Biomedical subjects

S Werner

Publications and source records attributed to S Werner.

At least 181 records · Page 10Linked to original sources

PubMed1993

Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis.

The actions of fibroblast growth factors (FGFs) are mediated via a family of four closely related FGF receptor genes (FGFRs 1-4). FGFR1, FGFR2, and FGFR4 have unique patterns of expression during embryogenesis suggesting that these receptors mediate different functions of FGFs during development. In the present study, we used in situ hybridization analysis to show that FGFR3 also has a unique pattern of expression during organogenesis. Like FGFR1 and FGFR2, FGFR3 was expressed in the germinal epithelium of the neural tube (9.5-16.5 days pc). However, at 1 day postpartum and in the adult brain, FGFR3 was expressed diffusely and localized in cells with morphologic characteristics of glia, a pattern distinctly different from the discrete neuronal expression of FGFR1. FGFR3 was also expressed at high levels in differentiating hair cells of the cochlear duct, but was not detected in other sensory epithelia. Outside the nervous system, the highest level of FGFR3 expression was found in the cartilage rudiments of developing bone. During endochondral ossification, FGFR3 was expressed exclusively in resting cartilage, a pattern distinct from FGFR1 and FGFR2 which are also expressed during this process. Unlike FGFR1 and FGFR2, FGFR3 was not detected in most other epithelial or mesenchymal tissues during these stages of organogenesis. The unique expression pattern of FGFR3 compared with the other FGF receptors strongly suggests that FGFR3 performs specific functions during organogenesis.

Animals↗

PubMed1993

Production of tremorgenic mycotoxins by isolates of Aspergillus fumigatus from sawmills in Sweden.

One hundred and six strains of A. fumigatus were isolated from 21 sawmills in Sweden, and 73 of these strains were examined for production of fumitremorgen B and verruculogen (tremorgenic mycotoxins) on YES-medium using thin layer chromatography (TLC). Twenty-three strains (32%) were tremorgen producers and 50 strains (68%) were non-producers. Tremorgenic mycotoxins were detected in conidia of seven A. fumigatus strains. The amount of toxin varied between 0.6-8.0 microgram/10(8) conidia (mean value 2.3 micrograms/10(8) conidia, equivalent with 0.18%). No production of the mycotoxin gliotoxin was detected in 6 strains of A. fumigatus. No tremorgens were detected during mould growth on wood substrates, in spite of the use of different wood species (Scots pine, Pinus sylvestris: Norway spruce, Picea abies and birch, Betula spp.), dried versus non-dried wood, bark (pine), leached wood, and wood after various sterilization methods.

Air Pollutants↗

PubMed1993

Isokinetic quadriceps training in patients with patellofemoral pain syndrome.

The aims of the present investigation were (a) to evaluate the effect of eccentric quadriceps training in patients with unilateral patellofemoral pain and (b) to compare the effect of eccentric and concentric quadriceps training in patients with bilateral patellofemoral pain. Fifteen patients (9 male and 6 female, aged 17-36 years with a mean of 27.5 years) participated in this study. Nine patients had unilateral pain and trained their painful leg eccentrically, while six had bilateral pain and trained one leg eccentrically and the other concentrically. Quadriceps muscle training was performed on a Kin-Com dynamometer at 90 degrees/s and 120 degrees/s angular velocity twice a week for 8 weeks. Before and after the treatment period the thigh muscle torques were measured on the Kin-Com dynamometer at 60 degrees/s, 90 degrees/s, 120 degrees/s and 180 degrees/s for quadriceps and at 60 degrees/s and 180 degrees/s for hamstrings. Nine controls, matched for gender and age with the group with unilateral pain, were tested in the same way on the Kin-Com dynamometer. For functional evaluation a knee score was calculated before training, after 8 weeks of training and at a mean of 3.4 years after completion of the training. After 8 weeks of training and at follow-up times of 1 and 3.4 years the patients were also questioned regarding whether or not they felt improvement from the training programme. To determine the degree of knee pain during the training Borg's pain scale was used. The results showed that, compared with the controls, the patients had a significantly lower knee extensor torque in their painful leg at all velocities measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Effect of taping the patella on concentric and eccentric torque and EMG of knee extensor and flexor muscles in patients with patellofemoral pain syndrome.

The acute effect of patella taping on torque and electromyographic (EMG) activity in maximal voluntary concentric and eccentric action of the knee extensor and flexor muscles in patients with patellofemoral pain syndrome was studied in 48 patients (62 knees). The patients (28 female, 20 male) were tested concentrically and eccentrically on a Kin-Com dynamometer with simultaneous EMG recording with the patella untaped and medially or laterally taped. Patients with clinically normal patellar mobility did not improve their quadriceps performance by taping of the patella; after medial taping they decreased their muscle torque during concentric work at 60 degrees/s (P < 0.05) and eccentric work at 180 degrees/s (P < 0.05). After lateral taping they decreased their muscle torque during concentric work at 60 degrees/s (P < 0.05) and eccentric work at both 60 degrees/s (P < 0.01) and 180 degrees/s (P < 0.05). Moreover, these patients also decreased their agonist EMG activity during concentric work at 60 degrees/s (P < 0.05) and 180 degrees/s (P < 0.05) and their antagonist EMG activity during eccentric work at 60 degrees/s (P < 0.01). Patients with a clinical lateral patellar hypermobility increased their knee extensor torque after medial taping at 60 degrees/s during both eccentric work (P < 0.01) and concentric work (P < 0.05). The greatest improvement in quadriceps performance, however, was in patients with a clinical medial patellar hypermobility. They increased their knee extensor torque after lateral taping during eccentric work at both 60 degrees/s (P < 0.001) and 180 degrees/s (P < 0.001) and during concentric work at 60 degrees/s (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Personality in patients with long-term patellofemoral pain syndrome.

Personality characteristics in patients with long-term patellofemoral pain were compared to those of matched controls and other groups both of non-patients and of psychiatric outpatients with character disorders. Personality was described using the self-administered dependency and alexithymia scales, the Karolinska Scales of Personality and the Rorschach inkblot method. The hypothesis was that the patellofemoral pain patients would have higher levels of anxiety, depression, helplessness, aggression and alexithymic characteristics than the matched controls. There were only a few significant differences between the knee patients and the matched controls. The Rorschach measures suggested significantly greater depression, hostility and passive attitude in the knee patients as compared to the reference data. There were no indications of the hypothesised alexithymic characteristics in the knee patients. If patellofemoral pain patients do not improve as expected, referral to a pain clinic with psychological expertise could be considered.

Adaptation, Psychological↗

PubMed1993

Electrical stimulation of vastus medialis and stretching of lateral thigh muscles in patients with patello-femoral symptoms.

Thirty patients with unilateral patello-femoral symptoms and a hypotrophic vastus medialis muscle were treated with transcutaneous electrical stimulation of the vastus medialis obliquus and stretching of the lateral thigh muscles twice daily for 10 weeks. Before and after treatment the position of the patella at fixed knee flexion angles and the area of the vastus medialis and vastus lateralis muscles were studied by computed tomography. Isokinetic quadriceps torque was registered with a Cybex II Dynamometer. An evaluation with a functional knee score was carried out. The healthy contralateral leg served as control in all the examinations. Clinically two-thirds of the patients had improved after 10 weeks of treatment and this improvement remained at follow-up 3.5 years later. The area of the vastus medialis and the quadriceps torque of the treated leg increased significantly, while the area of the vastus lateralis and the position of patella did not change. We conclude that transcutaneous electrical muscle stimulation of the vastus medialis and stretching of the lateral thigh muscles might be of benefit in patients with patello-femoral symptoms and a hypotrophic vastus medialis. An improvement after 10 weeks of treatment seems to predict a good long-term result.

Adolescent↗

PubMed1993

Growth hormone and insulin-like growth factor-1 in blood and urine as response markers during treatment of acromegaly with octreotide: a double-blind placebo-controlled study.

Growth hormone (GH), insulin-like growth factor-1 (IGF-1) and prolactin (PRL) in blood and urine were observed in 20 patients with acromegaly in a double-blind placebo-controlled 14-day clinical trial with the somatostatin analog octreotide. Hormones were determined by the same radioimmunoassays in blood and urine. Significant reduction of GH and IGF-1 during octreotide treatment compared to placebo was seen in blood but not in urine. Patients with diabetes mellitus, 2 of the 20 patients, showed notably increased urinary GH and IGF-1 in relation to blood levels. Therefore, results without the two diabetic patients were calculated, showing significant reduction of urinary GH and IGF-I during treatment on some, but not all observation days. The intraindividual variations of GH and IGF-1 were greater in urine than in blood. PRL levels were not significantly affected by octreotide either with or without the two diabetic patients. In conclusion, this study indicates, that GH and IGF-1 in blood are preferable to urinary GH and IGF-1 as response markers during treatment of acromegaly with octreotide. One disadvantage with urinary assessments of GH and IGF-1 in acromegaly seems to be the relatively higher excretion in patients with diabetes mellitus.

Acromegaly↗

PubMed1993

The short and long-term effects of octreotide on calcium homeostasis in patients with acromegaly.

OBJECTIVE: The somatostatin analogue octreotide (Sandostatin, Sandoz) is effective in reducing growth hormone levels in patients with acromegaly. Early and transient gastrointestinal side-effects are frequent. The aim was to evaluate whether gastrointestinal side-effects during the initial phase of octreotide treatment affect calcium homeostasis, and whether effects on calcium homeostasis are seen during long-term treatment with octreotide in patients with optimal effect on GH and subjectively normal gastrointestinal function. DESIGN: We first studied short-term treatment with octreotide during 14 days. From day 15 of the study medication was withdrawn, and on day 20 follow-up measurements were made. We then observed the effects of long-term treatment with octreotide. Mean duration of treatment until the day of blood sampling was 32 months (range 9-48 months). PATIENTS: Sixteen patients with acromegaly were studied, ten in the short-term study and ten in the long-term study; four were included in both. MEASUREMENTS: Serum levels of calcium, phosphate, PTH, alkaline phosphatase, 1,25(OH)2 Vit D, vitamin D-binding protein and sex hormone-binding globulin (SHBG) were measured before treatment (day 0) and on days 4, 6, 8, 14 and 20 during the short-term study and, except SHBG, before treatment and during therapy in the long-term study. RESULTS: During the short-term treatment mean (+/- SEM) serum calcium decreased significantly (on days 6 and 8, 2.21 +/- 0.08 and 2.15 +/- 0.09 mmol/l, respectively vs basal level, 2.38 +/- 0.08 mmol/l), whereas significant increments were seen in mean serum PTH (on day 14, 36 +/- 4 vs basal, 24 +/- 3 ng/l; ng/l divided by 9.425 = pmol/l), mean serum 1,25(OH)2 Vit D (on day 8, 112 +/- 7 vs basal 96 +/- 8 pmol/l), and 'free 1,25(OH)2 Vit D-index', i.e. molar ratio of 1,25(OH)2 Vit D and vitamin D-binding protein (on days 8 and 14, 1.72 +/- 0.09 x 10(-5) and 1.66 +/- 0.11 x 10(-5), respectively vs basal, 1.33 +/- 0.09 x 10(-5)). The changes were within the normal range. No changes were seen in serum phosphate, alkaline phosphatase, or vitamin D-binding protein. During the long-term study mean serum calcium and phosphate decreased significantly, 2.32 +/- 0.04 vs basal 2.42 +/- 0.04 mmol/l and 1.24 +/- 0.07 vs basal 1.40 +/- 0.09 mmol/l, respectively, whereas mean serum PTH increased significantly, 40 +/- 8 vs basal 21 +/- 5 ng/l. The changes were within the normal range. No changes were seen in serum alkaline phosphatase, 1,25(OH)2 Vit D, free 1,25(OH)2 Vit D-index, or vitamin D-binding protein. CONCLUSION: Altered calcium homeostasis during octreotide treatment in acromegaly is not only initial and temporary, but can also be seen after several years of treatment. The clinical relevance of these long-standing effects needs to be further investigated.

Acromegaly↗

PubMed1993

Women with prolactin-producing pituitary adenoma show decreased serum placental lactogen during pregnancy.

Prolactin (PRL), growth hormone (GH), placental lactogen (PL), chorionic gonadotropin (CG), estradiol (OE), progesterone (P4) and sex hormone-binding globulin (SHBG) were measured in serum throughout gestation in 9 women with PRL-producing pituitary adenomas. They had been treated at least 1 year with the dopamine agonist bromocriptine before pregnancy occurred. All women bore healthy babies of normal birthweight. Their PRL levels did not show the successive increase seen in normal pregnancies; serum PRL was unphysiologically increased in all patients up to the 20th week of gestation, whereafter PRL levelled off and fell within the normal range. Serum PL levels were lower in the women with prolactinoma compared to healthy pregnant women, despite normal placental weight. The serum GH levels in the patients determined with an immunoassay based on a monoclonal antibody, were low or nondetectable, similar to healthy pregnant controls. In contrast, high molecular weight GH in serum as determined with a monoclonal antibody which also recognizes PL appeared to be increased in comparison with healthy pregnant women. The serum levels of CG, OE, P4 and SHBG were all within the normal range. These results show that the unphysiological secretion of PRL in pregnant women with PRL-producing pituitary adenomas is associated with decreased serum levels of PL.

Adult↗

PubMed1993

Linkage analysis in German breast cancer families with early onset of the disease, using highly polymorphic markers from the chromosome 17q11-q24 region.

Linkage analysis in German breast cancer families with early onset of the disease by using six markers on chromosome 17q11-q24 has been carried out. In the region between markers D17S250 and GH, three markers showed positive LOD scores at an estimated distance of zero. Evidence for linkage is greatest for D17S250, with a LOD score of 2.42.

Adult↗

PubMed1992

Identification of the ubiquinone-binding site of NADH:ubiquinone oxidoreductase (complex I) from Neurospora crassa.

In order to localize the ubiquinone-binding site of complex I (NADH:ubiquinone oxidoreductase), a novel photoreactive ubiquinone analogue (Q0C7ArN3) has been synthesized. It is shown that the direct chemical precursor of this analogue (Q0C7ArNO2) and the analogue itself are accepted as substrates in an enzyme assay utilizing ubiquinone-depleted mitochondrial membranes of Neurospora crassa. The activity of the enzyme applying these derivatives is inhibited by 50% at a concentration of 9 and 20 microM rotenone. Photoaffinity labeling experiments were performed with both isolated complex I and whole mitochondrial membranes of N. crassa under various conditions. In each of these experiments a protein subunit with an apparent molecular mass of about 9.5 kDa was labeled with high specificity. Radioactive labeling was totally prevented by the addition of ubiquinone-2 at concentrations higher than 500 microM but was not affected by comparable concentrations of rotenone or other hydrophobic substances. In the labeling experiments using whole membranes, the labeling signal was dramatically increased in the presence of 1.5 mM NADH. These results strongly suggest that the ubiquinone analogue interacts specifically with the enzyme.

Affinity Labels↗

PubMed1992

Characterization of the 9.5-kDa ubiquinone-binding protein of NADH:ubiquinone oxidoreductase (complex I) from Neurospora crassa.

A small polypeptide subunit of the NADH:ubiquinone reductase (complex I) from Neurospora crassa has been identified by photoaffinity labeling to participate in the binding of ubiquinone [Heinrich, H., & Werner, S. (1992) Biochemistry (preceding paper in this issue)]. This polypeptide is further characterized by its primary structure and by an assessment of its localization within complex I. A lambda gt11 cDNA expression library was screened using a specific antibody directed against this individual subunit of complex I. Two groups of clones, coding for polypeptide subunits of the appropriate apparent molecular weight, were isolated. One group was shown to contain the relevant recombinants. The derived amino acid sequence for the 9.5-kDa ubiquinone-binding polypeptide shows a similarity with a putative ubiquinol-binding subunit (also a 9.5-kDa polypeptide) from complex III of bovine heart [Usui, S., Yu, L., & Tu, C.-A. (1990) Biochemistry 29, 4618-4626]. The polypeptide has a hydrophobic stretch of a sufficient length to span the membrane. It resists against extraction with NaBr or Na2CO3, and therefore probably is buried in the so-called hydrophobic membrane portion of complex I. This nuclearly-encoded subunit lacks a typical cleavable presequence and is imported into isolated mitochondria by a membrane potential-dependent process.

Amino Acid Sequence↗

PubMed1992

Primary structure and mitochondrial import in vitro of the 20.9 kDa subunit of complex I from Neurospora crassa.

The 20.9 kDa subunit of NADH:ubiquinone oxidoreductase (complex I) from Neurospora crassa is a nuclear-coded component of the hydrophobic arm of the enzyme. We have determined the primary structure of this subunit by sequencing a full-length cDNA and a cleavage product of the isolated polypeptide. The deduced protein sequence is 189 amino acid residues long and contains a putative membrane-spanning domain. Striking similarity over a 60 amino-acid-residue domain with the M (matrix) protein of para-influenza virus was found. No other relationship with already known sequences could be detected, leaving the function of this subunit in complex I still undefined. The biogenetic pathway of this polypeptide was studied using a mitochondrial import system in vitro. The 20.9 kDa subunit synthesized in vitro is efficiently imported into isolated mitochondria, where it obtains distinct features of the endogenous subunit. Our results suggest that the 20.9 kDa polypeptide is made on cytosolic ribosomes lacking a cleavable targeting sequence, interacts with the mitochondrial outer membrane (in a process that does not require an energized inner membrane), and is imported into mitochondria at contact sites. The 20.9 kDa subunit is then inserted into the inner membrane acquiring a topology similar to that of the already assembled subunit.

Amino Acid Sequence↗

PubMed1992

A naturally occurring secreted form of fibroblast growth factor (FGF) receptor 1 binds basic FGF in preference over acidic FGF.

Alternatively spliced variants of fibroblast growth factor receptor 1 mRNA are predicted to encode secreted forms and membrane-bound forms of receptors. The predicted amino acid sequences of these receptor variants differ in a portion of the extracellular region. In this study, we characterized the function of one of these splice variants which was predicted by its cDNA to be a secreted FGF receptor. We expressed this secreted form of the human FGFR1 (sFGFR1) in Chinese hamster ovary cells. The sFGFR1 protein oligomerized upon ligand binding. Surprisingly, the sFGFR1 preferentially bound basic FGF over acidic FGF. In cross-linking experiments, the sFGFR1 showed higher binding affinity for basic FGF (Kd approximately 30 nM) than for acidic FGF (Kd greater than 300 nM). These results suggest that this secreted form of FGF receptor has an unusual ligand binding specificity that may be important for its biological role in vivo.

Animals↗

PubMed1992

Large induction of keratinocyte growth factor expression in the dermis during wound healing.

Recent studies have shown that application of basic fibroblast growth factor (basic FGF) to a wound has a beneficial effect. However, it has not been assessed whether endogenous FGF also plays a role in tissue repair. In this study we found a 160-fold induction of mRNA encoding keratinocyte growth factor (KGF) 1 day after skin injury. This large induction was unique within the family of FGFs, since mRNA levels of acidic FGF, basic FGF, and FGF-5 were only slightly induced (2- to 10-fold) during wound healing, and there was no expression of FGF-3, FGF-4, and FGF-6 detected in normal and wounded skin. High levels of FGF receptor 1 and FGF receptor 2 mRNA and low levels of FGF receptor 3 mRNA were found in both normal and wounded skin. No change in the levels of these transcripts was detected during wound healing. In situ hybridization studies revealed highest levels of KGF mRNA expression in the dermis at the wound edge and in the hypodermis below the wound. In contrast, mRNA encoding the receptor of this growth factor (a splice variant of FGF receptor 2) was predominantly expressed in the epidermis. These results suggest that basal keratinocytes are stimulated by dermally derived KGF during wound healing and implicate a unique role of this member of the FGF family in wound repair.

Animals↗

PubMed1992

Thyrotropin-releasing hormone increases serum levels of growth hormone-releasing hormone and growth hormone in patients with acromegaly.

The effect of intravenous injection of thyrotropin-releasing hormone (TRH) on the plasma concentrations of growth hormone (GH) and growth hormone-releasing hormone (GHRH) was studied in seven patients with acromegaly and in five control subjects. TRH had no effect on plasma GH or GHRH in the five control subjects. A 'paradoxical' increase in plasma GH in response to TRH was observed in four of the seven patients with acromegaly. In these four patients plasma GHRH also increased in response to TRH. No TRH-induced increase in GHRH levels was observed in the other three patients with acromegaly who did not display an increase in GH in response to TRH. The present results imply that GHRH may be involved in the plasma GH response to TRH in patients with acromegaly.

Acromegaly↗

PubMed1992

Differential splicing in the extracellular region of fibroblast growth factor receptor 1 generates receptor variants with different ligand-binding specificities.

We have cloned a genomic region of the murine fibroblast growth factor (FGF) receptor 1 (FGFR1) gene that includes three alternative exons for the third immunoglobulinlike domain in the extracellular region of the receptor. The mRNA of one of these splice variants encodes a secreted receptor that lacks transmembrane and cytoplasmic sequences as well as a portion of the third immunoglobulinlike domain. Highest levels of mRNA encoding this variant were found in brain, skeletal muscle, and skin. We expressed this form of FGFR1 in CHO cells and showed that the recombinant secreted protein binds acidic FGF. We also discovered a novel alternative exon in the third immunoglobulinlike domain that encodes part of a transmembrane FGFR1 mRNA. This exon is highly homologous to the corresponding region of the keratinocyte growth factor receptor. Transcripts including this exon were present at highest levels in the skin. We cloned an FGFR1 cDNA which includes this exon and expressed this receptor variant in L6 rat skeletal muscle myoblasts. The new receptor variant had a 50-fold-lower affinity for basic FGF than does the published FGFR1 variant, whereas both forms of receptor bound acidic FGF with high affinity. These results show that the third immunoglobulinlike domain plays an important role in determining the binding specificities for different FGFs. Our data provide the first evidence that differential splicing in the extracellular region of a receptor gene generates receptor variants with different ligand-binding specificities.

Amino Acid Sequence↗

PubMed1992

Glucocorticoid receptor abnormalities in fibroblasts from patients with idiopathic resistance to dexamethasone diagnosed when evaluated for adrenocortical disorders.

A retrospective survey was accomplished on 420 consecutive patients who had undergone dexamethasone suppression tests between 1975-1988 due to suspected adrenal disorders. We found 7 patients in whom glucocorticoid resistance was apparent. They showed 4-6 abnormalities of the 7 investigations used: insensitivity to dexamethasone inhibition (n = 7), increased urinary cortisol (n = 3), glucocorticoid receptor (GR) thermolability (n = 4), decreased number of glucocorticoid receptors (n = 4), abnormal ligand affinity of GR (n = 4), abnormal basal GR mRNA expression (n = 4), and abnormal down-regulation of basal GR mRNA levels by dexamethasone (n = 1). The four patients with GR thermolability also showed increased basal GR mRNA levels. In the other patients the number of GR per cell was decreased without an up-regulation of GR mRNA. It is concluded that the syndromes of glucocorticoid resistance vary notably, clinically as well as biochemically; in patients evaluated for adrenocortical disorders the syndrome is apparently encountered in 1-2% of the patients.

Adrenal Cortex Diseases↗