Biomarkers in 5q-associated spinal muscular atrophy-a narrative review.

5q-associated spinal muscular atrophy (SMA) is a rare genetic disease caused by mutations in the SMN1 gene, resulting in a loss of functional SMN protein and consecutive degeneration of motor neurons in the ventral horn. The disease is clinically characterized by proximal paralysis and secondary skeletal muscle atrophy. New disease-modifying drugs driving SMN gene expression have been developed in the past decade and have revolutionized SMA treatment. The rise of treatment options led to a concomitant need of biomarkers for therapeutic guidance and an improved disease monitoring. Intensive efforts have been undertaken to develop suitable markers, and numerous candidate biomarkers for diagnostic, prognostic, and predictive values have been identified. The most promising markers include appliance-based measures such as electrophysiological and imaging-based indices as well as molecular markers including SMN-related proteins and markers of neurodegeneration and skeletal muscle integrity. However, none of the proposed biomarkers have been validated for the clinical routine yet. In this narrative review, we discuss the most promising candidate biomarkers for SMA and expand the discussion by addressing the largely unfolded potential of muscle integrity markers, especially in the context of upcoming muscle-targeting therapies. While the discussed candidate biomarkers hold potential as either diagnostic (e.g., SMN-related biomarkers), prognostic (e.g., markers of neurodegeneration, imaging-based markers), predictive (e.g., electrophysiological markers) or response markers (e.g., muscle integrity markers), no single measure seems to be suitable to cover all biomarker categories. Hence, a combination of different biomarkers and clinical assessments appears to be the most expedient solution at the time.

Impact of a bisphenol A, F, and S mixture and maternal care on the brain transcriptome of rat dams and pups.

Products containing BPA structural analog replacements have increased in response to growing public concern over adverse effects of BPA. Although humans are regularly exposed to a mixture of bisphenols, few studies have examined effects of prenatal exposure to BPA alternatives or bisphenol mixtures. In the present study, we investigate the effect of exposure to an environmentally-relevant, low-dose (150 ug/kg body weight per day) mixture of BPA, BPS, and BPF during gestation on the brain transcriptome in Long-Evans pups and dams using Tag RNA-sequencing. We also examined the association between dam licking and grooming, which also has enduring effects on pup neural development, and the transcriptomes. Associations between licking and grooming and the transcriptome were region-specific, with the hypothalamus having the greatest number of differentially expressed genes associated with licking and grooming in both dams and pups. Prenatal bisphenol exposure also had region-specific effects on gene expression and pup gene expression was affected more robustly than dam gene expression. In dams, the prelimbic cortex had the greatest number of differentially expressed genes associated with prenatal bisphenol exposure. Prenatal bisphenol exposure changed the expression of over 2000 genes in pups, with the majority being from the pup amygdala. We used Gene Set Enrichment Analysis (GSEA) to asses enrichment of gene ontology biological processes for each region. Top GSEA terms were diverse and varied by brain region and included processes known to have strong associations with steroid hormone regulation, cilium-related terms, metabolic/biosynthetic process terms, and immune terms. Finally, hypothesis-driven analysis of genes related to estrogen response, parental behavior, and epigenetic regulation of gene expression revealed region-specific expression associated with licking and grooming and bisphenol exposure that were distinct in dams and pups. These data highlight the effects of bisphenols on multiple physiological process that are highly dependent on timing of exposure (prenatal vs. adulthood) and brain region, and reiterate the contributions of multiple environmental and experiential factors in shaping the brain.

Corticosterone dynamically regulates retrotransposable element expression in the rat hippocampus and C6 cells.

The hippocampus is a highly plastic brain region sensitive to environmental stress. It shows dynamic changes in epigenetic marks associated with stress related learning. Previous work has shown that acute stress induces substantial transient changes in histone H3 lysine 9 trimethylation (H3K9me3). Moreover, increased H3K9me3 is enriched in hippocampal gene deserts accumulating within endogenous retroviruses and transposable elements. We have found that in response to acute glucocorticoid treatment, a similar change in global H3K9me3 is observed. However, when localized we found that H3K9me3 is markedly decreased at B2 short interspersed nuclear elements but not within intracisternal-A particle endogenous retroviruses. Further, decreased H3K9me3 valence within B2 elements was associated with increased transcript abundance. These data demonstrate the capacity for acute glucocorticoids to mobilize transposable elements via epigenetic unmasking. Reconciled with previous findings following acute stress, this suggests the capacity for mobile elements to potentially function as novel regulators given their dynamic regulation by stress and glucocorticoids.

[ENT surgery in anticoagulate patients]. / HNO-Chirurgie bei Patienten unter oraler Antikoagulation und Plättchenhemmer-Therapie.

BACKGROUND: In elective ENT surgery, one frequently sees -patients on oral anticoagulants and platelet inhibitors. While continuation of these therapies increases the risk of bleeding complications, indiscriminate discontinuation can have severe thromboembolic consequences. Furthermore, the number of -anticoagulants and platelet inhibitors in use has increased. The ENT-specialist is regulary confronted with the question of continuation, discontinuation, or bridging of this therapy. METHODS: Review of the available literature on bleeding complications associated with ENT interventions performed with and without anticoagulants. Overview of the indications for anticoagulants and the different mechansims of action and properties of the different agents. Development of protocols for risk stratification and for perioperative management. CONCLUSIONS: Patients on oral anticoagulants and platelet inhibitors have significant morbidity and mortality not only due to the underlying diseases, but also due to the perioperative management of these therapies. Perioperative management should be based on well-established treatment guidelines or, in high-risk patients, on multidisciplinary consultation. Even though the recommendations here are evidence-based and cover a multitude of clinical contingencies, they cannot replace clinical decision making, which must consider the specific characteristics and circumstances of the patient, the planned intervention, and the surgical environment.

High prevalence of undiagnosed impaired glucose regulation and diabetes mellitus in patients scheduled for an elective coronary angiography.

BACKGROUND: Impaired glucose regulation (IGR) and diabetes mellitus (DM) are amongst the main risk factors for developing coronary heart disease (CHD). The aim of this study was to investigate previously unknown glucose metabolism disorder in patients scheduled for an elective coronary angiography. METHODS: A total of 141 patients scheduled for coronary angiography without signs of acute myocardial ischemia or previous history of a glucose metabolism disorder were prospectively included in the study. An oral glucose tolerance test (OGTT) was performed in each patient. RESULTS: IGR was diagnosed in 40.4% (95% confidence interval 32.3-49.0) and undetected DM in 22.7% (16.1-30.5) of patients undergoing an elective coronary angiography. Depending on the severity of CHD, the percentage of IGR and DM increased up to 45.3% (34.6-56.5) and 26.7% (17.8-37.4) in the subgroup with the need of percutaneous angioplasty, while the corresponding proportions in the group without CHD were 30.3% (15.6-48.7) and 12.1% (3.4-28.2). The percentage of undiagnosed DM increased with the number of epicardial vessels involved. Using the recommended fasting plasma glucose value of > or = 126 mg/dl for the diagnosis of DM, we would have missed 71.9% of the patients with undiagnosed DM. If all patients with a fasting plasma glucose of > or = 90 mg/dl had been subjected to OGTT, 93.8% of DM would have been identified. CONCLUSIONS: Prevalences of DM and IGR are higher than expected in patients with CHD. An OGTT should be considered for all patients with a fasting plasma glucose > or = 90 mg/dl undergoing a coronary angiography.

Cardiogenic shock due to thrombotic thrombocytopenic purpura.

We report the case of a 49-year-old man with thrombotic thrombocytopenic purpura (TTP) leading to cardiogenic shock. Laboratory data were typical for TTP with thrombocytopenia and microangiopathic hemolytic anemia. The electrocardiogram recorded significant ST-segment elevations in the anterior and inferior leads. In addition' coronary angiography showed normal epicardial coronary arteries with slow flow. The patient died due to electromechanical dissociation six hours after admission. During autopsy typical features of thrombotic thrombocytopenic purpura were found. Histological preparation of the heart showed a diffuse myocardial necrosis due to microvascular thrombosis. Cardiac involvement is common in TTP but extended myocardial necrosis has been reported in only a few cases.

[Therapy options for Prinzmetal angina induced ventricular vulnerability]. / Therapieoptionen einer Prinzmetal-Angina induzierten ventrikulären Vulnerabilität.

We report about a 46 year old male, who survived sudden cardiac death caused by recurrent ventricular tachycardia as the clinical manifestation of a vasospastic right coronary artery. After implantation of an implantable cardioverter defibrillator, the patient did not respond to conservative treatment despite of different drug therapies. Therefore, the vasospastic right coronary artery was treated by a percutaneous transluminal coronary angioplasty and stenting, which could not reduce the occurrence of further tachycardias. Finally, the patient underwent an operative myocardial revascularization combined with sympathectomy. During the whole follow-up of six months no new episodes of ventricular tachyarrhythmias have occurred.

[Catheter ablation of ectopic atrial tachycardia by electrical pulmonary vein disconnection]. / Katheterablation einer ektopen atrialen Tachykardie mittels elektrischer Pulmonalvenendiskonnektion.

We report a 25-year-old female patient with a long history of symptomatic paroxysmal supraventricular tachycardia. Electroanatomic activation mapping demonstrated a focal tachycardia originating in the right upper pulmonary vein, 3 cm distal to the ostium. Due to the recent experiences in the management of focal atrial fibrillation with catheter ablation, direct ablation applied inside the pulmonary vein was avoided. Instead, an electrical disconnection of the pulmonary musculature from the left atrium guided by a circumferential 10-electrode mapping catheter was performed. The patient has since been asymptomatic during follow-up.

Molecular classification of human carcinomas by use of gene expression signatures.

Classification of human tumors according to their primary anatomical site of origin is fundamental for the optimal treatment of patients with cancer. Here we describe the use of large-scale RNA profiling and supervised machine learning algorithms to construct a first-generation molecular classification scheme for carcinomas of the prostate, breast, lung, ovary, colorectum, kidney, liver, pancreas, bladder/ureter, and gastroesophagus, which collectively account for approximately 70% of all cancer-related deaths in the United States. The classification scheme was based on identifying gene subsets whose expression typifies each cancer class, and we quantified the extent to which these genes are characteristic of a specific tumor type by accurately and confidently predicting the anatomical site of tumor origin for 90% of 175 carcinomas, including 9 of 12 metastatic lesions. The predictor gene subsets include those whose expression is typical of specific types of normal epithelial differentiation, as well as other genes whose expression is elevated in cancer. This study demonstrates the feasibility of predicting the tissue origin of a carcinoma in the context of multiple cancer classes.

Morphological differences of the internal thoracic artery in patients with and without coronary artery disease--evaluation by duplex-scanning.

OBJECTIVE: The internal thoracic artery is an established arterial graft for myocardial revascularisation, especially of the left anterior descending artery because of a higher patency rate compared to venous grafts. It has never been investigated, whether there are morphological differences in this vessel between patients with or without coronary artery disease or if they are comparable to morphological changes in the common carotid artery. METHODS: We investigated the internal thoracic artery and the common carotid artery of 24 patients (12 with coronary artery disease, 12 without coronary artery disease) with an ultrasonic system on both sides. The intima-media thickness and the diameter of both vessels were estimated. RESULTS: The intima-media-thickness of the internal thoracic artery was comparable in all patients, independent of the presence of a coronary artery disease (0.51+/-0.11 mm with coronary artery disease, 0.50+/-0.17 mm without coronary artery disease, P>0.05). Compared with this the intima-media-thickness of the common carotid artery was thicker in patients with coronary artery disease (0.84+/-0.13 mm with coronary artery disease, 0.73+/-0.07 mm without coronary artery disease, P< or or =0.014). There was no correlation between the thickness of the internal thoracic artery and the common carotid artery (r=0.018, P>0.05). CONCLUSIONS: It could be demonstrated for the first with non-invasive ultrasound, that the intima-media-complex of the internal thoracic artery is protected of the influence of arteriosclerosis. There are no morphological differences like the intima-media-thickness of the common carotid artery. The proven protective mechanism underlines the widespread use of the internal thoracic artery as a coronary artery bypass graft.

[Interventional therapy after failed fibrinolysis in acute myocardial infarct. Acute and long-term outcome of referral for rescue balloon angioplasty]. / Interventionelle Therapie nach fehlgeschlagener Fibrinolyse beim akuten Myokardinfarkt. Akut- und Langzeitergebnisse nach Verlegung zur "Rescue"-Ballonangioplastie.

BACKGROUND: The results from studies of coronary angioplasty after failed thrombolysis (rescue-PTCA) in acute myocardial infarction are contradictory. Long-term results were not presented till now. Therefore we analyzed the data from our registry of those patients whose acute and long-term results were available. PATIENTS AND METHODS: Data of 49 patients were analyzed who had been admitted for rescue-PTCA from other hospitals. Thrombolysis had to be started < 6 hours (mean 2.7 hours) from onset of symptoms. Rescue-PTCA had to be completed within < 24 hours (mean 10.5 hours). 37 patients received streptokinase, seven rt-PA, three urokinase and two prourokinase. Electrocardiographic and clinical criteria were used to define failure of thrombolysis. The data of the acute results were from a prospective registry and the long-term results came from clinical follow-up visits and a questionnaire sent to the patients. RESULTS: Mean age of the patients was 48.5 years (38-78 years), 45 male, nine patients in cardiogenic shock (18%), infarct related artery (IRA): RCA 22x, LAD 21x, LCX 5x, CABG 1x, single vessel disease 27x, multiple vessel disease 22x. Acute results: Initial IRA-TIMI flow 0 in 28 patients, 1 in twelve patients, 2 in 9 patients; after rescue-PTCA TIMI flow 1 in one patient, 2 in two patients, 3 in 46 patients (procedural success 94%). Hospital mortality 8.2% (four patients), all in cardiogenic shock. Early reocclusion rate 10%. Bleeding complications 14%, no fatal complications. Long-term results: Observation period 2.5 years in 42 patients (0.5-6.5 years). Three more deaths. Total mortality 14% (7/49). Angiographic follow-up: Ejection fraction initially 50%; 53% after 3 months. Repeat revascularization in 43% (15/35): Re-PTCA in 8/35, surgery in 6/35 patients, 1x transplantation. 80% of the patients were free from angina or heart failure. CONCLUSIONS: Rescue-PTCA in acute myocardial infarction has a high procedural success rate with a low hospital mortality. It is the treatment of choice for patients in cardiogenic shock. Transportation to an interventional center is safe. The reintervention rate is comparably high. The long-term results are good.

Robust parametric and semi-parametric spot fitting for spot array images.

In this paper we address the problem of reliably fitting parametric and semi-parametric models to spots in high density spot array images obtained in gene expression experiments. The goal is to measure the amount of label bound to an array element. A lot of spots can be modelled accurately by a Gaussian shape. In order to deal with highly overlapping spots we use robust M-estimators. When the parametric method fails (which can be detected automatically) we use a novel, robust semi-parametric method which can handle spots of different shapes accurately. The introduced techniques are evaluated experimentally.

[Aluminum dust lungs]. / Zur Kenntnis der Aluminiumstaublunge.

In general aluminium dust induced fibrosis of the lungs occurs very rarely. Based on an own observation of a clinical case the problem of clinical and pathological diagnosis is discussed. Aluminium was detected in the lung by histological, chemical and atomic absorption spectroscopy procedures. Anamnesis, epicrisis, clinical symptomatology and the result of autopsy permit to diagnose aluminium dust induced fibrosis of the lung, taking into consideration the detection of aluminium dust by chemical and atomic absorption spectroscopy methods.

Subcellular distribution of ependymins in goldfish brain measured by radioimmunoassay.

Goldfish CNS was fractionated by differential and density gradient centrifugation. The fractions obtained were characterized by marker enzymes typical of various subcellular organelles. They were further analyzed by radioimmunoassay for their contents of ependymins, two CNS glycoproteins known to participate in biochemical reactions after learning events. Ependymins were shown to be major constituents of the soluble cytoplasm (5.6% of the total protein content). The nuclear fraction was virtually devoid of ependymins (0.6% of protein). Small amounts were observed in the crude synaptosomal and microsomal fractions (1.0 and 3.5%, respectively). The highest steady-state concentration of ependymins, however, was measured in the brain extracellular fluid (15.6% of the protein), including the CSF. The specificity of the distribution was examined by intracerebroventricular injection of 125I-labeled ependymins as exogenous marker substances. No indication of an artificial redistribution of the radiolabel during homogenization and fractionation was obtained. The exogenous analogues of ependymins were, however, incorporated in vivo into organelles recovered in the nuclear and crude synaptosomal fractions. Our results suggest that ependymins may interact with synaptic membranes from the extracellular fluid, although so far no evidence for a specific receptor-type binding site could be obtained in vitro.

Regional distribution of ependymins in goldfish brain measured by radioimmunoassay.

Ependymins are goldfish glycoproteins known to participate in biochemical reactions of memory consolidation after an operant vestibulomotor training-task. The distribution of these proteins was analysed by means of a highly sensitive and specific radioimmunoassay. Ependymins were shown to be characteristic constituents of the nervous system, but they were virtually absent from all other tissues investigated. They were widely distributed over many brain regions and particularly enriched in mesencephalic structures. In the optic tectum, the tegmentum and in the vagal lobes ependymins constituted 3.2, 2.8 and 3.5%, respectively, of the total protein content. The highest steady-state concentration of ependymins (15.4% of protein) was measured, however, in the brain extracellular fluid including the cerebrospinal fluid. Lactate dehydrogenase activity was monitored to demonstrate that only negligible amounts of cytoplasmic constituents were released during the collection of extracellular proteins. Ependymin concentrations were lower in those brain areas which contain few cell bodies, but many glial and fibrous elements. The specific distribution of the intrinsic ependymins was compared with that of intracerebroventricularly injected [(125)I]-labeled ependymin. This exogenous marker substance was quickly incorporated and then cleared rapidly from the central nervous system with a half-life of 2 h. Our quantitative analysis of the distribution of ependymins reveals that they are specific major constituents of the goldfish nervous system. Their fast turnover, their wide distribution over many brain regions, with some enrichment in mesencephalic structures, and especially their very high concentration in the extracellular brain fluid suggest that ependymins may act on neuronal membranes from the extracellular fluid.

[Clinical light and electron microscopic findings in patients with late and early congestive cardiomyopathies (author's transl)]. / Klinische, licht-und elektroneumikroskopische Befunde bei frühen und fortgeschrittene Formen kongestiver Kardiomyopathien

Right of left ventricular biopsies were performed in 50 patients with late and early forms of congestive cardiomyopathy. Clinical data as well as light and electron microscopic findings are described. Chronical myocarditis could be detected by histological examination in three patients. Hypertrophy and degenerative changes of the heart muscle cells and interstitial fibrosis were the major morphological finding in the other cases. There is a good correlation between the severity of clinical symptoms and the extent of light and electron microscopical changes. In some patients with mild clinical symptoms advanced ultrastructural alternations were found.