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Biomedical subjects

D Pongratz

Publications and source records attributed to D Pongratz.

At least 55 records · Page 3Linked to original sources
PubMed2000

German open label trial of riluzole 50 mg b.i.d. in treatment of amyotrophic lateral sclerosis (ALS).

UNLABELLED: Riluzole is currently the only drug that holds any hope of prolonging life in amyotrophic lateral sclerosis (ALS) by slowing the rate of disease progression. METHODS AND RESULTS: Between 1995 and 1997 a total of 7916 ALS patients in 39 countries, were given 100 mg riluzole per day for a mean of 7.2 months. The present report focuses on the German results in comparison to the total population. Nine hundred and nineteen patients were treated in 25 German centres; 162 (17.6%) died from the disease during the course of the study. Serious adverse events attributed to the study medication occurred in 16 patients (1.7%). Most frequently these were reversible changes in liver enzymes (0.9%) occurring during the first 3 months, none resulted in death. In all, 413 patients (44.9%) reported an adverse event. The most frequent were reduced lung function (7.3%), nausea (7.1%), asthenia (5.8%), pneumonia (2.5%) and abdominal pain (2.5%). CONCLUSION: The results of the study allow the conclusion that riluzole is well tolerated. The majority of adverse events were symptoms of the underlying disease and were not attributed to riluzole. Overall the safety profile found in the German centres was very similar to the profile seen in the total patient population and was more favourable than in the two published double-blind studies [New Engl J Med 330 (1994) 585; Lancet 347 (1996) 1425].

Amyotrophic Lateral Sclerosis↗
PubMed2000

Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study.

The authors assessed the safety and efficacy of creatine monohydrate (Cr) in various types of muscular dystrophies in a double-blind, crossover trial. Thirty-six patients (12 patients with facioscapulohumeral dystrophy, 10 patients with Becker dystrophy, 8 patients with Duchenne dystrophy, and 6 patients with sarcoglycan-deficient limb girdle muscular dystrophy) were randomized to receive Cr or placebo for 8 weeks. There was mild but significant improvement in muscle strength and daily-life activities by Medical Research Council scales and the Neuromuscular Symptom Score. Cr was well tolerated throughout the study period.

Activities of Daily Living↗
PubMed2000

Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients.

Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. Using an assay that combines tRNA oxidation and circularization we have determined the relative amounts and states of aminoacylation of mutant and wild-type tRNAs in tissue samples from patients with MELAS syndrome (mito- chondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and MERRF syndrome (myoclonus epilepsy with ragged red fibers), respectively. In most, but not all, biopsies from MELAS patients carrying the A3243G substitution in the mitochondrial tRNA(Leu(UUR))gene, the mutant tRNA is under-represented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the A8344G substitution in the tRNA(Lys)gene neither the relative abundance nor the aminoacylation of the mutated tRNA is affected. Thus, whereas the A3243G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNA(Leu), the A8344G mutation does not affect tRNA(Lys)function in the same way.

Acylation↗
PubMed2000

High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study.

Sporadic inclusion body myositis (s-IBM) is an acquired inflammatory muscle disease of unknown cause. In general, s-IBM presents with slowly progressive, asymmetric weakness, and atrophy of skeletal muscle. There is a mild transitory or nil responsiveness to standard immunosuppressive treatment. A controlled cross-over study of 22 s-IBM patients over 3 months showed a partial improvement in those treated with high-dose intravenous immunoglobulin therapy (IVIG) versus placebo. The present study included 22 patients aged 32-75 years and with a mean duration of disease of 5.2+/-3.6 years. They were randomized by a double-blind, placebo-controlled, cross-over design to monthly infusions of 2 g/kg bodyweight IVIG or to placebo for 6 months each, followed by the alternative treatment. After 6 and 12 months the response to treatment was evaluated, using a modified Medical Research Council scale, Neuromuscular Symptom Score (NSS), the patient's own assessment of improvement, arm outstretched time, and electromyography. No serious side effects were seen, in particular no viral infection and no major cardiac or neurological complications. Overall there was no progression of the disease in 90% of patients, unlike that which might have been expected in untreated patients. A mild and significant improvement (11%) in clinical symptoms was found using NSS, but not with other test procedures. There was a trend to mild improvement in treated patients when using other tests. Individual responses to treatment was heterogeneous. The validity of this study may be reduced by mismatch of groups with regard to age at onset and variability in disease expression. The findings of this study largely confirm those of a previous IVIG trial. Treatment with IVIG may be mildly effective in s-IBM by preventing disease progression or inducing mild improvement. Long-term studies are needed to evaluate further the benefit of IVIG therapy in s-IBM.

Adult↗
PubMed2000

An inherited 4q35-EcoRI-DNA-fragment of 35 kb in a family with a sporadic case of facioscapulohumeral muscular dystrophy (FSHD).

We present a case of an adult male patient showing clinical, neurophysiological and histological signs consistent with the phenotype of facioscapulohumeral muscular dystrophy. On molecular testing with a 4q35-DNA-probe p13E-11 (D4F104S1), the patient, his clinically unaffected mother and two sisters shared a 4q35-EcoRI-DNA-fragment of 35 kb on the transition between FSHD1A-associated and polymorphic fragments. Explanatory hypotheses, such as reduced penetrance in females or a phenotype unlinked to the 4q35-locus are considered. Alternatively, additional changes in the unidentified FSHD1A gene could have caused the phenotype. Thus, in such rare cases, the diagnostic evidence of 4q35-EcoRI-fragments is still limited.

Adult↗
PubMed2000

Efficacy and tolerability of tropisetron in primary fibromyalgia--a highly selective and competitive 5-HT3 receptor antagonist. German Fibromyalgia Study Group.

OBJECTIVE: Based on a potential role for serotonin receptors in fibromyalgia, we investigated the efficacy and tolerability of treatment with tropisetron, a highly selective, competitive inhibitor of the 5-HT3 receptor. METHODS: In this prospective, multicenter, double-blind, parallel-group, dose-finding study, 418 patients suffering from primary fibromyalgia (ACR criteria) were randomly assigned to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily, respectively. The duration of treatment was 10 days. The clinical response was measured by changes in pain-score, visual analog scale (VAS), and the number of painful tender-points. RESULTS: Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) when compared with placebo (26.2%) (p=0.033). The absolute reduction in pain-score was -13.5% for 5 mg tropisetron, -13.0% for 10 mg tropisetron, and -6.3% for placebo (p<0.05). The effects of 15 mg tropisetron were similar to placebo, thus suggesting a bell-shaped dose-response curve. Compared with placebo, treatment with 5 mg tropisetron led to a significant improvement (p<0.05) in VAS, while a clear trend in terms of clinical benefit was seen with 10 mg tropisetron. The number of painful tender-points was also reduced significantly (p=0.002) in the 5 mg tropisetron group. Of interest, during the 12-month follow-up period, pain intensity of responders on 5 mg and 10 mg tropisetron was still markedly below baseline. The treatment was well tolerated, with gastro-intestinal complaints being the most frequently reported side effects, in keeping with the known safety profile for 5-HT3 receptor antagonists. CONCLUSIONS: This study demonstrates the efficacy of short-term treatment with 5 mg tropisetron once daily in primary fibromyalgia. Treatment was well tolerated and prolonged clinical benefits were seen.

Adolescent↗
PubMed2000

Successful management of polyneuropathy associated with IgM gammopathy of undetermined significance with antibody-based immunoadsorption.

Peripheral polyneuropathies associated with monoclonal IgM gammopathy of undetermined significance often have a progressive course and optimal treatment has not been established. We report on a patient diagnosed with polyneuropathy associated with benign IgM gammopathy, who was successfully treated with antibody-based immunoadsorption only. The neurological symptoms of the patient improved continuously over six months of treatment. Controlled trials should be performed to define this indication for antibody-based immunoadsorption therapy.

Humans↗
PubMed1999

A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin.

OBJECTIVE: Mutation analysis of the acetylcholine receptor (AChR) epsilon subunit gene in patients with sporadic or autosomal recessive congenital myasthenic syndromes (CMS). BACKGROUND: The nicotinic AChR of skeletal muscle is a neurotransmitter-gated ion channel that mediates synaptic transmission at the vertebrate neuromuscular junction. Mutations in its gene may cause congenital myasthenic syndromes. A recently described mutation in exon 12 of the AChR epsilon subunit (epsilon1267delG) disrupts the cytoplasmic loop and the fourth transmembrane region (M4) of the AChR epsilon subunit. METHODS: Forty-three CMS patients from 35 nonrelated families were clinically classified as sporadic cases of CMS (group III according to European Neuromuscular Centre consensus) and were analyzed for epsilon1267delG by PCR amplification and sequence analysis. RESULTS: The authors report the complete genomic sequence and organization of the gene coding for the epsilon subunit of the human AChR (accession number AF105999). Homozygous epsilon1267delG was identified in 13 CMS patients from 11 independent families. All epsilon1267delG families were of Gypsy or southeastern European origin. Genotype analysis indicated that they derive from a common ancestor (founder) causing CMS in the southeastern European Gypsy population. Phenotype analysis revealed a uniform pattern of clinical features including bilateral ptosis and mild to moderate fatigable weakness of ocular, facial, bulbar, and limb muscles. CONCLUSIONS: The mutation epsilon1267delG might be frequent in European congenital myasthenic syndrome patients of Gypsy ethnic origin. In general, patients (epsilon1267delG) were characterized by the onset of symptoms in early infancy, the presence of ophthalmoparesis, positive response to anticholinesterase treatment, and the benign natural course of the disease.

Adolescent↗
PubMed1999

Markedly different course of Friedreich's ataxia in sib pairs with similar GAA repeat expansions in the frataxin gene.

Friedreich's ataxia (FA) is most frequently caused by intronic trinucleotide repeat expansions in the frataxin gene on chromosome 9. The broad clinical spectrum includes late-onset FA (LOFA) and FA with retained reflexes (FARR). The size of the GAA expansions accounts for most, but not all, of the clinical variability. We report the unusual occurrence of LOFA and FARR in two siblings of patients with classical early-onset FA in two families. In spite of the markedly different course of the disease, the respective siblings harboured GAA repeat expansions of similar size in leucocytes. Since haplotype-related variability is not likely among siblings, we suppose that this intrafamilial phenotype variability is due to somatic mosaicism, with the more severely affected siblings harbouring the larger expansions in spinal cord and other affected tissues. In view of these results, genetic counseling and predictions on the course of FA are particularly difficult, even if an expansion mutation is found.

Adult↗
PubMed1999

Muscle and skin biopsies are a sensitive diagnostic tool in the diagnosis of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a microangiopathic syndrome. Although the defective gene has been identified, genetic analysis may be effort some due to its large size and various mutations. Providing a reliable diagnostic marker would therefore be helpful. Electron microscopy has revealed characteristic electron-dense granular deposits in the basal lamina of vessels of patients with CADASIL. We investigated the sensitivity of skin and muscle biopsies for diagnosing CADASIL. We examined 30 family members of three unrelated German families affected by CADASIL. In 14 of the 21 affected individuals we performed skin and muscle biopsies; two patients were clinically asymptomatic. Under electron microscopy all muscle and skin biopsy specimens showed patches of granular and electron-dense material in the basal layer of both arterioles and capillaries. These findings confirm that general microangiopathy is a typical feature of this syndrome and is present in the early phase of the disease with or without clinical manifestation. Thus, as electron microscopy of skin biopsy specimens can establish the diagnosis of CADASIL with high certainty, it may be considered the method of first choice.

Adult↗
PubMed1999

The diagnostic process in ALS.

A diagnosis of amyotrophic lateral sclerosis (ALS) is made by a process of elimination of other possible diseases. The time that elapses between the appearance of the first symptoms and diagnosis of ALS may be long, and may mean that the patient is passed from one specialist to another, or that the disease is misdiagnosed and treated incorrectly. It is likely that this period varies enormously in different countries, cultures and medical systems. An international survey was initiated to try and understand the relevant steps on the pathway to diagnosis of ALS, and to evaluate potential culture differences in this process. A pilot study was carried out in Germany, Spain and Sweden to evaluate the feasibility of the methodology. The pilot study showed that: (i) in most cases there was a long time lapse between the appearance of the patient's initial symptoms and their first visit to a general practitioner; (ii) there was often a long time lapse between the patient visiting a general practitioner and a neurologist; (iii) diagnosis was always made by a neurologist; and (iv) the time that elapsed before the neurologist announced the diagnosis to the patient differed from country to country. Education of general practitioners and other specialists about ALS is imperative. A follow-up study is now planned in various European countries and the USA to investigate whether similar results are found worldwide.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Neuromyotonia, myocloni, sensory neuropathy and cerebellar symptoms in a patient with antibodies to neuronal nucleoproteins (anti-Hu-antibodies).

A middle-aged patient presented with subacute muscular stiffness, myocloni of both extremity and facial muscles, gait ataxia and symmetrical distal painful paraesthesias. Electrophysiologically, neuromyotonia was confirmed. High titer anti-Hu antibodies were detected, but no other paraneoplastic antibodies were found. Small-cell lung cancer was diagnosed. Under chemotherapy tumor remission was achieved and, except for minor sensory deficits, neurological symptoms disappeared. This report shows that paraneoplastic syndromes associated with antibodies to neuronal nucleoproteins (anti-Hu antibodies) may be associated with a syndrome including neuromyotonia, sensory neuropathy, cerebellar symptoms and myocloni.

Antibodies, Neoplasm↗
PubMed1999

Detection of humoral rejection in human cardiac allografts by assessing the capillary deposition of complement fragment C4d in endomyocardial biopsies.

BACKGROUND: There are no well-established diagnostic criteria to detect humoral rejection in organ transplantation. The value of commonly used markers in immunohistochemistry, such as C1q, C3c, IgG, IgM and fibrinogen, is questioned by some groups. Complement fragment C4d is a more stable marker of complement activation as it is covalently bound to graft capillaries. C4d has been shown to identify clinically relevant, but otherwise undetectable humoral anti-graft reactions in human kidney transplants. METHODS: Immunohistochemical techniques were used to evaluate 155 endomyocardial biopsies from 56 heart transplant recipients less than 3 months post transplantation for the presence of capillary C4d staining. In a subset of patients, C4d staining was compared with C1q, C3c, IgM and fibrin staining and was correlated with clinical outcome. RESULTS: Within 3 months 9 of 56 patients died. Five of these nonsurvivors had prominent C4d staining (p < .05), whereas C1q, C3c and IgM showed no correlation with clinical outcome. Presence of fibrin correlated with clinical outcome and C4d staining (p < .05). CONCLUSIONS: The capillary deposition of complement split product C4d in human endomyocardial biopsies was significantly associated with graft loss. Determination of fibrin deposition may yield additional information to establish a diagnosis of humoral rejection. The immunohistochemical assessment of capillary deposition of C4d and fibrin appears to be an appropriate tool for the identification of patients, who may require additional or alternative immunosuppressive therapy targeted against the humoral immune system.

Adult↗
PubMed1999

Localization of transforming growth factor beta in association with neuromuscular junctions in adult human muscle.

Transforming growth factors-beta 1, 2, and 3 are known for their regulatory function in embryogenesis, fibrogenesis, and tissue repair of different cell types. A trophic function of TGF-beta subclasses for motoneurons has been shown in vitro. TGF-beta 1 is a potent survival factor for cultured embryonic rat motoneurons. In addition, TGF-beta 1 stimulates proliferation of rat Schwann cells. Recently, TGF-beta 2 has been reported to be associated with the subsynaptic nuclei of mature rat neuromuscular junctions. In this study, we investigated the expression of TGF-beta 1, 2, and 3 at neuromuscular junctions in skeletal muscle of 11 adults without neuromuscular disease. On muscle biopsies, neuromuscular junctions were depicted by acetylcholine esterase reaction and acetylcholine receptor antibodies. TGF-beta 1; 2, and 3 were stained immunohistochemically with monoclonal antibodies. Some muscle fibers showed low levels of inhomogeneous immunoreactivity for both TGF-beta 1 and TGF-beta 3. Intense immunoreactivity of TGF-beta 1 and 3 was shown at the postsynaptic area of neuromuscular junctions. TGF-beta 2 was expressed in the same subcellular distribution, but less strongly. In conclusion, the colocalization of TGF-beta with neuromuscular junctions may suggest a significant function in neuromuscular communication.

Acetylcholinesterase↗