Biomedical subjects
Publications and source records attributed to J Müller.
The multiplicity of information which electronmicroscopy has contributed to our knowledge of Candida albicans and its relationship to the human host is reviewed and by means of examples presented.
Human skin is repeatedly exposed to mechanical stretching in vivo, but in an ordinary culture of skin cells this prominent feature has been neglected. In order to study whether mechanical stretching plays a role for human melanocytes, we have established a culture technique to mimic this physical stretching: primary cultures of human melanocytes were plated on silicon supports, which undergo a stretching of about 10% of the initial length. After application of repeated stretching and relaxation for 4 days, cell count was significantly (about 40%) enhanced. In addition, we found approximately 2-fold increase in heat shock protein (HSP) 90, both at the protein and mRNA level. HSP 90 is known to bind to Raf-1 and, therefore, may contribute to the Raf-1-MEK (mitogen-activated protein-kinase kinase)-MAPK (mitogen-activated protein-kinase) signaling pathway. Disruption of the Raf-1-HSP 90 multimolecular complex by geldanamycin lead to a considerable decrease in melanocyte cell count. However, geldanamycin did not reverse the stretch-induced growth stimulation. Therefore, the stretch-mediated up-regulation of HSP 90 expression in melanocytes appears to be independent of stretch-mediated growth stimulation. These findings have strong implications for the in vitro cultivation of melanocytes for transplantation purposes.
Standing height, sitting height, armspan, subischial leg length, head circumference, and growth hormone-insulin-like growth factor I (IGF-I) axis were determined in 86 patients with osteogenesis imperfecta. The aim of this study was to determine standing height and body proportions and their variability among osteogenesis imperfecta types and collagen defects. Mean standing height was reduced in all groups of patients, to the greatest extent and variability in osteogenesis imperfecta type III/IV and in those with qualitative collagen defects. The mean standing height of patients with osteogenesis imperfecta was lower than that of their unaffected first degree family members. Truncal height of patients with osteogenesis imperfecta was reduced; head size was increased, and this was more pronounced in patients with osteogenesis imperfecta type III/IV and qualitative collagen defects than in patients with osteogenesis imperfecta type I and quantitative collagen defects. Mean concentrations of IGF-I and IGF binding protein 3 (IGFBP-3) were low, but most values were within age specific reference values. The reduction of standing height appears to correlate with osteogenesis imperfecta type and the type of collagen defect. A relatively short trunk is typical and head circumference and body length are disproportionate.
AIM: To investigate bone mineral status in patients with cystic fibrosis (CF). PATIENTS AND METHODS: Whole body bone mineral content (BMC), projected bone area, and bone mineral density (BMD) were determined by dual energy x ray absorptiometry in 134 patients with CF and compared with 396 healthy controls. RESULTS: In patients </= 19 years of age, BMD for age was normal in boys and marginally reduced in girls, whereas BMC for age was significantly reduced in both sexes. Height for age and bone area for height were significantly reduced, indicating "short" and "narrow" bones, whereas BMC for bone area was increased, indicating increased size corrected BMC. In patients > 19 years of age, BMD and BMC for age were significantly reduced. CONCLUSION: Short and narrow bones were the main reasons for reduced BMC for age in patients </= 19 years of age, indicating that treatment to prevent osteoporosis in younger patients should be directed at increasing bone size, whereas conventional treatment with calcium and vitamin D supplementation alone might not be as effective. Because of the significant decrease in BMD and BMC in adult patients, we fear that these patients may develop osteoporotic fractures prematurely.
OBJECTIVE: To quantitatively assess control of balance under static and dynamic conditions in patients with tonic and phasic cervical dystonia. METHODS: Ten patients with purely tonic cervical dystonia with fixed postural deviation and 20 patients with cervical dystonia with phasic head movements were investigated at least 3 months after botulinum toxin injections. Seventeen age matched volunteers served as controls. Static posturography was performed on a force platform; dynamic equilibrium was studied on a stabilometer, which requires the subject to continuously adapt upright posture to an unstable tilting surface. Measurements of maximum amplitude and linear displacement of the pivot were taken with open and closed eyes. RESULTS: Sway path values in static posturography were not significantly different between patients with cervical dystonia and controls. On dynamic posturography, patients with phasic cervical dystonia showed significantly higher platform measures (maximum amplitude and linear displacement of the pivot) with eyes open and closed By contrast, none of the dynamic platform measures differed significantly between patients with tonic cervical dystonia and controls. CONCLUSIONS: Normal measures of dynamic equilibrium in tonic cervical dystonia argue against a primary abnormality of balance control in cervical dystonia. Impaired dynamic equilibrium in phasic cervical dystonia is likely to reflect a disruption of vestibular input due to repetitive, involuntary head oscillations.
Males with the 45,X/46,XY karyotype and malformations of the external genitalia carry an increased risk of developing germ cell neoplasia of the gonads. We have studied gonadal tissue from 10 individuals, 0.3-17 years of age, with a male phenotype and either hypospadias and/or cryptorchidism. Four patients, 0.3-15 years of age, had carcinoma in situ, 1 boy had Sertoli-cell-only pattern and the remainder prepubertal histology. Gonadoblastoma or invasive carcinoma was not found. On the basis of our current knowledge we propose a strategy for management and follow-up of these boys in order to detect possible premalignant histological changes early and prevent development of a gonadal tumour.
OBJECTIVE: Assessment of growth disturbances in adults with a history of juvenile chronic arthritis (JCA). MATERIAL AND METHODS: Sixty-five subjects, 52 premenopausal females and 13 males with a mean age (range) of 32.2 years (22.3-49.4) participated. Mean age at disease onset was 5.7 years (0.8-15.8) and mean disease duration was 12.4 years (0.4-32). The follow-up time ranged from 18.7 to 46.9 years with a mean of 26.4 years. For each participant standard deviation scores (z-scores) for final height, delta-height (the difference between observed and expected height), armspan, subischial leg length and sitting height ratio, were calculated. RESULTS: The study group as a whole did not exhibit linear growth impairment. The categorical distribution of heights differed significantly from a expected distribution in a healthy population (p < 0.001). A height z-score < -2 SD was present in 10.7% of the study group, of whom all had polyarticular course of JCA. Polyarticular and systemic course of JCA (versus pauciarticular) (p = 0.022), systemic steroid treatment (p = 0.006) and Steinbrocker functional class II-IV (vs. I) in 1979 (p = 0.043) were variables associated with reduced delta-height. In linear regression analyses, disease severity defining variables were statistically significant predictors of reduced final height and armspan. 27% of the study subjects had significantly reduced arm span (p < 0.001). Subischial leg length and body proportions (sitting height ratio) were normal. CONCLUSION: Our findings suggest that functionally impaired polyarticular and systemic JCA patients treated with systemic steroids may be at an increased risk of developing reduced final height and armspan. Disease control achieved by an aggressive therapeutic approach, if possible with a minimal use of systemic steroids, may reduce growth impairment in JCA.
The insulin receptor (IR) in two brothers with a rare syndrome of congenital muscle fiber type disproportion myopathy (CFTDM) associated with diabetes and severe insulin resistance was studied. By direct sequencing of Epstein-Barr virus-transformed lymphocytes both patients were found to be compound heterozygotes for mutations in the IR gene. The maternal allele was alternatively spliced in exon 17 due to a point mutation in the -1 donor splice site of the exon. The abnormal skipping of exon 17 shifts the amino acid reading frame and leads to a truncated IR, missing the entire tyrosine kinase domain. In the correct spliced variant, the point mutation is silent and results in a normally translated IR. The paternal allele carries a missense mutation in the tyrosine kinase domain. All three cDNA variants were present in the lymphocytes of the patients. Purified IR from 293 cells overexpressing either of the two mutated receptors lacked basal or stimulated IR beta-subunit autophosphorylation. A third brother who inherited both normal alleles has an normal muscle phenotype and insulin sensitivity, suggesting a direct linkage of these IR mutations with the CFTDM phenotype.
Patient compliance is of vital importance for the outcome of any medical therapy. Compliance is especially a problem in long-term treatment of non-life threatening diseases, such as growth retardation in children. Until recently, all human growth hormone (hGH) products required a reconstitution process. Norditropin((R)) SimpleXx(TM) is a liquid formulation of the biosynthetic hGH product Norditropin((R)), and, together with an improved NovoPen((R)) 1.5, NordiPen(TM), and an auto-insertion device, PenMate(TM)/NordiPenMate(TM), it has been developed in order to ease the injection process for patients. A randomized, open, multicentre, crossover trial compared Norditropin((R)) SimpleXx(TM)/improved NovoPen((R)) 1.5 with freeze-dried Norditropin((R)) PenSet((R))/Nordiject((R)). A total of 67 children with GH deficiency, aged 5-18 years, were treated with either Norditropin((R)) SimpleXx(TM) for 6 weeks followed by Norditropin((R)) for 6 weeks or the opposite (sequences I and II, respectively). Acceptability/convenience and pain perception were evaluated by questionnaire after each period. The function and handling of the PenMate(TM) were evaluated in a Dutch trial by 27 GH-treated children with intrauterine growth retardation, aged 4-16 years, and their parents. All children were accustomed to using the Nordiject((R)) pen. The evaluation of the PenMate(TM) was based on a questionnaire. A similar trial was conducted in England, in which the NordiPen(TM) and the NordiPenMate(TM) were evaluated by 25 GH-treated children and their parents. Norditropin((R)) SimpleXx(TM) was found to be easier to inject by 64% of the children, and 98% of the children found the system easier to use overall. There was no difference in pain perception between the two administration systems, as judged by questionnaires and visual analogue scale score. Three out of four patients preferred to continue treatment with Norditropin((R)) SimpleXx(TM). The safety profiles of the two systems were similar. In the Dutch trial, the PenMate(TM) was found to be easy and safe to handle, even for very young children (aged 4-5 years). Of patients who took a long time to get used to the injections, 73% found that the new pen would help. A total of 88% of the children would prefer to use the PenMate(TM) in the future. Positive results of the handling tests were also reported in the British trial. The use of Norditropin((R)) SimpleXx(TM) and the auto-insertion device may improve patient compliance.
The ontogeny of expression of anti-Müllerian hormone (AMH) was examined by immunohistochemistry in 135 human gonadal tissue specimens of various developmental age, ranging from 6 weeks of fetal development to 38 yr of postnatal age. The series included specimens from normal testes and ovaries and from individuals either with pathological conditions affecting gonadal development or with idiopathic infertility manifested as azoospermia or severe oligozoospermia. AMH expression was found only in Sertoli and granulosa cells. A 6-week-old fetal testis at the indifferent gonad stage did not yet express AMH. The protein was first visible at 8.5 weeks of development, when sex cords have not yet been formed. Afterward, a majority of testicular specimens, including those from pathological conditions, strongly expressed AMH through fetal development and childhood until puberty. Markedly prolonged expression of AMH was observed in a 20-yr-old 46,XY female with androgen insensitivity syndrome, who retained prepubertal testicular morphology. In normal testes, the switch-off of AMH expression was usually associated with the appearance of primary spermatocytes, suggesting that their presence had an inhibitory effect on AMH. However, in adolescent boys lacking germ cells because of cancer treatment and in a majority of infertile adult men with idiopathic germ cell aplasia, AMH expression was also down-regulated despite the complete lack of spermatogenesis. The decrease in AMH expression thus reflects the terminal differentiation of Sertoli cells and is probably only partially dependent upon a regulatory factor associated with the onset of meiosis. In fetal ovaries, AMH was first detected at 36 weeks gestation in granulosa cells of preantral follicles. Thus, the onset of ovarian expression is at the end of fetal life and not in infancy as previously reported.
Excessive fatness is considered a frequent late complication of treatment for childhood acute lymphoblastic leukemia. Most previous studies, however, were based on body mass index (BMI) rather than more direct fat mass measurements. We studied 95 survivors of childhood acute lymphoblastic leukemia a median of 11 yr (range, 3-23 yr) after diagnosis. BMI values at diagnosis, at cessation of therapy, yearly thereafter for up to 10 yr, and at follow-up were compared with French reference values. Whole body percent fat was measured at follow-up by dual energy x-ray absorptiometry and compared with data from 463 local controls. Adjusted for sex and age, the mean BMI increased significantly during therapy and remained largely unchanged thereafter. At follow-up, BMI did not differ significantly between patients and local controls. On the other hand, the whole body percent fat was significantly increased (mean observed/predicted value, 21.8/19.0%; P < 0.0002). Twenty-five patients (26%) had a percent fat above the 90th percentile of the reference values, which indicates excessive fatness. Adjusted for sex and age, a higher percent fat was related to cranial irradiation or GH insufficiency, but not to sex, the cumulative doses of anthracyclines or corticosteroids, or the type of corticosteroid used. BMI was a poor measure of body fatness.
Polycomb group (PcG) proteins repress homeotic genes in cells where these genes must remain inactive during development. This repression requires cis-acting silencers, also called PcG response elements. Currently, these silencers are ill-defined sequences and it is not known how PcG proteins associate with DNA. Here, we show that the Drosophila PcG protein Pleiohomeotic binds to specific sites in a silencer of the homeotic gene Ultrabithorax. In an Ultrabithorax reporter gene, point mutations in these Pleiohomeotic binding sites abolish PcG repression in vivo. Hence, DNA-bound Pleiohomeotic protein may function in the recruitment of other non-DNA-binding PcG proteins to homeotic gene silencers.
OBJECTIVE: The aim of the present study was to investigate whether patients with cystic fibrosis (CF) are GH resistant with increased GH release and decreased concentrations of IGF-I as a result of malabsorption, increased catabolism and impaired glucose tolerance. DESIGN: Twenty CF patients were included, ten with normal glucose tolerance (five male, five female, median age 25.5 years (range 20-31)) and ten with diabetes mellitus (five male, five female, median age 25.3 years (range 17-45). Twenty healthy individuals served as controls (ten male, ten female, median age 28.4 years (range 18-36)). METHODS: GH status was evaluated by 12h spontaneous GH release during the night time, arginine-stimulated GH release and the basal concentrations of IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3). Twelve hour spontaneous GH profiles were estimated using a constant blood withdrawal technique with sampling every 30min and the Pulsar method was used for the analysis of profiles. RESULTS: No significant differences were found in spontaneous and stimulated GH release in CF patients compared with healthy controls, whereas IGF-I and IGFBP-3 were significantly decreased in CF patients compared with healthy controls. The combination of reduced IGF-I and IGFBP-3 with normal GH release points to a relative GH resistance or a disturbance in the pituitary axis in patients with CF. The spontaneous GH release, the stimulated GH release and the basal concentrations of IGF-I and IGFBP-3 were not significantly different in diabetic CF patients compared with CF patients with normal glucose tolerance and the presence of diabetes mellitus was not consistent with increased GH resistance in CF patients. CONCLUSION: CF patients with normal glucose tolerance and diabetic CF patients had normal GH release and decreased concentrations of IGF-I indicating a relative GH resistance.
The pathogenetic role of Mycobacterium tuberculosis (M. tuberculosis) in tuberculosis is well defined, whereas its role in sarcoidosis is controversial. In sarcoidosis, activation of T-helper cells is observed, which is comparable to tuberculosis. The aim of this study was first to investigate whether M. tuberculosis DNA could be retrospectively detected in samples of patients with clinically verified sarcoidosis by polymerase chain reaction (PCR) and second, to analyze the relationship between M. tuberculosis DNA positive samples and T-cell response in sarcoidosis patients. Formalin fixed paraffin-embedded lung tissues or cell sediments of bronchoalveolar lavage, respectively, from 65 patients with sarcoidosis and lung tissues from 40 tuberculosis patients were investigated by means of different PCR assays in comparison to control samples. The primers used were derived from insertion sequence IS 986/6110 specific for the M. tuberculosis complex (123 bp PCR) and from the gene encoding the 38 kDa protein antigen b (419 bp PCR). The 123 bp assay yielded a specificity of 97% and a sensitivity of 95%. In contrast, the 419 bp PCR method showed a lower sensitivity of only 8% likely because of possible DNA degradation during fixation and embedding procedures of the tissue and the fact that this PCR uses a single copy element as target. We amplified the M. tuberculosis complex specific 123 bp fragment in 64% of samples from sarcoidosis patients. The specificity of PCR products in these cases was confirmed by DNA sequencing. Interestingly in the M. tuberculosis positive sarcoidoses, we found increased serum levels of soluble interleukin-2 receptor in correlation to the sarcoidosis stages (p < 0.05). In conclusion, the determination of M. tuberculosis by PCR alone does not permit a differentiation between sarcoidosis and tuberculosis. However these results support the contention that M. tuberculosis may play a pathogenetic role at least in the part of sarcoidosis patients with elevated interleukin-2 receptor values.
OBJECTIVE: The aim of this study was to develop a questionnaire for measuring depressed patients' knowledge of their disease. METHODS: 55 patients suffering from depressive episodes answered a 77-items questionnaire. RESULTS: Item analysis showed a discriminative power higher than 30 for 40 items, all of which applied to one factor. The items were arranged into two thematically similar 20 items forms. We added four additional items (discriminative power between 0.20 and 0.29) because future research may lead to different results concerning discriminative power. The questionnaires DEWIPA-A and DEWIPA-B consists of 24 items each. The average difficulty is equal for both DEWIPA forms and they both possess significant discriminative power. CONCLUSIONS: Our results support the hypothesis that DEWIPA is a valid and reliable instrument to determine patients' knowledge of symptoms, causes and the psychopharmacological treatment of depression.
Transcription of the human 7SL RNA gene by RNA polymerase III depends on the concerted action of transcription factors binding to the gene-internal and gene-external parts of its promoter. Here, we investigated which transcription factors interact with the human 7SL RNA gene promoter and which are required for transcription of the human 7SL RNA gene. A-box/B-box elements were previously identified in 5S RNA, tRNA, and virus associated RNA genes and are recognized by transcription factor IIIC (TFIIIC). The gene-internal promoter region of the human 7SL RNA gene shows only limited similarity to those elements. Nevertheless, competition experiments and the use of highly enriched factor preparations demonstrate that TFIIIC is required for human 7SL transcription. The gene-external part of the promoter includes an authentic cAMP-responsive element previously identified in various RNA polymerase II promoters. Here we demonstrate that members of the activating transcription factor/cyclic AMP-responsive element binding protein (ATF/CREB) transcription factor family bind specifically to this element in vitro. However, the human 7SL RNA gene is not regulated by cAMP in vivo. Furthermore, in vitro transcription of the gene does not depend on ATF/CREB transcription factors. It rather appears that a transcription factor with DNA-binding characteristics like ATF/CREB proteins but otherwise different properties is required for human 7SL RNA transcription.
Several studies have now been published on the effect of one or several years of growth hormone treatment on growth and body composition of children with Prader-Willi syndrome. The majority of the patients have responded with greatly increased growth rate, decreased body fat and increased muscle volume. Many of these children seem to have a functional growth hormone deficiency, probably secondary to their hypothalamic dysfunction. Further studies are needed to establish the long-term effect of this treatment on somatic and psychological well-being.
Soluble interleukin-2-receptor-alpha (sIL-2Ralpha) serum concentrations were examined in chronic pancreatitis patients, patients with cystadenocarcinoma of the pancreas, patients with adenocarcinoma of the pancreas and healthy blood donors. sIL-2Ralpha serum concentrations in pancreatic cancer patients were significantly higher than those of normal control subjects or chronic pancreatitis patients. In patients with adenocarcinoma of the pancreas no significant differences were found between sIL-2Ralpha and tumor size, grading, resectability and lymph node involvement. In Kaplan-Meier regression analysis patients with adenocarcinoma of the pancreas with low sIL-2Ralpha levels (<500 U/ml) lived significantly shorter than patients with sIL-2Ralpha concentrations above 500 U/ml (P < 0.01), suggesting that determination of sIL-2Ralpha serum concentrations could provide additional important information about prognosis.