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Aim: This study aims to evaluate the diagnostic challenges and molecular aspects of pediatric gliomas, among the most common brain tumors in children, focusing on improving early detection and personalized treatment strategies., Methods: We conducted a comprehensive review of recent literature, examining current diagnostic techniques, including imaging and histopathological analysis, alongside molecular profiling methods such as next-generation sequencing (NGS) and methylation profiling., Results: The findings highlight significant diagnostic challenges due to the heterogeneity of pediatric gliomas. Molecular profiling has proven essential in identifying key genetic alterations, such as those in the H3F3A and MAPK pathway genes, offering insights into tumor behavior and therapeutic targets., Conclusions: Early and accurate diagnosis of pediatric gliomas is hampered by their molecular diversity. Integrating molecular diagnostics with traditional methods is crucial for enhancing diagnostic accuracy and guiding personalized treatment approaches.

Background: Gardner syndrome is a rare genetic cancer predisposition disorder characterized by intestinal polyposis, multiple osteomas, and soft and hard tissue tumors. Dental anomalies are present in approximately 30%-70% of patients with Gardner syndrome and can be discovered during routine dental examinations. However, sometimes the diagnosis is challenging due to the high clinical variability and incomplete clinical picture. Herein, we report a family with various dental and bone anomalies, in which the definitive diagnosis was established with the help of a comprehensive genetic analysis based on state-of-the-art next-generation sequencing technology. Case presentation: A 17-year-old female index patient presented with dental (caries, impacted, retained and anteriorly located teeth) and atypical bone anomalies not resembling Gardner syndrome. She was first referred to our Genetic Counselling Unit at the age of 11 due to an atypical bone abnormality identified by a panoramic X-ray. Tooth 3.6 was surgically removed and the histopathology report revealed a Paget's disease-like bone metabolic disorder with mixed osteoblastic and osteoclastic activity of the mandible. A small lumbar subcutaneous tumor was discovered by physical examination. Ultrasound examination of the tumor raised the possibility of a soft tissue propagation of chondromatosis. Her sister, 2 years younger at the age of 14, had some benign tumors (multiple exostoses, odontomas, epidermoid cysts) and impacted teeth. Their mother had also skeletal symptoms. Her lower teeth did not develop, the 9th-10th ribs were fused, and she complained of intermittent jaw pain. A cranial CT scan showed fibrous dysplasia on the cranial bones. Whole exome sequencing identified a heterozygous pathogenic nonsense mutation (c.4700C>G; p.Ser1567*) in the APC gene in the index patient's DNA. Targeted sequencing revealed the same variant in the DNA of the other affected family members (the sister and the mother). Conclusion: Early diagnosis of this rare, genetically determined syndrome is very important, because of the potentially high malignant transformation of intestinal polyps. Dentists should be familiar with the typical maxillofacial features of this disorder, to be able to refer patients to genetic counseling. Dental anomalies often precede the intestinal polyposis and facilitate the early diagnosis, thereby increasing the patients' chances of survival. Genetic analysis may be necessary in patients with atypical phenotypic signs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Antal, Zsigmond, Till, Orsi, Szanto, Büki, Kereskai, Herbert, Hadzsiev and Bene.)

Background: The clinical and genetic heterogeneity of diffuse large B-cell lymphoma (DLBCL) presents distinct challenges in predicting response to therapy and overall prognosis. The main objective of this study was to assess the application of the immunohistochemistry- and interphase fluorescence in situ hybridization (FISH)-based molecular markers in the diagnosis of DLBCL and its prognostic value in patients treated with rituximab-based immunochemotherapy., Methods: This is a multicenter, retrospective study, which analyzed data from 7 Hungarian hematology centers. Eligible patients were adults, had a histologically confirmed diagnosis of DLBCL, were treated with rituximab-based immunochemotherapy in the first line, and had available clinicopathological data including International Prognostic Index (IPI). On the specimens, immunohistochemistry and FISH methods were performed. Germinal center B-cell like (GCB) and non-GCB subtypes were classified by the Hans algorithm. Outcomes included overall survival (OS), event-free survival (EFS), and EFS at 2 years (EFS24). For survival analysis, we used Kaplan-Meier curves with the log-rank test and multivariate Cox regression., Results: A total of 247 DLBCL cases were included. Cases were positive for MYC, BCL2, BCL6, and MUM1 expression in 52.1%, 66.2%, 72.6%, and 77.8%, respectively. BCL6 translocation, BCL2 gene copy number (GCN) gain, IGH::MYC translocation, MYC GCN gain, IGH::BCL2 translocation, and BCL6 GCN gain were detected in 21.4%, 14.1%, 7.3%, 1.8%, 7.3%, and 0.9%, respectively. At a median follow-up of 52 months, 140 patients (56.7%) had disease progression or relapse. The Kaplan-Meier estimate for EFS24 was 56.2% (CI: 50.4-62.8%). In univariate analysis, only IPI and BCL6 expression were significant predictors of both OS and EFS, whereas MUM1 predicted EFS only. In multivariate analysis, the IPI score was a significant independent negative, whereas MIB-1 and BCL6 protein expressions were significant independent positive predictors of both OS and EFS., Conclusion: In our study, we found that only IPI, BCL6 protein expression and MIB-1 protein expression are independent predictors of survival outcomes in DLBCL. We did not find any difference in survival by GCB vs. non-GCB subtypes. These findings may improve prognostication in DLBCL and can contribute to designing further research in the area., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Balikó, Szakács, Kajtár, Ritter, Gyenesei, Farkas, Kereskai, Vályi-Nagy, Alizadeh and Pajor.)

Scots pine (SO) and clove (CO) essential oils (EOs) are commonly used by inhalation, and their main components are shown to reduce inflammatory mediator production. The aim of our research was to investigate the chemical composition of commercially available SO and CO by gas chromatography-mass spectrometry and study their effects on airway functions and inflammation in an acute pneumonitis mouse model. Inflammation was evoked by intratracheal endotoxin and EOs were inhaled three times during the 24 h experimental period. Respiratory function was analyzed by unrestrained whole-body plethysmography, lung inflammation by semiquantitative histopathological scoring, myeloperoxidase (MPO) activity and cytokine measurements. α-Pinene (39.4%) was the main component in SO, and eugenol (88.6%) in CO. Both SO and CO significantly reduced airway hyperresponsiveness, and prevented peak expiratory flow, tidal volume increases and perivascular edema formation. Meanwhile, inflammatory cell infiltration was not remarkably affected. In contrast, MPO activity and several inflammatory cytokines (IL-1β, KC, MCP-1, MIP-2, TNF-α) were aggravated by both EOs. This is the first evidence that SO and CO inhalation improve airway function, but enhance certain inflammatory parameters. These results suggest that these EOs should be used with caution in cases of inflammation-associated respiratory diseases.

Thyme (TO), cinnamon (CO), and Ceylon type lemongrass (LO) essential oils (EOs) are commonly used for inhalation. However, their effects and mechanisms on inflammatory processes are not well-documented, and the number of in vivo data that would be important to determine their potential benefits or risks is low. Therefore, we analyzed the chemical composition and investigated the activity of TO, CO, and LO on airway functions and inflammatory parameters in an acute pneumonitis mouse model. The components of commercially available EOs were measured by gas chromatography-mass spectrometry. Airway inflammation was induced by intratracheal endotoxin administration in mice. EOs were inhaled during the experiments. Airway function and hyperresponsiveness were determined by unrestrained whole-body plethysmography on conscious animals. Myeloperoxidase (MPO) activity was measured by spectrophotometry from lung tissue homogenates, from which semiquantitative histopathological scores were assessed. The main components of TO, CO, and LO were thymol, cinnamaldehyde, and citronellal, respectively. We provide here the first evidence that TO and CO reduce inflammatory airway hyperresponsiveness and certain cellular inflammatory parameters, so they can potentially be considered as adjuvant treatments in respiratory inflammatory conditions. In contrast, Ceylon type LO inhalation might have an irritant effect (e.g., increased airway hyperresponsiveness and MPO activity) on the inflamed airways, and therefore should be avoided.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To improve pre- and post-operative diagnosis and prognosis novel molecular markers are desirable. Here we used MALDI imaging mass spectrometry (IMS) and immunohistochemistry (IHC) to seek tumor specific expression of proteins and lipids in HNSCC samples. Among low molecular weight proteins visualized, S100A8 and S100A9 were found to be expressed in the regions of tumor tissue but not in the surrounding healthy stroma of a post-operative microdissected tissue. Marker potential of S100A8 and S100A9 was confirmed by immunohistochemistry of paraffin-embedded pathological samples. Imaging lipids showed a remarkable depletion of lysophosphatidylcholine species LPC[16:0], LPC[18:2] and, in parallel, accumulation of major glycerophospholipid species PE-P[36:4], PC[32:1], PC[34:1] in neoplastic areas. This was confirmed by shotgun lipidomics of dissected healthy and tumor tissue sections. A combination of the negative (LPC[16:0]) and positive (PC[32:1], PC[34:1]) markers was also applicable to uncover tumorous character of a pre-operative biopsy. Furthermore, marker potential of lysophospholipids was supported by elevated expression levels of the lysophospholipid degrading enzyme lysophospholipase A1 (LYPLA1) in the tumor regions of paraffin-embedded HNSCC samples. Finally, experimental evidence of 3D cell spheroid tests showed that LPC[16:0] facilitates HNSCC invasion, implying that HNSCC progression in vivo may be dependent on lysophospholipid supply. Altogether, a series of novel proteins and lipid species were identified by IMS and IHC screening, which may serve as potential molecular markers for tumor diagnosis, prognosis, and may pave the way to better understand HNSCC pathophyisiology., Competing Interests: CONFLICTS OF INTEREST These authors declatre no conflicts of interest., (Copyright: © 2020 Schmidt et al.)

The Transient Receptor Potential Ankyrin 1 (TRPA1) cation channel expressed on capsaicin-sensitive afferents, immune and endothelial cells is activated by inflammatory mediators and exogenous irritants, e.g., endotoxins, nicotine, crotonaldehyde and acrolein. We investigated its involvement in acute and chronic pulmonary inflammation using Trpa1 gene-deleted ( Trpa1 -/- ) mice. Acute pneumonitis was evoked by intranasal Escherichia coli endotoxin (lipopolysaccharide: LPS) administration, chronic bronchitis by daily cigarette smoke exposure (CSE) for 4 months. Frequency, peak inspiratory/expiratory flows, minute ventilation determined by unrestrained whole-body plethysmography were significantly greater, while tidal volume, inspiratory/expiratory/relaxation times were smaller in Trpa1 -/- mice. LPS-induced bronchial hyperreactivity, myeloperoxidase activity, frequency-decrease were significantly greater in Trpa1 -/- mice. CSE significantly decreased tidal volume, minute ventilation, peak inspiratory/expiratory flows in wildtypes, but not in Trpa1 -/- mice. CSE remarkably increased the mean linear intercept (histopathology), as an emphysema indicator after 2 months in wildtypes, but only after 4 months in Trpa1 -/- mice. Semiquantitative histopathological scores were not different between strains in either models. TRPA1 has a complex role in basal airway function regulation and inflammatory mechanisms. It protects against LPS-induced acute pneumonitis and hyperresponsiveness, but is required for CSE-evoked emphysema and respiratory deterioration. Further research is needed to determine TRPA1 as a potential pharmacological target in the lung.

Introduction: The potential of malignant transformation and its risk factors after bladder augmentation performed in childhood are still unknown. The necessity of surveillance cystoscopies and biopsies has been questioned in the past decade., Objective: In a previous study, the authors did not detect any malignancy after colocystoplasty (CCP) or gastrocystoplasty (GCP) during the short-term follow-up, however, various alterations of the mucosa were found. A correlation between the nature of histological changes and the frequency of bacterial colonization after CCP were also found. The authors hypothesized that a longer-term follow-up of their patients would reveal an increase in pathological change or show stronger association between the histological alteration, bacterial colonization, and/or stone formation., Patients and Methods: Thirty-five patients (20 cases of colocystoplasties - CCPs; 15 cases of gastrocystoplasties - GCPs) participated in the study published in 2002. All patients were followed biannually with endoscopic assessment and biopsies. Two independent pathologists, evaluated regular biopsies from the native bladder, from the segment used for augmentation and from the anastomosis line. Etiology, frequency of positive urine cultures, and stone events were recorded and compared with histological findings between groups and with the previously published results., Results: Continuous surveillance allowed the follow-up of 30 patients (CCP 19/20, GCP 11/15) for 20 and 15 years. No malignancies were identified. Results of biopsies showed significant difference between groups (summarized in the tables). Chronic inflammatory changes were found following both types of augmentations, but they were more common in the urothelium following GCP and more common in the colonic mucosa following CCP. The rate of metaplastic lesions was higher after gastrocystoplasty (GCP). Significant association was found between the etiologic factor and the nature of histological change after CCP, as metaplastic lesions occurred only in patients with bladder exstrophy. Stones occurred more frequently in exstrophy patients as well. The nature of the histological changes did not correlate with positive urine cultures in either of the groups. Significantly higher incidence of bacterial colonization and stone occurrence were found after CCP., Conclusions: Long-term follow-up of the patients failed to reveal an increase in pathological changes, and no malignancies were observed. According to the results of this study, etiology of bladder dysfunction and the type of augmentation might influence the histological alterations after augmentation cystoplasty. The efficiency of surveillance cystoscopies and biopsies are low. The present data suggest that surveillance cystoscopy and biopsy should not be routinely performed, and should be done only if the symptoms are suspicious for malignancy., (Copyright © 2019 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Introduction: Plasma cell myeloma is a hematological malignancy with heterogeneous genomic landscape and diverse clinical course. Recurrent chromosomal and subchromosomal aberrations commonly occur in this entity and are associated with the pathogenesis and progression of the disease. The identification of these alterations aids genetic characterization, classification and prognostication of patients. Aim: Molecular cytogenetic investigations of plasma cell myeloma patients treated at the University of Pécs Clinical Center and János Balassa County Hospital of Tolna County, Szekszárd, between 2005 and 2018 were evaluated in our study. Method: 231 patients were screened for genetic aberrations using fluorescence in situ hybridization. Translocations involving the immunoglobulin heavy chain gene, losses of 1p and 17p chromosome arms, gains of 1q chromosome arm and unbalanced aberrations of chromosome 13 were investigated. Losses and gains of 1p, 1q, 5q, 12p, 13q, 16q and 17p chromosome arms were analyzed using multiplex ligation-dependent probe amplification in 42 patients. During the investigated period, 116 bone marrow karyotyping was also performed. Results: In total, 233 genetic aberrations were identified using our targeted approaches; the frequency of specific aberrations correlated with data of the recent literature. Concordance of results gained by fluorescence in situ hybridization and multiplex ligation-dependent probe amplification was 96.2% by analyzing the same chromosome arms. The latter technique revealed 21 additional genetic aberrations in 16/42 patient samples (38%) as compared to fluorescence in situ hybridization. Conclusions: Our results suggest that the combined application of the two molecular cytogenetic methods may facilitate a more detailed characterization of genetic aberrations of plasma cell myeloma patients in Hungary. Orv Hetil. 2019; 160(24): 944-951.

Introduction: Prognostic impact of the detection of minimal residual disease (MRD) in multiple myeloma (MM) has been confirmed in numerous studies., Aim: Retrospective examination of our patient database (107 newly diagnosed multiple myelomas between 2007 and 2017). Flow cytometry (FCM) was performed as MRD assessment., Method: MRD assessment was performed in 56 patients (median age: 68 years), after induction treatment of multiple myeloma. The treatment contained bortezomib in 91%, autologous haematopoetic stem cell transplantation (ASCT) was perfomed in 50%. MRD detection was performed on bone marrow samples, predominantly in our hospital (BD FACScan, 3 colour, panel: CD38, CD138, CD19, CD45, CD56, CD28, CD117, cyKappa, cyLambda, 100 000 events)., Statistical Analysis: SPSS 13.0., Results: The progression-free survival (PFS) and the overall survival (OS) were significantly longer in MRD negative (n = 22) patients (PFS: 54 months, OS: 79% after 5 years) than MRD positive patients (n = 34, PFS: 22 months, OS 21% after 5 years, p = 0.001). Patients achieving complete response (CR) (n = 29) have different PFS (MRD negative CR: 60 months, MRD positive CR: 21 months, p<0.001). Patents achiving MRD negative very good partial response (n = 5) have similar PFS (54 months) as patients with MRD negative CR. The longest PFS (68 months) was observed in MRD negative patients, after ASCT (n = 11), while the PFS was significantly (p<0.001) shorter in patients who were MRD positive after ASCT (n = 18, PFS: 25 months), similarly in MRD positive patients without ASCT (n = 15, PFS 21 months). Cox regression analysis (stage, cytogenetic risk, ASCT) confirmed that MRD is an independent prognostic factor of PFS and OS. We did not find significant relationship between MRD and stage, cytogenetic risk, number of treatment cycles, ASCT., Conclusions: The depth of response after induction treatment of MM is an independent predictor of survival. MRD assessment with FCM is recommended to define response. Consideration of maintenance treatment in MRD positive patients and eradication of MRD are also recommended. Orv Hetil. 2019; 160(13): 502-508.

Cigarette smoke-triggered inflammatory cascades and consequent tissue damage are the main causes of chronic obstructive pulmonary disease (COPD). There is no effective therapy and the key mediators of COPD are not identified due to the lack of translational animal models with complex characterization. This integrative chronic study investigated cardiopulmonary pathophysiological alterations and mechanisms with functional, morphological and biochemical techniques in a 6-month-long cigarette smoke exposure mouse model. Some respiratory alterations characteristic of emphysema (decreased airway resistance: Rl; end-expiratory work and pause: EEW, EEP; expiration time: Te; increased tidal mid-expiratory flow: EF50) were detected in anaesthetized C57BL/6 mice, unrestrained plethysmography did not show changes. Typical histopathological signs were peribronchial/perivascular (PB/PV) edema at month 1, neutrophil/macrophage infiltration at month 2, interstitial leukocyte accumulation at months 3-4, and emphysema/atelectasis at months 5-6 quantified by mean linear intercept measurement. Emphysema was proven by micro-CT quantification. Leukocyte number in the bronchoalveolar lavage at month 2 and lung matrix metalloproteinases-2 and 9 (MMP-2/MMP-9) activities in months 5-6 significantly increased. Smoking triggered complex cytokine profile change in the lung with one characteristic inflammatory peak of C5a, interleukin-1α and its receptor antagonist (IL-1α, IL-1ra), monokine induced by gamma interferon (MIG), macrophage colony-stimulating factor (M-CSF), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) at months 2-3, and another peak of interferon-γ (IFN-γ), IL-4, 7, 13, 17, 27 related to tissue destruction. Transient systolic and diastolic ventricular dysfunction developed after 1-2 months shown by significantly decreased ejection fraction (EF%) and deceleration time, respectively. These parameters together with the tricuspid annular plane systolic excursion (TAPSE) decreased again after 5-6 months. Soluble intercellular adhesion molecule-1 (sICAM-1) significantly increased in the heart homogenates at month 6, while other inflammatory cytokines were undetectable. This is the first study demonstrating smoking duration-dependent, complex cardiopulmonary alterations characteristic to COPD, in which inflammatory cytokine cascades and MMP-2/9 might be responsible for pulmonary destruction and sICAM-1 for heart dysfunction., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The aim of this study was to evaluate the short and medium-term effects of radiofrequency (RF) and potassium titanyl phosphate (KTP) and neodymium-yttrium-aluminum garnet (Nd:YAG) laser treatment on the inferior turbinate mucosa in a porcine model. Following randomization, the inferior turbinates were treated either with RF submucosally or with the KTP or the Nd:YAG laser on the surface under videoendoscopic control. Tissue samples were taken at the end of postoperative weeks 1 and 6, and were evaluated macroscopically and histopathologically. Scanning electron microscopy was implemented to demonstrate the morphological changes in the respiratory epithelium. Six weeks following the RF procedure, the mucosa was intact in all cases, and the volume of the inferior turbinates was reduced in the majority of the cases. Although a volume reduction occurred in both laser groups, more complications associated with the healing procedure were noted. With hematoxylin and eosin and periodic acid-Schiff staining, intact epithelium, and submucosal glands remained after the RF procedures at the end of postoperative week 6. Following the KTP-laser intervention, necrotizing sialometaplasia and cartilage destruction occurred, and squamous metaplasia was also apparent in the Nd:YAG group. In both laser groups, dilated glands with excess mucus were seen. The scanning electron microscopic findings demonstrated that cilia were present in all cases. In conclusion, the medium-term macroscopic results were similar in all 3 groups, but the postoperative complications were less following the RF procedure. RF procedure is minimally invasive due to the submucosal intervention that leads to a painless, function preserving recovery.

Introduction: Bladder augmentation is widely used to treat otherwise unmanageable urinary incontinence. However, it is associated with a large number of complications, of which tumor formation is the most severe. Mucin proteins and MUC genes are linked, among others, to malignancies of the urinary bladder and the gastrointestinal system., Objective: To investigate histological alterations as well as changes in expression of MUC1 and MUC2 genes and proteins following different types of urinary bladder augmentation or substitution performed in children and adolescents., Patients and Methods: Between 1988 and 2013, 91 patients underwent urinary bladder augmentation or substitution at the study institute. Patients were included on whom cystoplasty had been performed 4 years previously or earlier, and could have been followed-up prospectively. Thus, 54 patients were involved in the study. In eight patients gastrocystoplasty was performed, in 17 patients ileocystoplasty, and in 22 patients colocystoplasty. Seven patients underwent bladder substitution using a colonic-segment. Biopsies were taken via cystoscopy from the native bladder, from the gastrointestinal segment used for augmentation, and from the anastomotic line between these two. One part of the samples was fixed in formaldehyde for routine histological processing. The other part of the biopsies was embedded into OCT medium, then cryosectioned and fluorescently double-immunostained for MUC1 and MUC2 proteins. Samples from the microscopically dysplastic lesions and from the 15-year-old or older biopsies were processed by laser capture microdissection, and then real-time PCR was done. Data were statistically analyzed by ANOVA and ordinary least squares regression tests., Results: One adenocarcinoma was found in a female patient, 11 years after colocystoplasty. There were no significant changes in the level of MUC1 and MUC2 proteins and gene expression in the urothelium and in the gastrointestinal segment used for augmentation following ileocystoplasty and gastrocystoplasty. Significant increase in MUC1 and decrease in MUC2 protein levels were detected following colocystoplasty in the large bowel segment used for augmentation, both with qualitative and quantitative methods (p < 0.05) (Figure). The uroepithelium showed no significant change. RT-PCR revealed progressive increase in MUC1 gene expression and decrease in MUC2 gene expression after colocystoplasty in the course of time. It also showed highly increased MUC1 gene expression and decreased MUC2 gene expression in the samples of patients., Conclusions: Alterations in gene expression of MUC1 and MUC2 might serve as promising markers for early detection of histological changes after colocystoplasty., (Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: The K/BxN serum-transfer arthritis is a widely-used translational mouse model of rheumatoid arthritis, in which the immunological components have thoroughly been investigated. In contrast, little is known about the role of sensory neural factors and the complexity of neuro-immune interactions. Therefore, we analyzed the involvement of capsaicin-sensitive peptidergic sensory nerves in autoantibody-induced arthritis with integrative methodology., Methods: Arthritogenic K/BxN or control serum was injected to non-pretreated mice or resiniferatoxin (RTX)-pretreated animals where capsaicin-sensitive nerves were inactivated. Edema, touch sensitivity, noxious heat threshold, joint function, body weight and clinical arthritis severity scores were determined repeatedly throughout two weeks. Micro-CT and in vivo optical imaging to determine matrix-metalloproteinase (MMP) and neutrophil-derived myeloperoxidase (MPO) activities, semiquantitative histopathological scoring and radioimmunoassay to measure somatostatin in the joint homogenates were also performed., Results: In RTX-pretreated mice, the autoantibody-induced joint swelling, arthritis severity score, MMP and MPO activities, as well as histopathological alterations were significantly greater compared to non-pretreated animals. Self-control quantification of the bone mass revealed decreased values in intact female mice, but significantly greater arthritis-induced pathological bone formation after RTX-pretreatment. In contrast, mechanical hyperalgesia from day 10 was smaller after inactivating capsaicin-sensitive afferents. Although thermal hyperalgesia did not develop, noxious heat threshold was significantly higher following RTX pretreatment. Somatostatin-like immunoreactivity elevated in the tibiotarsal joints in non-pretreated, which was significantly less in RTX-pretreated mice., Conclusions: Although capsaicin-sensitive sensory nerves mediate mechanical hyperalgesia in the later phase of autoantibody-induced chronic arthritis, they play important anti-inflammatory roles at least partially through somatostatin release., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (Tac4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions. Since there is no information on its functions in the airways, we investigated its role in endotoxin-induced pulmonary inflammation., Methods: Acute pneumonitis was induced in Tac4 gene-deleted (Tac4(-/-)) mice compared to C57Bl/6 wildtypes by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24h later. Semiquantitative histopathological scoring was performed; reactive oxygen species (ROS) production was measured with luminol bioluminescence, myeloperoxidase activity with spectrophotometry, and inflammatory cytokines with Luminex., Results: All inflammatory parameters, such as histopathological alterations (perivascular edema, neutrophil/macrophage accumulation, goblet cell hyperplasia), myeloperoxidase activity, ROS production, as well as interleukin-1beta, interleukin-6, tumor necrosis factor alpha, monocyte chemoattractant protein-1 and keratinocyte chemoattractant concentrations were significantly diminished in the lung of Tac4(-/-) mice. However, bronchial hyperreactivity similarly developed in both groups. Interestingly, in LPS-treated Tac4(-/-) mouse lungs, bronchus-associated, large, follicle-like lymphoid structures developed., Conclusions: We provide the first evidence that hemokinin-1 plays a crucial pro-inflammatory role in the lung by increasing inflammatory cell activities, and might also be a specific regulator of lymphocyte functions., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Pituitary adenylate cyclase-activating polypeptide (PACAP) expressed in capsaicin-sensitive sensory neurons and immune cells has divergent functions in inflammatory and pain processes. This study was undertaken to investigate the involvement of PACAP in a mouse model of rheumatoid arthritis., Methods: Arthritis was induced in PACAP(-/-) and wild-type (PACAP(+/+) ) mice by K/BxN serum transfer. General features of the disease were investigated by semiquantitative scoring, plethysmometry, and histopathologic analysis. Mechano- and thermonociceptive thresholds and motor functions were also evaluated. Metabolic activity was assessed by positron emission tomography. Bone morphology was measured by in vivo micro-computed tomography, myeloperoxidase activity and superoxide production by bioluminescence imaging with luminol and lucigenin, respectively, and vascular permeability by fluorescent indocyanine green dye study., Results: PACAP(+/+) mice developed notable joint swelling, reduced grasping ability, and mechanical (but not thermal) hyperalgesia after K/BxN serum transfer. In PACAP(-/-) mice clinical scores and edema were significantly reduced, and mechanical hyperalgesia and motor impairment were absent, throughout the 2-week period of observation. Metabolic activity and superoxide production increased in the tibiotarsal joints of wild-type mice but were significantly lower in PACAP(-/-) animals. Myeloperoxidase activity in the ankle joints of PACAP(-/-) mice was significantly reduced in the early phase of arthritis, but increased in the late phase. Synovial hyperplasia was also significantly increased, and progressive bone spur formation was observed in PACAP-deficient mice only., Conclusion: In PACAP-deficient mice with serum-transfer arthritis, joint swelling, vascular leakage, hyperalgesia, and early inflammatory cell accumulation are reduced; in the later phase of the disease, immune cell function and bone neoformation are increased. Elucidation of the underlying pathways of PACAP activity may open promising new avenues for development of therapy in inflammatory arthritis., (© 2014 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)