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.     

Röntgenologische Befunde zur Keimlage und zum Durchbruch der dritten Molaren

Zusammenfassung Keimlage und Durchbruchsweg der dritten Molaren, wie sie auf Orthopantomogrammen zu beobachten sind, wurden analysiert. Die Weisheitszahnkeime wurden nach ihrem Entwicklungsgrad (modifiziert nachGAT) eingeteilt und ihre Position nach den Parametern Platzangebot im retromolaren Raum, Position der M₃ zu den M₂, vertikale Position, vorliegende Rotation, sowie Zahnachsenwinkel M₁–M₃ bestimmt. In einer Querschnittsuntersuchung wurden 445 Orthopantomogramme von 245 Patienten ausgewertet. Die Ergebnisse dieser Untersuchung konnten in einer Longitudinalstudie mit 129 Patienten, bei denen zwei oder mehrere Orthopantomogramme direkt aufeinanderfolgender Entwicklungsstufen vorlagen, bestätigt werden. Es zeigt sich, daß eine sichere Prognose für eine spätere Einstellung oder Verlagerung der dritten Molaren des Unterkiefers, anhand der verwendeten Parameter nicht vor dem Übergang von Zahnbildungsphase 3 auf 4 möglich ist (Abbildung 7). Die Einstellung der oberen dritten Molaren erscheint in dem vorliegenden Patientengut wesentlich problemloser. Abweichungen vom regulären Durchbruchsweg wurden nur bei Weisheitszahnkeimen mit ausgeprägter primär dystoper Keimlage gefunden.

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Summary The position of the tooth follicle and the eruptive path of third molars was analysed with the help of orthopantomograms. The wisdom teeth follicles were classified according to their stage of development, and their position determined by the following parameters: space available in the retromolar area, relation of the third molars to the second molars, their vertical position, observed rotation and also the axial angle between the first and the third molars. A random sample study of 445 orthopantomograms of 245 patients was carried out. The results of this study could be confirmed in a longitudinal study conducted on 129 patients. The impaction of the third molar is a complex multifactorial mechanism. This study showed that it was not possible within the defined parameters, to predict the eruptive patterns of the mandibular third molars, until the transition of the tooth development from stage 3 to stage 4. The eruption of the maxillary third molars appeared to be relatively unproblematic in the study group. Deviations from the normal eruptive path were observed only in wisdom teeth with a pronounced primary ectopic position of the follicle.

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Résumé La position des follicules dentaires des dents de sagesse ainsi que le chemin suivi par les dents en formation ont été examinés tels qu'ils se présentent sur les orthopantomographies. Les follicules dentaires des dents de sagesse ont été classés d'après leur stade de développement et d'après leur position, définie par les paramètres suivants: «place disponible dans la sphère rétromolaire», «position des dents de sagesse par rapport aux dents de douze ans», «position verticale», «rotation constatée», «angle formé par les axes dentaires des dents de six ans jusqu' aux dents de sagesse». 445 orthopantomographies des 245 patients ont été analysées dans une étude horizontale. Les résultats de cette étude ont pu être confirmés par une analyse longitudinale faite à partir de 129 patients. Il apparait qu'on ne peut pas diagnostiquer avec certitude la future mise en place ou le déplacement des dents de sagesse du maxillaire inférieur à partir des paramètres utilisés avant le passage de la phase de formation no. 3 à la phase no. 4 (Fig. 7). La mise en place des dents de sagesse supérieures semble poser beaucoup moins de problèmes chez les patients examinés. Seules les dents de sagesse dont les follicules étaient nettement mal placés dès l'origine ont présenté des déviations dans le chemin suivi par la dent en formation.

     

Micturation related swelling of the scrotum

Unlike small inguinal and femoral bladder hernias, massive bladder hernias into the scrotum, also named scrotal cystoceles, are rare. We describe and discuss the clinical appearance and management of a patient with a micturation related unilateral swelling of the scrotum.     

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.     

Characterization of a CD46 transgenic pig and protection of transgenic kidneys against hyperacute rejection in non-immunosuppressed baboons

Human membrane cofactor protein (CD46) controls complement activation and when expressed sufficiently as a transgene protects xenografts against complement-mediated rejection, as shown here using non-immunosuppressed baboons and heterotopic CD46 transgenic pig kidney xenografts. This report is of a carefully engineered transgene that enables high-level CD46 expression. A novel CD46 minigene was validated by transfection and production of a transgenic pig line. Pig lymphocytes were tested for resistance to antibody and complement-mediated lysis, transgenic tissues were characterized for CD46 expression, and kidneys were transplanted to baboons without immunosuppression. Absorption of anti-Galalpha(1,3)Gal epitope (anti-GAL) serum antibodies was measured. Transgenic pigs expressed high levels of CD46 in all tissues, especially vascular endothelium, with stable expression through three generations that was readily monitored by flow cytometry of transgenic peripheral blood mononuclear cells (PBMC). Transgenic PBMC pre-sensitized with antibody were highly resistant to human complement-mediated lysis which readily lysed normal pig PBMC. Normal pig kidneys transplanted without cold ischemia into non-immunosuppressed adult baboons survived a median of 3.5 h (n = 7) whereas transgenic grafts (n = 9), harvested at approximately 24-h intervals, were either macroscopically normal (at 29, 48 and 68 h) or showed limited macroscopic damage (median > 50 h). Microscopic assessment of transplanted transgenic kidneys showed only focal tubular infarcts with viable renal tissue elsewhere, no endothelial swelling or polymorph adherence and infiltration by lymphocytes beginning at 3 days. Coagulopathy was not a feature of the histology in four kidneys not rejected and assessed at 48 h or later after transplantation. Baboon anti-GAL serum antibody titers were high before transplantation and, in one extensively analyzed recipient, reduced approximately 8-fold within 5.5 h. The data demonstrate that a single CD46 transgene controls hyperacute kidney graft rejection in untreated baboons despite the presence of antibody and complement deposition. The expression levels, tissue distribution and in vitro functional tests indicate highly efficient CD46 function, controlling both classical and alternative pathway complement activation, which suggests it might be the complement regulator of choice to protect xenografts.