A comprehensive review of upper reference limits reported for (high-)sensitivity cardiac troponin assays: the challenges that lie ahead

Abstract Cardiac troponins (cTn) are the preferred markers for the diagnosis of acute myocardial infarction (AMI). The guidelines recommend the use of the 99th percentile upper reference concentration of a healthy population as the diagnostic cut-off for AMI. However, a broad range of upper reference limits is still employed, complicating the diagnosis of AMI. This overview is meant to assist laboratory specialists to define an appropriate cut-off value for the diagnosis of AMI. Therefore, we provide an overview of the analytical performance and upper reference limits of seven (high-)sensitivity cTn assays: Roche high-sensitivity cTnT and ADVIA Centaur, Stratus CS, Dimension Vista, Vitros ECi, Access and Architect cTnI assays. It is shown that none of the reference populations completely met the guidelines, including those in package inserts. Forty percent of the studies collected less than the advised minimum of 300 subjects. Many studies (50%) did not report their inclusion criteria, while lower 99th percentile limits were observed when more stringent selection criteria were applied. Higher troponin cut-offs were found in men and elderly subjects, suggesting sex- and age-specific cut-offs would be considered. Therefore, there is still need for a large, rigorously screened reference population to more accurately establish cTn upper reference limits.     

Pericranial Tenderness in Females With Episodic Cervical Headache vs Asymptomatic Controls: A Cross-sectional Study

Objectives

The purpose of this study was to compare pericranial tenderness of females with episodic cervical headache vs matched asymptomatic controls.

Epidemiology of uveitis in juvenile idiopathic arthritis from a national paediatric rheumatologic and ophthalmologic database

BACKGROUND: Uveitis is a frequent and potentially vision-threatening manifestation of juvenile idiopathic arthritis (JIA). There are only a few population-based studies providing data on the frequency and severity of uveitis. METHODS: Documentation of patients with JIA was collected in a national database. An analysis of the paediatric rheumatologic and ophthalmologic data collected from all patients that were included in 2002 was performed. RESULTS: Uveitis was documented in 12 % of a total of 3271 JIA patients: extended oligoarthritis (25 %), persistent oligoarthritis (16 %), seronegative polyarthritis (4 %), seropositive polyarthritis (2 %), psoriatic arthritis (10 %), enthesitis-related arthritis (ERA) (7 %), systemic arthritis (1 %), other arthritis forms (11 %). Ophthalmologic data were available from 115 uveitis patients (28 %). Mean age at onset of uveitis was 5.2 (SD 3.2) years. JIA patients with uveitis were significantly younger at onset of arthritis (3.8 vs. 7.0 years), and were more often girls (74 vs. 63 %) or ANA-positive (86 vs. 42 %) than the patients without uveitis. Uveitis complications were present in 45 % at initial presentation of uveitis. After a mean duration of 5.6 years, complications were noted in 56 %, and included band keratopathy (29 %), posterior synechiae (27 %), cataract (26 %), glaucoma (8 %), and macula oedema (6 %). Final visual acuity was less than 20/50 in 31 % and less than 20/200 in 12 % of eyes. In patients with uveitis, immunosuppressive or immunomodulatory drugs were used significantly more often than in patients without uveitis (75 % vs. 43 %). CONCLUSIONS: The nationwide data documents the spectrum of uveitis in patients with JIA, the complications and the therapy for uveitis. The high rate of uveitis complications at the time of diagnosis points out the need for early ophthalmologic screening and therapy, and for a close collaboration between ophthalmologist and paediatric rheumatologist.     

PIWI Proteins Play an Antiviral Role in Lepidopteran Cell Lines

Insect antiviral immunity primarily relies on RNAi mechanisms. While a key role of small interfering (si)RNAs and AGO proteins has been well established in this regard, the situation for PIWI proteins and PIWI-interacting (pi)RNAs is not as clear. In the present study, we investigate whether PIWI proteins and viral piRNAs are involved in the immunity against single-stranded RNA viruses in lepidopteran cells, where two PIWIs are identified (Siwi and Ago3). Via loss- and gain-of-function studies in Bombyx mori BmN4 cells and in Trichoplusia ni High Five cells, we demonstrated an antiviral role of Siwi and Ago3. However, small RNA analysis suggests that viral piRNAs can be absent in these lepidopteran cells. Together with the current literature, our results support a functional diversification of PIWI proteins in insects.     

Generation of angiostatin-like fragments from plasminogen by prostate-specific antigen

Angiostatin, a potent inhibitor of angiogenesis, tumour growth and metastasis, is a biologically active fragment of plasminogen, containing the kringle domains 1-4. It is generated from plasminogen by limited proteolysis. We show that prostate-specific antigen (PSA), a serine proteinase secreted by human prostate and human prostate cancer cells, is able to convert Lys-plasminogen to biologically active angiostatin-like fragments, containing kringles 1-4, by limited proteolysis of peptide bond Glu439-Ala440 in vitro. In an in vitro morphogenesis assay, the purified angiostatin-like fragments inhibited proliferation and tubular formation of human umbilical vein endothelial cells with the same efficacy as angiostatin. This finding might help to understand growth characteristics of prostate cancer, which usually has low microvessel density and slow proliferation.     

Chronic uveitis in children with and without juvenile idiopathic arthritis: differences in patient characteristics and clinical course

OBJECTIVE: Anterior uveitis (AU) in childhood may be the first manifestation of juvenile idiopathic arthritis (JIA). We identified factors that may help to differentiate JIA-associated AU from the more common idiopathic AU (IAU) before the onset of arthritis. METHODS: Children with IAU and with JIA-associated AU were analyzed for their demographics, age at onset of uveitis, uveitis course and complications, ocular surgery, antiinflammatory medication, and best corrected visual acuity (BCVA). RESULTS: AU was associated with JIA in 88 cases, and was idiopathic in another 49. In the JIA group, 60% of patients were female compared to 47% in the IAU group (p = 0.154). Antinuclear antibody (ANA) was significantly more frequent in the JIA group (88% vs 33%; p < 0.001, OR 14.4, 95% CI 5.8-35.6). Insidious uveitis onset occurred more often in JIA than in IAU patients (67% vs 31%; p < 0.001, OR 4.6, 95% CI 2.2-9.8). Persistent uveitis was found in 82% of JIA patients, and in 57% of IAU patients (p = 0.003, OR 3.4, 95% CI 1.5-7.4). Median age of AU onset was 5 years in JIA and 9 years in IAU (p < 0.001). Uveitis complications at first presentation at our institutions were more frequent in JIA than in IAU patients (79% vs 61%; p = 0.027, OR 2.5, 95% CI 1.1-5.3). During followup, 69 surgical procedures (51% of patients, 1.31 per patient) were performed in the JIA group, and 18 in IAU patients (0.57 per patient) (p = 0.008). BCVA was better in the IAU patients at first presentation (p = 0.001). CONCLUSION: The IAU and JIA-associated AU in childhood differ in their clinical course. ANA positivity, presence of uveitis complications at first manifestation, insidious onset, duration over 3 months, BCVA of 20/50 or less, and an age of 3 years or younger might help to detect AU associated with JIA. JIA uveitis manifests earlier, has more complications, and more often requires systemic immunosuppression and surgical intervention.     

Tubal epithelial lesions in salpingo-oophorectomy specimens of BRCA-mutation carriers and controls

Objective

A precursor lesion for ovarian carcinoma, tubal intraepithelial carcinoma (TIC), has been identified in BRCA-mutation carriers undergoing prophylactic bilateral salpingo-oophorectomy (pBSO). Other lesions were also identified in fallopian tubes, but different terminology, interpretation, and lack of knowledge of normal epithelium, have hampered to unravel their possible role in carcinogenesis. The aim of this study is to classify tubal epithelial lesions in BRCA-mutation carriers and controls to enable comparison of prevalence, area of localization, and possible malignant potential.

Methods

Two hundred twenty-six BRCA1/2-mutation carriers were included; ovaries and fallopian tubes, embedded completely, were reviewed. Controls included 105 women who underwent BSO for non-malignant reasons. Tubal epithelial lesions included the following categories: hyperplasia, minor epithelial atypia, TIC, and invasive carcinoma.

Results

Tubal neoplasia was identified in 7.1% (invasive carcinoma, 0.9%; TIC, 6.2%) of BRCA-mutation carriers compared to none in controls (p = 0.004, Fisher's exact test). Hyperplasia and minor epithelial atypia were identified in 41.6% BRCA-mutation carriers and compared to 58.1% in controls (p = 0.005, Pearson's chi square). Invasive carcinoma and TIC showed preference for the fimbrial ends (p = 0.027, Pearson's chi square), while hyperplasia and minor epithelial atypia displayed more variation in localization.

Conclusions

Invasive tubal carcinoma and TIC were limited to BRCA-mutation carriers, whereas hyperplasia and minor epithelial atypia were commonly found in both BRCA-mutation carriers and controls. It is suggested that hyperplasia and minor atypia represent variations of normal tubal epithelium instead of premalignant lesions. Furthermore, total salpingectomy is strongly recommended as most but not all TIC occurred in the fimbriae.     

Pars plana vitrectomy with intravitreal triamcinolone: effect on uveitic cystoid macular oedema and treatment limitations

OBJECTIVE: To investigate the effect of pars plana vitrectomy (PPV) in combination with intraoperative intravitreal triamcinolone acetonide injection on the course of cystoid macular oedema (CME) in patients with uveitis. METHODS: Patients with uveitis with CME (n = 19) not responding to systemic corticosteroids and/or immunosuppression combined with acetazolamide were retrospectively studied after PPV with additional intravitreal injection of 4 mg triamcinolone acetonide. Patients had chronic anterior uveitis (n = 4), intermediate uveitis (n = 9), posterior uveitis (n = 3) or panuveitis (n = 3). Visual acuity tests, tonometry, fluorescein angiographic appearance and postoperative complications were analysed. Mean follow-up was 14 months (SD 4.6). RESULTS: CME improved in 58% of the patients within the first 6 weeks postoperatively. After 12 months, CME was further improved in 44% and worsened in another 12%. Improvement of visual acuity was noted in 42% after 3 months and in 28% after 12 months. Cataract progressed in 85% of the phacic patients postoperatively. Increased intraocular pressure was detected in 27% at 2 weeks and in 11% at 12 months after surgery. CONCLUSION: Uveitic CME that is unresponsive to systemic immunosuppression and acetazolamide may improve after PPV with additional intravitreal triamcinolone application. The effect seems to be transient in many of the patients. Frequent complications were cataract formation and ocular hypertension.