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Biomedical subjects

S H Appel

Publications and source records attributed to S H Appel.

At least 145 records · Page 8Linked to original sources
PubMed1989

Mental status assessment of insight and judgment.

Although a traditional part of the mental status examination, assessment of insight and judgment has received scant attention from researchers and clinicians. This is unfortunate, because few abilities are more crucial to decisions about whether a patient can continue to live independently or what level of supervision is needed. The authors discuss current and evolving methods for the assessment of insight and judgment, and also address neuroanatomic substrates and theoretical conceptions of these functions.

Aged↗
PubMed1988

Reduction of naturally occurring motoneuron death in vivo by a target-derived neurotrophic factor.

Treatment of chick embryos in ovo with crude and partially purified extracts from embryonic hindlimbs (days 8 to 9) during the normal cell death period (days 5 to 10) rescues a significant number of motoneurons from degeneration. The survival activity of partially purified extract was dose-dependent and developmentally regulated. The survival of sensory, sympathetic, parasympathetic, and a population of cholinergic sympathetic preganglionic neurons was unaffected by treatment with hindlimb extract. The massive motoneuron death that occurs after early target (hindlimb) removal was partially ameliorated by daily treatment with the hindlimb extract. These results indicate that a target-derived neurotrophic factor is involved in the regulation of motoneuron survival in vivo.

Ammonium Sulfate↗
PubMed1988

Purification of a skeletal muscle polypeptide which stimulates choline acetyltransferase activity in cultured spinal cord neurons.

Extracts of rat skeletal muscle contain neurotrophic factors which stimulate the development of choline acetyltransferase in embryonic day 14 rat spinal cord cultures. The trophic activity does not bind heparin-Sepharose or lectin affinity columns. However, mild acid treatment separates the trophic activity into soluble and insoluble fractions. The acid-insoluble activity has been purified 5000-fold to apparent homogeneity using preparative sodium dodecyl sulfate gel electrophoresis to achieve final purification. The purified factor migrates as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and isoelectric focusing, with an apparent molecular mass of 20 kDa and a pI of 4.8. The activity and apparent molecular weight of the purified factor are unaltered by treatment with reducing agents or incubation in acidic conditions. Activity, however, is destroyed by heating or protease treatment. Thus, the factor appears to be a single polypeptide without significant levels of glycosylation or charge microheterogeneity. These results represent the first purification of a neurotrophic factor from skeletal muscle. The physical properties and amino acid composition of this factor differ from those of nerve growth factor and heparin-binding growth factors, as well as from the neurotrophic factor from heart cell conditioned medium which induces cholinergic development in sympathetic neurons.

Aging↗
PubMed1988

A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis.

In a double-blind placebo-controlled trial of cyclosporine in amyotrophic lateral sclerosis, no differences were observed in the monthly rate of progression or the relative risk of progression in comparing 38 patients randomized to the placebo group and 36 patients randomized to the cyclosporine group. In comparing three subgroups of patients, cyclosporine appeared to benefit men who entered the study within 18 months of the onset of first symptoms, whereas it was of no value to women or to men who entered later than 18 months. For the men with recent onset of disease, the relative risk of progression was 0.403; the monthly rate of progression was 5.2 +/- 1.1 points with placebo and 3.5 +/- 0.7 points with cyclosporine. These provocative results support the need for a full study of cyclosporine in men with recent onset of disease.

Amyotrophic Lateral Sclerosis↗
PubMed1988

Depressed interferon gamma production and monocyte HLA-DR expression after severe injury.

Monocyte HLA-DR antigen expression and mitogen-stimulated interferon gamma production were measured sequentially on days 1, 3, 7, 14, and 21 after admission in 20 multiply injured patients (mean Injury Severity Score, 33). Ten patients recovered uneventfully and ten developed a major infection, three of whom died. Trauma resulted in immediate and profound depression of both interferon gamma production and monocyte HLA-DR antigen expression compared with controls. Interferon gamma remained below control levels for all days on which it was measured in all patients. In uninfected patients, interferon gamma production began to recover after day 7 and interferon gamma levels on day 21 were greater than on all other days. Monocyte HLA-DR antigen expression returned to normal between days 7 and 14 in uninfected patients, despite subnormal production of interferon gamma. Failure to increase interferon gamma production and monocyte HLA-DR antigen expression was associated with an episode of major infection. We postulate that stimulation of the immune system early after injury may reverse the defects reported and decrease the incidence of infection after severe trauma.

Adolescent↗
PubMed1988

Developmental discord among markers for cholinergic differentiation: in vitro time courses for early expression and responses to skeletal muscle extract.

The effects of skeletal muscle extract on the development of CAT, ACh synthesis, high affinity choline uptake, and AChE activities were studied in dissociated ventral spinal cord cultures prepared from 14-day gestational rat embryos. In the absence of muscle extract, the development of CAT and AChE follow biphasic time courses in which they show initial declines followed by periods of steadily increasing activity. In contrast, ACh synthesis and high affinity choline uptake both gradually increase throughout the entire culture period. The presence of muscle extract both prevents the initial decline of CAT and AChE as well as stimulates the rates of development of all four cholinergic markers; however, the degrees and time courses of stimulation differ markedly. The effects of muscle extract on the kinetic and pharmacological properties of ACh synthesis and choline uptake in rat ventral cord cultures were also investigated. Cells treated with muscle extract for 2 days express both high affinity (Km = 1.6 microM) and low affinity (Km = 22 microM) choline uptake mechanisms. Control cells, on the other hand, express only low affinity uptake at this stage but develop a high affinity uptake mechanism by Day 7. During this time both ACh synthesis and high affinity choline uptake become increasingly sensitive to inhibition by hemicholinium-3. These results demonstrate that skeletal muscle factors enhance the development of cholinergic properties in embryonic spinal cord cultures. However, differences in sensitivity to muscle extract concentration, time courses of development, and degrees of stimulation suggest that these changes may involve distinct cellular mechanisms which are differentially affected by skeletal muscle factors.

Acetylcholine↗
PubMed1988

Immunoglobulins from amyotrophic lateral sclerosis patients enhance spontaneous transmitter release from motor-nerve terminals.

Amyotrophic lateral sclerosis (ALS) is an incapacitating neuromuscular disease of unknown etiology. Although laboratory evidence is lacking, circumstantial evidence supports the importance of immune factors in the pathogenesis of ALS. In the present study immunoglobulins from 4 of 8 ALS patients induced a significant increase in spontaneous quantal transmitter release as monitored by miniature end-plate potential (MEPP) frequency in mouse phrenic nerve-diaphragm preparations at 23 degrees C, whereas immunoglobulins from normal individuals and from patients with other neuromuscular diseases had no effect. At 32 degrees C neither normal nor disease control immunoglobulins influenced MEPP frequency, but 8 of 11 ALS immunoglobulin samples produced a significant increase in spontaneous quantal transmitter release. The enhancing effect could be prevented by 10 mM Mg2+. No effects were noted on MEPP amplitude and muscle resting potential. These findings suggest that the presynaptic terminal of the motor neuron may be an early target and that immunological factors may play an important role in the disease process.

Amyotrophic Lateral Sclerosis↗
PubMed1988

Trophic factors in neurologic disease.

Recent studies suggest that diffusible factors released by neural targets enhance the survival, growth, and differentiation of neurons both peripherally and in the central nervous system. Evidence for such trophic factors exists for many of the neural systems involved in the degenerative neurologic diseases Alzheimer's disease, parkinsonism, and amyotrophic lateral sclerosis. It is our hypothesis that for each of these disorders there is both a primary insult and a secondary effect. The primary insult may have multiple etiologies, but the secondary effect is the result of retrograde degeneration. Such retrograde degeneration occurs because of an impairment of trophic factor function or an inadequacy of trophic effects to keep pace with the primary destructive process. Accordingly, it may be possible to exploit such trophic mechanisms to define further the pathobiology of neural degeneration and to develop specific treatments for currently incurable illnesses.

Alzheimer Disease↗
PubMed1988

The response of immunoglobulins to infection after thermal and nonthermal injury.

Traumatic and thermal injuries are leading causes of mortality and morbidity due to their high incidence of infection. Host defense is vital to recovery in these patients yet incompletely understood. On days 1, 7, and 14, serum immunoglobulins of the IgA, IgG, and IgM classes were measured in 46 consecutive patients who sustained severe trauma with an injury severity score of at least 20. The patients were divided into four groups: 1) an uneventful recovery group (n = 11) of nonthermal trauma patients who did not become infected; 2) an infected nonthermal group without splenectomy; 3) an infected group of burn patients; and 4) 12 patients who underwent splenectomy of which nine became infected following nonthermal trauma. In each patient group, IgA, IgG, and IgM were all reduced, and group 1 had a steady return to normal range. Group 2 patients exhibited supranormal responses in all 3 classes at one week and supranormal IgA and IgG responses at two weeks. In contrast, both infected burn and splenectomized patients had markedly reduced IgG and IgM levels compared with the group 2 patients (P less than 0.05). Splenectomy sharply reduced IgM response to infection at 7 and 14 days compared with nonsplenectomized infected posttraumatic patients. Immunoglobulin response after trauma depended on the type of injury, presence of infection, splenic function, and type of immunoglobulin. Recognition of immunoglobulin deficiencies in both the burn and splenectomized patient may permit focused therapy, such as specific replacement of these proteins.

Burns↗
PubMed1987

Distinct influences of nerve growth factor and a central cholinergic trophic factor on medial septal explants.

A central cholinergic trophic factor (C-CTF), previously reported in hippocampal extracts, enhances acetylcholine synthesis (ACh) and to a lesser extent choline acetyltransferase (ChAT) activity in cultured explants of the rat medial septal nucleus. Nerve growth factor (NGF) has been reported to enhance ChAT in several systems in vitro and in vivo, and clearly stimulates septal explants. At optimal concentrations of NGF and C-CTF, there is an additive effect on ChAT activity. The effects of NGF on ACh synthesis are minimal. Antibodies to NGF block effects of added NGF but have no effects on C-CTF activity. The ability of C-CTF to enhance ACh synthesis appears related to its ability to enhance the acetylation of the choline that has been taken up by a sodium dependent, high affinity transport system. Thus, actions of NGF and C-CTF appear qualitatively and quantitatively distinct, yet both can influence the cholinergic activity of the developing medial septal nucleus.

Acetylcholine↗
PubMed1987

A rating scale for amyotrophic lateral sclerosis: description and preliminary experience.

A rating scale has been developed to provide a quantitative estimate of clinical status and disease progression in amyotrophic lateral sclerosis (ALS). This scale includes assessment of swallowing, speech, and respiratory function, and both strength and function of upper and lower extremity musculature. The evaluation is relatively simple to perform and yields reproducible data for both a total ALS score and a score for each group of functions tested. A score of 30 points is normal; 164 points indicates maximal dysfunction. The total ALS score increased in a linear fashion in each of 74 patients followed for at least one year. Among patients, the rate of disease progression varied twenty-fold, with a continuous distribution from the slowest to most rapid course. Thirty-four percent of patients exhibited a rapid change of greater than 48 points in the year, predicting progression to a terminal stage in less than two years; 19% of patients exhibited a slow change of less than 13 points in one year, predicting progression to a terminal stage over at least five years. This ALS scoring system should permit more accurate assessment of drug efficacy in clinical trials and correlation of rates of progression with clinical variables.

Amyotrophic Lateral Sclerosis↗
PubMed1986

Soluble striatal extracts enhance development of mesencephalic dopaminergic neurons in vitro.

Recent studies have suggested that diffusible factors released by neural target tissues enhance survival, growth, and differentiation of neurons within the central, as well as the peripheral, nervous system. In this report, we use catecholamine cytofluorescence to demonstrate that a soluble factor from the striatum produces a 4-fold increase in number of catecholamine cytofluorescent-positive dopaminergic neurons in dissociated mesencephalon cultures prepared from embryonic 14-day-old rats. The same soluble extract enhances the number of neurites per cell and the length of neurites, and also produces a greater than 3.5-fold stimulation of high affinity dopamine uptake into neurons. Such stimulation is significantly reduced following trypsin treatment. The trophic effects on dopaminergic neurons are maximal in extracts of the striatum, but are also found in extracts of the hippocampus-entorhinal cortex-amygdaloid nucleus and the cerebral cortex, although they are less in extracts of the cerebellum, negligible in the olfactory bulb, and absent in the liver. With molecular sieving chromatography, the soluble factors stimulating high affinity dopamine uptake are partially separable from the factors stimulating neuronal high affinity GABA uptake. The approximate molecular weight of the factors influencing dopaminergic neurons is 1500-2200 Da.

Animals↗
PubMed1986

Amyotrophic lateral sclerosis. Associated clinical disorders and immunological evaluations.

We examined the family history and associated diseases in 58 patients with amyotrophic lateral sclerosis (ALS), as well as the T-cell phenotypes and functions in 46 consecutive patients with this disorder. A family history of thyroid disease was present in 19%, and an additional 21% of patients described family members with other possible autoimmune disorders. In 19% of the patients with ALS either past or present thyroid disease was documented. Eleven of 47 additional patients with ALS had significant elevations of microsomal and/or thyroglobulin antibody levels. The T-cell phenotypes and functions were comparable in the ALS and control groups, with the exception of the presence of Ia antigen. In patients with ALS, 11.9% of the T cells were positive for the la antigen, while in both a normal control population and a non-ALS neurologic disease population, only 6.4% of T cells have this antigenic determinant. These data support involvement of autoimmune mechanisms in ALS.

Adult↗
PubMed1986

Selective effects of skeletal muscle extract fractions on motoneuron development in vitro.

In vivo labeling of motoneurons with retrogradely transported wheat germ agglutinin, and in situ staining of cholinergic neurons with a monoclonal antibody against CAT, have been used as methods to identify motoneurons in cultures of dissociated 14 d embryonic rat ventral spinal cord. With these two different labeling techniques, we demonstrate that skeletal muscle extracts maintain motoneuron survival, and induce motoneuron morphologic and cholinergic differentiation in vitro. Further, we show that several partially purified muscle extract-derived proteins separately augment each of these specific parameters of motoneuron development. A 55,000 Da neutral glycoprotein specifically induces both ACh synthesis and motoneuron-selective process outgrowth and elongation, while a 1200-1500 Da peptide selectively augments both apparent motoneuron survival and ACh synthesis. A third trophic agent, a 33,000-35,000 Da acidic glycoprotein, induces process outgrowth in both motoneurons and nonmotoneurons of the ventral spinal cord, but has no effect on ACh synthesis.

Acetylcholine↗
PubMed1985

Low-molecular-weight peptide stimulates cholinergic development in ventral spinal cord cultures.

Skeletal muscle extract contains a previously undocumented 1300- to 1500-Da neurotrophic factor. Incubation of ventral spinal cord neurons in the presence of this factor enhances the rate of de novo acetylcholine synthesis two- to threefold over control cells, after 6 days in culture. This effect on cholinergic activity appears to be selective, since incubation with the factor results in only slight elevations of lactate dehydrogenase activity and DNA content, and no increase in the acetylcholinesterase activity. The 1300- to 1500-Da factor is acid-stable and partially sensitive to proteolysis by proteinase K, Staphylococcus aureus V8 protease, and subtilisin, but insensitive to trypsin. These results indicate that the active moiety is a peptide. The importance of peptides as neurotransmitters or neuromodulators is well accepted, but their role in the regulation of neuronal development is not widely appreciated. The present cholinergic neurotrophic peptide is distinct from previously characterized cholinergic trophic factors and represents the first example of a small, target-derived peptide which influences cholinergic development.

Acetylcholine↗
PubMed1985

Differential morphologic effects of two fractions from fetal calf muscle on cultured chick ciliary ganglion cells.

An extract of fetal calf striated muscle was found to support the survival, growth and differentiation of chick ciliary ganglion neurons in dissociated cell culture. The active material was precipitated in a single fraction by 35-60% ammonium sulfate. When this active fraction was passed over a concanavalin A-Sepharose column, only a portion of the activity was bound to the column and could be eluted by high salt. Both the bound and unbound fractions supported long-term neuronal survival and enhanced the neurons' capacity for acetylcholine synthesis. The two active fractions induced distinctly different morphologies in the cultures. The bound, salt-eluted fraction resulted in the extension of long, narrow multiply branched neurites with frequent varicosities, but it failed to support non-neuronal survival. The unbound, flow-through fraction caused the neurons to extend processes which aligned with each other and with the non-neuronal cells in dense networks. Striated muscle may thus possess the capacity to send more than one signal to modulate the development as well as maintain the survival of motor neurons.

Acetylcholine↗
PubMed1985

Trophic effects of skeletal muscle extracts on ventral spinal cord neurons in vitro: separation of a protein with morphologic activity from proteins with cholinergic activity.

Protein factors derived from skeletal muscle separately promote neurite elongation and acetylcholine synthesis in cultured rat ventral spinal neurons. Morphologic factor activity (neurite-inducing activity) is specifically found in rat skeletal muscle and cord neuron extracts, decreases with the postnatal age of the rats from which muscle extract is prepared, and increases in rat hindlimb muscle after 5 d of denervation. Cholinergic factor activity (acetylcholine synthesis-stimulating activity) is found in extracts of rat cerebral cortex and cardiac muscle in addition to spinal cord and skeletal muscle, increases with animal age, and decreases following 5 d of denervation. Biochemically, the factors responsible for these activities differ in their lability to denaturing conditions, apparent molecular weights, isoelectric points, and lectin-binding specificities. Under reducing conditions, morphologic activity is isolated in a single acidic glycoprotein with an Mr of 35,000, while acetylcholine synthesis-stimulating activity is found in multiple species of different molecular weights. Thus, acetylcholine synthesis-promoting activities and neurite growth-promoting activity appear to reside in different molecules. Significant purification of several of these factors has been achieved.

Acetylcholine↗