In connection with our studies on antibacterial compounds in the class of 5-dialkylaminomethylhydantoins against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains, ...some molecular modifications were attempted. The antibacterial activities of all of the synthesized hydantoin derivatives were evaluated. Among the hydantoin derivatives designed in this study, C2-symmetrical twin-drug type compound (7) showed the highest level of antibacterial activity against S. aureus strain.
Autophagy is a conserved process that enables catabolic and degradative pathways. Rab family proteins, which are active in the GTP-bound form, regulate the transport and fusion of autophagosomes. ...However, it remains unclear how each cycle of Rab activation and inactivation is precisely regulated. Here, we show that leucine-rich repeat kinase 1 (LRRK1) regulates autophagic flux by controlling Rab7 activity in autolysosome formation. Upon induction of autophagy, LRRK1 was recruited via an association with VAMP7 to the autolysosome, where it activated the Rab7 GTPase-activating protein (GAP) TBC1D2, thereby switching off Rab7 signaling. Consistent with this model, LRRK1 deletion caused mice to be vulnerable to starvation and disrupted autolysosome formation, as evidenced by the accumulation of enlarged autolysosomes with undegraded LC3-II and persistently high levels of Rab7-GTP. This defect in autophagic flux was partially rescued by a mutant form of TBC1D2 with elevated Rab7-GAP activity. Thus, the spatiotemporal regulation of Rab7 activity during tunicamycin-induced autophagy is regulated by LRRK1.
Transcatheter aortic valve implantation (TAVI) is criticized by some as an expensive treatment in super-elder patients with limited life expectancy. However, there is a knowledge gap regarding the ...magnitude of clinical benefit provided by TAVI in comparison with conservative management in patients with severe aortic stenosis (AS) in real clinical practice, which would be important in the decision making for TAVI.
We combined two independent registries, namely CURRENT AS and K-TAVI registries. CURRENT AS was a multicenter registry enrolling 3815 consecutive patients with severe AS irrespective to treatment modalities between January 2003 and December 2011. K-TAVI was a multicenter, prospective registry including 449 consecutive patients with severe AS, who underwent TAVI with SAPIEN XT balloon-expandable valves between October 2013 and June 2016. In these 2 registries, 449 patients received TAVI and 894 patients were managed with conservative strategy. We conducted propensity score matching and finally obtained a cohort of 556 patients (278 patients for each group) for the analysis. The primary outcome measures were all-cause death and heart failure (HF) hospitalization at 2-year.
The cumulative 2-year incidences of all-cause death and HF hospitalization were significantly lower in the TAVI group than in the conservative group (16.8% versus 36.6%, P<0.001, and 10.7% versus 37.2%, P<0.001). After adjusting the residual confounders, TAVI reduced the risks of all-cause death (HR, 0.46; 95%CI, 0.32-0.69; P = 0.0001) and HF hospitalizations (HR, 0.25; 95%CI, 0.16-0.40; P<0.0001) compared with conservative strategy. There was no difference in the cumulative incidence of non-cardiovascular death between the 2 groups.
TAVI in the early Japanese experience was associated with striking risk reduction for all-cause death as well as HF hospitalization as compared with the historical cohort of patients with severe AS who were managed conservatively just before introduction of TAVI in Japan.
Background
The annual incidence of sudden death has been reported to be low (<1%/year) in asymptomatic patients with severe aortic stenosis (AS), and there is a paucity of data on the risk factors of ...sudden death in patients with severe AS.
Methods and Results
We evaluated the incidence and risk factors of sudden death during the median follow‐up period of 1334 days in the Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis (CURRENT AS) registry enrolling 3815 consecutive patients with severe AS between 2003 and 2011. The mean age was 78 years, and the prevalences of male sex and prior myocardial infarction were 38% and 8%, respectively. Sudden death occurred in 175 patients without aortic valve replacement. The cumulative 5‐year incidences of sudden death, censored at aortic valve replacement, which accounted for the competing risk, were 9.2% in symptomatic patients and 7.2% (1.4%/year) in asymptomatic patients (P<0.001). Among 82 asymptomatic patients experiencing sudden death, 54 patients (66%) died abruptly without any preceding symptoms, and 35 (65%) of these sudden deaths occurred within 3 months of the last clinical follow‐up visit. Independent risk factors for sudden death were hemodialysis (hazard ratio HR 3.63; 95% confidence interval CI 2.42‐5.43), prior myocardial infarction (HR 2.11; 95% CI 1.28‐3.50), body mass index <22 (HR 1.51; 95% CI 1.03‐2.21), peak aortic jet velocity ≥5 m/s (HR 1.76; 95% CI 1.12‐2.78), and left ventricular ejection fraction <60% (HR 1.52; 95% CI 1.08‐2.14).
Conclusions
The incidence of sudden death in asymptomatic patients with severe AS might be higher than that reported in previous reports. Several baseline clinical and echocardiographic characteristics were associated with increased risk of sudden death.
Clinical Trial Registration
URL: www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000012140.
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rapidly progressive subtype of pulmonary hypertension (PH) associated with impaired right ventricular adaptation and very poor prognosis in ...cancer, and its rapid progression makes antemortem diagnosis and treatment extremely difficult. We describe the case of a 35‐year‐old woman who developed severe PH with subsequent circulatory collapse. The patient was clinically diagnosed with PTTM induced by lung adenocarcinoma harboring the c‐ros oncogene 1 (ROS1) rearrangement within 1–2 weeks, while hemodynamics were stabilized by rescue venoarterial extracorporeal membrane oxygenation support. Crizotinib, an oral tyrosine kinase inhibitor targeting anaplastic lymphoma kinase, MET, and ROS1 kinase domains dramatically resolved PH, resulting in more than 3 years of survival. Targeted gene‐tailored therapy with mechanical support can improve survival in PTTM.
The aim of this study was to evaluate the prognostic impact of left ventricular ejection fraction (LVEF) in patients with severe aortic stenosis (AS).
The prognostic impact of LVEF in severe AS ...remains controversial.
Among 3,815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the present study population consisted of 3,794 patients after excluding 21 patients without LVEF data. Patients were divided into 4 groups according to LVEF at index echocardiography (<50%, 50% to 59%, 60% to 69%, and ≥70%; conservative strategy: n = 388, n = 390, n = 1,025, and n = 800; initial aortic valve replacement strategy: n = 206, n = 170, n = 375, and n = 440). Echocardiographic data were site reported, and there was no echocardiography core laboratory.
In the conservative group, the cumulative 5-year incidence of the primary outcome measure (a composite of aortic valve–related death or heart failure hospitalization) was significantly higher in patients with LVEFs <50% and 50% to 59% than in those with LVEFs 60% to 69% and ≥70% (72.3%, 58.4%, 38.7%, and 35.0%, respectively, p < 0.001), whereas in the initial aortic valve replacement group, the negative effect of low LVEF was markedly attenuated (20.2%, 20.3%, 17.7%, and 12.4%, respectively, p = 0.03). After adjusting for confounders, LVEF <50% (hazard ratio: 1.82; 95% confidence interval: 1.44 to 2.28; p < 0.001) and 50% to 59% (hazard ratio: 1.77; 95% confidence interval: 1.42 to 2.20; p < 0.001) but not 60% to 69% (hazard ratio: 1.14; 95% confidence interval: 0.94 to 1.39; p = 0.17) were independently associated with poorer outcomes compared with LVEF ≥70% (reference) in the conservative group. In the initial aortic valve replacement group, the adjusted risk for the primary outcome measure was not significantly different across the 4 LVEF groups.
This study demonstrates that survival in patients with severe AS is impaired when LVEF is <60%, and these findings have implications for decision making with regard to the timing of surgical intervention.
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Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of ...mTOR-mediated signals in CD4(+) T cell responses, the involvement of mTOR in CD8(+) T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8(+) T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A(-/-) CD8(+) T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8(+) T cell responses were significantly impaired in SEMA4A(-/-) mice. Furthermore, SEMA4A(-/-) CD8(+) T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8(+) T cells. IFN-γ production and mTORC1 activity in SEMA4A(-/-) CD8(+) T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8(+) T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8(+) T cells, but also reveal a novel link between a semaphorin and mTOR signaling.
Prurigo nodularis, a chronic inflammatory skin condition, adversely affects the quality of life of affected individuals. Current treatment options for prurigo nodularis in Japan are limited.
To ...evaluate the optimal dose, efficacy, and safety of long-term treatment with nemolizumab in patients with prurigo nodularis in Japan.
In a 16-week, double-blind, phase II/III study, patients aged ≥13 years with prurigo nodularis were randomly assigned (1:1:1) to nemolizumab 30 mg, 60 mg, or placebo groups, with concomitant topical corticosteroids, every 4 weeks. The primary efficacy end point was the percentage change in the weekly mean Peak Pruritus Numerical Rating Scale (PP-NRS) score (range, 0 to 10, with higher scores indicating worse itching) from baseline to week 16. Secondary efficacy end points assessed the impact of treatment on pruritus, prurigo nodularis severity, sleep, and quality of life.
At week 16, the least-squares mean percentage change from baseline in the PP-NRS score was -61·1% in the nemolizumab 30 mg group (n = 77), -56·0% in the 60 mg group (n = 76), and -18·6% in the placebo group (n = 76). Differences between both nemolizumab groups and placebo were significant; the difference between the 30 mg and placebo groups was -42·5% (95% confidence interval CI, -51·9 to -33·1; P<0·0001), and between the 60 mg and placebo groups was -37·4% (95% CI, -46·7 to -28·1; P<0·0001). Nemolizumab-treated patients also had greater improvements in the number and severity of prurigo nodules, and in sleep and quality of life compared with the placebo group. Both nemolizumab doses were well tolerated.
Improvements in prurigo nodularis were greater following nemolizumab treatment, despite continuation of topical corticosteroids in both groups. (Funded by Maruho; jRCT number, 2011200017.).
Background Data are scarce on the role of aortic valve area (AVA) to identify those patients with asymptomatic severe aortic stenosis (AS) who are at high risk of adverse events. We sought to explore ...the prognostic impact of AVA in asymptomatic patients with severe AS in a large observational database. Methods and Results Among 3815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the present study included 1309 conservatively managed asymptomatic patients with left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on AVA (group 1: AVA >0.80 cm
, N=645; group 2: 0.8 cm
≥AVA >0.6 cm
, N=465; and group 3: AVA ≤0.6 cm
, N=199). The prevalence of very severe AS patients (peak aortic jet velocity ≥5 m/s or mean aortic pressure gradient ≥60 mm Hg) was 2.0%, 5.8%, and 26.1% in groups 1, 2, and 3, respectively. The cumulative 5-year incidence of AVR was not different across the 3 groups (39.7%, 43.7%, and 39.9%; P=0.43). The cumulative 5-year incidence of the primary outcome measure (a composite of aortic valve-related death or heart failure hospitalization) was incrementally higher with decreasing AVA (24.1%, 29.1%, and 48.1%; P<0.001). After adjusting for confounders, the excess risk of group 3 and group 2 relative to group 1 for the primary outcome measure remained significant (hazard ratio, 2.21, 95% CI, 1.56-3.11, P<0.001; and hazard ratio, 1.34, 95% CI, 1.01-1.78, P=0.04, respectively). Conclusions AVA ≤0.6 cm
would be a useful marker to identify those high-risk patients with asymptomatic severe AS, who might benefit from early AVR. Clinical Trial Registration URL: www.umin.ac.jp . Unique identifier: UMIN000012140.
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