non-AR Patients Research Articles

Anatomic Versus Non-anatomic Liver Resection for Intrahepatic Cholangiocarcinoma: A Systematic Review and Patient-Level Meta-Analysis.

The current standard treatment for intrahepatic cholangiocarcinoma (ICC) involves complete liver resection with negative surgical margins and lymphadenectomy, followed by adjuvant chemotherapy. Debate is ongoing regarding the necessity of systematic anatomic resection (AR). This study aimed to summarize existing literature to determine whether AR leads to better oncologic outcomes than non-AR for patients with resectable ICC. A systematic literature review (PubMed, Embase, and Google Scholar) was performed until December 2023. Only studies comparing the oncologic outcomes of AR and non-AR for ICC using propensityscorematching or inverse probability of treatmentweighting were considered. A meta-analysis of aggregated data for perioperative variables and a reconstructed patient-level meta-analysis for survival data were performed. Five articles were gathered (n = 930 patients after matching: 465 AR/465 non-AR patients). The overall survival (OS) rates were higher in the AR group than in the non-AR group at 1, 3, and 5 years (71.5%, 46.1% and 34.3% vs. 63.6%, 32.9%, and 24.8%, respectively; hazard ratio [HR] 0.74; 95% CI 0.63-0.87; P < 0.001). The same results were observed for the disease-free survival (DFS) rates (58.3%, 33.4%, and 24.5% for AR vs. 45.6%, 23.1%, and 17.4% for non-AR; HR 0.74; 95% CI 0.63-0.86; P < 0.001). The results were confirmed in the two-stage meta-analysis for OS (HR 0.73; P < 0.001) and DFS (HR 0.73; P < 0.001). No differences were observed between the two approaches in terms of operative time, intraoperative blood loss, overall and major morbidity, and hospital length of stay. By pooling the available evidence, the current study demonstrated that AR for ICC patients is associated with better OS and DFS without any negative impact on postoperative outcomes.

Nasal nitric oxide measurement in allergic rhinitis and non-allergic rhinitis: a meta-analysis.

The goal of this meta-analysis was to study nasal nitric oxide (nNO) measurements in allergic rhinitis (AR) and non-allergic rhinitis (non-AR). The protocol was registered with PROSPERO (no: CRD4202124828). Electronic databases from PubMed, Google Scholar, Scopus, Web of Science, and Cochrane were all thoroughly searched and studies were chosen based on the qualifying requirements. The quality of the studies was evaluated by Joanna Briggs Institute evaluation tools, and publication bias using funnel plots. The meta-analysis included 18 studies, whereas the systematic review included 20 studies, totaling 3097 participants (1581 AR, 458 non-AR, and 1058 healthy/control). Patients with AR had significantly greater nNO levels than the control group, although this did not change significantly before or after treatment. AR patients had significantly greater nNO levels than non-AR patients, but there was no significant difference between non-AR patients and healthy controls. Nineteen of the studies were of high quality and the remaining one was of moderate quality. nNO measurement has a promising role in the management of AR and non-AR patients, but more investigations are needed to document clinical benefits.

RBCK1 Overexpression Attenuates Inflammation and Mobility of Derp1-Induced Nasal Mucosal Cells by Downregulating NLRP3

Introduction: Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa, the incidence of which can reach 10–30% worldwide. RBCK1 (RANBP2-type and C3HC4-type zinc finger-containing 1) is a protein found in nasal epithelial cells; however, its function is not fully understood. Methods: In this study, RT-qPCR and Western blotting were used to detect RBCK1 expression in the nasal epithelial tissues of AR and non-AR patients. Next, an AR cell model was established by using the house dust mite allergen (Derp1), and the model cells were then transfected with RBCK1 or NLRP3 overexpression plasmids. Subsequently, RBCK1 expression was detected, and IL-18, IL-33, and LDH levels were determined with ELISA kits. NF-κB and p-NF-κB expression was monitored by Western blotting, and cell migration and invasion were assessed by transwell assays. Results: Our results showed that the AR model cells were successfully created by Derp1 stimulation and that BCK1 was expressed at low levels in the nasal epithelial tissues of AR patients and AR model cells. We also found that overexpression of RBCK1 could prevent inflammation and the migration and invasion of Derp1-mediated AR model cells. Moreover, NLRP3 was found to help prevent RBCK1 overexpression during the inflammation and mobility of AR model cells. Conclusions: RBCK1 overexpression suppressed the inflammatory and mobility progression of AR model cells by downregulating NLRP3. Our data suggest RBCK1 as an important target for AR therapy.

Development of an Allergic Rhinitis Diagnosis Application Using the Total Tear IgE Detection Kit for Examining Nasal Fluid: Comparison and Combination with the Conventional Nasal Smear Examination for Eosinophils

Allergic rhinitis (AR) is a type I allergic disease characterized by immunoglobulin E (IgE) -mediated hypersensitivity of the nasal mucosa. Here, we focused on a commercial test kit named Allerwatch® (AW) for the diagnosis of allergic conjunctivitis (AC) in which total tear IgE is qualitatively detected based on immunochromatography. We evaluated the usefulness of the AW test for detecting total IgE in the nasal discharge of AR and non-allergic rhinitis (non-AR) patients in comparison and combination with the conventional nasal smear examination for eosinophils. Using the AW test, total IgE in nasal fluid was detected in 64.76% of the AR patients and 11.11% of the non-AR patients, with a significant difference between the groups (p &lt; 0.001). As compared to non-AR, the sensitivity and specificity of the detection of total IgE in nasal fluid for detecting AR were 64.76% and 88.89%, respectively. In the AR patients, house dust mites (57.1% of patients) and Japanese cedar pollen (93.3% of patients) were the major sensitizing antigens. When we considered a positive result in either of the two examinations to indicate a positive result, the rate of positivity in AR patients increased to 78.10%. As compared to non-AR, the sensitivity and specificity of the combination of both examinations for detecting AR were 78.10% and 83.33%, respectively. The AW test in the nasal cavity and the qualitative measurement of total IgE in nasal fluid may enable the detection of allergic elements in patients who present to a medical institution with nasal symptoms. In addition, the detection rate is increased when combined with the nasal smear examination for eosinophils.

Low Incidence of Acute Antibody-Mediated Rejection after HLA Desensitization in Living Donor Kidney Transplant Recipients.

Desensitization allows the performance of human leukocyte antigen (HLA)-incompatible transplants. However, the incidence of acute rejection (AR) is high. This study aims to analyze the incidence of AR after transplantation with HLA-incompatible living donors in patients who underwent desensitization. Patients were immunosuppressed with tacrolimus, mycophenolic acid derivatives, and steroids after being desensitized with rituximab, plasma exchange, and/or immunoadsorption with specific cytomegalovirus immunoglobulins. A negative complement-dependent cytotoxicity or flow cytometry crossmatch and a donor-specific antibody titer < 1000 mean fluorescence intensity (MFI) were used to determine desensitization efficacy. A total of 36 patients underwent desensitization, and 27 (75%) were transplanted. After a follow-up of 58 ± 58 months (Min−Max: 0.13−169.5), five episodes of AR occurred: two antibody-mediated and three T-cell-mediated. No differences were found in baseline calculated panel-reactive antibodies (cPRA), class I or II MFI, number of antibodies, or Relative Intensity Scale (RIS) between AR and non-AR patients. Patients with antibody-mediated AR had higher cPRA (NS), MFI class I (p = 0.07) and class II (p = 0.006), and RIS (p = 0.01). The two patients with antibody-mediated AR and one patient with T-cell-mediated AR lost their grafts. In conclusion, the incidence of acute antibody-mediated rejection after desensitization was 7.4%, which occurred early post-transplantation in patients with high MFI and was associated with early graft loss.

Serum extracellular vesicle MicroRNAs as candidate biomarkers for acute rejection in patients subjected to liver transplant.

Acute rejection (AR) is a common and grave complication of liver transplantation (LT). The diagnosis of AR is challenging because it has nonspecific clinical features and requires invasive procedures. Since extracellular vesicles (EVs) are promising candidates as indicators for diagnosis of various diseases, this study aimed to identify serum EV microRNAs (miRNAs) as potential biomarkers for AR in patients subjected to LT. We collected clinical information and serum samples from the liver transplant recipients with and without AR (non-AR). EVs from the serum were isolated via ultracentrifugation and identified using transmission electron microscopy, nanoparticle tracking analysis, and western blotting. EV RNA was extracted and sequenced on an Illumina HiSeq 2500/2000 platform to identify differentially expressed miRNAs between the groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the target gene candidates of the differentially expressed miRNAs to test their functions in biological systems. Then, we validated 12 differentially expressed miRNAs by quantitative real-time PCR. The results demonstrated that 614 EV miRNAs were significantly altered (387 up regulated and 227 down regulated) between non-AR and AR patients. GO enrichment analysis revealed that these target genes were related to cellular processes, single-organism processes, biological regulation, metabolic processes, cells, cell parts, protein-binding processes, nucleoid binding, and catalytic activity. Furthermore, KEGG pathway analysis demonstrated that the target genes of the differentially expressed miRNAs were primarily involved in ubiquitin-mediated proteolysis, lysosomes, and protein processing in the endoplasmic reticulum. miR-223 and let-7e-5p in AR patients were significantly up-regulated compared to those in non-AR patients, whereas miR-199a-3p was significantly down-regulated, which was consistent with sequencing results. The expression of serum EV miRNAs (up-regulated: miR-223 and let-7e-5p and miR-486-3p; down regulated: miR-199a-3p, miR-148a-3p and miR-152-3p) in AR patients was significantly different from that in non-AR patients, and these miRNAs can serve as promising diagnostic biomarkers for AR in patients subjected to liver transplant.

Contemporary Incremental Healthcare Costs for Allergic Rhinitis in the United States.

Describe contemporary changes in healthcare expenditure and utilization associated with allergic rhinitis (AR) over the past decade. Cross-sectional analysis. Patients reporting a diagnosis of AR were extracted from the 2018 Medical Expenditure Panel Survey and linked to the consolidated expenditures file. AR patients were then compared to non-AR patients to demonstrate differences in healthcare utilization for office visits, emergency facility visits, and prescriptions. In addition, differences in total healthcare costs, office-based costs, and prescription costs were calculated, using demographic- and comorbidity-adjusted multivariate models. Results were compared to those obtained in 2007. In 2018, an estimated 1.94 ± 0.2 million adult patients reported AR (0.8% of the US population receiving medical care), a 90% decrease from the 17.8 ± 0.7 million patients seen in a formal healthcare setting for AR in 2007 (7.9%). AR patients still formally seen in 2018 had an average of 4.4 ± 1.3 more office visits (P= .001) and 9.7 ± 2.2 more prescription fills (P< .001) than non-AR patients. In contrast to the 2007 findings, there was no difference in total health care expenditure per person with AR per year. When comparing total healthcare expenditure between 2018 and 2007, there was a net decrease of $1,176 per person with AR per year (P< .01). Patients reporting AR in a formal healthcare encounter fell significantly over the past decade, and per-person expenditure associated with an AR diagnosis also decreased significantly. The transition of nasal corticosteroids to over-the-counter was potentially a key driver behind these changes. 3 Laryngoscope, 132:1510-1514, 2022.

Investigating the association between allergic diseases and COVID-19 in 400 Iranian patients.

Allergic diseases could play a role of a predisposing factor for coronavirus disease 2019 (COVID-19). The aim of this study was to investigate allergic comorbidity and its association in COVID-19 patients. Demographic data, clinical manifestations, laboratory reports, and radiologic findings, together with underlying comorbidity of patients, were studies. Allergic diseases were identified by using the standard GA2LEN questionnaire. The severity of COVID-19 was assessed by a visual analog scale (VAS) and an intensive care unit (ICU) report. Out of 400 COVID-19 patients admitted in the hospital, 158 (39.5%) presented with different allergic diseases, and a reverse association was observed between having allergic comorbidity and severity of COVID-19 infection (P = 0.005, relative risk = 0.96; 95% Confidence Interval (95% CI): 0.77-1.19). The respective frequency of asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS), atopic dermatitis, chronic urticaria, and food or drug allergy was 7.3%, 16%, 1.8%, 5%, 10% and 13.3%. Significantly, only AR was reversely associated with the severity of COVID-19 (P = 0.02, relative risk = 0.45; 95% CI: 0.77-1.19). Additionally, 43% of the patients presented hypoxemia, and 93.5% had chest CT scan involvement. Interestingly, patients with allergic diseases had significantly lower hypoxemia and chest CT involvement as compared with non-allergic patients (P = 0.002 and 0.003, respectively). The results of this study established that allergic diseases were not determined to be a predisposing factor for the severe acute respiratory syndrome (SARS) due to coronavirus 2 (SARS-CoV-2) infection. Significantly, AR patients developed mild clinical manifestations of COVID-19 and admitted to ICU as compared to non-AR patients.

Der p 1 Disrupts the Epithelial Barrier and Induces IL-6 Production in Patients With House Dust Mite Allergic Rhinitis.

Background: Dermatophagoides pteronyssinus 1/2 (Der p 1/Der p 2) are regarded as important allergens of house dust mite (HDM). However, the effect of both products on the epithelial barrier and immune response of patients with and without HDM allergic rhinitis (AR) remains unclear.Methods: Air–liquid interface (ALI) cultured human nasal epithelial cells (HNECs) derived from control subjects (non-AR) (n = 9) and HDM-AR patients (n = 9) were treated with Der P 1 and Der P 2, followed by testing the transepithelial electrical resistance (TEER), paracellular permeability of fluorescein isothiocyanate (FITC)-dextrans and immunofluorescence of claudin-1 and ZO-1. Interleukin-6 (IL-6) production was evaluated by ELISA.Results: Der p 1 reduced TEER significantly in a transient and dose-dependent manner in HNEC-ALI cultures from HDM-AR and non-AR patients, whilst the paracellular permeability was not affected. TEER was significantly reduced by Der p 1 at the 10-min time point in HDM-AR patients compared to non-AR patients (p = 0.0259). Compared to no-treatment control, in HNECs derived from HDM-AR patients, Der p 1 significantly cleaved claudin-1 after 30 min exposure (72.7 ± 9.5 % in non-AR group, 39.9 ± 7.1 % in HDM-AR group, p = 0.0286) and induced IL-6 secretion (p = 0.0271).Conclusions: Our results suggest that patients with HDM-AR are more sensitive to Der p 1 than non-AR patients with increased effects of Der p1 on the mucosal barrier and induction of inflammation, indicating an important role for Der p1 in sensitization and HDM-AR development.

A Retrospective Analysis of Outcomes Following Allogeneic Stem Cell Transplantation for Patients from Appalachian Counties

Introduction Socioeconomic status has been demonstrated to impact not only medical treatment patients receive, but also outcomes after treatment (Hastert, 2015; Hines, 2014; Kim, 2011; Hackley 2005). Prior studies assert that low income areas include patients with a later cancer stage at diagnosis, an older population, lower income households, a higher percentage of Medicaid population, and lower percentage of residents with a higher education (Hastert, 2015; Bradley, 2002; Lin, 2014). Patients from low income areas may have decreased access to healthcare and limited understanding of cancer treatment options. As a result, there may be differences in their medical treatment (Hines, 2014). The Appalachian Regional Commission (ARC) demonstrated that the Appalachian population in Ohio, Kentucky and Pennsylvania has a high percentage of poverty and lower education status (Vanderpool, 2019). The Appalachian population has more people living in rural environments, higher levels of obesity, and negative cancer beliefs (Vanderpool, 2019). SEER data combined with CIBMTR data demonstrated that patients from socially disadvantaged areas are referred for transplant less often, and data from Virginia shows a regional variation in referral for SCT for acute myeloid leukemia (AML) (Paulson, 2019; Arora, 2018). Our aim in this study was to determine if allogeneic stem cell transplant (ASCT) outcomes differ between Appalachian (AR) and non-Appalachian residents (non-AR). Methods A retrospective review of patient records was conducted for 1168 patients who underwent ASCT from 2008-2018 at The Ohio State University Wexner Medical Center. Patients were classified as either AR or non-AR based on zip code according to ARC designation. We compared the clinical and demographic variables between the patients from Appalachian area versus not, using Fisher exact test or chi-square test for categorical variables and the Wilcoxon rank sum test for the continuous variables. Overall survival (OS) and relapse-free survival (RFS) estimates were calculated by the Kaplan-Meier method and compared using the log-rank test. Cumulative incidence of acute GVHD, chronic GVHD, relapse and non-relapse mortality (NRM) were analyzed using Gray's test and accounting for competing risks, where the competing risks for aGVHD and cGVHD were relapse or death, the competing risk for relapse was death from any cause and the competing risk for NRM was death due to disease. Results Out of the 1168 patients included in our study, 887 (75.94%) were non-Appalachian and 291 (24.91%) were Appalachian residents. There was no significant difference in age (p 0.14) or gender (p 0.54) between the two groups. The non-AR group and AR group did have a statically significant difference (p &amp;lt;0.01) in the proportion of White and Black patients (Table 1). In both groups, the majority of patients were diagnosed with AML/CMML (42.19% non-AR, 40.55% AR). Other diseases represented included MDS/AA, ALL/PLL, CLL, NHL, CML, HD/HOD, MF, MM; there was no statistical significance with regard to disease distribution between the two populations (p 0.68). Disease related factors including performance status (graded by Karnofsky Score), remission status, comorbidity index, were similar between both groups-as were transplant related factors such as conditioning regimen, donor type, tissue type, CD 34 and CD 3 count (Table 2). BMT related milestones and complications such as days to engraftment, bacteremia, viremia, fungemia, hemorrhagic cystitis, VOD and pulmonary complications were not statistically significant between the two groups (Table 3). Cumulative incidence of those diagnosed with acute and chronic GVHD were not statistically significant between the groups (Graphs 1-2). Outcomes of non-AR and AR groups were compared; results demonstrated that relapse, relapse free survival, overall survival and non-relapse mortality were not statistically significant (Graphs 3-6). Conclusion Our analysis demonstrates that despite several barriers to medical care, AR patients have similar outcomes to non-AR patients after ASCT. As a result, we encourage providers not to view Appalachian residence as an indicator of poorer outcomes. Instead, we recommend supporting and referring Appalachian patients for transplant as aggressively as non-Appalachian patients. This single-institution study should be evaluated with a larger multi-center cohort. Disclosures Brammer: Seattle Genetics, Inc.: Speakers Bureau; Celgene Corporation: Research Funding. Efebera:Celgene: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria, Speakers Bureau; Ohio State University: Current Employment. Mims:Novartis: Speakers Bureau; Agios: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board. Vasu:Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy; Novartis: Consultancy, Research Funding; CRISPR: Consultancy.

Delayed Graft Function and Acute Rejection in Kidney Transplant Patients with Positive Panel-Reactive Antibody and Negative Donor-Specific Antibodies

Background: Delayed graft function (DGF) and acute rejection (AR) are common complications in kidney transplant patients. Objectives: The study evaluated DGF and AR in highly sensitized patients and their effects on kidney function for six months post-transplantation. Methods: We enrolled 95 patients with kidney transplants from living donors who were divided into two groups. Group 1 included 47 highly sensitized patients with panel reactive antibody (PRA) &lt; 20.0% and negative donor-specific antigen, and group 2 included 48 patients with negative PRA. All patients were followed for the state of DGF, AR, and kidney function for six months. Results: Group 1 showed a significantly higher proportion of DGF and AR than group 2 (27.7% versus 2.1%, P &lt; 0.001 and 14.9% versus 2.1%, P = 0.031, respectively). The rates of positive PRA in DGF and AR patients were significantly higher than those in non-DGF and non-AR patients (92.9% versus 42.0%, P &lt; 0.001 and 87.5% versus 46.0%, P = 0.031, respectively). Transplanted kidney function was significantly worse in patients with PRA and DGF and/or AR than in patients with negative PRA and non-DGF and non-AR only in the seventh-day post-transplantation. Conclusions: Kidney transplant in highly sensitized patients with positive PRA was related to the increased ratio of DGF and AR.

K121Q polymorphism in the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 gene is associated with acute kidney rejection.

The identification of risk factors for acute rejection (AR) may lead to strategies to improve success of kidney transplantation. Ectonucleotidases are ectoenzymes that hydrolyze extracellular nucleotides into nucleosides, modulating the purinergic signaling. Some members of the Ectonucleotidase family have been linked to transplant rejection processes. However, the association of Ectonucleotide Pyrophosphatase / Phosphodiesterase 1 (ENPP1) with AR has not yet been evaluated. The aim of this study was to evaluate the association between the K121Q polymorphism of ENPP1 gene and AR in kidney transplant patients. We analyzed 449 subjects without AR and 98 with AR from a retrospective cohort of kidney transplant patients from Southern Brazil. K121Q polymorphism was genotyped using allelic discrimination-real-time PCR. Cox regression analysis was used to evaluate freedom of AR in kidney transplant patients according to genotypes. Q allele frequency was 17.6% in recipients without AR and 21.9% in those with AR (P = 0.209). Genotype frequencies of the K121Q polymorphism were in Hardy-Weinberg equilibrium in non-AR patients (P = 0.70). The Q/Q genotype (recessive model) was associated with AR (HR = 2.83, 95% CI 1.08–7.45; P = 0.034) after adjusting for confounders factors. Our findings suggest a novel association between the ENPP1 121Q/Q genotype and AR in kidney transplant recipients.

Fas, FasL and Foxp3 gene expression in post-liver transplant autoimmune hepatitis patients with and without acute rejection.

Aim of the studyIn this study we investigated Fas, FasL and Foxp3 expression in relation to liver graft rejection and its severity in autoimmune hepatitis (AIH) patients.Material and methodsTwenty-three AIH patients including five post-transplant patients with acute rejection (AR) and 18 patients without AR (non-AR) were studied for Fas, FasL and Foxp3 gene expression in peripheral blood mononuclear cells on days 1, 3 and 7 after transplantation by real-time PCR. The relationships between gene expression and clinical features were determined.ResultsReal-time PCR showed various Fas gene expression levels with no significant difference between the days in AR patients (p = 0.52). In non-AR patients, Fas level increased from 0.98 ±0.24 fold on the first day to 1.89 ±0.42 fold on day 3 after transplantation (p < 0.01). In this group of patients, we also found a significant increase in FasL expression on day 7 (29.91 ±6.89 fold) compared to day 1 (13.50 ±7.44 fold, p < 0.05). Foxp3 gene expression in both groups showed decreased levels during the first week after transplantation. The decreased Foxp3 expression in AR patients was correlated with rejection activity index (r = 0.86, p < 0.0001).ConclusionsIncreased Fas and FasL gene expression levels in non-AR patients and decreased Foxp3 gene expression in both groups suggested the important role of these molecules in the alloreactive response after liver transplantation in AIH patients. Foxp3 expression might be useful for monitoring rejection severity.

Nasal Nitric Oxide Is Correlated With Nasal Patency and Nasal Symptoms.

PurposeNitric oxide (NO) is an important endogenous mediator in both upper and lower respiratory systems. The purpose of the present study was to extract nasal NO (nNO) normal range of Chinese adults and the internal influencing factors. The differences in nNO levels between rhinitis and asymptomatic atopic subjects, and the diagnostic value of nNO in allergic rhinitis (AR) were further investigated.MethodsOne thousand adults were recruited from the general public. Participants were divided into different subgroups according to the questionnaires and skin prick tests. In all of these subjects, nNO, fractional exhaled NO (FeNO) and nasal airflow resistance were measured. The normal ranges of nNO and FeNO, the differences between subgroups, and the correlations between NO (nNO and FeNO) and other internal factors were analyzed.ResultsBoth nNO and FeNO levels were significantly higher in AR patients than in healthy and asymptomatic atopic subjects. The nNO levels were significantly lower in asymptomatic atopic subjects than in normal adults. FeNO levels were significantly higher in non-AR patients than in the healthy and asymptomatic atopic adults. The cutoff value of nNO for the diagnosis of AR was 117.5 ppb (sensitivity, 50.9%; specificity, 63.9%). The nNO levels were correlated with FeNO levels, total nasal resistance measured at 75Pa, nasal volume within 0–7 cm from the anterior nares (V0–7cm) and nasal symptom visual analogue scale (VAS) scores, while the FeNO levels were correlated with age, height, weight, body surface area, nasal volume of V0–7cm and the nasal symptom VAS score.ConclusionsThe nNO level can be significantly different between healthy and AR patients and may be significantly correlated with nasal symptoms and nasal patency of rhinitis patients. However, the clinical value of nNO is still in the exploration stage.

Phase 1 pharmacokinetics and phase 3 efficacy of testosterone nasal gel in subjects with seasonal allergies.

NATESTO® testosterone nasal gel (TNG) is a liquid gel that is applied in the nose for the treatment of male hypogonadism. There is a reasonable concern that administration of TNG to patients with active rhinitis could modify absorption. Results from two clinical studies are reported wherein subjects with allergic rhinitis (AR) subjects are treated with TNG. The 24-hour pharmacokinetics (PK) and relative bioavailability of serum total testosterone (sTT) from TNG (11 mg tid ) were determined using a phase 1 Latin-square design with 18 eugonadal AR subjects crossed over between asymptomatic, symptomatic-untreated, and symptomatic-treated (oxymetazoline) conditions. Allergy symptoms, assessed using Total Nasal Symptom Score (TNSS), were induced using grass pollen in an allergy challenge chamber (ACC) prior to administration of TNG. The data are discussed in relation to results from a phase 3 study in 306 hypogonadal patients which compare clinical outcomes of AR and non-AR patients treated with TNG. PK analysis (Tmax, maximum observed concentration [Cmax], area under the curve [AUC]) of sTT showed no difference in the rate or extent of absorption of exogenous testosterone from TNG as a function of allergy symptoms. The relative bioavailability also showed all three conditions to be equivalent. However, pre-dose mean sTT in AR patients was 21-25% lower when symptomatic vs. asymptomatic, which is attributed to the allergic reaction. A large phase 3 study, based predominantly on PK measures of sTT, showed that clinical outcomes for AR and non-AR patients treated with TNG were identical, including the percentage of patients in the eugonadal range, hormone profiles, and adverse events. AR does not affect absorption of TNG. Patient outcomes for long-term treatment with TNG for up to one year are not dependent on AR history.

Effects of CPAP in patients with obstructive apnoea: is the presence of allergic rhinitis relevant?

The aim of the study is to compare the effects of continuous positive airway pressure (CPAP) on the nasal cavities of patients with obstructive sleep apnoea (OSA) and with or without allergic rhinitis (AR/nonAR). This paper is a prospective, longitudinal study. Thirty-four consecutive CPAP treatment-adherent patients with OSA (17 AR and 17 nonAR) were evaluated before and 2months after treatment, by means of clinical (otorhinolaryngological symptoms, daytime sleepiness, overall and rhinoconjunctivitis-specific quality of life), anatomical (otorhinolaryngological examination), functional (auditory function, tubal function, nasal airflow, and mucociliary clearance), and biological variables (nasal cytology). No humidifier or anti-allergy medicines were used during treatment. Before treatment, patients with AR presented a higher score, compared to nonAR in rhinitis symptoms (4.82±2.53 vs. 0.93±1.02, p=0.000), otologic symptoms (2.06±1.95 vs. 0.44±0.72, p=0.004), cutaneous/ocular symptoms (2.12±2.17 vs. 0.65±1.17, p=0.052), immunoglobulin E (181.82±126.09 vs. 66.13±97.97, p=0.004), and nasal neutrophils (14.42±31.94 vs. 0.16±0.39, p=0.031). After treatment, nonAR and AR groups improved in daytime sleepiness (11.53±4.60 vs. 7.53±2.87, p=0.000 and 13.76±4.93 vs. 7.53±4.41, p=0.001) respectively and increased nasal neutrophil (0.16±0.39 vs. 5.78±9.43, p=0.001 and 14.42±31.94 vs. 79.47±202.08, p=0.035). The symptoms and quality of life improved in patients with AR. NonAR patients, significantly increase nasal dryness (1.65±1.27 vs. 0.00, p=0.002) and mucociliary clearance times (38.59±24.90 vs. 26.82±23.18, p=0.016). CPAP produces inflammation with increased nasal neutrophil levels in AR and nonAR patients. Nevertheless, patients with AR observed an improvement in nasal symptoms and quality of life, whereas in patients without AR, a relevant worsening of nasal dryness and mucociliary transport was observed.

IL-25 Could Be Involved in the Development of Allergic Rhinitis Sensitized to House Dust Mite.

Background and Purpose When house dust mite (HDM), a common allergen, comes into the mucosal membrane, it may stimulate innate immunity. However, the precise role of interleukin- (IL-) 25 in the development of HDM-induced nasal allergic inflammation is still unclear. Therefore, we investigated the role of IL-25 in allergic rhinitis (AR) patients sensitized to HDM. Methods To confirm the production of IL-25 in human nasal epithelial cells (HNECs), we stimulated HNECs. IL-25 expression in the nasal mucosa from control, non-AR (NAR) patients, and HDM-sensitized AR patients was assessed using immunohistochemistry, and quantitative reverse transcription PCR. Correlations between IL-25 and other inflammatory markers were explored. Results An in vitro study showed significantly elevated concentrations of IL-25 in the HNEC samples with highest doses of HDM. Nasal tissues from AR patients sensitized to HDM showed significantly higher IL-25 expression, compared to those from the control or NAR patients. Moreover, the expression of IL-25 in nasal tissues from AR patients sensitized to HDM was positively associated with Th2 markers, such as ECP and GATA3. Conclusions IL-25 expression increased with high-dose HDM stimulation and was related to Th2 markers. Therefore, IL-25 neutralization might offer a new strategy for treating patients with HDM-sensitized AR.

High frequency of central memory regulatory T cells allows detection of liver recipients at risk of early acute rejection within the first month after transplantation.

Several studies have analyzed the potential of T regulatory cells (Treg cells) as biomarkers of acute rejection (AR). The aim of the present multicenter study was to correlate the percentage of peripheral Treg cells in liver graft recipients drawn at baseline up to 12 months after transplantation with the presence of AR. The percentage of central memory (cm) Treg cells (CD4(+)CD25(high)CD45RO(+)CD62L(+)) was monitored at pre-transplant and at 1 and 2 weeks, and 1, 2, 3 and 6 months and 1 year post-transplantation. The same validation standard operating procedures were used in all participating centers. Fifteen patients developed AR (23.4%). Hepatitis C virus recurrence was observed in 16 recipients, who displayed low peripheral blood cmTreg levels compared with patients who did not. A steady increase of cmTregs was observed during the first month after transplantation with statistically significant differences between AR and non-AR patients. The high frequency of memory Treg cells allowed us to monitor rejection episodes during the first month post-transplantation. On the basis of these data, we developed a prediction model for assessing risk of AR that can provide clinicians with useful information for managing patients individually and customizing immunosuppressive therapies.

Interleukin-17 gene expression and serum levels in acute rejected and non-rejected liver transplant patients.

Interleukin-17 (IL-17), as a potent proinflammatory cytokine, has a critical role in post liver transplant outcomes. However, there is not much information about the effects of IL-17 cytokine on acute liver rejection. To evaluate the role of IL-17 in post-liver transplant acute rejection. Ninety seven adult liver transplant patients who enrolled in this cross sectional study were divided into Non-Acute Rejected (Non-AR) and Acute Rejected (AR) patient groups. Three blood samples were collected from each patient in days 1, 4 and 7 post liver transplantation. The IL-17 mRNA levels were evaluated using an in-house real time PCR protocol. IL-17 protein levels were also analyzed in Non-AR, AR and also control groups using ELISA method. The IL-17 mRNA expression level continuously increased in AR patients in all days of follow-up post liver transplantation. IL-17 expression was, however, down regulated after day 4 post-transplant follow-up in Non-AR patients. Both IL-17 mRNA expression and protein levels were also significantly increased in AR patients compared with Non-AR ones. Based on these findings, significant increase of IL-17 mRNA and protein levels in AR patients highlights the important role of IL-17 in acute liver rejection.

Association of HLA‐G promoter and 14‐bp insertion–deletion variants with acute allograft rejection and end‐stage renal disease

The aim of this study was to investigate the HLA-G 14-bp insertion/deletion (I/D) polymorphism among end-stage renal disease (ESRD) patients. Cytomegalovirus (CMV) infection, acute allograft rejection (AR) and overall survival after renal transplantation was investigated in 300 ESRD patients and 302 age, sex and ethnicity-matched controls. Sequencing was performed to evaluate the impact of HLA-G promoter region single-nucleotide polymorphisms (SNPs) whereas semi-quantitative PCR method was used to determine the probable HLA-G expression pattern among ESRD and AR cases. Further, soluble human leukocyte antigen (HLA)-G (sHLA-G) expression levels were compared in AR vs non-AR cases in the light of HLA-G 14-bp I/D polymorphism. Increased risk was found for 14-bp D/D (deletion-DD) genotype and 14-bp D allele [DD: odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.03-2.06, P value = 0.0358; D: OR = 1.29, 95% CI = 1.03-1.62, P value = 0.0277], respectively for ESRD and CMV infection (DD: OR = 2.70, 95% CI = 1.45-5.05, P value = 0.0021; D: OR = 1.94, 95% CI = 1.22-3.08, P value = 0.0052). Nearly fourfold (OR = 3.62, 95%CI = 1.61-8.14, p = 0.0039) risk was observed for 14-bp I/I (insertion-II) genotype for AR. Survival analysis showed increased overall survival (OS) (AR or death) for 14-bp D/D genotype. HLA-G promoter region sequencing was carried out among 60 ESRD patients and 100 normal controls which showed increased risk for -964 G>A, -725 C>G/T and -486 A>C SNPs. -964 G>A and -725 C>G/T SNPs showed risk association for AR patients. High level of HLA-G transcripts was observed among non-AR patients. Further soluble HLA-G (sHLA-G) showed increased levels in ESRD patients (mean ± SEM; 62.16 ± 2.43 U/ml) as compared to controls (mean ± SEM; 21.06 ± 3.89 U/ml) (P = <0.0001). The 14-bp I/I, 14-bp I/D and 14-bp D/D genotypes showed significantly higher levels of sHLA-G among non-AR as compared to AR patients.