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Biomedical subjects

F Hefti

Publications and source records attributed to F Hefti.

At least 181 records · Page 10Linked to original sources
PubMed1988

Rescue of lesioned septal cholinergic neurons by nerve growth factor: specificity and requirement for chronic treatment.

We earlier reported that chronic intraventricular injections of NGF into adult rats with partial transection of the fimbria prevent the lesion-induced disappearance of cholinergic neurons in the medial septal nucleus and the diagonal band of Broca (Hefti, 1986). The present study assessed the specificity and treatment requirements of this effect of NGF. Immunohistochemical visualization of NGF receptors (NGF-R) revealed that these molecules are selectively located in forebrain cholinergic neurons of unlesioned brains. Fimbrial transection resulted in transient accumulation of NGF-R in proximal stumps of lesioned axons but failed to induce the expression of NGF-R by other cells in the septal area or near the lesion. Two to three weeks after lesioning, the number of septal neurons expressing NGF-R was reduced by approximately 50% in parallel with the reduction of the number of neurons expressing cholinergic marker enzymes. Repeated intraventricular NGF injections during 4 weeks prevented the disappearance of these cells. Fimbrial transections also reduced the number of septal GABAergic neurons visualized by glutamate decarboxylase immunohistochemistry. The loss of GABAergic neurons was not prevented by NGF. These findings suggest that NGF prevents the lesion-induced degeneration of cholinergic neurons by directly acting on NGF-R expressed by cholinergic cells and that NGF does not affect any neuron with an axonal lesion. Delayed start of the NGF treatment failed to prevent the disappearance of lesioned cholinergic neurons, providing evidence that NGF treatment indeed promotes the survival of these cells rather than simply upregulating the expression of transmitter-specific enzymes. A single injection of NGF at the time of the lesion was not sufficient to prevent the lesion-induced degeneration of cholinergic neurons. Furthermore, termination of chronic NGF treatment after 4 weeks was followed by loss of septal cholinergic neurons after an additional 4 weeks. These findings suggest that the continuous presence of NGF during more than 4 weeks is required to prevent the degeneration of cholinergic cells. The data are discussed in the context of a possible physiological role of NGF in the function of adult forebrain cholinergic neurons.

Acetylcholinesterase↗
PubMed1988

OAK knee evaluation. A new way to assess knee ligament injuries.

The Orthopädische Arbeitsgruppe Knie (OAK) documentation is based on clinical evaluation during functional knee stability testing near extension and near flexion. Increased compartmental translations and rotations, which result from structural defects because of anatomic lesions in a given knee injury, are clinically evaluated. The synopsis of the clinically detectable abnormal knee motion is graphically documented. A clinically applicable grading system of the true and reversed pivot shift phenomena completes the assessment of compartmental knee instability. Important contributing factors such as the constitutional laxity, the morphotype, and the range of motion are registered on the documentation form. The evaluation form presents four categories that represent subjective, objective, and functional criteria reflecting the overall results of repaired ligaments. This evaluation format establishes selected criteria to compare results from different centers.

Documentation↗
PubMed1987

Astrocytes protect cultured neurons from degeneration induced by anoxia.

Neurons grown in cultures of dissociated brain cells degenerate when exposed to anoxia and deprived of glucose. We have developed culture systems in which neurons can be grown in the presence or absence of astrocytes and have used them to study the influence of astrocytes on the neuronal degeneration induced by anoxia and glucopenia. Cultures were prepared from fetal rat forebrains. Mixed cultures contained neurons (identified by immunocytochemical staining of neuron-specific enolase, NSE) and about an equal number of non-neuronal cells (identified by glial fibrillary acid protein). Pure neuronal cultures were prepared by adding a cytostatic compound (cytosine arabinoside) to the medium. Treated cultures were exposed for 4 h to glucose-free medium and an atmosphere of 95% N2 and 5% CO2, whereas control cultures were left in the usual medium containing glucose and in an atmosphere composed of 95% air and 5% CO2. After an interval of 24 h, cultures were fixed, taken for NSE staining, and the number of surviving neurons was counted. Exposure to anoxia and glucopenia reduced the number of surviving neurons in pure neuronal cultures to 5-10% of control levels. In contrast, in mixed cultures 40-60% of the neurons survived these conditions. Anoxia without glucose deprivation reduced the number of surviving neurons in both types of cultures to the same extent as anoxia combined with glucopenia. Glucose deprivation alone was ineffective. The findings suggest a protective influence of astrocytes on neurons under anoxic conditions. gamma-D-Glutamylglycine protected neurons in both types of cultures from anoxia-induced degeneration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Nerve growth factor promotes development of the rat septo-hippocampal cholinergic projection in vitro.

There is now widespread evidence indicating that nerve growth factor (NGF) is involved in the function of central cholinergic neurons. Its possible role in the establishment of cholinergic fiber connectivities was studied in co-cultures of rat septum and hippocampus. Application of 100 ng/ml NGF greatly increased the number of acetylcholinesterase (AChE)-positive fibers which invaded the hippocampal slices, an effect which was accompanied by a more than 6-fold elevation of the two major cholinergic enzymes, choline acetyltransferase and AChE. In contrast, application of anti-NGF antiserum, but not a non-immune serum, reduced the number of AChE-positive fibers which grew into and remained within the hippocampal slices. Since no diffuse outgrowth of AChE-positive fibers from the septum was observed following application of NGF, these results suggest that NGF plays a role in the stabilization and long-term maintenance of the cholinergic septo-hippocampal projection in vitro.

Acetylcholinesterase↗
PubMed1987

Pharmacological activities in thermal proteins: relationships in molecular evolution.

The model of protobiological events that has been presented in these pages has increasing relevance to pharmacological research. The thermal proteins that function as key substances in the proteinoid theory have recently been found to prolong the survival of rat forebrain neurons in culture and to stimulate the growth of neurites. A search for such activity in thermal proteins added to cultures of modern neurons was suggested by the fact that some of the microspheres assembled from proteinoids rich in hydrophobic amino acids themselves generate fibrous outgrowths.

Amino Acids↗
PubMed1987

(1S,2R)-5-methoxy-1-methyl-2-(n-propylamino)tetralin ([+]-AJ-76) elevates transmitter synthesis in dopaminergic neurons surviving a partial nigrostriatal lesion.

(+)-AJ-76 is a novel compound with a spectrum of actions suggesting that it is a selective antagonist of dopamine (DA) autoreceptors. In animals with partial lesions of the dopaminergic nigrostriatal system, in which DA synthesis of surviving neurons was elevated, (+)-AJ-76 further increased DA synthesis above levels produced by the lesion alone. This finding suggests that (+)-AJ-76 might be of value in the treatment of Parkinson's disease.

Animals↗
PubMed1987

Effects of chronic therapy with cilazapril, a new angiotensin-converting enzyme inhibitor, on regional blood flows in conscious spontaneously hypertensive rats.

Cilazapril is a new potent inhibitor of the angiotensin-converting enzyme. The purpose of the present study was to evaluate the effects of chronic treatment with cilazapril on hemodynamics and regional blood flows in spontaneously hypertensive rats. Cilazapril or distilled water was given by gavage for 9 weeks to hypertensive rats at a dose of 10 mg/kg/day, and arterial blood pressure was monitored each week by an indirect method. After the 9 weeks of treatment, blood pressure was measured by a direct method, and regional blood flows, regional vascular resistances, and cardiac output and its distribution were measured with the radioactive microsphere technique. The cilazapril-treated group was compared with the group that received distilled water. Cilazapril had a very pronounced antihypertensive effect which was due to a general peripheral vasodilatation. The regional vascular resistances were decreased in all the organs except the heart. Cardiac output was unchanged, as well as its distribution. Heart rate was lower in the cilazapril-treated group than in the control group. Cardiac hypertrophy was reduced by cilazapril. We conclude that cilazapril is an antihypertensive agent which acts by dilating most of the peripheral vascular beds and which reduces cardiac hypertrophy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Nerve growth factor is a neurotrophic factor for forebrain cholinergic neurons; implications for Alzheimer's disease.

Findings obtained in recent years provide strong evidence that nerve growth factor (NGF) acts as a neurotrophic factor for cholinergic neurons of the mammalian forebrain. NFG receptors are exclusively localized on these neurons in the rat and human forebrain. NGF promotes survival, fiber elongation and expression of transmitter-specific enzymes of forebrain cholinergic neurons, in vivo and in vitro. In adult rats, intraventricular injections of NGF attenuate the degeneration of these cells after experimental lesions. These findings suggest that NGF might be able to attenuate the degeneration of cholinergic neurons occurring in Alzheimer's disease.

Alzheimer Disease↗
PubMed1986

1-Methyl-4-phenylpyridinium (MPP+) but not 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively destroys dopaminergic neurons in cultures of dissociated rat mesencephalic neurons.

Dopaminergic neurons were studied in cultures of dissociated cells from the ventral mesencephalon of fetal rat embryos (gestational day E15-16). After a week of growth, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) was added to the growth medium for 24 h. Dopaminergic neurons were then visualized with tyrosine hydroxylase (TH) immunocytochemistry or catecholamine (CA) cytofluorescence. Concentrations of MPTP in the range of 10 to 100 microM obliterated CA fluorescence without affecting the number of TH-positive neurons. At concentrations greater than 100 microM, MPTP decreased the number of TH-positive neurons as well as the number of all other cell types. MPP+ (0.1-10.0 microM) produced a decrease in the number of TH-positive neurons without decreasing the total number of all cell types. The findings indicate that MPP+ but not MPTP is able to selectively destroy rat dopaminergic neurons in our cultures. The selective toxicity of MPP+ for dopaminergic neurons was partially prevented by pretreatment and co-incubation with mazindol (a selective inhibitor of dopamine uptake) but not by desipramine or deprenil, in confirmation of the notion that MPP+ enters dopaminergic neurons by the specific uptake mechanism for dopamine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Long-term effects of nerve growth factor and neural transplants on behavior of rats with medial septal lesions.

The present experiment investigated the interaction between exogenous nerve growth factor (NGF) and intrahippocampal septal grafts on the behavior of rats after a medial septum lesion. Young female rats received a bilateral injection of a fetal septal cell suspension into the dorsal hippocampus either immediately (immediate grafts) or 8 days after the lesion (delayed grafts). For delayed grafts, a higher concentration of endogenous neurotrophic factors can be assumed to be present in the deafferentated host tissue at the time of transplantation. One group of rats with lesions received NGF with the immediate grafts, another group received NGF alone. A sham-operated group and 3 groups with lesions (and given either immediate or delayed intrahippocampal saline injections, or no other treatment) constituted controls. The animals were tested for spontaneous alternation and for performance in a radial 8-arm maze, 1, 5 and 9 months postoperatively. Medial septal lesions reduced spontaneous alternation but, 9 months after surgery, recovery was observed in both lesion-control rats and in rats with delayed grafts (but not with immediate grafts). In the radial maze task, lesions produced a persistent impairment, although both immediate and delayed grafts reduced this deficit several months after surgery (more markedly and rapidly in the case of delayed grafts). NGF, however, increased the maze learning deficit especially 5 months postoperatively. These latter results are in contrast to findings of earlier studies showing transient beneficial effects of NGF administration. It is suggested that the effects of NGF in the present study might be due to an enhanced sprouting of sympathetic fibers into the hippocampal formation.

Animals↗
PubMed1986

Localization of nerve growth factor receptors in cholinergic neurons of the human basal forebrain.

Nerve growth factor (NGF) receptors were visualized in the basal human forebrain using an immunohistochemical procedure with a monoclonal antibody previously shown to recognize human melanoma cell NGF receptors. The receptors were found to be exclusively located in the medical septal nucleus, the diagonal band of Broca, and the nucleus basalis. This location coincided with that of cell bodies of ascending cholinergic neurons of the basal forebrain. In addition, NGF receptor-positive cells were costained for acetylcholinesterase. These findings indicate that cholinergic neurons of the basal forebrain but none of the other neurons located in this area express receptors for NGF. Results suggest that NGF acts as a trophic factor for cholinergic neurons in the human brain in a similar way as has been established in recent years for the rat brain.

Acetylcholinesterase↗
PubMed1986

Effect of thyroid hormone analogs on the activity of choline acetyltransferase in cultures of dissociated septal cells.

Thyroid hormones influence the expression of transmitter-specific enzymes by central cholinergic neurons. Based on the fact that these cholinergic neurons degenerate selectively in human Alzheimer's disease, it was hypothesized that thyroid hormones might be beneficial in its treatment. However, since thyroid hormones influence the function of most peripheral organs, derivatives selective for central cholinergic neurons are necessary. The structural requirements of the receptor mediating the effects of the thyroid hormones on central cholinergic neurons were therefore compared with those of the receptors mediating actions on peripheral organs. Cultures were prepared of dissociated neurons from the septal area of fetal rat brains, and the differentiation of cholinergic neurons was assessed by measuring the activity of choline acetyltransferase (ChAT). Triiodothyronine (T3) was found to stimulate ChAT activity in a dose-dependent manner. The effect of T3 was additive to that of nerve growth factor. The potency of derivatives of T3 in elevating ChAT activity in the cultures was compared with their known anti-goiter activity determined in vivo and their binding affinity to the hepatic nuclear receptor measured in vitro. The findings indicate that the structural requirements of central and peripheral receptors are similar and that it therefore appears unlikely that analogs of thyroid hormones can be developed which selectively affect cholinergic neurons.

Animals↗
PubMed1986

Cholinergic denervation of the rat hippocampus by fimbrial transection leads to a transient accumulation of nerve growth factor (NGF) without change in mRNANGF content.

Unilateral stereotaxic fimbrial transection was used to disrupt the cholinergic pathway from the medial septum to the hippocampus in adult rats. The resulting alterations in hippocampal nerve growth factor (NGF) and mRNANGF levels were then analysed by two-site enzyme immunoassay and quantitative Northern blots, respectively. NGF levels did not change up to one week after lesion but had increased to 145% of contralateral control values by two weeks. In contrast, mRNANGF levels were not changed at this time point. Neither bilateral fimbrial transection, nor removal of the sympathetic innervation of hippocampal vasculature by excision of the superior cervical ganglia, led to more pronounced increases in NGF levels. These results are consistent with the concept that the magnocellular cholinergic neurons in the medial septum are constantly reducing hippocampal NGF levels by retrograde axonal transport.

Animals↗
PubMed1986

Nerve growth factor and Alzheimer's disease.

Alzheimer's disease is associated with a pronounced loss of the cholinergic neurons that form the ascending cholinergic projections of the basal forebrain. Even though the disease is also characterized by changes in other neuronal systems and by a high frequency of neuronal plaques and tangles, the cholinergic deficit seems to be a principal element responsible for the memory loss typical of Alzheimer's disease. This review summarizes findings in experimental animals which indicate that nerve growth factor (NGF), a well-characterized protein, acts as a neurotrophic factor for cholinergic neurons of the basal forebrain. NGF is present in the target areas of these cholinergic neurons and affects their survival, fiber growth, and expression of transmitter-specific enzymes. Furthermore, NGF is able to prevent the degeneration of cholinergic neurons in adult rats with experimental lesions mimicking the cholinergic deficit in Alzheimer's disease. These findings suggest that increasing the availability of NGF to human cholinergic cells might promote their survival in certain disease processes. Additional steps are discussed for establishing the possible involvement of NGF in the pathogenesis of Alzheimer's disease and the development of an effective therapy.

Alzheimer Disease↗
PubMed1986

[Long-term results in the treatment of clubfoot].

Long-term results in the treatment of congenital clubfoot are reported. The average follow-up time was 17.7 years (10-29.4 years). All 104 patients (148 clubfeet) were followed up personally. In addition to the clinical examination, a podogram was made and evaluated. Results were good to very good in 97% of patients with regard to complaints, in 83% concerning the level of functional ability, in 69% regarding clinical aspects of the foot, in 58% with regard to measurements of the podogram, and in 27% regarding movement. In clinical aspects and measurement of the podogram, significantly better results were obtained if the first operative correction took place within the first year of life. In patients in whom the anterior tibial tendon had been transferred, there was a higher percentage of falling medial arches. Patients in whom rotational osteotomy of the tibia had been carried out showed better foot position in relation to the femoral axis and worse foot position in relation to the malleolar axis than those in whom this operation had not been performed.

Achilles Tendon↗