Vernon W. Fischer

Progressive neuropathologic lesions in vitamin E-deficient rhesus monkeys.

A consistent group of progressive central and peripheral nervous system lesions developed in seven rhesus monkeys maintained on a vitamin E-deficient diet for 30 to 33 months. These lesions were absent from vitamin E-supplemented monkeys. The principal neuropathologic alteration was loss of sensory axons in the posterior columns, sensory roots, and peripheral nerves. Morphologic and morphometric studies indicated that the distal segments of the axons were affected most severely and large-caliber myelinated fibers are selectively involved. Swollen, dystrophic axons (spheroids) occurred infrequently. Degeneration and phagocytosis of small numbers of neuronal perikarya were observed in the dorsal root ganglia and the anterior horns. The number of affected neurons was not proportional to the number of affected axons. Accumulation of lipopigment was evident in neuronal perikarya and CNS endothelial cells. The nervous system lesions were usually accompanied by a chronic necrotizing myopathy. The neuropathologic lesions in vitamin E-deficient monkeys are compared with those in vitamin E-deficient rats and in humans with low serum vitamin E concentrations. A similar type of sensory axonopathy is associated with chronic deficiency of vitamin E in these three species.

Altered angioarchitecture in selected areas of brains with Alzheimer's disease

SummaryIt was the aim of this study to determine, qualitatively and quantitatively, alterations in the blood vessels of brains removed postmortem from patients with Alzheimers disease (AD), and to compare these findings with the appearance of cerebral blood vessels in a group of individuals without brain disorders. Celloidin sections of brain tissue from four cerebral areas, pre-frontal (Brodmanns area 9), basal forebrain, sensorimotor, and hippocampus, were subjected to an alkaline phosphatase reaction to facilitate the evaluation of the vascular distribution. The vascular density in five sections was determined by counting the number of vascular intersections with a microscopic test grid of 100 squares; ten fields per section were examined in this manner. Analysis of 16 AD and 6 control brains, showed that there was a striking and statistically significant reduction in the vascular net density specifically in the basal forebrain region and the hippocampus of AD brains. In addition, vessels in the AD brains exhibited extensive topographical changes, such as kinking and looping. These results indicate that modifications in vascular density are present in AD brains with a marked regional specificity.

Use of the inferior epigastric artery as a free graft for myocardial revascularization.

From March 1990 through January 1991, 47 patients undergoing myocardial revascularization had one (37) or both (10) inferior epigastric arteries (IEA) used as a conduit for bypass with 62 distal anastomoses. The internal thoracic artery (ITA) was used bilaterally in 41 patients and unilaterally in 6 with 100 distal anastomoses. Five patients had a single saphenous vein graft. In total, 167 anastomoses (3.55 per patient) were performed. Single IEA grafts were harvested through a paramedian incision and bilateral grafts, a midline incision. Harvest time was 36.5 minutes for IEA grafts and 29.6 minutes for ITA grafts (p less than 0.0001). Graft length was 11.9 cm for IEA grafts and 16.5 cm for ITA grafts (p less than 0.0001). Distal graft diameter was 2.0 mm for IEA grafts and 2.1 mm for ITA grafts (p less than 0.01). Graft flow was 49.7 mL/min for IEA grafts and 48.7 mL/min for ITA grafts. Microscopic assessment of segments of both the IEA and ITA from 14 patients revealed similar internal elastic laminae and an equal number of fenestrations. Combined intimal and medial thickness was comparable in both conduits. Medial elastic tissue was more prominent in ITA grafts and lacking in eight of the 14 IEA grafts. Gross plaque formation was noted in the proximal 1 to 3 cm of 50% of IEA grafts, but the lumen was not compromised and microscopic thickening was minimal. An unexpected finding was medial calcifications (Mönckebergs disease) in two of the 14 IEAs without associated atherosclerosis. There was one hospital death, one abdominal wound infection, and one instance of fat necrosis superficial to the sternum.(ABSTRACT TRUNCATED AT 250 WORDS)

A Primate Model of Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABA) in man is featured by the presence of IgE skin sensitizing and IgG precipitating antibodies against Aspergillus fumigatus (AF). An animal model of this disease was created. 2 monkeys immunized with AF produced IgG-precipitating antibody. Normal human serum was infused into both immunized and unimmunized monkeys and allergic human serum containing a high titer of IgE against AF was infused into another pair of immunized and unimmunized monkeys. All monkeys then received an aerosol of AF. Lung biopsies were obtained and light microscopic, immunofluorescent and electron microscopic studies were performed. Only the monkey with precipitating antibody to AF who received human allergic serum showed changes which included an interstitial cellular infiltrate containing large numbers of eosinophils, edema of the intra-alveolar spaces, thickening of the alveolar septa, intracellular and interstitial deposits of IgG and IgM and proliferation of collagen fibrils. No evidence of vasculitis was observed. This primate model of ABA should enhance our understanding of the inflammatory response and the immunologic processes in this disease.

Myocardial structure and capillary basal laminar thickness in experimentally diabetic rats

Abstract This study was designed to investigate myocardial abnormalities in general, and the extent of capillary basal laminar thickening (CBLT) in particular, in experimentally induced diabetic rats. For this purpose, buffered streptozotocin (70 mg/kg) was administered to 34 rats; control groups consisted of 18 rats, uninjected or buffer-injected only. Animals were sacrificed at monthly intervals up to 12 months and at 15 months following induction of the diabetes. Myocardial, renal, and skeletal muscular tissues, prepared for ultrastructural examination, were subjected to quantitative procedures, in order to obtain an index of CBLT. The results indicated that abnormal CBLT was present and relatable to the length of exposure to the hyperglycemia. Six months following induction, the increments in laminar thickening in diabetic rats significantly differed from those in normal maturing rats. In the diabetic myocardium CBLT represented the single, specific, and clearly identifiable strucutural abnormality. Increased CBLT was also observed within renal glomeruli and quadriceps in diabetic rats, to a more marked extent than that seen in the myocardium. Parenchymal changes in the three tissues under study were most pronounced in the kidneys of diabetic rats. These findings, paralleling previously published observations in human diabetics, fail to reveal morphologic evidence of an intrinsic diabetic cardiomyopathy and suggest that CBLT in experimentally diabetic rats is associated with the altered metabolic state in these animals.

Cerebrovascular Changes in Tocopheroldepleted Chicks, Fed Linoleic Acid

Chicks on an encephalomalacia-inducing diet (EID), lacking in tocopherol and augmented with linoleic acid, exhibit the following triad of fluorescence, light and electron microscopic changes, selectively affecting the endothelium of brain capillaries: 1) development of a gradually intensifying fluorescence, 2) increased deposition of acid phosphatase reaction products, 3) accumulation of electron-dense structures within the endothelial eytoplasm. These changes develop contemporaneously and coincide morphologically. The alterations precede the onset of pathologic lesions. They represent metabolic disturbances induced in cerebral endothelium by feeding the EID. Excessive ingestion of linoleic acid without antioxidant coverage could lead to peroxidative damage and degradation of subcellular constituents. Possibly the alterations reflect an early stage of ceroid formation associated with activation of endothelial lysosomes. The vascular changes may be a determining factor in the pathogenesis of nutritional encephalomalacia.

Thyrotoxic myopathy in mice: Accentuation by a creatine transport inhibitor☆

To demonstrate the importance of creatine and phosphocreatine in skeletal muscle during periods of metabolic stress, thyrotoxicosis was induced in mice fed the creatine transport inhibitor, beta-guanidinopropionic acid (beta-GPA). Adding 2% of beta-GPA to the diet of normal mice inhibited weight gain and caused a 75% reduction of creatine and phosphocreatine concentrations in skeletal muscle. Addition of 0.25% or 2% of thyroid powder to the diet of normal mice was associated with hyperactivity, cardiomegaly, and a high mortality rate. Superimposing thyrotoxicosis on mice already depleted of creatine and phosphocreatine resulted in degeneration of muscle fibers. These results indicate that high concentrations of creatine and phosphocreatine are essential for the maintenance of muscle integrity during periods of metabolic stress.

Peripheral nerve axonal dwindling with concomitant myelin sheath hypertrophy in experimentally induced diabetes.

SummaryAxons of the peripheral nervous system (PNS) are reduced in caliber in response to the experimental diabetic state. The cause of this reduced axonal size is disputed. Various theories include (a) axonal dwindling, (b) inhibition of growth, and (c) shrinkage due to serum hyperosmolarity. This study was designed to directly address these conflicting theories and to provide additional information on the character of the peripheral neuropathy resulting from an experimentally induced diabetic state.Four weeks, 6 and 12 months after establishing a streptozotocin-induced diabetic condition in rats, a morphometric evaluation of randomly selected cross sections of myelinated nerve fibers in the common peroneal nerve was performed on diabetic and age and weight-matched control animals.A reduction in the cross-sectional area of axons with a concomitant increase in the width of myelin sheaths was detected following 6 months of exposure to the diabetic state. Axons in rats diabetic for 12 months showed smaller cross-sectional areas than those seen in rats diabetic for only 6 months; hence, a dwindling in axonal caliber had occurred during this period. These findings indicate the presence of an axonopathy, associated with a myelin sheath alteration in the common peroneal nerve of the chronically diabetic rat.

Effects of β-guanidinopropionic acid on murine skeletal muscle

Abstract To evaluate the need for creatine and phosphocreatine in the maintenance of muscle fiber size, the effects of chronic depletion of these compounds were studied. Mice were fed a Chow diet containing 1% β-guanidinopropionic acid (β-GPA) to deplete skeletal muscle of creatine and phosphocreatine. β-GPA is a specific, competitive inhibitor of creatine transport across biological membranes. On this diet, the creatine concentration in tibialis anterior muscles decreased from 11.0 ± 3.6 (mean ± SD) to 3.7 ± 1.3 μmol wet weight, the phosphocreatine concentration decreased from 15.9 ± 3.3 to 2.8 ± 1.0, and the adenosine triphosphate concentration decreased from 6.0 ± 0.5 to 3.5 ± 0.3. Correlated with the diminished concentrations of these compounds was a selective 7 to 25% decrease in the diameter of type II muscle fibers. The presence of extra creatine in the diet prevented at least in part both the decrease in muscle fiber diameter and the biochemical changes. Mice fed β-GPA may serve as a model for the study of the pathogenesis of type II muscle fiber atrophy due to a specific, known biochemical defect.

EFFECT OF 1‐AMINOCYCLOPENTANE‐1‐CARBOXYLIC ACID (CYCLOLEUCINE) ON DEVELOPING RAT CENTRAL NERVOUS SYSTEM PHOSPHOLIPIDS

Treatment of developing rats with 1‐amino‐cyclopentane carboxylic acid (cycloleucine) resulted in changes in brain and spinal cord phospholipid content and fatty acid composition. General findings were a decrease in ethanolamine phospholipid content, and relative increase in the saturated fatty acid content of ethanolamine phospholipid. In all the different cycloleucine experiments conducted, there was consistently less fatty aldehyde present in the methylated ethanolamine phospholipid fatty acid‐fatty aldehyde fractions than in corresponding controls. In some experiments fatty aldehyde was almost completely absent, suggesting the presence of little plasmalogen. Changes in fatty acids of phosphatidyl choline, the other phospholipid examined in this manner, were generally minor. Administration of massive amounts of sodium propionate in addition to cycloleucine did not result in an appreciable odd‐chain fatty acid increase in the CNS.