コウサンキュウ セイ ボウコウ エン ノ 1 レイ

症例は36歳男性.頻尿,排尿時痛,残尿感および食思不振を主訴に近医受診.抗生剤投与されるも症状軽快せず,当院紹介受診となる.初診時検査で,白血球,好酸球,IgEの上昇を認め,経腹膀胱超音波検査,MRIで膀胱壁の著明な肥厚を認めた.また,膀胱鏡検査では膀胱三角部を除く膀胱粘膜の著明な浮腫状所見を認め,上部消化管内視鏡検査では胃粘膜及び十二指腸粘膜も同様の浮腫状所見であった.確定診断のため膀胱全層針生検を施行し,病理所見では膀胱平滑筋内に著明な好酸球浸潤を認めたため好酸球性膀胱炎と診断.点滴ステロイド療法を開始し,症状軽快,画像上も改善を認めステロイド内服に切り替えたのち退院した.A 36-years-old man with pollakisuria and digestive symptom was referred to our hospital. A blood test showed inclease of serum white blood cell,eosinophil and IgE. Imaging study showed thickening of bladder wall, and endoscopy of bladder and stomach showed severe mucosal edema. Because there was a suspicion of the allergic diseases, we carried out transabdominal needle biopsy of bladder. Because of the pathological finding of severe eosinophilic infiltration into smooth muscle of urinary bladder, we diagnosed a case of eosinophilic cystitis. After that we started up steroid therapy immediately, he was recovering from pollakisuria and digestive symptom

HIV-1 Vpr accelerates viral replication during acute infection by exploitation of proliferating CD4+ T cells in vivo.

The precise role of viral protein R (Vpr), an HIV-1-encoded protein, during HIV-1 infection and its contribution to the development of AIDS remain unclear. Previous reports have shown that Vpr has the ability to cause G2 cell cycle arrest and apoptosis in HIV-1-infected cells in vitro. In addition, vpr is highly conserved in transmitted/founder HIV-1s and in all primate lentiviruses, which are evolutionarily related to HIV-1. Although these findings suggest an important role of Vpr in HIV-1 pathogenesis, its direct evidence in vivo has not been shown. Here, by using a human hematopoietic stem cell-transplanted humanized mouse model, we demonstrated that Vpr causes G2 cell cycle arrest and apoptosis predominantly in proliferating CCR5(+) CD4(+) T cells, which mainly consist of regulatory CD4(+) T cells (Tregs), resulting in Treg depletion and enhanced virus production during acute infection. The Vpr-dependent enhancement of virus replication and Treg depletion is observed in CCR5-tropic but not CXCR4-tropic HIV-1-infected mice, suggesting that these effects are dependent on the coreceptor usage by HIV-1. Immune activation was observed in CCR5-tropic wild-type but not in vpr-deficient HIV-1-infected humanized mice. When humanized mice were treated with denileukin diftitox (DD), to deplete Tregs, DD-treated humanized mice showed massive activation/proliferation of memory T cells compared to the untreated group. This activation/proliferation enhanced CCR5 expression in memory CD4(+) T cells and rendered them more susceptible to CCR5-tropic wild-type HIV-1 infection than to vpr-deficient virus. Taken together, these results suggest that Vpr takes advantage of proliferating CCR5(+) CD4(+) T cells for enhancing viremia of CCR5-tropic HIV-1. Because Tregs exist in a higher cycling state than other T cell subsets, Tregs appear to be more vulnerable to exploitation by Vpr during acute HIV-1 infection

Effect of Vpr on apoptosis and its relevance in G₂ cell cycle arrest in infected humanized mice.

<p>Splenic MNCs of WT HIV-1-infected mice (n = 7), <i>vpr</i>-deficient HIV-1-infected mice (n = 7), and mock-infected mice (n = 9) at 7 dpi were analyzed by flow cytometry using anti-active CASP3 and anti-HIV-1 p24 antibodies without (A and B) or with (C) or Hoechst33342. (A and B) Effect of Vpr on apoptosis. The percentages of active CASP3⁺ cells in CD3⁺ CD8⁻ cells (A) and in each population (B) are shown, respectively. Representative histograms are shown on the right panel. The numbers in the histogram indicate the percentage of active CASP3⁺ cells in each population. (C) Relevance between G₂ arrest and apoptosis. The percentage of active CASP3⁺ cells in each population is shown. Representative histograms are respectively shown. The numbers in the histogram indicate the percentage of active CASP3⁺ cells in each population. Statistical differences were determined by Welch's <i>t</i> test, and statistically significant differences (<i>P</i><0.05) are shown as follows: mock versus WT HIV-1, black asterisk; mock versus HIV-1<i>Δvpr</i>, blue asterisk; and WT HIV-1 versus HIV-1<i>Δvpr</i>, red asterisk. NS, no statistical significance. Data represent mean ± SEM.</p

Dynamics of R5 WT and <i>vpr</i>-deficient HIV-1 infection in humanized mice.

<p>(A) Viral load in infected humanized mice. The amounts of viral RNA in the plasma of R5 WT HIV-1-infected mice (n = 30) and R5 <i>vpr</i>-deficient HIV-1-infected mice (n = 23) were routinely quantified. The horizontal broken line indicates the detection limit of the assay (1,600 copies/ml). (B and C) Infected cells in humanized mice. HIV-1-infected cells in the spleen of R5 WT HIV-1-infected mice (n = 19), R5 <i>vpr</i>-deficient HIV-1-infected mice (n = 10), and mock-infected mice (n = 10) at 7 dpi were analyzed by flow cytometry using an anti-HIV-1 p24 antibody. The percentages of p24⁺ cells in CD3⁺ CD8⁻ cells (B) and in each CD4⁺ T cell subset (C, left panel), and the MFI of p24 in p24⁺ cells of each CD4⁺ T cell subset (C, middle panel) are shown. Representative histograms are shown on the right panel. In panel B, the numbers in the histogram indicate the positivity. In panel C, the numbers in the histogram indicate the percentage of positive cells (left) and MFI values (right). Statistical difference was determined by Welch's <i>t</i> test, and statistically significant differences between WT HIV-1 versus HIV-1<i>Δvpr</i> (<i>P</i><0.05) are shown with red asterisks. NS, no statistical significance. Data represent mean ± SEM.</p

Effect of Vpr on G₂ cell cycle arrest in infected humanized mice.

<p>Splenic MNCs of WT HIV-1-infected mice (n = 12), <i>vpr</i>-deficient HIV-1-infected mice (n = 11), and mock-infected mice (n = 15) at 7 dpi were analyzed by flow cytometry using Hoechst33342 and an anti-HIV-1 p24 antibody. (A and B) The percentages of G₂M cells in CD3⁺ CD8⁻ cells (A) and in each population (B) are shown, respectively. Representative histograms are shown on the right panel. The black arrowhead indicates the peak of G₀G₁ cells, and the red arrowhead indicates the peak of G₂M cells. The numbers in the histogram indicate the percentage of G₂M cells in each population. (C) The percentage of p24⁺ cells in each population (left) and the MFI of p24 in p24⁺ cells of each population (middle). Representative histograms are respectively shown. The numbers in the histogram indicate the percentage of positive cells (left) and MFI values (right). Statistical differences were determined by Welch's <i>t</i> test, and statistically significant differences (<i>P</i><0.05) are shown as follows: mock versus WT HIV-1, black asterisk; mock versus HIV-1<i>Δvpr</i>, blue asterisk; and WT HIV-1 versus HIV-1<i>Δvpr</i>, red asterisk. NS, no statistical significance. Data represent mean ± SEM.</p

Dynamics of X4 WT and <i>vpr</i>-deficient HIV-1 infection in humanized mice.

<p>(A and B) CXCR4 expression on CD4⁺ T cell subsets in human and humanized mouse. Human CD4⁺ T cells isolated from the spleen of humanized mice (A, n = 8) and the PB of HIV seronegative humans (B, n = 6) were classified into Tn, Tm, and Treg as described in the legend of <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003812#ppat-1003812-g001" target="_blank">Figure 1</a>. Representative dot plots and histograms are shown on the left, and the percentages of CXCR4⁺ cells in each subset are shown on the right. In the left panels, the numbers in each histogram indicate the positivity. (C) Viral load in infected humanized mice. The amounts of viral RNA in the plasma of X4 WT HIV-1-infected mice (n = 13) and X4 <i>vpr</i>-deficient HIV-1-infected mice (n = 11) were routinely quantified. The horizontal broken line indicates the detection limit of the assay (1,600 copies/ml). (D) Longitudinal analyses of the dynamics of human CD4⁺ T cell subsets in the PB of infected humanized mice. The numbers of total CD4⁺ T cells, Tns, Tms, and Tregs in the PB of WT HIV-1-infected mice (n = 9), <i>vpr</i>-deficient HIV-1-infected mice (n = 9), and mock-infected mice (n = 8) were routinely quantified by flow cytometry and hematocytometry. (E and F) Cytopathic effect of WT and <i>vpr</i>-deficient HIV-1 in the spleen of humanized mice. The percentages of total CD4⁺ T cells, Tns, Tms, and Tregs in the splenic MNCs of WT HIV-1-infected mice (n = 8), <i>vpr</i>-deficient HIV-1-infected mice (n = 8), and mock-infected mice (n = 8) at 21 dpi were routinely quantified by flow cytometry. Representative dot plots (E) and summarized results (F) are shown, respectively. In panel E, the numbers on the right of the dot plots indicate the percentage of the cells in each quadrant. (G) The level of immune activation in infected humanized mice. The MFI of CD38 in memory CD8⁺ T cells in the spleen of WT HIV-1-infected mice (n = 5), <i>vpr</i>-deficient HIV-1-infected mice (n = 5), and mock-infected mice (n = 5) at 21 dpi was analyzed by flow cytometry. Representative histograms are shown on the right panel, and the numbers in the histogram indicate the MFI values. NS, no statistical significance. Data represent mean ± SEM.</p

Comparison of the profile of CD4⁺ T cell subsets between human and humanized mouse.

<p>Human CD4⁺ T cells isolated from the spleen of humanized mice (A and C, n = 8) and the PB of HIV seronegative humans (B and D, n = 6) and were classified into Tn (CD45⁺ CD3⁺ CD4⁺ CD45RA⁺ FOXP3⁻ cells), Tm (CD45⁺ CD3⁺ CD4⁺ CD45RA⁻ FOXP3⁻ cells), and Treg (CD45⁺ CD3⁺ CD4⁺ CD45RA⁻ FOXP3⁺ cells) by flow cytometry. Representative dot plots and histograms are shown on the left panels. The percentage of each subset in CD4⁺ T cells (A and B, top) and the percentages of the cells positive for CD25, CD127, CTLA4, CCR5, and MKI67 in each subset are respectively shown on the right panels. In the left panels, the numbers under the dot plots (A and B, top) indicate the percentage of the cells in each quadrant, and the numbers in each histogram indicate the positivity. Data represent mean ± SEM.</p

Augmentation of Vpr's effect and HIV-1 propagation by Treg depletion.

<p>(A to D) Evaluation of Treg depletion by treatment with DD. DD was administrated into humanized mice (n = 14) as described in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003812#s4" target="_blank">Materials and Methods</a>. (A and B) Specific depletion of Tregs by treatment with DD. The levels of human white blood cells (WBC; CD45⁺ cells) and CD4⁺ T cell subsets in PB of humanized mice before and after the DD treatment for 3 days were compared. Representatives (A) and the numbers of each human leukocytes in PB (B) are shown. In panel A, the numbers in the histogram indicate the percentage of CD4⁺ cells in CD45⁺ CD3⁺ cells, and the numbers on the right of the dot plots indicate the percentage of the cells in each quadrant. (C and D) Immune activation by treatment with DD. The percentages of MKI67⁺ cells in memory CD8⁺ T cells (C) and in each CD4⁺ T cell subset (D) in the spleen of humanized mice treated with (n = 5) or without (n = 8) DD for 7 days are shown, respectively. (E) Up-regulation of CCR5 expression by DD treatment. The percentage of CCR5⁺ cells in each CD4⁺ T cell subset in the spleen of humanized mice treated with (n = 5) or without (n = 8) DD for 7 days is shown. In panels C to E, the numbers in the histogram indicate positivity. (F to H) Dynamics of HIV-1 infection in DD-treated humanized mice. (F) The numbers of peripheral CD4⁺ T cells, Tns, Tms, and Tregs (F) and the amounts of viral RNA in the plasma (G) of R5 WT HIV-1-infected DD-treated mice (n = 13), R5 <i>vpr</i>-deficient HIV-1-infected DD-treated mice (n = 13), and mock-infected DD-treated mice (n = 8) were routinely quantified as described in the legends of <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003812#ppat-1003812-g002" target="_blank">Figure 2A</a> and <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003812#ppat-1003812-g003" target="_blank">3A</a>, respectively. In panel G, the broken black and blue lines indicate the averages of WT HIV-1-infected mice (n = 30) and <i>vpr</i>-deficient HIV-1-infected mice (n = 23) without DD treatment, which corresponds to the results shown in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003812#ppat-1003812-g003" target="_blank">Figure 3A</a>. The horizontal broken line indicates the detection limit of the assay (1,600 copies/ml). (H) Kinetics of viral expansion. The slopes of the amounts of viral RNA in the plasma of WT HIV-1-infected DD-treated mice (n = 13), <i>vpr</i>-deficient HIV-1-infected DD-treated mice (n = 13), WT HIV-1-infected mice (n = 30) and <i>vpr</i>-deficient HIV-1-infected mice (n = 23) until 7 dpi are shown. Statistical difference was determined by Welch's <i>t</i> test. In panels B to E, statistically significant differences (<i>P</i><0.05) are indicated by red asterisks. In panels F and G, statistically significant differences (<i>P</i><0.05) are shown as follows: mock versus WT HIV-1, black asterisk; mock versus HIV-1<i>Δvpr</i>, blue asterisk; and WT HIV-1 versus HIV-1<i>Δvpr</i>, red asterisk. In panel H, statistically significant differences (<i>P</i><0.05) are shown as follows: with and without DD treatment, black asterisk; and WT HIV-1 versus HIV-1<i>Δvpr</i>, red asterisk. NS, no statistical significance. Data represent mean ± SEM. NA, not analyzed.</p

Tolerability, Efficacy, and Safety of Bisoprolol vs. Carvedilol in Japanese Patients With Heart Failure and Reduced Ejection Fraction - The CIBIS-J Trial -

Background: The comparative tolerability, efficacy, and safety of bisoprolol and carvedilol have not been established in Japanese patients with heart failure and reduced ejection fraction (HFrEF). Methods and Results: The CIBIS-J trial is a multicenter, open-label, non-inferiority randomized controlled trial of bisoprolol vs. carvedilol in 217 patients with HFrEF (EF <= 40%). The primary endpoint was tolerability, defined as reaching and maintaining the maximum maintenance dose (bisoprolol 5 mg/day or carvedilol 20 mg/day) during 48 weeks of treatment. The primary endpoint was achieved in 41.4% of patients in bisoprolol (n=111) and 42.5% in carvedilol (n=106) groups. The non-inferiority of tolerability of bisoprolol compared with carvedilol was not supported, however, neither beta-blocker was superior with regard to tolerability. Heart rate (HR) decreased in both groups and its decrease from baseline was significantly greater in the bisoprolol group (20.3 vs. 15.4 beats/min at 24 week, P<0.05). Plasma B-type natriuretic peptide (BNP) levels decreased in both groups and the decrease was significantly greater in the carvedilol group (12.4 vs. 39.0 % at 24 weeks, P<0.05). Conclusions: There were no significant differences between bisoprolol and carvedilol in the tolerability of target doses in Japanese HFrEF patients. The clinical efficacy and safety were also similar despite the greater reduction in HR by bisoprolol and plasma BNP by carvedilol