Expression of myxovirus-resistance protein A: a possible marker of muscle disease activity and autoantibody specificities in juvenile dermatomyositis.

AIMS: To evaluate the relationship between expression of myxovirus-resistance protein A (MxA) protein on muscle biopsies by immunohistochemistry and disease activity in juvenile dermatomyositis (JDM) patients. Also, another aim was to investigate whether the expression of MxA is related with myositis-specific autoantibodies (MSA) status in JDM patients. METHODS: 103 patients (median aged 6.3, interquartile range 0.5-15.9) enrolled in the Juvenile Dermatomyositis Cohort and Biomarker Study (JDCBS). Muscle biopsies were stained with MxA and scored. Clinical data at initial presentation were collected and autoantibodies were analysed. Multiple linear regression analysis was performed to estimate the association between MxA expression on muscle fibres and muscle disease activity, and MSA status. RESULTS: Expression of MxA protein on JDM samples was identified in 61.2%. There was a significant association between MxA scores and Childhood Myositis Assessment Scale (CMAS) (P = 0.002), and Manual Muscle Testing of Eight Muscles (MMT8) (P = 0.026). CMAS and MMT8 scores were significantly lower in the group of patients with strong MxA expression. MxA scores differed according to MSA subgroups (P = 0.002). Patients with positive nuclear matrix protein 2 autoantibodies had strong MxA expression, whereas anti-melanoma differentiation-associated gene 5 positive patients had no or weak MxA expression. CONCLUSIONS: This study reveals the significant association between level of MxA expression on muscle fibres and clinical measures of muscular disease activity in JDM patients and MSA status. This confirms type I interferonopathies in muscle fibres of JDM patients which could help with improving treatment outcome in JDM patients and underscoring the distinct pathophysiological pathways in different MSA status.

Histological heterogeneity in a large clinical cohort of juvenile idiopathic inflammatory myopathy: analysis by myositis autoantibody and pathological features.

AIM: Juvenile idiopathic inflammatory myopathies have been recently reclassified into clinico-serological subgroups. Myopathological correlates of the subgroups are incompletely understood. METHODS: We studied muscle biopsies from 101 children with clinically and serologically defined juvenile idiopathic inflammatory myopathies from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review and C5b-9 complement analysis. RESULTS: Autoantibody data were available for 90/101 cases with 18/90 cases positive for anti-TIF1γ, 15/90 anti-NXP2, 11/90 anti-MDA5, 5/90 anti-Mi2 and 6/90 anti-PmScl. JDM biopsy severity scores were consistently low in the anti-MDA5 group, high in the anti-Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage-rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101) and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b-9-deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b-9 deposition. CONCLUSION: We have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes.

Dimensionality-Driven Metal-Insulator Transition in Spin-Orbit-Coupled SrIrO_{3}.

Upon reduction of the film thickness we observe a metal-insulator transition in epitaxially stabilized, spin-orbit-coupled SrIrO_{3} ultrathin films. By comparison of the experimental electronic dispersions with density functional theory at various levels of complexity we identify the leading microscopic mechanisms, i.e., a dimensionality-induced readjustment of octahedral rotations, magnetism, and electronic correlations. The astonishing resemblance of the band structure in the two-dimensional limit to that of bulk Sr_{2}IrO_{4} opens new avenues to unconventional superconductivity by "clean" electron doping through electric field gating.

Predictors of nonresponse to fluid restriction in hyponatraemia due to the syndrome of inappropriate antidiuresis.

BACKGROUND: Fluid restriction (FR), the first-line treatment for hyponatraemia due to the syndrome of inappropriate antidiuresis (SIAD), often does not lead to successful correction of hyponatraemia. Therefore, predictive markers of treatment response are desirable. We evaluated routinely measured serum (s) and urine (u) parameters, s-copeptin and s-mid-regional pro-atrial natriuretic peptide (s-MR-proANP), as possible predictors of FR response. METHODS: In this prospective observational study, we included patients with profound hyponatraemia (s-sodium <125 mmol L-1 ) due to SIAD. Patients were classified as FR responders (increase in s-sodium concentration of >3 mmol L-1 within 24 h) or nonresponders (increase of ≤3 mmol L-1 within 24 h). Initial laboratory parameters were compared between groups with logistic regression analysis. RESULTS: Of 106 SIAD patients analysed, 82 underwent treatment with FR; 48 (59%) patients showed a successful response to FR and 34 (41%) were considered nonresponders. High levels of u-sodium and u-osmolality were significantly associated with nonresponse to FR [odds ratio (OR) 15.0, 95% confidence interval (CI) 2.4-95.8, P = 0.004 and OR 34.8, 95% CI 1.2-1038.8, P = 0.041, respectively). The association of u-sodium and nonresponse remained significant also after adjustment for diuretic use. Lower levels of s-MR-proANP were associated with nonresponse (OR 0.03, 95% CI 0.003-0.3, P = 0.004), whereas s-copeptin was not significantly associated with response to FR. CONCLUSION: Easily measured laboratory parameters, especially u-sodium, correlate with therapeutic response and identify patients most likely to fail to respond to FR. Measurement of these parameters may facilitate early treatment choice in patients with SIAD.

Can tibio-femoral kinematic and kinetic parameters reveal poor functionality and underlying deficits after total knee replacement? A systematic review.

BACKGROUND: Extensive efforts have been made to understand joint kinematics and kinetics in total knee arthroplasty (TKA) in subjects with satisfactory outcomes during daily functional activities and clinical tests, but it remains unclear whether such movement characteristics hold the potential to indicate the underlying aetiology of unsatisfactory or bad TKA outcomes. PURPOSE: To investigate which kinematic and kinetic parameters assessed during passive clinical tests and functional activities of daily living are associated with poor functionality and underlying deficits after total knee replacement. METHODS: We focused on studies characterizing the kinematic or kinetic parameters of the knee joint that are associated with poor clinical outcome after TKA. Seventeen articles were included for the review, and kinematic and kinetic data from 719 patients with minimal follow up of 6 months were extracted and analyzed. RESULTS: Passive posterior translation at 90°flexionexhibited good potential for differentiating stable and unstable TKAs. Anterior-posterior (A-P) translation of the medial condyle at 0-30° and 30-60° flexion, A-P translation of the lateral condyle at 60-90°during closed chain exercises, as well asknee extension moment during stair ascent and descent, knee abduction moment during stair descent, knee internal rotation moment and plantar flexion moment during walking, 2ndpeak ground reaction force during stair ascent and walkingshowed the greatest promise as functional biomarkers for a dissatisfied/poor outcome knee after TKA. CONCLUSION: In this study, we systematically reviewed the state-of-the-art knowledge of kinematics and kinetics associated with functional deficits, and found 11 biomechanical parameters that showed promise for supportingdecision making in TKA.

In Vivo Elongation Patterns of the Collateral Ligaments in Healthy Knees During Functional Activities.

BACKGROUND: Improved knowledge of in vivo function of the collateral ligaments is essential for enhancing rehabilitation and guiding surgical reconstruction as well as soft-tissue balancing in total knee arthroplasty. The aim of this study was to quantify in vivo elongation patterns of the collateral ligaments throughout complete cycles of functional activities. METHODS: Knee kinematics were measured using radiographic images captured with a mobile fluoroscope while healthy subjects performed level walking, downhill walking, and stair descent. The registered in vivo tibiofemoral kinematics were then used to drive subject-specific multibody knee models to track collateral ligament elongation. RESULTS: The elongation patterns of the medial collateral ligament varied distinctly among its bundles, ranging from lengthening of the anterior fibers to shortening of the posterior bundle with increases in the knee flexion angle. The elongation patterns of the lateral collateral ligament varied considerably among subjects. It showed an average 4% shortening with increasing flexion until 60% to 70% of the gait cycle, and then recovered during the terminal-swing phase until reaching its reference length (defined at heel strike). CONCLUSIONS: The observed nonuniform elongation of the medial collateral ligament bundles suggests that single-bundle reconstruction techniques may not fully restore healthy ligament function. Moreover, the observed ligament elongation patterns indicate greater varus than valgus laxity in the loaded knee. CLINICAL RELEVANCE: Through providing key knowledge about the in vivo elongation patterns of the collateral ligaments throughout complete cycles of functional activities, this study offers in vivo evidence for benchmarking ligament reconstruction and soft-tissue balancing in total knee arthroplasty.

[Long-term analysis of disability pensions in survivors of the Holocaust: somatic and psychiatric diagnoses]. / Erwerbsminderung bei Holocaustopfern: eine langzeitkatamnestische Betrachtung somatischer und psychiatrischer Diagnosen unter Berücksichtigung des Gesamtschauaspekts.

OBJECTIVE: Survivors of the Holocaust are known to suffer more often from mental as well as somatic consequential illness. The assessment of the degree of disability and invalidity due to the persecution complies with the interaction of directly Holocaust-related mental and somatic primary injuries as well as physical, psychical and psychosocial disadvantages and illnesses acquired later on. METHODS: The presented descriptive as well as multivariate analyses included complete reports (expertise, medical records, physicians' assessments, witnessed hand-written notes of the patients) of 56 survivors of the Holocaust (36 women and 20 men). RESULTS: The disability pension reports of 56 Holocaust survivors (36 women and 20 men) were analysed referring to the diagnostic groups and socio-demographic aspects. In 92.3 % a psychiatric illness could be diagnosed within the first year after liberation. In a separate analysis of somatic diagnoses, gastrointestinal diseases were statistically significant more often in Holocaust survivors with a degree of disability of more than 30 % (chi-square χ (2) = 4.0; df = 1; p = 0.046). CONCLUSIONS: The question of an aggravation of psychiatrically relevant and persecution-associated symptomatology is mainly the objective of the expert opinion taking into account endogenous and exogenous factors such as so-called life events. Above all, newly acquired somatic diseases seem to be responsible for an aggravation of persecution-associated psychiatric symptoms, at least in the presented sample of Holocaust survivors.

Length-Change Patterns of the Collateral Ligaments During Functional Activities After Total Knee Arthroplasty.

This study aimed to quantify the elongation patterns of the collateral ligaments following TKA during functional activities of daily living. Using mobile video-fluoroscopy to capture radiographic images of the knee in a group of six patients, each with an ultra-congruent knee implant, tibiofemoral kinematics were reconstructed throughout complete cycles of level gait, downhill walking, stair descent, and squat activities. Kinematic data were then used to drive subject-specific multibody knee models to estimate length-change patterns of the LCL as well as three bundles of the MCL. In addition, a sensitivity analysis examined the role of the attachment site in the elongation patterns. Our data indicate a slackening of the LCL but non-uniform length-change patterns across the MCL bundles (ranging from lengthening of the anterior fibers to shortening of the posterior fibers) with increasing knee flexion angle. Near-isometric behavior of the intermediate fibers was observed throughout the entire cycle of the studied activities. These length-change patterns were found to be largely consistent across different activities. Importantly, length-change patterns were critically sensitive to the location of the femoral attachment points relative to the femoral component. Thus, in TKA with ultra-congruent implants, implantation of the femoral component may critically govern post-operative ligament function.

Author Correction: Tibio-Femoral Contact Force Distribution is Not the Only Factor Governing Pivot Location after Total Knee Arthroplasty.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Tibio-Femoral Contact Force Distribution is Not the Only Factor Governing Pivot Location after Total Knee Arthroplasty.

Total knee arthroplasty aims to mimic the natural knee kinematics by optimizing implant geometry, but it is not clear how loading relates to tibio-femoral anterior-posterior translation or internal-external pivoting. We hypothesised that the point of pivot in the transverse plane is governed by the location of the highest axial force. Tibio-femoral loading was measured using an instrumented tibial component in six total knee arthroplasty patients (aged 65-80y, 5-7y post-op) during 5-6 squat repetitions, while knee kinematics were captured using a mobile video-fluoroscope. In the range of congruent tibio-femoral contact the medial femoral condyle remained approximately static while the lateral condyle translated posteriorly by 4.1 mm (median). Beyond the congruent range, the medial and lateral condyle motions both abruptly changed to anterior sliding by 4.6 mm, and 2.6 mm respectively. On average, both the axial loading and pivot position were more medial near extension, and transferred to the lateral side in flexion. However, no consistent relationship between pivoting and load distribution was found across all patients throughout flexion, with R2 values ranging from 0.00 to 0.65. Tibio-femoral kinematics is not related to the load distribution alone: medial loading of the knee does not necessarily imply a medial pivot location.

Induced micronucleus frequencies in peripheral lymphocytes as a screening test for carriers of a BRCA1 mutation in breast cancer families.

Enhanced sensitivity to the chromosome-damaging effects of ionizing radiation is a feature of many cancer-predisposing conditions. It has been suggested that women with breast cancer are deficient in the repair of radiation-induced DNA damage. We have now investigated whether mutagen sensitivity is related to mutations in the breast cancer gene BRCA1. We studied the induction and repair of DNA damage in lymphocytes of women from families with familial breast cancer and breast and ovarian cancer. The mutagens used were gamma-irradiation and hydrogen peroxide and the DNA effects were determined with the micronucleus test and the comet assay. Women with a BRCA1 mutation (n = 12) and relatives without the familial mutation (n = 10) were compared to controls (i.e., healthy women without family history of breast or ovarian cancer; n = 17). Our results indicate a close relationship between the presence of a BRCA1 mutation and sensitivity for the induction of micronuclei. Compared to a concurrent control, 10 of 11 women with a BRCA1 mutation showed elevated radiation sensitivity. Of the 10 related women without the familial mutation, only 2 had clearly enhanced micronucleus frequencies. In addition to the sensitivity toward gamma-irradiation, hypersensitivity toward hydrogen peroxide was also observed, indicating that the mutagen sensitivity is not solely due to a defect in the repair of DNA double strand breaks. In contrast to the results with the micronucleus assay, we found no significant difference between women with and without a BRCA1 mutation with respect to the induction and repair of DNA damage in the comet assay. This finding suggests a normal rate of damage removal and points to a disturbed fidelity of DNA repair as a direct or indirect consequence of a BRCA1 mutation. Our results support the usefulness of induced micronucleus frequencies as a biomarker for cancer predisposition and suggest its application as a screening test for carriers of a BRCA1 mutation in breast cancer families.

Alterations in Krebs cycle enzyme activities and carbohydrate catabolism in two strains of Trypanosoma brucei during in vitro differentiation of their bloodstream to procyclic stages.

A rapid switch from a fermentative to a primarily oxidative type of glucose utilization was observed during in vitro differentiation of Trypanosoma brucei STIB348 and EATRO1244 bloodstream to procyclic trypomastigotes. In accordance with previously published reports bloodstream populations produced pyruvate as the major end product of glucose catabolism, together with very small amounts of CO2, succinate and glycerol. During differentiation pyruvate excretion decreased within 48 h to the low levels produced by 28-day procyclic stages. Concomitant with the decline in pyruvate formation, acetate appeared as a new product and the rates of respiratory CO2 increased considerably. The amount of carbon released with these compounds could account for nearly all of the glucose carbon consumed. Rates of glucose utilization and formation of acetate and CO2 in cells differentiated for 48 h were essentially the same as those found in 28-day procyclics. Succinate and glycerol excretion remained low during the entire transformation process, and no significant difference in the pattern and quantities of end products were found between the two trypanosome strains. During trypanosome differentiation the changes in metabolism were associated with marked alterations in enzyme activity levels. Activities of the tricarboxylic acid (TCA) cycle enzymes citrate synthase, isocitrate dehydrogenase (NAD+), succinate dehydrogenase and fumarase were not detectable in bloodstream trypomastigotes but appeared upon differentiation for 24 h. An exception was citrate synthase whose activity was not demonstrable until 48 h postinoculation into culture. After 48 h the majority of the TCA cycle enzyme activities continued to increase steadily until day 28. Pyruvate kinase activity decreased in differentiating cells after 48 h to about 25% of the level found in bloodstream trypomastigotes.(ABSTRACT TRUNCATED AT 250 WORDS)

First report of lymphatic mapping with isosulfan blue dye and sentinel node biopsy in cervical cancer.

BACKGROUND: Sentinel lymph node status provides important information about the status of the regional nodes in various malignant tumors. Our report describes a method of identifying the sentinel lymph nodes in cervical cancer. PATIENTS AND METHODS: In three cases of early cervical cancer, isosulfan blue dye was injected paracervically into each lateral fornix immediately before surgery. RESULTS: In all cases we identified two to three blue stained (sentinel) lymph nodes located either at the iliac artery or in the obturatory space. The blue colored nodes were positive for disease, all other pelvic lymph nodes removed were negative. CONCLUSIONS: Our findings demonstrate that preoperative lymphatic mapping with vital blue dye is an easy to perform technique to visualize sentinel lymph nodes in cervical cancer. Sentinel lymph node status may be representative of the pelvic lymph node status in cervical cancer and thus could provide important information for further treatment.

The influence of temperature during alkaline treatment and electrophoresis on results obtained with the comet assay.

The alkaline comet assay (single-cell gel electrophoresis) is becoming established as a genotoxicity test with many fold applications in vitro and in vivo. While the underlying principles are identical, various modifications of the method are in use which clearly affect the sensitivity and resolving power of the assay. One variable of potential importance that has been disregarded until now is temperature during alkaline treatment and electrophoresis. We therefore performed comet assay experiments with human blood and V79 Chinese hamster cells using two different temperatures (4 and 20 degrees C, i.e. room temperature) during alkaline treatment and electrophoresis. DNA damage was induced by the two standard mutagens gamma irradiation and methyl methanesulfonate (MMS). The results clearly indicate significant differences in the detection of background and mutagen-induced DNA damage at these two temperatures. Under otherwise identical test conditions (including the duration of alkaline treatment and electrophoresis), increased temperature during alkaline treatment and electrophoresis strongly enhances DNA migration. Our findings suggest that the comet assay should be performed under strictly controlled and reproducible temperature conditions. In any case the temperature during alkaline treatment and electrophoresis should be stated in a publication to allow for a critical evaluation of results obtained with the comet assay.

Comparative evaluation of the genotoxic properties of potassium bromate and potassium superoxide in V79 Chinese hamster cells.

The genotoxic potential of two oxidizing compounds, potassium bromate and potassium superoxide, was comparatively tested in various genotoxicity tests with V79 Chinese hamster cells. Both substances clearly induced cytotoxicity, chromosome aberrations and increased DNA migration in the alkaline comet assay. Using a modified comet assay protocol with FPG protein, a DNA repair enzyme which specifically nicks DNA at sites of 8-oxoguanines and formamidopyrimidines, we detected oxidative DNA base damage only after potassium bromate treatment. HPLC analysis also revealed significantly increased levels of 8-oxodeoxyguanosine after potassium bromate treatment but not after potassium superoxide treatment. Furthermore, potassium bromate clearly induced gene mutations at the HPRT locus while potassium superoxide only had a small effect on HPRT mutant frequencies. Molecular analysis of potassium bromate-induced mutations indicated a high portion of deletion mutations. Three out of four point mutations were G to T transversions which typically arise after replication of 8-oxoguanine. Our results suggest that the two oxidizing compounds induce specific patterns of genotoxic effects that reflect the types of DNA alterations induced by different reactive oxygen species (ROS).

Management of case fees and special charges with aid of the coding system "do it".

INTRODUCTION: With the German health care restructuring legislation ("Gesundheitsstrukturgesetz") the coding of diagnoses and operations according to ICD-9 and ICPM (OPS-301) was introduced for budget assignment ("Fallpauschalen/Sonderentgelte"). METHODS: Application of the structured coding system "do it" in orthopeadics and traumatology in combination with a surgical documentation system. Results of 8,664 documented operative cases within three years. RESULTS: In total, 11,854 ICD-9 or ICD-10 and 20,178 ICPM (OPS-301) were coded. 2,914 "Fallpauschalen" and/or 3,456 "Sonderentgelte" were found. The System achieved high acceptance due to its userfriendliness and simple functionality. DISCUSSION: In comparison with text- or thesaurus-based coding systems the "do it" coding system does not require any knowledge of the ICD or ICPM (OPS-301). It can be adapted to individual clinical requirements by implementing frequent diagnoses and individual therapy concepts. In combination with a medical information system the coding system can be integrated seamlessly into routine documentation.

[Langerhans-cell histiocytosis in children]. / Histiocytóza z Langerhansových bunek u detí.

Histiocytosis from Langerhans cells is a new term for a group of diseases formerly called histiocytosis X. In The Faculty Hospital Motol the authors treated between July 1974 and December 1980 84 children with this disease. Twenty one suffered from the malignant form (formerly Letterer-Siwe and Hand-Schüller-Christian disease) and in 63 patients the diagnosis of eosinophil granuloma was established. In 21 children with unequivocally malignant disease the authors started chemotherapy immediately after establishment of the diagnosis and in six they indicated in addition radiotherapy. Of these 21 children 16 are in complete remission and 5 children died from progression of the disease during treatment. In the group of 63 children with eosinophil granuloma in 44 only excochleation of the focus was performed. Chemotherapy was administered to 12 children, incl. 5 where it was combined with radiotherapy. A relapse of the disease was recorded in 8 children. At present all patients suffering from the disease are in complete remission.

Evaluation of an algorithm for intensive subcutaneous insulin therapy in noncritically ill hospitalised patients with hyperglycaemia in a randomised controlled trial.

BACKGROUND: Currently glycaemic targets of <7.8 mmol/l without hypoglycaemia are recommended for diabetic patients on general wards before meals. Efficient and safe strategies to achieve these targets with subcutaneous insulin injections outside the intensive care setting are not well established. The aim of this trial was to evaluate a subcutaneous insulin algorithm, which incorporates insulin resistance due to individual features and acute illness, for correction of hyperglycaemia in general medical wards. METHODS: This was a two-centre, randomised controlled trial in two Swiss hospitals. Patients with initial plasma glucose levels >8 mmol/l were randomised to either an intervention group or a control group. The primary endpoint was the time in the glycaemic target range (5.5-7.0 mmol/l) within the first 48 hours. RESULTS: Patients in the intervention group (n = 67) had significantly lower plasma glucose levels during the first 48 hours as compared with control patients (n = 63) (7.7 ± 3.0 mmol/l; mean ± standard deviation [SD]) vs 9.7 ± 3.9 mmol/l, p <0.0001). The intervention group reached the glycaemic target range earlier (median 9.5 vs 24.0 hours, p <0.0001) and remained longer in this range (difference: 9.5 hours, 95% confidence interval [CI] 5.1, 13.9). There were more episodes of mild hypoglycaemia in the intervention group (19.4% vs 6.3%, absolute difference 13.5%, 95%CI 1.8, 24.3), with no difference in rates of severe hypoglycaemia. CONCLUSIONS: Incorporation of insulin resistance factors into a subcutaneous insulin algorithm achieved early and sustained glycaemic control in noncritically ill patients admitted to general medical wards without apparent safety concerns. The overall clinical benefit of this strategy remains to be determined.