted in enteric nerve hyperplasia, which led to esophageal achalasia and intestinal pseudo-obstruction. Glial cell line-derived neurotrophic factor (GDNF) induced hyperactivation of ERK and Akt in enteric nerve cells. Anti-GDNF antibody administration corrected nerve hyperplasia in Sprouty2-deficient mice. We show Sprouty2 to be a negative regulator of GDNF for the neonatal development or survival of enteric nerve cells.     

Overexpression of lipoprotein lipase in transgenic rabbits leads to increased small dense LDL in plasma and promotes atherosclerosis

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Previous studies using transgenic mice and rabbits have demonstrated that high level of LPL activity in adipose and skeletal muscle protects against diet-induced hypercholesterolemia and subsequently prevents aortic atherosclerosis. However, it is unknown, per se, whether increased LPL activity itself is antiatherogenic, or whether the antiatherogenic effect of LPL is dependent upon the LPL lipid-lowering effect. To address this issue, we fed LPL transgenic and littermate rabbits diets containing different amounts of cholesterol (0.3-0.6%) adjusted to maintain their plasma cholesterol concentrations at similarly high levels for 16 weeks. We analyzed their lipoprotein profiles and compared their susceptibility to atherosclerosis. The results showed that the overexpression of LPL in transgenic rabbits reduced remnant lipoproteins (beta-VLDL, d<1.006 g/ml) but concomitantly led to a significant increase of the large (d=1.02-1.04 g/ml) and small LDLs (d=1.04-1.06 g/ml) compared to the amounts in control rabbits. Furthermore, we found that with equally high hypercholesterolemia, transgenic rabbits developed 1.8-fold more extensive aortic atherosclerosis than control rabbits. To examine the hypothesis that altered lipoprotein profiles may be responsible for the enhanced atherosclerosis in transgenic rabbits, we studied the atherogenic properties of apoB-containing lipoproteins in vitro. These studies revealed that small-sized LDLs of transgenic rabbits were more susceptible to copper-induced oxidation and had higher affinity to biglycan than large remnant lipoproteins. We conclude, therefore, that LPL exerts a dual function in terms of its atherogenicity, namely antiatherogenicity, through enhancing receptor-mediated remnant lipoprotein catabolism and proatherogenicity via the generation of a large amount of small-sized LDLs. At an equal atherogenic-cholesterol level, small and dense LDLs are more atherogenic than large remnant lipoproteins.     

B-1 cells are pivotal for in vivo inflammatory giant cell formation

The mechanisms that govern giant cell (GC) formation in inflammatory, neoplastic and physiologic conditions are far from being understood. Here, we demonstrate that B-1 cells are essential for foreign-body GC formation in the mouse. GCs were analysed on the surface of glass cover slips implanted into the subcutaneous tissue of the animals. It was demonstrated that GCs are almost absent on cover slips implanted into the subcutaneous tissue of BALB/c or CBA/N X-linked immunodeficient mice. As these animals do not have B-1 cells in the peritoneal cavity, they were reconstituted with B-1 cells obtained from cultures of adherent mouse peritoneal cells. Results showed that in B-1-reconstituted animals, the number of GCs on the implant surface surpassed the values obtained with preparations from wild animals. In animals selectively irradiated (pleural and peritoneal cavities) to deplete these cavities of B-1 cells, GCs were also not formed. Enriched suspensions of B-1 cells grown in culture were labelled with [(3)H]-tymidine and injected into the peritoneal cavity of naive mice before implantation of glass cover slips. After 4 days, about 17% of mononuclear cells had their nuclei labelled, and almost 70% of GCs had one or more of their nuclei labelled when analysed by histoautoradiographic technique. A few GCs expressed an immunoglobulin M when analysed by immunostaining and confocal microscopy. Overall, these data demonstrate that B-1 cells are pivotal in the mechanisms of foreign-body GC formation in the mouse.     

Citrobacter rodentium lifA/efa1 is essential for colonic colonization and crypt cell hyperplasia in vivo

Previously, we have identified a large gene (lifA, for lymphocyte inhibitory factor A) in enteropathogenic Escherichia coli (EPEC) encoding a protein termed lymphostatin that suppresses cytokine expression in vitro. This protein also functions as an adhesion factor for enterohemorrhagic E. coli (EHEC) and Shiga toxin-producing E. coli and is alternatively known as efa1 (EHEC factor for adherence 1). The lifA/efa1 gene is also present in Citrobacter rodentium, an enteric pathogen that causes a disease termed transmissible murine colonic hyperplasia (TMCH), which induces colitis and massive crypt cell proliferation, in mice. To determine if lifA/efa1 is required for C. rodentium-induced colonic pathology in vivo, three in-frame mutations were generated, disrupting the glycosyltransferase (GlM12) and protease (PrMC31) motifs and a domain in between that does not encode any known activity (EID3). In contrast to infection with wild-type C. rodentium, that with any of the lifA/efa1 mutant strains did not induce weight loss or TMCH. Enteric infection with motif mutants GlM12 and PrM31 resulted in significantly reduced colonization counts during the entire 20-day course of infection. In contrast, EID3 was indistinguishable from the wild type during the initial colonic colonization, but cleared rapidly after day 8 of the infection. The colonic epithelium of all infected mice displayed increased epithelial regeneration. However, significantly increased regeneration was observed by day 20 only in mice infected with the wild-type in comparison to those infected with lifA/efa1 mutant EID3. In summary, lifA/efa1 is a critical gene outside the locus for enterocyte effacement that regulates bacterial colonization, crypt cell proliferation, and epithelial cell regeneration.     

Heat-shock induced nuclear retention and recycling inhibition of importin alpha

Heat-shock induces a strong stress response and modifies all aspects of cellular physiology, which involves dynamic changes in the nucleocytoplasmic distributions of a variety of proteins. Many distinct nucleocytoplasmic transport pathways exist in eukaryotic cells, but how a particular transport pathway is regulated under different cellular conditions remains elusive. The finding of this study indicate that conventional nuclear import, which is mediated by importin alpha/beta, is down-regulated, while the nuclear import of 70 kD heat-shock cognate protein is up-regulated in heat-shock cells. Among the factors involved in the mediation of the conventional nuclear import, significant levels of importin alpha accumulate in the nucleus in response to heat-shock. An analysis of the behaviour of importin alpha with fluorescence recovery after photobleaching and fluorescence loss in photobleaching studies show that nuclear importin alpha becomes less mobile and its nucleocytoplasmic recycling is impaired in heat-shock cells. These data coincided well with biochemical and cytological studies. Our present data show that heat-shock induces the nuclear accumulation, nuclear retention, and recycling inhibition of importin alpha, resulting in the suppression of conventional nuclear import. This suggests a new regulatory mechanism for the adaptation of cells to environmental changes, such as heat-shock.     

Direct evidence for granuloma-inducing activity of interleukin-1. Induction of experimental pulmonary granuloma formation in mice by interleukin-1-coupled beads.

Pulmonary granulomas were induced in BALB/c mice by the intratracheal injection of Sephadex G-50 and latex beads. Very large granulomas developed around Sephadex G-50 beads. Minimal inflammation was produced in mice given latex beads. Aqueous extracts prepared from pulmonary granuloma lesions induced in mice by Sephadex G-50 beads contained high levels of interleukin-1 (IL-1) activity but not interleukin-2 (IL-2) activity. IL-1 activity in the extracts correlated with granuloma size. In a subsequent step, large granulomas were induced by the intratracheal injection of Sepharose 4B beads coupled to fractions of the extracts containing IL-1 activity (ie, granuloma-derived IL-1) prepared from Sephadex G-50-induced granulomatous lungs. In addition, large granulomas were induced by the intratracheal injection of recombinant IL-1-coated Sepharose 4B beads. In contrast, very small granulomas were seen when IL-2-coated or plain Sepharose 4B beads were injected into mice. These results indicate that IL-1 participates in the induction and/or expression of granulomas.     

Basic study on wartime reminiscences of older adults in Okinawa

This study investigated retrospectively the thoughts people had of World War II, especially the Battle of Okinawa at that time, and their current evaluation of their own wartime experience. A questionnaire survey was conducted, and 217 older adults, 114 women and 103 men between 65 and 88 years old, participated. Results indicated that men generally had more negative feelings than women at the end of the war. And psychological damages caused by traumatic war memories seemed to have persisted in not a few individuals in spite of over half a century since the end of the war. However, others had been more positive and accepting toward their wartime experiences. This difference appeared to be related to qualitative differences of various experiences, as well as the person's age. It is argued that a vigorous approach will be necessary for this sort of study of Japanese war victims from a number of viewpoints.