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This study investigated the long-term effect of insulin or the combination of insulin and an oral hypoglycemic compound (glipizide) on the skeletal muscle capillary basement membrane width in insulin-requiring diabetic patients. Seventy diabetic patients were randomized to treatment with either insulin-placebo or insulin-glipizide (5 mg/d) for 3 years. Of these, only 61 patients completed the study; 27 patients received insulin-placebo and 34 patients received insulin-glipizide. Three skeletal muscle (quadriceps femoris) biopsies were performed in all patients over a 3-year period. Glycosylated hemoglobin A1 was determined every 100 +/- 20 days, including plasma glucose levels. Muscle capillary basement membrane width was quantitated by a previously described method. After approximately 16 months, glycosylated hemoglobin A1 decreased significantly in each group from its baseline (P < 0.001 insulin-glipizide group and P < 0.025 insulin-placebo), although no statistically significant difference was seen between the two groups. After 3 years this decrease was statistically significant (P < 0.001) only in the insulin-glipizide group. At baseline, no statistically significant difference was found in the muscle capillary basement membrane width between the two groups. In spite of the significant decrease in glycosylated hemoglobin A1 in both groups after 14 to 16 months, only muscle capillary basement membrane width in the insulin-glipizide group decreased significantly compared with baseline. Patients receiving insulin-placebo showed a gradual increase in the muscle capillary basement membrane width, which after 3 years was significantly higher than baseline (P < 0.02). Although the mechanisms by which the addition of glipizide to insulin treatment reduced the thickening of the muscle capillary basement membrane are not clearly understood, the current findings suggest that diabetic microangiopathy is not necessarily progressive and that prophylaxis may be attained.

Histologic classification of renal glomerular lesions in 46 patients with systemic lupus erythematosus revealed 17 as having either focal proliferative (10 patients) or minimal mesangial proliferative (7 patients) glomerulonephritis. Six of the 17 have progressed to a diffuse proliferative glomerular lesion on subsequent renal biopsies, 9 months to 5 years later. Five had clinical deterioration at the time of follow-up biopsies; currently one is undergoing hemodialysis and four others have decreased renal function. Although a comparison of those who progressed with those who are stable revealed greater proteinuria in some of those who progressed, no other clinical features of the initial illness were different in the two groups, nor were differences between the two groups noted on light microscopic examination of initial renal biopsies. However, ultrastructurally, electron-dense deposits, especially those subendothelial in location, were noted along glomerular capillary basement membranes more frequently and in greater number in those who progressed. These findings suggest that lupus patients with a mild proliferative glomerulonephritis may have clinical and histologic progression of the renal disease, and those who progress cannot be clearly defined by clinical or light microscopic features. Ultrastructural demonstration of subendotheial deposits suggests a greater likelihood of subsequent progressive disease.

Forty-one patients with chemical diabetes had three oral glucose tolerance tests and underwent muscle biopsy three times over a period of three years. Twenty-three received glipizide and 18 placebo. Those taking placebo had an increase in the mean muscle capillary basement membrane width (p = 0.01), but those taking glipizide showed a decrease (p = 0.01) to values no different from those of nondiabetic subjects. Determinations of enzyme activities involved in the synthesis and degradation of glycoproteins revealed a three-year decrease (not significant) in muscle glucosyltransferase activity in the glipizide-treated patients, but a statistically significant difference (p less than 0.01) comparing the adjusted means of the two treatment groups. N-acetyl-beta-glucosaminidase activity was significantly increased in muscle from baseline values (p less than 0.01), with adjusted means also significantly different (p less than 0.01). The data suggest that changes in basement membrane and enzyme activities are correlated, and the latter may be a predictor to follow the development, progression, or regression of diabetic vasculopathy.

There is currently a need for diagnostic electron microscopy in both autopsy and surgical pathology. As more information emerges from the research laboratories, applied electron microscopy will grow in depth, and all large medical centers will need the expertise provided by a diagnostic electron microscopy laboratory. Many physicians other than electron microscopists find it essential to have an understanding of the contributions and limitations of electron microscopy. Education and training programs therefore must encompass not only paramedical personnel who prepare the electron micrographs and pathologists who are thoroughly trained in interpret the electron micrographs, but also other physicians and scientists who utilize the information obtained therefrom. Medical students should obtain sufficient background in normal and abnormal ultrastructure to enable them to interpret the medical literature, and the means to obtain this background should be available within the medical school curriculum. Some medical students will also desire more thorough training obtained by elective courses in electron microscopy. Pathology residents should obtain sufficient expertise during their residency to enable them to utilize the information produced by the electron microscopy laboratory. Certain pathology residents and some pathologists in practice prefer fellowships for more specialized training in electron microscopy. Four representative training programs in electron microscopy from Veterans Administration hospitals have been selected for presentation. Each emphasizes a different approach and different objectives.

The authors report their findings by electron microscopy after microsurgical subpial spinal cord transection in dogs. After cord transection, conspicuous myelin microcysts are formed in a background of otherwise intact cord tisue at a distance of 1 to 2 mm from the cut end of the cord, both proximal and distal to the transection, Seen through the electron microscope, the microcysts iss a myelin sac distended by fluid under pressure, containing a swollen axon filled with excessive axoplasmic organelles; that is, a terminal club. Later the microcysts and terminal clubs rupture. The large spaces within the microcysts are opened to heretofore small extracellular spaces and the spinal cord tissues are destroyed. Thus, microcysts are precursors of large cavitites seen at the ends of transcreted cord stumps. The formation of microcysts and their subsequent rupture, which leads to cord cavitation, is interpreted as an inherent response of cord tissue to injury, and the result of an abortive attempt at cord regeneration.

We performed three oral glucose-tolerance tests and three muscle biopsies over a period of approximately three years in 41 asymptomatic patients with chemical diabetes. At base line, 13 (32 per cent) had an increased capillary basement-membrane width in muscle. Twenty-three patients received glipizide, a new oral hypoglycemic compound, and 18 received placebo. In the patients receiving placebo the mean width of the muscle capillary basement membrane increased from 135.9 +/- 9.0 nm (S.E.M.) to 169.3 +/- 9.5 nm (P = 0.01), but in those receiving glipizide the value decreased to a level no different from that in subjects without diabetes: from 152.9 +/- 2.9 to 127.5 +/- 5.1 nm (P = 0.01). These findings suggest that microangiopathy, as indicated by an increased capillary basement-membrane width in muscle, may be present in a considerable number of patients with asymptomatic diabetes and that the changes can be reversed by early drug treatment.

This report describes a 31-year-old woman with evidences of selective adrenocorticotropic hormone deficiency associated with a remarkable pituitary lesion, lymphoid hypophysitis. Clinical manifestations of secondary hypocortisolism, which first appeared during the immediate postpartum period following normal pregnancy, included progressive weakness and mental aberrations, fasting hypoglycemia, transient hypercalcemia, and striking ECG changes. Sudden death resulted from cardiorespiratory collapse. Microscopic examination of the anterior pituitary disclosed focal fibrosis and extensive lymphocytic infiltrations with a marked reduction of basophils; immunostaining techniques demonstrated a selective loss of corticotropin-secreting cells. The histopathology of the pituitary and its association in this case with lymphoid thyroiditis suggest that selective damage to corticotrophs was due to an autoimmune process.

Three muscle biopsies were performed in 53 overt type 2 diabetics over a period of approximately 2 years. At baseline, 21 (40%) had an increased capillary basement membrane width in muscle. Thirty-five patients received glipizide and 18 received placebo. In the patients receiving placebo, the mean of the muscle capillary basement membrane width increased from 158.7 +/- 11.5 nm (SEM) to 170.9 +/- 14.7 nm (P = NS), but in those receiving glipizide the value decreased from 192.9 +/- 13.2 nm to 161.0 +/- 10.2 nm (P = 0.02). Plasma glucose and glycosylated hemoglobin A1 decreased significantly (P less than 0.001) after 2 years in patients receiving glipizide. In 15, mean glycosylated hemoglobin A1 reached a normal range, and mean basement membrane width decreased to a level close to that found in subjects without diabetes (P = NS). These findings are consistent with the hypothesis that effective response to oral medication can decrease the basement membrane thickening, suggesting that diabetic microangiopathy is not necessarily progressive.

Dogs were made alloxan-diabetic and randomly distributed into either of two prospective treatment groups. In one group it was intended that the metabolic signs of diabetes be controlled poorly, and commercial insulin was administered in doses inadequate to prevent chronic, severe hyperglycemia and glucosuria. In the other group it was intended that the metabolic disorder be well controlled, and the animals received food and commercial insulin twice daily such that the hyperglycemia and glucosuria became mild or infrequent. Experimental improvement of the carbohydrate disorder was accompanied by amelioration of hyperlipemia and other clinical signs of deficient insulin activity. By 60 months of diabetes, retinal capillary aneurysms, pericyte ghosts, obliterated vessels, and other microvascular abnormalities typical of diabetes were apparent in each animal of the poor-control group. Better control was found to reduce significantly the incidence and severity of microvascular lesions. The data suggest that the mechanism responsible for diabetic retinopathy is initiated as a result of deficient insulin activity and that the development of the microvascular complications of diabetes are preventable and may be inhibited by careful control of the metabolic disorder.

Three muscle biopsies were performed in 53 overt type II diabetics over a period of approximately 2 years. At baseline, 21 (40%) had an abnormally increased capillary basement membrane width in muscle. Thirty-five subjects received glipizide and 18, placebo. At baseline, no statistically significant difference was found in the muscle capillary basement membrane width between the two groups (P = NS). In the subjects receiving placebo, the mean width of the muscle capillary basement membrane increased (P = NS), but in those receiving glipizide, the mean decreased from 193 +/- 13 nm (SEM) to 161 +/- 10 nm (P = .02). Fasting plasma glucose and glycosylated hemoglobin A1 significantly decreased (P less than .001) after two years in those receiving glipizide. In 15 subjects, mean glycosylated hemoglobin A1 reached the normal range, and mean muscle capillary basement membrane width decreased to a level close to that found in subjects without diabetes (P = NS). Determinations of enzyme activities involved in the synthesis and degradation of glycoproteins revealed a 2-year significant decrease of muscle glucosyltransferase (synthesis) activity (P less than .01) in the glipizide-treated subjects as opposed to a significant increase (P less than .001) in those receiving placebo. Muscle N-acetyl-beta-glucosaminidase activity (degradation) was statistically increased (P less than .001) in those subjects taking glipizide, but decreased in those taking placebo (P less than .001).

The determination of the type of proliferative process in the pituitary causing clinical symptoms is quite difficult using classical morphologic techniques, including immunocytochemistry and electron microscopy. The problem is unusually difficult when the material received from the surgeon consists of 1-2 mm fragments of tissue removed from the sella turcica. Morphologic criteria were extensively discussed by other investigators in this symposium. This manuscript discusses the application of flow cytometry using formalin-fixed, paraffin-embedded tissues, in the diagnosis of pituitary lesions.

Diabetic glomerulosclerosis is a degenerative-proliferative lesion involving most glomeruli in the kidneys of all individuals with hereditary, pancreatic, or experimental diabetes mellitus. The exact nature of the lesion and its etiology remain unknown. Morphologically there appear to be two courses this disease may follow. There is a benign course, which occurred in 89 per cent of our series of adult diabetic patients, consisting of concurrent thickening of the capillary basement membranes and diffuse glomerulosclerosis. The benign course is slowly progressive over many years, and rarely leads to renal failure. The accelerated course, in our experience is always superimposed on the changes of the benign course, and consists of a more rapid progression with the development of glomerulocapillary microaneurysms. Kimmelstiel-Wilson nodules, exudative-deposit lesions, and glomerulocapsular adhesions leading to glomerular obliteration and renal failure. Data are presented to support the concept that large Kimmelstiel-Wilson nodules are formed by the organization of the glomerulocapillary microaneurysms.

Following transection of spinal cords, axoplasmic flow occurred in the axons both proximal and distal to the transection. In the proximal axonal stump, the direction of flow was proximo-distal whereas in the distal axonal stump the direction of flow was disto-proximal. Thus the flows in transected axons were all directed toward the point of transection. Electron microscopic observation of the spinal cord tissue bordering at the cut ends of spinal cord stumps showed various structural changes in the axons and myelin sheaths of the transected fibers near the cut ends which interfered with the axoplasmic flow leading to the formation of the terminal clubs. Five prototypes of changes in axons and myelin sheaths near the cut ends of fibers are described and the mechanism of terminal club formation is discussed. It seemed that the terminal clubs within the transected spinal cord stumps rere of the axoplasmic flow toward the cut ends of the fibers, and (2) interference by structural changes which developed within individual fibers consequent to spinal cord injury.

Monolayer tissue culture cells from benign nodular hyperplasia of the prostate transferred at 1-2 weeks intervals were examined under the electron microscope after the 3rd, 9th, and 10th transfers. Changes seen after 9 to 10 transfers were interpreted as an "aging process" and consisted of the presence of lysosomes of various types and variations in the mitochondria profile. These changes were described in detail and illustrated and compared to the ultrastructural appearance of monolayer cell cultures in the early transfer stage.