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Growing evidence suggests that sport-related concussion results in a robust inflammatory response that can be measured in serum or plasma and is predictive of symptom recovery. Recently, extracellular vesicles (EV) derived from serum or plasma have emerged as a promising source of biomarkers for neurological disorders like concussion because they may better reflect central immunological activity. However, the association of acute concussion with EV-associated cytokines has not yet been systematically studied in humans. We tested the hypothesis that EV-associated cytokines are elevated acutely and predictive of symptom duration following concussion in a cohort of high-school and collegiate football players. Players were enrolled and provided serum samples at a preseason baseline visit (N = 857). An additional blood draw was obtained in players that subsequently suffered a concussion (N = 23) within 6-hours post-injury and in matched, uninjured players (N = 44). Concentrations of Interleukin-6 (IL-6), IL-1ß, IL-1 receptor antagonist (IL-1RA), IL-10, and tumor necrosis factor were measured in EV and EV-depleted serum samples. EV-associated IL-6 was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). In EV-depleted samples, IL-1RA was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). Time-to-event analyses showed that post-injury EV-associated IL-6 levels were positively associated with the number of days that injured athletes reported symptoms (p < 0.05). These results highlight the potential of EV-associated cytokines as biomarkers of concussion.
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Traumatismos en Atletas , Conmoción Encefálica , Vesículas Extracelulares , Fútbol Americano , Citocinas , Fútbol Americano/lesiones , HumanosRESUMEN
BACKGROUND: Blast traumatic brain injury (TBI) and subconcussive blast exposure have been associated, pathologically, with chronic traumatic encephalopathy (CTE) and, clinically, with cognitive and affective symptoms, but the underlying pathomechanisms of these associations are not well understood. We hypothesized that exosomal microRNA (miRNA) expression, and their relation to neurobehavioral outcomes among Veterans with blunt or blast mild TBI (mTBI) may provide insight into possible mechanisms for these associations and therapeutic targets. METHODS: This is a subanalysis of a larger Chronic Effects of Neurotrauma Consortium Biomarker Discovery Project. Participants (n = 152) were divided into three groups: Controls (n = 35); Blunt mTBI only (n = 54); and Blast/blast+blunt mTBI (n = 63). Postconcussive and post-traumatic stress symptoms were evaluated using the NSI and PCL-5, respectively. Exosomal levels of 798 miRNA expression were measured. RESULTS: In the blast mTBI group, 23 differentially regulated miRNAs were observed compared to the blunt mTBI group and 23 compared to controls. From the pathway analysis, significantly dysregulated miRNAs in the blast exposure group correlated with inflammatory, neurodegenerative, and androgen receptor pathways. DISCUSSION: Our findings suggest that chronic neurobehavioral symptoms after blast TBI may pathomechanistically relate to dysregulated cellular pathways involved with neurodegeneration, inflammation, and central hormonal regulation.
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Traumatismos por Explosión , Conmoción Encefálica , Lesiones Traumáticas del Encéfalo , MicroARNs , Trastornos por Estrés Postraumático , Veteranos , Traumatismos por Explosión/complicaciones , Traumatismos por Explosión/genética , Traumatismos por Explosión/psicología , Conmoción Encefálica/complicaciones , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/genética , Explosiones , Humanos , MicroARNs/genética , Trastornos por Estrés Postraumático/complicaciones , Veteranos/psicologíaRESUMEN
The estimated mortality rates for breast and cervical cancer in Cambodia are high, perhaps because the Cambodian population lacks information about their detection and prevention. This cross-sectional study assessed the distribution of cervical cancers among and the behavioural and clinical characteristics of Cambodian women. It comprised 1039 Cambodian women who were interviewed between August 2013 and January 2016; the interviews were conducted in person using structured questionnaires. Among the participants, 801 (77.2%) and 709 (68.3%) had heard of cervical cancer and cervical cancer detection tests, respectively. However, 830 (80.2%) had never undergone a Pap smear, and 633 (60.9%) had never heard of breast self-examination. Despite the high mortality rates for breast and cervical cancer in Cambodia, only a small percentage of the participants had risk factors (e.g. smoking, alcohol consumption) for female cancers. A nationwide survey of the knowledge, attitudes and practices related to female cancers is recommended.Impact StatementWhat is already known on this subject? The estimated incidence and mortality rates of breast and cervical cancers in Cambodia are high. How much Cambodian women know about these cancers and whether they are receptive to cancer screening are questions requiring further study.What do the results of this study add? To our knowledge, this is the first study to describe the female cancer-related behavioural and clinical characteristics of Cambodian women. We show that rural Cambodian women are mostly unaware of breast and cervical cancer screening and that only a small percentage had risk factors for these cancers, despite the high incidence of these cancers in Cambodia.What are the implications of these findings for clinical practice and/or further research? Our findings potentially aid the design of programmes that increase awareness of breast and cervical cancers in Cambodia. Such programmes would be expected to reduce the incidence and mortality rates of these cancers in this country. Nationwide screening programmes for female cancers should be implemented in Cambodia.
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Neoplasias de la Mama/diagnóstico , Detección Precoz del Cáncer/psicología , Conocimientos, Actitudes y Práctica en Salud , Neoplasias del Cuello Uterino/diagnóstico , Adulto , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/psicología , Cambodia/epidemiología , Estudios Transversales , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/estadística & datos numéricos , Femenino , Conductas Relacionadas con la Salud , Humanos , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Población Rural/estadística & datos numéricos , Encuestas y Cuestionarios , Población Urbana/estadística & datos numéricos , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/psicologíaRESUMEN
In vascular smooth muscle, K+ channels, such as voltage-gated K+ channels (Kv), inward-rectifier K+ channels (Kir), and big-conductance Ca2+-activated K+ channels (BKCa), establish a hyperpolarized membrane potential and counterbalance the depolarizing vasoactive stimuli. Additionally, Kir mediates endothelium-dependent hyperpolarization and the active hyperemia response in various vessels, including the coronary artery. Pulmonary arterial hypertension (PAH) induces right ventricular hypertrophy (RVH), thereby elevating the risk of ischemia and right heart failure. Here, using the whole-cell patch-clamp technique, we compared Kv and Kir current densities (IKv and IKir) in the left (LCSMCs), right (RCSMCs), and septal branches of coronary smooth muscle cells (SCSMCs) from control and monocrotaline (MCT)-induced PAH rats exhibiting RVH. In control rats, (1) IKv was larger in RCSMCs than that in SCSMCs and LCSMCs, (2) IKv inactivation occurred at more negative voltages in SCSMCs than those in RCSMCs and LCSMCs, (3) IKir was smaller in SCSMCs than that in RCSMCs and LCSMCs, and (4) IBKCa did not differ between branches. Moreover, in PAH rats, IKir and IKv decreased in SCSMCs, but not in RCSMCs or LCSMCs, and IBKCa did not change in any of the branches. These results demonstrated that SCSMC-specific decreases in IKv and IKir occur in an MCT-induced PAH model, thereby offering insights into the potential pathophysiological implications of coronary blood flow regulation in right heart disease. Furthermore, the relatively smaller IKir in SCSMCs suggested a less effective vasodilatory response in the septal region to the moderate increase in extracellular K+ concentration under increased activity of the myocardium.
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BACKGROUND: Symptom assessment and quality of life (QoL) are considered two of the most important factors in the overall care of cancer patients. Although cancer is one of the leading causes of death after communicable disease in Cambodia, the QoL of Cambodian cancer patients has not been examined previously. This study aimed to describe the QoL of cancer patients in Cambodia. METHODS: A cross-sectional study was conducted with cancer patients who visited Khmer-Soviet Friendship Hospital in Phnom Penh. Two hundred patients participated in this study. The inventory comprised two previously validated scales: the Center for Epidemiological Studies Depression Scale-10 (CESD-10) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. Descriptive analyses, independent samples t-tests, and Pearson's correlation analysis were performed to examine the differences and relationship between study variables. RESULTS: The mean global health score was 51.62, and 58.5% of the participants had depressive symptom. The global health score was statistically significantly lower in depressive patients. The QoL was negatively correlated with depression, but positively and significant correlated with physical function, role function, emotional function, cognitive function, and social function. CONCLUSION: This study is the first to describe the QoL of Cambodian cancer patients. Our findings suggest that more attention should be paid to psychological concerns and symptom management in Cambodian cancer patients. Appropriate management could be effective in improving the QoL of cancer patients.
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Depresión/etiología , Neoplasias/psicología , Calidad de Vida , Adolescente , Adulto , Anciano , Cambodia , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Escalas de Valoración Psiquiátrica , Calidad de Vida/psicología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Free fatty acid (FFA) intake regulates blood pressure and vascular reactivity but its direct effect on contractility of systemic arteries is not well understood. We investigated the effects of saturated fatty acid (SFA, palmitic acid), polyunsaturated fatty acid (PUFA, linoleic acid), and monounsaturated fatty acid (MUFA, oleic acid) on the contractility of isolated mesenteric (MA) and deep femoral arteries (DFA) of Sprague-Dawley rats. Isolated MA and DFA were mounted on a dual wire myograph and phenylephrine (PhE, 1-10 µM) concentration-dependent contraction was obtained with or without FFAs. Incubation with 100 µM of palmitic acid significantly increased PhE-induced contraction in both arteries. In MA, treatment with 100 µM of linoleic acid decreased 1 µM PhE-induced contraction while increasing the response to higher PhE concentrations. In DFA, linoleic acid slightly decreased PhE-induced contraction while 200 µM oleic acid significantly decreased it. In MA, oleic acid reduced contraction at low PhE concentration (1 and 2 µM) while increasing it at 10 µM PhE. Perplexingly, depolarization by 40 mM KCl-induced contraction of MA was commonly enhanced by the three fatty acids. The 40 mM KCl-contraction of DFA was also augmented by linoleic and oleic acids while not affected by palmitic acid. SFA persistently increased alpha-adrenergic contraction of systemic arteries whereas PUFA and MUFA attenuated PhE-induced contraction of skeletal arteries. PUFA and MUFA concentration-dependent dual effects on MA suggest differential mechanisms depending on the types of arteries. Further studies are needed to elucidate underlying mechanisms of the various effects of FFA on systemic arteries.
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Hyperglycemia is associated with an increased risk of cardiovascular diseases. It has been demonstrated that chronic exposure to high glucose impaired endothelial functions. However, specific effects of short-term exposure to high glucose on vascular reactivity are controversial. Moreover, the combined effects of other metabolic substrates such as free fatty acids (FFA) on vascular reactivity remain poorly understood. Here we investigate the effects of short-term exposure to high glucose with or without other metabolic substrates including FFAs termed "nutrition full" (NF) solution, on mesenteric (MA) and deep femoral arteries (DFA) of rats. Arterial ring segments were mounted in a double-wire myograph. Contraction in response to phenylephrine (PhE) was determined in control (5 mM) and high glucose (23 mM, HG) environments over a 30 min period. In both arteries, PhE-inducedvasocontraction was enhanced by pre-incubation of HG solution. A combined incubation with HG and palmitic acid (100 µM) induced similar sensitization of PhE-contractions in both arteries. In contrast, high K+-induced contractions were not affected by HG. Interestingly, pre-incubation with NF solution decreased PhE-induced contraction in MA but increased the contraction in DFA. In NF solution, the HG-induced facilitation of PhE-contraction was not observed in MA. Furthermore, the PhE-induced contraction of DFA was attenuated by HG in NF solution. Our results demonstrate that the sensitization of PhE-induced arterial contraction by HG is differentially affected by other metabolic substrates. The conversation of skeletal arterial contractility by HG in NF solution requires careful interpretation of the previous in vitro studies where only glucose is included in physiological salt solutions. Further studies are required to elucidate the mechanism underlying the inconsistent effect of NF solution on MA and DFA.
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Postoperative Delirium (POD) can cause poor patient outcomes in older adults who undergo surgery. In this study, we tested plasma extracellular vesicle (EV) miRNAs obtained before the delirium event to find predictive POD biomarkers after spine surgery. We recruited patients who are over 70 years old and have undergone spine surgery. Finally, POD patients (n=31) were included, with no-POD patients matched in age, sex, medical history, and type of surgery (n=31). Peripheral blood was collected from patients in the operating room after the operation was completed. EVs were isolated from plasma, and the 798 miRNA expression level from EVs was measured using a NanoString platform. Sixty-two patients were included in the study; all were Korean, 67.7% were females, and the median age was 75 years. Preoperative medical history was not statistically different between no-POD and POD patients except for hypertension and the American Society of Anesthesiologists (ASA) physical status. From the miRNA profiling, we identified 142 significantly differentially expressed miRNAs in POD patients compared to no-POD patients, which are associated with psychological/neurological disorders. The top 10 differentially expressed miRNAs including miR-548ar-5p and miR-627-5p were all upregulated in POD patients and the results were validated using qRT-PCR from the independent sets of samples (n=96). We demonstrated the potential of plasma EV-miRNAs as predictive biomarkers to identify the risk group of POD after spine surgery. It also provides opportunities for future studies investigating the role of EV-miRNAs in delirium pathology.
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Food restriction (FR) enhances sensitivity to cardiopulmonary reflexes and α1-adrenoreceptors in females in the presence of hypotension. However, the effect of FR on cardiopulmonary and vascular function in males is not well-understood. This study examines the effects of FR on cardiopulmonary, isolated arterial function, and potential underlying mechanisms. Male Sprague-Dawley (SD) rats were randomly divided into 3 groups and monitored for 5 weeks: (1) control (n = 30), (2) 20% food reduction (FR20, n = 30), and (3) 40% food reduction (FR40, n = 30). Non-invasive blood pressure was measured twice a week. Pulmonary arterial pressure (PAP) was measured using isolated/perfused lungs. The isolated vascular reactivity was assessed using double-wire myographs. FR rats exhibited a lower mean arterial pressure and heart rate; however, only the FR40 group exhibited statistically significant differences. We observed that FR enhanced sensitivity (EC50) to vasoconstriction induced by the α1-adrenoreceptor phenylephrine (PhE) but not to serotonin, U46619, or high K+ in the mesenteric arteries. PhE-mediated vasoconstriction in the mesenteric arteries was eliminated in the presence of the eNOS inhibitor (L-NAME). In addition, incubation with NOX2/4 inhibitors (apocynin, GKT137831, and VAS2870) and the reactive oxygen species (ROS) scavenger inhibitor (Tiron) eliminated the differences in PhE-mediated vasoconstriction, but the cyclooxygenase inhibitor (indomethacin) in the mesenteric arteries did not. Augmentation of α1-adrenergic-mediated contraction via the inhibition of the eNOS-NO pathway increased the activation of ROS through NOX2/4 in response to FR. Reduced eNOS-NO signaling may be a pathophysiological counterbalance to prevent hypovolemic shock in response to FR.
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Adrenérgicos , Ingestión de Alimentos , Arterias Mesentéricas , Receptores Adrenérgicos alfa 1 , Vasoconstricción , Animales , Masculino , Ratas , Adrenérgicos/farmacología , Ingestión de Alimentos/fisiología , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Óxido Nítrico/metabolismo , Fenilefrina/farmacología , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Receptores Adrenérgicos alfa 1/fisiologíaRESUMEN
Traumatic brain injury (TBI) is a common cause of disability and fatality worldwide. Depending on the clinical presentation, it is a type of acquired brain damage that can be mild, moderate, or severe. The degree of patient's discomfort, prognosis, therapeutic approach, survival rates, and recurrence can all be strongly impacted by an accurate diagnosis made early on. The Glasgow Coma Scale (GCS), along with neuroimaging (MRI (Magnetic Resonance Imaging) and CT scan), is a neurological assessment tools used to evaluate and categorize the severity of TBI based on the patient's level of consciousness, eye opening, and motor response. Extracellular vesicles (EVs) are a growing domain, explaining neurological complications in a more detailed manner. EVs, in general, play a role in cellular communication. Its molecular signature such as DNA, RNA, protein, etc. contributes to the status (health or pathological stage) of the parental cell. Brain-derived EVs support more specific screening (diagnostic and prognostic) in TBI research. Therapeutic impact of EVs are more promising for aiding in TBI healing. It is nontoxic, biocompatible, and capable of crossing the blood-brain barrier (BBB) to transport therapeutic molecules. This review has highlighted the relationships between EVs and TBI theranostics, EVs and TBI-related clinical trials, and related research domain-associated challenges and solutions. This review motivates further exploration of associations between EVs and TBI and develops a better approach to TBI management.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Vesículas Extracelulares , Humanos , Encéfalo , Barrera HematoencefálicaRESUMEN
Objective: The aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes. Methods: This pilot study comprised two independent cohorts. The first cohort-part of a Traumatic Head Injury Neuroimaging Classification (THINC) study-with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort-with a mean age of 19 years-comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay. Results: Concentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690-0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT-/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT-/MRI-, n = 111) findings and UIC (P-values < 0.05). Conclusion: These findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions.
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BACKGROUND: Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion. METHODS: This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association-Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 h post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without sport-related concussion. RESULTS: A total of 140 athletes with concussion (79.3% males; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% males; 19.14 ± 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve (AUC) of 0.954 (95% confidence interval: 0.922â0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury. CONCLUSION: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.
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Traumatismos en Atletas , Conmoción Encefálica , Deportes , Masculino , Humanos , Femenino , Conmoción Encefálica/diagnóstico , Traumatismos en Atletas/diagnóstico , Estudios Prospectivos , alfa-Sinucleína , Estudios de Casos y Controles , Proteómica , BiomarcadoresRESUMEN
Blast exposures that occur during training are common in military personnel; however, the biomarkers that relate to these subtle injuries is not well understood. Therefore, the purpose of this study is to identify the acute biomarkers related to blast injury in a cohort of military personnel exposure to blast-related training. Thirty-four military personnel who participated in the training program were included in this study. Blood samples were collected before and after repetitive blast-related training on days 2 (n = 19) and days 7 (n = 15). Serum concentration (pg/mL) of tau, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau181 (p-tau181) were measured using an ultrasensitive immunoassay platform. We observed that serum p-tau181 concentrations were elevated after exposed to repetitive blast on days 2 (z = -2.983, p = 0.003) and days 7 (z = -2.158, p = 0.031). Serum tau (z = -2.272, p = 0.023) and NfL (z = -2.158, p = 0.031) levels were significantly elevated after exposure to repetitive blasts on days 7. Our findings indicate that blast exposure affects serum biomarkers indicating axonal injury.
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Background: Breast milk has abundant extracellular vesicles (EVs) containing various biological molecules (cargo), including miRNAs. EVs are not degraded in the gastrointestinal system and circulation; thus, breast milk EVs (bEVs) are expected to interact with other organs in breastfed infants and modify the gene expression of recipient cells using miRNAs. Maternal pre-pregnancy BMI is a critical factor influencing the composition of breast milk. Thus, in mothers with obesity, miRNAs in bEVs can be altered, which might be associated with adverse health outcomes in infants. In this study, we examined 798 miRNAs to determine which miRNAs are altered in the bEVs of mothers with obesity and their potential impact on breastfed infants. Methods: We recruited healthy nursing mothers who were either of normal weight (BMI < 25) or with obesity (BMI ≥ 30) based on their pre-pregnancy BMI, and delivered a singleton baby in the prior 6 months. EVs were isolated from breast milk with ultracentrifugation. bEV characteristics were examined by flow cytometry and fluorescence imaging of EV markers. A total of 798 miRNAs were screened using a NanoString human miRNA panel to find differentially expressed miRNAs in bEVs of mothers with obesity compared to mothers of normal weight. Results: We included 65 nursing mothers: 47 of normal weight and 18 with obesity based on pre-pregnancy BMI. After bEV isolation, we confirmed the expression of various EV markers. Out of 37 EV markers, CD326 (EpCaM) was the most highly expressed in bEVs. The most abundant miRNAs in bEVs include miR-30b-5p, miR-4454, miR-494-3p, and let-7 miRNAs. Target genes of the top 10 miRNAs were associated with cancer, prolactin pathway, EGFR, ErbB, and FoxO signaling pathway. In bEVs of mothers with obesity, 19 miRNAs were differentially expressed (adjusted p < 0.05 cut-off), which include miR-575, miR-630, miR-642a-3p, and miR-652-5p. These miRNAs and their target genes were associated with neurological diseases and psychological disorders. Conclusion: In this study, we characterized bEVs and demonstrated altered miRNAs in bEVs of mothers with obesity and identified the pathways of their potential target genes. Our findings will provide insight for future studies investigating the role of bEVs in breastfed infants.
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Moderate/severe traumatic brain injury (TBI) causes injury patterns with heterogeneous pathology producing varying outcomes for recovery. Extracellular vesicles (EVs) are particles containing a myriad of molecules involved in cell signaling. EVs may hold promise as biomarkers in TBI because of their encapsulation, including improved stability/decreased degradation. A subset of subjects with and without TBI from a prospective, observational trial of critically ill trauma patients were analyzed. Total EV levels of glial (glial fibrillary acidic protein; GFAP) and neuronal/axonal (ubiquitin carboxy-terminal hydrolase L1 [UCH-L1], neurofilament light chain [NfL], and total-tau) proteins were measured using single-molecule array technology. Protein levels were winsorized to address outliers and log transformed for analysis. Patients with multiple injuries (n = 41) and isolated body injury (n = 73) were of similar age and sex. Patients with multiple injuries were, as expected, more severely injured with higher Injury Severity Scores (29 [26-41] vs. 21 [14-26], p < 0.001) and lower Glasgow Coma Scale scores (12 [4-13] vs. 13 [13-13], p < 0.001). Total body EVs of GFAP, UCH-L1, and NfL were higher in those with multiple injuries (1768 [932-4780] vs. 239 [63-589], p < 0.001; 75.4 [47.8-158.3] vs. 41.5 [21.5-67.1], p = 0.03; 7.5 [3.3-12.3] vs. 2.9 [2.1-4.8], p < 0.001, respectively). There was a moderate correlation between the Head Abbreviated Injury Score and GFAP (free circulating rho = 0.62, EV rho = 0.64; both p < 0.001). Brain-derived proteins contained in EV holds promise as an informative approach to biomarker measurement after TBI in hospitalized patients. Future evaluation and longitudinal studies are necessary to draw conclusions regarding the clinical utility of these biomarkers.
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INTRODUCTION: Patients who had a mild ischaemic stroke who present with subtle or resolving symptoms sometimes go undiagnosed, are excluded from treatment and in some cases clinically worsen. Circulating immune cells are potential biomarkers that can assist with diagnosis in ischaemic stroke. Understanding the transcriptomic changes of each cell population caused by ischaemic stroke is critical because they work closely in a complicated relationship. In this study, we investigated peripheral blood mononuclear cells (PBMCs) transcriptomics of patients who had a stroke using a single-cell RNA sequencing to understand peripheral immune response after mild stroke based on the gene expression in an unbiased way. METHODS: Transcriptomes of PBMCsfrom 10 patients who had an acute ischaemic stroke within 24 hours after stroke onset were compared with 9 race-matched/age-matched/gender-matched controls. Individual PBMCs were prepared with ddSeqTM (Illumina-BioRad) and sequenced on the Illumina NovaSeq 6000 platform. RESULTS: Notable population changes were observed in patients who had a stroke, especially in NK cells and CD14+ monocytes. The number of NK cells was increased, which was further confirmed by flow cytometry. Functional analysis implied that the activity of NK cells also is enhanced in patients who had a stroke. CD14+ monocytes were clustered into two groups; dendritic cell-related CD14+ monocytes and NK cell-related CD14+ monocytes. We found CD14+ monocyte subclusters were dramatically reduced in patients who had a stroke. DISCUSSION: This is the first study demonstrating the increased number of NK cells and new monocyte subclusters of mild ischaemic stroke based on the transcriptomic analysis. Our findings provide the dynamics of circulating immune response that could assist diagnosis and potential therapeutic development of mild ischaemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Biomarcadores , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/genética , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/genética , Leucocitos Mononucleares/química , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/genéticaRESUMEN
Repetitive low-level blast exposure is one of the major occupational health concerns among US military service members and law enforcement. This study seeks to identify gene expression using microRNA and RNA sequencing in whole-blood samples from experienced breachers and unexposed controls. We performed experimental RNA sequencing using Illumina's HiSeq 2500 Sequencing System, and microRNA analysis using NanoString Technology nCounter miRNA expression panel in whole-blood total RNA samples from 15 experienced breachers and 14 age-, sex-, and race-matched unexposed controls. We identified 10 significantly dysregulated genes between experienced breachers and unexposed controls, with FDR corrected <0.05: One upregulated gene, LINC00996 (long intergenic non-protein coding RNA 996); and nine downregulated genes, IGLV3-16 (immunoglobulin lambda variable 3-16), CD200 (CD200 molecule), LILRB5 (leukocyte immunoglobulin-like receptor B5), ZNF667-AS1 (ZNF667 antisense RNA 1), LMOD1 (leiomodin 1), CNTNAP2 (contactin-associated protein 2), EVPL (envoplakin), DPF3 (double PHD fingers 3), and IGHV4-34 (immunoglobulin heavy variable 4-34). The dysregulated gene expressions reported here have been associated with chronic inflammation and immune response, suggesting that these pathways may relate to the risk of lasting neurological symptoms following high exposures to blast over a career.
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Objective: To investigate the plasma proteomic profiling in identifying biomarkers related to return to sport (RTS) following a sport-related concussion (SRC). Methods: This multicenter, prospective, case-control study was part of a larger cohort study conducted by the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium, athletes (n = 140) with blood collected within 48 h of injury and reported day to asymptomatic were included in this study, divided into two groups: (1) recovery <14-days (n = 99) and (2) recovery ≥14-days (n = 41). We applied a highly multiplexed proteomic technique that uses DNA aptamers assay to target 1,305 proteins in plasma samples from concussed athletes with <14-days and ≥14-days. Results: We identified 87 plasma proteins significantly dysregulated (32 upregulated and 55 downregulated) in concussed athletes with recovery ≥14-days relative to recovery <14-days groups. The significantly dysregulated proteins were uploaded to Ingenuity Pathway Analysis (IPA) software for analysis. Pathway analysis showed that significantly dysregulated proteins were associated with STAT3 pathway, regulation of the epithelial mesenchymal transition by growth factors pathway, and acute phase response signaling. Conclusion: Our data showed the feasibility of large-scale plasma proteomic profiling in concussed athletes with a <14-days and ≥ 14-days recovery. These findings provide a possible understanding of the pathophysiological mechanism in neurobiological recovery. Further study is required to determine whether these proteins can aid clinicians in RTS decisions.
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Thromboxane A2 (TXA2) promotes various physiological responses including pulmonary artery (PA) contraction, and pathophysiological implications have been suggested in cardiovascular diseases including pulmonary hypertension. Here, we investigated the role of TXA2 receptor (TP)-mediated signaling in the pathophysiology of pulmonary arterial hypertension (PAH). The sensitivity of PA to the contractile agonist could be set by relaxing signals such as the nitric oxide (NO), soluble guanylate cyclase (sGC), and cGMP-dependent kinase (PKG) pathways. Changes in the TP agonist (U46619)-induced PA contraction and its modulation by NO/cGMP signaling were analyzed in a monocrotaline-induced PAH rat model (PAH-MCT). In the myograph study, PA from PAH-MCT showed higher responsiveness to U46619, that is decreased EC50. Immunoblot analysis revealed a lower expression of eNOS, sGC, and PKG, while there was a higher expression of RhoA-dependent kinase 2 (ROCK2) in the PA from PAH-MCT than in the control. In PAH-MCT, the higher sensitivity to U46619 was reversed by 8-Br-cGMP, a membrane-permeable cGMP analog, but not by the NO donor, sodium nitroprusside (SNP 30 µM). In contrast, in the control PA, inhibition of sGC by its inhibitor (1H- [1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ), 10 µM) lowered the threshold of U46619-induced contraction. In the presence of ODQ, SNP treatment had no effect whereas the addition of 8-Br-cGMP lowered the sensitivity to U46619. The inhibition of ROCK by Y-27632 attenuated the sensitivity to U46619 in both control and PAH-MCT. The study suggests that the attenuation of NO/cGMP signaling and the upregulation of ROCK2 increase the sensitivity to TXA2 in the PAH animal, which might have pathophysiological implications in patients with PAH.
RESUMEN
Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are commonly experienced after exposure to highly stressful events, including physical trauma, yet, biological predictors remain elusive. Methylation of DNA may provide key insights, as it likely is reflective of factors that may increase the risk in trauma patients, as DNA methylation is altered by previous stressors. Here, we compared DNA methylation patterns using bisulfite sequencing in patients with a physical trauma that required more than a 24-h hospitalization (n = 33). We then compared DNA methylation in patients who developed and compared the following groups (1) PTSD and MDD; n = 12), (2) MDD (patients with MDD only; n = 12), and (3) control (patients who did not have PTSD or MDD; n = 9), determined by the PTSD Checklist (PCL-5) and Quick Inventory of Depressive Symptomatology (QIDS) at 6-months follow-up. We identified 17 genes with hypermethylated cytosine sites and 2 genes with hypomethylated sites in comparison between PTSD and control group. In comparison between MDD and control group, we identified 12 genes with hypermethylated cytosine sites and 6 genes with hypomethylated sites. Demethylation of these genes altered the CREB signaling pathway in neurons and may represent a promising therapeutic development target for PTSD and MDD. Our findings suggest that epigenetic changes in these gene regions potentially relate to the onset and symptomology of PTSD and MDD and could be used as potential biomarkers in predicting the onset of PTSD or MDD following traumatic events.