Long-term effectiveness of right septal pacing vs. right apical pacing in patients with atrioventricular block

AbstractBackgroundLong-term right ventricular apical (RVA) pacing increases the risk of heart failure (HF) by inducing ventricular dyssynchronization. Although recent studies suggest that right ventricular septal (RVS) pacing results in improved short-term outcomes, its long-term effectiveness remains unclear.Methods and resultsThis study investigated 149 consecutive patients who underwent implantation of a dual chamber pacemaker for atrioventricular block with either RVS-pacing between July 2007 and June 2010 or RVA-pacing between January 2003 and June 2007. The endpoint was defined as death and hospitalization due to heart failure (HF). The rates of mortality and hospitalization due to HF were significantly lower in the RVS-pacing group than that in the RVA-pacing group (event free RVS: 1 year, 98% and 2 years, 98%; RVA: 1 year, 85% and 2 years, 81%; p<0.05). None of the patients died from HF in the RVS-pacing group, while 4 patients died from HF in the RVA-pacing group within 2 years after pacemaker implantation. The paced QRS interval was significantly shorter with RVS pacing than with RVA pacing at different times after pacemaker implantation (RVS: immediately 157.8±24.0ms, after 3 months 157.3±17.5ms, after 6 months 153.6±21.7ms, after 12 months 153.6±19.4ms, after 24 months 149.3±24.0ms vs. RVA: immediately 168.3±23.7ms, after 3 months 168.7±26.0ms, after 6 months 168.0±22.8ms, after 12 months 171.2±22.3ms, after 24 months 176.1±25.5ms; p<0.05).ConclusionsRVS pacing is feasible and safe with more favorable clinical benefits than RVA pacing

Root PRR7 improves the accuracy of the shoot circadian clock through nutrient transport

The circadian clock allows plants to anticipate and adapt to periodic environmental changes. Organ- and tissue-specific properties of the circadian clock and shoot-to-root circadian signaling have been reported. While this long-distance signaling is thought to coordinate physiological functions across tissues, little is known about the feedback regulation of the root clock on the shoot clock in the hierarchical circadian network. Here, we show that the plant circadian clock conveys circadian information between shoots and roots through sucrose and K⁺. We also demonstrate that K+ transport from roots suppresses the variance of period length in shoots and then improves the accuracy of the shoot circadian clock. Sucrose measurements and qPCR showed that root sucrose accumulation was regulated by the circadian clock. Furthermore, root circadian clock genes, including PSEUDO-RESPONSE REGULATOR7 (PRR7), were regulated by sucrose, suggesting the involvement of sucrose from the shoot in the regulation of root clock gene expression. Therefore, we performed time-series measurements of xylem sap and micrografting experiments using prr7 mutants and showed that root PRR7 regulates K⁺ transport and suppresses variance of period length in the shoot. Our modeling analysis supports the idea that root-to-shoot signaling contributes to the precision of the shoot circadian clock. We performed micrografting experiments that illustrated how root PRR7 plays key roles in maintaining the accuracy of shoot circadian rhythms. We thus present a novel directional signaling pathway for circadian information from roots to shoots and propose that plants modulate physiological events in a timely manner through various timekeeping mechanisms

Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer.

Despite recent progress in therapeutic strategies, prognosis of metastatic triple-negative breast cancer (TNBC) remains dismal. Evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1s) is critical for the generation of CD8+ T cells that mediate the regression of mammary tumors and potentiate anti-PD-1/PD-L1 therapeutic efficacy. However, it remains unknown whether this strategy is effective against metastatic TNBC, which is poorly responsive to immunotherapy. Here, using a mouse model of TNBC, we established orthotopic mammary tumors and brain metastases, and treated mammary tumors with in situ immunomodulation (ISIM) consisting of intratumoral injections of Flt3L to mobilize cDC1s, local irradiation to induce immunogenic tumor cell death, and TLR3/CD40 stimulation to activate cDC1s. ISIM treatment of the mammary tumor increased circulating T cells with effector phenotypes, and infiltration of CD8+ T cells into the metastatic brain lesions, resulting in delayed progression of brain metastases and improved survival. Furthermore, although anti-PD-L1 therapy alone was ineffective against brain metastases, ISIM overcame resistance to anti-PD-L1 therapy, which rendered these tumor-bearing mice responsive to anti-PD-L1 therapy and further improved survival. Collectively, these results illustrate the therapeutic potential of multimodal intralesional therapy for patients with unresectable and metastatic TNBC

Fibroblast growth factor 23 mediates the phosphaturic actions of cadmium

Phosphaturia has been documented following cadmium (Cd) exposure in both humans and experimental animals. The fibroblast growth factor 23 (FGF23)/klotho axis serves as an essential phosphate homeostasis pathway in the bone-kidney axis. In the present study, we investigated the effects of Cd on phosphate (Pi) homeostasis in mice. Following Cd injection into WT mice, plasma FGF23 concentration was significantly increased. Urinary Pi excretion levels were significantly higher in Cd-injected WT mice than in control group. Plasma Pi concentration decreased only slightly compared with control group. No change was observed in plasma parathyroid hormone and 1,25-dihydroxy vitamin D3 in both group of mice. We observed a decrease in phosphate transport activity and also decrease in expression of renal phosphate transporter SLC34A3 [NaPi-IIc/NPT2c], but not SLC34A1 [NaPi-IIa/NPT2a]. Furthermore, we examined the effect of Cd on Npt2c in Npt2a-knockout (KO) mice which expresses Npt2c as a major NaPi co-transporter. Injecting Cd to Npt2aKO mice induced significant increase in plasma FGF23 concentration and urinary Pi excretion levels. Furthermore, we observed a decrease in phosphate transport activity and renal Npt2c expression in Cd-injected Npt2a KO mice. The present study suggests that hypophosphatemia induced by Cd may be closely associated with the FGF23/klotho axis

Identification and functional analysis of a splice variant of mouse sodium-dependent phosphate transporter Npt2c

Mutations in the SLC34A3 gene, a sodium-dependent inorganic phosphate (Pi) cotransporter, also referred to as NaPi IIc, causes hereditary hypophosphatemic rickets with hypercalciuria (HHRH), an autosomal recessive disorder. In human and rodent, NaPi IIc is mainly localized in the apical membrane of renal proximal tubular cells. In this study, we identified mouse NaPi IIc variant (Npt2c-v1) that lacks the part of the exon 3 sequence that includes the assumed translation initiation site of Npt2c. Microinjection of mouse Npt2c-v1 cRNA into Xenopus oocytes demonstrated that Npt2c-v1 showed sodium-dependent Pi cotransport activity. The characterization of pH dependency showed activation at extracellular alkaline-pH. Furthermore, Npt2c-v1 mediated Pi transport activity was significantly higher at any pH value than those of Npt2c. In an in vitro study, the localization of the Npt2c-v1 protein was detected in the apical membrane in opossum kidney cells. The expression of Npt2c-v1 mRNA was detected in the heart, spleen, testis, uterus, placenta, femur, cerebellum, hippocampus, diencephalon and brain stem of mouse. Using mouse bone primary cultured cells, we showed the expression of Npt2c-v1 mRNA. In addition, the Npt2c protein was detected in the spermatozoa head. Thus, Npt2c-v1 was expressed in extra-renal tissues such as epididymal spermatozoa and may function as a sodium-dependent phosphate transporter

Recurrence of Atrial Fibrillation within Three Months after Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation : Analysis Using an External Loop Recorder with Auto-trigger Function

Pulmonary vein isolation (PVI) via catheter ablation has been shown to be a highly effective option for patients with symptomatic paroxysmal atrial brillation (AF). The recurrence of AF within 3 months after PVI is not considered a failure of the ablation procedure because early recurrence of AF is not always associated with late recurrence. We examined the usefulness of an external loop recorder with auto-trigger function (ELR-AUTO) to detect AF following PVI to characterize early recurrence and determine the implication of AF within 3 months after PVI. The study included 53 consecutive patients with symptomatic paroxysmal AF (age, 61.6 ± 12.6 years ; 77％ male) who underwent PVI, and were fitted with an ELR-AUTO for 7 ± 2 days within 3 months after PVI. Of the 33 patients(62.2％) who did not have AF within the 3-month period, only 1 patient had AF recurrence at 12 months. Seven of 20 patients (35％) who experienced AF within 3 months had symptomatic AF recurrence at 12 months. The sensitivity, specificity, positive predictive value, and negative predictive value of early AF recurrence for late recurrence was 87.5％, 71.1％, 35.0％, and 96.9％, respectively. Thus, AF recurrence detected by ELR-AUTO within 3 months after PVI can predict late AF recurrence. Freedom from AF in the firrst 3 months following ablation significantly predicts long-term freedom from AF. An ELR-AUTO is useful for detecting symptomatic and asymptomatic AF

Effects of Musical Activities on Children in Japan with Diverse Cultural or Lingual Backgrounds: Enhancing Children’s Emotional Well-being

Recently, due to an increase in children from diverse cultural and lingual backgrounds in Japan, arts activities that help them to maintain stable emotions and strengthen their sense of self-esteem have become as important as linguistic education. This study aims to clarify the effects of musical activities on foreign children living in Japan. Nine children aged four to eight years attending extracurricular Japanese language classes participated in a music workshop. A questionnaire based on the mood checklist was administered before and after the workshop. The results showed that the positive mood state (pleasantness, relaxation) decreased slightly, and the negative mood state (anxiety) increased, despite eight out of nine children answering, “I really enjoyed myself.” On individual examination, one of the children showed an increase in the positive mood state and a decrease in the negative mood state. Six children registered positive mood changes or maintained the highest score for positive mood or the lowest score for negative mood. The two children did not exhibit any productivity. Based on the results of the mood checklist and the children’s individual situations, most of the children had some positive changes after the workshop. In conclusion, the results suggest that musical activities can positively affect children’s emotions, and percussion performance can contribute to an increased positive mood with a feeling of satisfaction.This research was supported by JSPS KAKENHI Grant Number JP19K0276

若年者を基準とした高齢者の歩行動作評価の試み

2011年の報告によれば，日本では65歳以上の高齢者人口は2975万人で，総人口に占める割合，いわゆる高齢化率は23.3％となった．このように増加している高齢者が健康な老後を送るためには，高齢者個々人が日々QOL（Quality of Life：生活の質）の維持・向上に努めることが大切である．QOL維持のためには，ADL（Activities of Daily Living：日常生活動作）を支障なく遂行出来る事が必要不可欠と考えられる．そして，ADLの中でも特に様々な活動の根幹となる動作である歩行は重大な役割を担っている．したがって，高齢者が自身の歩行能力とその改善点を具体的に知ることは重要であろう．また，同様に，高齢者に自身の歩行能力とその改善点をエビデンスをもって示すことはバイオメカニクス分野における重要な研究課題と位置付けられるであろう．本研究では若年者から高齢者までの広範な年齢層の男女の歩行動作について2次元動作分析を行い，次の二点を遂行することを目的とした．①若年者の歩行動作のバラつきの度合いと若年者からの歩行動作の逸脱度に基づき高齢者を含む各年代と若年者の歩行動作比較を行い，加齢に伴って変化する動作の特定を行うこと②高齢者の歩行動作評価を行い，歩行動作の改善点を提示する方法について検討すること研究対象とした被験者は健康な21歳から86歳までの男性117名，および19歳から82歳までの女性177名であり，年齢によって男性は4群，女性は8群に分けた．これらの被験者の歩行動作をビデオカメラまたはモーションキャプチャーシステムを用いて計測し，歩行中のキネマティクスおよびキネティクスなどの歩行パラメータを算出した．そして，若年者からの歩行動作の逸脱度を検討するために各パラメータについて被験者ごとに重み付きZスコアを算出した．分散分析を用いて各重み付きZスコアを各年齢群間で比較した結果，年齢と共に有意な変化を示すパラメータを特定し，男性及び女性の加齢に伴う歩行動作の変化を明らかにすることができた．また，レーダーチャートを利用して被験者ごとの各重み付けZスコアの値に注目することにより，若々しい歩行動作を行うための改善点を具体的な改善内容，目標数値と共に被験者へ提示する方法を提案できた．電気通信大学201

Clinical and immunological relevance of SLAMF6 expression in the tumor microenvironment of breast cancer and melanoma

Abstract Compelling evidence shows that the frequency of T cells in the tumor microenvironment correlates with prognosis as well as response to immunotherapy. However, considerable heterogeneity exists within tumor-infiltrating T cells, and significance of their genomic and transcriptomic landscape on clinical outcomes remains to be elucidated. Signaling lymphocyte activation molecule 6 (SLAMF6) is expressed on intra-tumoral progenitor-exhausted T cells, which exhibit the capacity to proliferate, self-renew and produce terminally-exhausted T cells in pre-clinical models and patients. Here, we investigated the impact of SLAMF6 expression on prognosis in two immunologically different tumor types using publicly available databases. Our findings demonstrate that high SLAMF6 expression is associated with better prognosis, expression of TCF7 (encoding T-cell factor 1), and increased gene signatures associated with conventional type 1 dendritic cells and effector function of T cells in melanoma and breast cancer. Single-cell profiling of breast cancer tumor microenvironment reveals SLAMF6 expression overlaps CD8 T cells with a T-effector signature, which includes subsets expressing TCF7, memory and effector-related genes, analogous to progenitor-exhausted T cells. These findings illustrate the significance of SLAMF6 in the tumor as a marker for better effector responses, and provide insights into the predictive and prognostic determinants for cancer patients