An enzyme-linked immunoassay for ferritin in human serum and rat plasma and the influence of the iron in serum ferritin on serum iron measurement, during acute hepatitis

To measure human serum ferritin and rat plasma ferritin a non-competitive enzyme-linked immunoassay has been developed using horseradish peroxidase as the enzyme. In this assay it proved necessary to use heated rat plasma to obtain reproducible ferritin values. The heating procedure caused a loss of 38% of the plasma ferritin. Rat plasma ferritin values have been corrected for this loss. The standard deviation, from duplicate normal human and rat samples is 10 ng ferritin/ml serum and 69 ng/ml plasma, respectively. (The mean ferritin concentrations are: in human sera, 82 ng/ml and in rat plasma 762 ng/ml.) Mean recovery of added liver ferritin in the human serum is 104% +/- 4% (+/-S.E.M') and in the rat plasma 101% +/- 3% (+/- S.E.M.). Normal ferritin concentrations varied in the human material between 30 ng/ml and 300 ng/ml serum, and in the rat plasma between 500 ng/ml and 1300 ng/ml. During increased body iron and acute hepatitis the ferritin concentrations, in patients as well as in rats, exceeded the upper limit of the normal values in most cases. During human hepatitis high serum ferritin levels combined with high serum iron levels were measured. The high serum iron concentrations could not be explained by the high serum ferritin concentrations, even if the iron content of the ferritin is supposed to be high.     

Hexokinase III, cyclin A and galectin-3 are overexpressed in malignant follicular thyroid nodules

Background Distinguishing malignant thyroid nodules in patients with follicular cytology by fine‐needle aspiration (FNA) remains problematic. The large majority of thyroid nodules (> 85%) are overtreated. Therefore, a clear need exists to develop more accurate initial diagnostic tests for follicular thyroid nodules. Galectin‐3 is the most recent promising marker to aid discrimination between benign and malignant thyroid lesions; however, this biomarker can be absent in follicular malignancies. Aims This study was undertaken to determine whether additional biomarkers can help to discriminate between benign and malignant thyroid nodules. Methods Surgical specimens of 36 patients with benign (n = 12) and malignant (n = 24) thyroid nodules showing follicular cytology were assessed by immunohistochemistry for the expression of galectin‐3 and novel biomarkers. Results Expression of hexokinase III (HK III) (P = 0·000) cyclin A (P = 0·002) and galectin‐3 (P = 0·003) differed significantly between benign and malignant thyroid nodules. HK III had a sensitivity of 79% [95% confidence interval (CI) 60–91] and a specificity of 100% (95% CI 76–100) in predicting malignancy. Galectin‐3 had a sensitivity of 79% (95% CI 56–91) and a specificity of 75% (95% CI 47–91) in predicting malignancy. Combining HK III, cyclin A and galectin‐3 in a parallel test increased the sensitivity to 96% (95% CI 80–99) while the specificity remained at a high level of 75% (95% CI 47–91). Leave‐one‐out cross‐validation demonstrated a stable predictive validity of a model based on HK III, cyclin A and galectin‐3. Conclusions In this study, we have demonstrated that in addition to galectin‐3, HK III and cyclin A profiles could be important biomarkers in predicting malignancy in follicular thyroid nodules. The use of these biomarkers may allow an accurate preoperative diagnosis of thyroid cancer, which can be cost saving and may avoid serious morbidity such as vocal cord paralysis. The value of the suggested biomarkers warrants further evaluation in a large prospective study on cytological samples of follicular thyroid nodules.     

Cognitive versus automatic mechanisms of mood induction differentially activate left and right amygdala

The amygdala plays a key role in emotional processing. The specific contribution of the amygdala during the experience of one's own emotion, however, remains controversial and requires clarification. There is a long-standing debate on hemispheric lateralization of emotional processes, yet few studies to date directly investigated differential activation patterns for the left and right amygdala. Limited evidence supports right amygdala involvement in automatic processes of emotion and left amygdala involvement in conscious and cognitively controlled emotion processing. The present study investigated differential contributions of the left and right amygdala to cognitive and automatic mechanisms of mood induction. Using functional magnetic resonance imaging (fMRI), we examined hemispheric amygdala responses during two mood induction paradigms: a purely visual method presenting face stimuli and an audiovisual method using faces and music. Amygdala responses in 30 subjects (16 females) showed differences in lateralization patterns depending on the processing mode. The left amygdala exhibited comparable activation levels for both methods. The right amygdala, in contrast, showed increased activity only for the audiovisual condition and this activity was increasing over time. The left amygdala showed augmented activity with higher intensity ratings of negative emotional valence. These results support a left-lateralized cognitive and intentional control of mood and a right-sided more automatic induction of emotion that relies less on explicit reflection processes. The modulation of the left amygdala responses by subjective experience may reflect individual differences in the cognitive effort used to induce the mood. Thus, the central role of the amygdala may not be restricted to the perception of emotion in others but also extend into processes involved in regulation of mood.     

Rationale and strategies for reevaluating the ACR20

OBJECTIVE: To assess whether the American College of Rheumatology response criteria ACR20 should be replaced by another definition of response with enhanced discriminant validity. METHODS: We worked with statisticians to define over 100 different ways of defining response, including dichotomous definitions (e.g., ACR20; ACR50; ACR70; low disease activity), ordinal definitions (EULAR response; ACR20, ACR50, ACR70), disease activity indexes [Disease Activity Score (DAS); Disease Activity Index, SDAI], continuous definitions (mean percentage improvement in all core set measures; nACR, ACRn), and hybrid definitions (ACR20, ACR50, ACR70 defined for a patient as 0, 1, 2, 3 scale with continuous measures between intervals) along with variations on each of these approaches (e.g., percentage vs absolute change in DAS; e.g., measures requiring vs not requiring joint count improvement). To test clinical validity, we administered a survey using patients from a trial who had various levels of improvement and asked rheumatologists whether and by how much these patients improved. For Sn-to-Chge, we are collecting data from large disease modifying antirheumatic drug multicenter trials in rheumatoid arthritis and ranking candidate definitions of response on their average p values in distinguishing active treatment from placebo or combination compared to single comparator. RESULTS: We surveyed 52 rheumatologists about which trial patients had improved and by how much. Trial data were obtained and tested for sensitivity to change. CONCLUSION: A rigorous data-driven consensus process was used to reassess the ACR20.     

Markers for type II collagen breakdown predict the effect of disease-modifying treatment on long-term radiographic progression in patients with rheumatoid arthritis

OBJECTIVE: To investigate in a randomized clinical trial setting with an aggressive combination-therapy arm and a mild-monotherapy arm, whether therapy-induced changes in urinary C-terminal crosslinking telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) predict 5-year radiographic progression in patients with rheumatoid arthritis (RA). METHODS: Patients had participated in the COBRA (Combinatietherapie Bij Reumato?de Artritis) trial comparing aggressive step-down combination therapy (the COBRA regimen, including temporary high-dose prednisolone, temporary low-dose methotrexate, and sulfasalazine [SSZ]) and mild monotherapy (SSZ). Urinary CTX-I and CTX-II levels were measured at baseline and 3, 6, 9, and 12 months after initiation of treatment. Radiographs were scored according to the modified Sharp/van der Heijde method (mean of 2 independent readers who were aware of the sequence). Individual long-term radiographic progression was estimated, using baseline radiographs and all radiographs obtained during the followup period, by simple linear regression analysis (curve fitting). RESULTS: Both COBRA therapy and SSZ monotherapy produced a significant decrease in urinary CTX-I and CTX-II levels at 3 months, and this decrease was amplified at 6 months. COBRA therapy suppressed CTX-II (change from baseline levels -36% and -43% at 3 and 6 months, respectively), but not CTX-I, significantly better than did SSZ (-17% and -21% at 3 and 6 months, respectively) at 3 and 6 months. The magnitude of the decrease in urinary CTX-II levels at 3 months significantly predicted long-term (5-year) radiographic progression (beta = 0.48 [95% confidence interval (95% CI) 0.13, 0.83]). This effect was independent of the change in disease activity and inflammation indices at 3 months. Patients whose CTX-II levels were normalized (<150 ng/mmoles of urinary creatinine) at 3 months had a significantly higher chance of radiographic stability (no progression over 5 years) than did patients whose CTX-II levels were increased both at baseline and at 3 months (odds ratio 4.5 [95% CI 1.5, 13]). CONCLUSION: The individual CTX-II response measured after 3 months of therapy in patients with active RA who had increased CTX-II levels at baseline independently predicts long-term radiographic progression. Urinary CTX-II levels may be used as early markers of treatment efficacy in patients with RA.     

Minimal clinically important improvement and patient acceptable symptom state for subjective outcome measures in rheumatic disorders

The concepts of minimal clinically important improvement (MCII) and patient acceptable symptomatic state (PASS) could help in interpreting results of trials involving patient-reported outcomes by translating the response at the group level (change in mean scores) into more clinically meaningful information by addressing the patient level as "therapeutic success (yes/no)." The aims of the special interest group (SIG) at OMERACT 8 were to discuss specific issues concerning the MCII and PASS concepts, especially the wording of the external anchor questions used to determine the MCII and PASS estimates, and to move toward a consensus for the cutoff values to use as the MCII and PASS in the different outcome criteria. The purpose of this SIG at OMERACT 8 was to inform participants of the MCII and PASS concepts and to agree on MCII and PASS values for pain, patient global assessment, and functional impairment.