Maturation of bone marrow lymphocytes. I. Quantitative rosetting methods of detecting Fc and complement receptors and surface immunoglobulin.

Cytocentrifuge rosetting procedures were developed for use with bone marrow cells to quantitate Fc and complement receptors (FcR, CR) and surface IgM on marrow small lymphocytes. Cell suspensions from 9–11-week-old C3H mice were mixed (1 : 30) with washed sheep red blood cells (SRBC) coated with either mouse anti-SRBC serum (for FcR), rabbit anti-SRBC stroma serum plus mouse serum (for CR) or goat anti-mouse IgM serum (for IgM). Centrifuged cell pellets were incubated for 30 min at either 37°C (FcR, CR) or 0°C (IgM) and examined in stained cytocentrifuge preparations. Small lymphocytes were defined as non-DNA-synthesizing lymphocytes smaller than 10 μm nuclear diameter. Many of these cells in the bone marrow formed specific rosettes for FcR (25%), CR (18%) and surface IgM (39%). The incidence of FcR- and CR-bearing small lymphocytes relative to IgM-bearing small lymphocytes was lower in the marrow than in the blood, spleen and lymph nodes. Rosette size ranged from 4 to > 20 SRBC per lymphocyte but tended to be smaller in the marrow and blood than in the spleen and lymph nodes. The methods and results are discussed as a basis for studies of B lymphocyte maturation and lymphocyte heterogeneity in the bone marrow.     

Airway mucosal permeability in the Ascaris suum-sensitive rhesus monkey.

The permeability of the airways to technetium 99m-labeled albumin was measured in Ascaris suum-sensitive rhesus monkeys. All 8 animals were skin-sensitive to Ascaris suum (AA) antigen, 4 being respiratory responders (R) and 4 nonresponders (NR) to aerosolized antigen. In the absence of antigen challenge there were no differences in the accumulation in the blood of radioactive material from the tracheobranchial tree between the R and NR animals. After a five-minute challenge with aerosolized AA, there was a threefold increase in the rate of accumulation of radioactive material in the blood over control for the R group with no effect noted in the NR group. Gel filtration data indicated that the radioactivity in the blood most likely represented low molecular weight albumin fragments, resulting from spontaneous degradation of Tc-albumin, that crossed the mucosa and partially bound to circulating albumin. It is concluded that hyperpermeability of the airway mucosa probably is not a factor that contributes to the selective responsiveness of the R group to aerosolized antigen, and that airway permeability is increased consequent to the allergic reaction mediating acute bronchoconstriction.     

Elastosis in benign and malignant breast disease

Elastosis, the presence of clumps of elastic fibers, is known to occur frequently in association with breast carcinoma. To test the hypothesis that the degree of elastosis increases progressively in fibrocystic disease with the severity of epitheliosis (epithelial hyperplasia, papillomatosis; widely believed to be the only premalignant component of fibrocystic disease) and increases further with intraductal and infiltrating duct carcinoma, breast tissue stained for elastic fibers from 84 women in the fifth decade of life was studied. Fourteen cases were evaluated in each of six disease categories: fibrocystic disease without epitheliosis; fibrocystic disease with epitheliosis, graded subjectively as mild, moderate, or severe (based on the degree of epithelial hyperplasia); intraductal carcinoma; and infiltrating duct carcinoma of the breast. Periductal elastosis and stromal elastosis were graded on a scale of 0 to 4 (absent to massive). The grades of both periductal elastosis and stromal elastosis were compared with those for the six disease categories ranked by increasingly advanced disease. The results indicate that the grades of periductal elastosis (Spearman rank correlation coefficient [R] = 0.54; P less than 0.001) and stromal elastosis (R = 0.75; P less than 0.001) increase progressively with the severity of breast disease.     

Innervation of forebrain regions by medullary noradrenaline neurons, a biochemical study in cats with central tegmental tract lesions

In order to determine quantitatively the relative contribution of medullary noradrenaline neurons to the noradrenaline terminal innervation of forebrain regions in the cat, bilateral lesions of the central tegmental tract were performed at the level of the caudal pons in adult cats. The results indicate that the medullary neurons provide approximately 75% of the total noradrenaline innervation to the hypothalamus, only 20–25% of that of the thalamus and midbrain and no measurable contribution to the noradrenaline innervation of the cerebral cortex or hippocampus. These results are comparable to previous ones of bilateral locus coeruleus lesions in the cat which showed that the locus coeruleus neurons provide approx. 15% of the total noradrenaline innervation to the hypothalamus, 60% of that to the thalamus and midbrain and the entire innervation to the cerebral cortex and hippocampus.     

Localization of antigen in experimental bronchoconstriction in guinea pigs

These experiments were done to examine the position of the antigen in the tracheobronchial mucosa in a situation in which the antigen caused allergic bronchoconstriction. Guinea pigs were sensitized to the tracer protein, horseradish peroxidase (M.W. 40,000), and these animals were challenged with an aerosol of this antigen while lung mechanics were measured. We found that airways resistance rose significantly in sensitized animals (p < 0.02) while nonsensitized animals exposed to the same aerosol showed no change. The animals were sacrificed and the antigen was localized with an electron microscopic histochemical technique. Studies were also done with isolated, perfused lungs from sensitised animals challenged intravenously with the antigen. In both the in vivo studies, in which bronchoconstriction was demonstrated, and the in vitro studies, in which mediator release was demonstrated, the antigen had a superficial distribution and was not seen to penetrate the epithelial or endothelial layers. These findings suggest that the antigen-antibody reaction may occur at these sites.     

Effect of remote aortic injury and thrombosis on cholesterol atherosclerosis

Recent tissue culture studies indicate that platelet factors enhance lipoproteins to stimulate proliferation of smooth muscle cells, a key event in atherogenesis. It was of interest to determine if continued remote aortic injury and thrombosis can increase the severity of hypercholesterolemia induced atherosclerosis. Four groups of rabbits were studied, two groups fed 0.5 g cholesterol per day, one group with and one group without massive abdominal aortic white mural non-occlusive thrombosis and injury induced with a permanent indwelling catheter, and two groups fed 1 g cholesterol per day, one group with and one group without similar thrombosis and injury. Serum lipids in the four groups were qualitatively and quantitatively not significantly different from each other at 4, 8, and 12 weeks. When they were sacrificed at 12 weeks the percent intimal surface area in the thoracic aorta (48 ± 22) and arch (75 ± 28) of the rabbits with thrombosis and fed 0.5 g cholesterol per day was significantly (p < 0.01) greater than the percent intimal area (20 ± 14) and (24 ± 18) of the rabbits without thrombosis. The percent intimal area with lesions in the rabbits fed 1 g cholesterol per day with thrombosis (59 ± 25) and (84 ± 30) was significantly greater (p < 0.01) than the percent area (24 ± 29) and (32 ± 32) of the rabbits without thrombosis. Since the effects could not be attributed to differing serum lipid levels it is possible that the increased severity of atherosclerosis in the remote arch and thoracic aorta was related to increased permeability, cell proliferation or collagen synthesis possibly stimulated by circulating factors released from the remote massive non-occlusive thrombus or from circulating platelets activated by contact with the injured abdominal aortic wall.     

Demonstration of a nonadrenergic inhibitory nervous system in the trachea of the guinea pig

A nonadrenergic inhibitory nervous system has been demonstrated in the guinea pig trachea. Electrical field stimulation of this system, in the presence of adrenergic and cholinergic blockade, resulted in relaxation of tracheal rings contracted by the mediators of immediate hypersensitivity or histamine. The relaxation was blocked by tetrodotoxin, which indicated that nerve stimulation was responsible for the relaxation. The gastrointestinal tract, which has a similar embryological origin to the respiratory tract, also has a nonadrenergic inhibitory system. In the gastrointestinal tract, this system is thought to be responsible for the relaxation phase of peristalsis, and absence of this system, in the colon and the rectum, is thought to be an explanation for the spastic bowel in Hirschsprung's disease. It is possible that an abnormality of the respiratory nonadrenergic inhibitory system may play a role in the pathogenesis of the hyperreactive airways in asthma. The airways, due to a lack of inhibition, may be either partially contracted or unable to relax, and thus appear hyperreactive to stimuli.     

Shock-related injury of pancreatic islets of langerhans in newborn and young infants

Variable degrees of injury of the pancreatic islets of Langerhans, with sparing of the acinar pancreas, were observed in three infants (age range, 1 day to 3 months) who died of profound shock. The duration of shock varied from 19 to 48 hours. In two of the infants, the shock stemmed from hypovolemia; in the remaining infant, the shock followed blood loss, sepsis, and heart failure. The islet lesions were devoid of cellular infiltrates, hemorrhage, and fibrin thrombi. Tissue manifestations of shock included acute renal tubular necrosis, massive hepatic centrilobular necrosis, ischemic enteropathy, and "shock" lung. Study of pancreatic sections from 30 children (age range, 13 hours to 15 years) with clinical and/or morphologic evidence of shock showed no additional instances of islet injury. These findings suggest that pancreatic islets in the young may be vulnerable to shock-induced ischemia. Studies are in progress in an animal model to test this hypothesis.     

Precocious thymic involution manifest by epithelial injury in the acquired immune deficiency syndrome

Thymuses from six heterosexual Haitian patients with the acquired immune deficiency syndrome (AIDS) were studied by light microscopy and the findings were compared with those from three control groups. The control groups included 1) five age-matched Haitian hospital patients; 2) ten age- and sex-matched Montreal patients who had died suddenly or had had brief illnesses; and 3) 20 middle-elderly Montreal patients who had experienced chronic, wasting illnesses or prolonged hospitalization. Thymuses from patients with AIDS demonstrated pronounced involution, effacement of the cortex and medulla, marked thymocyte depletion, variable degrees of plasma cell infiltration and fibrosis, and, above all, absence of Hassall's corpuscles. Thymuses from Haitian and Montreal control subjects who had died suddenly or had brief illnesses demonstrated minimal involution and abundant Hassall's corpuscles. Although thymuses from 12 of the chronically ill control subjects demonstrated marked involution, architectural effacement, and absence of Hassall's corpuscles, partial architectural preservation and variable numbers of Hassall's corpuscles were observed in eight of these subjects. Thus, the extent of thymic involution observed in patients with AIDS antedates that incurred with aging and supersedes that induced by sustained stress and inanition. The loss of Hassall's corpuscles in patients with AIDS suggests that the thymic epithelium either incurs a form of injury or undergoes precocious involution during the illness. Whether this lesion is central to the pathogenesis of AIDS or merely a reflection of intense, sustained stress coupled with accelerated physiologic involution is unknown. It is possible that the disappearance of Hassall's corpuscles may indicate important, although as yet cryptic events within the thymic microenvironment in this syndrome.     

Identification of human reagins isolated with immunosorbent as IgE

An immunosorbent prepared by attaching covalently the constituents of the aqueous extract of ragweed pollen to aminocellulose was used to remove reagins from a fraction of allergic serum enriched with respect to skin-sensitizing activity. The adsorbed antibodies were eluted with a solution of 2M NaI, pH 9.1, or of glycine-HCl, pH 2.5. The presence of ragweed-binding IgE antibodies in these eluates was revealed by radioimmunoelectrophoresis and radio-Ouchterlony analysis. Guinea pigs, which had been rendered tolerant to normal human cord serum proteins, were immunised with these eluates and produced anti-IgE antibodies, as demonstrated by radioimmunodiffusion and by reversed PCA in monkeys. These results confirm that human reagins elicited to the allergens of ragweed pollen belong to the IgE class of immunoglobulins.     

Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson's disease

Background

Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered.

Anticipatory HR deceleration as a function of perceived control and probability of aversive loud noise: A deployment of attention account

Five groups of 10 undergraduate subjects each participated in an experiment to examine the effects of perceived control over, and the probability of occurrence of, noxious (white-noise) stimulation on anticipatory heart rate (HR) deceleration. All groups performed an arithmetic task, the numbers for which were changed on each of the 20 trials, but three groups were defined as active groups since they were instructed that the occurrence of noxious stimulation was contingent upon their performance on the task. The actual probability of occurrence of noxious stimulation (i.e., either 0.9, 0.5 or 0.1) was manipulated between these three groups. A fourth (passive) group (0.5 probability of occurrence) was instructed as to the non-contingent relationship between performance and the aversive white noise. The last group was a control group which only performed the task, and thus both provided an estimate of the rate of return to baseline following the expected HR acceleration to the task and eliminated the need for a within-subject control period to assess HR deceleration. The results indicated that all active and passive groups produced significant HR decelerations, relative to the control group, prior to the noxious stimulus. However, all active groups (regardless of probability levels) displayed significantly greater, and required more trials to maximally develop, anticipatory deceleration than the passive group. In addition, the results for the active groups revealed a direct relationship between the probability of occurrence of noxious stimulation and the magnitude of anticipatory deceleration. It is argued that the results cannot be adequately accommodated by the preparatory-adaptive-response theory. A deployment-of-attention account is suggested since it appears both to account for the obtained pattern of results completely and to generate additional testable predictions for the future.     

Monocyte function in ageing humans

Peripheral blood monocytes from hospitalised patients >60 years of age and <35 yeras, and those from healthy normal controls <35 years, were tested for a range of functional and physiological properties, comprising chemotaxis under agarose, the ability to phagocytose and kill Candida albicans, adhesion to glass and spreading on glass. No significant difference was found between young and old groups, nor between hospitalized and non-hospitalized groups in respect of any parameter. There was some decline in phagocytosis and in spreading in a very old subgroup (>75 years), but this was not statistically significant. This study showed that phagocytic cell function in the elderly does not decline at the same rate as the specific immune response and thus cannot directly account for the increased incidence of infection in the aged.     

Alteration of T cell function in healthy persons with a history of thymic x-irradiation.

The possible late effects of x-irradiation to the infantile thymus were investigated by studying immune functions in 12 healthy persons with a history of thymic x-irradiation and healthy control subjects. No differences were found in serum immunoglobulin values, humoral antibody levels, lymphocyte counts, and lymphocyte reactivity to phytochemagglutinin, vaccinia virus, purified protein derivative (PPD), and allogeneic cells. The irradiation group exhibited cellular hyperresponsiveness to streptoskinase-streptodornase (SK-SD). In contrast, mean skin and in vitro lymphocyte responses to Candida albicans were depressed in the patients with thymic irradiation. A dissociation of these two Candida responses was found in only 1 of 14 healthy control subjects but in 7 of 12 irradiated individuals. While thymic irradiation did not result in impaired immunologic defenses leading to clinical disease, it caused alterations in T cell responses similar to those reported in patients with chronic mucocutaneous candidiasis.     

EEG differences as a function of creativity, stage of the creative process, and effort to be original

Results of two experiments examining the relationship between creativity and EEG alpha wave presence are reported. In Experiment 1, it was found that more creative subjects exhibited higher alpha indices during an analogue of creative inspiration than during an analogue of creative elaboration. This pattern was not found in less creative subjects. In Experiment 2 a similar effect was found in a more controlled setting and shown to be specific to creative subjects when they are instructed to be original but not when they are given no such instructions. No consistent relationship between creativity and basal EEG alpha activity was found.     

Changes in corticosteroid usage by chronic asthma patients during a year of cromoglycate treatment

Fifteen chronic asthmatic, steroid-dependent subjects were treated for one year with disodium cromoglycate (DSCG) while their previous maintenance steroid dosage was gradually reduced or withdrawn. Twelve asthma indices were monitored concurrently so that the observed steroid dose reduction could be related to the degree of control of the chronic asthma. In view of the characteristically varying course of the disease, the observed changes over the whole year were expressed in terms of average and maximum values. The timing and duration of the study were such as to obviate the influence of seasonally determined improvement trends that otherwise may confound drug-related change. A statistically significant reduction in steroid usage was observed in this group of patients and sustained during the year of cromoglycate treatment. The average reduction of the group over the year was 29 per cent, and the median reduction was 33 per cent. Within the group 11 of 15 reduced steroid usage; 3 who had required maintenance prednisone doses above 15 mg. daily were successfully reduced to lower dosage; 4 were converted to alternate-day therapy and stabilized there, whereas conversion attempts had previously failed; in 2 the maintenance steroid regimen was terminated. The possibility that the reduced steroid requirements might be due to the natural course of the disease rather than to the DSCG treatment cannot be entirely excluded.