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(Immunodeficiency was suggested by extensive varicella skin changes—disseminated blisters and erosions—affecting multiple dermatomes, and lymphopenia.) Consider investigations for other potential causes of immunocompromise—for example, HIV infection, intra-abdominal malignancy, haematological malignancy. 3 What is the most likely diagnosis? Degenerative changes affecting the vertebral column are also present A systemic review and meta-analysis supported the association between herpes zoster and occult cancer, particularly in the case of haematological malignancies.12 It remains unclear whether extensive or clinically atypical herpes zoster, or both is a stronger marker of occult malignancy. Patient consent obtained. 1 Schmidt SA Mor A Schønheyder HC Sørensen HT Dekkers OM Cronin-Fenton D. Herpes zoster as a marker of occult cancer: A systematic review and meta-analysis.

Background: The measurement of multiple protein biomarkers may refine risk stratification in clinical settings. This concept has stimulated development of multiplexed immunoassay platforms that provide multiple, parallel protein measurements on the same specimen. Content: We provide an overview of antibody-based multiplexed immunoassay platforms and discuss technical and operational challenges. Multiplexed immunoassays use traditional immunoassay principles in which high-affinity capture ligands are immobilized in parallel arrays in either planar format or on microspheres in suspension. Development of multiplexed immunoassays requires rigorous validation of assay configuration and analytical performance to minimize assay imprecision and inaccuracy. Challenges associated with multiplex configuration include selection and immobilization of capture ligands, calibration, interference between antibodies and proteins and assay diluents, and compatibility of assay limits of quantification. We discuss potential solutions to these challenges. Criteria for assessing analytical multiplex assay performance include the range of linearity, analytical specificity, recovery, and comparison to a quality reference method. Quality control materials are not well developed for multiplexed protein immunoassays, and algorithms for interpreting multiplex quality control data are needed. Summary: Technical and operational challenges have hindered implementation of multiplexed assays in clinical settings. Formal procedures that guide multiplex assay configuration, analytical validation, and quality control are needed before broad application of multiplexed arrays can occur in the in vitro diagnostic market.

Background: Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. Methods: Published reports relevant to use of tumor markers for 5 cancer sites—testicular, prostate, colorectal, breast, and ovarian—were critically reviewed. Results: For testicular cancer, α-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are recommended for diagnosis/case finding, staging, prognosis determination, recurrence detection, and therapy monitoring. α-Fetoprotein is also recommended for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign prostatic disease when total PSA is <10 μg/L. In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, postoperative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing may be used for screening asymptomatic adults 50 years or older. For breast cancer, estrogen and progesterone receptors are mandatory for predicting response to hormone therapy, human epidermal growth factor receptor-2 measurement is mandatory for predicting response to trastuzumab, and urokinase plasminogen activator/plasminogen activator inhibitor 1 may be used for determining prognosis in lymph node–negative patients. CA15-3/BR27–29 or carcinoembryonic antigen may be used for therapy monitoring in advanced disease. CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in postmenopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer. Conclusions: Implementation of these recommendations should encourage optimal use of tumor markers.

Many men develop a rising PSA after initial therapy for prostate cancer. While some of these men will develop a local or metastatic recurrence that warrants further therapy, others will have no evidence of disease progression. We hypothesized that an expression biomarker panel can predict which men with a rising PSA would benefit from further therapy. A case-control design was used to test the association of gene expression with outcome. Systemic (SYS) progression cases were men post-prostatectomy who developed systemic progression within 5 years after PSA recurrence. PSA progression controls were matched men post-prostatectomy with PSA recurrence but no evidence of clinical progression within 5 years. Using expression arrays optimized for paraffin-embedded tissue RNA, 1021 cancer-related genes were evaluated-including 570 genes implicated in prostate cancer progression. Genes from 8 previously reported marker panels were included. A systemic progression model containing 17 genes was developed. This model generated an AUC of 0.88 (95% CI: 0.84-0.92). Similar AUCs were generated using 3 previously reported panels. In secondary analyses, the model predicted the endpoints of prostate cancer death (in SYS cases) and systemic progression beyond 5 years (in PSA controls) with hazard ratios 2.5 and 4.7, respectively (log-rank p-values of 0.0007 and 0.0005). Genes mapped to 8q24 were significantly enriched in the model. Specific gene expression patterns are significantly associated with systemic progression after PSA recurrence. The measurement of gene expression pattern may be useful for determining which men may benefit from additional therapy after PSA recurrence.

The diagnosis of cholangiocarcinoma is often difficult, making management approaches problematic. A reliable serum tumor marker for cholangiocarcinoma would be a useful additional diagnostic test. Previous studies have demonstrated that elevated serum concentrations of CA 19-9, a tumor-associated antigen, have good sensitivity and specificity for cholangiocarcinoma in patients with primary sclerosing cholangitis. However, the value of this tumor marker for cholangiocarcinoma unassociated with primary sclerosing cholangitis is unclear. Thus, the aims of this study were to determine the usefulness of a serum CA 19-9 determination in the diagnosis of de novo cholangiocarcinoma. We prospectively measured serum CA 19-9 concentrations in patients with cholangiocarcinoma (n = 36), nonmalignant liver disease (n = 41), and benign bile duct strictures (n = 26). Serum CA 19-9 concentrations were measured by an immunoradiometric assay (CIS Bio International) without knowledge of the clinical diagnosis. The sensitivity of a CA 19-9 value >100 U/ml in diagnosing cholangiocarcinoma was 53%. When compared with the nonmalignant liver disease and the benign bile duct stricture groups, the true negative rates were 76% and 92%, respectively. Patients with unresectable cholangiocarcinoma had significantly greater mean CA 19-9 concentrations compared to patients with resectable cholangiocarcinoma. These data suggest that the serum CA 19-9 determination is a useful addition to the available tests for the differential diagnosis of cholangiocarcinoma.

This 2-year controlled, randomized, double-blind study examined the effects of dehydroepiandrosterone (DHEA) in women and DHEA or testosterone in men, as compared with placebo. Neither DHEA nor low-dose testosterone replacement in the elderly subjects had physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life. The results of this study do not support the use of these agents as antiaging supplements. Neither DHEA nor low-dose testosterone replacement in elderly subjects had physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life. The results of this study do not support the use of these agents as antiaging supplements. With the rapid increase in the population of people 60 years of age and older, considerable research is being focused on how to prevent or delay age-related disabilities. One approach is to replace hormones whose levels decline with age. Levels of dehydroepiandrosterone (DHEA) and its sulfated form, the most abundant steroid hormone in the circulation, decline from the third decade onward. 1 , 2 Studies in animals have shown beneficial effects of DHEA on many age-related changes in body composition and in conditions such as diabetes mellitus and cardiovascular disease. 3 These findings in experimental models have generally been supported by observational studies . . .

The relationship between socioeconomic status (SES), asthma and mortality is complex and multifaceted, and it is not established if educational level modifies the association between asthma and mortality. The aim was to study the association between asthma and mortality in Sweden and Norway and to what extent educational level modifies this association. Within the Nordic EpiLung Study, >56,000 individuals aged 30-69 years participated in population-based surveys on asthma and associated risk factors in Sweden and Norway during 2005-2007. Data on educational level and 10-year all-cause mortality were linked by national authorities. The fraction of mortality risk attributable to asthma was calculated, and Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for mortality related to asthma, stratified by educational level. In total, 5.5% of all deaths was attributed to asthma. When adjusted for potential confounders, the HR for mortality related to asthma was 1.71 (95% CI 1.52-1.93). Those with primary level of education had higher hazard of all-cause death related to asthma than those with tertiary level (HR 1.80, 95% CI 1.48-2.18, vs HR 1.39, 95% CI 0.99-1.95). Asthma was associated with an overall 71% increased all-cause mortality and 5.5% of deaths can be attributed to asthma. Educational levels modified the risk of mortality associated with asthma, with the highest risk among those with primary education.

Background: Zn-α2 glycoprotein (ZAG) is a relatively abundant glycoprotein that has potential as a biomarker for prostate cancer. We present a high-flow liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for measuring serum ZAG concentrations by proteolytic cleavage of the protein and quantification of a unique peptide. Methods: We selected the ZAG tryptic peptide 147EIPAWVPEDPAAQITK162 as the intact protein for quantification and used a stable isotope-labeled synthetic peptide with this sequence as an internal standard. Standards using recombinant ZAG in bovine serum albumin, 50 g/L, and a pilot series of patient sera were denatured, reduced, alkylated, and digested with trypsin. The concentration of ZAG was calculated from a dose–response curve of the ratio of the relative abundance of the ZAG tryptic peptide to internal standard. Results: The limit of detection for ZAG in serum was 0.08 mg/L, and the limit of quantification was 0.32 mg/L with a linear dynamic range of 0.32 to 10.2 mg/L. Replicate digests from pooled sera run during a period of 3 consecutive days showed intraassay imprecision (CV) of 5.0% to 6.3% and interassay imprecision of 4.4% to 5.9%. Mean (SD) ZAG was higher in 25 men with prostate cancer [7.59 (2.45) mg/L] than in 20 men with nonmalignant prostate disease [6.21 (1.65) mg/L, P = 0.037] and 6 healthy men [3.65 (0.71) mg/L, P = 0.0007]. Conclusions: This LC-MS/MS assay is reproducible and can be used to evaluate the clinical utility of ZAG as a cancer biomarker.

Cardiovascular disease (CVD) susceptibility differs between men and women and varies with ethnicity. This variability is not entirely explained by conventional CVD risk factors. We examined differences in circulating levels of 47 novel protein markers of CVD in 2561 men and women of African-American (AA) and non-Hispanic White (NHW) ethnicity, enrolled at geographically distinct sites. Participants (1,324 AAs, mean age 63.5 y, 71% women; 1,237 NHWs, mean age 58.9 y, 57% women) belonged to sibships ascertained on the basis of hypertension. Solid-phase immunoassays and immunoturbidometric, clot-based, chromogenic, and electrophoretic assays were used to measure the 47 protein markers in plasma or serum. Marker levels were log transformed and outliers were adjusted to within 4 SD. To identify markers independently associated with sex or ethnicity, we employed multivariable regression analyses that adjusted for conventional risk factors, prior history of CVD, medication use and lifestyle factors (physical activity, alcohol consumption and education). Generalized estimating equations were used to correct for intrafamilial correlations. After adjustment for the above covariates, female sex was associated with higher levels of 29 markers and lower levels of 6 markers. Female sex was independently associated with higher levels of several inflammatory markers as well as lipoproteins, adipokines, natriuretic peptides, vasoconstrictor peptides and markers of calcification and thrombosis. AA ethnicity was associated with higher levels of 19 markers and lower levels of 6 markers, including higher levels of several inflammatory makers, higher leptin and lower adiponectin levels, lower levels of vasodilator-natriuretic peptides, higher levels of vasoconstrictor-antidiuretic peptides and markers of calcification and thrombosis. Plasma levels of several novel protein markers of CVD differ significantly in the context of sex and ethnicity. These results have implications for individualized CVD risk assessment.

BACKGROUND The use of multiple biomarkers representing various etiologic pathways of atherosclerosis may improve the prediction of interindividual variation in the ankle-brachial index (ABI). To this end, we investigated associations of 47 candidate biomarkers with the ABI and presence of peripheral arterial disease (PAD) in African-Americans (AAs) and non-Hispanic whites (NHWs). METHODS Study participants included 1,291 AAs (71.1% women, mean age, 63.4±9.3 years) and 1,152 NHWs (57.5% women, mean age 58.5±10.1 years) belonging to hypertensive sibships. Peripheral arterial disease was defined as an ABI ≤ 0.90. Circulating levels of 47 candidate biomarkers were log-transformed before analysis because of skewed distribution. Multivariate regression analyses were used to identify biomarkers associated with ABI or PAD independently of age, sex, conventional risk factors, and medication use. RESULTS After adjustment for covariates, higher levels of nine biomarkers were associated with a lower ABI in AAs (all P ≤ 0.005); these biomarkers were C-reactive protein (CRP), interleukin-6, tumor necrosis factor receptor-II (TNF-R II), lipoprotein(a), N-terminal pro-brain natriuretic peptide (NT-proBNP), pro-atrial natriuretic peptide, C-terminal pro-arginine vasopressin, osteoprotegerin, and fibrinogen. Three biomarkers - myeloperoxidase, NT-proBNP, and D-dimer - were associated with ABI in NHWs (all P ≤ 0.01). C-reactive protein, interleukin-6, TNF-R II, lipoprotein(a), NT-proBNP, pro-atrial natriuretic peptide, D-dimer, and fibrinogen were associated with PAD (all P ≤ 0.005) in AAs after adjustment for covariates. None of the biomarkers were independently associated with PAD in NHWs. CONCLUSION A multimarker approach improved the prediction of interindividual variation in the ABI in AAs and NHWs, and improved prediction of the presence of PAD in AAs.