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F Hefti

Publications and source records attributed to F Hefti.

At least 37 records · Page 2Linked to original sources
PubMed1998

Distinct mechanism for antidepressant activity by blockade of central substance P receptors.

The localization of substance P in brain regions that coordinate stress responses and receive convergent monoaminergic innervation suggested that substance P antagonists might have psychotherapeutic properties. Like clinically used antidepressant and anxiolytic drugs, substance P antagonists suppressed isolation-induced vocalizations in guinea pigs. In a placebo-controlled trial in patients with moderate to severe major depression, robust antidepressant effects of the substance P antagonist MK-869 were consistently observed. In preclinical studies, substance P antagonists did not interact with monoamine systems in the manner seen with established antidepressant drugs. These findings suggest that substance P may play an important role in psychiatric disorders.

Adolescent↗
PubMed1998

Cerebellar brain-derived neurotrophic factor-TrkB defect associated with impairment of eyeblink conditioning in Stargazer mutant mice.

In the spontaneous ataxic mutant mouse stargazer, there is a selective reduction of brain-derived neurotrophic factor (BDNF) mRNA expression in the cerebellum. BDNF protein levels in the cerebellum are reduced by 70%. Despite normal levels of full-length and truncated TrkB receptor, constitutive and neurotrophin-4/5-induced tyrosine phosphorylation was significantly reduced in several signal transduction molecules, including phospholipase-Cgamma1, erk1, and erk2. Morphological examination revealed an increased number of external granule cells at postnatal day 15 and the presence of abnormal neurons resembling immature granule cells in the adult. These abnormalities are associated with a severe impairment in the acquisition of classical eyeblink conditioning, indicating cerebellar malfunction. Our data suggest that normal BDNF expression and TrkB signal transduction in the cerebellum are necessary for learning and plasticity in this model.

Animals↗
PubMed1998

Regionally specific induction of BDNF and truncated trkB.T1 receptors in the hippocampal formation after intraseptal injection of kainic acid.

The septo-hippocampal cholinergic and GABAergic systems were lesioned with single unilateral injections of kainic acid (KA) into the septum to further characterize the role of these afferents in the regulation of hippocampal brain-derived neurotrophic factor (BDNF) expression. Nearly all cells expressing choline acetyltransferase, trkA or glutamic acid decarboxylase mRNA disappeared in the medial septum 7 days after the neurotoxin administration. The lesion resulted in a complete loss of CA3 pyramidal cells, and robust increases in BDNF mRNA levels in hippocampal granular dentate cells and in the amygdala. There were rapid transient increases of BDNF mRNA levels in the hippocampal formation and cortex. In addition, we found a strong induction of truncated trkB.T1 mRNA receptors in the stratum radiatum and stratum oriens of the CA3 subfield. The prolonged induction of BDNF mRNA levels suggests an important role of this neurotrophin, possibly mediated by truncated trkB receptors, in the regulation of hippocampal plasticity following injury.

Animals↗
PubMed1998

Discoid lateral meniscus in children. Long-term follow-up after total meniscectomy.

We retrospectively reviewed the long-term results of total meniscectomy performed in seventeen knees (fourteen children) to treat a discoid lateral meniscus. The mean duration of follow-up was 19.8 years (range, 12.5 to 26.0 years). On the basis of the rating system of the International Knee Documentation Committee, seven knees were normal (grade A), six were nearly normal (grade B), three were abnormal (grade C), and one was severely abnormal (grade D) at the latest follow-up evaluation. Ten of the seventeen knees had clinical symptoms of osteoarthrosis. Radiographs were available for fifteen of the knees at the latest follow-up evaluation. Eleven of the treated knees could be compared with the uninvolved, contralateral knee. Ten knees had osteoarthrotic changes, such as flattening of the lateral femoral condyle, formation of a ridge along the lateral femoral condyle, and spurring and sclerosis of the tibial plateau. Osteochondritis dissecans developed in two knees, nine and twenty years after the initial meniscectomy.

Adolescent↗
PubMed1997

[Injury of the dens axis in early childhood. Clinical case report and discussion].

Because of the special features of the subdental synchondrosis, fractures of the odontoid process in childhood can be seen as a separate entity. The subdental synchondrosis must be regarded as sort of an intervertebral disc and not as a growth plate. Among the generally rare fractures of the cervical spine in children this type ist the most common. Usually conservative treatment with a cast-fixation like the halo fixateur or the minerva jacket leads to consolidation. We report on the case of a 2-year-old girl with a fracture of the odontoid process who developed a unilateral syndrome hours after the accident. The treatment was conservative with a halo-like cast fixation. Nine weeks after the fixation bony consolidation was achieved and the cast could be removed. In the first days after fixation full neurological recovery had occurred. In early childhood (till the 7th year of life) according to the literature, patterns of neurologic dysfunction are incomplete injuries of the spinal cord and have the potential for recovery [4, 5, 7, 9, 10, 12].

Child, Preschool↗
PubMed1997

[Open reduction technique].

Closed reduction of a hip dislocation will prove even more difficult if the dislocation has existed over a longer period of time. The indication is based on several principles: An open reduction may be carried out only after an unsuccessful attempt to perform a closed reduction or at a fixed age limit (12 or 24 months) or based upon arthrographic findings. In our department, for babies up to the age of 12 months, we always try to perform a closed reduction. Between 12 to 24 months, arthrographic findings will determine the choice of method. After the age of two, as a rule, we use an open reduction. The preliminary treatment consists of longitudinal traction. Current methods of approach to the hip joint are the medial approach according to Ludloff or the frontal approach by means of an inguinal incision. With the medial approach, there is greater risk of damaging the circumflex artery; also, a higher rate of avascular necrosis of the femoral head has been observed. Therefore, we only practice the ventral approach. Mainly for cosmetic reasons, however, instead of using the Smith-Petersen procedure, we apply a pure inguinal incision proximal to the inguinal ligament. The approach is found by detaching the muscle tissue at the anterior and interior iliac spine. Medially and laterally of the pelvic ridge, though, the tissue may be left. The joint capsule may be opened in the shape of a T or a V. A t-shape incision offers a better survey, whereby the risk of damaging a vessel is somewhat higher. In addition to resection of the teres ligament, it is necessary to indent the transverse acetabular ligament. Often, aponeurotic recession of the psoas tendon must be performed as well and the labrum indented and pushed outwards before reduction. The risk of insufficient development of the acetabulum can be minimized only if the femoral head is optimally centered. If the femoral head is in a high position (i.e., if the upper ridge of the femoral metaphysis lies higher than the triradiate cartilage), a shortening osteotomy of the femur should always be performed. This is the only possibility of repositioning the femoral head without exercising exaggerated pressure. On the other hand, we are rather reticent to perform a pelvic osteotomy at the time of repositioning. For children under 2 years of age, we recommend to that the acetabulum be allowed to develop and that a pelvic osteotomy be performed at a lager period if necessary. Postoperative treatment is given for a period of 12 weeks in a hip-leg cast in the Fettweis position, followed by another 3 months in a splint. Possible complications are redislocations, avascular necrosis of the femoral head and persistent acetabular dysplasia. An optimal technique will considerably reduce the risks of such complications.

Acetabulum↗
PubMed1997

Ligand-induced down-regulation of Trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons.

Chronic exposure of brain neurons to nerve growth factor in vitro and in vivo results in increased levels of the nerve growth factor receptor TrkA. In contrast, in the present study, we have found that chronic exposure of rat embryonic cortical neurons to brain-derived neurotrophic factor (BDNF) leads to a pronounced reduction of the levels of protein and messenger RNA for the full-length but not the truncated BDNF receptor TrkB. Similar effects were observed with the other TrkB ligands neurotrophin-3 and neurotrophin-4/5. After pretreatment with BDNF, neurotrophin-3 or neurotrophin-4/5, subsequent tyrosine phosphorylation responses of the remaining Trks to the same factors were greatly reduced. Three days exposure of rat embryonic cortical neurons to BDNF induced an absolute refractory period of several hours, with no subsequent response to the same factor. Similar but less pronounced refractory effects were observed with neurotrophin-3 and neurotrophin-4/5. Our results suggest a negative regulatory effect of BDNF and other TrkB ligands on TrkB receptors. Down-regulation of the TrkB response by its ligands might play a role in the control of BDNF action during early development, when BDNF levels significantly increase. Our findings are also of potential clinical relevance, since the possibility of ligand-induced down-regulation of the receptor response needs to be addressed when considering BDNF or other neurotrophins for the therapy of neurodegeneration.

Animals↗
PubMed1997

Axotomized septal cholinergic neurons rescued by nerve growth factor or neurotrophin-4/5 fail to express the inducible transcription factor c-Jun.

The inducible transcription factor c-Jun increases in neurons in response to axotomy by unknown mechanisms, and it has been postulated that c-Jun may regulate genes involved in promoting either degeneration or regeneration of axotomized neurons. In this report, we investigated the effect of daily or twice daily intraventricular administration of the neurotrophins nerve growth factor or neurotrophin-4/5 on the decrease in choline acetyltransferase expression and the increase in c-Jun expression in rat medial septum/diagonal band neurons three, seven and 14 days following unilateral, complete, fornix fimbria lesion. We also examined whether medial septum/diagonal band neurons might die by apoptosis within two weeks of fornix fimbria lesion using terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labelling. Our results show that both nerve growth factor and neurotrophin-4/5 maintain the phenotype of basal forebrain cholinergic neurons following axotomy. Furthermore, using double-labelling immunofluorescence, we found that while c-Jun was expressed in cholinergic neurons in control-treated rats seven days following fornix fimbria lesion, cholinergic neurons rescued by either nerve growth factor or neurotrophin-4/5 in neurotrophin-treated rats failed to express c-Jun. At no time-point (three, seven or 14 days post-axotomy) did any neurons in the medial septum/diagonal band stain positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling, suggesting that medial septum/diagonal band neurons do not undergo apoptosis within the first two weeks following axotomy at the time-points observed by us. Therefore, these results show that both nerve growth factor and neurotrophin-4/5 rescue the phenotype of axotomized cholinergic neurons and that these rescued neurons fail to express c-Jun in response to axotomy. In addition, since neither nerve growth factor nor neurotrophin-4/5 induced c-Jun in medial septum/diagonal band cholinergic neurons, it seems unlikely that the neurotrophic effects of nerve growth factor and neurotrophin-4/5 on cholinergic neurons are mediated via c-Jun expression. Furthermore, since axotomy failed to increase terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labelling in septal neurons, it appears unlikely that c-Jun expression in these axotomized neurons is related to neuronal degeneration via apoptosis.

Animals↗
PubMed1997

Protective effects of neurotrophin-4/5 and transforming growth factor-alpha on striatal neuronal phenotypic degeneration after excitotoxic lesioning with quinolinic acid.

Lesioning of the mammalian striatum with the excitotoxin quinolinic acid results in a pattern of neuropathology that resembles that of post mortem Huntington's disease brain. Certain neurotrophic factors can rescue degenerating cells in a variety of lesion types, including those produced by neurotoxins. Several neurotrophic factors promote the survival of striatal neurons and/or are localized within the striatum. Of these factors, neurotrophin-4/5 and transforming growth factor-alpha were chosen for administration to rats lesioned with quinolinic acid. Adult rats received a single unilateral intrastriatal injection of quinolinic acid (120 nmol) and either trophic factors or the control protein cytochrome c for seven days thereafter. The pattern of phenotypic degeneration was assessed by immunocytochemical labeling of various striatal neuronal populations at five rostrocaudal levels. Quinolinic acid produced a preferential loss in the number of cells immunoreactive for glutamate decarboxylase, with a relative sparing of the number of choline acetyltransferase-immunoreactive cells and, to a lesser degree, calretinin-immunoreactive cells. None of these phenotypic populations was protected by either neurotrophin-4/5 or transforming growth factor-alpha. In contrast, when glutamate decarboxylase cells were alternatively identified by calbindin immunolabeling, both factors were found to have partially reversed the loss in the number of calbindin-positive cells induced by excitolesioning. In addition, the loss in the number of parvalbumin-immunopositive cells due to quinolinic acid was partially reversed by neurotrophin-4/5, while the loss in the number of NADPH-diaphorase-stained cells was partially reversed by transforming growth factor-alpha. These findings reveal a new population of striatal cells, calretinin neurons, that are relatively resistant to quinolinic acid toxicity and that neurotrophin-4/5 and transforming growth factor-alpha partially protect against the phenotypic degeneration of striatal cell populations in an in vivo animal model of Huntington's disease.

Animals↗
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↗