Pathologic alterations in podocytes lead to failure of an essential component of the glomerular filtration barrier and proteinuria in chronic kidney diseases. Elevated levels of saturated free fatty ...acid (FFA) are harmful to various tissues, implemented in the progression of diabetes and its complications such as proteinuria in diabetic nephropathy. Here, we investigated the molecular mechanism of palmitate cytotoxicity in cultured mouse podocytes. Incubation with palmitate dose-dependently increased cytosolic and mitochondrial reactive oxygen species, depolarized the mitochondrial membrane potential, impaired ATP synthesis and elicited apoptotic cell death. Palmitate not only evoked mitochondrial fragmentation but also caused marked dilation of the endoplasmic reticulum (ER). Consistently, palmitate upregulated ER stress proteins, oligomerized stromal interaction molecule 1 (STIM1) in the subplasmalemmal ER membrane, abolished the cyclopiazonic acid-induced cytosolic Ca(2+) increase due to depletion of luminal ER Ca(2+). Palmitate-induced ER Ca(2+) depletion and cytotoxicity were blocked by a selective inhibitor of the fatty-acid transporter FAT/CD36. Loss of the ER Ca(2+) pool induced by palmitate was reverted by the phospholipase C (PLC) inhibitor edelfosine. Palmitate-dependent activation of PLC was further demonstrated by following cytosolic translocation of the pleckstrin homology domain of PLC in palmitate-treated podocytes. An inhibitor of diacylglycerol (DAG) kinase, which elevates cytosolic DAG, strongly promoted ER Ca(2+) depletion by low-dose palmitate. GF109203X, a PKC inhibitor, partially prevented palmitate-induced ER Ca(2+) loss. Remarkably, the mitochondrial antioxidant mitoTEMPO inhibited palmitate-induced PLC activation, ER Ca(2+) depletion and cytotoxicity. Palmitate elicited cytoskeletal changes in podocytes and increased albumin permeability, which was also blocked by mitoTEMPO. These data suggest that oxidative stress caused by saturated FFA leads to mitochondrial dysfunction and ER Ca(2+) depletion through FAT/CD36 and PLC signaling, possibly contributing to podocyte injury.
Background
Chronic rhinosinusitis (CRS) is an inflammatory process in the nasal cavity and paranasal sinuses, and bacteria have been considered to be a cause. Indeed, recent evidence indicates that ...bacteria‐derived extracellular vesicles (EV) appear to be an important causative agent of inflammatory diseases. Here, we aimed to evaluate the diversity of nasal microbiota and their secreted EV in patients with CRS.
Methods
Nasal lavage (NAL) fluid samples were obtained from five patients with CRS with polyposis, three patients with CRS without polyposis, and three non‐CRS controls. After preparation of bacteria and EV from samples using differential centrifugation, genomic DNA was extracted and 16S‐rDNA amplicons were subjected to high‐throughput pyrosequencing on a Roche 454 GS‐FLX platform.
Results
Metagenomics showed that bacteria composition was positively correlated with EV composition. Samples from patients with CRS had greater bacterial abundance and lower diversity, both from bacteria and the EV portion of samples, compared with non‐CRS samples. At each phylogenetic level, Bacteroidetes decreased while Proteobacteria increased in the CRS group at the phylum level. At the genus level, Prevotella spp. decreased in the CRS group, while Staphylococcus spp. increased from both bacteria and EV. Moreover, Staphylococcus aureus and its secreting EV compositions were higher in samples from CRS with polyps compared with CRS without polyps.
Conclusions
These results suggest that patients with CRS have altered nasal microbiota and decreased diversity in bacterial compositions as well as increased S. aureus abundance in those patients with polyps.
Background
Although transarterial chemoembolization is recommended as the standard treatment for Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma (BCLC‐B HCC), other treatments ...including liver resection have been used. This study aimed to determine the survival benefit of treatment strategies including resection for BCLC‐B HCC compared with non‐surgical treatments.
Methods
The nationwide multicentre database of the Korean Liver Cancer Association was reviewed. Patients with BCLC‐B HCC who underwent liver resection as a first or second treatment within 2 years of diagnosis and patients who received non‐surgical treatment were selected randomly. Survival outcomes of propensity score‐matched groups were compared.
Results
Among 887 randomly selected patients with BCLC‐B HCC, 83 underwent liver resection as first or second treatment and 597 had non‐surgical treatment. After propensity score matching, the two groups were well balanced (80 patients in each group). Overall median survival in the resection group was better than that for patients receiving non‐surgical treatment (50·9 versus 22·1 months respectively; P < 0·001). The 1‐, 2‐, 3‐ and 5‐year overall survival rates in the resection group were 90, 88, 75 and 63 per cent, compared with 79, 48, 35 and 22 per cent in the no‐surgery group (P < 0·001). In multivariable analysis, non‐surgical treatment only (hazard ratio (HR) 3·35, 95 per cent c.i. 2·16 to 5·19; P < 0·001), albumin level below 3·5 g/dl (HR 1·96, 1·22 to 3·15; P = 0·005) and largest tumour size greater than 5·0 cm (HR 1·81, 1·20 to 2·75; P = 0·005) were independent predictors of worse overall survival.
Conclusion
Treatment strategies that include liver resection offer a survival benefit compared with non‐surgical treatments for potentially resectable BCLC‐B HCC.
Selected patients benefit
There are inconsistencies in the literature regarding the prevalence and assessment of chemotherapy-induced peripheral neuropathy (CIPN). This study explored CIPN natural history and its ...characteristics in patients receiving taxane- and platinum-based chemotherapy.
Multi-country multisite prospective longitudinal observational study. Patients were assessed before commencing and three weekly during chemotherapy for up to six cycles, and at 6,9, and 12 months using clinician-based scales (NCI-CTCAE; WHO-CIPN criterion), objective assessments (cotton wool test;10 g monofilament); patient-reported outcome measures (FACT/GOG-Ntx; EORTC-CIPN20), and Nerve Conduction Studies.
In total, 343 patients were recruited in the cohort, providing 2399 observations. There was wide variation in CIPN prevalence rates using different assessments (14.2-53.4%). Prevalence of sensory neuropathy (and associated symptom profile) was also different in each type of chemotherapy, with paclitaxel (up to 63%) and oxaliplatin (up to 71.4%) showing the highest CIPN rates in most assessments and a more complex symptom profile. Peak prevalence was around the 6-month assessment (up to 71.4%). Motor neurotoxicity was common, particularly in the docetaxel subgroup (up to 22.1%; detected by NCI-CTCAE). There were relatively moderately-to-low correlations between scales (r
= 0.15,p < 0.05-r
= 0.48 p < 0.001), suggesting that they measure different neurotoxicity aspects from each other. Cumulative chemotherapy dose was not associated with onset and course of CIPN.
The historical variation reported in CIPN incidence and prevalence is possibly confounded by disagreement between assessment modalities. Clinical practice should consider assessment of motor neuropathy for neurotoxic chemotherapy. Current scales may not be all appropriate to measure CIPN in a valid way, and a combination of scales are needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We observe experimentally the spontaneous formation of star-shaped surface patterns in driven Bose-Einstein condensates. Two-dimensional star-shaped patterns with l -fold symmetry, ranging from ...quadrupole (l = 2) to heptagon modes (l = 7), are parametrically excited by modulating the scattering length near the Feshbach resonance. An effective Mathieu equation and Floquet analysis are utilized, relating the instability conditions to the dispersion of the surface modes in a trapped superfluid. Identifying the resonant frequencies of the patterns, we precisely measure the dispersion relation of the collective excitations. The oscillation amplitude of the surface excitations increases exponentially during the modulation. We find that only the l = 6 mode is unstable due to its emergent coupling with the dipole motion of the cloud. Our experimental results are in excellent agreement with the mean-field framework. Our work opens a new pathway for generating higher-lying collective excitations with applications, such as the probing of exotic properties of quantum fluids and providing a generation mechanism of quantum turbulence.
There are a few reports regarding the outcome evaluation of balloon-expandable intracranial stent placement (BEICS). The purpose of our study was to evaluate the outcome and factors related to the ...adverse events (AEs) of BEICS.
We evaluated 100 consecutive patients who underwent BEICS. We assessed the procedural success (residual stenosis < 50%), AEs (minor strokes, major strokes, and death), clinical outcome, and restenosis (> 50%) at 6 months. We also analyzed 18 factors including symptom patterns related to AE rate. Symptom patterns revealed 1) stable patients (n = 73) with improving, stationary, or resolved symptoms; and 2) unstable patients (n = 27) with gradual worsening or fluctuating symptoms (National Institutes of Health Stroke Scale NIHSS > or = 4) within 2 days before stent placement.
The procedural success rate was 99%. Overall, there were 10 (10%) AEs within the 6 months: 4 (4%) minor strokes, 3 (3%) major strokes, and 3 (3%) deaths including a death from myocardial infarction. AE rate was 4.1% in stable and 25.9% in unstable patients. Restenosis at 6 months revealed 0% (0/59). Good outcome (modified Rankin Scale < or = 2) at 6 months was 97% (71/73) in stable and 67% (18/27) in unstable patients. Stepwise logistic regression model revealed that symptom pattern (unstable versus stable) was the only significant risk factor (OR, 8.167; 95% CI, 1.933-34.500; P = .004).
BEICS revealed a low AE and good outcome rate at 6 months, especially in the stable patients. Midterm outcome was also favorable in the unstable patient group.
The fractionalization of elementary excitations in quantum spin systems is a central theme in current condensed matter physics. The Kitaev honeycomb spin model provides a prominent example of exotic ...fractionalized quasiparticles, composed of itinerant Majorana fermions and gapped gauge fluxes. However, identification of the Majorana fermions in a three-dimensional honeycomb lattice remains elusive. Here we report spectroscopic signatures of fractional excitations in the harmonic-honeycomb iridates β- and γ-Li2IrO3. Using polarization-resolved Raman spectroscopy, we find that the dynamical Raman response of β- and γ-Li2IrO3 features a broad scattering continuum with distinct polarization and composition dependence. The temperature dependence of the Raman spectral weight is dominated by the thermal damping of fermionic excitations. These results suggest the emergence of Majorana fermions from spin fractionalization in a three-dimensional Kitaev-Heisenberg system.
Objective
To estimate the current prevalence rates and decadal trends of gout and hyperuricemia in the US, as well as the prevalence of urate‐lowering therapy (ULT) among gout patients, using ...2007–2016 data from a nationally representative survey of American men and women (the National Health and Nutrition Examination Survey NHANES).
Methods
Using data from 5,467 participants in the NHANES 2015–2016, we estimated the most recent prevalence rates of gout and hyperuricemia. When the NHANES was conducted, all participants were asked about their history of gout (as diagnosed by a health professional) and medication use. Hyperuricemia was defined as having a serum urate level of >7.0 mg/dl in men and >5.7 mg/dl in women. We examined decadal trends in these estimates using data from the NHANES 2007–2016 and investigated ULT usage trends using the NHANES 2007–14 (the most recent data available to date).
Results
In 2015–2016, the prevalence of gout was 3.9% among adults in the US (9.2 million people), with 5.2% 5.9 million in men and 2.7% 3.3 million in women. Mean serum urate levels were 6.0 mg/dl in men and 4.8 mg/dl in women, and hyperuricemia prevalence rates were 20.2% and 20.0%, respectively. The prevalence rates of gout and hyperuricemia remained stable between 2007 and 2016 (P for trend > 0.05). The prevalence of ULT use among patients with gout was 33% in 2007–2014 and remained stable over time (P for trend > 0.05).
Conclusion
In this nationally representative survey sample of adults in the US, the prevalence rates of gout and hyperuricemia remained substantial, albeit unchanged, between 2007 and 2016. Despite these rates, only one‐third of gout patients were receiving ULT.
Objective
To compare the efficacy of two types of progestogen therapy for preventing preterm birth (PTB) and to review the relevant literature.
Design
A multicentre, randomised, open‐label, ...equivalence trial and a meta‐analysis.
Setting
Tertiary referral hospitals in South Korea.
Population
Pregnant women with a history of spontaneous PTB or short cervical length (<25 mm).
Methods
Eligible women were screened and randomised at 16‒22 weeks of gestation to receive either 200 mg of vaginal micronised progesterone daily (vaginal group) or an intramuscular injection of 250 mg 17α‐hydroxyprogesterone caproate weekly (IM group). Stratified randomisation was carried out according to participating centres and indications for progestogen therapy. This trial was registered at ClinicalTrials.gov (NCT02304237).
Main outcome measure
Preterm birth (PTB) before 37 weeks of gestation.
Results
A total of 266 women were randomly assigned and a total of 247 women (119 and 128 women in the vaginal and IM groups, respectively) were available for the intention‐to‐treat analysis. Risks of PTB before 37 weeks of gestation did not significantly differ between the two groups (22.7 versus 25.8%, P = 0.571). The difference in PTB risk between the two groups was 3.1% (95% CI −7.6 to 13.8%), which was within the equivalence margin of 15%. The meta‐analysis results showed no significant differences in the risk of PTB between the vaginal and IM progestogen treatments.
Conclusion
Compared with vaginal progesterone, treatment with intramuscular progestin might increase the risk of PTB before 37 weeks of gestation by as much as 13.8%, or reduce the risk by as much as 7.6%, in women with a history of spontaneous PTB or with short cervical length.
Tweetable
Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation.
Tweetable
Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation.
The capability of monitoring the differentiation process in living stem cells is crucial to the understanding of stem cell biology and the practical application of stem-cell-based therapies, yet ...conventional methods for the analysis of biomarkers related to differentiation require a large number of cells as well as cell lysis. Such requirements lead to the unavoidable loss of cell sources and preclude real-time monitoring of cellular events. In this work, we report the detection of microRNAs (miRNAs) in living human mesenchymal stem cells (hMSCs) by using polydopamine-coated gold nanoparticles (Au@PDA NPs). The PDA shell facilitates the immobilization of fluorescently labeled hairpin DNA strands (hpDNAs) that can recognize specific miRNA targets. The gold core and PDA shell quench the fluorescence of the immobilized hpDNAs, and subsequent binding of the hpDNAs to the target miRNAs leads to their dissociation from Au@PDA NPs and the recovery of fluorescence signals. Remarkably, these Au@PDA–hpDNA nanoprobes can naturally enter stem cells, which are known for their poor transfection efficiency, without the aid of transfection agents. Upon cellular uptake of these nanoprobes, we observe intense and time-dependent fluorescence responses from two important osteogenic marker miRNAs, namely, miR-29b and miR-31, only in hMSCs undergoing osteogenic differentiation and living primary osteoblasts but not in undifferentiated hMSCs and 3T3 fibroblasts. Strikingly, our nanoprobes can afford long-term tracking of miRNAs (5 days) in the differentiating hMSCs without the need of continuously replenishing cell culture medium with fresh nanoprobes. Our results demonstrate the capability of our Au@PDA–hpDNA nanoprobes for monitoring the differentiation status of hMSCs (i.e., differentiating versus undifferentiated) via the detection of specific miRNAs in living stem cells. Our nanoprobes show great promise in the investigation of the long-term dynamics of stem cell differentiation, identification and isolation of specific cell types, and high-throughput drug screening.
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