Delineation Between T- and B-Suppressive Molecules From Human Seminal Plasma: I. Partial Characterization of a 180-kD Protein Inhibiting the B Response to T-Independent Antigens

ABSTRACT: The immunosuppressive activity of fractionated human seminal plasma (SP) was investigated both in vitro (on human lymphocytes) and in vivo with Balb/ c mice. SP fractionation by dialysis allowed delineation of the major suppressor factors according to their respective sizes—small (< 12kD) or large (> 12kD). In vitro, large molecules were found to suppress the B-cell proliferative response induced by the Nocardia mitogen, while small molecules suppressed the T-cell proliferation induced by phytohemagglutinin. In vivo, immunosuppression was obtained almost exclusively on T-independent responses after preliminary treatments either with unfractionated SP or with large SP molecules. Both type 1 and type 2 T-independent responses were suppressed, as evidenced by plaque-forming cells and antibody assays. In contrast, no immunosuppression was found in vivo after treatment by small SP molecules. Purification of the B-cell suppressor by gel filtration and high-performance liquid chromatography, as well as by preparative isofocusing, indicated that its molecular weight was 180 kD and its isoelectric charge was between pH 5 and 6. This factor is a protein, as evidenced by pronase digestion. A possible role for this molecule in the protection of sperm against the female immune system is discussed.     

EFFECTS OF PROTRACTED HYPOTHYROIDISM ON PITUITARY FUNCTION AND STRUCTURE IN ENDEMIC CRETINISM

Pituitary function and structure were assessed in 69 endemic cretins from western China. In hypothyroid cretins (TSH greater than 10 mIU/l), CT imaging of the pituitary revealed adenoma in five of 20 (25%) and partially empty sella (PES) in a further eight of 20 (40%). The majority of tumours were microadenomas and showed a relation with higher levels of serum TSH but not with duration of hypothyroidism. Dynamic pituitary testing with TRH and GnRH in four patients with adenoma on CT gave a flat TSH response but significant rises in serum PRL, GH, LH and FSH concentrations. Hyperprolactinaemia (greater than 350 mIU/l) was present in hypothyroid cretins only (13 of 26; 50%) and serum PRL showed a curvilinear relation with serum TSH levels (r = 0.7, P less than 0.0001). Hypogonadism was seen in approximately half the cretins with high PRL levels. Our data suggest that severe protracted thyroid hormone deficiency may result in thyrotrophin adenomas of the pituitary gland. Disturbances of growth, puberty, and sexual function in endemic cretins are explained by the secondary effects of thyroid hormone deficiency on pituitary function.     

Hepatic Sarcoidosis with Portal Hypertension. A Report of Seven Cases with a Review of the Literature

We have reviewed the clinical, histological and hemodynamicfeatures of sarcoidosis complicated by portal hypertension inseven patients and in 40 previously reported cases. Young blackpatients of either sex and white females over 40 years wereselectively affected. In 12 of these 47 patients, portal hypertensionappeared to be a consequence of cirrhosis due to longstandingintrahepatric cholestasis; in white patients, this conditionwas clinically, histologically, and serologically indistinguishablefrom primary biliary cirrhosis. In most of the other patients,portal hypertension was the predominant and often the presentingsymptom of hepatic sarcoidosis; in these patients portal hypertensionwas due to a presinusoidal block probably determined by portalgranulomas, with or without superimposed sinusoidal block determinedby fibrosis. Corticosteroids did not prevent the developmentof portal hypertension.     

Interatrial Conduction in Patients Undergoing AV Stimulation: Effects of Increasing Right Atrial Stimulation Rate

To evaluate the frequency of spontaneous or rate dependent interatrial blocks, the interatrial conduction time (IACT) was studied on 100 consecutive patients (mean age 78.3 ±7.8 years) during a transvenous dual chamber pacemaker implant. The spontaneous interatrial conduction time (SIACT) was measured from the intrinsic deflection (ID) of the unipolar right atrial signal to the ID of the left atrial signal recorded in a bipoiar way by an esophageal lead. The paced interatrial conduction time (PIACT) was measured from the stimulus artifact to the left atrial ID, when the atrium was paced at a slightly higher rate than the spontaneous rate and during incremental atrial pacing. From these measurements, the maximum increase ofPIACT (MIPIACT) was deduced. In this elderly population, the PIACT was similar (117 ± 26.9 msec) to the data in the literature. However, there were large interindividual variations that were also found in SIACT. We found a close correlation between SIACT and PIACT (P < 0.0001). PIACT was on average 50 msec longer than SIACT. SIACT increased with age (P < 0.03). The MIPIACT was 15.3 ± 15.2 msec. In the majority of patients, the MIPIACT was > 10 msec, and even reached 90 msec in one patient. MIPIACT was longer in patients with a PIACT exceeding 110 msec (P < 0.004). Based on IACT alone, the AV interval must be lengthened on average by 50 msec when changing from atrial tracking-ventricular pacing to atrial pacing-ventricular pacing, but large individual differences must be kept in mind. Elderly people should probably have a longer AV delay.     

Application of histamine or serotonin to the hypoglossal nucleus increases genioglossus muscle activity across the wake–sleep cycle

The decrease in genioglossus (GG) muscle activity during sleep, especially rapid eye movement (REM) or paradoxical sleep, can lead to airway occlusion and obstructive sleep apnoea (OSA). The hypoglossal nucleus innervating the GG muscle is under the control of serotonergic, noradrenergic and histaminergic neurons that cease firing during paradoxical sleep. The objectives of this study were to determine the effect on GG muscle activity during different wake–sleep states of the microdialysis application of serotonin, histamine (HA) or noradrenaline (NE) to the hypoglossal nucleus in freely moving cats. Six adult cats were implanted with electroencephalogram, electro-oculogram and neck electromyogram electrodes to record wake–sleep states and with GG muscle and diaphragm electrodes to record respiratory muscle activity. Microdialysis probes were inserted into the hypoglossal nucleus for monoamine application. Changes in GG muscle activity were assessed by power spectrum analysis. In the baseline conditions, tonic GG muscle activity decreased progressively and significantly from wakefulness to slow-wave sleep and even further during slow-wave sleep with ponto-geniculo-occipital waves and paradoxical sleep. Application of serotonin or HA significantly increased GG muscle activity during the wake–sleep states when compared with controls. By contrast, NE had no excitatory effect. Our results indicate that both serotonin and HA have a potent excitatory action on GG muscle activity, suggesting multiple aminergic control of upper airway muscle activity during the wake–sleep cycle. These data might help in the development of pharmacological approaches for the treatment of OSA.     

Haemodynamic effects of molsidomine and propranolol in patients with cirrhosis

Propranolol and molsidomine have both been shown to decrease the hepatic venous pressure gradient in patients with cirrhosis. The present study aimed at assessing the effects of the combination of these two drugs on splanchnic and systemic haemodynamics of cirrhotic patients. Fifteen patients with biopsy proven alcoholic cirrhosis had haemodynamic measurements under basal conditions, 60  min after oral administration of 4  mg molsidomine then 15  min after intravenous administration of 15  mg propranolol. As compared with baseline values, molsidomine was found to decrease mean arterial pressure (−7.9%, P <0.01), cardiac output (−7.3%, P <0.01), pulmonary wedged pressure (−45.8%, P <0.05) and hepatic venous pressure gradient (−11.7%, P <0.01). Propranolol decreased heart rate (−21%, P <0.01), further decreased cardiac output (−20.6%, P <0.01) and hepatic venous pressure gradient (−10.5%, P <0.01). As a whole, molsidomine plus propranolol decreased mean arterial pressure (−8%, P <0.01), heart rate (−19%, P <0.01), cardiac output (−26.5%, P <0.01) and hepatic venous pressure gradient (−21%, P <0.01). Pulmonary wedged pressure, liver blood flow and hepatic intrinsic clearance of indocyanine green were not significantly changed by the association of molsidomine and propranolol. We conclude that in patients with cirrhosis, molsidomine and propranolol potentiate their effects on hepatic venous pressure gradient. Such a combination could therefore prove useful in the treatment of portal hypertension.     

Phenylethylamide derivatives of the C-terminal tetrapeptide of gastrin

Peptide analogues of the C-terminal tetrapeptide of gastrin in which the phenyl-alanine had been replaced were synthesized and their biological activity on acid secretion evaluated. Compounds Boc-Trp-Leu-Asp phenylethylamide 6, Boc-β-Ala-Trp-Leu-Asp phenylethylamide 9, Boc-Trp-Leu-Asp p-fluorophenylethylamide 19, Boc-Trp-ø(CH₂NH)-Leu-Asp phenylethylamide 23, Boc-Trp-Leu-Asp 2,2-diphenylethylamide 15, and Boc-D Trp-Leu-Asp 2,2-diphenylethylamide 21, in which the phenylalanine had been replaced by phenylethylamine, p-fluorophenylethylamine or 2,2-diphenylethylamine were synthesized. None of these derivatives showed activity on acid secretion in the anaesthetized rat at doses as high as 5 mg/kg. However, they were potent inhibitors of gastrin-induced acid secretion, with ED₅₀ varying from 0.1 to 0.6 mg/kg.     

Ultrastructural Aspects of Crystal-Like Inclusions in a Case of IgA Plasma Cell Proliferation

A case of apparently benign plasma cell proliferation is described. Needle-like paracrystalline inclusions were observed in numerous plasma cells outside the cisternae of the rough endoplasmic reticulum. They had a dense protein core surrounded by a layer of carbohydrate. They were found only in plasma cells secreting IgA-kappa immunoglobulin, but did not react with labelled specific antisera. A small amount of paraprotein IgA-kappa was found in the serum but no Bence-Jones protein could be detected in the urine. These observations suggest that these plasma cells synthesize normal IgA immunoglobulin and accumulate abnormal protein in the form of paracrystalline inclusions.