Search

The risks of leaflet thrombosis and the associated cerebral thromboembolism are unknown according to different anticoagulation dosing after transcatheter aortic valve replacement (TAVR). The aim was to evaluate the incidence of leaflet thrombosis and cerebral thromboembolism between low-dose (30 mg) or standard-dose (60 mg) edoxaban and dual antiplatelet therapy (DAPT) after TAVR. In this prespecified subgroup analysis of the ADAPT-TAVR trial, the primary endpoint was the incidence of leaflet thrombosis on 4-dimensional computed tomography at 6-months. Key secondary endpoints were new cerebral lesions on brain magnetic resonance imaging and neurological and neurocognitive dysfunction. Of 229 patients enrolled in this study, 118 patients were DAPT group and 111 were edoxaban group (43 [39.1%] 60 mg vs 68 [61.3%] 30 mg). There was a significantly lower incidence of leaflet thrombosis in the standard-dose edoxaban group than in the DAPT group (2.4% vs 18.3%; odds ratio [OR] 0.11; 95% confidence interval [CI], 0.01-0.55; P =.03). However, no significant difference was observed between low-dose edoxaban and DAPT (15.0% vs 18.3%; OR 0.79; 95% CI, 0.32-1.81; P =.58). Irrespective of different antithrombotic regiments, the percentages of patients with new cerebral lesions on brain MRI and worsening neurological or neurocognitive function were not significantly different. In patients without an indication for anticoagulation after TAVR, the incidence of leaflet thrombosis was significantly lower with standard-dose edoxaban but not with low-dose edoxaban, as compared with DAPT. However, this differential effect of edoxaban on leaflet thrombosis was not associated with a reduction of new cerebral thromboembolism and neurological dysfunction. OAC = Oral anticoagulation; SLT = Subclinical leaflet thrombosis; TIA = Transient ischemic attack [Display omitted] [ABSTRACT FROM AUTHOR]

Hypertension adds to the pressure overload on the left ventricle (LV) in combination with aortic valve (AV) disease, but the optimal blood pressure (BP) targets for patients with AV disease remain unclear. We tried to investigate whether intensive BP control reduces LV hypertrophy in asymptomatic patients with aortic stenosis (AS) or aortic regurgitation (AR). A total of 128 hypertensive patients with mild to moderate AS (n = 93) or AR (n = 35) were randomly assigned to intensive therapy, targeting a systolic BP <130 mm Hg, or standard therapy, targeting a systolic BP <140 mm Hg. The primary end point was the change in LV mass from baseline to the 24-month follow-up. Secondary end points included changes in severity of AV disease, LV volumes, ejection fraction and global longitudinal strain (GLS). The treatment groups were generally well balanced regarding the baseline characteristics. The mean (±SD) age of the patients was 68 ± 8 years and 48% were men. The mean BP was 145 ± 12/81 ± 10 mm Hg at baseline. Medication at baseline was similar between the 2 groups. The 2 treatment strategies resulted in a rapid and sustained difference in systolic BP (P <.05). At 24-month, the mean systolic BP was 129 ± 12 mm Hg in the intensive therapy group and 135 ± 14 mm Hg in the standard therapy group. No patient died or underwent AV surgery during follow-up in either of the groups. LV mass was changed from 189.5 ± 41.3 to 185.6 ± 41.5 g in the intensive therapy group (P =.19) and from 183.8 ± 38.3 to 194.0 ± 46.4 g in the standard therapy group (P <.01). The primary end point of change in LV mass was significantly different between the intensive therapy and the standard therapy group (-3.9 ± 20.2 g vs 10.3 ± 20.4 g; P =.0007). The increase in LV mass index was also significantly greater in the standard therapy group (P =.01). No significant differences in secondary end points (changes in severity of AV disease, LV volumes, ejection fraction and GLS) were observed between the treatment groups. Among hypertensive patients with AV disease, intensive hypertensive therapy resulted in a significant reduction in LV hypertrophy, although progression of AV disease was similar between the treatment groups. http://ClinicalTrials.gov (Number NCT03666351) Effects of Intensive Blood Pressure Control on Left Ventricular Hypertrophy in Aortic Valve Disease AR, Aortic regurgitation; AS, Aortic stenosis; AV, Aortic valve; BP, Blood pressure; HT, Hypertension; LV, left ventricle [Display omitted] [ABSTRACT FROM AUTHOR]

Sarcopenia, known as physical frailty, is highly prevalent in older patients and is related to adverse outcomes after cardiac surgery. However whether sarcopenia assessment can reclassify an individual patient's risk, which is estimated by Society of Thoracic Surgeons–predicted risk of mortality scores in patients who undergo surgical aortic valve replacement, is unclear. This retrospective, single-center, cohort study comprised 874 patients aged ≥65 years who underwent surgical aortic valve replacement between 2009 and 2016. Total skeletal muscle area was calculated using height squared (cm2/m2) and was measured by preoperative computed tomography at the third lumbar vertebra inferior border using machine learning–based analysis. Sex-specific Z-scores were calculated, and patients in the lowest Z-score tertile were considered to have sarcopenia. The primary endpoint was 30-day mortality, and secondary endpoints were in-hospital events, 1-year mortality, and long-term mortality. Thirty-day mortality, 30-day in-hospital events, and 1-year mortality rates were 4.7%, 17.6%, and 8.0%, respectively. As the Z-score decreased, the odds of an early adverse event showed a stepwise increase. Sarcopenia was independently associated with higher 30-day mortality, 30-day in-hospital events, and 1-year mortality. Reclassification analyses showed improvements in the ability to predict early adverse events after adding the Z-scores over and above The Society of Thoracic Surgeons–predicted risk of mortality scores (all P <.005). Sarcopenic patients had significantly higher risks of early adverse events and long-term mortality after undergoing surgical aortic valve replacement than nonsarcopenic patients. Sarcopenia determined by preoperative computed tomography can enhance the prediction of postoperative outcome risk. [Display omitted] [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the incidence and prognostic significance of prosthesis-patient mismatch (PPM) after transcatheter aortic valve replacement (TAVR) according to racial groups. PPM after TAVR may be of more concern in Asian populations considering their relatively small annular and valve sizes compared with Western populations. TP-TAVR (Transpacific TAVR Registry) was an international multicenter cohort study of patients with severe aortic stenosis who underwent TAVR in the United States and South Korea from January 2015 to November 2019. PPM was defined as moderate (0.65-0.85 cm2/m2) or severe (<0.65 cm2/m2) at the indexed effective orifice area. The primary outcome was a composite of death, stroke, or rehospitalization at 1 year. Among 1,101 eligible patients (533 Asian and 569 non-Asian), the incidence of PPM was significantly lower in the Asian population (33.6%; moderate, 26.5%; severe, 7.1%) than in the non-Asian population (54.5%; moderate, 29.8%; severe, 24.7%). The 1-year rate of the primary outcome was similar between the PPM and non-PPM groups (27.5% vs 28.1%; P = 0.69); this pattern was consistent between Asian (25.4% vs 25.2%; P = 0.31) and non-Asian (28.7% vs 32.1%; P = 0.97) patients. After multivariable adjustment, the risk for the primary outcome did not significantly differ between the PPM and non-PPM groups in the overall population (HR: 0.95; 95% CI: 0.74-1.21), in Asian patients (HR: 1.07; 95% CI: 0.74-1.55), and in non-Asian patients (HR: 0.86; 95% CI: 0.63-1.19). In this study of patients with severe aortic stenosis who underwent TAVR, the incidence of PPM was significantly lower in Asian patients than in non-Asian patients. The 1-year risk for the primary composite outcome was similar between the PPM and non-PPM groups regardless of racial group. (Transpacific TAVR Registry [TP-TAVR]; NCT03826264) [Display omitted] [ABSTRACT FROM AUTHOR]

In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin. The Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo. We show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the Senp2 promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (Acsl1) or carnitine palmitoyl transferase 1b (Cpt1b). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice. We demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO. • Leptin directly activates AMPK and STAT3 through leptin receptor in skeletal muscle. • Leptin increases transcription of Senp2 through STAT3 activation. • Leptin increases expression of FAO-related genes through PPAR desumoylation by SENP2. • Leptin increases FAO acutely by AMPK and later by the STAT3/SENP2 pathway. [ABSTRACT FROM AUTHOR]

The biochemical characterization of virulence factors from entomopathogenic bacteria is important to understand entomopathogen-insect molecular interactions. Pseudomonas entomophila is a typical entomopathogenic bacterium that harbors virulence factors against several insects. However, the molecular actions of these factors against host innate immune responses are not clearly elucidated. In this study, we observed that bean bugs ( Riptortus pedestris ) that were injected with P. entomophila were highly susceptible to this bacterium. To determine how P. entomophila counteracts the host innate immunity to survive within the insect, we purified a highly enriched protein with potential host insect-killing activity from the culture supernatant of P. entomophila . Then, a 45-kDa protein was purified to homogeneity and identified as AprA which is an alkaline zinc metalloprotease of the genus Pseudomonas by liquid chromatography mass spectrometry (LC-MS). Purified AprA showed a pronounced killing effect against host insects and suppressed both host cellular and humoral innate immunity. Furthermore, to show that AprA is an important insecticidal protein of P. entomophila , we used an aprA -deficient P. entomophila mutant strain (Δ aprA ). When Δ aprA mutant cells were injected to host insects, this mutant exhibited extremely attenuated virulence. In addition, the cytotoxicity against host hemocytes and the antimicrobial peptide-degrading ability of the Δ aprA mutant were greatly decreased. These findings suggest that AprA functions as an important insecticidal protein of P. entomophila via suppression of host cellular and humoral innate immune responses. [ABSTRACT FROM AUTHOR]

All- trans -retinoic acid (RA) is a bioactive derivative of vitamin A that serves as an activating ligand for nuclear transcription factors, retinoic acid receptors. RA biosynthesis is initiated by the enzymes that oxidize retinol to retinaldehyde. It is well established that retinol dehydrogenase 10 (RDH10, SDR16C4), which belongs to the 16C family of the short chain dehydrogenase/reductase (SDR) superfamily of proteins, is the major enzyme responsible for the oxidation of retinol to retinaldehyde for RA biosynthesis during embryogenesis. However, several lines of evidence point towards the existence of additional retinol dehydrogenases that contribute to RA biosynthesis in vivo . In close proximity to RDH10 gene on human chromosome 8 are located two genes that are phylogenetically related to RDH10 . The predicted protein products of these genes, retinol dehydrogenase epidermal 2 (RDHE2, SDR16C5) and retinol dehydrogenase epidermal 2-similar (RDHE2S, SDR16C6), share 59% and 56% sequence similarity with RDH10, respectively. Previously, we showed that the single ortholog of the human RDHE2 and RDHE2S in frogs, Xenopus laevis rdhe2, oxidizes retinol to retinaldehyde and is essential for frog embryonic development. In this study, we explored the potential of each of the two human proteins to contribute to RA biosynthesis. The results of this study demonstrate that human RDHE2 exhibits a relatively low but reproducible activity when expressed in either HepG2 or HEK293 cells. Expression of the native RDHE2 is downregulated in the presence of elevated levels of RA. On the other hand, the protein encoded by the human RDHE2S gene is unstable when expressed in HEK293 cells. RDHE2S protein produced in Sf9 cells is stable but has no detectable catalytic activity towards retinol. We conclude that the human RDHE2S does not contribute to RA biosynthesis, whereas the low-activity RA-sensitive human RDHE2 may have a role in adjusting the cellular levels of RA in accord with specific physiological conditions. [ABSTRACT FROM AUTHOR]

Background The rates of stent failure after percutaneous coronary intervention have decreased since the introduction of the drug-eluting stent (DES). However, chronic kidney disease (CKD) and diabetes mellitus (DM) remain strong clinical predictors of poor prognosis despite DES implantation. Sarpogrelate, a selective serotonin (5-hydroxytryptamine (HT)2a [5-HT2A]) receptor antagonist, has antiproliferative effects, reducing neointimal hyperplasia and smooth muscle cell proliferation, as well as potent antiplatelet action, inhibiting 5-HT-induced platelet aggregation. However, efficacy and safety data for sarpogrelate in patients with CKD or DM are limited. We aim to determine whether sarpogrelate has beneficial effects in patients with CDK or DM treated with DES implantation. Methods/design The SERENADE trial is a multicenter, open-label, prospective, randomized study that will test the superiority of triple anti-platelet therapy (TAT; aspirin, clopidogrel, and sarpogrelate) to conventional dual antiplatelet therapy (DAT; aspirin and clopidogrel) in preventing late lumen loss 9 months after the index procedure in patients with CKD or DM. A total of 220 patients diagnosed with coronary artery disease with DM or CKD will be randomized to the TAT or DAT groups (1:1 ratio) after DES implantation. The primary endpoint is late lumen loss at 9 months assessed by quantitative coronary angiography. Secondary efficacy endpoints are composites of major adverse cardiovascular events including cardiac death, nonfatal myocardial infarction, and target lesion revascularization. Secondary safety endpoints are major bleeding events and hepatic or renal impairment. Discussion The SERENADE trial will provide insight on the efficacy of adjunctive therapy with sarpogrelate after DES implantation for patients with high-risk profiles such as CKD or DM. Trial registration National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov NCT02294643). [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to determine the outcomes of bursoscopic ossicle excision in young and active patients with unresolved Osgood-Schlatter disease. Methods This retrospective study included 18 male military recruits. A direct bursoscopic ossicle excision was performed using low anterolateral and low anteromedial portals. Outcomes were evaluated using the Lysholm knee score, pain score on a visual analog scale (VAS) (from 0 to 10), and Tegner activity scale score. In addition, patients were asked whether they could kneel or squat and whether they were able to return to their duty after surgery. Patient satisfaction was evaluated using the VAS and by asking whether patients thought that the prominence of the tibial tuberosity was reduced and whether they would recommend the same surgical treatment to others. Complications after surgery were also evaluated. Results The mean Lysholm knee score was 71 preoperatively and improved to 99 after surgery. The mean VAS pain score was 6.5 in the preoperative period and decreased to 0.9 after surgery. In addition, the mean Tegner activity scale score improved from 2.7 preoperatively to 6.2 at final follow-up. However, 4 patients were not able to return to their duty, and 4 patients still had difficulties with kneeling after surgery. A superficial infection occurred in 1 patient, and a recurrent ossicle formation was found in 1 patient. Of 18 patients, 17 were satisfied with their surgical outcomes, and the mean VAS score for patient satisfaction was 8.8. Furthermore, all but 1 patient would recommend the same surgical treatment to others. However, 6 patients did not believe that the prominence of the tibial tuberosity was reduced. Conclusions Bursoscopic ossicle excision showed satisfactory outcomes in selective young and active patients with persistent symptoms. However, bursoscopic surgery showed limitation in reducing the prominence of the tibial tuberosity. Level of Evidence Level IV, therapeutic case series. [ABSTRACT FROM AUTHOR]

Highlights: [•] This is a study investigating the mechanism of repetitive transcranial magnetic stimulation in the cellular level. [•] Repetitive transcranial magnetic stimulation over the cerebellum has effects on glucose metabolism in the cerebellar cortex. [•] Repetitive transcranial magnetic stimulation could change gene expression and protein synthesis in the cerebellar synapse. [Copyright &y& Elsevier]

The adipose tissue is a key site regulating energy metabolism. One of the contributing factors behind this is browning of white adipose tissue (WAT). However, knowledge of the intracellular determinants of the browning process remains incomplete. By generating adipocyte-specific Senp2 knockout (Senp2 -aKO) mice, here we show that SENP2 negatively regulates browning by de-conjugating small ubiquitin-like modifiers from C/EBPβ. Senp2 -aKO mice are resistant to diet-induced obesity due to increased energy expenditure and heat production. Senp2 knockout promotes beige adipocyte accumulation in inguinal WAT by upregulation of thermogenic gene expression. In addition, SENP2 knockdown promotes thermogenic adipocyte differentiation of precursor cells isolated from inguinal and epididymal WATs. Mechanistically, sumoylated C/EBPβ, a target of SENP2, suppresses expression of HOXC10, a browning inhibitor, by recruiting a transcriptional repressor DAXX. These findings indicate that a SENP2-C/EBPβ-HOXC10 axis operates for the control of beige adipogenesis in inguinal WAT. [Display omitted] • Adipocyte-specific S enp2 knockout mice are resistant to diet-induced obesity • Senp2 knockout promotes beige adipocyte accumulation in WAT • Suppression of HOXC10 is essential for beige adipogenesis in iWAT • Sumoylated C/EBPβ suppresses HOXC10 expression by recruiting the corepressor DAXX Browning of white adipose tissue is a potential way to suppress obesity. Here, Lee et al. identify SENP2, a SUMO de-conjugating enzyme, as a browning inhibitor. Beige adipocytes are accumulated in white adipose tissue of adipocyte-specific SENP2 knockout mice. Increase of C/EBPβ sumoylation suppresses HOXC10 transcription, which promotes beige adipogenesis. [ABSTRACT FROM AUTHOR]

Purpose: The primary aim was to determine the rate and risk factors of double biodegradable femoral cross-pin breakage after anterior cruciate ligament reconstruction using a hamstring autograft. In addition, we compared clinical outcomes and magnetic resonance imaging (MRI) findings related to grafts for knees with and without a broken cross-pin. Methods: A retrospective review of 53 knees (53 patients) was performed. Cross-pin breakage was determined by follow-up MRI. Age, sex, weight, height, presence of a posterior transcortical cross-pin breach, time between surgery and follow-up MRI, graft diameter, and cross-pin position (superior or inferior) were included in the analysis. Differences in Lysholm knee scores, International Knee Documentation Committee grades, anterior laxity, and pivot-shift test results were examined in relation to cross-pin breakage. In addition, anterior cruciate ligament graft integrity and osseous graft integration by MRI were assessed and compared between knees with broken cross-pins and knees with intact cross-pins. Results: A cross-pin was broken in 25 of 53 knees. A cross-pin posterior transcortical breach was the only factor found to be significantly correlated with cross-pin breakage (odds ratio, 6.117; P = .033) by univariate analysis. No significant differences in clinical outcomes were found to be related to cross-pin breakage, but femoral tunnel enlargement was more frequent in knees with breakage than in those without (P = .002). Conclusions: Breakage of biodegradable cross-pins used for femoral fixation is relatively common but did not affect clinical outcomes. However, femoral tunnel enlargement was found to be greater in knees with a broken cross-pin. The only significant relation found was between a cross-pin posterior transcortical breach and breakage, which suggests that pin breakage is related to a technical error. These findings should be borne in mind when a double biodegradable cross-pin is being considered for femoral fixation. Level of Evidence: Level IV, therapeutic case series. [Copyright &y& Elsevier]

The enzymes responsible for the rate-limiting step in retinoic acid biosynthesis, the oxidation of retinol to retinaldehyde, during embryogenesis and in adulthood have not been fully defined. Here, we report that a novel member of the short chain dehydrogenase/reductase superfamily, frog sdr16c5, acts as a highly active retinol dehydrogenase (rdhe2) that promotes retinoic acid biosynthesis when expressed in mammalian cells. In vivo assays of rdhe2 function show that overexpression of rdhe2 in frog embryos leads to posteriorization and induction of defects resembling those caused by retinoic acid toxicity. Conversely, antisense morpholino-mediated knockdown of endogenous rdhe2 results in phenotypes consistent with retinoic acid deficiency, such as defects in anterior neural tube closure, microcephaly with small eye formation, disruption of somitogenesis, and curved body axis with bent tail. Higher doses of morpholino induce embryonic lethality. Analyses of retinoic acid levels using either endogenous retinoic acid-sensitive gene hoxd4 or retinoic acid reporter cell line both show that the levels of retinoic acid are significantly decreased in rdhe2 morphants. Taken together, these results provide strong evidence that Xenopus rdhe2 functions as a retinol dehydrogenase essential for frog embryonic development in vivo. Importantly, the retinol oxidizing activity of frog rdhe2 is conserved in its mouse homologs, suggesting that rdhe2-related enzymes may represent the previously unrecognized physiologically relevant retinol dehydrogenases that contribute to retinoic acid biosynthesis in higher vertebrates. [ABSTRACT FROM AUTHOR]

Abstract: The liver is the most important tissue site in the body for uptake of postprandial retinoid, as well as for retinoid storage. Within the liver, both hepatocytes and hepatic stellate cells (HSCs) are importantly involved in retinoid metabolism. Hepatocytes play an indispensable role in uptake and processing of dietary retinoid into the liver, and in synthesis and secretion of retinol-binding protein (RBP), which is required for mobilizing hepatic retinoid stores. HSCs are the central cellular site for retinoid storage in the healthy animal, accounting for as much as 50–60% of the total retinoid present in the entire body. The liver is also an important target organ for retinoid actions. Retinoic acid is synthesized in the liver and can interact with retinoid receptors which control expression of a large number of genes involved in hepatic processes. Altered retinoid metabolism and the accompanying dysregulation of retinoid signaling in the liver contribute to hepatic disease. This is related to HSCs, which contribute significantly to the development of hepatic disease when they undergo a process of cellular activation. HSC activation results in the loss of HSC retinoid stores and changes in extracellular matrix deposition leading to the onset of liver fibrosis. An association between hepatic disease progression and decreased hepatic retinoid storage has been demonstrated. In this review article, we summarize the essential role of the liver in retinoid metabolism and consider briefly associations between hepatic retinoid metabolism and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. [Copyright &y& Elsevier]

Abstract: Retinol dehydrogenase 12 (RDH12) is a microsomal enzyme that catalyzes the reduction of all-trans-retinaldehyde to all-trans-retinol when expressed in cells. Mutations in RDH12 cause severe retinal degeneration; however, some of the disease-associated RDH12 mutants retain significant catalytic activity. Our previous study (Lee et al., 2010 ) demonstrated that the catalytically active T49M and I51N variants of RDH12 undergo accelerated degradation through the ubiquitin–proteosome system, which results in reduced levels of these proteins in the cells. Here, we investigated whether the stabilization of T49M or I51N RDH12 protein levels through the inhibition of proteosome activity or improved folding could rescue their retinaldehyde reductase activity. For the T49M variant, the inhibition of proteosome activity resulted in an increased level of T49M protein in the microsomal fraction. The higher level of the T49M variant in microsomes correlated with the higher microsomal retinaldehyde reductase activity. T49M-expressing living cells treated with the inhibitors of proteosome activity or with dimethyl sulfoxide exhibited an increase in the conversion of retinaldehyde to retinol, consistent with the recovery of functional RDH12 protein. On the other hand, accumulation of the I51N variant in the microsomes did not result in higher retinaldehyde reductase activity of the microsomes or cells. These results provide a proof of concept that, at least in the case of the T49M variant, the prevention of accelerated degradation could lead to restoration of its function in the cells. This finding justifies further search for more efficient and clinically relevant compounds for stabilizing the T49M variant activity. [Copyright &y& Elsevier]

Abstract: Background: In chordates, retinoid metabolism is an important target of short-chain dehydrogenases/reductases (SDRs). It is not known whether SDRs play a role in retinoid metabolism of protostomes, such as Drosophila melanogaster. Methods: Drosophila genome was searched for genes encoding proteins with ∼50% identity to human retinol dehydrogenase 12 (RDH12). The corresponding proteins were expressed in Sf9 cells and biochemically characterized. Their phylogenetic relationships were analyzed using PHYLIP software. Results: A total of six Drosophila SDR genes were identified. Five of these genes are clustered on chromosome 2 and one is located on chromosome X. The deduced proteins are 300 to 406 amino acids long and are associated with microsomal membranes. They recognize all-trans-retinaldehyde and all-trans-3-hydroxyretinaldehyde as substrates and prefer NADPH as a cofactor. Phylogenetically, Drosophila SDRs belong to the same branch of the SDR superfamily as human RDH12, indicating a common ancestry early in bilaterian evolution, before a protostome–deuterostome split. Conclusions: Similarities in the substrate and cofactor specificities of Drosophila versus human SDRs suggest conservation of their function in retinoid metabolism throughout protostome and deuterostome phyla. General significance: The discovery of Drosophila retinaldehyde reductases sheds new light on the conversion of β-carotene and zeaxantine to visual pigment and provides a better understanding of the evolutionary roots of retinoid-active SDRs. [Copyright &y& Elsevier]

Abstract: The mRNA encoding a putative human enzyme named Epidermal Retinol Dehydrogenase 2 (RDH-E2) was found to be significantly elevated in psoriatic skin [Y. Matsuzaka, K. Okamoto, H. Tsuji, T. Mabuchi, A. Ozawa, G. Tamiya, H. Inoko, Identification of the hRDH-E2 gene, a novel member of the SDR family, and its increased expression in psoriatic lesion, Biochem. Biophys. Res. Commun. 297 (2002) 1171–1180]. This finding led the authors to propose that RDH-E2 may be involved in the pathogenesis of psoriasis through its potential role in retinoic acid biosynthesis and stimulation of keratinocyte proliferation. However, enzymatic activity for RDH-E2 has never been demonstrated. RDH-E2 is a member of the short-chain dehydrogenase/reductase (SDR) superfamily of proteins, and is most closely related to the group of SDRs comprised of both NAD+- and NADP+-dependent enzymes with activities toward retinoid and steroid substrates. In this study, we began the characterization of RDH-E2 protein in order to determine whether it might play a role in retinoic acid biosynthesis. The results of this study show that, similarly to other SDR-type retinol dehydrogenases, RDH-E2 appears to be associated with the membranes of endoplasmic reticulum. Furthermore, RDH-E2 expressed in Sf9 insect cells as a fusion to the C-terminal His6-tag and purified using Ni2+-affinity chromatography recognizes all-trans-retinol and all-trans-retinaldehyde as substrates and exhibits a strong preference for NAD+/NADH as cofactors. Specific activity of RDH-E2 toward all-trans-retinoids is much lower than that of other retinoid-active SDRs, such as human RoDH4 or RDH10. The preference for NAD+ suggests that RDH-E2 is likely to function in the oxidative direction in vivo, further supporting its potential role in the oxidation of retinol to retinaldehyde for retinoic acid biosynthesis in human keratinocytes. [Copyright &y& Elsevier]

Abstract: Mutations in human Retinol Dehydrogenase 12 (RDH12) are known to cause photoreceptor cell death but the physiological function of RDH12 in photoreceptors remains poorly understood. In vitro, RDH12 recognizes both retinoids and medium-chain aldehydes as substrates. Our previous study suggested that RDH12 protects cells against toxic levels of retinaldehyde and retinoic acid [S.A. Lee, O.V. Belyaeva, I.K. Popov, N.Y. Kedishvili, Overproduction of bioactive retinoic acid in cells expressing disease-associated mutants of retinol dehydrogenase 12, J. Biol. Chem. 282 (2007) 35621–35628]. Here, we investigated whether RDH12 can also protect cells against highly reactive medium-chain aldehydes. Analysis of cell survival demonstrated that RDH12 was protective against nonanal but not against 4-hydroxynonenal. At high concentrations, nonanal inhibited the activity of RDH12 towards retinaldehyde, suggesting that nonanal was metabolized by RDH12. 4-Hydroxynonenal did not inhibit the RDH12 retinaldehyde reductase activity, but it strongly inhibited the activities of lecithin:retinol acyl transferase and aldehyde dehydrogenase, resulting in decreased levels of retinyl esters and retinoic acid and accumulation of unesterified retinol. Thus, the results of this study showed that RDH12 is more effective in protection against retinaldehyde than against medium-chain aldehydes, and that medium-chain aldehydes, especially 4-hydroxynonenal, severely disrupt cellular retinoid homeostasis. Together, these findings provide a new insight into the effects of lipid peroxidation products and the impact of oxidative stress on retinoid metabolism. [Copyright &y& Elsevier]

Paravalvular regurgitation (PVR) has been known to be the primary determinant of poor left ventricular (LV) mass regression after transcatheter aortic valve replacement (TAVR). However, the incidence of significant PVR has been reduced considerably as TAVR technology evolved rapidly. This study aimed to investigate the time course and impact of LV mass index (LVMi) regression on long-term clinical outcomes in severe aortic stenosis (AS) patients without significant PVR after TAVR. Of 412 patients who underwent TAVR, 146 who had LV hypertrophy (LVMi ≥115 g/m2 for men and ≥ 95 g/m2 for women) at baseline and were alive at one year after TAVR were enrolled. The primary outcome was cardiovascular deaths and the impact of LVMi regression on clinical outcomes were examined. The patients with significant PVR were excluded. During a median follow-up of 40 months (interquartile range, 26–58 months), 9 (6.2%) cardiovascular deaths, 21 (14.4%) all-cause deaths, and 9 (6.2%) hospitalizations occurred. In the multivariable analysis, the percentage change of LVMi was an independent predictor of cardiovascular deaths (adjusted hazard ratio [HR], 1.03; 95% confidential interval [CI], 1.01–1.05; P = 0.010), and composite outcome of cardiovascular deaths and rehospitalization for heart failure (adjusted HR, 1.02; 95% CI, 1.00–1.04; P = 0.022). Baseline LVMi, eccentric hypertrophy, and TAVR-induced left bundle branch block were independently associated with LVMi regression. In patients with severe AS who received successful TAVR without significant PVR, the degree of LVMi regression is an independent predictor of postoperative outcomes after TAVR. • Paravalvular regurgitation (PVR) is the primary determinant of poor left ventricular mass (LVM) regression after TAVR. • This study shows an association between clinical outcomes and LVM regression in patients without significant PVR after TAVR. • The long-term outcomes after TAVR were associated with the percentage change of LVM index (LVMi). • Higher rates of eccentric hypertrophy and post-TAVR-induced LBBB were associated with lesser LVMi regression. • In patients with eccentric hypertrophy, efforts should be made to minimize the risk of post-TAVR-induced LBBB. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that gut symbionts modulate insect development and reproduction. However, the mechanisms by which gut symbionts modulate host physiologies and the molecules involved in these changes are unclear. To address these questions, we prepared three different groups of the insect Riptortus pedestris : Burkholderia gut symbiont-colonized (Sym) insects, Burkholderia -non-colonized (Apo) insects, and Burkholderia -depleted (Sym Burk- ) insects, which were fed tetracycline. When the hemolymph proteins of three insects were analyzed by SDS-PAGE, the hexamerin-α, hexamerin-β and vitellogenin-1 proteins of Sym-adults were highly expressed compared to those of Apo- and Sym Burk- -insects. To investigate the expression patterns of these three genes during insect development, we measured the transcriptional levels of these genes. The hexamerin-β gene was specifically expressed at all nymphal stages, and its expression was detected 4–5 days earlier in Sym-insect nymphs than that in Apo- and Sym Burk- -insects. However, the hexamerin-α and vitellogenin-1 genes were only expressed in adult females, and they were also detected 6–7 days earlier and were 2-fold higher in Sym-adult females than those in the other insects. Depletion of hexamerin-β by RNA interference in 2nd instar Sym-nymphs delayed adult emergence, whereas hexamerin-α and vitellogenin-1 RNA interference in 5th instar nymphs caused loss of color of the eggs of Sym-insects. These results demonstrate that the Burkholderia gut symbiont modulates host development and egg production by regulating production of these three hemolymph storage proteins. [ABSTRACT FROM AUTHOR]

We introduce a new programmable illumination strategy for Fourier ptychographic microscopy (FPM), utilizing a high-resolution organic light-emitting diode (OLED) display screen at the vicinity of the sample to achieve super-resolution and quantitative phase imaging of biological samples. High-density pixels in the OLED screen allow for the angle-scanning illumination required for FP by placing the sample slide directly on the screen, where multiple images of the sample are captured while scanning the pixels on the screen. We discuss the design of the OLED-FP illumination and the corresponding image reconstruction strategies and experimentally validate the super-resolution and phase imaging capabilities of FP using a smartphone screen as illumination. Further, we extend our method to patterned illumination strategies, which multiplexes multiple illumination pixels to achieve full-field FP imaging with a reduced number of measurements, where we identify an optimal illumination pattern and density to maximize the imaging speed without sacrificing the image quality. Our approach offers a simple and compact programmable illuminator that can effectively transform any microscope into a compact FPM with resolution improvement and phase imaging capabilities. • High-resolution display screen was utilized as a programmable light source for Fourier ptychographic microscopy (FPM). • The small pixel pitch of OLED displays allows for FP imaging devices to place samples directly on the display screen. • Position-dependent illumination k-vectors and finite extent of illumination angles were considered. • Random illumination with optimal pixel density for efficient full-field FP reconstruction was identified. • Clinical microscopy samples, including blood smear and histological tissue, were successfully imaged with our OLED-FP. [ABSTRACT FROM AUTHOR]

Recently, we have reported the structural determination of antimicrobial peptides (AMPs), such as riptocin, rip-defensin, and rip-thanatin, from Riptortus pedestris . However, the biological roles of AMPs in the host midgut remain elusive. Here, we compared the expression levels of AMP genes in apo-symbiotic insects with those of symbiotic insects. Interestingly, the expression level of rip-thanatin was only significantly increased in the posterior midgut region of symbiotic insects. To further determine the role of rip-thanatin, we checked antimicrobial activity in vitro . Rip-thanatin showed high antimicrobial activity and had the same structural characteristics as other reported thanatins. To find the novel function of rip-thanatin, rip-thanatin was silenced by RNA interference, and the population of gut symbionts was measured. When rip-thanatin was silenced, the symbionts' titer was increased upon bacterial infection. These results suggest that rip-thanatin functions not only as an antimicrobial peptide but also in controlling the symbionts’ titer in the host midgut. [ABSTRACT FROM AUTHOR]

Abstract: Zearalenone (ZEN) and its metabolites are commonly found in many food commodities and are known to cause reproductive disorders and genotoxic effects. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). Although many studies have demonstrated the cytotoxic effects of these metabolites, the mechanisms by which α-ZOL or β-ZOL mediates their cytotoxic effects appear to differ according to cell type and the exposed toxins. We evaluated the toxicity of α-ZOL and β-ZOL on RAW264.7 macrophages and investigated the underlying mechanisms. β-ZOL not only more strongly reduced the viability of cells than did α-ZOL, but it also induced cell death mainly by apoptosis rather than necrosis. The ZEN metabolites induced loss of mitochondrial membrane potential (MMP), mitochondrial changes in Bcl-2 and Bax proteins, and cytoplasmic release of cytochrome c and apoptosis-inducing factor (AIF). Use of an inhibitor specific to c-Jun N-terminal kinase (JNK), p38 kinase or p53, but not pan-caspase or caspase-8, decreased the toxin-induced generation of reactive oxygen species (ROS) and also attenuated the α-ZOL- or β-ZOL-induced decrease of cell viability. Antioxidative enzyme or compounds such as catalase, acteoside, and (E)-1-(3,4-dihydroxyphenethyl)-3-(4-hydroxystyryl)urea suppressed the ZEN metabolite-mediated reduction of cell viability. Further, knockdown of AIF via siRNA transfection diminished the ZEN metabolite-induced cell death. Collectively, these results suggest that the activation of p53, JNK or p38 kinase by ZEN metabolites is the main upstream signal required for the mitochondrial alteration of Bcl-2/Bax signaling pathways and intracellular ROS generation, while MMP loss and nuclear translocation of AIF are the critical downstream events for ZEN metabolite-mediated apoptosis in macrophages. [Copyright &y& Elsevier]

To compare the surgical outcomes of simple frenotomy and the 4-flap Z-frenuloplasty according to the articulation test values and tongue-tie classification in patients with ankyloglossia with articulation difficulty. prospective randomized study. Tertiary academic center. and methods: Children with ankyloglossia with articulation difficulty were randomly divided into 2 groups for surgical treatment. Patients were evaluated for the tongue-tie classification and articulation test before surgery. Three months after the operation, the frenulum classification and articulation test were re-evaluated to compare the differences in surgical outcome between the two surgical methods. Out of 37 patients, 19 underwent the 4-flap Z-frenuloplasty and 18, the simple frenotomy. No differences were observed in the baseline characteristics of the patients assigned to both groups. Changes in the tongue-tie classification and improvement in the articulation test results were observed with both the surgical methods. Both surgical groups had significant improvement in the speech articulation test (consonants) but there was no difference in the speech outcomes between the surgical groups. Although there was no significant difference in the surgical outcome between the two surgical methods, ankyloglossia patients showed improvement in a Korean speech articulation test 3 months after undergoing surgery to release the lingual frenulum. [ABSTRACT FROM AUTHOR]