Relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection

To test the hypothesis that rhinovirus (RV)-induced immune responses influence the outcome of RV infections, we inoculated 22 subjects with allergic rhinitis or asthma with RV16. Nasal secretions and induced sputum were repeatedly sampled over the next 14 d. RV16 infection increased nasal granulocyte colony-stimulating factor (G-CSF) and interleukin (IL)-8, which was accompanied by neutrophilia in blood and nasal secretions. Nasal G-CSF correlated closely with increased blood neutrophils (r(s) = 0.69, p < 0.005), whereas nasal neutrophils correlated with both G-CSF (r(s) = 0.87, p < 0.001) and IL-8 (r(s) = 0.75, p < 0.001). Although similar relationships were present in sputum, changes in sputum neutrophils and G-CSF with RV16 infection were relatively modest. In addition, virus-induced changes in the sputum interferon-gamma-to-IL-5 messenger RNA ratio were inversely related to both peak cold symptoms (r(s) = -0.60, p < 0.005) and the time to viral clearance (undetectable picornavirus RNA). These results indicate that airway IL-8 and G-CSF are closely associated with virus-induced neutrophilic inflammation during an experimental RV infection in atopic volunteers. In addition, the balance of airway T-helper cell type 1 (Th1)- and Th2-like cytokines induced by RV infection may help determine the clinical outcome of common cold infections, raising the possibility that the individual subject's immune response, rather than atopic status per se, is important in this regard.     

The prevalence and incidence of clinical and asymptomatic Lyme borreliosis in a population at risk

A past history of clinical Lyme borreliosis and the 6-month incidence of clinical and asymptomatic Lyme borreliosis was studied prospectively in a high-risk population. In the spring, blood samples were drawn from 950 Swiss orienteers, who also answered a questionnaire. IgG anti-Borrelia burgdorferi antibodies were detected by ELISA. Positive IgG antibodies were seen in 248 (26.1%), in contrast to 3.9%-6.0% in two groups of controls (n = 101). Of the orienteers, 1.9%-3.1% had a past history of definite or probable clinical Lyme borreliosis. Six months later a second blood sample was obtained from 755 participants, 558 (73.9%) of whom were seronegative initially; 45 (8.1%) had seroconverted from negative to positive. Only 1 (2.2%) developed clinical Lyme borreliosis. Among all participants, the 6-month incidence of clinical Lyme borreliosis was 0.8% (6/755) but was much higher (8.1%) for asymptomatic seroconversion (45/558). In conclusion, positive Lyme serology was common in Swiss orienteers, but clinical disease occurred infrequently.     

Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease

Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21‐linked frontotemporal dementia‐amyotrophic lateral sclerosis (FTD‐ALS). We here report the prevalence of the expansion in a hospital‐based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat‐primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD‐ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD‐ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.     

Accuracy of supplementary serologic testing for human T-lymphotropic virus types I and II in US blood donors. Retrovirus Epidemiology Donor Study

Blood donations in the United States have been screened for antibody to human T-lymphotropic virus type I (HTLV-I) by HTLV-I enzyme immunoassay (EIA) since November 1988. Specimens repeatedly found to be reactive by EIA undergo confirmation by supplementary serologic tests. We assessed the accuracy of blood center testing of 994 HTLV-I EIA repeat-reactive specimens in five US blood centers between November 1988 and December 1991. Of 410 confirmed HTLV-I/II donations, 407 (99.3%) were infected with HTLV-I/II, as determined by polymerase chain reaction (PCR) (403 cases) and by repeat serologic testing (4 cases). The three false- positive results occurred in the first year of testing. Of 425 HTLV- indeterminate specimens, 6 (1.4%) were found to be infected by PCR (5 with HTLV-II and 1 with HTLV-I). None of 159 confirmatory test-negative donations was PCR positive. Of HTLV-I/II-seropositive specimens, 80.2% to 95.4% could be typed as HTLV-I or HTLV-II by type-specific serologic assays. These results support recommendations that HTLV-I/II- seropositive donors should be advised that they are infected with HTLV- I, HTLV-II, or HTLV-I/II (depending on results of type-specific assays). HTLV-indeterminate donors should be advised that their results only rarely indicate HTLV infection. HTLV confirmatory test-negative donors should be reassured that they are not infected with HTLV-I or HTLV-II.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.     

CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome

Formation of metastases in the lungs is the major cause of death in patients suffering from osteosarcoma (OS). Metastases at presentation and poor response to preoperative chemotherapy are strong predictors for poor patient outcome. The elucidation of molecular markers that promote metastasis formation and/or chemoresistance is therefore of importance. CD44 is a plasma membrane glycoprotein that binds to the extracellular matrix component hyaluronan (HA) and has been shown to be involved in metastasis formation in a variety of other tumors. Here we investigated the role of CD44 expression on OS tumor formation and metastasis. High CD44 expression, evaluated with a tissue microarray including samples from 53 OS patients and stained with a pan‐CD44 antibody (Hermes3), showed a tendency (p < 0.08) to shortened overall survival. However, nonresponders and patients with lung metastases and high CD44 expression had significantly poorer prognosis than patients with low CD44 expression. Overexpression of the standard CD44 isoform (CD44s) and its HA‐binding defective mutant R41A in osteoblastic SaOS‐2 cells resulted in HA‐independent higher migration rates and increased chemoresistance, partially dependent on HA. In an orthotopic mouse model of OS, overexpression of CD44s in SaOS‐2 cells resulted in an HA‐dependent increased primary tumor formation and increased numbers of micrometastases and macrometastases in the lungs. In conclusion, although CD44 failed to be an independent predictor for patient outcome in this limited cohort of OS patients, increased CD44 expression was associated with even worse survival in patients with chemoresistance and with lung metastases. CD44‐associated chemoresistance was also observed in vitro, and increased formation of lung metastases was found in vivo in SCID mice. © 2013 American Society for Bone and Mineral Research.