Search

The authors have previously reported myalgic hyperalgesia as a useful localizing sign in "low-back sprain" patients with no physical findings. This paper describes some other subtle signs related to the phenomenon of denervation supersensitivity which is well known to physiologists and clinicians involved in peripheral nerve disease, yet its related signs have not been applied to low-back pain. Following denervation of some neurons, muscle and peripheral receptors become supersensitive to transmitter substances and to different forms of stimuli. Since the peripheral nerve is a mixed nerve, findings are multiphasic and include autonomic dysfunction, trophic changes, cutaneous and myalgic hyperalgesia, and increased muscle tone. One or more of these signs occurred in 30 patients with secondary low-back pain but less often in 30 patients with primary or mechanical low-back pain; their presence, though slight, in asymptomatic controls may identify those individuals with a vulnerable back.

Instrumental conditioning techniques were used to obtain objective evidence of differences in behavioral arousal between the spontaneously hypertensive rat (SHR) and the normotensive ancestral Wistar Kyoto (WKY) strain. Subjective emotionality ratings previously indicated that the genetically hypertensive rats were more active and aggressive than their normotensive cousins. In a lengthy series of operant conditioning sessions using a small number of adult female SHR and WKY rats, hyperarousal in the SHR was confirmed by their significantly higher response outputs on either response contingent or time contingent schedules of reinforcement. Conditioned emotionality tests during this series of experiments also suggested hyperarousal and aggressiveness in the SHR, since the fear-conditioned stimulus suppressed bar-pressing in the SHR much less than in the WKY. Further experiments with young prehypertensive SHR rats provided the same evidence of hyperresponsivity in the SHR compared to the WKY strain. Furthermore, these young SHR failed to develop hypertension by the end of the study (14 weeks of age), while their nonconditioned SHR cousins had become clearly hypertensive by the same age. This suggests that factors related to the conditioning methods modified the development of high blood pressure in this animal model of essential hypertension.

Biphasic electrical stimulation of the nucleus locus coeruleus (LC) produced frequency-related pressor responses associated with increased heart rate in normotensive rats (WKY) at both 50 and 100 microamperemeter. In contrast, spontaneously hypertensive rats (SHR) demonstrated small depressor responses at 50 microamperemeter and 50 Hz, but no consistent pressure or heart rate changes at either 50 or 100 muA stimulation. The LC pressor threshold current (current necessary to increase arterial pressure by greater than or equal 10 mm Hg) was higher in SHR than WKY (136 +/- 5 muA vs. 84 +/- 7 muA; P less than 0.001); and only the SHR LC demonstrated a depressor threshold (current necessary to reduce arterial pressure by greater than or equal to 10 mm Hg) (53 +/- 3 muA). These threshold current levels did not seem to change with acute alterations of arterial pressure produced by either bilateral carotid artery occlusion or caortid sinus stimulation. Therefore, these studies indicate altered levels of responsiveness of the SHR LC to stimulation but that the pressor function of the LC does not seem to be importantly involved in further elevation of abnormally high arterial pressure in the SHR.

Further progress in understanding T-cell interactions in autoimmune thyroid disease would be possible if T-cell lines and clones could be established. We have therefore examined peripheral blood lymphocyte proliferation in response to a variety of thyroid antigens in Graves' disease and Hashimoto's thyroiditis. A number of different culture conditions were used but in all cases the frequency and magnitude of positive responses were low, the maximum stimulation found for any individual culture with antigen being less than 4-fold above background proliferation. In addition we have examined the blastogenic response of Graves' lymphocytes from thyroid, cervical lymph node and thymus. Positive responses were again found but the stimulation produced by antigen was only 3-fold above background. These results are compatible with recent findings in experimental autoimmune thyroiditis and suggest either that very few antigen-specific T cells are involved in the autoimmune process or that antigen-specific cells exist which can suppress the proliferative response in vitro. It therefore seems unlikely that randomly collected peripheral blood T cells from patients with autoimmune thyroid disease can be sufficiently stimulated by thyroid autoantigens to establish lines or clones without additional manoeuvres such as fractionation into subsets.

Hepatic dearterialization was performed in 9 adult dogs. Evaluation of the technique was based on clinical and laboratory assessment of physiologic and pathologic changes related to the procedure. All dogs had hematologic and histopathologic evidence of transient hepatic ischemia that was reflected by minimal post-operative morbidity.

Two recent studies have reported that antithyroid drugs inhibit killer (K) and natural killer (NK) cell function in vitro, which could be relevant to the changes in these cell populations during treatment of Graves' disease. In contrast to these reports we have found no in vitro effect of pharmacologically relevant concentrations of methimazole (MMI) (100 mumol/l) on (i) NK cell function using K562 cells or MOLT-4 cells as targets, (ii) K cell function using antibody-dependent cytotoxicity assays with L929 cells or thyroid-antigen-coated chick red cells, or (iii) monocyte-dependent cytotoxin-mediated killing of L929 cells. Enhanced cytotoxicity was found with 1 mmol/l MMI in some of these assays but this was not consistent since it occurred only in certain individual cultures. Since we have shown previously that 100 mumol/l MMI inhibits oxygen radical generation, the present results add to the evidence that these radicals are not directly involved in cell-mediated cytotoxicity and do not support the concept that antithyroid drugs have a significant effect on antibody-dependent cell-mediated cytotoxicity in Graves' disease.

In patients with low-back injury the motor points of some muscles may be tender. Of fifty patients with low-back "strain", twenty-six had tender motor points and twenty-four did not, while forty-nine of fifty patients with radicular signs and symptoms suggesting disc involvement had tender motor points, and the one without such tender points had a hamstring contusion which limited straight leg raising. Of fifty controls with no back disability, only seven had mild tender points after strenuous activity, while forty-six of another fifty controls with occasional back discomfort had mild motor-point tenderness. In all instances the tender motor points were located in the myotomes corresponding to the probable segmental levels of spinal injury and of root involvement, when present. Patients with low-back strain and no tender motor points were disabled for an average of 6.9 weeks, while those with the same diagnosis but tender motor points were disabled for an average of 19.7 weeks, or almost as long as the patients with signs of radicular involvement, who were disabled for an average of 25.7 weeks. Tender motor points may therefore be of diagnostic and prognostic value, serving as sensitive localizers of radicular involvement and differentiating a simple mechanical low-back strain from one with neural involvement.

The effects of hyperthyroidism on experimental autoimmune thyroiditis were investigated in the rat. Rats were given T4 twice daily by sc injection in amounts sufficient to raise circulating hormone levels 10-fold 4 h after administration. Thyroiditis was induced by immunization with rat thyroglobulin (Tg) in complete Freund's adjuvant, and the severity of the disease was assessed by comparison with saline-treated controls. Thymic and splenic hypertrophy were found in T4-treated animals, whereas lymph node wt decreased. The levels of Tg antibodies did not differ between animals given saline and those given T4, but the expected sustained rise in control animals was not seen in those treated with T4; in addition, there was a significant decrease in the amount of Tg antibody produced by in vitro culture of lymph node lymphocytes from T4-treated rats. Continuous T4 administration lowered the number of T cells in the circulation, but the number of phenotypically identified helper cells remained the same. The most striking effects of T4 were to ameliorate the intensity of histologically defined thyroiditis and lower the response of lymph node T cells to the nonspecific mitogen, phytohemagglutinin. These results show that excessive T4 does not, as previously suggested, enhance the immune response in autoimmune thyroid disease: on the contrary, suppression is found with the dose and model we have used. In view of the magnitude of this effect, it is now important to identify the site of T4 action and investigate how this effect contributes to the autoimmune response in Graves' disease.

The spontaneously hypertensive rat (SHR) is an excellent model of essential hypertensive disease. Hyperreactivity has been postulated as a contributing factor in the development of high blood pressure in the SHR and in man. In the maturing organism recurring hypertensive stesss responses may promote permanent vascular changes and result in a fixed hypertension. Simple behavioral activity and emotionality rating scales were used to compare a large number of SHR with equally large groups of closely-related and distantly-related normotensive rats. As predicted, the SHR were clearly more active and emotional than their ancestral Wistar Kyoto (WKY) strain. However, the distantly-related normotensive Wistars did not differ from the SHR in either activity or emotionality. These results indicate that behavior and hypertension are not necessarily related in the rat. Nonetheless, the behavioral differences between the SHR and their closest genetic match, the WKY, suggest that arousal and blood pressure levels may be causally linked in this case of naturally occurring hypertension.

The deamination of methylamine (MA) by amine oxidase enzymes has been studied and compared with that of benzylamine (BZ) in homogenates of rat aorta and human umbilical artery by means of a radiochemical assay to estimate the radiolabelled deaminated metabolites produced, and also a spectrophotometric assay to measure H2O2 formation during the metabolism of these substrates. The effects of various inhibitors used in these assays suggest that a semicarbazide-sensitive amine oxidase (SSAO) is predominantly if not wholly responsible for the deamination of both MA and BZ in these tissues. MA was found to have a relatively higher apparent Km (102 microM in aorta; 779 microM in umbilical artery) than BZ (6.8 microM in aorta; 207 microM in umbilical artery) for metabolism by SSAO in these tissues. However, these large differences between species in the apparent Km values for each amine indicate that the biochemical properties of SSAO in human and rat vasculature are not identical. SSAO in human umbilical artery was particularly active towards MA, with a Vmax which was approximately 70% greater than that for BZ as substrate, whereas in rat aorta the Vmax for MA was around 60% of that for BZ. MA is known to occur endogenously in man and other species, and the possibility that it may be a physiological substrate in vivo for SSAO is discussed.

We have used an automatic cell harvester and micro culture techniques to examine the accumulation of [35S]methimazole by monocytes, macrophages and lymphocytes. Significant temperature-dependent accumulation of the drug was found in resting monocytes and macrophages; this was increased up to 4-fold by phagocytosis. Lymphocytes accumulated little or no drug and myeloma and leukaemic cell lines accumulated none. These results show that two interrelated cells with endogenous peroxidatic activity take up the antithyroid drug methimazole providing further support for the concept that immunosuppression by this drug in Graves' disease is mediated via an action on antigen-presenting cells.