Citations

Abstract The advent of improved biomarkers promises to enhance the clinical care for patients with rheumatoid arthritis (RA) and other immune-mediated disorders. We have developed an innovative approach to broadly assess the cytokine responsiveness of human PBMCs using a multistimulant panel and multiplexed immunoassays. The objective of this study was to demonstrate this concept by determining whether cytokine profiles could discriminate RA patients according to disease stage (early versus late) or severity. A 10-cytokine profile, consisting of IL-12, CCL4, TNF-α, IL-4, and IL-10 release in response to stimulation with anti-CD3/anti-CD28, CXCL8 and IL-6 in response to CMV and EBV lysate, and IL-17A, GM-CSF, and CCL2 in response to human heat shock protein 60, easily discriminated the early RA group from controls. These data were used to create an immune response score, which performed well in distinguishing the early RA patients from controls and also correlated with several markers of disease severity among the patients with late RA. In contrast, the same 10-cytokine profile assessed in serum was far less effective in discriminating the groups. Thus, our approach lays the foundation for the development of immunologic “signatures” that could be useful in predicting disease course and monitoring the outcomes of therapy among patients with immune-mediated diseases.

Abstract Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for hetero geneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies. Cancer Epidemiol Biomarkers Prev; 19(2); 600–4

Abstract We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat containing, nuclear envelope 1 (SYNE1), which is involved in nuclear organization and structural integrity, function of the Golgi apparatus, and cytokinesis. An isoform encoded by SYNE1 has been reported to be downregulated in ovarian and other cancers. rs2295190 was genotyped in an additional 12 studies through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190 was not associated with risk. These data provide suggestive evidence that the rs2295190 T allele, or another allele in linkage disequilibrium with it, may be associated with increased risk of invasive ovarian cancer. Cancer Epidemiol Biomarkers Prev; 19(1); 244–50

Abstract Eosinophil granule proteins are deposited in cutaneous lesions in many human diseases, but how these proteins contribute to pathophysiology is obscure. We injected eosinophil cationic protein (ECP or RNase 3), eosinophil-derived neurotoxin (EDN or RNase 2), eosinophil peroxidase (EPO), and major basic protein-1 (MBP1) intradermally into guinea pig and rabbit skin. ECP and EDN each induced distinct skin lesions at ≥2.5 μM that began at 2 days, peaking at ∼7 days and persisting up to 6 wk. These lesions were ulcerated (ECP) or crusted (EDN) with marked cellular infiltration. EPO and MBP1 (10 μM) each produced perceptible induration and erythema with moderate cellular infiltration resolving within 2 wk. ECP and EDN localized to dermal cells within 2 days, whereas EPO and MBP1 remained extracellular. Overall, cellular localization and RNase activity of ECP and EDN were critical for lesion formation; differential glycosylation, net cationic charge, or RNase activity alone did not account for lesion formation. Ulcerated lesions from patients with the hypereosinophilic syndrome showed ECP and EDN deposition comparable to that in guinea pig skin. In conclusion, ECP and EDN disrupt skin integrity and cause inflammation. Their presence in ulcerative skin lesions may explain certain findings in human eosinophil-associated diseases.

Objective: The primary aim of this prospective study was to examine the role of several aspects of spirituality in maintaining abstinence from alcohol for one year in persons treated for alcohol dependence. The roles of alcohol abstinence self-efficacy and Alcoholics Anonymous affiliation were also examined. Method: Seventy-four adults with alcohol dependence who had completed a three-week outpatient addiction program participated in this study. Instruments used included the Spiritual Well-Being Scale, Duke Religion Index, Brief Religious Coping Scale, Alcohol Abstinence Self-Efficacy Scale, and Alcoholics Anonymous Affiliation Scale. Abstinence data was collected from participants and collaterals three, six, and twelve months after treatment discharge. Demographics, discharge measures, and the change in scores from admission to discharge were compared between those with and without 12-month alcohol abstinence using logistic regression or Fisher's exact tests. Results: Twenty-eight participants were categorized as continuously abstinent for one year. The strongest associations between 12 month abstinence and the variables of interest were discharge scores of abstinence self-efficacy and existential well-being, and increases during treatment in scores of private spiritual practices. Increased age demonstrated a significant association with positive outcome. Conclusion: The associations of private spiritual practices, existential well-being, and abstinence self-efficacy with one year of continuous abstinence following treatment discharge suggest the importance of addressing issues related to these variables during alcoholism treatment. More research is needed to understand the role of these variables in promoting and maintaining abstinence and to determine whether or not a related intervention would improve abstinence rates.

Abstract The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r2 = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07–1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01–1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region. [Cancer Res 2009;69(6):2349–57]

Abstract We examined whether monoclonal gammopathy of undetermined significance (MGUS) is increased in first-degree relatives of multiple myeloma (MM) or MGUS patients. Probands were recruited from a population-based prevalence study (MGUS) and the Mayo Clinic (MM). Serum samples were collected from first-degree relatives older than 40 years and subjected to electrophoresis and immunofixation. The prevalence of MGUS in relatives was compared with population-based rates. Nine-hundred eleven relatives of 232 MM and 97 MGUS probands were studied. By electrophoresis, MGUS was detected in 55 (6%) relatives, and immunofixation identified 28 additional relatives for an age- and sex-adjusted prevalence of 8.1% (95% CI, 6.3 to 9.8). The prevalence of MGUS in relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, 21.0% for ages 40-49, 50-59, 60-69, 70-79, ≥ 80 years, respectively; P < .001). Using similar MGUS detection methods, there was a higher risk of MGUS in relatives (age-adjusted risk ratio [RR], 2.6; 95% CI, 1.9 to 3.4) compared with the reference population. The increased risk was seen among relatives of MM (RR, 2.0; 95% CI, 1.4 to 2.8) and MGUS probands (RR, 3.3; 95% CI, 2.1 to 4.8). The increased risk of MGUS in first-degree relatives of MGUS or MM patients implies shared environment and/or genetics.

Objectives:This guideline provides evidence‐based recommendations on managing benign paroxysmal positional vertigo (BPPV), which is the most common vestibular disorder in adults, with a lifetime prevalence of 2.4 percent. The guideline targets patients aged 18 years or older with a potential diagnosis of BPPV, evaluated in any setting in which an adult with BPPV would be identified, monitored, or managed. This guideline is intended for all clinicians who are likely to diagnose and manage adults with BPPV.Purpose:The primary purposes of this guideline are to improve quality of care and outcomes for BPPV by improving the accurate and efficient diagnosis of BPPV, reducing the inappropriate use of vestibular suppressant medications, decreasing the inappropriate use of ancillary tests such as radiographic imaging and vestibular testing, and to promote the use of effective repositioning maneuvers for treatment. In creating this guideline, the American Academy of Otolaryngology—Head and Neck Surgery Foundation selected a panel representing the fields of audiology, chiropractic medicine, emergency medicine, family medicine, geriatric medicine, internal medicine, neurology, nursing, otolaryngology–head and neck surgery, physical therapy, and physical medicine and rehabilitation.ResultsThe panel made strong recommendations that 1) clinicians should diagnose posterior semicircular canal BPPV when vertigo associated with nystagmus is provoked by the Dix‐Hallpike maneuver.The panel made recommendations against 1) radiographic imaging, vestibular testing, or both in patients diagnosed with BPPV, unless the diagnosis is uncertain or there are additional symptoms or signs unrelated to BPPV that warrant testing; and 2) routinely treating BPPV with vestibular suppressant medications such as antihistamines or benzodiazepines.The panel made recommendations that 1) if the patient has a history compatible with BPPV and the Dix‐Hallpike test is negative, clinicians should perform a supine roll test to assess for lateral semicircular canal BPPV; 2) clinicians should differentiate BPPV from other causes of imbalance, dizziness, and vertigo; 3) clinicians should question patients with BPPV for factors that modify management including impaired mobility or balance, CNS disorders, lack of home support, and increased risk for falling; 4) clinicians should treat patients with posterior canal BPPV with a particle repositioning maneuver (PRM); 5) clinicians should reassess patients within 1 month after an initial period of observation or treatment to confirm symptom resolution; 6) clinicians should evaluate patients with BPPV who are initial treatment failures for persistent BPPV or underlying peripheral vestibular or CNS disorders; and 7) clinicians should counsel patients regarding the impact of BPPV on their safety, the potential for disease recurrence, and the importance of follow‐up.The panel offered as options that 1) clinicians may offer vestibular rehabilitation, either self‐administered or with a clinician, for the initial treatment of BPPV and 2) clinicians may offer observation as initial management for patients with BPPV and with assurance of follow‐up.The panel made no recommendation concerning audiometric testing in patients diagnosed with BPPV.Disclaimer:This clinical practice guideline is not intended as a sole source of guidance in managing benign paroxysmal positional vertigo. Rather, it is designed to assist clinicians by providing an evidence‐based framework for decision‐making strategies. The guideline is not intended to replace clinical judgement or establish a protocol for all individuals with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem. ® 2008 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.