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Biomedical subjects

F Hefti

Publications and source records attributed to F Hefti.

At least 55 records · Page 3Linked to original sources
PubMed1997

Arthrogrypotic joint contracture at the knee and the foot: correction with a circular frame.

The purpose of this study was to investigate the efficacy of an external fixator (Ilizarov apparatus) for the treatment of severe joint contractures in patients with arthrogryposis multiplex congenita. Thirteen knees and 16 feet were treated in 13 patients at an average age of 11.9 years. The knee flexion contractures were corrected from 38.9 degrees preoperatively to a mean of 6.5 degrees postoperatively and to 17.3 degrees at follow-up (34 months). In the foot deformities, the equinus position was corrected from 29.7 degrees to 7.8 degrees on average. This external fixator is an efficient tool for correction of deformities in arthrogryposis.

Adolescent↗
PubMed1997

Pharmacology of neurotrophic factors.

The field of neurotrophic factor pharmacology emerged during the past decade with the discovery that these proteins can counteract neuronal atrophy and death in the adult nervous system. These concepts are being tested in clinical trials. Therapeutic use of neurotrophic proteins seems practical for diseases of the peripheral nervous system (PNS), where they can be given by systemic administration. For diseases of the CNS, special administration strategies will have to be developed to deliver the neurotrophic factors into the brain. The development of small molecule mimetics represents an alternative approach that is actively pursued to provide brain-penetrant neurotrophics.

Alzheimer Disease↗
PubMed1997

Elevated mRNA expression of brain-derived neurotrophic factor in retinal ganglion cell layer after optic nerve injury.

PURPOSE: Recent studies show that exogenous brain-derived neurotrophic factor (BDNF) can promote retinal ganglion cell survival in vivo and in vitro. BDNF is expressed by a subpopulation of cells in the ganglion cell layer (GCL). To investigate whether endogenous BDNF may play a role in neuronal protection after ganglion cell trauma, BDNF expression in the retina was examined after optic nerve (ON) injury. METHODS: The optic nerve in Sprague-Dawley rats was crushed intraorbitally posterior to the optic disc. For controls, the optic nerve on the opposite side in each animal was similarly exposed but was not crushed. After intervals of 6 hours to 6 weeks, eye tissues were processed for in situ hybridization, Northern blot, and RNase protection assay using radiolabeled rat riboprobes. RESULTS: After ON injury, BDNF expression was significantly elevated in cells restricted to the GCL, and more cells demonstrated expression of BDNF than were observed in the controls. Elevated BDNF expression was first observed at 24 hours, peaked at 48 hours, and declined to the basal level 2 weeks after ON injury. Quantitative analysis showed a fivefold to sixfold increase in the number of BDNF-positive cells and a 54% increase in BDNF signal intensity in individual cells in the GCL 48 hours after ON injury. In control retinas without ON injury, BDNF expression was localized to some cells in the GCL, as was observed in normal eyes without surgery. Northern blot and RNase protection assay demonstrated a 38% elevation in BDNF expression above control levels 48 hours after ON injury. CONCLUSIONS: These results indicate that cells in the GCL can upregulate gene expression of BDNF in response to ganglion cell axonal injury and suggest that endogenous BDNF may contribute to a natural neuroprotective process after ON injury.

Animals↗
PubMed1997

[Direct screw repair of spondylolysis with the hooked screw].

The majority of patients with symptomatic spondylolysis can be treated conservatively. Only when symptoms persist in spite of conservative treatment surgery may be indicated. In young patients, however, fusion of a mobile segment should be avoided, but a direct repair of the pars defect can be attempted. This procedure allows complete healing and possibly avoids degeneration of the intervertebral disk. For this purpose Morscher developed the hook screw, which connects the arch with the anterior articular process. It allows compression of the defect without crossing the defect with the screw. A follow-up study of the first 33 patients with a follow-up time of 3.5 years on average showed a good subjective result in 79% of the patients. In patients younger than 20 years of age, however, the result was good in 87.5% of cases. The reason for the better results in young patients is that in older patients the origin of the pain is often not the pars defect, but the degeneration of the intervertebral disk. Direct repair of spondylolysis is therefore indicated when pain persists after 6 months of conservative treatment or there is a progressive olisthesis of not more than 10 mm. After the end of growth an MRI study of the intervertebral discs should show whether there is degeneration or not. Direct repair is indicated only in the absence of disc degeneration. After the age of 25 years this procedure should not be carried out.

Adolescent↗
PubMed1996

Characterization of a multicomponent receptor for GDNF.

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for central and peripheral neurons, and is essential for the development of kidneys and the enteric nervous system. Despite the potential clinical and physiological importance of GDNF, its mechanism of action is unknown. Here we show that physiological responses to GDNF require the presence of a novel glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) that is expressed on GDNF-responsive cells and binds GDNF with a high affinity. We further demonstrate that GDNF promotes the formation of a physical complex between GDNFR-alpha and the orphan tyrosin kinase receptor Ret, thereby inducing its tyrosine phosphorylation. These findings support the hypothesis that GDNF uses a multi-subunit receptor system in which GDNFR-alpha and Ret function as the ligand-binding and signalling components, respectively.

Amino Acid Sequence↗
PubMed1996

NT-4/5 protects against adrenalectomy-induced apoptosis of rat hippocampal granule cells.

Adrenalectomy (ADX) in rats has been shown to induce apoptosis of hippocampal granule cells. We tested whether neurotrophins are able to protect hippocampal neurons in this neurodegeneration model. Acid fucshsin stain was used to identify pyknotic cells in ADX rats treated for 4 days with NT-3, NT-4-5 or cytochrome-C, as a control protein. Cytochrome-C injections slightly decreased cell death on the ipsilateral side. NT-3 did not further promote this effect. Significantly less cell death was observed bilaterally in hippocampus treated with NT-4/5. TUNEL end labeling also confirmed the results. Our results demonstrated that NT-4/5, but not NT-3, promotes hippocampal neuron survival in adrenalectomized rats. They further show that injections of a control solution can induce a local protective effect.

Adrenalectomy↗
PubMed1996

Selective failure of brain-derived neurotrophic factor mRNA expression in the cerebellum of stargazer, a mutant mouse with ataxia.

In search of the possible involvement of neurotrophic factors in inherited neurological disease, we examined brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) mRNA expression patterns in the ataxic mutant mouse stargazer (stg). Using in situ hybridization, we found a selective and near total reduction in BDNF mRNA in the cerebellar granule cell layer. NT-3 or NGF mRNA expression in the cerebellum was normal. Northern blot analysis demonstrated a 70% reduction in BDNF mRNA in the whole cerebellum. BDNF mRNA levels in other mutant brain regions were unchanged. Absence of BDNF mRNA in granule cells was observed at postnatal age (P15), coincident with the onset of ataxia, and expression levels failed to follow the developmental increase found in the wild type at later ages (P20 and P30). Despite the severe BDNF reduction, in situ hybridization patterns for both the full-length and the truncated BDNF TrkB receptor mRNA were unaltered. No major cytoarchitectural abnormalities were apparent in the stg/stg cerebellum. BDNF expression in a related ataxic mutant, tottering, was unaltered. These data show that BDNF can be regulated selectively in distinct brain regions, possibly by differential activation of its multiple promoters. Absence of cerebellar granule cell BDNF mRNA in stg/stg mice demonstrates that sustained expression of this neurotrophin is not required for cell survival in the developing cerebellar cortex. Our data, in contrast, suggest a role of BDNF in maturation of specific cerebellar neurons and pathways. Early failure of cerebellar BDNF expression may be related to the ataxic phenotype in stg mice.

Animals↗
PubMed1996

Intraparenchymal NGF injections in adult and aged rats induce long-lasting Trk tyrosine phosphorylation.

Neurotrophic factors, particularly the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and related molecules are proposed for the experimental treatment of neurode-generative disease. Earlier observations had suggested down-regulation of the neurotrophin receptor response with chronic stimulation. We therefore tested for effects of acute and chronic NGF treatment in vivo on the tyrosine phosphorylation response of Trk-type neurotrophin receptors in adult and aged rats. Rats were treated for 1 week with daily injections of NGF directly into the striatum. Surprisingly, this chronic neurotrophin treatment induced long-lasting tyrosine phosphorylation of Trk type receptors beyond the last injection. A similar result was obtained with 1 week of daily injections of BDNF into the hippocampus. Persistent TRK tyrosine phosphorylation was also observed after single neurotrophin injections. With 1 microgram of NGF injected, Trk-type receptors were maximally stimulated from immediately after the injection until 3 days after the treatment. Maintaining Trk tyrosine phosphorylation required maintained energy levels in the tissue. Incubation of microslices of brain tissue from NGF-injected animals in glucose-free buffer completely abolished all Trk tyrosine phosphorylation signals. Recovery of tissue in presence of glucose restored the signals in microslices derived from NGF-injected animals, in absence of acute NGF treatment. This result, together with dose-response comparisons after 2-h and 2-day survival times suggest that Trk protein remains tyrosine phosphorylated due to trophic protein which is only slowly being cleared out of the tissue during several days after the injection. Experiments with aged rats indicated similar extent and duration of Trk receptor activation after NGF administration in young adult and in aged brain.

Age Factors↗
PubMed1996

Regulated release and polarized localization of brain-derived neurotrophic factor in hippocampal neurons.

The site and regulation of neurotrophic factor release from neurons is poorly understood. We used a combination of model cell lines and primary culture systems to study the polarity of BDNF sorting and the regulation of its release from hippocampal neurons. Transfection and expression of a human BDNF cDNA in a mouse pituitary cell line, AtT20, resulted in the colocalization of BDNF with the secretory granule marker, chromogranin A. Furthermore, stimulation of these cells with 56 mM KCl or with 5 mM 8-bromo-cAMP increased the release of BDNF approximately 10-to 15-fold within 30 min. To study BDNF release from primary cultures of hippocampal neurons, cells were infected with a defective Herpes Simplex Viral (HSV) vector expressing human BDNF. Depolarizing conditions increased the release of BDNF 5-fold from these cells, further verifying that secretion is regulated. Immunocytochemical analysis using highly specific antibodies determined that endogenous BDNF was predominantly localized to the somatodentritic domain of hippocampal neurons. These findings support the view that BDNF functions as a target-derived signal for afferents to hippocampal pyramidal cells and that it may serve as a regulator of hippocampal plasticity.

Animals↗
PubMed1996

Neurotrophin-4/5 treatment reduces infarct size in rats with middle cerebral artery occlusion.

The aim of this study was to determine whether neurotrophin-4/5 (NT-4/5) treatment alters infarction volume following permanent focal cerebral ischemia in the rat. Permanent focal cerebral ischemia was produced in adult male rats by intraluminal occlusion of the right middle cerebral artery. NT-4/5 was administered intraventricularly one day before and immediately following occlusion. Rats were sacrificed at 1, 4 and 7 days after occlusion. NT-4/5 treatment reduced infarction volume by 34% when compared to control rats 1 day after occlusion. Infarction volume was unaltered by treatment 4 to 7 days after occlusion. Middle cerebral artery occlusion led to a significant reduction in levels of mRNAs coding for catalytic and truncated TrkB receptors. This expression was unaffected by NT-4/5 treatment.

Animals↗
PubMed1996

Neurotrophin-4/5 selectively protects nigral calbindin-containing neurons in rats with medial forebrain bundle transections.

Three neurotrophic factors associated with the nigrostriatal dopaminergic system were tested for their trophic potential to rescue degenerating substantia nigra dopaminergic neurons in adult rats with transections of the medial forebrain bundle. Axotomy of nigral dopaminergic neurons results in a retrograde degeneration of their cell bodies. Unilateral transections resulted in a partial reduction of the number of dopaminergic neurons as identified by immunocytochemistry for tyrosine hydroxylase to approximately half of the number of neurons present on the intact contralateral substantia nigra. A similar percentage loss was found for the subpopulation of nigral neurons which contain the calcium binding protein calretinin. In contrast, the small subpopulation of neurons which contain calbindin was less sensitive to the lesion and showed only mild loss in the number of cells, which was reduced to 87% of control. Neurotrophin-4/5, transforming growth factor alpha or basic fibroblast growth factor were infused supranigrally for two weeks after transection. None of the trophic factors tested reversed the loss of tyrosine hydroxylase-positive or calretinin-positive cells. In contrast, neurotrophin-4/5, but not transforming growth factor alpha or basic fibroblast growth factor, was found to reverse the axotomy-induced loss of calbindin-positive neurons and indeed increased the number of cells to 45% above control levels. In addition, neurotrophin-4/5 elevated the number of calbindin-containing neurons in intact unlesioned animals to 15% above control. These findings suggest that neurotrophin-4/5 selectively acts on nigral calbindin neurons following medial forebrain bundle transection and prevents these cells from degenerating.

Animals↗
PubMed1996

GDNF induces a dystonia-like state in neonatal rats and stimulates dopamine and serotonin synthesis.

To test whether glial cell line-derived neurotrophic factor (GDNF) regulates the development of nigral dopaminergic neurons in vivo, neonatal rats received bilateral injections of GDNF into the striatum. Injections at postnatal day 2 induced a unique transient behavioral pattern characterized by forelimb hyperflexure, clawed toes of all limbs, and a kinked tail. Parallel to the behavioral changes, the levels of striatal and ventral mesencephalic dopamine and serotonin were increased from 60% to 100% with a proportional increase of principal metabolite levels. GDNF increased tyrosine hydroxylase activity in the ventral mesencephalon, but did not affect striatal activity of choline acetyltransferase and GABA uptake. GDNF failed to induce sprouting of dopaminergic neurites. Our findings suggest that during development striatal GDNF regulates the capacity of dopaminergic and of serotonergic neurons for neurotransmitter production and release.

Animals↗
PubMed1996

[Open laser surgery on the locomotor apparatus].

The first applications of laser in surgery of the locomotor apparatus in the early 1980s used the haemostatic properties of laser to diminish the amount of substitution of coagulation factors in haemophiliac patients. Only since the early 1990s has a device been available in corporating the pulsed holmium:YAG laser which works in a fluid medium without relevant side effects. Apart from haemostasis, the cutting function and tissue ablation, together with the thermal shrinking effect, are exploited in arthroscopy and percutaneous disc decompression. Now that the biophysical mechanisms of action have been elucidated, nothing stands in the way of the use of infrared lasers in open surgery of the locomotor apparatus in some indications. In a prospective clinical study we included 30 consecutive patients who underwent open laser surgery from November 1992 to August 1994, for the following indications: the sparing haemostatic tissue ablation was used for synovectomy or for bony resection in osteophytes and osteochondromas of different locations, an osteoid osteoma and a painful sacral hyperplasia in the presence of incomplete sacral meningomyelocele. With bleeding eliminated, the shaping was much easier. The non-ablative shrinking produced less tissue loss and a stabilizing strengthening of tissue at the margins of soft tissue resections, e.g. in jumper's knee, tennis elbow and Achilles tendon cysts. All laser functions that are useful in open surgery have also been used in sequestered disc herniations that are inaccessible a percutaneous procedure and, in spinal decompression, for remodelling of the posterior spine contour. An analgesic effect of laser limited the postoperative administration of analgesic drugs to an average of 3 days. No complications related to the laser treatment were observed. At follow-up 12-21 months after operation, 25 of the 30 patients in this heterogeneous population showed complete or near-total healing of the operated pathological finding, and a further 3 patients showed significant improvement. To what extent these very encouraging results will persist will be shown by long-term observation.

Bone Diseases↗
PubMed1996

Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: comparison between intraparenchymal and intraventricular administration.

Penetration into the brain is an important consideration in the pharmacological use of neurotrophic factors for the treatment of brain neurodegeneration, e.g., in Alzheimer's disease. Furthermore, intracerebroventricular treatment with nerve growth factor (NGF) has been found to induce side effects, including aberrant sympathetic sprouting and weight loss. Such findings suggest that direct intraparenchymal application of minimal amounts of trophic factors might be therapeutically desirable. We compared the effectiveness of intrastriatal and intracerebroventricular administrations of NGF on striatal cholinergic neurons in adult rats. Daily intrastriatal administration for 1 week of > or = 50 ng of NGF resulted in an increase in mRNA levels for choline acetyltransferase (ChAT) in striatal cholinergic cells to approximately 2-fold over control. A daily intraventricular dose of 4.5 micrograms of NGF was required for a similar response. Both 5 and 50 ng of NGF/day failed to induce an effect on transmembrane protein tyrosine kinase trkA mRNA levels, but injections of 750 or 1500 ng/day of NGF up-regulated trkA mRNA expression to approximately 2-fold of control. NGF delivered intracerebroventricularly failed to induce an observable change in striatal trkA mRNA, even at a dosage of 4.5 micrograms of NGF/day. These quantitative differences in NGF actions were reflected at the level of NGF receptors. Using Western blotting procedures, we found pronounced tyrosine phosphorylation of Trk-type proteins 2 hr after intrastriatal injection of 50 ng of NGF. Maximal responses were seen with either 150 or 750 ng of NGF. For maximal activation of Trks by intraventricular NGF injection, 4.5 micrograms of NGF was required. Taken together, our results strongly favor intraparenchymal injections or infusions of NGF, and possibly other trophic factors, for therapeutical applications to maximize the effects on the targeted neuronal populations and to minimize undesirable side effects.

Animals↗
PubMed1996

Relation of femoral to tibial torsion in children measured by ultrasound.

To study the relation between femoral and tibial torsion, we measured their values by ultrasound (US) in 97 normal children in two groups (aged 6 and 15 years). Anteversion was measured between the anterior aspect of the femoral neck and the axis of the femoral condyles, and tibial torsion as the difference of the proximal to the distal posterior tibial planes. The mean value of anteversion was 37 degrees in the younger group and 24 degrees in the older group. The mean value of tibial torsion was 18 degrees in both groups. We found neither side- nor sex-dependent differences in both age groups. There was no relation between both values.

Adolescent↗
PubMed1995

Heterodimeric neurotrophins induce phosphorylation of Trk receptors and promote neuronal differentiation in PC12 cells.

Neurotrophins are a family of highly conserved proteins that affect the development and maintenance of distinct neuronal populations. Neurotrophins exist in vivo as homodimers, but we show that neurotrophins can exist as heterodimers in vitro and are pluripotent, being able to bind and to activate different Trk tyrosine kinase receptors as well as promote neuronal differentiation in PC12 cells as effectively as wild type homodimers. These asymmetric neurotrophin dimers allow unique characterization of neurotrophin structure-function relationships with Trk receptors. The chimeric Trk activities of these heterodimers suggest an alternative model of neurotrophin-Trk receptor activation in which the critical Trk-interacting elements may be attributed to a single protomer.

Animals↗