Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves' ophthalmopathy.

BACKGROUND: Intravenous methylprednisolone pulses (IVMP) are more efficacious and better tolerated than oral prednisone in Graves' ophthalmopathy (GO) patients. However, acute and severe liver damage has been reported in sporadic cases during IVMP, resulting in fatal acute liver failure in four patients so far. The mechanism causing the liver damage is incompletely understood. DESIGN: We performed a prospective observational study in 13 patients with dysthyroid optic neuropathy (group A) and in 14 patients with moderately severe GO (group B) who were treated with high-dose (group A) or low-dose (group B) IVMP; cumulative steroid doses were 8.45 g in group A and 4.5 g in group B, and follow-up time was 24 weeks. MAIN OUTCOME: Slight increases in serum aminotransferases (in alanine aminotransferase [ALAT] more than in aspartate aminotransferase [ASAT]) were observed, in seven patients exceeding the upper normal limit of 40 U/L. These changes were more prominent in group A than in group B as was also evident from a decrease in ASAT/ALAT ratio in group A but not in group B. Changes in serum aminotransferases occurred especially in the first 6 weeks of IVMP, becoming smaller thereafter with the decrease in steroid dosage. Pretreatment liver steatosis or diabetes were not related to liver damage, but preexistent viral hepatitis was. CONCLUSION: IVMP in GO patients causes dose-dependent liver damage by a direct toxic effect of glucocorticoids on hepatocytes. Nevertheless, IVMP seems to be pretty safe if cumulative doses exceeding 8 g are avoided and liver function is checked before and at regular intervals during pulse therapy.     

Matrix production and remodeling capacity of cardiomyocyte progenitor cells during in vitro differentiation

Cell-based therapy has emerged as a treatment modality for myocardial repair. Especially cardiac resident stem cells are considered a potential cell source since they are able to differentiate into cardiomyocytes and have improved heart function after injury in a preclinical model for myocardial infarction. To avoid or repair myocardial damage it is important not only to replace the lost cardiomyocytes, but also to remodel and replace the scar tissue by "healthy" extracellular matrix (ECM). Interestingly, the role of cardiac stem cells in this facet of cardiac repair is largely unknown. Therefore, we investigated the expression and production of ECM proteins, matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in human cardiomyocyte progenitor cells (CMPCs) undergoing differentiation towards the cardiomyogenic lineage. Our data suggest that CMPCs have the capacity to synthesize and modulate their own matrix environment, especially during differentiation towards the cardiomyogenic lineage. While undifferentiated CMPCs expressed collagen I, III, IV and fibronectin, but no elastin, during the process of differentiation the expression of collagen I, III, IV and fibronectin increased and interestingly also elastin expression was induced. Furthermore, undifferentiated CMPCs express MMP-1 -2 and -9 and upon differentiation the expression of MMP-1 decreased, while the expression of MMP-2 and MMP-9, although the latter only in the early stage of differentiation, increased. Additionally, the expression of TIMP-1, -2 and -4 was induced during differentiation. This study provides new insights into the matrix production and remodeling capacity of human CMPCs, with potential beneficial effects for the treatment of cardiac injury.     

Clinical utility of therapeutic drug monitoring in biological disease modifying anti-rheumatic drug treatment of rheumatic disorders: a systematic narrative review

Introduction: Biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs) have improved the treatment outcomes of inflammatory rheumatic diseases including Rheumatoid Arthritis and spondyloarthropathies. Inter-individual variation exists in (maintenance of) response to bDMARDs. Therapeutic Drug Monitoring (TDM) of bDMARDs could potentially help in optimizing treatment for the individual patient.

Areas covered: Evidence of clinical utility of TDM in bDMARD treatment is reviewed. Different clinical scenarios will be discussed, including: prediction of response after start of treatment, prediction of response to a next bDMARD in case of treatment failure of the first, prediction of successful dose reduction or discontinuation in case of low disease activity, prediction of response to dose-escalation in case of active disease and prediction of response to bDMARD in case of flare in disease activity.

Expert opinion: The limited available evidence does often not report important outcomes for diagnostic studies, such as sensitivity and specificity. In most clinical relevant scenarios, predictive value of serum (anti-) drug levels is absent, therefore the use of TDM of bDMARDs cannot be advocated. Well-designed prospective studies should be done to further investigate the promising scenarios to determine the place of TDM in clinical practice.     

Updating the Evidence on Functional Capacity Evaluation Methods: A Systematic Review

Objectives To synthesize the evidence on the psychometrics functional capacity evaluation (FCE) methods. Methods A systematic literature search in nine databases. The resulting articles were screened based on predefined in- and exclusion criteria. Two reviewers independently performed this screening. Included studies were appraised based on their methodological quality. Results The search resulted in 20 eligible studies about nine different FCE methods. The Baltimore Therapeutic Equipment work simulator showed a moderate predictive validity. The Ergo-Kit (EK) showed moderate variability and high inter- and intra-rater reliability. Low discriminative abilities and high convergent validity were found for the EK. Concurrent validity of the EK and the ERGOS Work Simulator was low to moderate. Moderate to high test–retest, inter- and intra-reliability was found in the Isernhagen Work-Systems (IWS) FCE. The predictive validity of the IWS was low. The physical work performance evaluation (PWPE) showed moderate test–retest reliability and moderate to high inter-rater reliability. Low internal and external responsiveness were found for the PWPE, predictive validity was high. The predictive validity of the short-form FCE was also high but need to be further examined on several psychometric properties. Low discriminative and convergent validity were found for the work disability functional assessment battery. The WorkHab showed moderate to high test–retest, inter- and intra-rater reliability. Conclusion Well-known FCE methods have been rigorously studied, but some of the research indicates weaknesses in their reliability and validity. Future research should address how these weaknesses can be overcome.     

Physical health status of older adults with severe mental illness: The PHiSMI‐E cohort study

The objective was to use various somatic parameters as basis for investigating the physical health of older adults with severe mental illnesses (SMI). A cross‐sectional study design is performed by using baseline data from the Physical Health in SMI‐elderly (PHiSMI‐E) study. Data were collected using the Nursing Monitoring of Somatic Status and Lifestyle – Mental Health instrument in adults aged over 60 with SMI in a large Dutch mental health institute. Ninety‐nine elderly SMI patients were included. Somatic comorbidity (84.8%), use of somatic medication (77.7%) and polypharmacy (67.7%) were prevalent. Extrapyramidal symptoms were experienced by 51% of patients, mainly in the subgroup with psychotic disorders (75.6%). Unhealthy diet was reported in 16.2%, obesity in 27.3%, and physical inactivity in 57.6%. Fatigue (67.7%) and dry mouth (66.6%) were the commonest reported physical symptoms. Mean VAS score (scale 0–10) indicating participants’ self‐perceived physical health was 6.7 (SD ± 1.6). After division of the total patient group into tertiles based on the VAS scores, the lowest tertile was characterized by less physical activity, unhealthier diet, more use of medication, more fatigue, somnolence, and inner agitation. In conclusion, impaired physical health status was common in these older patients with SMI. Although they had more psychiatric and somatic comorbidity than adult SMI patients described in the literature, they had a healthier lifestyle. To reduce morbidity and premature mortality in these frail patients, it is essential that healthcare providers are aware of the high prevalence of somatic comorbidity and symptoms, and of their interactions with the psychiatric disorders. This study improves our understanding of differences in vulnerability factors of older patients with SMI. The (early) detection of somatic comorbidities may improve long‐term health outcomes of these patients.     

Assessment of coronary artery calcium by using volumetric 320-row multi-detector computed tomography: comparison of 0.5 mm with 3.0 mm slice reconstructions

The purpose of this study was to assess the performance of 0.5 versus 3.0 mm slice reconstructions in depicting coronary calcium with special attention to patients having zero calcium scores at 3.0 mm reconstructions by using computed tomography (CT). Imaging was performed by volumetric 320-detector row CT. Scans of 100 patients with a negative and 100 patients with a positive Agatston score at 3.0 mm reconstructions were consecutively selected. Non-overlapping volume sets with 3.0 and 0.5 mm slice thickness were reconstructed from the same raw data and Agatston and volume scores were obtained. The Wilcoxon signed ranks test was used to determine statistical differences between 3.0 and 0.5 mm calcium scores. Agatston and volume scores obtained at 0.5 mm were significantly higher than at 3.0 mm reconstructions (mean Agatston score: 266 ± 495 vs. 231 ± 461. Mean volume score: 223 ± 399 vs. 206 ± 385, both P < 0.01). In 21% of patients with zero 3.0 mm Agatston scores, a positive Agatston and/or volume score was found at 0.5 mm reconstructions. With volumetric 320-detector row CT, prospective ECG-triggered calcium scoring at 0.5 mm compared to 3.0 mm reconstructions leads to an increase in Agatston and volume scores and small amounts of coronary calcium are earlier depicted. This may be of special interest in patients with zero calcium scores with traditional 3.0 mm measures, where 0.5 mm reconstructions may help in superior depicting or ruling out coronary artery disease.     

Screw versus suture button in treatment of syndesmosis instability: Comparison using weightbearing CT scan

BackgroundThe superiority of screw or suture button fixation for syndesmotic instability remains debatable. Our aim is to compare radiographic outcomes of screw and suture button fixation of syndesmotic instability using weight bearing CT scan (WBCT).MethodsTwenty patients with fixation of unilateral syndesmotic instability were recruited and divided among two groups (screw = 10, suture button = 10). All patients had WBCT of both ankles ≥12 months postoperatively.ResultsIn suture button group, injured side measurements were significantly different from normal side for syndesmotic area (P = 0.003), fibular rotation (P = 0.004), anterior difference (P = 0.025) and direct anterior difference (P = 0.035). In screw group, syndesmotic area was the only significantly different measurement (P = 0.006).ConclusionWhile both screw and suture button didn’t completely restore the syndesmotic area as compared to the contralateral uninjured ankle, external malrotation of the fibula was uniquely associated with suture button fixation.Level of EvidenceIII Retrospective Cohort Study     

MR-plastination-arthrography: a new technique used to study the distal tibiofibular syndesmosis

Purpose  The purpose of this study was to describe a new technique called MR plastination arthrography to study both intra- and extra-articular anatomy. Materials and methods  In six human cadaveric lower legs MR arthrography was performed in either a one-step or two-step procedure. In the former a mixture of diluted Gadolinium and dyed polymer was injected. In the latter the dyed polymer was injected after arthrography wih diluted Gadolinium. Three-millimeter slices of these legs, obtained in a plane identical to that of the MR images, were plastinated according to the E12 technique of von Hagens. The plastination slices were subsequently compared with the MR images. Results  The one-step procedure resulted in an inhomogeneous arthrogram. The two-step procedure resulted in a good correlation between the high-resolution MR images and plastination slices, as expressed by a good comparison of anatomic detail of the small syndesmotic recess. Conclusions  Images of the distal tibiofibular syndesmosis obtained with plastination arthrography correlated well with images acquired by MR arthrography when performed in a two-step procedure.     

Trabeculated right ventricular free wall in the chicken heart forms by ventricularization of the myocardium initially forming the outflow tract

Recent molecular lineage analyses in mouse have demonstrated that the right ventricle is recruited from anterior mesoderm in later stages of cardiac development. This is in contrast to current views of development in the chicken heart, which suggest that the initial heart tube contains a subset of right ventricular precursors. We investigated the fate of the outflow tract myocardium using immunofluorescent staining of the myocardium, and lineage tracer, as well as cell death experiments. These analyses showed that the outflow tract is initially myocardial in its entirety, increasing in length up to HH24. The outflow tract myocardium, subsequently, shortens as a result of ventricularization, contributing to the trabeculated free wall, as well as the infundibulum, of the right ventricle. During this shortening, the overall length of the outflow tract is maintained because of the formation of a nonmyocardial portion between the distal myocardial border and the pericardial reflections. Cell death and transdifferentiation were found to play a more limited contribution to the initial shortening than is generally appreciated, if they play any part at all. Cell death, nonetheless, plays an important role in the disappearance of the myocardial collar that continues to invest the aorta and pulmonary trunk around HH30, and in the separation of the intrapericardial arterial vessels. Taken together, we show, as opposed to some current beliefs, the development of the arterial pole is similar in mammals and birds.