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.     

The association of HIV viral load with indirect markers of liver injury

This study assessed the association of HIV RNA with indirect markers of liver injury including FIB-4 index, liver enzymes and platelet counts in a high-risk Hispanic population. The data were derived from a prospective study that included 138 HIV/hepatitis C (HCV)-coinfected and 68 HIV-infected participants without hepatitis C or B co-infection (mono-infected). In unadjusted analyses, detectable HIV viral load (vs undetectable, <400 copies/mL) was associated with a 40% greater odds (OR 1.4, 95% CI: 1.1-1.9, P = 0.016) of FIB-4 > 1.45 in the HIV/HCV-coinfected group and 70% greater odds of FIB-4 > 1.45 (OR 1.7, 95% CI: 1.0-2.8; P = 0.046) in the HIV-mono-infected group. In multivariable analyses, a 1 log(10) increase in HIV RNA was associated with a median increase in FIB-4 of 12% in the HIV/HCV-coinfected group and 11% in the HIV-mono-infected group (P < 0.0001). Among the HIV/HCV-coinfected group, the elevating effect of HIV RNA on FIB-4 was strongest at low CD4 counts (P = 0.0037). Among the HIV-mono-infected group, the association between HIV RNA and FIB-4 was independent of CD4 cell counts. HIV RNA was associated with alterations in both liver enzymes and platelet counts. HIV antiretroviral therapy was not associated with any measure of liver injury examined. This study suggests that HIV may have direct, injurious effects on the liver and that HIV viral load should be considered when these indirect markers are used to assess liver function.     

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.     

Hair Mercury and Fish Consumption in Residents of O‘ahu,Hawai‘i

Recent studies have established that men are susceptible to cardiotoxicity from methylmercury exposure, which also poses risks to the pregnant woman. Hair samples were obtained and questionnaires for methylmercury exposure assessment were administered to 110 adults (57 men, 53 women) throughout O‘ahu, Hawai‘i during December 2010 to January 2011. Hair samples were analyzed for total mercury with a direct mercury analyzer. Men ≥ 46 years had a median of 2.0 µg/g, which was above the reference dose of 1 µg/g, as compared to younger men with a median 1.0 µg/g (P < 0.05). Hair concentrations from older women had a median of 1.2 µg/g of mercury compared to 0.6 µg/g for younger women. Additionally, 38% of women of childbearing age had a Hazard Index > 1.0. This indicates that both men and women were at risk for excessive methylmercury exposure. In the final regression model, male gender, age > 45 years, length of residency > 10 years in Hawai‘i, and fish consumption frequency > 1 meal per week were significant factors in increased hair mercury levels. Following safe fish consumption practices allows residents to reap health benefits of fish consumption without excessive toxicant exposure.     

Usefulness of left ventricular mass in predicting recovery of left ventricular systolic function in patients with symptomatic idiopathic dilated cardiomyopathy

Prognosis of idiopathic dilated cardiomyopathy (IDC) is variable. We determined the prognostic value of left ventricular (LV) mass and systolic and diastolic function in patients with IDC of <12 months duration. Clinical and echocardiographic assessment was performed at baseline and at 8+/-6 months follow-up in 25 patients (47+/-13 years) with IDC and an LV ejection fraction (LVEF1) of <40% (22+/-7%). Based on a follow-up LVEF (LVEF2) of < or >40%, patients were divided into unimproved (n = 13, LVEF2 = 21+/-9%) and improved groups (n = 12, LVEF2 = 51+/-11%). There was no difference in the LVEF1 (22+/-8% vs. 22+/-6%), LV end-systolic (5.7+/-0.8 vs. 5.8+/-0.9 cm) or end-diastolic (6.5+/-0.6 vs. 6.6+/-0.9 cm) dimension, wall stress (102+/-26 vs 99+/-28 g/cm2), end-systolic (1.7+/-0.3 vs. 1.8+/-0.2) or end-diastolic (1.7+/-0.3 vs. 1.6+/-0.1) sphericity, dp/dt (582+/-163 vs. 678+/-222 mm Hg/s), or right ventricular fractional shortening (20+/-9% vs. 27+/-7%, p = 0.06) in unimproved and improved groups. LV mass was lower (1.00+/-0.21 vs. 1.38+/-0.27 g/ml, p = 0007) and mitral inflow E-wave deceleration time shorter (97+/-42 vs. 164+/-58 ms, p = 0007) in the unimproved versus the improved group. On Pearson correlation analysis, LV mass (r = 0.62, p = 0.001), deceleration time (r = 0.68, p = 0.0002), wall motion score index (r = -0.47, p = 02), and dp/dt (r = 0.52, p = 03) were the significant predictors of LVEF2. There was correlation between LV mass (grams per milliliter) and deceleration time (r = 0.61, p = 0.001). During follow-up, death occurred in 1, and readmission for worsening heart failure in 4 patients in the unimproved group versus no hospitalization in the improved group. Thus, in patients with recent onset IDC, LV mass and diastolic function determine late outcome.