Severity-dependent Manner Research Articles

Circulating metabolome in relation to cognitive impairment: a community-based cohort of older adults.

The role of circulating metabolome in cognitive impairment is inconclusive, and whether the associations are in the severity-dependent manner remains unclear. We aimed to identify plasma metabolites associated with cognitive impairment and evaluate the added predictive capacity of metabolite biomarkers on incident cognitive impairment beyond traditional risk factors. In the Rugao Longevity and Ageing Study (RuLAS), plasma metabolome was profiled by nuclear magnetic resonance spectroscopy. Participants were classified into the cognitively normal, moderately impaired, and severely impaired groups according to their performance in two objective cognitive tests. A two-step strategy of cross-sectional discovery followed by prospective validation was applied. In the discovery stage, we included 1643 participants (age: 78.9 ± 4.5 years) and conducted multinomial logistic regression. In the validation stage, we matched 68 incident cases of cognitive impairment (moderately-to-severely impaired) during the 2-year follow-up with 204 cognitively normal controls by age and sex at a 1:3 ratio, and conducted conditional logistic regression. We identified 28 out of 78 metabolites cross-sectionally related to severely impaired cognition, among which IDL particle number, ApoB in IDL, leucine, and valine were prospectively associated with 28%, 28%, 29%, and 33% lower risk of developing cognitive impairment, respectively. Incorporating 13 metabolite biomarkers selected through Lasso regression into the traditional risk factors-based prediction model substantially improved the ability to predict incident cognitive impairment (AUROC: 0.839 vs. 0.703, P < 0.001; AUPRC: 0.705 vs. 0.405, P < 0.001). This study identified specific plasma metabolites related to cognitive impairment. Incorporation of specific metabolites substantially improved the prediction performance for cognitive impairment.

The metabolic and physiologic impairments underlying long COVID associated exercise intolerance.

Data from invasive CPET (iCPET) revealed long COVID patients have impaired systemic oxygen extraction (EO2), suggesting impaired mitochondrial ATP production. However, it remains uncertain whether the initial severity of SARS-CoV-2 infection has implications on EO2 and exercise capacity (VO2) nor has there been assessment of anerobic ATP generation in long COVID patients. iCPET was performed on 47 long COVID patients (i.e., full cohort; n = 8 with severe SARS-CoV-2 infection). In a subset of patients (i.e., metabolomic cohort; n = 26) metabolomics on venous and arterial blood samples during iCPET was performed. In the full cohort, long COVID patients exhibited reduced peak EO2 with reduced peak VO2 (90 ± 17% predicted) relative to cardiac output (118 ± 23% predicted). Peak VO2 [88% predicted (IQR 81% - 108%) vs. 70% predicted (IQR 64% - 89%); p = 0.02] and EO2 [0.59(IQR 0.53-0.62) vs. 0.53(IQR 0.50-0.48); p = 0.01) were lower in severe versus mild infection. In the metabolomic cohort, 12 metabolites were significantly consumed, and 41 metabolites were significantly released (p-values < 0.05). Quantitative metabolomics demonstrated significant increases in inosine and succinate arteriovenous gradients during exercise. Peak VO2 was significantly correlated with peak venous succinate (r = 0.68; p = 0.0008) and peak venous lactate (r = 0.49; p = 0.0004). Peak EO2 and consequently peak VO2 impact long COVID patients in a severity dependent manner. Exercise intolerance associated with long COVID is defined by impaired aerobic and anaerobic energy production. Peak venous succinate may serve as a potential biomarker in long COVID.

Abstract Tu051: ROR2 Drives Right Ventricular Failure Via Proteostatic Imbalances

Background: No therapies exist to treat right ventricular failure (RVF), in part because RVF molecular drivers have been incompletely studied. We recently identified that the developmentally restricted noncanonical WNT receptor ROR2 is re-expressed in a severity-dependent manner in human RVF. Here we test in mice if, and how, the re-expression of Ror2 causes RVF. Methods/Results: We find in neonatal rat ventricular myocytes (NRVMs) that Ror2 overexpression (Ror2 OE ) both activates protein translation and reduces Hspa1a/b mRNA and Hsp70 protein, resulting in increased protein turnover, fragmented sarcomeres, intercalated disc disruption, reduced cell major axis, impairment of contractile and relaxation kinetics, and ectopy. Ror2 knockdown (Ror2 KD ) results in opposing phenotypes. Hsp70 overexpression or proteasome inhibition rescues many of the Ror2 OE phenotypes, demonstrating their causal involvement. NRVM proteomic analysis indicates that Ror2 OE activates an ERK/p90RSK/Eef2 pathway that is known to regulate translation extension. In vivo, cardiac Ror2 OE in mice causes RV dilation and dysfunction, intercalated disc disruption, reduced Hspa1b (encoding for Hsp70), proteasome activation, and reduced cardiomyocyte ubiquitin staining. The mouse pulmonary artery banding (PAB) model of RVF reveals similar Ror2 induction and proteasome activation. Ror2 KD by AAV9 in PAB reduces RV dilation and improves RV systolic and diastolic function. Finally, in cardiac samples from human RVF, we find evidence for a similar ROR2-responsive proteostatic imbalance with increased proteasome activity and ubiquitin as well as markers of increased ERK and p90RSK. Conclusions: ROR2 is induced in human and mouse RVF, and mechanistic studies in NRVMs and mice show that the induction of ROR2 causes RVF by disrupting the proteostatic balance of translation, folding, and turnover. Knockdown or suppression of ROR2 may serve as a novel RVF therapeutic target.

Stretch-Induced Injury Affects Cortical Neuronal Networks in a Time- and Severity-Dependent Manner.

Traumatic brain injury (TBI) is the leading cause of accident-related death and disability in the world and can lead to long-term neuropsychiatric symptoms, such as a decline in cognitive function and neurodegeneration. TBI includes primary and secondary injury, with head trauma and deformation of the brain caused by the physical force of the impact as primary injury, and cellular and molecular cascades that lead to cell death as secondary injury. Currently, there is no treatment for TBI-induced cell damage and neural circuit dysfunction in the brain, and thus, it is important to understand the underlying cellular mechanisms that lead to cell damage. In the current study, we use stretchable microelectrode arrays (sMEAs) to model the primary injury of TBI to study the electrophysiological effects of physically injuring cortical cells. We recorded electrophysiological activity before injury and then stretched the flexible membrane of the sMEAs to injure the cells to varying degrees. At 1, 24, and 72h post-stretch, we recorded activity to analyze differences in spike rate, Fano factor, burstlet rate, burstlet width, synchrony of firing, local network efficiency, and Q statistic. Our results demonstrate that mechanical injury changes the firing properties of cortical neuron networks in culture in a time- and severity-dependent manner. Our results suggest that changes to electrophysiological properties after stretch are dependent on the strength of synchronization between neurons prior to injury.

DOP37 Noninvasive assessment of gut function using transcriptional recording sentinel cells

Abstract Background Bacteria within the human gut continuously adapt their gene expression to environmental conditions that are associated with diet, health, and disease. Noninvasive measurements of bacterial gene expression patterns throughout the intestine are important to understand in vivo microbiota physiology and pathophysiology. Current methods do not offer sufficient information about transient or proximal events within the intestine without using indirect or invasive approaches that disturb normal physiology and are inapplicable to clinical practice. Methods Here we used transcriptional recording sentinel cells that through a reverse transcriptase-Cas1–Cas2 complex record their own short-lived mRNA expression into long-lived DNA-based CRISPR arrays to report on gut function. We colonized gnotobiotic mice with E. coli sentinel cells and performed Record-seq on fecal samples to reconstruct their cellular histories as they passed along the gastrointestinal tract. Results Upon colonization of the mouse intestine, sentinel cells reported on diet, inflammation, and microbial interactions. Through transcriptome-scale information, Record-seq elucidated E. coli’s adaptations to intraluminal conditions including pH, oxygen levels, and ion availability. Unlike RNA-seq, Record-seq performed on stool samples retained information from proximal gut sections to noninvasively report on the luminal conditions in vivo. In a mouse model of inflammatory bowel disease, Record-seq not only diagnosed the inflammation in a severity-dependent manner but also revealed pathological gut conditions such as mucus depletion and hyperoxygenation. Conclusion Transcriptional recording sentinel cells noninvasively report on gut function and reveal environmental cues such as diet, inflammation, and microbial interactions, even in proximal gut sections that are otherwise unamenable to unbiased diagnostic interrogation.

Stratification of βSβ+ Compound Heterozygotes Based on L-Glutamine Administration and RDW: Focusing on Disease Severity.

Sickle cell disease (SCD) is heterogeneous in terms of manifestation severity, even more so when in compound heterozygosity with beta-thalassemia. The aim of the present study was to stratify βSβ+ patient blood samples in a severity-dependent manner. Blood from thirty-two patients with HbS/β-thalassemia compound heterozygosity was examined for several parameters (e.g., hemostasis, inflammation, redox equilibrium) against healthy controls. Additionally, SCD patients were a posteriori (a) categorized based on the L-glutamine dose and (b) clustered into high-/low-RDW subgroups. The patient cohort was characterized by anemia, inflammation, and elevated coagulation. Higher-dose administration of L-glutamine was associated with decreased markers of inflammation and oxidation (e.g., intracellular reactive oxygen species) and an altered coagulation profile. The higher-RDW group was characterized by increased hemolysis, elevated markers of inflammation and stress erythropoiesis, and oxidative phenomena (e.g., membrane-bound hemoglobin). Moreover, the levels of hemostasis parameters (e.g., D-Dimers) were greater compared to the lower-RDW subgroup. The administration of higher doses of L-glutamine along with hydroxyurea seems to attenuate several features in SCD patients, probably by enhancing antioxidant power. Moreover, anisocytosis may alter erythrocytes' coagulation processes and hemolytic propensity. This results in the disruption of the redox and pro-/anti-inflammatory equilibria, creating a positive feedback loop by inducing stress erythropoiesis and, thus, the occurrence of a mixed erythrocyte population.

Recovery from Traumatic Brain Injury Is Nociceptin/Orphanin FQ Peptide Receptor Genotype-, Sex-, and Injury Severity-Dependent.

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, and survivors often experience mental and physical health consequences that reduce quality of life. We previously reported that blockade of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor reduced tissue damage markers produced by blast TBI. The goal of this study was to determine the extent to which N/OFQ and NOP receptor levels change following mild (mTBI) and moderate TBI (modTBI) and whether the absence of the NOP receptor attenuates TBI-induced sequelae. Male and female NOP receptor knockout (KO) or wild-type (WT) rats received craniotomy-only (sham) or craniotomy plus mTBI, or modTBI impact to the left cerebral hemisphere. Neurologic and vestibulomotor deficits and nociceptive hyperalgesia and allodynia found in WT male and female rats following mTBI and modTBI were greatly reduced or absent in NOP receptor KO rats. NOP receptor levels increased in brain tissue from injured males but remained unchanged in females. Neurofilament light chain (NF-L) and glial fibrillary acidic protein (GFAP) expression were reduced in NOP receptor KO rats compared with WT following TBI. Levels of N/OFQ in injured brain tissue correlated with neurobehavioral outcomes and GFAP in WT males, but not with KO male or WT and KO female rats. This study reveals a significant contribution of the N/OFQ-NOP receptor system to TBI-induced deficits and suggests that the NOP receptor should be regarded as a potential therapeutic target for TBI. SIGNIFICANCE STATEMENT: This study revealed that nociceptin/orphanin FQ peptide (NOP) receptor knockout animals experienced fewer traumatic brain injury (TBI)-induced deficits than their wild-type counterparts in a sex- and injury severity-dependent manner, suggesting that NOP receptor antagonists may be a potential therapy for TBI.

Increased Interleukin-17-Producing γδT Cells in the Brain Exacerbate the Pathogenesis of Sepsis-Associated Encephalopathy and Sepsis-Induced Anxiety in Mice.

Overactivated microglia play a key role in sepsis-associated encephalopathy (SAE), although the involvement of T cells is unclear. γδT cells in the brain and meninges regulate normal fear responses via interleukin (IL)-17 in healthy mice. In our sepsis model, the mice showed exacerbated anxious behavior at 10 days post-induction (dpi). At 8 dpi, IL-17 mRNA was significantly upregulated in the brains of septic mice compared with those of control mice. Simultaneously, the number of γδT cells increased in the brains of septic mice in a severity-dependent manner. Additionally, IL-17-producing γδT cells, expressing both the C-X-C motif receptor (CXCR) 6 and the C-C motif receptor (CCR) 6, increased in mice brains, dependent on the severity of sepsis. The frequency of γδT cells in the meninges fluctuated similarly to that in the brain, peaking at 8 dpi of sepsis. Behavioral tests were performed on septic mice after the continuous administration of anti-γδTCR (α-γδTCR) or anti-IL-17A (α-IL-17A) antibodies to deplete the γδT cells and IL-17A, respectively. Compared with IgG-treated septic mice, α-γδTCR- and α-IL-17A-treated septic mice showed suppressed microglial activation and improvements in anxious behavior. These results suggested that CCR6+CXCR6+ IL-17-producing γδT cells in the brain and meninges promote the exacerbation of SAE and sepsis-induced psychological disorders in mice.

The same boat, different storm: stress volatile emissions in response to biotrophic fungal infections in primary and alternate hosts

ABSTRACT Rust infection results in stress volatile emissions, but due to the complexity of host-pathogen interaction and variations in innate defense and capacity to induce defense, biochemical responses can vary among host species. Fungal-dependent modifications in volatile emissions have been well documented in numerous host species, but how emission responses vary among host species is poorly understood. Our recent experiments demonstrated that the obligate biotrophic crown rust fungus (P. coronata) differently activated primary and secondary metabolic pathways in its primary host Avena sativa and alternate host Rhamnus frangula. In A. sativa, emissions of methyl jasmonate, short-chained lipoxygenase products, long-chained saturated fatty acid derivatives, mono- and sesquiterpenes, carotenoid breakdown products, and benzenoids were initially elicited in an infection severity-dependent manner, but the emissions decreased under severe infection and photosynthesis was almost completely inhibited. In R. frangula, infection resulted in low-level induction of stress volatile emissions, but surprisingly, in enhanced constitutive isoprene emissions, and even severely-infected leaves maintained a certain photosynthesis rate. Thus, the same pathogen elicited a much stronger response in the primary than in the alternate host. We argue that future work should focus on resolving mechanisms of different fungal tolerance and resilience among primary and secondary hosts.

Obesity induces male mice infertility via oxidative stress, apoptosis, and glycolysis.

The current declining trend in male fertility parallels the increasing prevalence of obesity worldwide. This paper revealed that the poor in vitro fertilization rates and decreased sperm motility in obese mice due to excessive oxidative stress enhanced apoptosis and impaired glucose metabolism in the testes. Obesity is an urgent public health problem in recent decades, linked to reduced reproductive potential, and negatively affects the success of assisted reproduction technology. The aim of this study is to investigate the mechanisms underlying impaired male fertility caused by obesity. Male C57BL/6 mice fed a high-fat diet for 20 weeks served as mouse models with moderate (20% < body fat rate (BFR) < 30%) and severe obesity (BFR > 30%). Our results showed poor in vitro fertilization rates and decreased sperm motility in obese mice. Abnormal testicular structures were identified in male mice with moderate and severe obesity. The expression level of malondialdehyde increased with obesity severity. This finding indicates that oxidative stress plays a role in male infertility caused by obesity, which was further confirmed by the decreased expression of nuclear factor erythroid 2-related factor 2, superoxide dismutase, and glutathione peroxidases. Our study also found that the expression of cleaved caspase-3 and B-cell lymphoma-2 showed an obesity severity-dependent manner indicating that apoptosis is highly correlated with male infertility caused by obesity. Moreover, the expression of glycolysis-related proteins, including glucose transporter 8, lactate dehydrogenase A, monocarboxylate transporter 2 (MCT2), and MCT4, decreased significantly in the testes of obese male mice, suggesting energy supply for spermatogenesis is impaired by obesity. Taken together, our findings provide evidence that obesity impairs male fertility through oxidative stress, apoptosis, and blockage of energy supply in the testes and suggest that male obesity influences fertility through complex and multiple mechanisms.

Severe Anemia Causes Chronic Hypoxia and Alters Hematopoiesis in Liver of Murine Neonates

Background: Anemia is nearly universal in preterm infants and is associated with increased morbidity and mortality worldwide. We have recently described that the anemia associated “leaky gut” phenotype that leads to monocyte infiltration in intestine and RBC-transfusion activates these cells, resulting in necrotizing enterocolitis (NEC). In this study, we are investigating the effects of phlebotomy-induced severe anemia on hypoxia in the liver and the liver’s hematopoietic response. Methods: C57BL/6 mouse pups were studied in 3 groups (n=6 each): (1) naïve controls; (2) moderately anemic (hematocrit [hct] 27-32%); and (3) severely anemic (hct 20-24%). Pups were rendered severely anemic by facial vein phlebotomies on P2, 4, 6, 8, and 10. For moderately anemic, phlebotomized on P2, P6 and P10 only. Hypoxyprobe (pimonidazole hydrochloride) was administered i.p (60mg/kg body weight) to all groups of mice, 4 hours prior to sacrifice (P10) to evaluate hypoxia. On P11, the liver tissue was extracted and used for histology, protein analysis and flow cytometry. Immunostaining was performed on tissue sections of liver by using anti-GFP-pimonidazole. The liver protein samples were subjected to western immunoblotting for hypoxia-inducible factors (HIF-1α, HIF-2 and HIF-3). Single cell suspensions from liver tissue were stained with antibodies against SCA-1, cKit, CD16/32, CD34, CD135, CD48, CD41 and CD150, then these cells were acquired by BD LSRII-flow cytometry followed by FlowJo gating of hematopoietic progenitors (HSC), multipotent progenitors (MPP), common myeloid progenitors (CMP) and granulocyte macrophage progenitors (GMP). Results: Severely anemic liver sections showed stronger immunoreactivity for pimonidazole (fluorescence AFU, 74 ± 6.8; mean ± SE) than did moderately anemic liver, which showed minimal staining (32 ± 2.4; mean ± SE). No immunostaining was seen in controls (13 ± 0.9; mean ± SE), indicating that hypoxia was induced in the liver of anemic pups in a severity-dependent manner. In immunoblotting, we have detected an increased HIF-3 expression and decreased HIF-1α and HIF-2 expression in P10 livers of the severely anemic group, with opposite results seen in the livers of moderately anemic and control livers. We have also found that HIF-3 expression gradually increased after each phlebotomy, but HIF-1α and HIF-2 was suppressed in control mice. These findings indicate that progressive phlebotomy may induce chronic hypoxia in the liver, with gradually increased expression of HIF-3. Flow analysis showed higher frequencies (%) of stem cell progenitors, LSK cells, LT-HSC, MPP with increased GMP in severe anemia compared to moderate anemia and controls, showing that anemia-associated hypoxia skews the hematopoietic system toward granulocyte production. Conclusions: Severe anemia-associated chronic hypoxia state in the liver leads to increased expression of HIF-3 and alters the hematopoietic pool with increased production of granulocytes. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Elevated IFNA1 and suppressed IL12p40 associated with persistent hyperinflammation in COVID-19 pneumonia.

Despite of massive endeavors to characterize inflammation in COVID-19 patients, the core network of inflammatory mediators responsible for severe pneumonia stillremain remains elusive. Here, we performed quantitative and kinetic analysis of 191 inflammatory factors in 955 plasma samples from 80 normal controls (sample n = 80) and 347 confirmed COVID-19 pneumonia patients (sample n = 875), including 8 deceased patients. Differential expression analysis showed that 76% of plasmaproteins (145 factors) were upregulated in severe COVID-19 patients comparedwith moderate patients, confirming overt inflammatory responses in severe COVID-19 pneumonia patients. Global correlation analysis of the plasma factorsrevealed two core inflammatory modules, core I and II, comprising mainly myeloid cell and lymphoid cell compartments, respectively, with enhanced impact in a severity-dependent manner. We observed elevated IFNA1 and suppressed IL12p40, presenting a robust inverse correlation in severe patients, which was strongly associated with persistent hyperinflammation in 8.3% of moderate pneumonia patients and 59.4% of severe patients. Aberrant persistence of pulmonary and systemic inflammation might be associated with long COVID-19 sequelae. Our comprehensive analysis of inflammatory mediators in plasmarevealed the complexity of pneumonic inflammation in COVID-19 patients anddefined critical modules responsible for severe pneumonic progression.

Impact of SARS-CoV-2 infection on the profiles and responses of innate immune cells after recovery.

BackgroundsSARS-CoV-2 infection results in a broad spectrum of clinical outcomes, ranging from asymptomatic to severe symptoms and death. Most COVID-19 pathogenesis is associated with hyperinflammatory conditions driven primarily by myeloid cell lineages. The long-term effects of SARS-CoV-2 infection post recovery include various symptoms.MethodsWe performed a longitudinal study of the innate immune profiles 1 and 3 months after recovery in the Thai cohort by comparing patients with mild, moderate, and severe clinical symptoms using peripheral blood mononuclear cells (n = 62).ResultsSignificant increases in the frequencies of monocytes compared to controls and NK cells compared to mild and moderate patients were observed in severe patients 1–3 months post recovery. Increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were observed in all recovered patients, even after 3 months. Increased IL-6 and TNFα levels in monocytes were observed 1 month after recovery in response to lipopolysaccharide (LPS) stimulation, while decreased CD86 and HLA-DR levels were observed regardless of stimulation. A multiplex analysis of serum cytokines performed at 1 month revealed that most innate cytokines, except for TNFα, IL4/IL-13 (Th2) and IFNγ (Th1), were elevated in recovered patients in a severity-dependent manner. Finally, the myelopoiesis cytokines G-CSF and GM-CSF were higher in all patient groups. Increased monocytes and IL-6- and TNFα-producing cells were significantly associated with long COVID-19 symptoms.ConclusionsThese results reveal that COVID-19 infection influences the frequencies and functions of innate immune cells for up to 3 months after recovery, which may potentially lead to some of the long COVID symptoms.

Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity.We investigated the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], glial fibrillary acidic protein [GFAP] and total tau) and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza.During hospitalisation, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort.A distinct process characterised by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP.These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible

Functional Impairment of Endothelial Colony Forming Cells (ECFC) in Patients with Severe Atherosclerotic Cardiovascular Disease (ASCVD).

Endothelial dysfunction is a key factor in atherosclerosis. However, the link between endothelial repair and severity of atherosclerotic cardiovascular disease (ASCVD) is unclear. This study investigates the relationship between ASCVD, markers of inflammation, and circulating endothelial progenitor cells, namely hematopoietic cells with paracrine angiogenic activity and endothelial colony forming cells (ECFC). Two hundred and forty-three subjects from the TELARTA study were classified according to the presence of clinical atherosclerotic disease. ASCVD severity was assessed by the number of involved vascular territories. Flow cytometry was used to numerate circulating progenitor cells (PC) expressing CD34 and those co-expressing CD45, CD34, and KDR. Peripheral blood mononuclear cells ex vivo culture methods were used to determine ECFC and Colony Forming Unit- endothelial cells (CFU-EC). The ECFC subpopulation was analyzed for proliferation, senescence, and vasculogenic properties. Plasma levels of IL-6 and VEGF-A were measured using Cytokine Array. Despite an increased number of circulating precursors in ASCVD patients, ASCVD impaired the colony forming capacity and the angiogenic properties of ECFC in a severity-dependent manner. Alteration of ECFC was associated with increased senescent phenotype and IL-6 levels. Our study demonstrates a decrease in ECFC repair capacity according to ASCVD severity in an inflammatory and senescence-associated secretory phenotype context.

Melatonin alleviates the adverse effects of water stress in adult olive cultivars (Olea europea cv. Sevillana & Roughani) in field condition

Olive trees are considered among the most resilient crops in Mediterranean basin. However, prolonged water stress may adversely affect plant productivity and quality of fruits and oil. Therefore, it is essential to design new agronomic strategies to improve plant water stress tolerance and secure yield and product stability of this important agricultural crop. Under water deficit, plants cope with serious threats, and melatonin (MEL), as a versatile signaling biomolecule, can play a crucial role in morphological and physiological modifications of plants able to enhance drought stress tolerance. In this view, the current research aimed at elucidating the potential beneficial role of exogenous foliar application of MEL (0 and 100 µM) to Sevillana and Roughani olive cultivars under different water stress levels (100%, 75%, and 50% ET). In particular, the morphological, physiological and biochemical changes occurring in leaves treated with or without MEL and the quality of fruits and oil were discussed. A decrease of electrolyte leakage (EL) and malondialdehyde (MDA) content as well as an increase of relative water content (RWC) in MEL-sprayed leaves of drought stress trees were observed. The application of MEL was also associated with higher K+ to Na+ ratio, Ca2+ content, phenolic and soluble carbohydrates contents and a lower decline chlorophyll (Chl) levels. MEL-treated leaves also showed higher catalase (CAT) and peroxidase (POD) activities, responsible for scavenging reactive oxygen species (ROS) generated during drought stress in a severity-dependent manner. MEL-foliar application enhanced the oil content and yield in the olive fruits in both cultivars compared to the untreated ones. Since MEL was also able to exert a beneficial effect on both Sevillana and Roughani cultivar trees by improving their crop water productivity (WPc) under water deficit, it can be considered an effective eco-friendly candidate to minimize the detrimental consequences of water stress.

Predialysis serum lactate levels could predict dialysis withdrawal in Type 1 cardiorenal syndrome patients.

SummaryBackgroundRenal replacement therapy (RRT) is an effective rescue therapy for Type 1 cardiorenal syndrome (CRS). Previous studies have demonstrated that type 1 CRS patients with severe renal dysfunction were susceptible to sepsis, and that serum lactate has been correlated with the risk of mortality in patients with sepsis. However, the association between serum lactate level and the prognosis of type 1 CRS patients requiring RRT is unknown.MethodsAn inception cohort of 500 type 1 CRS patients who received RRT in a tertiary-care referral hospital in Taiwan from August 2011 to January 2018 were enrolled. The outcomes of interest were dialysis withdrawal and 90-day mortality. The results were further externally validated using sampling data of type 1 CRS patients requiring dialysis from multiple tertiary-care centers.FindingsThe 90-day mortality rate was 52.8% and the incidence rate of dialysis withdrawal was 34.8%. Lower pre-dialysis lactate was correlated with a higher rate of dialysis withdrawal and lower rate of mortality. Generalized additive model showed that 4.2 mmol/L was an adequate cut-off value of lactate to predict mortality. Taking mortality as a competing risk, Fine-Gray subdistribution hazard analysis further indicated that a low lactate level (≦ 4.2 mmol/L) was an independent predictor for the possibility of dialysis withdrawal, as also shown in external validation. The interaction of quick Sequential Organ Failure Assessment score and lactate was associated with dialysis dependence in a disease severity-dependent manner. Furthermore, the associations between hyperlactatemia and dialysis dependence were consistent in the patients with and without sepsis.InterpretationSerum lactate level is accurate and capable of forecasting the prognosis along with qSOFA severity for clinical decision-making for treating type 1 CRS patients. Further studies are needed to validate our results.FundingThis study was supported by grants from Taiwan National Science Council [104–2314-B-002–125-MY3,106–2314-B-002–166-MY3,107–2314-B-002–026-MY3], National Taiwan University Hospital [106-FTN20,106-P02,UN106–014,106-S3582,107-S3809,107-T02,PC1246,VN109–09,109-S4634,UN109–041], Ministry of Science and Technology of the Republic of China [MOST106–2321-B-182–002,106-2314-B-182A-064,MOST107–2321-B-182–004,MOST107-2314-B-182A-138, MOST108–2321-B-182–003,MOST109–2321-B-182–001, MOST108-2314-B-182A-027], Chang Gung Memorial Hospital [CMRPG-2G0361,CMRPG-2H0161,CMRPG-2J0261, CMRPG-2K0091], and Ministry of Health and Welfare of the Republic of China [PMRPG-2L0011].

The effect of gall mites (Acariformes, Eriophyoidea) on leaf morphology and pigment content of deciduous trees in West Siberia

Phytophagous mites of the superfamily Eriophyoidea are capable of inducing gall formation on various organs of higher vascular plants. However, the question of how gallogenesis affects leaf assimilation surface and photosynthetic activity of the host plants is poorly understood. We have examined the influence of gall-forming mites from the genera Eriophyes and Acalitus on leaf size, shape and photosynthetic pigment content in five deciduous tree species near the city of Tyumen, West Siberia. The gall mite infestation resulted in chlorosis, destruction of photosynthetic apparatus in gall-infected leaf parts, leaf deformation and a decrease in leaf area. The magnitude of the effects on leaf size and shape varied among the studied mite–tree systems and did not depend on the infection severity. On the contrary, chlorophyll and carotenoid amounts per leaf decreased in an infection severity-dependent manner in all mite–host plant variants. Mite-induced galls did not influence the pigment concentration in green uninfected gaps between galls. Additionally, the chlorophyll amount in the infected leaves has decreased due to the destruction of the pigment complex in the galled leaf areas and a decrease of the whole-leaf area. As a result, the losses of chlorophylls and carotenoids in leaves of all studied trees were directly related to the infection severity (quantified as the proportion of damaged leaf area to the total leaf area). Our results may help developing an approach to assess the effect of gall mites on the chlorophyll content and the photosynthetic productivity of trees, based on the direct or remote analysis of damaged leaf surface.

Congenital Hypothyroidism Can Dictate the Mode of Delivery and Intra-Labor Medication Usage

Background: Pregnancy and parturition reflect the complex interaction between physiological conditions of the mother and her offspring, and fetal health characteristics may affect maternal health throughout pregnancy and delivery. We aimed to investigate the characteristics of the mother-infant dyad of term infants detected as having congenital hypothyroidism (CH). Methods: A retrospective cohort study of 108,717 term infants delivered liveborn at Lis Maternity and Women's Hospital between 2010 and 2017. Infants were detected by the National Newborn Screening Program as having CH (131, 0.12%). Three years of surveillance in the Pediatric Endocrine Clinic revealed that 65 infants had transient CH and 66 had permanent CH. Data on maternal, pregnancy, delivery, and perinatal characteristics of the mother-infant dyads were retrieved from the hospital's electronic database. Results: Mode of delivery differed: a higher proportion of deliveries of CH infants required vacuum assistance, and more infants with CH were born through a cesarean section compared with the general population (p < 0.001). Medication during labor also differed, with higher rates of oxytocin (p < 0.001) and antibiotics (p = 0.008) administered to mothers of CH infants. A multivariate logistic regression model revealed an increased demand for oxytocin administration during the labor of a CH infant in a hypothyroidism severity-dependent manner, expressed as a threefold risk associated with permanent but not transient CH. Conclusions: Our findings of increased utilization of medical interventions during the labor and delivery of CH infants suggest that the prenatal fetal thyroid function may affect the development and progress of labor and delivery, in response to oxytocin.

Epidermal Protein C Levels Correspond to Local Injury Severity and Increased Clinical Support in Burn Patients

The protein C (PC) system has proven to be a crucial cascade in systemic inflammatory and coagulopathic disorders such as severe sepsis and, more recently, in severe burns. We aimed to conflate our recent systemic findings with further investigations in the local tissue effects of a severe burn injury on the expression of PC and its main receptor endothelial protein C receptor (EPCR). Of the 86 patients enrolled in our recent study, 34 consented to biopsies of both normal and burn edge tissue. These were examined histologically and immunostained for PC, EPCR, and CD68. The burn samples expressed lower PC (p = 0.0027) and higher EPCR (p = 0.0253) than the normal samples in a histological severity-dependent manner. There was also a negative association between PC expression and CD68 positive macrophage infiltration (τb = −0.214, p = 0.020), which was expectedly higher in burn edge samples (p &lt; 0.0005). Interestingly, while there were no correlations between tissue and plasma PC or EPCR, local PC expression was also prognostic of our previously established outcome of a patient requiring increased medical support (OR 0.217 (95%CI 0.052 to 0.901), p = 0.035). The results suggest that local PC cascade changes from a burn injury may be a separate process to the systemic effects and that the local levels may provide useful information in addition to the diagnostic and prognostic abilities we previously found in the circulating PC system.