Leslie O. Simpson

Basement Membranes and Biological Thixotropy: A New Hypothesis

&NA; As the evolutionary descendants of the fresh water coelenterate mesogloea, basement membranes with similar chemical composition and physical characteristics to mesogloea are able to undergo deformation and flow. On the basis of studies on duodenal villous, skin, capillary and glomerular capillary basement membranes it is proposed that the function of basement membranes, whether in normal or pathological situations, can be explained as resulting from their thixotropic nature, that is, the capacity to undergo localized reduction in viscosity without change in temperature, followed by a comparatively slow recovery to their original consistency. The structural characteristics which provide the unique properties of biological thixotropes are probably similar to those of other thixotropic systems, in that they have an internal structure formed from anisometric particles. It is considered that biological thixotropes have an internal structure composed of rod or fibre‐like units arranged into a comparatively loosely bonded anisometric lattice which is fully hydrated, with water as the dispersed phase. Reduction in viscosity occurs, when, as a result of the localized application of external energy, lattice units are displaced and fall free in the dispersion medium. Re‐formation of the lattice and restoration of normal viscosity is achieved by the random redistribution of lattice units by Brownian movement. This time‐dependent phase means that the deformed area of the lattice will exhibit reduced viscosity until lattice re‐formation has been achieved. Thixotropic membranes with these features would permit small molecules and solutes to pass freely through the lattice. Larger molecules, motile cells and motile organisms would need to cause a localized deformation of the gel lattice in order to traverse the membrane. The energy needed to deform the gel could be obtained from increased intracapillary pressure, or by the expenditure of energy on the part of motile cells or organisms. Increased permeability of capillary basement membranes probably is due to the thixotropic nature of the membrane, the extent to which basement membrane is covered by endothelium and the level of intracapillary blood pressure. In other sites basement membranes are freely penetrated by cell processes, pseudopodia of motile cells and by motile organisms, all of which are able to exert localized pressure adequate to deform the membrane gel.

Red cell and hemorheological changes in multiple sclerosis

&NA; Blood rheology in multiple sclerosis (MS) was investigated in 15 subjects with varying degrees of locomotor difficulties who were members of the local MS Society. Control data were obtained from blood samples from 25 male and 25 female normal blood donors. Whole blood viscosity was measured and blood filterability was assessed. Six MS females provided blood samples for scanning electron microscopy. Erythrocyte membrane fatty acids and phospholipids were assayed. Whole blood viscosity in MS females was higher than controls at 3 of 4 shear rates (p < 0.001) but in MS males blood viscosity was higher only at shear rate of 1.0 s−1 (p<0.05). MS erythrocyte filtration rates were significantly lower than controls (p<0.001). Leucocyte counts in MS were greater than controls both in males (p <0.01) and females (p < 0.001). MS erythrocyte morphology was greatly different from controls (p<0.0001) and erythrocyte membranes contained less sphingomyelin than controls (p<0.01) but more phosphatidylinositol plus phosphatidylserine (p<0.02). We conclude that, because our findings indicate an identifiable and potentially correctable abnormality, it is possible to envisage an inhibition of the progressive nature of MS, with the hope of a better prognosis for patients.

A reappraisal of the influence of blood rheology on glomerular filtration and its role in the pathogenesis of diabetic nephropathy

The basic assumptions concerning the mechanisms of normal glomerular filtration are discussed. Attention is drawn to blood rheologic changes that follow glomerular filtration and influence postglomerular blood flow adversely. It is proposed that the blood rheologic changes will increase the resistance to flow in the peritubular plexus commensurate with the dimensions of the capillaries and blood viscosity in accordance with the general principles of the Poiseuille formula, even though blood is a non-Newtonian fluid. For this reason, the conditions of flow in the plexus must be a determinant of intraglomerular capillary pressure. When blood rheology is abnormal, as in insulin-dependent diabetic patients, the abnormality will be amplified by glomerular filtration and it is suggested that the consequences will be manifest as problems of blood flow in the peritubular plexus. As the increase in postglomerular intravascular pressure needed to restore the rate of blood flow to normal necessitates dilation of the afferent arteriole and possibly more proximal vessels, such changes will result in an increase in intraglomerular pressure. The increase in pressure that increases filtration is therefore a direct consequence of abnormal blood rheology. This concept provides a basis for understanding the mechanism of diabetic proteinuria and for other proteinurias associated with abnormal blood rheology. A possible role for altered blood rheology in the pathogenesis of both focal and total glomerulosclerosis is discussed, and the potential benefits of agents that improve blood rheology are outlined.

Basal Processes on Duodenal Epithelial Cells of Man, Mouse and Rat

&NA; Localized ischaemia of duodenal mucosa Induced either by ligation or cautery of a small branch of the coeliac artery resulted in the loss of epithelial cells of duodenal villi in young mature inbred mice. Biopsies from normal human duodenum and mouse duodenum placed in non‐oxygenated physiological saline for 20 min showed a similar loss of epithelial cells. In all cases, scanning electron microscope (SEM) examination revealed that processes extended from the base of epithelial cells through the underlying basement membrane. When duodenal tissues were bathed in solutions of EDTA or sodium azide, basal processes were not seen by SEM. Transmission electron microscopy (TEM) of duodenal tissues from man, rat, and mouse revealed basal processes. Because all duodenal epithelial cells appear to have basal processes, it is proposed that they may play an important role in moving absorbed substances across the villous basement membrane barrier along an intracellular concentration gradient, and in thus facilitating absorption. There are no indications which would suggest that basal processes are the result of a pathological process, and the presence of similar basal processes in other tissues is noted.

A new periodontal membrane biology based upon thixotropic concepts

The biology of the periodontal membrane is not completely understood, and tissue changes associated with orthodontic tooth movement are assumed to be the result of a recoverable pathologic process. The response of this tissue to dynamic loading may, however, be explained by changes in viscosity of the collagenous matrix.

Blood Rheology and Myalgic Encephalomyelitis: A Pilot Study

&NA; The blood rheology of EDTA‐anticoagulated blood samples from blood donors and subjects considered to have myalgic encephalomyelitis was assessed by multiple shear rate viscometry and by multiple‐pressure filterability. Although average viscosities of the two groups were different, the differences did not reach statistical significance. In contrast, the data from multiple‐pressure filtration of whole blood showed significant differences between females at the lowest (2.5 cm of water) filtration pressure. It appears that the acute phase of the disorder is associated with changes in blood rheology which could impair microcirculatory blood flow. In contrast, the chronic state does not appear to be associated with rheological abnormalities.

A Mouse Model of Spontaneous Renal Hypertension. Blood Pressure, Heart Weight, Kidney Weight and Proteinuria Relationships in Nzb X Ouw F1 Hybrid Female Mice

&NA; Data concerning blood pressure, kidney weight, heart weight and proteinuria were obtained from different groups of BW mice. Relatively early in life, systolic blood pressures as measured by a tail‐cuff method, were above the upper limits of normal, continued to rise with increasing age and had peak average values coinciding with the peak death period and increased proteinuria. Any relationships which might exist among age, body weight and heart weight or kidney weight were sought by computerized polynomial multivariate analysis. It was found that, although there was only a slight effect with increasing body weight, both heart weight and kidney weight showed a steady increase with increasing age. These data support the proposal that the BW female mouse is a good model of spontaneous renal hypertension.

Experimental granulomatous inflammation: I. Gross and light microscopical observations in freund Adjuvant-Sensitized cavies following the injectionof killed tubercle bacilli

The tuberculous granuloma, induced by injection of microgram doses of killed mycobacteria into guinea pigs sensitized by injection of Freund adjuvant is immunologically mediated. Formation of the granuloma is preceded by development within 24 h of a lymphocyte-dominated mononuclear cell response typical of a delayed hypersensitivity (type IV immune response) reaction. About the sixth day, following a marked decrease in intensity of the cellular reaction, a nodule containing monocytes and macrophages develops at the injection site. With increasing numbers of monocytes and macrophages the nodule forms a non-caseating granuloma with giant cells but dominated by epithelioid cells and reaching a maximum size about 3 wk after injection. Thereafter the granuloma undergoes gradual demolition being replaced and surrounded by fibroblasts and collagen deposition. The very delayed nature of this immune response as well as its histological character appear clearly to separate it from classical cell-mediated and humoral immune responses. These facts justify the hypothesis of a third type of (usually protective) immune response characterized histologically by the development of an epithelioid cell granuloma and determined by the nature of the antigenic material and the reactivity of the host. The initial polymorphonuclear leucocyte reaction to injection of mycobacteria, being similar in sensitized and control animals, does not appear to be under immunological control.

Coronary Heart Disease: Animal Fat on Trial: A Rebuttal

the pediatric and adult age groups in this study are closely similar to those reported.’ Since the policy of our pediatricians is not to biopsy children who have steroid-sensitive nephrotic syndrome, the number of biopsies showing minimal change neprhotic syndrome in the pediatric age group probably represents only a small proportion of these cases. Judging from the results reported,’ I believe that a similar policy had been adopted by the pediatricians in the other two hospitals in Hong Kong, though this has not been stated in that paper. Subsets of our patients with IgA neprh~pathy~. ’ and lupus nephritis4 have been the subject of detailed studies. Sham et have shown a positive correlation of membranous glomerulonephritis with hepatitisB surface antigenemia and absent correlation with other glomerular diseases in our patients.

Pseudo-Lymphocyte Monocytes–The Memory Cells Responsible for the Development of Epithelioid Cell Granulomata. A New Hypothesis

&NA; This hypothesis proposes that, in individuals with an appropriate genetic background, monocyte memory cells are formed when histiocytes and macrophages undergo mitosis following first exposure to a granulomagenic agent and circulate as pseudolymphocytes in the lymphocyte null cell population. It is proposed that epithelioid cell granulomata develop from a clone of cells formed from monocyte memory cells on the second or subsequent exposure to the same granulomagenic agent. Epithelioid cell granuloma formation is therefore not dependent on T‐cell function, although the cellular nature of the granuloma appears to depend upon the nature of a concomitant but independent classical immune response. The implications of pseudolymphocyte memory cells on the development of granulomata of both exogenous and endogenous origin, and the relationships between lymphocytes and cells of the monocytic phagocyte series are discussed.