Phenotype and cytokine production of Lamina Propria Mononuclear Cells from Endoscopic Biopsy Specimens in Untreated Patients with Ulcerative Colitis

The phenotype of, and the production of interleukinl-β(Ｉ L-1β)and interleukin 6(IL、-6)by lamina propria mononuclear cells (LPMNC) were studied in 25 patients with ulcerative colitis (UC) (11 with untreated active disease and 14 inactive disease), and 18 control subjects. The percentage of CD4+ cells, CD20+ cells, CD3+, CD25+ cells and CD3+, HLA-DR+ cells was significantly higher in patients with active UC than in control patients, however, the percentage of CD8+ cells was significantly lower in patients with active UC than in patients with inactive UC and controls. IL-1 β was detected in nine of the ll patients(82%) with active UC but in only two of the 14 patients (14 %) with inactive UC and three of the 18 control subjects (17 %). The amount of IL-6 in patients with active UC was significantly higher than in patients with inactive UC and in controls. These results suggest that IL-1β and IL-6 mediate immune responses, and may be associated with inflammation and the etiopathogenesis of UC

Effects of Dexamethasone on Interleukin-6 and Immunoglobulins Production by Lamina Propria Mononuclear Cells Isolated from Biopsy Specimens in Patients with Ulcerative Colitis

Lamina propria mononuclear cells (LPMNC) were isolated from 20 untreated patients with active ulcerative colitis (UC) and 11 patients with inactive UC. All patients with active UC were first attacks, and were not being treated with any drugs. The effects of dexamethasone on production of interleukin-6 (IL-6) and immunoglobulins by LPMNC were assessed. IL-6 production by LPMNC, stimulated by pokeweed mitogen (PWM), was higher in patients with active UC (663.3±213.1 pg/ml) compared with normal controls (129.0 ±39.0 pg/ml) and patients with inactive UC (219.6 ± 63.4 pg/ ml). IgG was produced in greater amount by the LPMNC from patients with active UC (1395.5 ± 876.6 ng/ml) than by those from controls (413.0 ± 471.2 ng/ml) and patients with inactive UC (488.3±552.0 ng/ml) (p < 0.001). The amount of IgA and IgM did not vary among three groups. Dexamethasone suppressed the production of IL-6 and IgA, IgG and IgM by PWM-stimulated LPMNC in a dose-dependent manner in the dose range between 10-5and 10-2 mg/dl. We speculate that the suppression of IL-6 production by dexamethasone will contribute to the suppression of UCassociated inflammatio

KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels

KUS121は新規の心不全治療薬となる --Ca2+負荷なしに血行動態を改善--. 京都大学プレスリリース. 2023-12-15.[Aims] As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhibit the ATPase activity of valosin-containing protein, maintain cellular ATP levels, and manifest cytoprotective effects in several pathological conditions. The aim of this study is to determine the therapeutic effect of KUS121 on HF models. [Methods and results] Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a transverse aortic constriction (TAC)-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca²⁺ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors. [Conclusions] KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF

Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan

[Background] Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). [Methods] This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. [Results] Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6–1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2–2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8–3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). [Conclusions] New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD

Sodium Channelopathy Underlying Familial Sick Sinus Syndrome With Early Onset and Predominantly Male Characteristics

Background-Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identifcation of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. Methods and Results-We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identifed 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was signifcantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3±0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9±3.4 years). Conclusions-The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations

Reduced mortality during the COVID-19 outbreak in Japan, 2020: a two-stage interrupted time-series design.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to be a major global health burden. This study aims to estimate the all-cause excess mortality occurring in the COVID-19 outbreak in Japan, 2020, by sex and age group. METHODS: Daily time series of mortality for the period January 2015-December 2020 in all 47 prefectures of Japan were obtained from the Ministry of Health, Labour and Welfare, Japan. A two-stage interrupted time-series design was used to calculate excess mortality. In the first stage, we estimated excess mortality by prefecture using quasi-Poisson regression models in combination with distributed lag non-linear models, adjusting for seasonal and long-term variations, weather conditions and influenza activity. In the second stage, we used a random-effects multivariate meta-analysis to synthesize prefecture-specific estimates at the nationwide level. RESULTS: In 2020, we estimated an all-cause excess mortality of -20 982 deaths [95% empirical confidence intervals (eCI): -38 367 to -5472] in Japan, which corresponded to a percentage excess of -1.7% (95% eCI: -3.1 to -0.5) relative to the expected value. Reduced deaths were observed for both sexes and in all age groups except those aged <60 and 70-79 years. CONCLUSIONS: All-cause mortality during the COVID-19 outbreak in Japan in 2020 was decreased compared with a historical baseline. Further evaluation of cause-specific excess mortality is warranted

A distinct subtype of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder: adult patients with chronic active Epstein-Barr virus infection-like features

The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onse

Molecular analysis of the BCR-ABL1 kinase domain in chronic-phase chronic myelogenous leukemia treated with tyrosine kinase inhibitors in practice: Study by the Nagasaki CML Study Group

An appropriate trigger for BCR-ABL1 mutation analysis has not yet been established in unselected cohorts of chronic-phase chronic myelogenous leukemia patients. We examined 92 patients after 12 months of tyrosine kinase inhibitor (TKI) treatment in Nagasaki Prefecture, Japan. Univariate analysis revealed that significant factors associated with not attaining a major molecular response (MMR) were the presence of the minor BCR-ABL1 fusion gene, a low daily dose of TKI, and the emergence of BCR-ABL1 kinase domain mutations conferring resistance to imatinib. Factors associated with the loss of sustained MMR were a low daily dose of TKI and the emergence of alternatively spliced BCR-ABL1 mRNA with a 35-nucleotide insertion. Taken together, our results suggest that the search for BCR-ABL1 mutations should be initiated if patients have not achieved MMR following 12 months of TKI treatment