Krankenanstalt Rudolfstiftung

Vienna, Austria

Krankenanstalt Rudolfstiftung

Vienna, Austria
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Finsterer J.,Krankenanstalt Rudolfstiftung | Ohnsorge P.,European Academy For Environmental Medicine Ev
Regulatory Toxicology and Pharmacology | Year: 2013

Cardiovascular disease may be induced or worsened by mitochondrion-toxic agents. Mitochondrion-toxic agents may be classified as those with or without a clinical effect, those which induce cardiac disease only in humans or animals or both, as prescribed drugs, illicit drugs, exotoxins, or nutritiants, as those which affect the heart exclusively or also other organs, as those which are effective only in patients with a mitochondrial disorder or cardiac disease or also in healthy subjects, or as solid, liquid, or volatile agents. In humans, cardiotoxic agents due to mitochondrial dysfunction include anthracyclines (particularly doxorubicin), mitoxantrone, cyclophosphamide, cisplatin, fluorouracil, imatinib, bortezomib, trastuzumab, arsenic trioxide, cyclosporine-A, zidovudine, lamotrigine, glycosides, lidocain, isoproterenol, nitroprusside, pivalic acid, alcohol, cocaine, pesticides, cadmium, mycotoxins, cyanotoxins, meat meal, or carbon monoxide. Even more agents exhibit cardiac abnormalities due to mitochondrion-toxicity only in animals or tissue cultures. The mitochondrion-toxic effect results from impairment of the respiratory chain, the oxidative phosphorylation, the Krebs cycle, or the β-oxidation, from decrease of the mitochondrion-membrane potential, from increased oxidative stress, reduced anti-oxidative capacity, or from induction of apoptosis. Cardiac abnormalities induced via these mechanisms include cardiomyopathy, myocarditis, coronary heart disease, arrhythmias, heart failure, or Takotsubo syndrome. Discontinuation of the cardiotoxic agent results in complete recovery in the majority of the cases. Antioxidants and nutritiants may be of additional help. Particularly coenzyme-Q, riboflavin, vitamin-E, vitamin-C, l-carnitine, vitamin-D, thiamin, folic acid, omega-3 fatty acids, and d-ribose may alleviate mitochondrial cardiotoxic effects. © 2013 Elsevier Inc.


Finsterer J.,Krankenanstalt Rudolfstiftung | Soraru G.,University of Padua
Journal of Molecular Neuroscience | Year: 2016

Spinal and bulbar muscular atrophy (SBMA) is regarded as a disorder with adult onset between third and fifth decade of life. However, there is increasing evidence that SBMA may start already before adulthood. The present study investigated the following: (1) Which clinical manifestations have been described so far in the literature as initial manifestations? (2) Which was the age at onset of these manifestations? and (3) Is age at onset dependent on the CAG-repeat length if non-motor manifestations are additionally considered? Data for this review were identified by searches of MEDLINE using appropriate search terms. Onset manifestations in SBMA can be classified as frequent, rare, motor, non-motor, or questionable. Frequent are muscle weakness, cramps, fasciculations/twitching, tremor, dysarthria, dysphagia, or gynecomastia. Rare are myalgia, easy fatigability, exercise intolerance, polyneuropathy, hyper-CKemia, under-masculinized genitalia, scrotal hypospadias, microphallus, laryngospasm, or oligospermia. Questionable manifestations include sensory disturbances, cognitive impairment, increased pituitary volume, diabetes, reduced tongue pressure, elevated creatine-kinase, or low androgens/high estrogens. Age at onset is highly variable ranging from 4–76 years. Non-motor manifestations develop usually before motor manifestations. Age at onset depends on what is considered as an onset manifestation. Considering non-motor onset manifestations, age at onset is independent of the CAG-repeat size. In conclusion, age at onset of SBMA depends on what is regarded as onset manifestation. If non-motor manifestations are additionally considered, age at onset is independent of the CAG-repeat length. Since life expectancy is hardly reduced in SBMA, re-investigation of patients from published studies with regard to their initial disease profiles is recommended. © 2015, Springer Science+Business Media New York.


Stollberger C.,Steingasse | Finsterer J.,Krankenanstalt Rudolfstiftung
Current Pharmaceutical Design | Year: 2010

Arrhythmias in left ventricular hypertrabeculation/noncompaction (LVHT) comprise sustained or non-sustained ventricular tachycardia (VT) (n=135), atrial fibrillation (AF) (n=96) AV block (n=55) and QT prolongation (n=47). The prevalence differs between children and adults. In children most frequent are WPW-syndrome (n=24), AV block (n=24), VT (n=17) and bradycardia (n=15). In adults most frequent arrhythmias are VT (n=118), AF (n=95), QT prolongation (n=42) and AV block (n=31). Some arrhythmias are more frequently reported in children than in adults like WPW-syndrome (24 vs. 17 patients), second-degree AV block (4 vs. 0 patients), brady cardia (15 vs. 3 patients) and ventricular fibrillation (VF) (9 vs. 5 patients). There are nearly no pediatric cases with AF (1 vs. 95 patients). In 120 patients implantable cardioverters/defibrillators have been implanted for primary or secondary prevention of sudden cardiac death. The pathomechanisms of arrhythmias in LVHT are largely unknown, especially if patients with LVHT and neuromuscular disorders are more prone to arrhythmias than patients without. There is a need to clarify risk factors for VT or VF because 19% of LVHT patients with VT or VF have a normal systolic function and demonstration of systolic dysfunction is no reliable risk marker. Data about long-term follow-up of LVHT patients with implanted cardioverters/defibrillators are necessary since the indication for prophylactic implantation is still unclear. AF in LVHT increases the embolic risk, thus it would be useful to know which LVHT patients who have sinusrhythm at baseline are prone to develop AF in order to start early with anticoagulant therapy. © 2010 Bentham Science Publishers Ltd.


Finsterer J.,Krankenanstalt Rudolfstiftung | Frank M.,Krankenanstalt Rudolfstiftung
Current Topics in Medicinal Chemistry | Year: 2013

Drug repurposing (drug repositioning, drug reprofiling, drug retasking) gains increasing importance as the development of new drugs becomes increasingly expensive. Though only a few compounds have been approved for new indications in the field of metabolic disorders, there are a number of substances which have the potential to become reprofiled in a new indication. Generally, reprofiled drugs for metabolic disorders can be classified in three groups. Group A contains those of which both, the original and repurposed indication, concern metabolic disorders. Group B comprises drugs, which were originally approved for non-metabolic disorders but show beneficial effects for metabolic disorders after repurposing. Group C comprises drugs, which were originally approved for metabolic disorders and are effective for non-metabolic disorders in their repurposed indication. Repurposed drugs in the field of metabolic disorders of group A include tetra-hydrobiopterin, originally indicated for phenylketonuria and now also approved for tetrahydrobiopterindeficiency, coenzyme-Q, originally approved for primary coenzyme-Q deficiency and reprofiled for statin-myopathy, and colesevelam, originally approved to reduce elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) and now being approved for type-2-diabetes. An example of group C is phenylbutyrate, which was originally approved for urea-cycle disorders and meanwhile gained approval for progressive familial intrahepatic cholestasis type 2 due to mutations in the ABCB11 gene. Still additional compounds used to treat metabolic (non-metabolic) disorders show promising effects in non-metabolic (metabolic disorders) after repurposing in cell and tissue models. Future investigations will need to identify which candidate drugs may leave the pipeline status to acquire approval for new indications. © 2013 Bentham Science Publishers.


Finsterer J.,Krankenanstalt Rudolfstiftung
European Journal of Paediatric Neurology | Year: 2010

Treatment of mitochondrial disorders (MIDs) is a challenge since there is only symptomatic therapy available and since only few randomized and controlled studies have been carried out, which demonstrate an effect of some of the symptomatic or supportive measures available. Symptomatic treatment of MIDs is based on mainstay drugs, blood transfusions, hemodialysis, invasive measures, surgery, dietary measures, and physiotherapy. Drug treatment may be classified as specific (treatment of epilepsy, headache, dementia, dystonia, extrapyramidal symptoms, Parkinson syndrome, stroke-like episodes, or non-neurological manifestations), non-specific (antioxidants, electron donors/acceptors, alternative energy sources, cofactors), or restrictive (avoidance of drugs known to be toxic for mitochondrial functions). Drugs which more frequently than in the general population cause side effects in MID patients include steroids, propofol, statins, fibrates, neuroleptics, and anti-retroviral agents. Invasive measures include implantation of a pacemaker, biventricular pacemaker, or implantable cardioverter defibrillator, or stent therapy. Dietary measures can be offered for diabetes, hyperlipidemia, or epilepsy (ketogenic diet, anaplerotic diet). Treatment should be individualized because of the peculiarities of mitochondrial genetics. Despite limited possibilities, symptomatic treatment should be offered to MID patients, since it can have a significant impact on the course and outcome. © 2009 European Paediatric Neurology Society.


Finsterer J.,Krankenanstalt Rudolfstiftung
Journal of the Neurological Sciences | Year: 2011

Mitochondrial disorders (MIDs) occasionally manifest as polyneuropathy either as the dominant feature or as one of many other manifestations (inherited mitochondrial neuropathy). MIDs in which polyneuropathy is the dominant feature, include NARP syndrome due to the transition m.8993T>, CMT2A due to MFN2 mutations, CMT2K and CMT4A due to GDAP1 mutations, and axonal/demyelinating neuropathy with external ophthalmoplegia due to POLG1 mutations. MIDs in which polyneuropathy is an inconstant feature among others is the MELAS syndrome, MERRF syndrome, LHON, Mendelian PEO, KSS, Leigh syndrome, MNGIE, SANDO; MIRAS, MEMSA, AHS, MDS (hepato-cerebral form), IOSCA, and ADOA syndrome. In the majority of the cases polyneuropathy presents in a multiplex neuropathy distribution. Nerve conduction studies may reveal either axonal or demyelinated or mixed types of neuropathies. If a hereditary neuropathy is due to mitochondrial dysfunction, the management of these patients is at variance from non-mitochondrial hereditary neuropathies. Patients with mitochondrial hereditary neuropathy need to be carefully investigated for clinical or subclinical involvement of other organs or systems. Supportive treatment with co-factors, antioxidants, alternative energy sources, or lactate lowering agents can be tried. Involvement of other organs may require specific treatment. Mitochondrial neuropathies should be included in the differential diagnosis of hereditary neuropathies. © 2011 Elsevier B.V.


Finsterer J.,Krankenanstalt Rudolfstiftung
Journal of the Neurological Sciences | Year: 2010

Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare, adult-onset, X-linked, recessive trinucleotide, polyglutamine (poly-G) disorder, caused by expansion of an unstable CAG-tandem-repeat in exon 1 of the androgen-receptor (AR) gene on chromosome Xq11-12. Poly-Q-expanded AR accumulates in nuclei, undergoes fragmentation and initiates degeneration and loss of motor neurons and dorsal root ganglia. Phenotypically, patients present with weakness and wasting of the facial, bulbar and extremity muscles, sensory disturbances, and endocrinological disturbances, such as gynecomastia and reduced fertility. In the limb muscles weakness and wasting may be symmetric or asymmetric, proximal or distal, or may predominate at the lower or upper limb muscles. There may be mild to severe hyper-CK-emia, elevated testosterone or other sexual hormones, abnormal motor and sensory nerve conduction studies, and neuropathic or rarely myopathic alterations on muscle biopsy. BSMA is diagnosed if the number of CAG-repeats exceeds 40. No causal therapy is available but symptomatic therapy may be beneficial for weakness, tremor, endocrinological abnormalities, muscle cramps, respiratory failure, or dysphagia. The course is slowly progressive and the ability to walk lost only late in life. Only few patients require ventilatory support and life expectancy is only slightly compromised. © 2010 Elsevier B.V.


Finsterer J.,Krankenanstalt Rudolfstiftung | Burgunder J.-M.,University of Bern
European Journal of Medical Genetics | Year: 2014

Background: Genetic background and pathogenesis of motor neuron diseases (MNDs) have been increasingly elucidated over recent years. Aims: To give an overview about publications during the last year concerning the genetic background and phenotypic manifestations of MNDs, such as familial or sporadic amyotrophic lateral sclerosis (fALS, sALS), spinal muscular atrophies (SMA), bulbospinal muscular atrophy (BSMA), and unclassified MNDs. Methods: Pubmed search for literature about ALS, SMA, and BSMA for the period 10/2012 to 9/2013. Results: An increasing number of mutated genes is recognised in fALS but also sALS patients. Genes mutated in sALS include C9orf72, SOD1, TARDBP, FUS, UBQL2, SQSTM1, DCTN1, and UNC13A. Juvenile (onset <20. y) and adult ALS (early onset 20-60. y, late onset >60. y) are differentiated. Juvenile fALS is most frequently caused by mutations in ALS2, SETX, spatacsin, or Sigmar1 and adult fALS by mutations in C9orf72, SOD1, TARDBP, and FUS. Onset, phenotype, progression, and outcome of ALS are variable between different mutations, different genes, and different countries. Differentiation between sALS and fALS cases becomes artificial. Conclusions: Further progress has been made over the last year in the clarification and understanding of the aetiology and pathogenesis of MNDs. However, further effort is needed to answer the many remaining questions. © 2014 Elsevier Masson SAS.


Finsterer J.,Krankenanstalt Rudolfstiftung
BMC Musculoskeletal Disorders | Year: 2012

Background: Biomarkers of peripheral muscle fatigue (BPMFs) are used to offer insights into mechanisms of exhaustion during exercise in order to detect abnormal fatigue or to detect defective metabolic pathways. This review aims at describing recent advances and future perspectives concerning the most important biomarkers of muscle fatigue during exercise. Results: BPMFs are classified according to the mechanism of fatigue related to adenosine-triphosphate- metabolism, acidosis, or oxidative-metabolism. Muscle fatigue is also related to an immunological response. impaired calcium handling, disturbances in bioenergetic pathways, and genetic responses. The immunological and genetic response may make the muscle susceptible to fatigue but may not directly cause muscle fatigue. Production of BPMFs is predominantly dependent on the type of exercise. BPMFs need to change as a function of the process being monitored, be stable without appreciable diurnal variations, correlate well with exercise intensity, and be present in detectable amounts in easily accessible biological fluids. The most well-known BPMFs are serum lactate and interleukin-6. The most widely applied clinical application is screening for defective oxidative metabolism in mitochondrial disorders by means of the lactate stress test. The clinical relevance of most other BPMFs, however, is under debate, since they often depend on age, gender, physical fitness, the energy supply during exercise, the type of exercise needed to produce the BPMF, and whether healthy or diseased subjects are investigated. Conclusions: Though the role of BPMFs during fatigue is poorly understood, measuring BPMFs under specific, standardised conditions appears to be helpful for assessing biological states or processes during exercise and fatigue. © 2012 Finsterer; licensee BioMed Central Ltd.


Finsterer J.,Krankenanstalt Rudolfstiftung | Cripe L.,Nationwide Childrens Hospital
Nature Reviews Cardiology | Year: 2014

Treatment of cardiac disease in patients with dystrophinopathies substantially improves outcomes. In this Review, we summarize and discuss findings from the past 20 years and future perspectives for therapeutic options to treat cardiovascular disease in these patients. Their cardiac disease can be subclinical or symptomatic. Presymptomatic treatment with angiotensin- converting-enzyme inhibitors, angiotensin-II-receptor blockers, β-blockers, or mineralocorticoid-receptor antagonists is a well-established method to delay the clinical manifestations of cardiac disease. Treatment of patients with dystrophinopathy and symptomatic cardiac disease, such as heart failure or arrhythmia, follows well-established guidelines for the general treatment of cardiac disease. These treatments improve outcomes, particularly when supported by noncardiovascular measures in the advanced stages of cardiac involvement. Patients with dystrophinopathies and cardiac disease can also benefit from optimal management of scoliosis, noninvasive positive pressure ventilation, and from pain therapy. Molecular therapies for treating cardiac diseases in patients with dystrophinopathies are experimental, but promising. © 2014 Macmillan Publishers Limited. All rights reserved.

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