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Biomedical subjects

C Kilo

Publications and source records attributed to C Kilo.

At least 55 records · Page 3Linked to original sources
PubMed1985

Value of glucose control in preventing complications of diabetes.

Many functional, biochemical, and morphologic changes occur in diabetes in animal models and in humans. The responses of humans and animals to treatment with insulin indicate that these changes are induced by the diabetic milieu and are indirect or direct consequences of insulin deficiency and/or hyperglycemia. Guidelines for acceptable laboratory values in controlling diabetes are presented, as is evidence supporting a metabolic basis for vascular complications of the disease. On the basis of the results of a recently published prospective study of 59 patients with diabetes, fluorophotometry is cited as a technique that may predict development of retinopathy.

Adult↗
PubMed1985

Pericyte degeneration and acellular capillaries are increased in the feet of human diabetic patients.

Ultrastructural morphometry was used to quantify capillary basement membrane width, pericyte coverage of capillaries, pericyte degeneration, and the extent of acellular capillaries in skeletal muscle obtained at autopsy from neck, thigh, calf and foot of five male and four female diabetic subjects and an equal number of sex- and age-matched nondiabetic subjects. Within diabetic or nondiabetic subjects, the trend for all four parameters to increase in frequency or magnitude in the order neck less than thigh less than calf was highly significant; the only statistically significant difference between calf and foot muscles for any of the four parameters was capillary basement membrane width for nondiabetic subjects, which was significantly thinner in foot than in calf muscle (t = 2.45; p less than 0.05). Pericyte coverage of capillaries did not differ between diabetic and nondiabetic subjects for each muscle examined; however, capillary basement membrane width, the frequency of pericyte debris and acellular capillaries were increased significantly in the lower extremity muscles of diabetic compared to nondiabetic subjects, and the magnitude of the difference between these two groups increased in the order thigh less than calf less than foot. The observations that pericyte degeneration and acellular capillaries are present in skeletal muscle as well as in retinal microvessels suggest that common pathophysiological mechanisms may contribute to vascular disease in these two very different tissues. The additional finding that relative differences between diabetic and nondiabetic subjects, in the frequency and magnitude of these changes, increase in the order neck less than calf less than foot is consistent with the marked increase in peripheral vascular disease and gangrene in the lower extremities of diabetic patients.

Adult↗
PubMed1985

Tissue differences in vascular permeability changes induced by histamine.

A new method is described for assessing changes in vascular permeation by albumin in multiple tissues of the same animal in response to intravascular injection of vasoactive agents. Following intravenous injection of 51Cr-RBC, 125I-BSA, and 57Co-EDTA, a test substance (i.e., histamine) is injected intravascularly or subcutaneously. Eight minutes later approximately 2.0 ml of blood is withdrawn and the heart is severed from the great vessels. Samples of tissue are then taken for determination of water content and for the ratio of counts in 125I and 51Cr in each tissue. That ratio is then divided by the corresponding ratio of the same isotopes in the blood. If the resulting quotient is greater than 1, it indicates that the volume of distribution of 125I in the tissues is greater than the ratio of plasma to red cells in large blood vessels and is indicative of permeation of the vasculature by albumin into the extravascular space. With this technique we have demonstrated that following intravenous injection of histamine, albumin permeation of vessels in the cecum is increased much more than for vessels in any other tissue in the body including skin and muscle. Following intravenous injection of 1.5 mg/kg histamine, albumin permeation in the cecum is increased 4-fold while that in skin is unchanged, except at sites where histamine also has been injected subcutaneously where it is increased 1.7-fold by 3 microgram and 10-fold by 15 micrograms of histamine. The magnitude of increases in albumin permeation of the vasculature after intravenous injection of 7.5 mg/kg of histamine was: cecum--5.1 X greater than pancreas--2.8 X greater than small intestine--2.7 X greater than cremaster and stomach--2.0 X greater than eye and aorta--1.9 X greater than fat--1.7 X greater than skin--1.6 X greater than diaphragm and forelimb--1.5 X. Even at this high dose of histamine, tissue to blood isotope ratio (tbir)-I/Cr values were not increased for heart, brain, kidney, lung, or testis. These findings attest to marked tissue differences in sensitivity to histamine-induced changes in vascular permeation by albumin. The additional that histamine-induced tbir-I/Cr increases in most tissues far exceed tbir-Co/Cr increases indicates that the increase in albumin permeation of vessels is mediated in large part by an increased rate of diffusion (rather than filtration) via an increase in the number and/or size of vascular pores large enough to accommodate albumin.

Animals↗
PubMed1985

Hyaluronidase does not prevent deterioration of vascular functional integrity during reperfusion after no-flow ischemia in isolated rabbit hearts.

Effects of hyaluronidase on myocardial water content and distribution, and on coronary vascular hemodynamics and endothelial cell transport function were assessed in isolated rabbit hearts during 3.5 hours of reperfusion after 30 minutes of global, no-flow ischemia. In nonischemic control hearts, perfusion pressure, left ventricular end-diastolic pressure, maximum +dP/dt, and intravascular clearance of radiolabeled albumin remained constant during 5 hours of continuous perfusion, while the mean-transit time and vascular into extravascular space clearance of radiolabeled albumin increased 1.5X and 2.5X baseline, respectively. During reperfusion after 30 minutes of no flow, perfusion pressure increased 53% and interstitial fluid volume increased 2-fold, while left ventricular end-diastolic pressure and maximum +dP/dt returned to control levels. The rate of intravascular clearance of radiolabeled albumin decreased 38%, and the mean-transit time and vascular-into-extravascular space clearance of albumin increased approximately 3X and 5X baseline, respectively. Hyaluronidase blocked the ischemia-reperfusion-induced increases in total water content and in interstitial fluid volume and reduced the increases in perfusion pressure and mean-transit time of radiolabeled albumin by 40% and 45%, respectively, but did not prevent the increase in albumin vascular-into-extravascular space clearance and the decrease in albumin clearance from the coronary vasculature. These findings indicate that hyaluronidase does not prevent ischemia-reperfusion-induced increases in albumin permeation of the coronary vasculature, and suggest that its protective effect on ischemic myocardium is mediated, instead, by reducing interstitial edema and vascular resistance.

Animals↗
PubMed1985

Albumin permeation of new vessels is increased in diabetic rats.

125I-bovine serum albumin (BSA) permeation of the vasculature of 3-wk-old granulation tissue (induced by subcutaneous implantation of polyester fabric) formed in the diabetic milieu was assessed in female BB/W, spontaneously diabetic rats and in male, Sprague-Dawley rats with streptozocin-induced diabetes as well as in corresponding nondiabetic controls. Albumin permeation of new granulation tissue vessels was markedly increased in both groups of diabetic animals relative to that of nondiabetic controls, while albumin permeation of vessels in most other tissues did not differ for controls and diabetics. These observations indicate that the functional integrity of new vessels formed in the diabetic milieu is impaired: (1) to a greater extent than that of older vessels formed before induction of diabetes and (2) relative to new vessels in nondiabetics. The implication of these observations is that molecular constituents of vessels synthesized in the diabetic milieu are quantitatively and/or qualitatively abnormal and/or their incorporation into vessels is defective.

Animals↗
PubMed1985

Sorbinil prevents diabetes-induced increases in vascular permeability but does not alter collagen cross-linking.

In recent studies we have demonstrated a marked increase in albumin permeation of new vessels formed by angiogenesis (in subcutaneous tissue) in the diabetic milieu. Likewise, lysyl oxidase-mediated collagen cross-linking is markedly increased in the scar tissue associated with angiogenesis. The present studies were undertaken to determine whether sorbinil, a chemical inhibitor of aldose reductase that has been shown to prevent and reverse diabetic cataracts and neuropathy, also could prevent the vascular permeability and collagen cross-linking changes in this model. Vascular permeation by 125I-BSA, collagen cross-linking, and tissue levels of sorbitol, myo-inositol, and scyllo-inositol were assessed in male Sprague-Dawley rats 3 wk after injection of streptozocin and induction of angiogenesis and collagen synthesis in polyester fabric implanted subcutaneously. Sorbinil (approximately 25 mg/kg/day) added to the diet of diabetic rats reduced the diabetes-induced increases in albumin permeation by 80%, completely prevented diabetes-induced changes in tissue levels of sorbitol and myo-inositol, and markedly reduced diabetes-induced changes in tissue levels of scyllo-inositol. In contrast, sorbinil had no effect on plasma glucose levels or collagen solubility (an index of collagen cross-linking). These observations indicate that increased vascular permeability associated with diabetes is linked to imbalances in sorbitol/inositol metabolism. These findings also indicate that diabetes-induced increases in vascular permeability and in collagen cross-linking are independent phenomena and diabetes-induced increases in vascular permeability are largely preventable by treatment with an aldose reductase inhibitor in the face of high plasma glucose levels.

Albumins↗
PubMed1985

Granulation tissue: a new model for studies of vascular complications of diabetes.

New vessels and type I collagen formed in the diabetic milieu differ markedly from vessels and collagen formed in nondiabetic animals. The vessels in diabetic animals are permeated by albumin much more readily than normal and the collagen is much more extensively crosslinked than normal. This is the first animal model in which increased vascular permeability analogous to that observed in human diabetics can be readily produced and quantified. Two important implications of these observations are: 1) vascular and connective tissue constituents formed in the diabetic milieu are functionally and structurally compromised and 2) injury of any kind which leads to proliferative responses and increased turnover of molecular constituents of vessels may increase the rate of development and progression of "diabetic" vascular disease.

Animals↗
PubMed1985

Age-related changes in deformability of human erythrocytes.

The present study was designed to further the characterization of age-related changes in the deformability of human erythrocytes. The top (approximately young) and bottom (approximately old) 10% fractions of density-separated red cells from ten normal donors were subjected to graded levels of shear stress in a rheoscope. Measurements were made of steady-state elongation (cells tank treading in a state of dynamic equilibrium) and the time course of shape recovery following abrupt cessation of shear. In parallel with the rheologic experiments, several physical and chemical properties were assayed to determine correlates of mechanical properties. These included mean cell volume, mean corpuscular hemoglobin concentration, type A1 hemoglobin, glucosylation of membrane proteins, and membrane phospholipid and protein concentration. The microrheologic observations revealed that only about 90% of the old cells retained their capacity to tank tread. However, the tank-treading cells elongated less than their younger counterparts at corresponding levels of shear stress, thus demonstrating a reduced level of deformability. Further analysis of the data indicates that increases in membrane viscosity and elastic modulus along with a significant loss in excess surface area contribute to the limitation of the ability of the older cells to change shape.

Adult↗
PubMed1985

Microrheologic investigation of erythrocyte deformability in diabetes mellitus.

This study was undertaken to determine whether diabetes alters the viscoelastic properties of erythrocytes. The oldest and youngest 10% fractions of circulating red cells were separated by centrifugation of freshly drawn blood obtained from ten diabetics with disease of one to 20 years' duration and from an equal number of age- and sex-matched control subjects. Cells from each fraction were suspended in phosphate-buffered saline, and their rheologic behavior was examined in a rheoscope. The elongation of cells, the percentage of cells that tank-treaded in response to shear stress, tank-treading frequency, and the rate of recovery of cell shape upon cessation of shear stress were determined in the oldest and youngest 10% of cells for diabetics as well as for controls. All four parameters were virtually identical for diabetics and controls. Additional aliquots of cells were taken for assessment of nonenzymatic glucosylation of hemoglobin and cell membrane protein. The absence of any measurable difference in rheologic behavior of cells from diabetic and control subjects, despite substantial differences in nonenzymatic glucosylation of hemoglobin and cell membrane proteins, suggests that the magnitude of glucosylation observed in these cellular constituents does not alter the viscoelastic properties of the cells. The implication of these observations is that microvascular complications of diabetes are not attributable to altered deformability of red cells.

Adult↗
PubMed1985

Pericyte form and distribution in rat retinal and uveal capillaries.

Ultrastructural morphometric techniques were used to assess differences in endothelial cells and in pericyte structure and distribution in rat retinal and uveal capillaries. Retinal capillaries were significantly smaller than those in the three different uveal vascular beds, all of which were similar in size. Approximately 10% of the capillaries in the retina and choroid were formed by three endothelial cells, compared with 30% and 46% of capillaries sampled from ciliary processes and iris, respectively. The percentage of the capillary circumference covered by pericytes (46-58%) and the percentage of capillary sections with pericyte nuclei (12-16%) were similar in retina, iris, and ciliary processes. Corresponding data for the choriocapillaris indicated that pericyte coverage of these capillaries was approximately 50% of that observed in the other eye microcirculations. The number of pericyte processes per capillary varied markedly in the different vasculatures, with an average of three for capillaries in the retina and choriocapillaris and nine to eleven for capillaries in the iris and ciliary processes. These marked differences in capillary dimensions are consistent with the well-known capillary hemodynamic and functional differences of these tissues; however, the significance of the differences in pericyte shape, frequency and distribution in the different vasculatures of the eye is less clear.

Animals↗
PubMed1983

Capillary basement membranes in diabetes.

In discussions of vascular complications of diabetes the fact that capillary basement membranes are, in general, thickened (CBMT) in poorly controlled diabetics is no longer at issue. However, three important questions concerning the pathophysiologic significance of CBMT remain unanswered: (1) How and why do capillary basement membranes thicken in diabetes? (2) What is the functional significance of capillary basement membrane changes in diabetes? (3) What is the nature of the relationship of CBMT to other forms of diabetic vascular disease; in particular, is CBMT observed in tissues amenable to needle biopsy, i.e., skeletal muscle, useful in identifying individuals at high risk for developing clinically significant retinopathy, nephropathy, or atherosclerotic vascular disease? In this survey, we will consider the nature of capillary basement membrane changes in diabetes and subsequently address the above questions.

Basement Membrane↗
PubMed1983

Muscle capillary basement membrane width and its relationship to diabetes mellitus in monozygotic twins.

Quadriceps (Q) and gastrocnemius (G) muscle capillary basement membrane width (CBMW) were measured in 18 pairs of monozygotic (MZ) twins. Thirteen of these twin pairs were discordant for insulin-dependent diabetes (IDD) and five pairs were concordant for either IDD (two pairs) or for non-insulin-dependent diabetes (NIDD). In 12 of the 13 nondiabetic (ND) twin mates of IDD, 50 oral glucose tolerance tests performed in the years before or after determination of CBMW revealed mean blood glucose levels in the 36-52 percentile range, compared with normal controls. The mean (+/-SD) age at the onset of IDD in discordant twins was 18.7 +/- 10.1 (range 8-37) yr and the mean duration of discordance at the time of biopsy was 13.6 +/- 8.3 (range 3-32) yr. CBMW data were compared within each twin (Q versus G) and between twin mates and age- and sex-matched controls. Overall, CBMW of IDD twins was greater than that of their ND twin mates. Differences between IDD and ND twins, however, were much more marked in gastrocnemius (1859 +/- 643 versus 1222 +/- 307 A, P less than 0.0003) than in quadriceps (1291 +/- 319 versus 1112 +/- 302 A; P less than 0.04). CBMW in gastrocnemius was significantly thicker than that in the quadriceps of IDD twins (t = 4.55, P less than 0.0008) but not in their ND twin mates (t = 1.15, P less than 0.27). CMBW was significantly thicker in IDD than in their ND twin mates (in quadriceps and/or gastrocnemius) in 10 of the 12 twin pairs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

Muscle capillary basement membrane in identical twins discordant for insulin-dependent diabetes.

Although hereditary factors clearly modulate susceptibility to develop diabetes, their role as determinants of vascular complications associated with diabetes remains unclear. These studies were undertaken to further assess the extent to which capillary basement membrane thickening (CBMT) is governed by metabolic derangements associated with relative or absolute insulin deficiency versus genetic determinants of vascular disease closely linked to but independent of those modulating susceptibility to develop relative or absolute insulin deficiency. Quadriceps muscle capillary basement membranes obtained by needle biopsy were examined in eight pairs of identical twins discordant for insulin-dependent diabetes (IDD) for 11-29 yr. Biopsy material from one of the diabetic twins was technically unsuitable for study. The average CBM width of the IDD twins was found to be significantly thicker than that of their nondiabetic (ND) twin mates (t = 2.50, P less than 0.025). Three IDD, but none of the ND twins, had basement membrane width values in excess of 95% upper tolerance intervals for age- and sex-matched controls with no family history of diabetes. The absence of CBMT in all of the ND twins and in four of the IDD twins with diabetes of 15-24 yr duration argues against the existence, in this group of subjects, of hereditary determinants of diabetic vascular disease linked to those governing susceptibility to develop diabetes. In addition, the absence of CBMT in four subjects with IDD of 15-24 yr duration is consistent with evidence from other studies indicating that diabetic microangiopathy is not an inevitable consequence of the diabetic milieu.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1982

Glycosylation of human glomerular basement membrane collagen: increased content of hexose in ketoamine linkage and unaltered hydroxylysine-O-glycosides in patients with diabetes.

To study the glycosylation of glomerular basement membrane collagen (GBMC) in diabetes, kidneys were obtained at autopsy from 5 patients with insulin-requiring diabetes of long duration and diabetic complications, and from 5 control subjects. Glomeruli were prepared by sieving and collagen was isolated by limited pepsin proteolysis followed by salt precipitations. Amino acid analyses of the collagen preparations, after acid hydrolysis, indicated a composition consistent with that of type IV collagen. No differences in the relative contents of various amino acids, and in particular, 3-hydroxyproline, 4-hydroxyproline and hydroxylysine, were noted between diabetic and control samples. Non-enzymatic glucosylation was assessed by measuring hexose in ketoamine linkage with thiobarbituric acid after conversion to 5-hydroxymethylfurfural. In 4 of the 5 patients studied, glucosylation values exceeded the mean +2 S.D. of the controls; in the fifth subject glucosylation was in the high normal range. No correlation between the severity of diabetes and hexose content of GBMC was noted, however. In further studies, enzymatic glycosylation of GBMC was assayed after alkaline hydrolysis by separation of glucosylgalactosyl-O-hydroxylysine, galactosyl-O-hydroxylysine, and unsubstituted hydroxylysine in an amino acid analyzer. No differences in the relative contents of hydroxylysine-O-glycosides were evident between diabetic and control GBMC. The results suggest that non-enzymatic glucosylation, but not glycosylation catalyzed by collagen glucosyl and galactosyl transferases, is increased in diabetes. The increased carbohydrate content of collagen may lead to decreased turnover and/or excessive accumulations of basement membrane collagen thus contributing to the vascular complications of diabetes.

Adult↗
PubMed1981

The natural history of retinopathy in insulin-dependent juvenile-onset diabetes.

We determined the cross-sectional natural history of retinopathy by prospective study of 461 insulin-dependent juvenile-onset diabetics. In so doing, we compared the sensitivity of ophthalmoscopy, photography, and fluorescein angiography in detecting retinopathy. Photography was far more reliable than ophthalmoscopy in detecting early retinopathy and equivalent to angiography. Retinopathy was not present at diagnosis of diabetes. After a lag period, the prevalence of retinopathy rose in sigmoidal fashion, reaching 50% at just over seven years duration, and asymptotically approaching 90% at 17--50 years. Proliferative retinopathy was first seen at 13 years duration, and its prevalence rose to 26% at 26--50 years. From the natural history we computed the dimensions of a proposed clinical trial to test the effect of tight metabolic control in prevention of retinopathy.

Diabetes Mellitus, Type 1↗