The diagnostic value of 14-3-3η protein levels in patients with rheumatoid arthritis.

14-3-3η may represent a useful diagnostic biomarker for rheumatoid arthritis (RA). We assessed the prevalence and serum levels of 14-3-3η in patients with RA and in patients with other rheumatic diseases. Serum levels of 14-3-3η were measured in 96 patients with RA, in 101 patients with other rheumatic diseases, and in 66 healthy subjects. All of the sera samples were evaluated by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). Median (IQR) 14-3-3η levels were significantly higher in the early RA group [0.25 ng/ml (0.075-3.11)] and in patients with established RA [0.15 ng/ml (0.08-1.26)] than in healthy subjects [0 ng/ml (0-0)] and disease controls: SLE [0.01 ng/ml (0-0.055)], AS [0.05 ng/ml (0-0.255)], and PsA [0.01 ng/ml (0-0.065)]. The prevalence of 14-3-3η positivity in patients with early RA was 58%, significantly higher than that in disease controls and healthy subjects (p < 0.001). In patients with established RA, this prevalence was 43%, and it was significantly higher than that in patients with other rheumatic diseases and healthy subjects (p < 0.05), excluding the AS group (p = 0.054). In the early RA cohort, the positivity for 14-3-3η, RF, and anti-CCP was 58%, 67%, and 71%, respectively. Eighty-two percent of the patients in this cohort were positive for at least one of these biomarkers. The concentration of 14-3-3η protein may be used to distinguish between patients with early RA and patients with other rheumatic diseases.

Association between specimen length and diagnostic yield of temporal artery biopsy.

OBJECTIVES: Temporal artery biopsy (TAB) is performed in patients suspected of giant cell arteritis (GCA). Inadequate TAB specimen length is considered a possible explanation for a negative biopsy in patients with GCA. We investigated the association between specimen length and diagnostic yield of TAB. METHOD: We conducted a retrospective analysis of 240 patients who underwent TAB in a single hospital between 2000 and 2015. Patients were diagnosed with GCA based on positive TAB or, when TAB was negative, on clinical grounds that fulfilled the American College of Rheumatology (ACR) 1990 criteria. Baseline clinical and laboratory features and TAB length were obtained from medical records. Among patients diagnosed with GCA, the rate of TAB positivity was calculated according to biopsy length (< 5, 5-9, 10-14, and ≥ 20 mm). RESULTS: Out of 240 patients, 88 were diagnosed with GCA: 62 had a positive TAB and 26 were diagnosed based on clinical grounds despite a negative TAB. Among those who were diagnosed with GCA, the length of the TAB specimen was similar in those with a positive and a negative TAB (1.13 ± 1.68 mm vs. 1.15 ± 0.61 mm, respectively, p = 0.928). The TAB positivity rate was similar among all ranges of biopsy length [< 5 mm: 7/10 (70%); 5-9 mm: 22/31 (71%); 10-14 mm: 11/16 (69%); 15-19 mm: 11/16 (69%); ≥ 20 mm: 11/15 (73%, p = ns] and was similar to the overall biopsy positivity rate. CONCLUSIONS: Specimen length is not associated with diagnostic yield of TAB.

Is temporal artery biopsy essential in all cases of suspected giant cell arteritis?

OBJECTIVES: Temporal artery biopsy (TAB) is performed in cases of suspected giant cell arteritis (GCA), and is the gold-standard for diagnosis of the disease. Current American College of Rheumatology (ACR) classification criteria may aid in the diagnosis of GCA. We aimed to assess whether TAB is essential in all cases of suspected GCA, or whether ACR criteria can replace the need for this procedure in some cases. METHODS: Retrospective analysis of 216 patients who underwent TAB in a single hospital between 2000 and 2013. Pre-TAB and post-TAB ACR criteria were calculated. Sensitivity and specificity of ACR criteria for the diagnosis of GCA were assessed. RESULTS: Overall, 55 patients had histological evidence of GCA.Out of 161 patients with negative TAB findings, 34 were diagnosed with GCA, and 127 were not diagnosed with GCA. Sensitivity of TAB for the diagnosis of GCA was 61.7%. Sensitivity and specificity of ACR criteria for diagnosis of GCA before performing TAB were 68.5% and 58%, respectively. Sensitivity and specificity of ACR criteria after performing TAB biopsy were 89.8% and 64.5%, respectively. CONCLUSIONS: Temporal artery biopsy should be performed in the majority of patients with suspected GCA, and may be obviated only in patients with a pre-TAB ACR score of ≤ 1. In all other cases, when GCA is suspected, ACR criteria should not be a substitute to TAB, as they are not highly specific.

Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA.

Human altruism is a widespread phenomenon that puzzled evolutionary biologists since Darwin. Economic games illustrate human altruism by showing that behavior deviates from economic predictions of profit maximization. A game that most plainly shows this altruistic tendency is the Dictator Game. We hypothesized that human altruistic behavior is to some extent hardwired and that a likely candidate that may contribute to individual differences in altruistic behavior is the arginine vasopressin 1a (AVPR1a) receptor that in some mammals such as the vole has a profound impact on affiliative behaviors. In the current investigation, 203 male and female university students played an online version of the Dictator Game, for real money payoffs. All subjects and their parents were genotyped for AVPR1a RS1 and RS3 promoter-region repeat polymorphisms. Parents did not participate in online game playing. As variation in the length of a repetitive element in the vole AVPR1a promoter region is associated with differences in social behavior, we examined the relationship between RS1 and RS3 repeat length (base pairs) and allocation sums. Participants with short versions (308-325 bp) of the AVPR1a RS3 repeat allocated significantly (likelihood ratio = 14.75, P = 0.001, df = 2) fewer shekels to the 'other' than participants with long versions (327-343 bp). We also implemented a family-based association test, UNPHASED, to confirm and validate the correlation between the AVPR1a RS3 repeat and monetary allocations in the dictator game. Dictator game allocations were significantly associated with the RS3 repeat (global P value: likelihood ratio chi(2) = 11.73, df = 4, P = 0.019). The association between the AVPR1a RS3 repeat and altruism was also confirmed using two self-report scales (the Bardi-Schwartz Universalism and Benevolence Value-expressive Behavior scales). RS3 long alleles were associated with higher scores on both measures. Finally, long AVPR1a RS3 repeats were associated with higher AVPR1a human post-mortem hippocampal messenger RNA levels than short RS3 repeats (one-way analysis of variance (ANOVA): F = 15.04, P = 0.001, df = 14) suggesting a functional molecular genetic basis for the observation that participants with the long RS3 repeats allocate more money than participants with the short repeats. This is the first investigation showing that a common human polymorphism, with antecedents in lower mammals, contributes to decision making in an economic game. The finding that the same gene contributing to social bonding in lower animals also appears to operate similarly in human behavior suggests a common evolutionary mechanism.

Concurrent substance use and outcome in combined behavioral and naltrexone therapy for opiate dependence.

UNLABELLED: The effect of concurrent nonopiate drug use on outcome of treatment for opiate dependence. METHOD: Forty-seven opiate-dependent patients received a 6-month course of outpatient treatment with naltrexone and cognitive-behavioral therapy (behavioral naltrexone therapy, BNT) at a university-based research clinic. Opiate-negative urines and naltrexone ingestion were rewarded with monetary vouchers. Abstinence from other drugs was encouraged verbally, but no contingencies were placed on nonopiate drug use. The proportions of all urines (collected twice weekly) positive for cocaine, cannabis, and benzodiazepines over the course of treatment were evaluated as predictors of outcome of opiate dependence treatment, as measured by proportion of opiate-positive urines, days retained in treatment, and proportion of naltrexone doses taken, using Pearson product moment correlations and one-way analysis of variance (ANOVA). RESULTS: The majority of patients (78%) used a nonopiate drug at least once during the trial. There were no significant correlations between concurrent drug use measures and opiate dependence treatment outcomes, indicating no simple linear relationship between these measures. However, when concurrent drug use was trichotomized into abstinent, intermittent, and heavy use groups, groups with intermittent use had superior outcome compared to both abstinent and heavy use groups in several contrasts. CONCLUSIONS: Intermittent use of nonopiate drugs is common during outpatient treatment for opiate dependence and may be a favorable prognostic indicator. This may support a "harm reduction" approach as opposed to a strict abstinence-oriented approach. Further research is needed to identify the optimal therapeutic stance toward other drug use during treatment for opiate dependence.

Inverse relation between levels of p27(Kip1) and of its ubiquitin ligase subunit Skp2 in colorectal carcinomas.

BACKGROUND: Previous studies have shown that low levels of p27(Kip1), an inhibitor of G1 cyclin-dependent kinases, are associated with high aggressiveness and poor prognosis in a variety of cancers. Decreased levels of p27 are caused, at least in part, by acceleration of the rate of its ubiquitin-mediated degradation. In cultured cells and cell-free biochemical systems, it has been shown that p27 is targeted for degradation by a ubiquitin ligase complex that contains Skp2 (S-phase kinase-associated protein 2) as the specific substrate-recognizing and rate-limiting subunit. This investigation was undertaken to examine the possible relation between levels of p27 and of its specific ubiquitin ligase subunit Skp2 in human cancers. METHODS: Quick-frozen colorectal tumor samples from 20 patients were homogenized at 0 degrees C in buffer containing a mixture of protease inhibitors. Samples were separated by electrophoresis on sodium dodecyl sulfate-polyacrylamide gels, transferred to nitrocellulose, and probed with highly specific monoclonal antibodies directed against Skp2 and p27. The expression of Skp2 also was examined by immunohistochemistry using formalin fixed, paraffin embedded tissue sections from the same cases. RESULTS: A strongly significant inverse correlation was found between levels of Skp2 and p27 (r = -0.812; P < 0.0001). Thus, decreased levels of p27 were associated with strongly increased levels of Skp2, whereas high levels of p27 coincided with low levels of Skp2. Immunohistochemical examination of Skp2 expression agreed with immunoblot analysis in 89% of cases. CONCLUSIONS: The results are compatible with the notion that increased expression of Skp2 may have a causative role in decreasing the levels of p27 in aggressive colorectal carcinomas.

The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27.

The cyclin-dependent kinase (CDK) inhibitor p27 is degraded in late G1 phase by the ubiquitin pathway, allowing CDK activity to drive cells into S phase. Ubiquitinylation of p27 requires its phosphorylation at Thr 187 (refs 3, 4) and subsequent recognition by S-phase kinase associated protein 2 (Skp2; refs 5-8), a member of the F-box family of proteins that associates with Skp1, Cul-1 and ROC1/Rbx1 to form an SCF ubiquitin ligase complex. However, in vitro ligation of p27 to ubiquitin could not be reconstituted by known purified components of the SCFSkp2 complex. Here we show that the missing factor is CDK subunit 1 (Cks1), which belongs to the highly conserved Suc1/Cks family of proteins that bind to some CDKs and phosphorylated proteins and are essential for cell-cycle progression. Human Cks1, but not other members of the family, reconstitutes ubiquitin ligation of p27 in a completely purified system, binds to Skp2 and greatly increases binding of T187-phosphorylated p27 to Skp2. Our results represent the first evidence that an SCF complex requires an accessory protein for activity as well as for binding to its phosphorylated substrate.