Tracked ultrasound registration for intraoperative navigation during pediatric bone tumor resections with soft tissue components: a porcine cadaver study.

PURPOSE: Resection of pediatric osteosarcoma in the extremities with soft tissue involvement presents surgical challenges due to difficult visualization and palpation of the tumor. Therefore, an adequate image-guided surgery (IGS) system is required for more accurate tumor resection. The use of a 3D model in combination with intraoperative tracked ultrasound (iUS) may enhance surgical decision making. This study evaluates the clinical feasibility of iUS as a surgical tool using a porcine cadaver model. METHODS: First, a 3D model of the porcine lower limb was created based on preoperative scans. Second, the bone surface of the tibia was automatically detected with an iUS by a sweep on the skin. The bone surface of the preoperative 3D model was then matched with the bone surface detected by the iUS. Ten artificial targets were used to calculate the target registration error (TRE). Intraoperative performance of iUS IGS was evaluated by six pediatric surgeons and two pediatric oncologic orthopedists. Finally, user experience was assessed with a post-procedural questionnaire. RESULTS: Eight registration procedures were performed with a mean TRE of 6.78 ± 1.33 mm. The surgeons agreed about the willingness for clinical implementation in their current clinical practice. They mentioned the additional clinical value of iUS in combination with the 3D model for the localization of the soft tissue components of the tumor. The concept of the proposed IGS system is considered feasible by the clinical panel, but the large TRE and degree of automation need to be addressed in further work. CONCLUSION: The participating pediatric surgeons and orthopedists were convinced of the clinical value of the interaction between the iUS and the 3D model. Further research is required to improve the surgical accuracy and degree of automation of iUS-based registration systems for the surgical management of pediatric osteosarcoma.

An extremely rare case of pseudomelanosis of the urinary bladder.

Pseudomelanosis (PM) is a rare, benign, condition that is characterized by deposition of melanin and/or melanin-like pigment in mucosal cells and macrophages and is best known as the entity pseudomelanosis coli. Pseudomelanosis primary of the urinary bladder has been reported only in a handful of cases worldwide. This article reports an extremely rare case of pseudomelanosis of the urinary bladder in a 79-year-old male with a history of macroscopic painless hematuria.

Treatment planning facilitates clinical decision making for hyperthermia treatments.

Background: Treatment quality is important in clinical hyperthermia. Guideline-based treatment protocols are used to determine system settings and treatment strategies to ensure effective tumor heating and prevent unwanted treatment-limiting normal tissue hot spots. Realizing both these goals can prove challenging using generic guideline-based and operator-dependent treatment strategies. Hyperthermia treatment planning (HTP) can be very useful to support treatment strategies. Although HTP is increasingly integrated into the standard clinical workflow, active clinical application is still limited to a small number of hyperthermia centers and should be further stimulated.Purpose: This paper aims to serve as a practical guide, demonstrating how HTP can be applied in clinical decision making for both superficial and locoregional hyperthermia treatments.HTP in clinical decision making: Seven problems that occur in daily clinical practice are described and we show how HTP can enhance insight to formulate an adequate treatment strategy. Examples use representative commercially available hyperthermia devices and cover all stages during the clinical workflow. Problems include selecting adequate phase settings, heating ability analysis, hot spot suppression, applicator selection, evaluation of target coverage and heating depth, and predicting possible thermal toxicity in case of an implant. Since we aim to promote a general use of HTP in daily practice, basic simulation strategies are used in these problems, avoiding a need for the application of dedicated advanced optimization routines that are not generally available.Conclusion: Even fairly basic HTP can facilitate clinical decision making, providing a meaningful and clinically relevant contribution to maintaining and improving treatment quality.

Following the Mangroves: diversification in the banded lampeye Aplocheilichthys spilauchen (Duméril, 1861) (Cyprinodontiformes: Procatopodidae) along the Atlantic coast of Africa.

Available ecological information, an extensive distributional range, conflicting osteological data, and a proposed early Miocene origin provide the impetus for the present study which investigates genetic structuring, biogeographic, and phylogenetic relationships within the Aplocheilichthys spilauchen lineage. Through the analysis of the mitochondrial gene COI, species delimitation methods (ABGD, GB, GMYC, bPTP) were applied, recognizing 6-7 OTUs with absolute pairwise genetic distances ranging between 8 and 22%. The onset of diversification is estimated to be within the middle Miocene and both dispersal and vicariance-shaped A. spilauchen diversity and distribution, as suggested by time-calibrated and ancestral range reconstruction (S-DIVA) analyses. We report for the first time, a pattern of diversification within a lineage of brackish water fish that is concordant with the historical distribution of coastal mangroves forests, shaped by a series of historical events that likely affected forest cover since the middle Miocene (e.g. major climate shifts and sea-level fluctuations, onset of the modern Congo River outlet, increased volcanism in the Cameroon Volcanic Line). SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1007/s10750-020-04497-3) contains supplementary material, which is available to authorized users.

How to achieve safe, high-quality clinical studies with non-Medicinal Investigational Products? A practical guideline by using intra-bronchial carbon nanoparticles as case study.

BACKGROUND: Clinical studies investigating medicinal products need to comply with laws concerning good clinical practice (GCP) and good manufacturing practice (GMP) to guarantee the quality and safety of the product, to protect the health of the participating individual and to assure proper performance of the study. However, there are no specific regulations or guidelines for non-Medicinal Investigational Products (non-MIPs) such as allergens, enriched food supplements, and air pollution components. As a consequence, investigators will avoid clinical research and prefer preclinical models or in vitro testing for e.g. toxicology studies. THE AIM OF THIS ARTICLE IS TO: 1) briefly review the current guidelines and regulations for Investigational Medicinal Products; 2) present a standardised approach to ensure the quality and safety of non-MIPs in human in vivo research; and 3) discuss some lessons we have learned. METHODS AND RESULTS: We propose a practical line of approach to compose a clarifying product dossier (PD), comprising the description of the production process, the analysis of the raw and final product, toxicological studies, and a thorough risk-benefit-analysis. This is illustrated by an example from a human in vivo research model to study exposure to air pollutants, by challenging volunteers with a suspension of carbon nanoparticles (the component of ink cartridges for laser printers). CONCLUSION: With this novel risk-based approach, the members of competent authorities are provided with standardised information on the quality of the product in relation to the safety of the participants, and the scientific goal of the study.

[A Pair of Siblings with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis and a Novel Thr462Lysfs Mutation in the TBK1 Gene]. / Ein Geschwisterpaar mit frontotemporaler Lobärdegeneration und amyotropher Lateralsklerose und einer neuen Mutation im TBK1-Gen (Thr462Lysfs).

We report on a pair of siblings with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) and a novel Thr462Lysfs mutation in the TANK-binding kinase 1 (TBK1) gene identified through the European Early-Onset Dementia Consortium. The patients presented at the age of 77 and 75 years and displayed dementia and bulbar symptoms as well as progressive paresis. After a progressive course, both of them died only a few months after diagnosis. Most recently, TBK1 mutations were identified in patients with FTD and ALS. A loss of expression of the mutant allele, leading to 50 % reduced TBK1 protein levels, seems to be causative. The occurrence of TBK1 mutations in FTD and ALS underlines the fact that FTD and ALS are part of the same disease spectrum. For future therapeutic trials, characterization of TBK1 mutation carriers in presymptomatic cohorts, such as the genetic frontotemporal dementia initiative (GENFI), is of great importance.

The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter.

Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.

Allergic sensitization is associated with inadequate antioxidant responses in mice and men.

BACKGROUND: Allergies arise from aberrant Th2 responses to allergens. The processes involved in the genesis of allergic sensitization remain elusive. Some allergens such as derived from house dust mites have proteolytic activity which can induce oxidative stress in vivo. A reduced capacity of the host to control oxidative stress might prime for allergic sensitization. METHODS: Two different strains of mice were compared for their antioxidant and immune response to HDM. Protease activity of the HDM extract was reduced to investigate its role in oxidative stress induction in the airways and whether this induction could determine allergic sensitization and inflammation. The role of oxidative stress in allergic sensitization was also investigated in humans. An occupational cohort of animal workers was followed for the development of sensitization to rodent urinary proteins. Levels of oxidative stress in serum and antioxidant responses by PBMCs were determined. RESULTS: Susceptibility to allergic sensitization to mite allergens in mice was highly dependent on host genetic background and was associated with oxidative stress in the lungs before allergen exposure and poor antioxidant response after allergen exposure. Reduction in mite protease activity limited its capacity to induce oxidative stress and allergic inflammation in mice. We showed that also in human subjects, oxidative stress before allergen exposure and poor antioxidant responses were associated with predisposition to occupational allergy. CONCLUSION: Our study indicates that oxidative stress condition before allergen exposure due to an inadequate antioxidant response may prime for allergic Th2 responses.

Lipopolysaccharide amplifies eosinophilic inflammation after segmental challenge with house dust mite in asthmatics.

BACKGROUND: House dust contains mite allergens as well as bacterial products such as lipopolysaccharide (LPS). Asthma exacerbations are associated with the level of exposure to allergens and LPS. LPS can potentiate allergen effects in steroid-naïve patients. Long-acting ß2-agonists (LABA) were shown to inhibit LPS-induced bronchial inflammation in healthy volunteers. The aim of this study was to assess the effect of LPS on the allergen-induced eosinophilic inflammation [primary endpoints: eosinophil counts and eosinophil cationic protein (ECP)] induced by bronchial instillation of house dust mite (HDM) in patients with asthma on maintenance treatment with inhaled corticosteroids (ICS). METHODS: Thirty-two nonsmoking asthmatics with HDM allergy were treated with run-in medication (fluticasone propionate 100 µg bid) during 2 weeks before the study day. All patients underwent bronchial challenge with HDM, and half of them were randomized to receive additional LPS. Both groups were randomized to receive pretreatment with a single inhalation of 100 µg salmeterol 30 min before bronchial segmental challenge. Six hours later, bronchoalveolar lavage (BAL) was collected for leukocyte cell count, differentials, and cellular activation markers. RESULTS: Challenge with HDM/LPS induced a significant increase in eosinophil cationic protein (P = 0.036) and a trend toward an increase in BALF eosinophils as compared to HDM challenge. CONCLUSION: Lipopolysaccharide promotes eosinophilic airway inflammation in patients with asthma despite being on maintenance treatment with ICS.

In vitro biomechanical comparison of the effects of cerclage wires, an intramedullary pin and the combination thereof on an oblique osteotomy of the canine tibia.

OBJECTIVE: To compare the in vitro biomechanical effects of single loop cerclage wires, an intramedullary pin and the combination thereof as applied to an oblique mid-diaphyseal osteotomy of canine tibiae. METHODS: Three groups of nine bones with long oblique osteotomies were repaired with the following methods: 1) Three single loop cerclage wires and a transcortical skewer pin, 2) intramedullary pinning with a smooth Steinmann pin, and 3) a combination of both methods. The repaired constructs were tested in a single cycle four-point-bending test to failure. Load displacement curves were drawn and the following parameters were calculated or extrapolated: Stiffness, load at yield, and force resisted at 2 mm actuator displacement. The latter was determined to demonstrate the difference in the amount of energy absorbed between the different groups. RESULTS: The stiffness and force resisted at 2 mm displacement of the groups with cerclage wires were significantly higher than the group with an intramedullary pin alone (p ≤0.05). The differences in stiffness (p = 0.15) and force required at 2 mm displacement (p = 0.56) between cerclage wires and the combination of cerclage wires and intramedullary pins were not significant. CLINICAL RELEVANCE: Cerclage wire repair results in higher stiffness than repair with an intramedullary pin. When cerclage wires are combined with an intramedullary pin, the intramedullary pin does not provide protection to the cerclage wire repair and the wires or the bone under the wires has to fail before the pin resists significant load.

[Severe bronchial asthma]. / Ernstig asthma bronchiale.

The term 'difficult-to-treat asthma' indicates that the asthma is not sufficiently controlled despite prescription of high doses of asthma medication. The term 'severe asthma' is used when the asthma is still insufficiently controlled after exclusion or treatment of any complicating factors; an important complicating factor is poor compliance. Recent studies have focused on the heterogeneous character of asthma and on the definition of specific phenotypes, with the aim of developing phenotype-specific treatments. Treatment options for severe asthma are only partly evidence based. The decision to implement additional therapy for severe asthma depends on the individual patient, the asthma phenotype, and the adverse-event profile of the treatment. Many of the additional therapies should be given as a trial treatment under strict control, especially when efficacy has not been convincingly scientifically proven.

Effect of a combined surgery, re-irradiation and hyperthermia therapy on local control rate in radio-induced angiosarcoma of the chest wall.

PURPOSE: Radiation-induced angiosarcoma (RAS) of the chest wall/breast has a poor prognosis due to the high percentage of local failures. The efficacy and side effects of re-irradiation plus hyperthermia (reRT + HT) treatment alone or in combination with surgery were assessed in RAS patients. PATIENTS AND METHODS: RAS was diagnosed in 23 breast cancer patients and 1 patient with melanoma. These patients had previously undergone breast conserving therapy (BCT, n = 18), mastectomy with irradiation (n=5) or axillary lymph node dissection with irradiation (n = 1). Treatment consisted of surgery followed by reRT + HT (n = 8), reRT + HT followed by surgery (n = 3) or reRT + HT alone (n = 13). Patients received a mean radiation dose of 35 Gy (32-54 Gy) and 3-6 hyperthermia treatments (mean 4). Hyperthermia was given once or twice a week following radiotherapy (RT). RESULTS: The median latency interval between previous radiation and diagnosis of RAS was 106 months (range 45-212 months). Following reRT + HT, the complete response (CR) rate was 56 %. In the subgroup of patients receiving surgery, the 3-month, 1- and 3-year actuarial local control (LC) rates were 91, 46 and 46 %, respectively. In the subgroup of patients without surgery, the rates were 54, 32 and 22 %, respectively. Late grade 4 RT toxicity was seen in 2 patients. CONCLUSION: The present study shows that reRT + HT treatment--either alone or combined with surgery--improves LC rates in patients with RAS.

Tumour basement membrane laminin expression predicts outcome following curative resection of pancreatic head cancer.

BACKGROUND: Although widely fragmented BMs have been associated with adverse outcome in several cancer types, comparatively little is known with respect to its effect on the prognosis of pancreatic cancer. The aim of the current study was therefore to determine the prognostic value of tumour basement membrane (BM) continuity in two anatomically closely related, however, prognostically different tumours, pancreatic head- and periampullary cancer. METHODS: Tumour BM continuity was determined by immunohistochemical staining of its two major components, laminin and collagen type IV. Associations were made with recurrence free survival (RFS), cancer-specific survival (CSS), overall survival (OS) and conventional prognostic factors. RESULTS: Fifty-nine and 61% of pancreatic head and periampullary tumours, respectively, showed limited BM laminin expression. Whereas 43% and 41% of pancreatic head and periampullary cancers, respectively, showed limited BM collagen type IV expression. Limited BM laminin was associated with poor outcome following curative resection of pancreatic head cancer (P=0.034, 0.013 and 0.017 for RFS, CSS and OS, respectively). Two and a half times as many patients with ≥ 25% BM laminin were recurrence free and alive 5 years following resection compared with those with limited BM laminin. Although staining patterns of both BM components were weakly correlated with each other, BM collagen type IV expression was not significantly associated with outcome in either tumour type. CONCLUSION: Discontinuous BMs, determined by laminin expression, are associated with poor outcome following curative resection of pancreatic head cancer.

Expression and prognostic significance of thymidylate synthase (TS) in pancreatic head and periampullary cancer.

BACKGROUND: Pancreatic cancer has a dismal prognosis. Attempts have been made to improve outcome by several 5-FU based adjuvant treatment regimens. However, the results are conflicting. There seems to be a continental divide with respect to the use of 5-FU based chemoradiotherapy (CRT). Furthermore, evidence has been presented showing a different response of pancreatic head and periampullary cancer to 5-FU based CRT. Expression of thymidylate synthase (TS) has been associated with improved outcome following 5-FU based adjuvant treatment in gastrointestinal cancer. This prompted us to determine the differential expression and prognostic value of TS in pancreatic head and periampullary cancer. PATIENTS AND METHODS: TS protein expression was studied by immunohistochemistry on original paraffin embedded tissue from 212 patients following microscopic radical resection (R0) of pancreatic head (n = 98) or periampullary cancer (n = 114). Expression was investigated for associations with recurrence free (RFS), cancer specific (CSS) and overall survival (OS), and conventional prognostic factors. RESULTS: High cytosolic TS expression was present in 26% of pancreatic head tumours and 37% of periampullary tumours (p = .11). Furthermore, TS was an independent factor predicting favourable outcome following curative resection of pancreatic head cancer (p = .003, .001 and .001 for RFS, CSS and OS, respectively). In contrast, in periampullary cancer, TS was not associated with outcome (all p > .10). CONCLUSION: TS, was found to be poorly expressed in both pancreatic head and periampullary cancer and identified as an independent prognostic factor following curative resection of pancreatic head cancer.

The role of pathology in small renal mass laparoscopic cryoablation.

Objective. We evaluated histological outcome of intraoperative biopsies at laparoscopic renal mass cryoablation (LCA), prevalence of peritumoral fat tissue invasion, and risk of tract seeding. Methods. Patients were biopsied 3-5 times (16-gauge). Histology was analyzed by general pathologists and reviewed. Peritumoral fat was histologically examined. The trocar used for biopsy-guidance was examined by cytology. Records were studied for reporting tract metastasis. Results. 77 biopsied renal masses with mean ± SD diameter 30 ± 7.4 mm were histologically classified by primary and review pathology revealing 64 and 62 malignancies, 13 and 15 benign lesions, respectively. In 30/34, the fat covered a carcinoma but revealed no malignancy. Cytology showed no malignant cells but was inconclusive in 1 case. No tract metastasis occurred. Conclusions. The use of an intraoperative biopsy protocol provides histological diagnosis of all renal masses. No existence of peritumoral fat tissue invasion or tract seeding was found.

Increase in allergen-specific IgE and ex vivo Th2 responses after a single bronchial challenge with house dust mite in allergic asthmatics.

BACKGROUND: Airway responsiveness to allergen in patients with allergic asthma is studied by bronchial allergen challenge. Although the typical features of the early and late responses on lung function and bronchial inflammation after allergen challenge are well known, little has been reported as yet on any changes in systemic allergic and immunologic parameters after 4-6 weeks. METHODS: In a clinical study, 27 subjects with allergic asthma and house dust mite (HDM) allergy underwent a bronchial allergen challenge with HDM. Blood samples were collected before and 5 weeks after allergen challenge. Serum levels of total IgE and allergen-specific IgE were measured, and peripheral blood mononuclear cells were isolated and stimulated ex vivo with HDM to determine the allergen-specific T-cell cytokine response. RESULTS: Five weeks after bronchial allergen challenge with HDM, the amount of circulating IgE against HDM and the major allergenic components Der p1 and Der p2 was significantly increased (10.8% and 8.8%, respectively). IgE antibodies against other environmental allergens decreased (grass pollen) or remained unchanged (cat dander). Allergen-induced Th2-cytokine production was also significantly increased (P< 0.001, P=0.014, and P=0.006 for IL-4, IL-5, and IL-13, respectively). The increase in Der p1- and Der p2-specific IgE in serum correlated with increased numbers of Th2-cytokine-producing cells (Rs=0.56, P=0.002 and Rs=0.54, P=0.004 for IL-4 and IL-13, respectively). CONCLUSIONS: A single bronchial allergen challenge with HDM is accompanied by increased levels of allergen-specific IgE for HDM in serum and an enhanced Th2 response to HDM still detectable 5 weeks after challenge.

Pneumoconiosis and emphysema in construction workers: results of HRCT and lung function findings.

OBJECTIVES: To evaluate the prevalence of HRCT findings in construction workers previously surveyed by chest radiographs classified according to ILO guidelines. To examine the association between HRCT findings and exposure to quartz containing dust, and lung function. METHODS: The study comprised a questionnaire, dynamic and static lung function measurements, single-breath CO diffusion capacity, chest radiographs and HRCT in 79 individuals. Certified 'B' readers coded radiographs according to the ILO classification. HRCT scans were read according to an international classification system. A qualitative exposure index for cumulative respiratory quartz on a 10-point scale was used. RESULTS: Agreement between HRCT readers was good (κ>0.60), except for irregular opacities (κ=0.23). In ILO category 0/0, 8% HRCT round, 22% irregular and/or linear opacities and 41% HRCT emphysema was found. HRCT round opacities was associated with high cumulative quartz exposure (OR 7.1; 95% CI 1.3 to 37.8). Emphysema was associated with smoking (OR 10.1; 95% CI 1.2 to 84.2) and showed a reduction in T(L,CO,sb). HRCT round opacities was not associated with lung function. Current smoking was negatively associated with FEV1/FVC ratio and positively with RV/TLC ratio, and showed a reduction in T(L,CO,sb) (13.4%), adjusted for different HRCT findings. CONCLUSIONS: Low grade silicosis cannot be excluded in workers with normal chest radiographs (ILO 0/0). In relatively highly exposed construction workers, a sevenfold increased risk of simple (nodular) silicosis was found. Emphysema on HRCT was associated with current or former smokers, but not with exposure, and contributed to reduced diffusion capacity. Airflow limitation was mainly determined by current smoking and was not associated with simple (nodular) silicosis.

Synbiotics reduce allergen-induced T-helper 2 response and improve peak expiratory flow in allergic asthmatics.

BACKGROUND: Previous studies suggest that pre/probiotics can be used in the prevention and treatment of early allergic disease in newborns and young children. OBJECTIVE: To determine the effect of treatment with synbiotics (90% short-chain galacto-oligosaccharides, 10% long-chain fructo-oligosaccharides: Immunofortis(®) and Bifidobacterium breve M-16V) on allergic responses in adults with established allergic asthma. Primary outcome was allergen-induced bronchial inflammation as represented by eosinophil counts. METHODS: Twenty-nine patients with asthma and house dust mite (HDM) allergy were randomized in a double-blind, parallel design to receive placebo or synbiotics for 4 weeks. At study entry and after treatment, a bronchial allergen challenge with HDM was performed, followed by lung function tests, collection of blood (in/ex vivo IL-5) and induced sputum (inflammatory parameters). During treatment, a diary was kept with peak expiratory flow (PEF) and asthma scores. RESULTS: Treatment did not affect the allergen-induced increase in sputum eosinophils at 6 and 24 h after challenge. Likewise, other parameters for bronchial inflammation and early and late changes in lung function did not differ upon treatment. Both the morning and evening PEF, however, significantly increased during synbiotics treatment (morning P = 0.003, evening P = 0.011). Also, the increase in serum IL-5 after allergen challenge was significantly inhibited by synbiotics (P = 0.034), as was ex vivo allergen-induced Th2-cytokine (IL-5 and IL-4+ IL-13) production by PBMCs (P = 0.046). In vivo (24 h) and ex vivo IL-5 production were associated. CONCLUSION: Four-week treatment with synbiotics had no effect on bronchial inflammation and LAR, but did significantly reduce systemic production of Th2-cytokines after allergen challenge and improved PEF.

IgG4 antibodies against rodents in laboratory animal workers do not protect against allergic sensitization.

BACKGROUND: The modified Th2 response, defined as an IgG4 response in the absence of IgE, is suggested to protect against the development of allergic sensitization. However, studies suggesting this protective effect all had a cross-sectional design, making it impossible to study the development of both responses. AIM OF THE STUDY: We aimed to study the dynamics in IgG4 antibodies in relation to allergic sensitization in an occupational cohort of starting laboratory animal workers. Moreover, we studied the relation between exposure, antibody responses, atopy and self reported allergic symptoms. METHODS: A total of 110 starting animal workers were followed for 2 years. IgG4 antibodies against rats and mice were assessed. Workers were tested for allergic sensitization and exposure to animal allergens was estimated. Symptom status was assessed using questionnaires. RESULTS: Rat and mouse specific IgG4 antibodies were present before the development of allergy and did not significantly change over time. Allergic sensitization was related to exposure and atopic status but high levels of IgG4 showed no protective effect. In contrary, workers that developed mouse specific sensitization during follow up had higher levels of mouse specific IgG4. Symptoms were related to allergic sensitization and IgG4 levels did not influence that relationship. CONCLUSIONS: IgG4 antibodies are present before IgE antibodies develop and IgG4 levels are stable over time. In our occupational cohort, the modified Th2 response had no protective effect on development of sensitization or allergic symptoms.