Activated T-cells and macrophages in the cerebrospinal fluid and the spinal meningeal exudate in chronic relapsing experimental allergic encephalomyelitis

An analysis has been made of the cell types which mark with monoclonal antibodies against T cells, macrophages and the IL-2 receptor (anti-Tac) in the blood, cerebrospinal fluid (CSF) and spinal meningeal exudates taken from guinea pigs in the relapse and remission stages of chronic relapsing experimental allergic encephalomyelitis (CR-EAE). Whilst the T-cell and macrophage content of blood remained unchanged throughout the course of CR-EAE, T cells accounted for the majority of the CSF pleocytosis associated with relapsing disease but both T cells and macrophages populated the meningeal exudate in substantial numbers. Activated T cells (Tac+) rose in number in blood only after the onset of relapse but formed a far higher proportion of the CSF pleocytosis or meningeal exudate than in paired blood samples. Meningeal exudate cells from Freund's adjuvant-inoculated, but not uninoculated animals, also showed an increase in Tac+ cell levels. In addition, the meningeal exudate contained a substantial number of cells which did not label with anti-T or anti-macrophage antibodies and which did not vary in absolute numbers throughout the course of disease.     

Menstrual disturbance and hypersecretion of progesterone in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

OBJECTIVE While menstrual disturbance is often quoted as a feature of congenital adrenal hyperplasia (CAH), little is known about the mechanism of this symptom. We set out to determine the relationship between menstrual pattern and biochemical characteristics of women with CAH due to 21-hydroxylase deficiency. PATIENTS AND DESIGN All 21 female patients with classic CAH attending the adult endocrinology clinics at The Middlesex Hospital were reviewed. Their ages at menarche and menstrual pattern were recorded and blood samples were taken in the follicular phase of the menstrual cycle when on their usual maintenance therapy. MEASUREMENTS Measurements Of serum LH, FSH, progesterone, 17α-hydroxyprogesterone, testosterone, androstenedione and plasma renin activity were recorded. Urinary steroid profiles were obtained by gas chromatography and mass spectrometry. Molecular genetic analysis of the 21-hydroxylase gene was performed on leucocyte DNA. RESULTS In the 18 patients who had spontaneous menarche the degree of menstrual disturbance and progesterone excess was related to the effectiveness of adrenal suppressive therapy. Three out of 21 patients, however, failed to experience menarche on standard medical therapy. These patients with primary amenorrhoea were characterized by reduced endometrial thickening, by non-suppressible serum progesterone concentrations despite suppression of 17α-hydroxyprogesterone levels and by the presence of progesterone metabolites in urinary steroid profiles. Molecular genetic analysis did not differentiate between patients with raised progesterone concentrations and those without. CONCLUSION A subgroup of women with congenital adrenal hyperplasia have the triad of non-suppressible serum progesterone of adrenal origin, primary amenorrhoea and Infertility due to failure of endometrial thickening. The characteristic urinary steroid profile best distinguishes this subgroup of women from others with Congenital adrenal hyperplasia and menstrual disturbance due to inadequate adrenal suppression.     

Genetics: The tyrosine kinase domain of the insulin receptor gene is normal in women with hyperinsulinaemia and polycystic ovary syndrome

The cause of hyperinsulinaemia in polycystic ovary syndrome(PCOS) is unknown, but two recent reports have implicated mutationsof the tyrosine kinase domain of the insulin receptor gene intwo patients. We have undertaken amplification of the insulinreceptor gene using the polymerase chain reaction and single-strandedconformational polymorphism analysis in 22 hyperinsulinaemicpatients with PCOS. Of these patients, 50% were polymorphicin exon 17 of the insulin receptor gene, but none of the alterationsin sequence has been associated with insulin resistance. Thegenomic sequences in exons 18-21 were normal in all patients.We conclude that mutations involving the tyrosine kinase domainof the insulin receptor gene are a rare cause of insulin resistancein the PCOS.     

Chronic relapsing experimental allergic encephalomyelitis: Inhibition of lymphocyte mitogenesis by disease-related serum factors

Peripheral blood mononuclear cells (PBMC) from strain 13 guinea pigs at various stages of chronic relapsing experimental allergic encephalomyelitis (CREAE) showed significantly reduced reactivity to the polyclonal T cell mitogens, phytohaemagglutinin and concanavalin A. Serum taken at the same time revealed an increase in inhibitors of lymphocyte mitogenesis. The factors identified appeared to inhibit the initial stages of lymphocyte proliferation: they were not cytotoxic for lymphocytes nor were they complement-dependent.     

Chronic relapsing experimental allergic encephalomyelitis: cerebrospinal fluid cytology and a comparison with meningeal and spinal cord pathology

Cerebrospinal fluid (CSF) was taken from strain 13 guinea pigs in various stages of chronic relapsing experimental allergic encephalomyelitis, the spinal cords removed for histological examination and meningeal stretch preparations made. CSF cells were counted and characterized by morphological studies, anti-IgG and alpha-naphthyl acetate esterase (ANAE) staining. Approximately 65% of normal CSF lymphocytes were ANAE positive and 10% stained with anti-IgG. No polymorphonuclear leucocytes were seen. Five out of eight relapsing animals had raised cell counts (up to 152/μl) as did three animals in remission. There was no change in the proportion of various types of CSF cells where increased numbers were recorded. Infiltrating cells in spinal cord sections and meningeal preparations were similarly characterized and the results compared with CSF cell findings. Animals in relapse which had, in addition, macroscopically visible cord plaques showed the most severe infiltrative changes in spinal cord tissue and in the meninges. There were differences between the proportion of various types of CSF cells and meningeal infiltrate cells on ANAE staining reaction. In general there were far more lymphocyte-type cells in the CSF but more monocyte-type cells in meningeal infiltrates.     

The effect of penicillamine on vitamin B6 function in man

The erythrocyte alanine aminotransferase (Ala-AT) activity, measured in vitro, of rheumatoid arthritis patients under treatment with penicillamine was markedly stimulated by the addition of excess pyridoxal-5′-phosphate (PLP). This indicates that penicillamine can produce a deficiency of vitamin B₆, possibly by reacting chemically with the coenzyme PLP or by inhibiting PLP synthesis. The deficiency, though demonstrable by biochemical tests, was not accompanied by clinical signs of vitamin B₆ lack, and it would not justify the administration of a pyridoxine supplement to penicillamine-treated patients except in those of low nutritional status. In addition to its effect on the coenzyme PLP penicillamine also decreased the concentration of the erythrocyte Ala-AT apoenzyme.