R.A. Brown

TREATMENT OF ACUTE PARACETAMOL POISONING

Abstract Five cases of acute self-poisoning with paracetamol, one of them fatal, are described. The clinical effects included electrocardiographic evidence of myocardial damage, hypoalbuminaemia, a bleeding state, and liver-cell damage; necropsy findings included massive liver necrosis, renal distal tubular necrosis, and cerebral œdema. The treatment favoured is immediate gastric lavage, forced diuresis, intravenous hydrocortisone, and an antihistamine. Ordinary dialysis is of no value, although the addition of plasma to the dialysate might be beneficial.

Histometric study of the localisation of lymphocyte subsets and accessory cells in human Mantoux reactions.

Intradermal injection of purified protein derivative produced typical delayed type hypersensitivity reactions in five healthy human subjects. The major subpopulations of lymphocytes and certain accessory cells were located in frozen sections of biopsies of the lesions with monoclonal antibodies and immunohistochemical staining. The densities (expressed as number/unit area for comparison) of the different types of cells were counted at various microanatomical locations in the tissue. The inflammatory cells were concentrated in narrow zones, initially (24 h) only surrounding small blood vessels but later (48-96 h) also around sweat ducts. Lymphocytes were the predominant cell type at these sites with T4 and T8 cells randomly intermixed at a ratio similar to that in the mononuclear cell fraction of the peripheral blood samples removed at the time of biopsy. There was also a scanty diffuse infiltrate in the intervening dermis, but here the T4:T8 ratio was significantly lower than that in the peripheral blood or perivascular cuffs. There was considerable intersubject variation in the relative preponderance of T8 cells in the diffuse infiltrate. The results suggest that there is no subset selection in the initial emigration of lymphocytes through vascular endothelium in the delayed hypersensitivity reaction, but that the subsets behave differently during the subsequent migration through the tissues. It remains to be determined whether the extent to which T8 cells migrate more rapidly than T4 cells through the tissues may influence the reaction at the site of entry of organisms or antigens into the body by altering the balance of the immunoregulatory lymphocyte subsets. This may underlie some of the differences in susceptibility to infection between subjects and determine the type of granuloma that develops in a particular patient.

Morphometric analysis of breast carcinoma: association with survival.

In a retrospective study of 126 cases of infiltrating ductal adenocarcinoma of the breast the percentage area of sections of each neoplasm occupied by malignant cells was assessed by morphometry. The duration of postoperative survival was related to the area occupied by tumour cells within a neoplasm; the greater the tumour cell area to stroma the more prolonged the survival. This variable seemed to be independent of histological grade and was of greater prognostic importance than the diameter of the neoplasm. Furthermore, combination of percentage of tumour area with histological grade provided greater information on the survival characteristics of these patients. Extensive tumour necrosis was a particularly poor prognostic feature.

Effect of histamine and prostaglandin E2 on the microcirculation in the skin

The response of the, cutaneous microvasculature to two vasoactive mediators, histamine and prostaglandin E2, was measured by laser Doppler velocimetry. Four concentrations of histamine (1.01 to 65.1×10−5M, in fourfold dilutions) were injected intradermally into the forearms of six healthy subjects: Prostaglandin E2 (1.77 to 114.0×10−8M, also in fourfold dilutions) was injected several weeks later. The blood flow at the injection site was measured by laser Doppler velocimetry at five minute intervals until the response resolved. Both mediators produced hyperaemia with markedly accelerated cutaneous blood flow. Analysis of the dose response data showed that, for a given mediator, the differences in responses between subjects were not substantial and, in particular, that the kinetics of the decay of hyperaemia did not vary significantly between subjects. The response to histamine differed from that to Prostaglandin E2 in terms of time to maximum response, duration of maximum response and coefficient of decay.

Relationship between radiological classification and the serological and haematological features of untreated pulmonary tuberculosis in Indonesia

Immunological and metabolic responses were studied in 110 patients with newly diagnosed pulmonary tuberculosis and 32 healthy controls from similar socioeconomic backgrounds. The severity of lung involvement was assessed radiologically, but this was not related to the current features of cell mediated immunity or to those of many aspects of the serological response to Mycobacterium tuberculosis. However, the patients with more extensive pulmonary tuberculosis showed higher titres of IgG2 antibody to whole killed M. tuberculosis and to the ML34 epitope shared by many species of mycobacteria. The patients with more extensive pulmonary tuberculosis showed a more marked metabolic response to infection as manifested by changes in serum levels of acute phase reactant proteins. Accordingly, the metabolic responses are considered to be more likely to prove of value in clinical monitoring of patients for severity of infection, or of reactivation of infection with M. tuberculosis, than immunological responses.

Mechanisms of phytohaemagglutinin (PHA) stimulation of normal human lymphocytes: ‘trigger’, ‘push’ or both?

Abstract. The growth in volume of human peripheral blood lymphocytes after stimulation with various concentrations of PHA was measured with an electronic particle counter. The percentage of growing cells and averaged values describing their growth rates during the elapsed period of culture were estimated by fitting to the observed data the volume distributions derived from a mathematical model. With sub‐optimal doses, the percentage of cells stimulated, and their incremental growth rate, increased with increasing dose of PHA, but the time‐course of recruitment into the G1‐phase was similar with all PHA concentrations studied. The results provide strong support for the ‘trigger’ hypothesis that there is a distribution of stimulation thresholds within the lymphocyte population: consequently, increasing mitogen concentration will be expected to result in increased numbers of responding cells within the suboptimal concentration range.

Skin test responsiveness to four new tuberculins in patients with chronic obstructive airways disease receiving short term high doses of, or long term maintenance treatment with, prednisolone: clinical appearances and histometric studies.

The response to skin testing with tuberculins extracted from various species of mycobacteria was studied in 49 patients from Dundee with chronic obstructive airways disease. Seventeen had never been treated with steroids (group 1), 17 were receiving short term high doses of prednisolone (group 2) and did not have impaired Synacthen tests; 15 were receiving long term maintenance treatment and did have impaired Synacthen tests (group 3). Erythematous and indurated reactions were seen in a few patients, more commonly to antigens from Mycobacterium tuberculosis than to the other species: neither of the latter treatment groups showed appreciable reduction in reactivity compared with that of the group 1 patients. The number and microanatomical distribution of the T4 and T8 lymphocytes and the M3 bearing monocytes and macrophages was studied immunocytochemically in cryostat sections of biopsy specimens from the antigen injection sites. The density of these cells was significantly less in clinically negative reactions than in those with erythema or induration, but was unrelated to the presence or absence of a history of treatment with prednisolone. The T4:T8 ratio in the section as a whole was similar to that of the peripheral blood, but T8 cells were relatively more common in the perivascular and periappendicular foci, and T4 lymphocytes were predominant in the diffuse component of the infiltrate. I12 receptor bearing lymphocytes were uncommon: such cells were least common in the clinically negative reactions, but the number and distribution were apparently unrelated to the presence or absence of prednisolone treatment. It was concluded that currently accepted regimens of treatment with prednisolone did not reduce the effector arm of type IV (delayed type hypersensitivity) responses and so are unlikely to compromise this aspect of protective immunity.

The sensitivity of peripheral blood lymphocytes to growth inhibition by hydrocortisone is not determined by their OKT4:OKT8 ratio

Normal adult human subjects show considerable variation in sensitivity to depression of the activation phase of mitogen-induced lymphocyte growth by the natural glucocorticoid, hydrocortisone. In a study of 21 subjects, the slope of the log-dose response to hydrocortisone was unrelated to the relative numbers of cells in the two major T-cell subpopulations stained by the OKT4 and OKT8 monoclonal antibodies. It is concluded that the extent of the glucocorticoid-induced suppression of early mitogen-stimulated lymphocyte growth is probably not determined by relative numbers of the various immunoregulatory lymphocytes.

Suppression of growth of PHA-stimulated human lymphocytes by a novel steroid (RU 28 362) lacking the 21-OH group

RU 28 362 is a novel synthetic steroid (lacking the 21-OH group) which reacts exclusively with the glucocorticoid receptor. It is therefore chemically different from the other natural and synthetic glucocorticoids in common use which also bind to a lesser extent to receptors for other classes of steroids. Aspects of the immunosuppressive effect of RU 28 362 were studied by comparing its suppressive effects on PHA-stimulated growth of human lymphocytes with those of hydrocortisone, betamethasone and the inactive analogue, 21-deoxyhydrocortisone. RU 28 362 was more potent than either hydrocortisone or betamethasone, but all three glucocorticoids had a parallel dose-response curve in suppression of the increase in cell volume that occurs with activation during the first day in culture. In studies on the time of appearance and density of IL-2 receptors during the first 3 days in culture, RU 28 362 was also somewhat more inhibitory and had a steeper dose-response curve than hydrocortisone or betamethasone. RU 28 362 was much more inhibitory and had a steeper dose-response curve than either hydrocortisone or betamethasone in inhibiting [3H]-TdR incorporation by 3-day PHA stimulated cultures. 21-deoxyhydrocortisone did not inhibit any aspect of PHA-stimulated lymphocyte growth.