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Homologous recombination in embryonic stem cells was used to prepare transgenic mice with an inactivated Col2a1 gene for collagen 11, the major protein component of the extracellular matrix of cartilage. Heterozygous mice had a minimal phenotype. Homozygous mice developed into fetuses that were delivered vaginally but died either just before or shortly after birth. The cartilage in the mice consisted of highly disorganized chondrocytes with a complete lack of extracellular fibrils discernible by electron microscopy. There was no endochondrial bone or epiphyseal growth plate in long bones. However, many skeletal structures such as the cranium and ribs were normally developed and mineralized. The results demonstrate that a well-organized cartilage matrix is required as a primary tissue for development of some components of the vertebrate skeleton, but it is not essential for others.

We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

BackgroundTo identify the prognostic factors for survival in patients with interstitial pneumonia with autoimmune features (IPAF) who meet the serological domain of the IPAF criteria.MethodsWe retrospectively analysed 99 IPAF patients who met the serological domain and were hospitalised at the Respiratory Medicine Unit of Kurashiki Central Hospital from 1999 to 2015. The high-resolution computed tomography findings were usual interstitial pneumonia (UIP; n = 1), non-specific interstitial pneumonia (NSIP; n = 63), NSIP with organizing pneumonia (OP) overlap (n = 15), and OP (n = 20). One patient who had radiological UIP pattern, and met the serological and clinical domains was excluded. The clinical characteristics, radiological findings, administered therapy, and prognosis of the remaining 98 IPAF patients who met the serological and morphological domains were analysed.ResultsThe median age of the 98 IPAF patients was 68 years, and 41 (41.8%) of them were men. Twelve (12.2%) of the 98 IPAF patients developed other characteristics and were diagnosed with connective tissue disease (CTD) later during the median follow-up of 4.5 years. Univariate Cox analysis revealed systemic sclerosis (SSc)-specific and SSc-associated antibodies (ANA nucleolar pattern, ANA centromere pattern, anti-ribonucleoprotein and anti-Scl-70) positive IPAF, radiological NSIP pattern, bronchoalveolar lavage fluid lymphocytes >15%, and age as significant prognostic factors for survival. Multivariate Cox analysis revealed radiological NSIP pattern (hazard ratio [HR], 4.48; 95% confidence interval [CI], 1.28–15.77, p = 0.02) and age (HR, 1.07; 95% CI, 1.02–1.11, p = 0.01) were significantly associated with worse survival.ConclusionsWe confirmed that radiological NSIP pattern and age are poor prognostic factors for the survival of IPAF patients. This study suggested that the autoantibodies that are highly specific for certain connective tissue diseases might be less important for the prognosis of IPAF compared with the radiological-pathological patterns. The relatively high proportion of IPAF patients who developed CTD later suggests the importance of careful observation for evolution to CTD in IPAF.

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Objective The aim of this study was to describe the epidemiology, clinical features, antimicrobial treatment, and outcomes of patients with nursing and healthcare-associated pneumonia (NHCAP); a new category of pneumonia proposed by the Japanese Respiratory Society. Methods We conducted a retrospective analysis of a prospectively collected database of patients with NHCAP and community-acquired pneumonia (CAP) hospitalized at a single center between January 2008 and December 2010, and compared their clinical characteristics. The criteria for NHCAP were as follows: (1) residence in a nursing home or an extended-care ward, (2) a discharge from a hospital in the preceding 90 days, (3) an elderly or handicapped patient who needs long-term care, (4) a patient who regularly requires vascular access in an outpatient setting. Results A total of 442 NHCAP patients and 451 CAP patients were evaluated. The NHCAP patients were older and had a higher frequency of underlying diseases. Aspiration was thought to be associated with the NHCAP in 63% of patients. Streptococcus pneumoniae was the leading pathogen in both groups, whereas the frequency of multidrug-resistant pathogens was higher in the NHCAP patients. The most frequently used antimicrobials in NHCAP patients were penicillins with beta-lactamase inhibitors. The in-hospital mortality and recurrence rates were significantly higher in NHCAP patients than in CAP patients (13.1% vs. 5.1%, p<0.001 and 18.8% vs. 5.5%, p<0.001). Conclusion The clinical picture of NHCAP is consistent with that of HCAP described in the past. It is thought to be of benefit to modify the healthcare-associated pneumonia (HCAP) criteria considering the healthcare and social health insurance system in Japan.

IntroductionCongenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness within the first two years of life. Collagen VI-related muscle disorders have recently emerged as one of the most common types of CMD. COL6 CMD is caused by deficiency and/or dysfunction of extracellular matrix (ECM) protein collagen VI. Currently, there is no specific treatment for this disabling and life-threatening disease. The primary cellular targets for collagen VI CMD therapy are fibroblasts in muscle, tendon and skin, as opposed to muscle cells for other types of muscular dystrophies. However, recent advances in stem cell research have raised the possibility that use of adult stem cells may provide dramatic new therapies for treatment of COL6 CMD.MethodsHere, we developed a procedure for isolation of human stem cells from the adipose layer of neonatal skin. The adipose-derived stem cells (ADSC) were examined for expression of ECM and related genes using gene expression array analysis. The therapeutic potential of ADSC was assessed after a single intramuscular transplantation in collagen VI-deficient mice.ResultsAnalysis of primary cultures confirmed that established ADSC represent a morphologically homogenous population with phenotypic and functional features of adult mesenchymal stem cells. A comprehensive gene expression analysis showed that ADSC express a vast array of ECM genes. Importantly, it was observed that ADSC synthesize and secrete all three collagen VI chains, suggesting suitability of ADSC for COL6 CMD treatment. Furthermore, we have found that a single intramuscular transplantation of ADSC into Col6a1−/−Rag1−/− mice under physiological and cardiotoxin-induced injury/regeneration conditions results in efficient engraftment and migration of stem cells within the skeletal muscle. Importantly, we showed that ADSC can survive long-term and continuously secrete the therapeutic collagen VI protein missing in the mutant mice.ConclusionsOverall, our findings suggest that stem cell therapy can potentially provide a new avenue for the treatment of COL6 CMD and other muscular disorders and injuries.