BackgroundThe intestine is one of the first affected organs in Parkinson’s disease (PD). PD subjects show abnormal staining for Escherichia coli and α-synuclein in the colon.MethodsWe recruited 52 PD patients and 36 healthy cohabitants. We measured serum markers and quantified the numbers of 19 fecal bacterial groups/genera/species by quantitative RT-PCR of 16S or 23S rRNA. Although the six most predominant bacterial groups/genera/species covered on average 71.3% of total intestinal bacteria, our analysis was not comprehensive compared to metagenome analysis or 16S rRNA amplicon sequencing.ResultsIn PD, the number of Lactobacillus was higher, while the sum of analyzed bacteria, Clostridium coccoides group, and Bacteroides fragilis group were lower than controls. Additionally, the sum of putative hydrogen-producing bacteria was lower in PD. A linear regression model to predict disease durations demonstrated that C. coccoides group and Lactobacillus gasseri subgroup had the largest negative and positive coefficients, respectively. As a linear regression model to predict stool frequencies showed that these bacteria were not associated with constipation, changes in these bacteria were unlikely to represent worsening of constipation in the course of progression of PD. In PD, the serum lipopolysaccharide (LPS)-binding protein levels were lower than controls, while the levels of serum diamine oxidase, a marker for intestinal mucosal integrity, remained unchanged in PD.ConclusionsThe permeability to LPS is likely to be increased without compromising the integrity of intestinal mucosa in PD. The increased intestinal permeability in PD may make the patients susceptible to intestinal dysbiosis. Conversely, intestinal dysbiosis may lead to the increased intestinal permeability. One or both of the two mechanisms may be operational in development and progression of PD.

We have hypothesized that T cell cytokines participate in the pathogenesis of graft arterial disease (GAD). This study tested the consequences of IFN-␥ deficiency on arterial and parenchymal pathology in murine cardiac allografts. Hearts from C-H-2 bm12 KhEg (bm12, H-2 bm12 ) were transplanted into C57/B6 (B6, H-2 b ), wild-type, or B6 IFN-␥ -deficient (GKO) recipients after immunosuppression by treatment with anti-CD4 and anti-CD8 mAbs. In wild-type recipients, myocardial rejection peaked at 4 wk, (grade 2.1 Ϯ 0.3 out of 4, mean Ϯ SEM, n ϭ 9), and by 8-12 wk evolved coronary arteriopathy. At 12 wk, the GAD score was 1.4 Ϯ 0.3, and the parenchymal rejection grade was 1.2 Ϯ 0.3 ( n ϭ 8). In GKO recipients of bm12 allografts, myocardial rejection persisted at 12 wk (grade 2.5 Ϯ 0.3, n ϭ 6), but no GAD developed (score: 0.0 Ϯ 0.0, n ϭ 6, P Ͻ 0.01 vs. wild-type). Mice treated with anti-IFN-␥ mAbs showed similar results. Isografts generally showed no arterial changes. In wild-type recipients, arterial and parenchymal cells showed increased MHC class II molecules, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 compared to normal or isografted hearts. The allografts in GKO recipients showed attenuated expression of these molecules ( n ϭ 6). Thus, development of GAD, but not parenchymal rejection, requires IFN-␥ . Reduced expression of MHC antigens and leukocyte adhesion molecules may contribute to the lack of coronary arteriopathy in hearts allografted into GKO mice. ( J. Clin. Invest. 1997. 100:550-557.)

This paper proposes a new MOS-gate transistor structure (IEGT) for the first time, that realizes enhanced electron injection so that the carrier distribution takes a form similar to that of a thyristor and a low forward voltage drop is attained even for 4500 V devices.A developed simple analytical one dimensional model can predict a sufficiently accurate current voltage curve and clarifies a new design criterion for IEGT operation, A fabricated 4500 V IEGT realized a 2 . 5 V forward voltage drop at 100 A/cmz. The IEGT had a current density over ten times that of the conventional trench gate IGBT at 2 . 5 V forward voltage drop, An operation mode of IEGT has been theoretically and experimentally confirmed. IEDM Technical b e s t .

In solid-tissue allografts, donor vascular cells as well as recipient inflammatory cells can express MHC class II molecules. However, it is uncertain how much residual donor endothelium persists and to what extent donor versus recipient MHC class II expression can contribute to the ongoing immune response, especially in long-term grafts. To establish the origin of class-II-expressing cells in the allograft, we evaluated the expression of donor- or recipient-specific MHC class II molecules in murine cardiac allografts. Donor hearts from BALB/c (H-2d) mice were transplanted into C57BL/6 (B6, H-2b) recipients; B6 isografts served as controls. Untreated allografts ceased functioning at approximately 7 days with severe parenchymal rejection. Allografts from recipients treated with anti-CD4 and anti-CD8 MAbs after transplantation were explanted at 8 to 12 weeks and demonstrated intimal fibroproliferative lesions with a mild parenchymal mononuclear cell infiltrate. Class II expression in isografts was limited to epicardial macrophages. Both acutely rejecting and long-term allografts contained abundant macrophages expressing recipient class II molecules. Occasional cells (passenger leukocytes) in untreated, acutely rejecting allografts bore donor class II molecules; long-term allografts contained few such cells. In contrast, vascular endothelial and medial smooth muscle cells consistently expressed donor class II molecules. These results suggest that ongoing MHC class II expression in donor vascular cells, as well as in recipient macrophages, may contribute to sustained activation of host T cells with consequent release of cytokines that ultimately promote the development of graft arteriosclerosis.

Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of meclozine administration in clinical settings, we investigated the effects of meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without meclozine treatment. In Fgfr3(ach) mice, meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, meclozine also increased bone growth in wild-type mice. The plasma concentration of meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of meclozine in a growth period suggests potential clinical feasibility of meclozine for the improvement of short stature in ACH.

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Interplay between T-helper-1 (Th1) and T-helper-2 (Th2) cells is considered important in the development of acute allograft rejection and many other immune-mediated disease processes. Existing methods for evaluating expression of Th1 and Th2 cytokines, including reverse transcriptase polymerase chain reaction (RT-PCR), RNase protection assay (RPA), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) all have limitations; alternate techniques to quantify cell populations expressing specific cytokine proteins, generate statistically analyzable data, and allow simultaneous identification of cytokine-secreting cell type are needed. To this end, we adapted a flow cytometric technique for intracellular cytokine immunofluorescence staining for use with cells isolated from solid tissue. To demonstrate the utility of the method, we determined the number of CD4+ and CD8+ cells secreting the prototypical Th1 and Th2 cytokines, interferon (IFN)-gamma, and interleukin (IL)-4 in acutely rejecting murine cardiac allografts. We also measured the cytokine production via ELISA, RPA, and semiquantitative competitive RT-PCR. The number of CD4+ cells producing IFN-gamma increased as rejection proceeded, in agreement with previous data; we detected no IL-4 production at any time, although relatively low numbers of IL-10-producing cells were identified. In addition, a high percentage of CD8+ cells, which outnumber CD4+ cells at day 6 after transplant, also produce IFN-gamma, suggesting that cytotoxic lymphocytes contribute significantly to the local cytokine milieu. This new application of intracellular cytokine staining provides a powerful methodology for studying transplantation immunology. The method may also be easily adapted to the study of other immune-mediated processes.

Exercise hyperpnea was compared in 5 asthmatics 25 yr after bilateral carotid body resection (BR), 4 others 19 yr after unilateral resection (UR), and 12 controls (C) matched for age and pulmonary flow limitation. In the BR group, ventilation rose less with exercise, mostly because BR experienced less tachypnea. End-tidal PCO2 rose 5.8 +/- 3.2 (P less than 0.05) to 46 Torr at 50 W. In UR and C the same load did not increase PETCO2 significantly (+2.1 and +1.4 Torr, respectively). Arterial-end-tidal PCO2 differences before and 15--45 s postexercise were insignificant in all three groups. Heart rate and blood pressure rose equally in the three groups, suggesting that the ventilatory effects were not secondary to blood flow differences and disclosing no evidence of baroreceptor denervation during glomectomy.