Search PubMed⌕ Search

Biomedical subjects

A G Engel

Publications and source records attributed to A G Engel.

At least 91 records · Page 5Linked to original sources
PubMed1994

Patch-clamp analysis of the properties of acetylcholine receptor channels at the normal human endplate.

Normative data were obtained on the kinetic properties of the acetylcholine receptor (AChR) channel at the human motor endplate by patch-clamp analysis. Single channel currents were recorded from 34 endplates of 8 nonweak subjects in the presence of 1 micron acetylcholine (ACh) at 22 +/- 0.5 degrees C. The vast majority of channels opened to a conductance of about 60 pS. The dwell-time distributions of these channels were well described as the sum of two exponential functions. The mean duration of the dominant longer component was 1.9 ms for the open intervals and 3.04 ms for the bursts. At three endplates, a small proportion of the channels had lower conductance and longer open time, resembling immature AChR channels. At 28 endplates it was also possible to obtain an estimate of the rate constant for channel closure (alpha) and approximate estimates for the rate constants of channel opening (beta) and ACh dissociation (k-2). Estimates of k-2 varied by 15% with methods of estimation. This is attributed to errors inherent in estimating the duration of the briefest channel events. The normative data will be useful for evaluating pathologic alterations in the kinetic properties of the AChR channel found in some congenital myasthenic syndromes.

Humans↗
PubMed1994

The immunobiology of muscle.

Skeletal muscle can be both the site and target of immune reactions. Here, Reinhard Hohlfeld and Andrew Engel consider the role of muscle as an immunological microenvironment and discuss the immunological properties of human muscle cells. Furthermore, they provide a brief overview of autoimmune diseases of muscle and of other conditions in which intramuscular immune reactions play a role. Finally, they discuss the immunological problems of novel gene therapies that rely on muscle cells as vehicles for gene transfer.

Animals↗
PubMed1994

Human muscle glycogenosis due to phosphorylase kinase deficiency associated with a nonsense mutation in the muscle isoform of the alpha subunit.

Heritable phosphorylase kinase (Phk) deficiency is responsible for several forms of glycogen storage disease in humans and animals that differ in mode of inheritance and tissue-specificity. Mutations affecting different subunits and isoforms of Phk are expected to contribute to this heterogeneity. In the present study, we have investigated a case of muscle-specific, adult-onset Phk deficiency. The coding sequences of three candidate genes were analyzed by RT-PCR and sequencing: the muscle isoform of the alpha subunit (alpha M), a muscle-specifically expressed exon of the beta subunit, and the muscle isoform of the gamma subunit. Whereas the latter two sequences were found to be normal, we identified a nonsense mutation in alpha M. The condition of this patient therefore is a human homolog of the X-linked muscle Phk deficiency of I-strain mice. To our knowledge, this is the first description of a human Phk deficiency mutation.

Amino Acid Sequence↗
PubMed1994

Aberrant splicing in adult onset glycogen storage disease type II (GSDII): molecular identification of an IVS1 (-13T-->G) mutation in a majority of patients and a novel IVS10 (+1GT-->CT) mutation.

Two newly identified splice site mutations (IVS1 -13T-->G and IVS10 +1GT-->CT) were found in a patient with adult onset of the autosomal recessive disorder glycogen storage disease type II (GSDII). The IVS1 -13T-->G transversion in the acceptor splice site was found on one allele in over two thirds of adult onset GSDII patients studied (28/41), but was not seen in 58 normal or 12 infantile onset GSDII chromosomes. Molecular analysis of cDNA from the index patient and four additional, ethnically different, individuals carrying the IVS1 -13T-->G transversion showed splicing out of the first coding exon as well as rare utilization of a cryptic splice site in the exon. An IVS10 +1GT-->CT transversion, unique to the index patient, was detected on the second chromosome. The IVS10 +1GT-->CT results in splicing out of exon 10 including part of the enzyme catalytic site. Additionally, a large deletion encompassing exon 18, previously described in four unrelated patients, was also detected in three unrelated adult GSDII patients, two of whom carried the IVS1 -13T-->G transversion. The frequency of the IVS1 splice site mutation suggests that detection of this mutation could potentially aid in the diagnosis of the phenotypically variable syndrome of adult onset GSDII. The finding that the -13T-->G mutation is a very common mutation in adult onset GSDII patients of varying ethnic and racial backgrounds, suggests that it is either an ancient mutation or confers a selective advantage. Although to our knowledge these are the first splice site mutations to be reported for GSDII, additional splice site mutations are likely and could provide the basis for later onset disease in GSDII.

Adult↗
PubMed1994

Expression of cell adhesion molecules in inflammatory myopathies and Duchenne dystrophy.

Cell adhesion molecules participate in target-effector cell interactions in cell-mediated cytotoxicity and in leukodiapedesis in inflammatory diseases. Two ligand-receptor pairs may play a role in the adhesion of cytotoxic T cells to their targets: 1) intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1), and 2) LFA-3 and CD2. We therefore immunolocalized these molecules in myopathies where there is evidence for T cell-mediated myocytotoxicity, namely inclusion body myositis, polymyositis, and Duchenne dystrophy. Autoaggressive inflammatory cells close to invaded muscle fibers showed an increased expression of ICAM-1 and LFA-1. The nonnecrotic muscle fibers invaded by autoaggressive cells expressed ICAM-1 where their surfaces faced the invading cells. That immunoreactivity for ICAM-1 on the invading cells was distinct from that on the opposite muscle fiber surface was established by colocalization of ICAM-1 with the sarcolemmal marker dystrophin (or beta-spectrin) and was also confirmed by confocal microscopy. Leukodiapedesis in inflamed tissues is mediated by ICAM-1, LFA-3, vascular cell adhesion molecule-1 (VCAM-1), and E-selectin associated with endothelial cells. In dermatomyositis ICAM-1 was strongly expressed on endothelial cells of perimysial arterioles and venules and on some perifascicular capillaries. In all the other myopathies ICAM-1 and LFA-3 expressions were increased on endothelia of capillaries surrounded by inflammatory cells. VCAM-1 was detected in few arterioles in all diseases. E-selectin was not detected at any site in any disorder.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Adhesion Molecules↗
PubMed1994

1,1'-Ethylidenebis[tryptophan] induces pathologic alterations in muscle similar to those observed in the eosinophilia-myalgia syndrome.

1,1'-Ethylidenebis[tryptophan] (EBT), a derivative of L-tryptophan (LT), is a trace contaminant in batches of LT implicated by epidemiologic evidence in the pathogenesis of the eosinophilia-myalgia syndrome (EMS). We treated female Lewis rats with EBT or unimplicated LT (4 mg per 100 grams daily) by intraperitoneal injection. No rash or weakness occurred in either group. All three EBT rats had a few necrotic muscle fibers. In two rats, perimysium and fascia were abnormally thickened and infiltrated with lymphocytes, macrophages, and sparse eosinophils; two rats had sparse perineurial inflammatory cells. Rats treated with unimplicated LT showed no abnormality. These findings replicate an important feature of human EMS and support the epidemiologic evidence linking EBT to the pathogenesis of the human disease.

Animals↗
PubMed1994

Congenital myasthenic syndromes.

The congenital myasthenic syndromes are uncommon but challenging disorders. They can arise from presynaptic defects that reduce quantal size or alter quantal release or from postsynaptic defects that impair quantal efficiency. This article reviews the pathologic mechanisms as well as the clinical and laboratory diagnosis in the syndromes characterized to date.

Humans↗
PubMed1993

Ephedrine: effects on neuromuscular transmission.

(-)-Ephedrine has been used in the treatment of patients with myasthenia gravis. To investigate the possible effects of ephedrine on neuromuscular transmission, canine intercostal muscle endplates were studied by microelectrode techniques. At concentrations less than 10(-4) M, ephedrine had no effect on neuromuscular transmission. At a concentration of 10(-4) M, ephedrine increased the quantal content of the endplate potential by 21%. The presynaptic store of acetylcholine quanta available for immediate release was unchanged, but the probability of quantal release was increased by 16%. At this concentration, ephedrine decreased the amplitude of the miniature endplate potential by 38%. In the presence of 10(-3) M ephedrine, the miniature endplate potentials and currents became undetectable. The kinetic properties of the acetylcholine receptor channel were studied by analysis of acetylcholine-induced endplate current noise. At 10(-4) M, ephedrine reduced the channel conductance by 43% but had no effect on the open time. At 5 x 10(-4) M, ephedrine reduced the channel conductance by 84% and increased the open time by 23 percent.

Animals↗
PubMed1993

Newly recognized congenital myasthenic syndrome associated with high conductance and fast closure of the acetylcholine receptor channel.

We describe here a new congenital myasthenic syndrome associated with a kinetic abnormality of the acetylcholine receptor (AChR) channel. The propositus had poor suck and cry after birth. Subsequently, she had intermittent ocular symptoms and fatigued abnormally on exertion. At age 9 years, significant weakness was detected only in the frontalis, levator palpebrae, and neck flexor muscles. Electromyography showed no decrement in limb muscles but single-fiber examination of the facial muscles was consistent with a neuromuscular transmission defect. The ocular symptoms responded partially to pyridostigmine, but the abnormal fatigability did not. Tests for anti-AChR antibodies were negative. A younger sister had elements of the same disease. An intercostal muscle specimen was obtained from the propositus at age 9 years for endplate studies. The quantal content of the endplate potential was normal. Miniature endplate currents were abnormally large and their decay time constant was abnormally short. AChR channel properties were studied by analysis of acetylcholine-induced current noise. The mean single-channel conductance was increased 1.7-fold and the mean channel open time was 30% shorter than normal. The number of AChR per endplate was normal. Electron microscopy of most endplates showed no abnormality, but a few were degenerating or simplified. The channel abnormality may stem from a point mutation in an AChR subunit affecting a single amino acid residue lining the pore of the AChR channel. The mechanism by which the physiological abnormality produces clinical symptoms is not known, but possible explanations are considered.

Adult↗
PubMed1993

Congenital myasthenic syndromes: I. Deficiency and short open-time of the acetylcholine receptor.

A 5.5-year-old girl had myasthenic symptoms since birth. Tests for antiacetylcholine receptor (AChR) antibodies were negative. To investigate the character of the neuromuscular transmission defect, an intercostal muscle specimen was obtained at age 27 months. Immune deposits were absent from the endplates. On electron microscopy, most postsynaptic regions appeared normal, but the density of AChR on the junctional folds was diffusely reduced. In vitro microelectrode studies revealed that the number of transmitter quanta released by nerve impulse was normal. The amplitude of miniature of endplate potentials and currents was abnormally low. A study of the kinetic properties of AChR by analysis of acetylcholine-induced current noise demonstrated a significant decrease in mean channel open-time; the mean channel conductance was normal. The safety margin of neuromuscular transmission in this disorder is likely to be compromised by the deficiency and abnormal kinetic properties of AChR. The findings are unique among those patients with congenital AChR deficiency described to date.

Acetylcholinesterase↗
PubMed1993

Congenital myasthenic syndromes: II. Syndrome attributed to abnormal interaction of acetylcholine with its receptor.

A 21-year-old woman had myasthenic symptoms since birth that responded poorly to anticholinesterase therapy. Tests for acetylcholine receptor (AChR) antibodies were negative. An intercostal muscle specimen was obtained to investigate the character of the neuromuscular transmission defect. There were no immune deposits at the endplates. The quantal content of the endplate potential was normal. Miniature endplate potentials and currents were very small, but the number of AChR per endplate was normal. On electron microscopy, the synaptic vesicles were of normal size, the junctional folds were intact, and the density and distribution of AChR on the folds was normal. The kinetic properties of AChR were studied by analysis of acetylcholine (ACh)-induced current noise. The mean single channel conductance was normal. The noise power spectrum was abnormal, containing two components of different time course. This could result from an abnormal interaction of ACh with AChR, or from two populations of AChR at the endplate. The second possibility is unlikely because if two populations of AChR were present at the endplate, then both would have to have low conductance to explain the small miniature endplate current, but the average conductance of the channels that did open was normal.

Acetylcholine↗