Definition and diagnostic criteria of sleep-related hypermotor epilepsy

The syndrome known as nocturnal frontal lobe epilepsy is recognized worldwide and has been studied in a wide range of clinical and scientific settings (epilepsy, sleep medicine, neurosurgery, pediatric neurology, epidemiology, genetics). Though uncommon, it is of considerable interest to practicing neurologists because of complexity in differential diagnosis from more common, benign sleep disorders such as parasomnias, or other disorders like psychogenic nonepileptic seizures. Moreover, misdiagnosis can have substantial adverse consequences on patients' lives. At present, there is no consensus definition of this disorder and disagreement persists about its core electroclinical features and the spectrum of etiologies involved. To improve the definition of the disorder and establish diagnostic criteria with levels of certainty, a consensus conference using formal recommended methodology was held in Bologna in September 2014. It was recommended that the name be changed to sleep-related hypermotor epilepsy (SHE), reflecting evidence that the attacks are associated with sleep rather than time of day, the seizures may arise from extrafrontal sites, and the motor aspects of the seizures are characteristic. The etiology may be genetic or due to structural pathology, but in most cases remains unknown. Diagnostic criteria were developed with 3 levels of certainty: witnessed (possible) SHE, video-documented (clinical) SHE, and video-EEG-documented (confirmed) SHE. The main research gaps involve epidemiology, pathophysiology, treatment, and prognosis.

Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group

BACKGROUND AND OBJECTIVES: There are no widely accepted criteria for the definition of hematopoietic stem cell transplant -associated microangiopathy (TAM). An International Working Group was formed to develop a consensus formulation of criteria for diagnosing clinically significant TAM. DESIGN AND METHODS: The participants proposed a list of candidate criteria, selected those considered necessary, and ranked those considered optional to identify a core set of criteria. Three obligatory criteria and four optional criteria that ranked highest formed a core set. In an appropriateness panel process, the participants scored the diagnosis of 16 patient profiles as appropriate or not appropriate for TAM. Using the experts' ratings on the patient profiles as a gold standard, the sensitivity and specificity of 24 candidate definitions of the disorder developed from the core set of criteria were evaluated. A nominal group technique was used to facilitate consensus formation. The definition of TAM with the highest score formed the final PROPOSAL. RESULTS: The Working Group proposes that the diagnosis of TAM requires fulfilment of all of the following criteria: (i) >4% schistocytes in blood; (ii) de novo, prolonged or progressive thrombocytopenia (platelet count <50 x 109/L or 50% or greater reduction from previous counts); (iii) sudden and persistent increase in lactate dehydrogenase concentration; (iv) decrease in hemoglobin concentration or increased transfusion requirement; and (v) decrease in serum haptoglobin. The sensitivity and specificity of this definition exceed 80%. INTERPRETATION AND CONCLUSIONS: The Working Group recommends that the presented criteria of TAM be adopted in clinical use, especially in scientific trials.

Evaluation of healing criteria for success after periapical surgery

INTRODUCTION: In periapical surgery, the absence of standardization between different studies makes it difficult to compare the outcomes. OBJECTIVE: To compare the healing classification of different authors and evaluate the prognostic criteria of periapical surgery at 12 months. MATERIAL AND METHODS: 278 patients (101 men and 177 women) with a mean age of 38.1 years (range 11 to 77) treated with periapical surgery using the ultrasound technique and a 2.6x magnifying glass, and silver amalgam as root-end filling material were included in the study. Evolution was analyzed using the clinical criteria of Mikkonen et al., 1983; radiographic criteria of Rud et al., 1972; the overall combined clinical and radiographic criteria of von Arx and Kurt, 1999; and the Friedman (2005) concept of functional tooth at 12 months of surgery. RESULTS: After 12 months, 87.2% clinical success was obtained according to the Mikkonen et al., 1983 criteria; 73.9% complete radiographic healing using Rud et al. criteria; 62.1% overall success, following the clinical and radiographic parameters of von Arx and Kurt, and 91.9% of teeth were functional. The von Arx and Kurt criteria was found to be the most reliable. CONCLUSION: Overall evolution according to von Arx and Kurt agreed most closely with the other scales.

Implications of proposed fibromyalgia criteria across other functional pain syndromes

OBJECTIVES In 2010, the American College of Rheumatology (ACR) proposed new criteria for the diagnosis of fibromyalgia (FM) in the context of objections to components of the criteria of 1990. The new criteria consider the Widespread Pain Index (WPI) and the Symptom Severity Score (SSS). This study evaluated the implications of the new diagnostic criteria for FM across other functional pain syndromes. METHOD A cohort of 300 consecutive in-patients with functional pain syndromes underwent a diagnostic screen according to the ACR 2010 criteria. Additionally, systematic pain assessment including algometric and psychometric data was carried out. RESULTS Twenty-five patients (8.3%) had been diagnosed with FM according to the ACR 1990 criteria. Twenty-one of them (84%) also met the new ACR 2010 criteria. In total, 130 patients (43%) fulfilled the new ACR 2010 criteria. A comparison of new vs. old cases showed a high degree of conformity in most of the pain characteristics. The new FM cases, however, revealed a pronounced heterogeneity in the anatomical pain locations, including several types of localized pain syndromes. Furthermore, patients fulfilling the ACR 2010 FM criteria differed from those with other functional pain syndromes; they had increased pain sensitivity scores and increased psychometric values for depression, anxiety, and psychological distress (p<0.01). CONCLUSIONS FM according to the ACR 2010 criteria describes the 'severe half' of the spectrum of functional pain syndromes. By dropping the requirement of 'generalized pain', these criteria result in a blurring of the distinction between FM and more localized functional pain syndromes.

Prediction of Psychosis by Mismatch Negativity

BACKGROUND: To develop risk-adapted prevention of psychosis, an accurate estimation of the individual risk of psychosis at a given time is needed. Inclusion of biological parameters into multilevel prediction models is thought to improve predictive accuracy of models on the basis of clinical variables. To this aim, mismatch negativity (MMN) was investigated in a sample clinically at high risk, comparing individuals with and without subsequent conversion to psychosis. METHODS: At baseline, an auditory oddball paradigm was used in 62 subjects meeting criteria of a late risk at-state who remained antipsychotic-naive throughout the study. Median follow-up period was 32 months (minimum of 24 months in nonconverters, n = 37). Repeated-measures analysis of covariance was employed to analyze the MMN recorded at frontocentral electrodes; additional comparisons with healthy controls (HC, n = 67) and first-episode schizophrenia patients (FES, n = 33) were performed. Predictive value was evaluated by a Cox regression model. RESULTS: Compared with nonconverters, duration MMN in converters (n = 25) showed significantly reduced amplitudes across the six frontocentral electrodes; the same applied in comparison with HC, but not FES, whereas the duration MMN in in nonconverters was comparable to HC and larger than in FES. A prognostic score was calculated based on a Cox regression model and stratified into two risk classes, which showed significantly different survival curves. CONCLUSIONS: Our findings demonstrate the duration MMN is significantly reduced in at-risk subjects converting to first-episode psychosis compared with nonconverters and may contribute not only to the prediction of conversion but also to a more individualized risk estimation and thus risk-adapted prevention.

Validation of the Swiss Monte Carlo Plan for a static and dynamic 6 MV photon beam

Monte Carlo (MC) based dose calculations can compute dose distributions with an accuracy surpassing that of conventional algorithms used in radiotherapy, especially in regions of tissue inhomogeneities and surface discontinuities. The Swiss Monte Carlo Plan (SMCP) is a GUI-based framework for photon MC treatment planning (MCTP) interfaced to the Eclipse treatment planning system (TPS). As for any dose calculation algorithm, also the MCTP needs to be commissioned and validated before using the algorithm for clinical cases. Aim of this study is the investigation of a 6 MV beam for clinical situations within the framework of the SMCP. In this respect, all parts i.e. open fields and all the clinically available beam modifiers have to be configured so that the calculated dose distributions match the corresponding measurements. Dose distributions for the 6 MV beam were simulated in a water phantom using a phase space source above the beam modifiers. The VMC++ code was used for the radiation transport through the beam modifiers (jaws, wedges, block and multileaf collimator (MLC)) as well as for the calculation of the dose distributions within the phantom. The voxel size of the dose distributions was 2mm in all directions. The statistical uncertainty of the calculated dose distributions was below 0.4%. Simulated depth dose curves and dose profiles in terms of [Gy/MU] for static and dynamic fields were compared with the corresponding measurements using dose difference and γ analysis. For the dose difference criterion of ±1% of D(max) and the distance to agreement criterion of ±1 mm, the γ analysis showed an excellent agreement between measurements and simulations for all static open and MLC fields. The tuning of the density and the thickness for all hard wedges lead to an agreement with the corresponding measurements within 1% or 1mm. Similar results have been achieved for the block. For the validation of the tuned hard wedges, a very good agreement between calculated and measured dose distributions was achieved using a 1%/1mm criteria for the γ analysis. The calculated dose distributions of the enhanced dynamic wedges (10°, 15°, 20°, 25°, 30°, 45° and 60°) met the criteria of 1%/1mm when compared with the measurements for all situations considered. For the IMRT fields all compared measured dose values agreed with the calculated dose values within a 2% dose difference or within 1 mm distance. The SMCP has been successfully validated for a static and dynamic 6 MV photon beam, thus resulting in accurate dose calculations suitable for applications in clinical cases.

Linear sclerodermic lupus erythematosus, a distinct variant of linear morphea and chronic cutaneous lupus erythematous

Overlap syndromes represent disorders that combine diagnostic criteria of two or more different connective tissue diseases.

Design and construction of a new Drosophila species, D.synthetica, by synthetic regulatory evolution

Here, I merge the principles of synthetic biology1,2 and regulatory evolution3-11 to create a new species12-15 with a minimal set of known elements. Using preexisting transgenes and recessive mutations of Drosophila melanogaster, a transgenic population arises with small eyes and a different venation pattern that fulfills the criteria of a new species according to Mayr's "Biological Species Concept"7,10. The genetic circuit entails the loss of a non-essential transcription factor and the introduction of cryptic enhancers. Subsequent activation of those enhancers causes hybrid lethality. The transition from "transgenic organisms" towards "synthetic species", such as Drosophila synthetica, constitutes a safety mechanism to avoid hybridization with wild type populations and preserve natural biodiversity16-18. Drosophila synthetica is the first transgenic organism that cannot hybridize with the original wild type population but remains fertile when crossed with other transgenic animals.

Sarcomatous evolution of oligodendroglioma ("oligosarcoma"): confirmatory report of an uncommon pattern of malignant progression in oligodendroglial tumors

By analogy to gliosarcoma, the neologism "oligosarcoma" is to describe an uncommon form of biphasic central nervous system tumor composed of contiguous neuroepithelial and mesenchymal elements, each of which individually meet the criteria of oligodendroglioma and sarcoma, respectively. By virtue of its distinctive genotype (codeletion 1p/19q), oligodendroglioma is a particularly inviting paradigm to test the assumption that such mixed tumors are clonally derived from a glial primary. We observed this constellation in a 41-year-old male who underwent two resection procedures for a recurring right frontal tumor at five years' interval. On imaging, both lesions were contrast-enhancing, and measured 7 cm × 7 cm × 6.8 cm and 7 cm × 6.5 cm × 4cm, respectively. Following the first operation, temozolomide monotherapy was administered. Whereas initial histology showed conventional anaplastic oligodendroglioma, the recurrence consisted mostly of a fibrosarcoma-like, fascicular neoplasm that was immunoreactive for vimentin, smooth muscle actin, S100 protein, and focally epithelial membrane antigen. In between, a subset of otherwise indistinguishable spindle cells expressed GFAP, and focally merged with residues of oligodendroglioma. Molecular testing for loss of heterozygosity confirmed codeletion of 1p/19q in both the primary tumor and the sarcomatous recurrence. Similarly, generalized immunoreactivity for the mutant R132H form of isocitrate dehydrogenase in both lesions indicated an identical mutation of the IDH1 gene. By the above standards, biologically consistent "oligosarcomas" are felt to be exceedingly rare, and possibly participate of a nosologically heterogeneous group of combined glial/mesenchymal lesions that may also include iatrogenically induced second malignancies as well as true collision tumors.

The significance of the sympathetic nervous system in the pathophysiology of periodic leg movements in sleep

STUDY OBJECTIVES: Periodic leg movements in sleep (PLMS) are frequently accompanied by arousals and autonomic activation, but the pathophysiologic significance of these manifestations is unclear. DESIGN: Changes in heart rate variability (HRV), HRV spectra, and electroencephalogram (EEG) spectra associated with idiopathic PLMS were compared with changes associated with isolated leg movements and respiratory-related leg movements during sleep. Furthermore, correlations between electromyographic activity, HRV changes, and EEG changes were assessed. SETTING: Sleep laboratory. PATIENTS: Whole-night polysomnographic studies of 24 subjects fulfilling the criteria of either periodic leg movements disorder (n = 8), obstructive sleep apnea syndrome (n = 7), or normal polysomnography (n = 9) were used. MEASUREMENTS AND RESULTS: Spectral HRV changes started before all EEG changes and up to 6 seconds before the onset of all types of leg movements. An initial weak autonomic activation was followed by a sympathetic activation, an increase of EEG delta activity, and finally a progression to increased higher-frequency EEG rhythms. After movement onset, HRV indicated a vagal activation, and, the EEG, a decrease in spindle activity. Sympathetic activation, as measured by HRV spectra, was greater for PLMS than for all other movement types. In EEG, gamma synchronization began 1 to 2 seconds earlier for isolated leg movements and respiratory-related leg movements than for PLMS. Significant correlations were found between autonomic activations and electromyographic activity, as well as between autonomic activations and EEG delta activity, but not between higher-frequency EEG rhythms and EMG activity or HRV changes. CONCLUSIONS: These results suggest a primary role of the sympathetic nervous system in the generation of PLMS.

Contractile performance of adult ventricular rat cardiomyocytes is not directly jeopardized by NO/cGMP-dependent induction of pro-apoptotic pathways

The activation of NO/cGMP pathways can induce pro-apoptotic pathways in cardiomyocytes although only a small number of cardiomyocytes fulfill the criteria of apoptosis. The same pathways reduce the contractile performance of cardiomyocytes. In the present study, we tested the hypothesis that exposure of cells to NO/cGMP for 24 h decrease their contractile performance due to an activation of pro-apoptotic pathways. Experiments were performed on freshly isolated and cultured adult ventricular rat cardiomyocytes. Cells were incubated with 8-bromo-cyclo-GMP (100 nmol/L-1 micromol/L), the NO donor SNAP (1 nmol/L-100 micromol/L), or the guanylyl cyclase activator YC-1 (3 micromol/L). Cell shortening, contraction and relaxation velocities, and diastolic cell lengths were determined at beating frequencies of 0.5, 1, and 2 Hz 24 h later. The activation of pro-apoptotic pathways was determined by staining of cardiomyocytes with an antibody directed against active caspase-3 and quantification of the number of apoptotic cells (annexin staining). Caspase-3 activation and an increase in the number of apoptotic cells was observed, but only at the highest concentrations tested (8-bromo-cyclo-GMP: 1-10 mmol/L; SNAP: 1-100 micromol/L). At these concentrations, none of the drugs decreased the mean cell shortening of cardiomyocytes. However, at concentrations lower than those required for induction of apoptotic cell death, the diastolic cell lengths and sarcomere lengths increased but cell shortening decreased. In conclusion, low concentrations of either NO or cGMP cause a desensitization of myofibrils, as indicated by elongated cell shapes, increased sarcomere lengths and reduced load-free cell shortening. High concentrations of NO/cGMP induce caspase-3 activation and increase the number of cells fulfilling the criteria of apoptotic cell death but did not impair cell function. Therefore, induction of apoptotic cell death per se seems not to contribute to the loss of contractile efficiency on the cellular level.

Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis

ABSTRACT: INTRODUCTION: In transgenic animal models of sepsis, members of the Bcl-2-family of proteins regulate lymphocyte apoptosis and survival of sepsis. This study investigates the gene regulation of pro- and anti-apoptotic members of the Bcl-2-family of proteins in patients with early stage severe sepsis. METHODS: In this prospective case-control study patients were recruited from three intensive care units in a university hospital. Sixteen patients were enrolled as soon as they fulfilled the criteria of severe sepsis. Ten critically ill but non-septic patients and eleven healthy volunteers served as controls. Blood samples were immediately obtained at inclusion. To confirm the presence of accelerated apoptosis in the patient groups, caspase-3 activation and phosphatidylserine (PS) externalization in CD4+, CD8+ and CD19+ lymphocyte subsets were assessed by flow cytometry. Specific mRNA's of Bcl-2 family members were quantified from whole blood by real-time polymerase chain reaction. To test for statistical significance, Kruskal-Wallis testing with Dunn's multiple comparison test for post hoc testing was performed. RESULTS: In all lymphocyte populations caspase-3 (p<0.05) was activated, which was reflected in an increased PS externalization (p<0.05). Accordingly, lymphocyte counts were decreased in early severe sepsis. In CD4+ T-cells (p<005) and in B-cells (p<0.001) the Bcl-2 protein was decreased in severe sepsis. Gene expression of the BH3-only Bim was massively upregulated as compared to critically ill patients (p<0.001) and 51.6 fold as compared to healthy controls (p<0.05). Bid was increased 12.9 fold compared to critically ill (p<0.001). In the group of the mitochondrial apoptosis-inducers, Bak was upregulated 5.6 fold, while the expression of Bax showed no significant variations. By contrast, the pro-survival members Bcl-2 and Bcl-xl were both downregulated in severe sepsis (p<0.001, p<0.05). CONCLUSIONS: In early severe sepsis a gene expression pattern with induction of the pro-apoptotic Bcl-2 family members Bim, Bid and Bak and a downregulation of the anti-apoptotic Bcl-2 and Bcl-xl was observed in peripheral blood. This constellation may affect cellular susceptibility to apoptosis and complex immune dysfunction in sepsis.

Issues of spectral quality in clinical 1H-magnetic resonance spectroscopy and a gallery of artifacts

In spite of the facts that magnetic resonance spectroscopy (MRS) is applied as clinical tool in non-specialized institutions and that semi-automatic acquisition and processing tools can be used to produce quantitative information from MRS exams without expert information, issues of spectral quality and quality assessment are neglected in the literature of MR spectroscopy. Even worse, there is no consensus among experts on concepts or detailed criteria of quality assessment for MR spectra. Furthermore, artifacts are not at all conspicuous in MRS and can easily be taken for true, interpretable features. This article aims to increase interest in issues of spectral quality and quality assessment, to start a larger debate on generally accepted criteria that spectra must fulfil to be clinically and scientifically acceptable, and to provide a sample gallery of artifacts, which can be used to raise awareness for potential pitfalls in MRS.

The role of psychological stress in inflammatory bowel disease: quality assessment of methods of 18 prospective studies and suggestions for future research

BACKGROUND: Enquiries among patients on the one hand and experimental and observational studies on the other suggest an influence of stress on inflammatory bowel diseases (IBD). However, since this influence remains hypothetical, further research is essential. We aimed to devise recommendations for future investigations in IBD by means of scrutinizing previously applied methodology. METHODS: We critically reviewed prospective clinical studies on the effect of psychological stress on IBD. Eligible studies were searched by means of the PubMed electronic library and through checking the bibliographies of located sources. RESULTS: We identified 20 publications resulting from 18 different studies. Sample sizes ranged between 10 and 155 participants. Study designs in terms of patient assessment, control variables, and applied psychometric instruments varied substantially across studies. Methodological strengths and weaknesses were irregularly dispersed. Thirteen studies reported significant relationships between stress and adverse outcomes. CONCLUSIONS: Study designs, including accuracy of outcome assessment and repeated sampling of outcomes (i.e. symptoms, clinical, and endoscopic), depended upon conditions like sample size, participants' compliance, and available resources. Meeting additional criteria of sound methodology, like taking into account covariates of the disease and its course, is strongly recommended to possibly improve study designs in future IBD research.