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S vom Dahl

Publications and source records attributed to S vom Dahl.

At least 19 recordsLinked to original sources
PubMed2001

Cell hydration controls autophagosome formation in rat liver in a microtubule-dependent way downstream from p38MAPK activation.

Autophagic proteolysis in rat liver is under the control of the cellular hydration state. Because the morphological site of swelling-dependent proteolysis regulation has not yet been identified, the formation of autophagosomes was investigated with transmission electron microscopy in slices from perfused livers. In livers from fed rats, hypo-osmotic exposure (185 mosmol/l) led within 30 min to a decrease in fractional cytoplasmic autophagosome volume that was sensitive to colchicine and p38(MAPK) inhibition. Similarly, the decrease in autophagosome volume, but not the increase in cell volume caused by insulin or glutamine/glycine, was strongly inhibited by colchicine and SB 203580, an inhibition of p38(MAPK) activation. Immune complex assays from perfused liver showed that hypo-osmotic activation of p38(MAPK) was not inhibited by colchicine. Further, experiments using confocal laser microscopy in cultivated hepatocytes incubated with mouse-derived anti-(alpha-tubulin) showed that microtubular structures were not influenced by the inhibition of p38(MAPK) by SB 203580. It is concluded that the sequestration of autophagic vacuoles is a major site of proteolysis regulation by cell hydration. Swelling-induced activation of p38(MAPK) is required for this process and occurs upstream of the putative microtubule regulation site.

Animals↗
PubMed2001

[Diagnosis and therapy of Gaucher disease. Current recommendations of German therapy centers in the year 2000].

BACKGROUND: Gaucher's disease is the autosomally recessively inherited deficiency of the lysosomal enzyme glucocerebrosidase. Increasing storage of glucocerebrosides leads to a multisystem disease, the prevalence of which is about 1:40,000 in central Europe and up to 1:2,000 in some other countries (e.g. Israel). The acute and chronic neuronopathic forms of the disease (formerly defined as Gaucher types 2 and 3) account for only 5 to 10% of all Gaucher patients in Central Europe and Germany and are thus less frequent than the non-neuronopathic disease (formerly defined as Gaucher type 1). Gaucher's disease is usually associated with spleno- and hepatomegaly, fatigue, skeletal complications, and several corresponding hematological and laboratory abnormalities. In 5 to 10% of the patients there are also central nervous symptoms such as myoclonic seizures, oculomotoric apraxia and a slight mental retardation. METHODS: Four specialized centers care for more than 2/3 of all German Gaucher patients today. These centers present their consensus recommendations for state-of-the-art diagnosis and treatment of Gaucher's disease. RESULTS: Recent epidemiological data indicate that only 10 to 20% of all Gaucher patients are correctly diagnosed (and treated) in Germany. The diagnosis today can be done in all patients by noninvasive methods, i.e. determination of the glucocerebrosidase activity in peripheral leukocytes and of the genetic defect. The current enzyme replacement therapy with glucocerebrosidase has proven effective to improve and often normalize hematological abnormalities, hepatosplenomegaly, skeletal complications and quality of life, provided that the therapy is started early and is given at adequate dosages. CONCLUSION: In view of the availability of an effective therapy, efforts should be made to increase the awareness of Gaucher's disease in differential diagnosis, to help to diagnose the disease with noninvasive techniques at early stages, and to provide practical guidelines for adequate treatment.

Chromosome Aberrations↗
PubMed2001

Magnetic resonance imaging of bone marrow changes in Gaucher disease during enzyme replacement therapy: first German long-term results.

OBJECTIVE: Since 1991, enzyme replacement therapy (ERT) has been available for patients with Gaucher disease in Germany. The aim of this study was to analyse the MR pattern of bone marrow involvement and response to ERT in Gaucher disease type I. PATIENTS AND DESIGN: Thirty patients with Gaucher disease type I had MRI examinations prior to initiation of ERT with alglucerase/imiglucerase and during follow-up. Median MR follow-up and duration of ERT were 36 months. Coronal T1- and T2-weighted spin-echo images of the lower extremities were obtained to evaluate changes in the appearance of yellow marrow. MR images were categorized as having either a homogeneous (type A) or non-homogeneous patchy (type B) appearance of bone involvement and response to ERT was assessed by two radiologists. RESULTS: Overall, 19 of 30 patients (63%) showed an increased signal intensity on T1- and T2-weighted images after 36 months of ERT, consistent with partial reconversion of fatty marrow during treatment. Focal bone lesions surrounded by a low signal intensity (SI) rim did not respond to ERT, suggesting bone infarcts. Of the 11 patients with bone infarcts (low SI rim lesion), 82% had the non-homogeneous type B pattern (P=0.0021). In 86% of patients with splenectomy, bone infarcts were seen (P<0.05). CONCLUSIONS: MRI using T1- and T2-weighted spin-echo sequences is a valuable, non-invasive method for monitoring bone marrow response in patients receiving ERT. A non-homogeneous patchy signal intensity of bone marrow involvement correlates with the presence of bone infarcts (P=0.0021).

Adult↗
PubMed2001

[Gaucher disease: MR evaluation of bone marrow features during treatment with enzyme replacement].

PURPOSE: Enzyme replacement therapy (ERT) arrests and reverses the hematological and visceral symptoms of adult Gaucher disease, the most frequent lysosomal storage disorder. There are only a few studies available evaluating bone disease during ERT. The aim of this study was to investigate the features of bone marrow (bm) by magnetic resonance imaging (MRI) in these patients during ERT. MATERIALS AND METHODS: MRI was performed prospectively in thirty adult type I Gaucher patients before and during ERT with a mean follow-up of 3 years. Spin-echo sequences (T(1)/T(2)) of the lower extremities were obtained and the reconversion (response) or lack of reconversion (non-response) to fatty marrow during treatment was analyzed. The morphological features of bm involvement, a homogeneous or non-homogeneous distribution of bm changes and focal bone lesions surrounded by a rim of reduced signal intensity (SI), were analyzed. RESULTS: Infiltration of bm by Gaucher cells is characterized by a reduction of SI on both T(1)- and T(2)-weighted sequences. Bone marrow responses were seen in 19 patients (63 %) during treatment. Focal bone lesions, surrounded by a rim of reduced SI, did not respond to ERT and correlated with a non-homogenous distribution of bone involvement and splenectomy. CONCLUSION: In adult patients with type I Gaucher disease receiving ERT, treatment effects on bone disease can be demonstrated by MRI using Spin-echo sequences due to the partial reconversion of fat marrow. A non-homogeneous type of signal appearance and a status post splenectomy correlate with the presence of bone infarcts.

Adult↗
PubMed2000

Type I gaucher disease: extraosseous extension of skeletal disease.

OBJECTIVE: To investigate the frequency and morphology of extraosseous extension in patients with Gaucher disease type I. DESIGN AND PATIENTS: MRI examinations of the lower extremities were analyzed in 70 patients with Gaucher disease type I. Additionally, the thoracic spine and the midface were investigated on MRI in two patients. RESULTS: Four cases are presented in which patients with Gaucher disease type I and severe skeletal involvement developed destruction or protrusion of the cortex with extraosseous extension into soft tissues. In one patient, Gaucher cell deposits destroyed the cortex of the mandible and extended into the masseter muscle. In the second patient, multiple paravertebral masses with localized destruction of the cortex were apparent in the thoracic spine. In the third and fourth patient, cortical destruction with extraosseous tissue extending into soft tissues was seen in the lower limbs. CONCLUSIONS: Extraosseous extension is a rare manifestation of Gaucher bone disease. While an increased risk of cancer, especially hematopoietic in origin, is known in patients with Gaucher disease, these extraosseous benign manifestations that may mimic malignant processes should be considered in the differential diagnosis of extraosseous extension into soft tissues. A narrow neck of tissue was apparent in all cases connecting bone and extraosseous extensions.

Adult↗
PubMed2000

Extraosseous manifestation of Gaucher's disease type I: MR and histological appearance.

Gaucher's disease type I is the most prevalent lysosomal storage disorder caused by an autosomal-recessive inherited deficiency of glucocerebrosidase activity with secondary accumulation of glucocerebrosides within the lysosomes of macrophages. The storage disorder produces a multisystem disease characterized by progressive visceral enlargement and gradual replacement of bone marrow with lipid-laden macrophages. Skeletal disease is a major source of disability in Gaucher's disease. Extraosseous extension of Gaucher cells is an extremely rare manifestation of skeletal Gaucher's disease. This is a report on the MRI and histopathological findings of an extraosseous Gaucher-cell extension into the midface in a patient with Gaucher's disease.

Biopsy↗
PubMed2000

Decrease of plasma taurine in Gaucher disease and its sustained correction during enzyme replacement therapy.

Gaucher disease is caused by an autosomal-recessive deficiency of glucocerebrosidase. Cells of monocytic/macrophagic origin accumulate glucosylceramide. This leads to hepatosplenomegaly, bone destruction, thrombocytopenia and anemia. Enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase leads to normalization of these parameters. The way of macrophage activation in Gaucher disease is not known. Recently, the osmolytes taurine, betaine and inositol were identified as important regulators of macrophage function in liver. Therefore, the role of plasma taurine in Gaucher disease as a primarily macrophage-derived disease was studied. Fasting plasma levels were measured from blood samples of healthy control subjects (n = 29, m:f = 11:18, mean age 37 +/- 3 years), from untreated Gaucher patients (n = 16, m:f = 7:9, mean age 44 +/- 4 years) and those treated for 37 +/- 2 months (n = 54, m:f = 19:35, mean age 47 +/- 2 years). Amino acid analysis was carried out in a BioChrom amino acid analyzer. In the untreated patients, plasma taurine was 45 +/- 3 microM, as compared to the controls with a plasma taurine of 63 +/- 4 microM (p < 0.01). The average increase of plasma taurine during the first year of ERT was 18 +/- 8 microM (n = 10). Patients treated for an average of 37 months (range 1-9 years of ERT) had a plasma taurine of 65 +/- 4 microM (n = 54), which was not different from the controls. It is concluded that Gaucher patients show decreased plasma taurine levels and that therapy of Gaucher disease might correct this. It has to be established, whether decreased taurine availability is a cofactor of the permanent activation of glucosylceramide-storing monocytes/macrophages in this disease.

Adult↗
PubMed1999

Release of osmolytes from perfused rat liver on perivascular nerve stimulation: alpha-adrenergic control of osmolyte efflux from parenchymal and nonparenchymal liver cells.

The effects of perivascular nerve stimulation and phenylephrine on osmolyte release were studied in the intact perfused rat liver and isolated liver parenchymal cells (PC) and nonparenchymal cells. In the perfused liver, electrical stimulation of perivascular nerves (20 Hz/2 ms/20 V) led to a phentolamine-sensitive increase of cell hydration by 6.5% +/- 1.2% (n = 3) and a transient phentolamine-sensitive stimulation of taurine and inositol, but not betaine, release. These nerve effects were mimicked by phenylephrine, but not prostaglandin F2alpha, and were not affected by sodium nitroprusside (SNP) or ibuprofen. Nerve stimulation-induced taurine, but not inositol, release was inhibited by 4, 4'-di-isothiocyanatostilbene-2,2'-disulphonic acid (DIDS) (50 micromol/L). Single-cell fluorescence studies with isolated liver PC, Kupffer cells (KC), sinusoidal endothelial cells (SEC), and hepatic stellate cells (HSC) revealed that phenylephrine induced an increase in cytosolic free Ca2+ only in PC and HSC, but not in KC and SEC, whereas extracellular uridine triphosphate (UTP) produced Ca2+ transients/oscillations in all liver cell types studied. Phenylephrine had no effect on osmolyte release from isolated KC and SEC, but increased taurine (but not inositol) release from PC and inositol (but not taurine) efflux from HSC. The data suggest that: 1) liver cell hydration and-consecutively-osmolyte content are modulated by hepatic nerves via an alpha-adrenergic mechanism, which does not involve eicosanoids or hemodynamic changes; 2) that PC and HSC are the primary targets for nerve-dependent alpha-adrenergic activation, whereas 3) KC and SEC probably do not express alpha-adrenoceptors coupled to Ca2+ mobilization or osmolyte efflux.

Adrenergic alpha-Agonists↗
PubMed1999

Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase -1 exon 8 splice junction mutation.

A 36-year-old woman was admitted for hepatosplenomegaly and anemia. Bone marrow cytology showed "sea-blue histiocytes", vacuolated macrophages and plasma cells. As primary liver disease, malignancy or hematologic disorders were excluded, and plasma chitotriosidase activity was increased 27-fold over control, the presence of a lysosomal storage disease was suspected. Biochemical analysis of skin fibroblasts revealed normal glucocerebrosidase and sphingomyelinase activity, but lipid analysis showed a more than 15-fold accumulation of cholesterol esters within the cells. The activity of lysosomal acid lipase (LAL) in fibroblast homogenates was decreased to 12% of control subjects. Mutational analysis of the patient's blood showed the homozygous G-->A mutation at position -1 of the exon 8 splice donor site (E8SJM-allele) known for adult cholesteryl ester storage disease (CESD); the polymorphic background was that of the complex haplotype -6Thr, 2Gly, 894 G-->A. Based on clinical, laboratory, cytological and and biochemical findings, CESD can clearly be separated from other more frequent inherited lysosomal storage diseases, e.g. atypical forms of Gaucher disease.

Adult↗
PubMed1998

First long-term results of imiglucerase therapy of type 1 Gaucher disease.

BACKGROUND/AIMS: In the early 1990s, enzyme replacement therapy with modified placental glucocerebrosidase (alglucerase, Genzyme Corporation, Cambridge, MA, USA) was shown to arrest or reverse complications and to improve quality of life in patients with type 1 Gaucher's disease. More recently, modified recombinant glucocerebrosidase (imiglucerase, Genzyme Corporation) has been shown to be safe, effective and clinically equivalent to alglucerase by two studies which presented data for 12 months' follow-up. This case report, with 30 months' follow-up, represents the first publication of long-term results of imiglucerase therapy of type 1 Gaucher's disease in Europe. METHODS: Retrospective analysis of safety and efficacy of 30 months' imiglucerase infusions, 40 U/kg body weight every 2 weeks for 17 months, then 60 U/kg every 2 weeks for 13 months, in an elderly male patient with severe type 1 Gaucher's disease. RESULTS: No adverse reactions occurred, and anti-imiglucerase antibody assay was negative at 17 months. Clinically, the patient responded rapidly and markedly. Within several months, bone pain decreased notably, enabling him to abandon crutches. Abdominal pain abated, fatigue decreased and physical fitness and general well-being improved. Nosebleeds and haematomas ceased. Dosage increase massively reduced hepatosplenomegaly and produced much greater improvement in laboratory values, especially platelet count. Bone pain diminished further, so that this formerly disabled patient now walks and climbs stairs without complains. Also of note, aminotransferases, gamma-GT, total protein, and prothrombine time improved, suggesting improvement of liver function. CONCLUSIONS: This case documents long-term safety and efficacy of recombinant enzyme replacement in type 1 Gaucher's disease.

Adult↗
PubMed1998

[Uveitis masquerade syndrome in Gaucher disease. Causal treatment by alglucerase substitution therapy].

BACKGROUND: Gaucher's disease, a sphingolipidose transmitted by autosomal-recessive inheritance, is caused by a deficiency of the lysosomal enzyme beta-glucocerebrosidase which is responsible for hydrolysation of glucocerebroside to ceramid and glucose. Thus glucocerebroside is accumulated in the reticuloendothelial cells of spleen, liver and bone marrow and pathognomonic Gaucher's cells are formed. CASE REPORT: In May 1997 a 42-year-old female patient presented with left-sided intermediate uveitis of unknown origin and decreasing visual acuity to perception of hand movements and intact projection of light since September 1996. To exclude a systemic disease a thorough medical examination--showing hepatoslpenomegaly, anemia, thrombocytopenia and bone lesions--was initiated and revealed advanced M. Gaucher (Type I) by bone marrow punction. Intravenous therapy with alglucerase was administered promptly. After five months of treatment vitreous opacities resolved almost completely and visual acuity increased to 0.7. CONCLUSIONS: The dramatic improvement occurred under treatment with alglucerase after no response to steroid treatment. Thus intermediate uveitis with severe vitritis can be interpreted as uveitis masquerade syndrome with M. Gaucher. To the best of our knowledge, this is the first case of M. Gaucher presenting initially as intermediate uveitis and showing successful clinical improvement during administration of alglucerase.

Adult↗
PubMed1997

Liver cell hydration.

Liver cells possess potent mechanisms to maintain their volume, i.e., their hydration state. These volume-regulatory mechanisms, however, are apparently not designed to maintain absolute cell volume constancy; they rather act as dampeners to prevent excessive cell volume deviations, which would otherwise result from cumulative substrate uptake or anisotonic stress. Furthermore, these volume-regulatory mechanisms can even be activated in the resting state by hormones and other stimuli, and by that means cell volume changes are effected secondarily. Thus, liver cell hydration can change within minutes under the influence of aniso-osmolarity, hormones, nutrients, and oxidative stress. Such short-term modulation of cell volume within a narrow range acts as an independent and potent signal which modifies hepatocellular metabolism and gene expression. Accordingly, cell volume homeostasis involves the integration of events that allow cell hydration to play a physiologic role as a regulator of cell function.

Animals↗
PubMed1997

Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver.

BACKGROUND & AIMS: Tauroursodeoxycholate (TUDCA) is widely used in the treatment of cholestatic liver disease. The purpose of this study was to elucidate molecular mechanisms underlying its beneficial effect. METHODS: TUDCA-induced signaling towards bile acid excretion was studied in 24-hour-cultured rat hepatocytes and perfused rat liver. RESULTS: In rat hepatocytes, TUDCA (> 100 mumol/L) led within 10 minutes to an activation of the mitogen-activated protein (MAP)-kinases extracellular signal-regulated kinase (Erk)-1 and Erk-2. Erk activation by TUDCA was insensitive to inhibition of protein kinase C, tyrosine kinases, and G-protein function. TUDCA-induced Erk activation, however, was abolished in the presence of PD098059, a MAP-kinase kinase (MAP-kinase/Erk-kinase [MEK]) inhibitor and after elevation of intracellular adenosine 3',5'-cyclic monophosphate. Thus, TUDCA signaling towards MAP kinases is different from hypo-osmotic MAP-kinase activation, which is sensitive to inhibitors of tyrosine kinases and G-protein function. Addition of dibutyryl-adenosine 3',5'-cyclic monophosphate or PD098059 also abolished the stimulatory effect of TUDCA (20 mumol/L) on taurocholate excretion in perfused rat liver, whereas tyrosine kinase inhibition was ineffective. CONCLUSIONS: TUDCA signaling towards bile acid secretion is mediated by an Raf/MEK-dependent activation of MAP kinases. Although both TUDCA and hypo-osmotic hepatocyte swelling lead to MAP-kinase activation and a stimulation of bile acid secretion, different upstream signaling events are involved.

1-Methyl-3-isobutylxanthine↗