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Biomedical subjects

R Yarom

Publications and source records attributed to R Yarom.

At least 37 records · Page 2Linked to original sources
PubMed1988

Down's syndrome: abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn-superoxide dismutase.

To investigate the possible involvement of Cu/Zn-superoxide dismutase (CuZnSOD) gene dosage in the neuropathological symptoms of Down's syndrome, we analyzed the tongue muscle of transgenic mice that express elevated levels of human CuZnSOD. The tongue neuromuscular junctions (NMJ) in the transgenic animals exhibited significant pathological changes, namely, withdrawal and destruction of some terminal axons and the development of multiple small terminals. The ratio of terminal axon area to postsynaptic membrane decreased, and secondary folds were often complex and hyperplastic. The morphological changes in the transgenic NMJ were similar to those previously seen in muscles of aging mice and rats as well as in tongue muscle of patients with Down's syndrome. The findings suggest that CuZnSOD gene dosage is involved in the pathological abnormalities of tongue NMJ observed in Down's syndrome patients.

Age Factors↗
PubMed1988

Reduced negative surface charge on arterial endothelium of diabetic rats.

Cationized ferritin binding was used to measure negative surface charge on endothelium of large arteries in streptozotocin-induced diabetic rats and normal control rats. The negative charge was significantly lower in the diabetic animals (p less than 0.01). This change, possibly related to glycosylation, may lead to altered vascular permeability and may be of importance in the vascular pathology of diabetes.

Animals↗
PubMed1988

Premature aging changes in neuromuscular junctions of transgenic mice with an extra human CuZnSOD gene: a model for tongue pathology in Down's syndrome.

We examined the tongue muscles in several strains of transgenic mice carrying the human Zn-Cu superoxide dismutase (CuZnSOD) gene. The presence of the extra gene was confirmed in mated progeny and the gene product activity was measured in the tongue and found to be much higher than in normal littermate controls. Using electron microscopic morphometry, the neuromuscular junctions of the transgenic mice showed significant changes resembling excessive aging, with atrophy, degeneration, withdrawal, and sometimes destruction of the terminal axons, as well as the development of multiple small terminals. The myofibers showed little change except for slight hypertrophy and an increased variability in size. They also had more megamitochondria, fat droplets and lipofuscin bodies. Excess CuZnSOD generates H2O2 and hydroxyl radicals which affect both NMJ membranes and plasticity, and which may produce premature aging. The findings resemble those observed in tongues of patients with Down's syndrome, in whom an extra CuZnSOD gene is present as part of the trisomy of chromosome 21.

Aging↗
PubMed1987

Platelet pathology in minimal curve idiopathic scoliosis: an attempt to predict curve progression.

Platelets from adolescents with minimal curve scoliosis (mcs) (7-18 degrees) and healthy control subjects were examined for morphometry under the electron microscope and tested for calcium content and surface negative charge. These parameters have previously been found to be abnormal in severe idiopathic scoliosis (is) patients. Significantly more patients than control subjects showed deviations from normal in all tests. Two tests in particular, the average number of dense bodies per cell and an increased surface negative charge, were the most frequent abnormalities. In an attempt to assess the possibility of using platelet tests for prediction of curve progression, statistical comparisons were made and discriminant scores were generated for each patient. The results were compared with the clinical findings after a 2- to 3.5-year follow-up. The predictions proved to be incorrect although each of the five patients who had curve progression had some platelet abnormality. It is concluded that although platelet pathology does occur in early idiopathic scoliosis, it cannot be used as a prognostic indicator of curve progression.

Adolescent↗
PubMed1987

T-2 toxin effect on rat aorta: cellular changes in vivo and growth of smooth muscle cells in vitro.

Rats were injected intraperitoneally with T-2 toxin and their aortas were studied by light and electron microscopy. The growth of smooth muscle cell explants taken from the tunica media of aortas of similarly treated animals was observed. A single large dose (2 mg/kg) or four injections of 0.3 mg/kg T-2 toxin caused damage and occasional necrosis of endothelial cells, accumulation of basement membrane-like material in the intima, and swelling and activation of smooth muscle cells in the tunica media. Three or more weeks after the last injection of 0.3 mg/kg T-2 toxin the endothelial cells were normal but an excess of fragmented intimal basement membrane-like material persisted and smooth muscle cells were still activated. Outgrowths from explants of aortic tunica media taken within 1 week of the last dose of T-2 toxin showed marked inhibition of smooth muscle cell growth. Three or more weeks after the toxin, the explants showed significantly increased outgrowths. These findings suggest that T-2 toxin causes early endothelial and smooth muscle cell injury accompanied by inhibition of smooth muscle cell growth in culture. This is followed by stimulation of the proliferative capacity of smooth muscle cells in vitro. If a similar mechanism is operative in vivo, it could explain the chronic vascular changes observed after limited exposure to T-2 toxin.

Animals↗
PubMed1987

Elevated concentrations of elements and abnormalities of neuromuscular junctions in tongue muscles of Down's syndrome.

X-ray spectrometry was used to measure the concentrations of calcium, iron, copper and zinc in tongue muscles from patients with Down's syndrome (DS) undergoing partial glossectomy. Similar measurements on samples from autopsies served as controls. Electron microscopy was used to examine neuromuscular junctions. The calcium and copper were significantly elevated and correlated in DS while the iron and zinc showed little change. The copper increase is probably connected with the known high level of Zn-Cu superoxide dismutase (SOD), coded for by chromosome 21. (In DS there is a trisomy 21). The excess of SOD may interfere with free radicals needed for excitation-contraction coupling and may be instrumental in damaging junctional membranes. The high calcium may result from such membrane damage. It is suggested that neuromuscular junction pathology, either genetic or free radical induced, may cause the tongue weakness in DS.

Adolescent↗
PubMed1987

Cutaneous injury by topical T-2 toxin: involvement of microvessels and mast cells.

Topical applications of various doses of T-2 toxin to rats led to delayed skin reactions. Following a dose-dependent latent period of 12-24 hr, there appeared vascular dilation, stasis, edema and mononuclear cell infiltration, with many degranulating mast cells. These signs were earliest and strongest in the subcutis. Epidermal necrosis occurred 1-2 days later and was probably caused secondarily by ischemia, due to microcirculatory failure. Ultrastructurally, endothelial cells of small vessels were the earliest sites of change. While intercellular junctions remained closed and pinocytosis decreased, the cytoplasm contained many ribosomes, vacuoles, and abnormal mitochondria. Another early effect of topical T-2 toxin was an increase in number and degranulation of mast cells, especially in the subcutis. The resemblance of the skin injury to that produced by irradiation is noted.

Animals↗
PubMed1987

'Illegitimate' recombination events in polyoma-transformed rat cells.

In the LPT line of polyoma (Py)-transformed rat cells, amplification of the integrated viral DNA and of cell nucleotide sequences flanking the viral integration site, can be induced either spontaneously or by treatment with carcinogens. We show here that the amplified DNA includes interspersed viral and cellular sequences generated by 'illegitimate' recombination events. Genomic libraries have been prepared in phage lambda vectors from LPT cells treated with the inducing agent mitomycin C and from untreated LPT cells. Four phages, including viral-cell DNA recombinants, have been isolated from these libraries. Sequencing through the recombination sites revealed the following characteristics: (i) The crossover points map at four different positions in the viral DNA and at four different positions in the flanking cell DNA. (ii) There are very short homologous sequences of 1, 2, or 4 bp, at the recombination sites. (iii) Aside from the exchanges between the viral and the cellular DNA, no further rearrangements occurred around the new viral-cellular DNA junctions. (iv) Next to the recombination sites, there are blocks of homopurine-homopyrimidine sequences, which may assume a structure that differs from the Watson-Crick double helix. (v) Clustered homologous sequence blocks of up to 10 bp are present less than 200 bp away from the recombination sites. These homologies are not in register. Based on these results, we propose a model that may account for these recombination events and, more generally, for recombination events that occur during gene amplification in mammalian cells.

Animals↗
PubMed1987

Cardiovascular pathology induced by passive transfer of splenic cells from syngeneic rats treated with T-2 toxin.

Mononuclear cells were separated from spleens and lymph nodes of Lewis rats treated 5 weeks previously with repeated small doses of T-2 toxin or solvent only. The cells from each site were then injected intraperitoneally into 4 groups of syngeneic Lewis rats. The animals injected with spleen cells from T-2 toxin-treated donors developed marked cardiovascular changes which were similar to those due to T-2 toxin itself. Rats injected with lymph node cells as well as those given each kind of cell from solvent-treated donors showed only occasional mild vascular changes. The changes seen after splenic cell transfer may be due to superinduction of interleukin 2 by T-2 toxin.

Animals↗
PubMed1987

Musculoskeletal symptoms as a presenting sign of long-standing hypothyroidism.

Muscle and joint pains and/or weakness are not usually stressed as central symptoms in hypothyroidism. Two cases of long-standing hypothyroidism presenting with prominent myopathic symptoms are described. The first patient presented with a 12-year history of proximal myopathy, arthropathy and skin abnormalities, and florid primary myxedema was diagnosed. No evidence for a systemic autoimmune process was found. The second patient had been treated with irradiation to the neck 23 years before admission and presented with clinical and laboratory signs of both proximal myopathy and hypothyroidism. Thyroid hormone replacement resulted in a complete recovery of all the musculoskeletal symptoms, with reversion to normal of the very high muscle enzyme levels in both patients. The cases presented illustrate that hypothyroidism can lead to the development of a variety of muscular, rheumatic and dermatologic syndromes easily confused with dermatomyositis or other collagen diseases.

Adult↗
PubMed1986

Capillary ATPase inactivation in early myocardial ischaemia.

The Wachstein-Meisel ATPase reaction can be used in formalin-fixed, postmortem material to demonstrate the microvasculature in the human myocardium. In cases of sudden or rapid cardiac death, the disappearance of enzymatic activity in capillary walls was observed earlier than other light-microscopic signs of damage. This was especially marked in the subendocardial regions. The staining of capillaries was found to be positive again in the varying stages of organization. Fibrotic scars were devoid of staining. The findings besides being of practical value in the diagnosis of early myocardial necrosis, support the theory that loss of capillary metabolic and functional integrity occurs early in ischaemia; it promotes the 'no reflow' phenomenon and may contribute towards myofibre necrosis.

Adenosine Triphosphatases↗
PubMed1986

Myofibers in tongues of Down's syndrome.

Muscle samples from the anterior part of the tongue in 15 patients with Down's syndrome (undergoing partial glossectomy), and 6 post-mortem controls, were examined histochemically. In most cases there was a Type 2 myofiber hypertrophy and preponderance, with frequent type 'grouplet' formation. In four cases examined ultrastructurally, hyperplastic, disorganized and atrophic neuromuscular junctions were seen. These preliminary ultrastructural findings suggest that synaptic morphometry could be a rewarding method of studying neuromuscular deficits in Down's syndrome.

Adenosine Triphosphatases↗
PubMed1986

T-2 toxin effect on cultured myocardial cells.

Beat rate, contractility and viability of cultured myocardial cells perfused with solutions containing various concentrations of T-2 toxin were studied. While doses below 50 micrograms/ml had no immediate effect, those above 250 micrograms/ml decreased beat rate and amplitude. After 10-30 min of perfusion most cells stopped beating and did not restart after withdrawal of toxin. Nevertheless, most cells remained viable as judged by morphology and trypan blue exclusion. A 24-h exposure to doses of 5 or 2.5 micrograms/ml of toxin decreased the beat rate and inotropic responses of the myocytes. After 48 h cell death ensued. Thus T-2 toxin has some direct toxicity to myocardial cells but the lethal dose seems too high to make this the cause of cardiovascular failure.

Animals↗
PubMed1986

Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries.

We studied six patients who suffered from angina pectoris but had angiographically patent major coronary arteries. Two of the patients suffered also from congestive heart failure. Three patients had supraventricular tachyarrhythmias. Three patients had conduction disturbances. During coronary angiography the patients had significantly reduced flow velocity of angiographic contrast medium compared with that in a control group. Echocardiographic and Doppler flow studies showed a tendency for symmetrical thickening of the left ventricular wall, enlargement of the right ventricle, and reduced compliance of both ventricles. Right ventricular endomyocardial biopsy revealed pathologic small coronary arteries with fibromuscular hyperplasia, hypertrophy of the media, myointimal proliferation, and endothelial degeneration. Capillaries had swollen endothelial cells encroaching on the lumen. Myocardial hypertrophy, lipofuscin deposition, and patchy fibrosis were also observed. These cases show that small-vessel coronary artery disease can cause classic angina pectoris. The diagnosis can be suspected when the coronary angiogram shows large patent arteries with slow flow of the angiographic contrast medium and it can be confirmed by endomyocardial biopsy.

Adult↗
PubMed1986

T-2 toxin effect on the ultrastructure of myocardial microvasculature.

The effect of T-2 toxin on the ultrastructure of coronary microvasculature was studied in rats injected intraperitoneally and in rats hearts perfused with the toxin. The capillaries were most severely damaged and were often disrupted. The plasma membrane of endothelial cells seemed to be the first structure affected. A direct cytotoxicity of T-2 toxin to the myocardial capillary lining cells seems to be the pathogenical mechanism of injury. The abundance of mast cells in several of the hearts examined suggests a role for their vasoactive products in the genesis of the capillary lesions.

Animals↗
PubMed1985

Zinc-induced platelet aggregation is mediated by the fibrinogen receptor and is not accompanied by release or by thromboxane synthesis.

We demonstrate that zinc (0.1 to 0.3 mmol/L) induces aggregation of washed platelet suspensions. Higher concentrations (1 to 3 mmol/L) of zinc were needed to aggregate platelets in platelet-rich plasma obtained from blood anticoagulated with low-molecular-weight heparin, probably due to the binding of zinc to the plasma proteins. Zinc-induced aggregation of normal washed platelets required added fibrinogen and no aggregation occurred with thrombasthenic platelets or with normal platelets pretreated with a monoclonal antibody (10E5) that blocks the platelet fibrinogen receptor. These data indicate that the platelet membrane fibrinogen receptor-glycoproteins IIb and IIIa mediate the effect of zinc. Zinc-induced aggregation was blocked by the agent TMB-8, which interferes with the internal calcium flux, and by prostacyclin, which elevates platelet cyclic adenosine monophosphate levels. Zinc-induced aggregation was not accompanied by thromboxane synthesis or by the secretion of dense-body serotonin and was not affected by preexposure of platelets to acetylsalicylic acid. Experiments with creatine phosphate/creatine phosphokinase showed that the zinc effect on platelets was independent of extracellular adenosine diphosphate (ADP). Zinc had an additive effect when platelet aggregation was stimulated with subthreshhold concentrations of collagen or ADP. Together with the known effects of nutritional zinc on in vivo bleeding, on platelet aggregation, and on lipid metabolism, the results suggest that zinc may have an important bearing on normal hemostasis, thrombosis, and atherosclerosis.

Adenosine Diphosphate↗
PubMed1984

Mapping of polyadenylated transcripts of a monkey lymphotropic papova virus.

Polyadenylated transcripts of a monkey lymphotropic papovavirus (LPV), which can be propagated in monkey and human lymphoblastoid cell lines, were identified and mapped. Polyadenylated RNA was purified from cells of the human line BJA/B infected with LPV, and was hybridized with various LPV DNA fragments. The hybrids were treated with S1 endonuclease and analyzed by alkaline gel electrophoresis. This analysis revealed two groups of RNA molecules encoded in two regions of the LPV genome. One group includes four colinear transcripts of 2.3, 2.1, 1.85, and 1.2 kb, whose polyadenylated termini map at a single site on the LPV DNA. The second group includes two less-abundant transcripts of 1.8 and 1.95 kb. The polarities of the LPV transcripts were determined by hybridizing cDNA complementary to their 3' termini with LPV DNA fragments. The two groups were found to have opposite polarities. It is shown that the four major transcripts can be aligned with, and may be functionally related to, SV40 and polyoma virus "late" mRNAs. It is also inferred that the 1.8- and 1.95-kb RNA species may be functionally related to the "early" transcripts of these papovaviruses.

Animals↗