A mouse model of spontaneous renal hypertension. blood pressure, heart weight, kidney weight and proteinuria relationships in NZB x OUW F1 hybrid female mice.

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.

Basal processes on duodenal epithelial cells of man, mouse and rat.

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.

Blood rheology and myalgic encephalomyelitis: a pilot study.

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.

Experimental granulomatous inflammation: I. Gross and light microscopical observations in freund adjuvant-sensitized Cavies following the injection of 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.

Experimental granulomatous inflammation: II. Effect of injection of intact and disrupted killed tubercle bacilli into Freund adjuvant-sensitized Cavies.

The reaction of Freund adjuvant-immunized cavies to subsequent injection of Mycobacterium tuberculosis H37Ra is confirmed as an immunologically mediated phenomenon. Ultrasonic disruption of mycobacteria to be injected as "challenge" markedly increases the intensity of the consequent 24-48 h reaction and subsequent fibrosis in Freund adjuvant-sensitized cavies and has an apparently inhibiting effect on the extent of subsequent granuloma formation with marked reduction of the density of epithelioid cells. From this study, the 24-48 h reaction to injection of M. tuberculosis into sensitized animals appears clearly to be separable from subsequent granuloma formation depending upon the integrity or otherwise of the injected myocobacteria used as the challenge injection material.

Red cell and hemorheological changes in multiple sclerosis.

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 less than 0.001) but in MS males blood viscosity was higher only at shear rate of 1.0 s-1 (p less than 0.05). MS erythrocyte filtration rates were significantly lower than controls (p less than 0.001). Leucocyte counts in MS were greater than controls both in males (p less than 0.01) and females (p less than 0.001). MS erythrocyte morphology was greatly different from controls (p less than 0.0001) and erythrocyte membranes contained less sphingomyelin than controls (p less than 0.01) but more phosphatidylinositol plus phosphatidylserine (p less than 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.

Pseudo-lymphocyte monocytes--the memory cells responsible for the development of epitheloid cell granulomata. A new hypothesis.

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.

Blood rheology in IgA nephropathy.

Blood rheology was measured in 35 patients with IgA nephropathy (IgAN) and compared with age and sex-matched normal controls. Whole blood viscosity, red blood cell deformability and plasma viscosity were significantly altered in patients with IgAN. A correlation between determinants of blood rheology and clinical indices of IgAN was found. The factor(s) causing the rheological abnormalities was (were) not defined. Increased blood viscosity may cause intraglomerular pressure to rise and filtration to increase and may contribute to the development of mesangial lesions. It is proposed that abnormal blood rheology may be a causal factor in the pathogenesis of IgAN.

The etiopathogenesis of premenstrual syndrome as a consequence of altered blood rheology: a new hypothesis.

The multisystem symptoms of premenstrual syndrome (PMS), the variable nature of their occurrence and their relatively rapid disappearance with the onset of bleeding are highly suggestive of a systemic factor as the causal agent of the disorder. Reports of increased blood viscosity and enhanced red blood cell (RBC) hydration provide a basis for proposing that PMS is the consequence of an aberration of the change in blood viscosity which occurs in the third week of the normal menstrual cycle. The seriousness of the viscosity-impaired capillary blood flow will be greatest in organs and capillary beds with the smallest capillaries. Such an assumption implies that those women who suffer from PMS will be individuals whose capillaries are smaller in size than non-sufferers. The frequency of occurrence of fluid retention as a symptom suggests that the specific etiologic agent could be a reduction in RBC deformability as a consequence of impaired linoleic acid metabolism or high levels of noradrenaline or hypothyroidism or combinations of the three factors. If poorly deformable RBCs are involved then the use of agents such as evening primrose oil or fish oil to improve RBC deformability could ameliorate the symptoms of PMS. It is speculated that similar changes in RBC deformability should occur at other times of hormonal change. Health problems occurring during pregnancy, or after parturition, or after cessation of ovarian function might be caused by or exacerbated by reduced RBC deformability.

Smoking, abnormal haemorheology and the pathogenesis of coronary heart disease.

Presently held views on the cause of coronary heart disease (CHD) considers hypertension, hypercholesterolemia and cigarette smoking to be the major risk factors. Large scale intervention trials which sought to evaluate the contribution of the major risk factors have failed to provide clear-cut results. Another significant, but clinically unrecognised factor in CHD is abnormal haemorheology which is exacerbated by smoking, and is associated with decreased RBC filterability. It is proposed that coronary heart disease may result directly from haemorheologic causes but occurs more often when lesions in two or more coronary arteries are associated with increased blood viscosity and poorly deformable RBCs. Treatment should be aimed at reducing blood viscosity and RBC stiffening.

Increased blood viscosity as the pathogenic agent in minimal change nephrosis: a new hypothesis.

It is proposed that minimal change nephrosis (MCN) is the result of impaired glomerular blood flow to slightly increased blood viscosity or to an abnormality of an autoregulatory mechanism controlling glomerular perfusion pressure or to unusually small efferent arterioles, or to combinations of these factors. The functional response to any of such changes would be an increase in intraglomerular pressure. If the pressure exceeded a critical level albumin would be able to pass into Bowman's space after deforming the pressure-dependent thixotropic basement membrane. In response to the presence of albumin in Bowman's space, epithelial cell foot process retraction would be initiated. The concentration of albumin capable of stimulating this reversible change in unknown. If it can be shown that MCN is a consequence of increased blood viscosity, then drugs having direct effects on blood viscosity might offer alternatives to steroid treatment.

Spleen and liver weight changes in NZB mice with haemolytic anaemia.

Spleen and liver weights from 998 NZB mice were subjected to computerised multivariate analysis. 3-dimensional graphs relating predicted spleen and liver weights to age and bodyweight were prepared and the relationship of the fitted surface to the histology and pathological autoantibody is discussed. On the basis of spleen weight increase, red-cell destruction throughout the greater part of life seems to be mainly intrasplenic, while intrahepatic destruction does not become important until later, when it is probably a dominant feature in the terminal period of the disease. Only limited organ weight increases occur in breeding females, and it is suggested that pregnancy lessens the effect of the haemolytic disease, the 'protective' effect extending long after the cessation of breeding.

An NZB virus or NZB mice with viral infections?

Evidence for and against the possibility that the autoimmune disease of NZB mice has a viral aetiology is presented. It is considered that the case for a viral aetiology is unproven, although the possibility exists that virus may be present in incomplete form. Widely varying experimental results can be expected in experiments involving NZB mice until acceptable standards of mouse strain definition are laid down. Thus the comparison of results obtained from studies of NZB mice of diverse origin may invite misleading conclusions.

The origins of some hitherto undescribed inbred mouse strains.

The origins of 7 inbred mouse strains (OUBW, OUCW, OUGW, OUYW, OUBCr, OUF and OUW) are reported. 6 of these strains have been in existence for a number of years, and 4 of them have not been mentioned in the literature. 2 of the strains have been referred to in published work, but because of incorrect designation may have caused some confusion. The remaining strain (OUBCr), which has considerable research potential, has been developed from a mutation in an NZB subline.

Nondiscocytic erythrocytes in myalgic encephalomyelitis.

Blood samples from 102 volunteers who believed they suffered from myalgic encephalomyelitis were photographed in a scanning electron microscope at 500x. All identifiable cells were counted and classified on the basis of their shape. The frequency of each cell shape was expressed as a percentage of the total number of cells counted in the sample. The resulting data were compared with that from 52 healthy controls and 99 cases of multiple sclerosis which had been selected randomly by a computer from a panel of 229 cases in a concurrent study. Samples from subjects with myalgic encephalomyelitis had the lowest percentages of normal red cells and the highest incidence of cup forms. The results provide evidence that myalgic encephalomyelitis has an organic cause. Quantitative analysis of red cell shape may assist in the diagnosis of myalgic encephalomyelitis.

Factors influencing the cyclical symptoms relating to the menstrual cycle.

One hundred and thirty-four volunteers were asked to weigh themselves at the same time each day and to make a daily assessment of a small number of symptoms related to their menstrual cycles. Details were requested of the nature of any pain relieving drugs used and of the days on which they were taken. In addition they were asked to provide information about their age, smoking habits and regular medication. Information relating to 346 cycles was obtained in this way. Symptom scores based upon the frequency and severity of 6 common symptoms occurring between days 5 and 14 compared with the symptoms scores for the last 5 days of the cycle provided a basis for categorising cycles into 3 groups. Group A cycles had a virtual absence of symptoms. Group B cycles were characterised by symptoms which were clustered towards the end of the cycle while group C had symptoms throughout the cycle. Women with cyclical symptoms (group B) were not different in age, menstrual characteristics or smoking habits from women whose cycles fell into groups A and C but their premenstrual changes in bodyweight were greater. The use of pain relieving drugs was not related to symptoms grouping and was similar in all groups. It is concluded that the scores from 6 common symptoms relating to 2 or 3 successive cycles can identify women with cyclical symptoms which may be diagnostic of premenstrual syndrome and the method could be useful in selecting subjects for studies of the syndrome.

Red cell shape changes following trigger finger fatigue in subjects with chronic tiredness and healthy controls.

AIMS: To investigate the possibility of a correlation between the percentage of nondiscocytic erythrocytes and muscle fatiguability in subjects with the symptom of chronic tiredness. METHODS: Sixty nine volunteers suffering from persisting or intermittent tiredness and 72 healthy controls provided 3-drop samples of venous blood for red cell shape analysis before and after inducing fatigue in the trigger finger muscles by repeatedly pulling the trigger of an antique revolver. Elapsed time and the number of pulls were recorded. A work index was calculated from the number of trigger pulls divided by the time in seconds then multiplied by the number of trigger pulls. RESULTS: Subjects with tiredness had fewer discoid cells (males 62.5% vs 69.2%, p = 0.029; females 65.8% vs 71.8%, p = 0.002) than controls. They also had fewer trigger pulls (males 62.3 vs 84.0, p = 0.003; females 29.5 vs 36.8, p = 0.042) and lower "work indices" (males 75.6 vs 104.7, p = 0.001; females 26.1 vs 39.6, p = 0.001) than controls at the first trigger pulling. After 5 minutes rest the number of trigger pulls for males was fewer than the controls (56.0 vs 64.2) but the difference was not significant, but the female values (24.3 vs 33.2) were significantly different (p = 0.008). Work indices for both sexes were significantly different from controls (males p = 0.020, females p = 0.001). CONCLUSIONS: The association of increased nondiscocytes and impaired muscle function could indicate a cause and effect relationship. This would be in agreement with the physiological concept of fatigue as a consequence of inadequate oxygen delivery.

Changes in red cell shape in healthy elderly subjects taking low dose fish oil: pilot study.

OBJECTS: to investigate the effects of low dose fish oil on red cell shape and blood pressure in healthy elderly subjects during a 16 week treatment and an eight week follow-up. METHODS: red cell shape analysis by scanning electron microscopy with data analysis by repeated measures analysis of variance. RESULTS: in the preoil blood samples the percentage of cells with surface changes was much higher than that of younger healthy subjects (24.0% vs 14.4%). While taking fish oil the percentage of cells with surface changes declined to a minimum at the end of the eighth week, steadily increased during the next eight weeks then declined during the eight week follow up. Mean blood pressures were not altered by the fish oil although that of five subjects taking different types of antihypertensive drugs tended to show greater fall in blood pressure than those not on drugs. CONCLUSION: that dietary supplementation with low dose fish oil was associated with changes in red cell shape. The observed changes are currently inexplicable.

Chronic tiredness and idiopathic chronic fatigue--a connection?

Evidence is adduced to support the proposal that pathological fatigue is a consequence of impaired capillary blood flow resulting in inadequate oxygen delivery, which is in accordance with physiological concepts of fatigue. Case reports are presented.