Background Intraoperative hypotension (IOH) has been associated with increased postoperative morbidity and mortality, emphasizing the importance of maintaining hemodynamic stability during general ...anesthesia. The Hypotension Prediction Index (HPI) is a recently developed tool obtained from the arterial pressure waveform for predicting the likelihood of hypotension and reflecting the level of hemodynamic instability (HI). Methods In this retrospective observational cohort study, we analyzed anonymized data that were prospectively collected in patients having major abdominal surgery in six Spanish centers during 2022. We analyzed data from patients who underwent general anesthesia and required intraoperative monitoring with the Hemosphere monitoring system and HPI software. We defined five patterns of HI using a decision-making algorithm based on cardiovascular pathophysiology: absolute and relative hypovolemia, vasoplegia, and myocardial depression with and without vasoplegia. Results After analyzing 2,038 hours of hemodynamic monitoring from 393 patients, 1,946 episodes of HI were identified. Vasoplegia was the most common type of HI, accounting for 50.1% HI episodes. Absolute and relative hypovolemia were the next most frequent types, contributing 30.7% and 15.5% of the HI episodes. Conclusions We identified five distinct patterns of hemodynamic instability based on the evaluation of hemodynamic parameters underlying arterial hypotension during general anesthesia for patients undergoing major abdominal surgery. Vasoplegia was found to be the most frequent type. These novel classifications can help guide targeted treatment strategies for managing hemodynamic instability and reducing the risk of intraoperative hypotension.
Tatton-Brown-Rahman (TBRS) syndrome is a recently described overgrowth syndrome caused by loss of function variants in the DNMT3A gene. This gene encodes for a DNA methyltransferase 3 alpha, which is ...involved in epigenetic regulation, especially during embryonic development. Somatic variants in DNMT3A have been widely studied in different types of tumors, including acute myeloid leukemia, hematopoietic, and lymphoid cancers. Germline gain-of-function variants in this gene have been recently implicated in microcephalic dwarfism. Common clinical features of patients with TBRS include tall stature, macrocephaly, intellectual disability (ID), and a distinctive facial appearance. Differential diagnosis of TBRS comprises Sotos, Weaver, and Malan Syndromes. The majority of these disorders present other clinical features with a high clinical overlap, making necessary a molecular confirmation of the clinical diagnosis. We here describe seven new patients with variants in DNMT3A, four of them with neuropsychiatric disorders, including schizophrenia and psychotic behavior. In addition, one of the patients has developed a brain tumor in adulthood. This patient has also cerebral atrophy, aggressive behavior, ID, and abnormal facial features. Clinical evaluation of this group of patients should include a complete neuropsychiatric assessment together with psychological support in order to detect and manage abnormal behaviors such as aggressiveness, impulsivity, and attention deficit-hyperactivity disorder. TBRS should be suspected in patients with overgrowth, ID, tall stature, and macrocephaly, who also have some neuropsychiatric disorders without any genetic defects in the commonest overgrowth disorders. Molecular confirmation in these patients is mandatory.
Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore ...patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence.
ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362.
Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio RR 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21).
Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable.
UK Medical Research Council and Health Technology Assessment Programme.
•Relations between germination behavior and temperature were established•Thermal requirements for germination varied between populations•Variation in thermal requirements were associated with local ...population environments•Harsh environment populations showed higher thermal restrictions for germination
Seed germination is one of the earliest phenotypes expressed by plants, and the accuracy to germinate in the correct time and place is essential for plant population fitness. Cues that regulate germination have been exhaustively characterized in laboratory experiments. However, the way in which seed populations respond to these cues and the ecological meanings of this phenomenon are scarcely known. To help filling this gap, we studied the thermic regulation of seed germination and its link with local climatic characteristics in Festuca pallescens populations, an iconic perennial grass species of Patagonia. By coupling thermal time models with field and environmental data, we evaluated seed responsiveness to temperature during germination of nine Festuca pallescens populations distributed across their complete longitudinal range in North Patagonia. The idea behind this experimental design was to search for inter-population differences in early life traits relevant for recruitment of the species, and associate seed traits with local environmental characteristics. F. pallescens populations showed strong differences in seed sensitivity to temperature for the thermal regulation of the germination rate, described by the population mean thermal time for germination (θ(50)) and its standard deviation (σθ). The greatest values of θ(50) and σθ corresponded to populations inhabiting harsh environments. Moreover, θ(50) of the different populations showed strong correlations with their local thermal environmental parameters, indicating a relation between seed physiological traits and climate across the longitudinal gradient. We did not observe inter-population differences in the minimum temperature that allows germination (Tb = -0.47 ± 0.19 °C). Higher θ(50) and σθ in populations from harsh climates may constitute a strategy of the species to increase fitness in hostile habitats, preventing anticipated germination and promoting a slower seed bank depletion in regions where establishment is highly limited.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally ...indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD.
We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs.
To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.
Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, ...motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders.
We performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect.
We found seven JMJD1C variants that were not present in any control sample (~ 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity.
Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.
The production of J/ψ mesons in proton–proton collisions at √s = 7 TeV is studied with the LHCb detector at the LHC. The differential cross-section for prompt J/ψ production is measured as a function ...of the J/ψ transverse
momentum pT and rapidity y in the fiducial region pT ∈ 0; 14 GeV/c and y ∈ 2.0; 4.5. The differential cross-section and fraction of J/ψ from b-hadron decays are also measured in the same pT and y ranges. The analysis is based on a data sample corresponding to an integrated luminosity of 5.2 pb−1. The measured cross-sections integrated over the fiducial region are 10.52 ± 0.04 ± 1.40+1.64 −2.20 µb for prompt J/ψ production and 1.14 ± 0.01 ± 0.16 µb for J/ψ from b-hadron decays, where the first uncertainty is statistical and the second systematic. The prompt J/ψ production cross-section is obtained assuming no J/ψ polarisation and the third error indicates the acceptance uncertainty due to this assumption.
The obtaining of nanocarriers of gene material and small drugs is still an interesting research line. Side-effects produced by the toxicity of several pharmaceutics, the high concentrations needed to ...get therapeutic effects, or their excessive use by patients have motivated the search for new nanostructures. For these reasons, cationic metallo-liposomes composed by phosphatidylcholine (PC), cholesterol (CHO) and RuC1C19 (a surfactant derived from the metallic complex Ru(bpy)32+) were prepared and characterized by using diverse techniques (zeta potential, dynamic light scattering and electronic transmission microscopy –TEM-). Unimodal or bimodal populations of spherical aggregates with small sizes were obtained depending on the composition of the liposomes. The presence of cholesterol favored the formation of small aggregates. ct-DNA was condensed in the presence of the liposomes investigated. In-vitro assays demonstrated the ability of these nanoaggregates to internalize into different cell lines. A positive gene transfection into human bone osteosarcoma epithelial cells (U2OS) was also observed. The RuC1C19 surfactant was used as sensor to quantify the binding of DNA to the liposomes. Doxorubicin was encapsulated into the metallo-liposomes, demonstrating their ability to be also used as nanocarriers of drugs. A relationship between then encapsulation percentage of the antibiotic and the composition of the aggregates has been established.
is a filamentous, saprophytic fungus, whose colonization occurs mainly in cereal grains and oilseeds once harvested. Under certain conditions, it could produce mycotoxins called aflatoxins, known as ...powerful human liver carcinogens. The aim of the present study was to describe the antifungal activity of extracts of
, a species from northern Argentina (Oriental Chaco), against
. The antifungal activities of different collection sites are reported. The extracts exhibited a minimum inhibitory concentration of 125 µg/mL, and the differences between the treatments and the inoculum control were 11 mm of
and 10 mm of
in colony growth. Moreover, hyphae treated with the extracts stained blue with Evans blue showed alterations in the membrane and/or cell wall, allowing the dye income. Bio-guided fractionation, High Performance Liquid Chromatography diode array ultraviolet/visible (HPLC UV/VIS DAD), and Ultra-High Performance Liquid Chromatography Electrospray Ionization Mass Spectrometry (UPLC ESI-MS) analyses were conducted to characterize the extracts and their active fractions. The HPLC UV/VIS DAD analysis allowed the determination of the presence of flavonoids (flavonols and flavones), coumarins, terpenes, and steroids. UPLC ESI/MS analysis of active fractions revealed the presence of Kaempferol, Apigenin, Naringenin, Chrysin and Daidzein.
Motor neuron degeneration and neuroinflammation are the most striking pathological features of amyotrophic lateral sclerosis (ALS). ALS currently has no cure and approved drugs have only a modest ...clinically therapeutic effect in patients. Drugs targeting different deleterious inflammatory pathways in ALS appear as promising therapeutic alternatives. Here, we have assessed the potential therapeutic effect of an electrophilic nitroalkene benzoic acid derivative, (
E
)-4-(2-nitrovinyl) benzoic acid (BANA), to slow down paralysis progression when administered after overt disease onset in SOD1
G93A
rats. BANA exerted a significant inhibition of NF-κB activation in NF-κB reporter transgenic mice and microglial cell cultures. Systemic daily oral administration of BANA to SOD1
G93A
rats after paralysis onset significantly decreased microgliosis and astrocytosis, and significantly reduced the number of NF-κB-p65-positive microglial nuclei surrounding spinal motor neurons. Numerous microglia bearing nuclear NF-κB-p65 were observed in the surrounding of motor neurons in autopsy spinal cords from ALS patients but not in controls, suggesting ALS-associated microglia could be targeted by BANA. In addition, BANA-treated SOD1
G93A
rats after paralysis onset showed significantly ameliorated spinal motor neuron pathology as well as conserved neuromuscular junction innervation in the skeletal muscle, as compared to controls. Notably, BANA prolonged post-paralysis survival by ~30%, compared to vehicle-treated littermates. These data provide a rationale to therapeutically slow paralysis progression in ALS using small electrophilic compounds such as BANA, through a mechanism involving microglial NF-κB inhibition.
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