Influence of sensitization and allergen provocation procedures on the development of allergen-induced bronchial hyperreactivity in conscious, unrestrained guinea-pigs

The effects of different sensitization and allergen provocation regimens on the development of allergen-induced bronchial hyperreactivity (BHR) to histamine were investigated in conscious, unrestrained guinea-pigs. Similar early and late phase asthmatic reactions, BHR for inhaled histamine after the early (6 h) as well as after the late reaction (24 h), and airway inflammation were observed after a single allergen provocation in animals sensitized to produce mainly IgG or IgE antibodies, respectively. Repeating the allergen provocation in the IgE-sensitized animals after 7 days, using identical provocation conditions, resulted in a similar development of BHR to histamine inhalation. Repetition of the allergen provocation during 4 subsequent days resulted in a decreased development of BHR after each provocation, despite a significant increase in the allergen provocation dose necessary to obtain similar airway obstruction. The number of inflammatory cells in the bronchoalveolar lavage was not significantly changed after repeated provocation, when compared with a single allergen provocation. Finally, we investigated allergen-induced bronchial hyperreactivity by repetition of the sensitization procedure at day 7 and 14 (booster), followed by repeated allergen provocation twice a week for 5 weeks. Surprisingly, no BHR to histamine could be observed after either provocation, while the number of inflammatory cells in the bronchoalveolar lavage fluid after 5 weeks was enhanced compared with controls. These data indicate that both IgE and IgG sensitized guinea-pigs may develop bronchial hyperreactivity after a single allergen provocation. Repeated allergen exposure of IgE sensitized animals causes a gradual fading of the induced hyperreactivity despite the on-going presence of inflammatory cells in the airways, indicating a mechanism of reduced cellular activation

Prescription of the first prosthesis and later use in children with congenital unilateral upper limb deficiency: A systematic review

Background: The prosthetic rejection rates in children with an upper limb transversal reduction deficiency are considerable. It is unclear whether the timing of the first prescription of the prosthesis contributes to the rejection rates. Objective: To reveal whether scientific evidence is available in literature to confirm the hypothesis that the first prosthesis of children with an upper limb deficiency should be prescribed before two years of age. We expect lower rejection rates and better functional outcomes in children fitted at young age. Methods: A computerized search was performed in several databases (Medline, Embase, Cinahl, Amed, Psycinfo, PiCarta and the Cochrane database). A combination of the following keywords and their synonyms was used: "prostheses, upper limb, upper extremity, arm and congenital''. Furthermore, references of conference reports, references of most relevant studies, citations of most relevant studies and related articles were checked for relevancy. Results: The search yielded 285 publications, of which four studies met the selection criteria. The methodological quality of the studies was low. All studies showed a trend of lower rejection rates in children who were provided with their first prosthesis at less than two years of age. The pooled odds ratio of two studies showed a higher rejection rate in children who were fitted over two years of age ( pooled OR 3.6, 95% CI 1.6-8.0). No scientific evidence was found concerning the relation between the age at which a prosthesis was prescribed for the first time and functional outcomes. Conclusion: In literature only little evidence was found for a relationship between the fitting of a first prosthesis in children with a congenital upper limb deficiency and rejection rates or functional outcomes. As such, clinical practice of the introduction of a prosthesis is guided by clinical experience rather than by evidence-based medicine

Gender specific effects of the calcium channel TRPV4 on osteoporotic fracture risk and osteoblast-osteoclast coupling

TRPV4 is a member of the transient receptor potential (TRP) superfamily and responds to an array of stimuli, including osmolarity, pH and pressure. Recent findings showing that TRPV4 deficiency leads to reduced sensing of mechanical stimuli led us to explore the role of TRPV4 in bone. TRPV4 mRNA was abundantly expressed in both osteoblasts and osteoclasts as assessed by qPCR. Femoral cortical and trabecular bone mass as assessed by microcomputed tomography was higher in male TRPV4 knockout mice compared to wild type mice. Despite thicker bone structures, cortical porosity was increased in the male TRPV4 knockout mice leading to reduced bone strength as assessed by 3-point bending. Osteoclast and osteoblast differentiation and function was studied, using bone marrow cultures from wildtype and TRPV4 knockout mice. Osteoclast numbers as well as the formation of resorption pits were significantly reduced in cultures of TRPV4 knockout mice compared to wildtype littermates. In contrast, osteoblast differentiation and matrix mineralization was significantly increased in TRPV4 knockout bone marrow cultures. None of these parameters were significantly different in bones and bone marrow cultures of female knock out mice. These data implicate a gender-specific osteoblast–osteoclast uncoupling and support the observed increase in bone mass in male TRPV4 deficient mice. To assess the possible impact of TRPV4 on osteoporotic outcome in humans, we extracted data from the genome-wide association study within the Rotterdam Study. Two single nucleotide polymorphisms (SNPs) in the TRPV4 gene showed strong associations with osteoporotic fracture risk fragility fracture risk and hip fracture risk in men, but not in women. This was not affected after adjusting for height, weight, age and bone mineral density (BMD). In conclusion, TRPV4 plays an important role in male but not female bone biology. Apparently, the increased periosteal bone apposition fails to overcome the increased cortical porosity, leading to reduced bone strength in TRPV4 deficient male mice. In line with the gender-specific findings in mice, variations in the TRPV4 gene are predicting fracture risk in men but not in women

A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-OA consortium

To identify the susceptibility gene in hand osteoarthritis (OA) the authors used a two-stage approach genome-wide association study using two discovery samples (the TwinsUK cohort and the Rotterdam discovery subset; a total of 1804 subjects) and four replication samples (the Chingford Study, the Chuvasha Skeletal Aging Study, the Rotterdam replication subset and the Genetics, Arthrosis, and Progression (GARP) Study; a total of 3266 people). Five single-nucleotide polymorphisms (SNPs) had a likelihood of association with hand OA in the discovery stage and one of them (rs716508), was successfully confirmed in the replication stage (meta-analysis p = 1.81×10−5). The C allele conferred a reduced risk of 33% to 41% using a case–control definition. The SNP is located in intron 1 of the A2BP1 gene. This study also found that the same allele of the SNP significantly reduced bone density at both the hip and spine (p<0.01), suggesting the potential mechanism of the gene in hand OA might be via effects on subchondral bone. The authors' findings provide a potential new insight into genetic mechanisms in the development of hand OA

Laminin α4 contributes to airway remodeling and inflammation in asthma

Airway inflammation and remodeling are characteristic features of asthma, both contributing to airway hyperresponsiveness (AHR) and lung function limitation. Airway smooth muscle (ASM) accumulation and extracellular matrix deposition are characteristic features of airway remodeling, which may contribute to persistent AHR. Laminins containing the α2 chain contribute to characteristics of ASM remodeling in vitro and AHR in animal models of asthma. The role of other laminin chains, including the laminin α4 and α5 chains, which contribute to leukocyte migration in other diseases, is currently unknown. The aim of the current study was to investigate the role of these laminin chains in ASM function and in AHR, remodeling and inflammation in asthma. Expression of both laminin α4 and α5 was observed in the human and mouse ASM bundle. In vitro, laminin α4 was found to promote a pro-proliferative, pro-contractile and pro-fibrotic ASM cell phenotype. In line, treatment with laminin α4 and α5 function-blocking antibodies reduced allergen-induced increases in ASM mass in a mouse model of allergen-induced asthma. Moreover, eosinophilic inflammation was reduced by the laminin α4 function-blocking antibody as well. Using airway biopsies from healthy subjects and asthmatic patients, we found inverse correlations between ASM α4 chain expression and lung function and AHR, whereas eosinophil numbers correlated positively with expression of laminin α4 in the ASM bundle. This study for the first time indicates a prominent role for laminin α4 in ASM function and in inflammation, AHR and remodeling in asthma, whereas the role of laminin α5 is more subtle