Biomedical subjects

S Hermann

Publications and source records attributed to S Hermann.

At least 19 recordsLinked to original sources

PubMed2006

Selenium and antioxidant vitamin status of elderly German women.

OBJECTIVE: Low antioxidant intake and status have been shown to be associated with an elevated risk for various diseases. Data on the status of antioxidant vitamins, selenium and coenzyme Q10 of younger female seniors are scarce. The aim of this study was to assess the status of these antioxidants, as well as influencing factors such as dietary intake, anthropometric data and educational level in female seniors (60-70 years) in Germany. DESIGN: Dietary intake of alpha-tocopherol, beta-carotene and ascorbic acid was determined by a 3-day diet record. Serum concentrations of alpha-tocopherol, beta-carotene, ascorbic acid, selenium and coenzyme Q10 were measured. Anthropometric measures, socioeconomic and educational status were assessed. SETTING: In total, 178 elderly women without severe diseases in the region of Hannover, Germany, were included in the study. The mean (+/- s.d.) age and BMI of the women was 63.2 (2.73) years and 25.6 (3.77) kg/m2, respectively. The study participants were generally better educated than the overall German female population. RESULTS: Dietary intake of the ascorbic acid and alpha-tocopherol was below RDA in six and 75% of the women, respectively. In comparison to estimated desirable serum concentrations of alpha-tocopherol, ascorbic acid, beta-carotene and selenium, lower concentrations were found in 23, 1, 6, and 39% of the women, respectively. Ascorbic acid (r = 0.205, P = 0.009) and beta-carotene (r = 0.173, P = 0.025) intake were significantly associated with serum concentrations. Beta-carotene concentrations were influenced by the type of diet, BMI, and school education (R2 = 0.128, P < 0.001). Serum selenium was positively associated with alcohol intake (r = 0.229, P = 0.003). Neither employment nor vocational training was predictive for the serum concentrations of antioxidant vitamins, selenium or coenzyme Q10. CONCLUSIONS: Poor status of selenium and alpha-tocopherol is highly prevalent even among younger, well-educated female seniors, whereas ascorbic acid and beta-carotene status seems sufficient in most women.

Aged↗

PubMed2006

HLA-DRB10826 and HLA-DQB10627, two novel class II alleles identified in blood stem cell donors of Caucasian origin.

This report describes two novel HLA class II alleles, HLA-DRB1*0826 and HLA-DQB1*0627, that have been identified in two unrelated voluntary blood stem cell donors of Caucasian origin. HLA-DRB1*0826 is characterized by a nucleotide substitution (G to T) in exon 2 at position 163, leading to an amino acid exchange from argenine to leucine. The donor phenotype is HLA-A*0301,*2902; B*3501,*4403; Cw*0401,*1601; DRB1*0101,*0826; DQB1*0402, *0501. The HLA-DQB1*0627 alleles contain a nucleotide substitution at position 184 (T to C) resulting in an amino acid exchange from tyrosine to histidine. Family segregation analysis revealed that the HLA-DQB1*0627 allele belongs to the haplotype A*0101, B*1517, Cw*0701, DRB1*1302, DQB1*0627. The donor phenotype is HLA-A*0101; B*0801,*1517; Cw*0701; DRB1*1302,*1501; DQB1*0602,*0627.

Alleles↗

PubMed2005

Staging in childhood lymphoma: differences between FDG-PET and CT.

AIM: The clinical value of positron emission tomography using fluorine-18 fluoro-deoxy-glucose (FDG-PET) in the staging of adult lymphoma has been shown in many studies. However, there are only few data regarding childhood lymphoma. The purpose of this retrospective study was to compare the staging of childhood lymphoma using FDG-PET and the established computed tomography (CT). METHOD: Whole-body FDG-PET was performed in 25 children with histologically proven Hodgkin's disease (n = 18) and non-Hodgkin's lymphoma (n = 7) using a dedicated PET. The findings were compared with the CT results. Both examinations, FDG-PET and CT, were assessed by two experienced physicians. In each patient, 30 regions were analysed (22 nodal, 8 extranodal). Each region was assessed using a five value scale (definitely/probably positive, equivocal, probably/definitely negative). RESULTS: 662 regions (470 nodal, 192 extranodal) were compared. 91 regions (81 nodal, 10 extranodal; 14%) were concordant positive and 517 regions (347 nodal, 170 extranodal; 78%) were concordant negative. In 47 regions, 48 discordant findings (7%) were described: 27 findings (22 nodal, 5 extranodal) were positive using FDG-PET and negative using CT whereas 21 findings (17 nodal, 4 extranodal) were positive using CT and negative using PET. A total of 7 regions (1%) were judged equivocal in one imaging modality (1 FDG-PET, 6 CT). Using FDG-PET as compared to CT, resulted in a higher staging in 4 of 25 patients and in a lower staging in 2 of 25 patients. CONCLUSION: Staging of childhood lymphoma using FDGPET shows differences compared with CT resulting in a different staging in 6 of 25 patients. Prospective studies are required to evaluate the impact of these discrepancies on the clinical management of pediatric patients.

Adolescent↗

PubMed2004

[The new indicator set for health reporting activities in the German States].

In May 2003, the third revised version of the indicator set for health reporting activities was confirmed by the health ministries of all German States (Bundesländer). Modeled on the restructured indicator set which has been annotated with meta-data descriptions, most Bundesländer have now started to collect data for their specific health reporting activities. Thanks to the support provided by national data holders and the Federal Statistical Office, it has been possible to further enlarge the database and for the first time also ensure access via the Federal Statistical Office. In this contribution the authors describe the methodological and statistical principles of the indicator set. Another aspect is the benefit of the indicator set for the health reporting activities in the German States.

Aged↗

PubMed2003

Peracute onset of severe tumor lysis syndrome immediately after 4 Gy fractionated TBI as part of reduced intensity preparative regimen in a patient with T-ALL with high tumor burden.

We report a 30-year-old patient with therapy-refractory T-ALL undergoing unrelated allogeneic PBSCT. He developed severe tumor lysis syndrome (TLS) with extreme biochemical changes, cardiac and neurological symptoms and dialysis-dependent acute renal failure after TBI (4 Gy) on the first day of reduced intensity conditioning (RIC) for unrelated allogeneic PBSCT. The patient's clinical condition was stabilized after beginning daily hemodialysis and treatment for disturbed electrolytes, metabolic acidosis and plasma coagulation, as well as reduction of uric acid by rasburicase. The conditioning therapy and the allogenic PBSCT were scheduled according to the preparative regimen. According to our knowledge, severe TLS induced by 4 Gy TBI has not been reported so far. Regimen-related toxicity using RIC regimen was mild, allowing 30-50% of the patients to have an entirely outpatient transplantation. However, we would like to point out that severe TLS could also complicate PBSCT using RIC regimens in patients with relatively radiation-sensitive malignancies and high tumor burden.

Adult↗

PubMed2003

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability.

Gastric cancer is highly refractory to DNA-damaging therapies. We therefore studied both gene mutation and protein expression of p53 and Bax in a cohort of 116 patients with gastric cancer who underwent R0-resection with a curative intent. Bax mutation was independent from severe microsatellite instability (MSI), that is, global mismatch repair deficiency as determined by analysis of BAT-25/BAT-26 microsatellite markers. Thus, Bax-frameshift mutation is a feature of tumors with low MSI. In contrast and as expected, no p53 mutations were observed in the microsatellite instable tumors. p53 Mutation or p53 overexpression did not have an impact on disease prognosis. p53-Inactivation was, however, associated with an extremely poor prognosis in the subgroup of patients with Bax-mutated tumors. Thus, we show for the first time that the combined mutation of p53 and Bax, two key regulators of the mitochondrial apoptosis pathway, results in an extremely aggressive tumor biology and poor clinical prognosis.

Apoptosis↗

PubMed2003

Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy.

Inactivation of p53 has been shown to correlate with poor prognosis and drug resistance in malignant tumors. Nevertheless, few reports have directly shown such effects in primary tumor cells. Here, we investigated the p53 mutational status in 138 B-CLL samples and compared these findings with drug and gamma-irradiation sensitivity profiles. p53 mutations resulted not only in a shorter survival but, notably also in selective resistance to alkylating agents, fludarabine and gamma-irradiation. In contrast, no such effect was observed for vincristine, anthracyclines and glucocorticoids. Thus, these latter compounds induce cell death at least in part by p53-independent pathways. Interestingly, p53 mutations clustered in patients who had received prior chemotherapy. In fact, we show for the first time that treatment with DNA-damaging alkylating agents correlates with occurrence of p53 mutations in a clinical setting. This finding may explain at least to some extent the development of resistance to second-line anticancer chemotherapy.

Antineoplastic Agents, Alkylating↗

PubMed2002

[Increased response rate with rituximab in relapsed and refractory follicular and mantle cell lymphomas -- results of a prospective randomized study of the German Low-Grade Lymphoma Study Group].

BACKGROUND AND OBJECTIVE: Rituximab has shown a high activity in relapsed follicular lymphomas when given alone. Further on, phase-II-studies indicate that its addition to chemotherapy may improve the response rate substantially. However, so far, prospective randomized studies have not been available. PATIENTS AND METHODS: In 1998 the GLSG started a multicenter trial in patients with relapsed or refractory indolent lymphoma or mantle cell lymphoma. A fludarabine-containing regimen (FCM) was chosen for salvage therapy, with fludarabine 25 mg/m(2)/d 1-3, cyclophosphamide 200 mg/m(2) d 1-3 and mitoxantrone 8 mg/m(2) d 1. A total of four courses, every 4 weeks were given. Patients were prospectively randomized for FCM alone or the immunochemotherapy with R-FCM (375 mg/m(2) one day before FCM) RESULTS: About 147 randomized patients 93 had follicular, 40 mantle cell and 14 lymphoplasmocytic/-cytoid lymphoma. Statistical analysis was performed by sequential testing and indicated for 94 fully evaluable patients a significant advantage for the R-FCM-arm, with an overall response rate of 83 % as compared to 58%, when treated with FCM alone (CR: 35 % vs. 13 %). Similar improvements of remission rate were detected in the different lymphoma subgroups, especially in MCL (OR: 65 % vs. 33 %). Both treatment options were associated with hematological toxicities of grade III and IV, but well tolerated; infectious complications were rare, with no difference between the two treatment groups. CONCLUSION: This prospectively randomized trial demonstrates for the first time a significant improvement of the combined immunochemotherapy related to the remission rate in patients with relapsed or refractory indolent lymphoma.

Adult↗

PubMed2002

[Valence of F-18-FDG-PET in the diagnosis of malignant lymphoma].

PET enables tomographic imaging and quantification of molecular metabolism with high temporal and spatial resolution. For routine clinical questions in oncology F-18-labeled fluorodeoxyglucose is the tracer of choice. In malignant lymphoma staging, response control and follow-up studies are valid indications. The initial glucose-uptake and especially the response of metabolism to therapy are in correlation with the outcome of the disease. Complementary to conventional staging PET is able to detect further lymphnode manifestation or extranodal involvement that can result in up-staging. Down-staging is less frequent. In follow-up studies PET is valuable, to assess therapy response, to differentiate viability of lymphoma from fibrous remnants at end of therapy and to detect relapse at an early stadium. In this context it proves to be superior to conventional tomographic imaging. In individual cases relevant therapeutic consequences arise from the metabolic PET-informations. Whether in future PET will be able to partially replace conventional imaging and whether it withstands to cost/effectiveness analysis requires additional prospective studies.

Blood Glucose↗

PubMed2001

How transcriptional activators bind target proteins.

The product of the proto-oncogene c-myc influences many cellular processes through the regulation of specific target genes. Through its transactivation domain (TAD), c-Myc protein interacts with several transcription factors, including TATA-binding protein (TBP). We present data that suggest that in contrast to some other transcriptional activators, an extended length of the c-Myc TAD is required for its binding to TBP. Our data also show that this interaction is a multistep process, in which a rapidly forming low affinity complex slowly converts to a more stable form. The initial complex formation results from ionic or polar interactions, whereas the slow conversion to a more stable form is hydrophobic in nature. Based on our results, we suggest two alternative models for activation domain/target protein interactions, which together provide a single universal paradigm for understanding activator-target factor interactions.

Binding Sites↗

PubMed2001

Bax expression in benign and malignant thyroid tumours: dysregulation of wild-type P53 is associated with a high Bax and P21 expression in thyroid carcinoma.

The purpose of our study was to determine the expression of the pro-apoptotic BAX protein in relation to the mutational status of BAX and p53 (as transcriptional activator of the BAX gene) in benign and malignant thyroid tissue. In 47 patients with thyroid tumours (14 follicular and 3 papillary carcinomas, 14 adenomas and 16 goitres), the DNA was screened for mutations of BAX (exon 1-6) and p53 (exon 5-8) by single-strand conformation polymorphism polymerase chain reaction (SSCP-PCR). Furthermore, the protein expression of BAX, p53 and p21 (which is also increased transcriptionally by p53) was investigated by immunohistochemistry. Surprisingly, we observed elevated BAX levels in patients with thyroid carcinomas compared with patients with adenomas (unpaired t-test: p<0.05) or with goitres (p<0.02). This is in clear contrast to other carcinomas where BAX is frequently inactivated which correlates to a poor prognosis (Sturm et al. J. Clin. Oncol. 1999;17:1364-74.). There were no significant differences of the BAX levels between goitres or the adenomas. In the SSCP-PCR analysis, no BAX mutations were detectable. P53 mutation analysis by SSCP-PCR did not reveal any functional p53 mutations in the patients with carcinomas, adenomas or goitres. Nevertheless, patients with carcinomas showed an overexpression (preferentially cytoplasmic) of p53 protein compared with patients with benign tumours (p<0.05). The absence of p53 mutations suggests that the overexpressed p53 is wild type. This is in line with the expression profile of BAX and p21, which showed a higher protein expression in these p53 positive tumours (p<0.05 in the carcinomas compared with the non-malignant lesions). Consequently, the overexpressed p53 might be a correlate for dysregulation without loss of function. This, in turn, might be a reason for the good outcome of some patients with thyroid cancer.

Adenocarcinoma, Follicular↗

PubMed2001

Older patients with high-risk fungal infections can be successfully allografted using non-myeloablative conditioning in combination with intensified supportive care regimens.

Leukaemic patients with advanced disease and severe fungal infections as well as older patients with substantial co-morbidity are usually excluded from conventional allotransplantation because of increased morbidity and mortality. We approached allogeneic transplantation in four patients with a median age of 62 years (one chronic myeloid leukaemia in blast crisis, one high-risk acute myeloid leukaemia (AML) in first complete remission (CR1), one AML in 2nd relapse, one AML in CR2 with pre-existing fungal lung infections (two aspergillus, two mucor) and additional co-morbidity (diabetes n = 2, aortic aneurysm n = 1, arterial sclerosis n = 2) by combining non-myeloablative conditioning with an intensified supportive care regimen, including amphotericin B and 4-12 (median 9) prophylactic granulocyte transfusions from granulocyte colony-stimulating factor (G-CSF)-stimulated volunteer donors. G-CSF was also given to patients until neutrophil recovery. All four patients recovered to a neutrophil count of 0.5 x 109/l after a median of 11.5 d (range 11-13 d). Prophylactic granulocyte transfusions also reduced the need for platelet transfusions and minimized mucositis. All patients were discharged at a median of 25 d (range 18-59 d) and are alive and well after a median follow-up of > 390 d (range 336-417 d) without evidence of leukaemia. Regression of the fungal lesions was documented in three patients, with a slight progression detected by computerized tomography scan of the chest in one patient. We conclude that pulmonary fungal infections are not a contraindication for allogeneic stem cell transplantation, if non-myeloablative conditioning regimens are used in combination with granulocyte transfusions, intravenous amphotericin B and G-CSF.

Acute Disease↗

PubMed2001

A new approach to evaluating intestinal acute graft-versus-host disease by transabdominal sonography and colour Doppler imaging.

An objective and non-invasive method to assess the extent, severity, course and prognosis of acute graft-versus-host disease (aGvHD) of the gastrointestinal tract would be of great importance. As high-resolution ultrasonography (HRU) and colour Doppler imaging (CDI) are used in inflammatory and ischaemic bowel diseases, we introduced these techniques to evaluate acute intestinal GvHD. In this study, 12 patients with suspected intestinal and/or severe cutaneous aGvHD were investigated by HRU and CDI. The structure and thickness of the bowel wall and the blood flow pattern in the superior mesenteric artery (SMA) as well as in the bowel wall were evaluated. All patients showed thickened bowel wall segments, especially in the ileocaecal region. Even in patients without any clinical signs of intestinal involvement (3/12), sonographic changes were observed. In six patients with severe diarrhoea, sonographic signs of secretory diarrhoea were observed. In 4/12 patients, an increased arterial blood flow in the bowel wall was demonstrated as a typical characteristic of an inflammatory bowel process. In contrast, in 4/12 patients, ischaemic bowel wall lesions with high-resistance flow pattern in the SMA were found. These patients did not respond to immunosuppressive therapy and died. In conclusion, HRU is a useful tool for detecting acute bowel GvHD even before clinical symptoms. Moreover, HRU and CDI can be applied to define the severity of aGvHD and to identify patients with a poor prognosis.

Acute Disease↗

PubMed2001

Peritoneal sclerosis in peritoneal dialysis patients related to dialysis settings and peritoneal transport properties.

BACKGROUND: Peritoneal sclerosis is a histopathologic finding that is probably causative of long-term system failure in peritoneal dialysis (PD). It may be due to uremic toxicity and the influence of peritoneal dialysate components. We intended to clarify to which degree peritoneal fibrosis and vascular changes were associated with the modalities of PD and the peritoneal transport characteristics. METHODS: Peritoneal biopsies of 41 patients suffering from end-stage renal disease were examined. Sixteen patients were at the initiation of dialysis treatment, and 25 patients were studied during chronic PD treatment [9 patients on continuous ambulatory PD (CAPD) and 16 patients on automatic PD (APD)]. Twenty nonuremic patients undergoing abdominal surgery served as the controls. Samples were taken from the parietal peritoneum under standardized conditions and were examined by light microscopy using different staining techniques, semiquantitative grading, and computer-based histomorphometry. RESULTS: A marked loss of mesothelial cells during PD treatment was only observed in cases with two or more preceding episodes of peritonitis, but an increase of the submesothelial fibrous tissue was a common finding and was related to the cumulative glucose load on PD. Patients on PD also had a significantly increased density of small vessels and capillaries in the submesothelial peritoneal layer (12.8 +/- 6.9 per field vs. 6.6 +/- 2.9 in normal controls, P < 0.01). The wall/lumen index of the vessels was increased indicating vascular sclerosis. The degree of vascularization correlated with the amount of fibrous tissue. Patients characterized as high transporters according to the peritoneal equilibration test (PET) had an increased submesothelial fibrous layer. Patients on APD tended to have an increased membrane diameter submesothelial stroma and vascularization (P = NS), although they were treated for a shorter period of time than the CAPD group. Some of the morphologic changes described could already be observed in uremic patients before the onset of dialysis. CONCLUSION: Further research focusing on the clinical and biochemical backgrounds leading to peritoneal membrane changes is of major importance for developing strategies to improve long-term survival on PD.

Adult↗

PubMed2001

A novel target recognition revealed by calmodulin in complex with the basic helix--loop--helix transcription factor SEF2-1/E2-2.

Calmodulin is the predominant intracellular receptor for Ca(2+) signals, mediating the regulation of numerous cellular processes. It can inhibit the DNA binding of basic helix--loop--helix transcription factors by a direct interaction of a novel type. To structurally characterize this novel calmodulin-target interaction, we decided to study the complex of calmodulin with a dimeric peptide corresponding to the DNA-binding domains of the dimeric basic helix-loop-helix transcription factor SEF2-1 (SEF2-1mp) using NMR. Here, we report that the stoichiometry of the calmodulin:SEF2-1mp complex is one dimeric peptide binding two calmodulin molecules. We also report the 1H, 13C, and 15N resonance assignments and the secondary structure of calmodulin in this for NMR large (approximately 38 kD) complex, as well as the 1H assignments and secondary structure of SEF2-1mp. In addition, we determined the amide proton exchange rates of calmodulin and measured intermolecular calmodulin:SEF2-1mp and calmodulin:calmodulin NOE contacts. The isotope-filtered experiments show a large number of SEF2-1mp to calmodulin NOE contacts indicating that a tight complex is formed, which is confirmed by an intermolecular calmodulin:calmodulin NOE contact. The secondary structure and amide proton exchange data show that the binding does not occur via the classical wraparound binding mode. Instead, the data indicate that calmodulin interacts with SEF2-1mp in a more open conformation, although the hydrophobic surfaces of the N- and C-terminal domains still form the main interaction sites. Interactions involving charged residues are also identified in agreement with the known relatively high sensitivity of the binding to ionic strength. Finally, the peptide does not form an alpha-helix as in the classical wraparound binding mode.

Amino Acid Sequence↗

PubMed2000

Subthreshold oscillation of the membrane potential in magnocellular neurones of the rat supraoptic nucleus.

Electrophysiological properties and ionic basis of subthreshold oscillation of the membrane potential were examined in 104 magnocellular neurones of the rat supraoptic nucleus using intracellular recording techniques in a brain slice preparation. Subthreshold oscillation of the membrane potential occurring in all neurones examined was voltage dependent. Oscillation was initiated 7-12 mV negative to the threshold of fast action potentials. Oscillation was the result of neither excitatory nor inhibitory synaptic activity nor of electric coupling. Frequency analyses revealed a broad band frequency distribution of subthreshold oscillation waves (range 10-70 Hz). The frequency band of 15-33 Hz was observed in neurones depolarized close to the threshold of discharge. Subthreshold oscillation was blocked by TTX (1.25-2.5 microM) as well as by TEA (15 mM). Subthreshold oscillation was not blocked by low Ca(2+)-high Mg(2+) superfusate, CdCl(2), TEA (1-4.5 mM), 4-aminopyridine, apamin, charybdotoxin, iberiotoxin, BaCl(2), carbachol and CsCl. During application of TTX, stronger depolarization induced high-threshold oscillation of the membrane potential at a threshold of about -32 mV. These oscillation waves occurred at a mean frequency of about 35 Hz and were blocked by CdCl(2). Effects of ion channel antagonists suggest that subthreshold oscillation is generated by the interaction of a subthreshold sodium current and a subthreshold potassium current. The generation of high-threshold oscillation during TTX involves a high-threshold calcium current. Subthreshold oscillation of the membrane potential may be important for the inter-neuronal synchronization of discharge and for the amplification of synaptic events.

Anesthetics, Local↗

PubMed2000

A novel type of calmodulin interaction in the inhibition of basic helix-loop-helix transcription factors.

Calmodulin is the predominant intracellular receptor for Ca(2+) signals, mediating the regulation of numerous cellular processes. Previous studies have shown that calcium-loaded calmodulin can bind to and inhibit the activity of certain basic helix-loop-helix (bHLH) transcription factors. The basic sequence within the bHLH domain is the primary target for calmodulin binding, and sequences modulating the calmodulin interaction reside directly N-terminal to the basic sequence. Here we show that the interaction of calmodulin with bHLH proteins is of a novel type, displaying characteristics very different from those of previously characterized calmodulin-target complexes. We show that calmodulin interacts much stronger with a dimeric basic sequence than with the monomeric form. The calmodulin-bHLH protein complex contains equimolar amounts of calmodulin and bHLH chains. The interaction is unusual in being to a large extent polar in nature, and it is highly resistant to tested calmodulin inhibitors. Both the N-terminal and C-terminal domains of calmodulin can independently bind to and inhibit the DNA binding of bHLH proteins. The C-terminal domain preferentially binds to the basic sequence, whereas the N-terminal domain is essential for the effect of the modulatory sequence. We propose a model for the calmodulin-bHLH complex where two calmodulin molecules interact with one bHLH dimer, with one domain of calmodulin preferentially binding to the basic sequence of bHLH proteins and the other domain interacting with the modulatory sequence.

Amino Acid Sequence↗

PubMed2000

Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of arylsulfatase A. Here we describe a hitherto unknown arylsulfatase A allele carrying a E312D missense mutation and characterize the effects of this and three previously described missense mutations, G86D, Y201C, and D255H, on arylsulfatase A. In transfection experiments no enzyme activity can be expressed from arylsulfatase A cDNAs coding for the D255H substituted enzyme, whereas Y201C and E312D mutations were associated with low amounts of residual enzyme activity. All amino acid substitutions lead to a decreased stability of the mutant enzyme, and metabolic labeling experiments indicated that except for the E312D substitution the mutations cause arrest of the mutant arylsulfatase A polypeptides in a prelysosomal compartment.

Adolescent↗