The Role of the Second Extracellular Loop of Norepinephrine Transporter, Neurotrophin-3 and Tropomyosin Receptor Kinase C in T Cells: A Peripheral Biomarker in the Etiology of Schizophrenia

The neurobiology of schizophrenia is multifactorial, comprising the dysregulation of several biochemical pathways and molecules. This research proposes a peripheral biomarker for schizophrenia that involves the second extracellular loop of norepinephrine transporter (NEText), the tropomyosin receptor kinase C (TrkC), and the neurotrophin-3 (NT-3) in T cells. The study of NEText, NT-3, and TrkC was performed in T cells and plasma extracted from peripheral blood of 54 patients with schizophrenia and 54 healthy controls. Levels of NT-3, TrkC, and NET were significantly lower in plasma and T cells of patients compared to healthy controls. Co-immunoprecipitation (co-IPs) showed protein interactions with Co-IP NEText–NT-3 and Co-IP NEText–TrkC. Computational modelling of protein–peptide docking by CABS-dock provided a medium–high accuracy model for NT-3–NEText (4.6935 Å) and TrkC–NEText (2.1365 Å). In summary, immunocomplexes reached statistical relevance in the T cells of the control group contrary to the results obtained with schizophrenia. The reduced expression of NT-3, TrkC, and NET, and the lack of molecular complexes in T cells of patients with schizophrenia may lead to a peripheral dysregulation of intracellular signaling pathways and an abnormal reuptake of norepinephrine (NE) by NET. This peripheral molecular biomarker underlying schizophrenia reinforces the role of neurotrophins, and noradrenergic and immune systems in the pathophysiology of schizophrenia.

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Direct evidence for a key role of protein kinase C in the development of vasospasm after subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/jns.1992.76.4.0635 ◽

1992 ◽

Vol 76 (4) ◽

pp. 635-639 ◽

Cited By ~ 68

Author(s):

Shigeru Nishizawa ◽

Nobukazu Nezu ◽

Kenichi Uemura

Keyword(s):

Signal Transduction ◽

Protein Kinase C ◽

Protein Kinase ◽

Direct Evidence ◽

Control Group ◽

Content Type ◽

Kinase C ◽

Protein Kinase C Activity ◽

Fine Print

✓ Vascular contraction is induced by the activation of intracellular contractile proteins mediated through signal transduction from the outside to the inside of cells. Protein kinase C plays a crucial role in this signal transduction. It is hypothesized that protein kinase C plays a causative part in the development of vasospasm after subarachnoid hemorrhage (SAH). To verify this directly, the authors measured protein kinase C activity in canine basilar arteries in an SAH model with (γ-32P)adenosine triphosphate and the data were compared to those in a control group. Protein kinase C is translocated to the membrane from the cytosol when it is activated, and the translocation is an index of the activation; thus, protein kinase C activity was measured both in the cytosol and in the membrane fractions. Protein kinase C activity in the membrane in the SAH model was remarkably enhanced compared to that in the control group. The percentage of membrane activity to the total was also significantly greater in the SAH vessels than in the control group, and the percentage of cytosol activity in the SAH group was decreased compared to that in the control arteries. The results indicate that protein kinase C in the vascular smooth muscle was translocated to the membrane from the cytosol and was activated when SAH occurred. It is concluded that this is direct evidence for a key role of protein kinase C in the development of vasospasm.

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Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells

Molecular and Cellular Biology ◽

10.1128/mcb.12.7.3305-3312.1992 ◽

1992 ◽

Vol 12 (7) ◽

pp. 3305-3312

Author(s):

M Izquierdo ◽

J Downward ◽

J D Graves ◽

D A Cantrell

Keyword(s):

T Cells ◽

Protein Kinase C ◽

Protein Kinase ◽

Kinase Inhibitor ◽

Antigen Receptor ◽

Permeabilized Cell ◽

Regulatory Pathways ◽

Kinase C ◽

Stimulation Of

T-lymphocyte activation via the antigen receptor complex (TCR) results in accumulation of p21ras in the active GTP-bound state. Stimulation of protein kinase C (PKC) can also activate p21ras, and it has been proposed that the TCR effect on p21ras occurs as a consequence of TCR regulation of PKC. To test the role of PKC in TCR regulation of p21ras, a permeabilized cell system was used to examine TCR regulation of p21ras under conditions in which TCR activation of PKC was blocked, first by using a PKC pseudosubstrate peptide inhibitor and second by using ionic conditions that prevent phosphatidyl inositol hydrolysis and hence diacylglycerol production and PKC stimulation. The data show that TCR-induced p21ras activation is not mediated exclusively by PKC. Thus, in the absence of PKC stimulation, the TCR was still able to induce accumulation of p21ras-GTP complexes, and this stimulation correlated with an inactivation of p21ras GTPase-activating proteins. The protein tyrosine kinase inhibitor herbimycin could prevent the non-PKC-mediated, TCR-induced stimulation of p21ras. These data indicate that two mechanisms for p21ras regulation coexist in T cells: one PKC mediated and one not. The TCR can apparently couple to p21ras via a non-PKC-controlled route that may involve tyrosine kinases.

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Role of Regulatory B Cells in the Progression of Cervical Cancer

Mediators of Inflammation ◽

10.1155/2019/6519427 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Zhifang Chen ◽

Yuejie Zhu ◽

Rong Du ◽

Nannan Pang ◽

Fengbo Zhang ◽

...

Keyword(s):

Cervical Cancer ◽

T Cells ◽

Cancer Patients ◽

Intraepithelial Neoplasia ◽

Serum Levels ◽

Hpv Infection ◽

Control Group ◽

Cell Percentage

This study is to investigate the role of regulatory B (Breg) cells in cervical cancer. In total, 70 cases of cervical cancer, 52 cases of cervical intraepithelial neoplasia (CIN), and 40 normal controls were enrolled. The percentage of Breg cells was detected by flow cytometry. Serum levels of IL-10 were measured by ELISA. The correlation between Breg cells and the clinical characterizations of cervical cancer was analyzed. The inhibition effect of Breg cells on CD8+ T cells was tested by blocking IL-10 in vitro. The percentage of CD19+CD5+CD1d+ Breg cells and the level of IL-10 of patients with cervical cancer or CIN were significantly higher than those in the control group (P<0.05). And the postoperative levels of Breg cells and IL-10 were significantly lower than the preoperative levels (P<0.05). Breg cells and the IL-10 level were positively correlated in cervical cancer patients (r=0.516). In addition, the Breg cell percentage was closely related to the FIGO stages, lymph node metastasis, tumor differentiation, HPV infection, and the tumor metastasis of cervical cancer (P<0.05). The Breg cell percentage was negatively correlated with CD8+ T cells of cervical cancer patients (r=‐0.669). The level of IL-10 in the culture supernatant of Bregs treated with CpG was significantly higher than that of non-Bregs (P<0.05). After coculture with Bregs, the quantity of CD8+ T cells to secrete perforin and Granzyme B was significantly decreased, and this effect was reversed after blocking IL-10 by a specific antibody. Breg cells are elevated in cervical cancer and associated with disease progression and metastasis. Moreover, they can inhibit the cytotoxicity of CD8+ T cells.

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Study of the Relationship between Microbiome and Colorectal Cancer Susceptibility Using 16SrRNA Sequencing

BioMed Research International ◽

10.1155/2020/7828392 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17 ◽

Cited By ~ 6

Author(s):

Wanxin Liu ◽

Ren Zhang ◽

Rong Shu ◽

Jinjing Yu ◽

Huan Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Gut Microbiota ◽

Cancer Susceptibility ◽

Precancerous Lesions ◽

Bacterial Community Composition ◽

Intestinal Flora ◽

Control Group ◽

Healthy Controls ◽

Healthy Individuals

A lot of previous studies have recently reported that the gut microbiota influences the development of colorectal cancer (CRC) in Western countries, but the role of the gut microbiota in Chinese population must be investigated fully. The goal of this study was to determine the role of the gut microbiome in the initiation and development of CRC. We collected fecal samples of 206 Chinese individuals: 59 with polyp (group P), 54 with adenoma (group A), 51 with colorectal cancer (group CC), and 42 healthy controls (group HC).16S ribosomal RNA (rRNA) was used to compare the microbiota community structures among healthy controls, patients with polyp, and those with adenoma or colorectal cancer. Our study proved that intestinal flora, as a specific indicator, showed significant differences in its diversity and composition. Sobs, Chao, and Ace indexes of group CC were significantly lower than those of the healthy control group (CC group: Sobs, Chao, and Ace indexes were 217.3 ± 69, 4265.1 ± 80.7, and 268.6 ± 78.1, respectively; HC group: Sobs, Chao, and Ace indexes were 228.8 ± 44.4, 272.9 ± 58.6, and 271.9 ± 57.2, respectively). When compared with the healthy individuals, the species richness and diversity of intestinal flora in patients with colorectal cancer were significantly reduced: PCA and PCoA both revealed that a significant separation in bacterial community composition between the CC group and HC group (with PCA using the first two principal component scores of PC1 14.73% and PC2 10.34% of the explained variance, respectively; PCoA : PC1 = 14%, PC2 = 9%, PC3 = 6%). Wilcox tests was used to analyze differences between the two groups, it reveals that Firmicutes (P=0.000356), Fusobacteria (P=0.000001), Proteobacteria (P=0.000796), Spirochaetes (P=0.013421), Synergistetes (P=0.005642) were phyla with significantly different distributions between cases and controls. The proportion of microorganism composition is varying at different stages of colon cancer development: Bacteroidetes (52.14%) and Firmicutes (35.88%) were enriched in the healthy individuals; on the phylum level, the abundance of Bacteroidetes (52.14%-53.92%-52.46%–47.06%) and Firmicutes (35.88%-29.73%-24.27%–25.36%) is decreasing with the development of health-polyp-adenomas-CRC, and the abundance of Proteobacteria (9.33%-12.31%-16.51%–22.37%) is increasing. PCA and PCOA analysis showed there was no significant (P<0.05) difference in species similarity between precancerous and carcinogenic states. However, the composition of the microflora in patients with precancerous lesions (including patients with adenoma and polyp) was proved to have no significant disparity (P<0.05). Our study provides insights into new angles to dig out potential biomarkers in diagnosis and treatment of colorectal cancer and to provide scientific advice for a healthy lifestyle for the sake of gut microbiota.

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Autologous Gamma-Delta T (GD-T) Cells in Acute Myeloid Leukemia (AML): Potential Immune Effector Cells for Minimal Disease?.

Blood ◽

10.1182/blood.v104.11.2538.2538 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2538-2538

Author(s):

Joerg M. Aswald ◽

Xing-Hua Wang ◽

Sandra Aswald ◽

Loralyn A. Benoit ◽

Mark Minden ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Interferon Gamma ◽

Residual Disease ◽

Blast Cell ◽

Healthy Controls ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells

Abstract Prolonging event-free survival of AML with autologous activated immune cells is a promising concept. GD-T cells are a rare circulating lymphocyte population (1%) and a component of the innate immune system capable of exerting anti-neoplastic activity. Their role as potential anti-cancer immune effector cells deserves further exploration. It is noteworthy that GD-T cells are over-represented in reactive regions surrounding melanoma lesions. While patients with an accumulation of GD-T cells showed a survival benefit over those who did not, such increases were not present in patients with metastatic disease and high tumor cell burden (Bachelez, J. Invest. Dermatol.98:369,1992). Little is known about the role of GD-T cells as immuno-effectors, their absolute numbers in peripheral blood or the feasibility of purifying functional GD-T cells from patients with AML. We are interested in testing the clinical feasibility of using GD-T cells freshly purified from PB against minimal residual disease in AML. As a first step towards achieving this goal, we compared circulating GD-T cell levels sequentially in 33 AML patients with 20 healthy adult volunteers. We used ultra-low volume multi-color flow-cytometry and microbeads to measure absolute numbers of GD-T cells in PB. Functional studies were done by the chromium release assay and single-cell intra-cellular interferon-gamma detection. We observed that AML patients with a high leukemic blast cell burden (e.g. prior to chemotherapy) had marginally decreased GD-T cell levels compared with healthy controls: median 38/μl, Q1-Q3, 27–86/μl, versus median 83/μl, Q1-Q3, 45–122/μl, respectively, p= 0.051. We re-examined the AML patients at several time points after induction therapy and observed significantly increased numbers of GD-T cells in patients with lower but detectable residual disease (either molecular maker positive or borderline bone marrow blast infiltration by morphology) compared to patients with persistently high blast cell burden: median 105/μl, Q1-Q3, 105–133/μl versus median, 7/μl, Q1-Q3, 6–15/μl; p=0.008. Patients with residual disease also showed significantly higher numbers of absolute GD-T cells per microliter blood compared to those retested after they had achieved complete remission (CR); p=0.0025. In CR, GD-T cell counts remained lower than those of healthy individuals: median 33/μl, Q1-Q3, 22–35/μl versus median 83/μl, Q1-Q3, 45–122/μl; p=0.030. Interestingly, we found a sharp increase (on average, 4.9-fold higher than values obtained in CR) in GD-T levels at the time of very early morphologic (n=3) or molecular relapse (n=2). Hence, we were interested in studying the functional properties of the GD-T cells from AML patients. We were able to isolate functional GD-T cells from the PB of patients with AML in CR-1 in sufficient numbers and purity to assay for interferon-gamma and found that similar numbers of GD-T cells expressed the Th1 cytokine compared with healthy controls: 84% versus 93% of all GD-T cells, respectively. We also showed that GD-T cells were able to kill leukemic target cells (AML-OCI2) in vitro more efficiently than CD3+ T cells. Our data suggest that further studies to investigate the potential therapeutic role of autologous GD-T cells in patients with AML in CR are warranted.

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Platelets from Patients with Myocardial Infarction Can Activate T Cells in Vitro

Blood ◽

10.1182/blood.v126.23.3448.3448 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3448-3448 ◽

Cited By ~ 1

Author(s):

Elena E. Solomou ◽

Vasilios Gizas ◽

Theodora Babali ◽

Angelos Perperis ◽

Evgenia Verigou ◽

...

Keyword(s):

Myocardial Infarction ◽

T Cells ◽

T Cell ◽

Unstable Angina ◽

T Cell Activation ◽

Healthy Subjects ◽

Cell Activation ◽

Control Group ◽

Healthy Controls

Abstract Specific aim: Our aim was to examine whether T cells can be activated by the circulating activated platelets from patients with myocardial infarction (with ST elevation-STEMI) Methods: After written informed consent was obtained, peripheral blood mononuclear cells (PBMCs) were isolated from heparinized venous blood obtained from 20 patients with STEMI (18 men and 2 women) at the time of hospital admission at diagnosis, before receiving any treatment, as well as 5 days and 30 days later. We also analyzed 10 healthy subjects (8 men and 2 women), and 5 patients with unstable angina who served as the disease control group. PBMCs were analyzed by flow cytometry with the following markers and their isotypic controls: CD4, CD25, CD69, and FOXP3. We also isolated platelet rich plasma or plasma alone from the patients and the healthy subjects, and used in mixed cultures with PBMCs. Results: We first examined T cell activation by measuring CD69 expression on CD4 T cells following incubation with platelets obtained from patients with STEMI. T cells treated with platelets from patients with STEMI showed increased expression of CD69 (as an activation marker) compared with T cells treated with platelets from healthy subjects (p<0.05, Figure 1). There was no T cell activation following incubation with plasma alone from patients or healthy controls. We then examined the percentages of CD4+CD25+hi (regulatory T cells). There was no statistical difference in Tregs between patients at presentation and controls (healthy subjects and disease control group). Five days later, patients with STEMI displayed increased levels of Tregs compared with the 2 control groups; one month later, Treg numbers returned to the initial presentation levels (p<0.05, Figure 2) Conclusion: To our knowledge we describe for the first time that platelets from patients with STEMI can activate T cells in vitro. In patients with STEMI, an increase in Tregs possibly in an effort to suppress immune system activation secondary to platelet activation, appears shortly after the infarct and normalizes a month later. Figure 1. T cell activation after treatment with platelets from patients with STEMI compared with the platelets from healthy controls or plasma alone Figure 1. T cell activation after treatment with platelets from patients with STEMI compared with the platelets from healthy controls or plasma alone Figure 2. Increased T regs in patients with STEMI , 5 days after admission (STEMI EXIT) ( UA;unstable angina, STEMI 1mfup; STEMI after one month) Figure 2. Increased T regs in patients with STEMI , 5 days after admission (STEMI EXIT) ( UA;unstable angina, STEMI 1mfup; STEMI after one month) Disclosures No relevant conflicts of interest to declare.

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T-cell subpopulations in chronic lymphocytic leukemia: abnormalities in distribtuion and in in vitro receptor maturation

Blood ◽

10.1182/blood.v54.2.540.bloodjournal542540 ◽

1979 ◽

Vol 54 (2) ◽

pp. 540-544 ◽

Cited By ~ 1

Author(s):

NE Kay ◽

JD Johnson ◽

R Stanek ◽

SD Douglas

Keyword(s):

T Cells ◽

T Cell ◽

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Control Group ◽

Healthy Controls ◽

Cell Subpopulations ◽

T Cell Subpopulations ◽

T Cell Membrane

Purified human thymus-derived (T) lymphocytes were analyzed by detection of Fc receptors for either IgG or IgM in healthy controls and in patients with chronic lymphocytic leukemia (CLL). There was a significant and persistent increase in the numbers of T cells bearing receptors for IgG (Fc gamma) in CLL patients in comparison to the controls. After an in vitro culture period, there was a significantly decreased appearance of cells with IgM receptors (Fcmu) in CLL patients in comparison to the control group. These results indicate an imbalance in circulating T-cell subpopulations for CLL patients. In addition, an in vitro defect in CLL T-cell membrane receptor appearance is present.

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Elevated coinhibitory molecule TIGIT mediates T cell exhaustion in septic patients

10.21203/rs.3.rs-475376/v1 ◽

2021 ◽

Author(s):

Yini Sun ◽

Renyu Ding ◽

Yukun Chang ◽

Jiuming Li ◽

Xiaochun Ma

Keyword(s):

T Cells ◽

T Cell ◽

Crucial Role ◽

Cell Function ◽

Inflammatory Responses ◽

Ex Vivo ◽

Healthy Controls ◽

T Cell Exhaustion ◽

Cell Exhaustion

Abstract Background: Sepsis-induced T cell exhaustion that is characterized by upregulated coinhibitory molecules and decreased cytokines release plays a crucial role in the immunosuppression during sepsis. Although PD-1 has shown a promising target to interfere with T cells dysfunction, the role of other coinhibitory receptors in sepsis remains largely elusive. Recently, it has been demonstrated that the coinhibitory molecule TIGIT more reliably identified exhausted T cells than PD-1. The aim of the study was to identify the expression of TIGIT on lymphocytes and the crucial role of TIGIT in modulating T cell function in septic patients. Methods: Twenty-five patients with sepsis and seventeen healthy controls were prospectively enrolled. Peripheral blood was obtained from septic patients within 24 hours after diagnosis of sepsis, as were healthy controls. TIGIT and other coinhibitory/costimulatory molecules expression on lymphocyte subsets was quantitated by flow cytometry. The relationship between TIGIT expression and clinical parameters was simultaneously evaluated. The function T cell from septic patients was assayed via stimulated cytokine secretion. Ex vivo functional assays were also conducted.Results: In the early stage of sepsis, patients exhibited higher levels of TIGIT on T cells relative to healthy donors, especially in the septic shock patients. Elevated frequencies of TIGIT + T cells positively correlated with the severity of organ failure and inflammatory responses in septic patients. TIGIT + T cells expressed higher levels of PD-1 and lower CD226. Further, elevated expression of TIGIT inhibited the release of cytokines including TNF, IFN-γ and IL-2 by CD4 + and CD8 + T cells. Strikingly, ex vivo blockade of TIGIT using anti-TIGIT antibody restored the frequencies of cytokine-producing T cells. Conclusions: These data illustrate TIGIT as a novel marker of exhausted T cells and suggest TIGIT may be a novel immunotherapeutic target during sepsis.

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Association of NOS3 gene with metabolic syndrome in hypertensive patients

Thrombosis and Haemostasis ◽

10.1160/th04-02-0103 ◽

2004 ◽

Vol 92 (08) ◽

pp. 413-418 ◽

Cited By ~ 35

Author(s):

Maria Fernandez ◽

Rocio Ruiz ◽

Maria Gonzalez ◽

Reposo Ramirez-Lorca ◽

Carmen Couto ◽

...

Keyword(s):

Metabolic Syndrome ◽

Geographical Area ◽

Allelic Frequency ◽

Control Group ◽

Risk Haplotype ◽

Healthy Controls ◽

Hypertensive Patients ◽

Genotypic Distribution ◽

Nos3 Gene

SummaryRecent data from animal models indicate that the eNOS null mice present a phenotype that resemble the human metabolic syndrome (hypertension, insulin resistance and hypertriglyceridemia). In this work, we have studied whether NOS3 gene, previously related to endothelial dysfunction, might have a role in metabolic syndrome susceptibility in hypertensive patients. To carry out the study, we genotyped 105 hypertensive patients ≤ 60 years old with two polymorphisms of NOS3 gene: 1132 T>C and 7164 G>T (GeneBank:AF519768.1).To check the allelic frequency of these polymorphisms in our geographical area, we also genotyped 94 unselected healthy controls (control group). To perform sample genotyping, we designed a novel FRET system coupled to real time PCR. There were no differences in genotypic distribution or allelic frequency between hypertensive patients and the control group. However, we observed that 786CC genotype was significantly more frequent in hypertensive patients with metabolic syndrome than in those without the syndrome (p=0.0022). When both polymorphisms were analyzed, we identified the 786C894G as the risk haplotype for metabolic syndrome susceptibility (p=0.011). These data suggest a role of the NOS3 gene in the pathogenesis of metabolic syndrome in hypertensive patients.

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Fractional Exhaled Nitric Oxide Measurement in Pulmonary Hypertension: A Follow-Up Study

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029617702243 ◽

2017 ◽

Vol 24 (3) ◽

pp. 483-488 ◽

Cited By ~ 3

Author(s):

Nilay Orak Akbay ◽

Zuleyha Bingol ◽

Esen Kiyan ◽

Ekrem Bilal Karaayvaz ◽

Ahmet Kaya Bilge ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Pulmonary Function Tests ◽

Exhaled Nitric Oxide ◽

World Health ◽

Control Group ◽

Healthy Controls ◽

Fractional Exhaled Nitric Oxide

Pulmonary hypertension (PH) is a fatal disease although significant improvements in treatment are achieved. Easily implemented and noninvasive prognostic techniques are needed while following-up these patients. The aim was to investigate the role of fractional exhaled nitric oxide (FeNO) in follow-up for patients with PH. In this longitudinal study, patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH) who were seen in PH Outpatient Clinic, Istanbul Faculty of Medicine, Istanbul University, were enrolled in the study. Echocardiography, 6-minute walking test, brain natriuretic peptide, and FeNO measurements were performed, and World Health Organization functional class was evaluated to all patients at baseline, and third, and sixth months. Right-heart catheterization and pulmonary function tests at the time of diagnosis were recorded. The study comprised 31 patients (23 women, 8 men; mean age: 53.4 ± 17.1 years) with PAH (n = 19) and CTEPH (n = 12) and 80 healthy controls. Patients with PH had lower FeNO values than the control group (16.5 ppb vs 19.8 ppb; P < .05). Fractional exhaled nitric oxide values did not change during follow-up and did not correlate with other follow-up measures except tricuspid annular plane systolic excursion values. Fractional exhaled nitric oxide was higher in the idiopathic PAH subgroup at baseline and at third month than patients with PAH associated with other diseases. Fractional exhaled nitric oxide did not change in patients who had clinical deterioration. As a conclusion; Patients with PH had lower FeNO values than healthy controls, but FeNO did not change significantly during follow-up. Large-scale studies with prolonged follow-up periods are needed to understand the role of FeNO in the follow-up of the patients with PH.

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