Aggressive behavior linked to corticotropin-reactive autoantibodies.

BACKGROUND: Altered stress response is characteristic for subjects with abnormal aggressive and antisocial behavior, but the underlying biological mechanisms are unclear. We hypothesized that autoantibodies (autoAbs) directed against several stress-related neurohormones may exist in aggressive subjects. METHODS: Using enzyme-linked immunosorbent assay, we studied whether autoAbs directed against corticotropin (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH), oxytocin, and vasopressin are present in serum of male subjects with conduct disorder and prisoners with history of violence. Healthy blood donors served as control subjects. RESULTS: Both conduct disorder and prisoners groups displayed strongly increased levels of ACTH-reactive immunoglobulin G (IgG) and immunoglobulin M (IgM) autoAbs compared with control subjects. Levels of oxytocin-reactive IgM autoAbs were slightly increased in both groups of aggressive subjects, whereas levels of vasopressin-reactive IgG and IgM autoAbs were lower only in conduct disorder. No differences in the levels of alpha-MSH-reactive autoAbs were found between aggressive and control subjects. CONCLUSIONS: High levels of ACTH-reactive autoAbs as well as altered levels of oxytocin- and vasopressin-reactive autoAbs found in aggressive subjects may interfere with the neuroendocrine mechanisms of stress and motivated behavior. Our data suggest a new biological mechanism of human aggressive behavior that involves autoAbs directed against several stress-related neurohormones.     

Morphology of corticotectal cells in the primary visual cortex of hooded rats

In primary visual cortex of hooded rats, pyramidal cells in layer V may be classified as long, medium, or short, on the basis of the layer in which the apical dendrite terminates. The present study determines which of these types of pyramidal cells project to the superior colliculus. Two different strategies were used to label corticotectal cells with horseradish peroxidase (HRP). In the first set of experiments, a large number of corticotectal cells were labeled by retrograde transport following injection of HRP into the superior colliculus. In the second set of experiments, single unit recording was used to identify corticotectal cells physiologically by antidromic activation from the superior colliculus. These cells were then impaled and labeled by intracellular iontophoresis of HRP. The results from both techniques suggest that only long pyramidal cells send an axon to the superior colliculus. These cells are distinguished by an apical dendrite that extends into layer I. We conclude that in hooded rats corticotectal cells in primary visual cortex are the long pyramids in layer V.     

Antigenicity of low molecular weight surfactant species.

The authors tested the antigenicity of human lung surfactant isolated from amniotic fluid. Mice and rabbits were immunized. Rabbit polyclonal antisera to these surfactant preparations were absorbed with normal human plasma proteins. Polyclonal antisera reacted with both high molecular weight (35 kd) surfactant apoprotein and to lower molecular weight species, both 18 kd and 9 kd. Mice were used to generate monoclonal antibodies to surfactant. Enzyme-linked immunosorbant assay was used to identify five monoclonal antibodies that reacted with surfactant. By Western blot analysis, all of these recognized a low molecular weight surfactant species (9 kd) that could be either SP-B or SP-C. One reacted with a 37 kd protein in the surfactant preparation, consistent with SP-A. One monoclonal antibody also recognized a higher molecular weight species (44 kd) of unknown origin. The ability of antisera and monoclonal antibodies to inhibit the functional activity of surfactant was assayed using a pulsating bubble surfactometer. Rabbit polyclonal antisera inhibited initial surface adsorption to equilibrium surface tension and increased the minimum surface tension after 1 and 5 minutes of initiation of pulsations. This inhibitory activity of the antisera was noted in divalent F(ab')2 fragments. Monovalent F(ab) fragments and control normal rabbit sera did not inhibit surfactant function in this assay. Of the anti-surfactant monoclonal antibodies that reacted with surfactant by ELISA and Western blot, three inhibited its capacity to lower surface tension on the pulsating bubble apparatus. The other two monoclonal antibodies showed no functional inhibitory activity. It is concluded that both the 35 kd SP-A and the 9 kd proteins of human surfactant are highly immunogenic and partially crossreactive. Resulting antibodies could alter the ability of surfactant to perform its physiologic function, ie, to lower surface tension.     

Langerhans cells and serum precipitating antibodies against fungal antigens in bronchioloalveolar cell carcinoma: possible association with pulmonary eosinophilic granuloma

In an ultrastructural study of 37 cases of bronchioloalveolar cell carcinoma (BAC), we identified seven cases (19%) in which Langerhans cells (LC) were closely associated with tumor cells. Serum precipitating antibodies against Aspergillus species and/or thermophilic actinomyces were present in five BAC patients whose tumors contained LC and in six patients whose tumors lacked LC. In a simultaneous study we identified marked atypical bronchiolar and alveolar lining cell hypertrophy and hyperplasma in pulmonary eosinophilic granuloma (PEG). Our data plus current information suggesting that PEG is a form of hypersensitivity pneumonitis support our hypothesis that those cases of BAC in which LC are present may arise in localized or diffuse pulmonary scars caused by PEG.     

Evaluation of a novel bis-naphthalimide anticancer agent,DMP 840, against human xenografts derived from adult,juvenile, and pediatric cancers

The new bis-naphthalimide antitumor agent (R,R)2,2-[1,2-ethanediylbis[imino(1-methyl-2.1-ethanediyl)]-bis {5-nitro-1H-benz[de]-isoquinoline-1,3-2H) dione} dimethanesulfonate (DMP 840) was evaluated against parental and multidrug-resistant human KB cell lines in vitro and against these lines growing as xenografts in immunedeprived mice. In vitro, KB8-5 cells were 50-fold resistant to vincristine but only 16-fold resistant to DMP 840 as measured by clonogenic survival. For in vivo evaluation, DMP 840 was given by i. v. injection daily for 9 days or for 5 days/week for 2 consecutive weeks [(dx5)2]. In contrast to the cross-resistance of KB cell lines in vitro, both KB3-1 and KB8-5 tumors were highly and equally sensitive to DMP 840; only KB3-1 xenografts demonstrated sensitivity to vincristine, which was consistent with the in vitro results. DMP 840 was also evaluated against a panel of human tumors comprising colon adenocarcinoma and rhabdomyosarcoma xenografts. Against eight lines of colon adenocarcinoma, DMP 840 caused a high frequency of partial and complete regressions in two lines and significant inhibition of growth in two lines. DMP 840 caused complete regressions in five of six lines of advanced rhabomyosarcomas, demonstrating a broad range of effective dose levels. The pattern of activity against this tumor panel was similar but not identical to that of two inhibitors of topoisomerase I. There was no cross-resistance to DMP 840 in xenografts selected for resistance to vincristine or in a rhabdomyosarcoma selected for resistance to the topoisomerase I inhibitor topotecan. In contrast, a colon tumor selected for topotecan resistance was completely resistant to DMP 840. Slight cross-resistance to DMP 840 was demonstrated in a rhabdomyosarcoma xenograft that was selected for primary resistance to melphalan and was cross-resistant to topoisomerase I inhibitors. The pattern of activity and cross-resistance in these tumors was compared with that shown by two agents that inhibit topoisomerase I: topotecan and CPT-11.This work was supported in part by CA23099, Cancer Center Support (CORE) grant CA21675, The Du Pont Merck Pharmaceutical Company, and by American Lebanese Syrian Associated Charities (ALSAC)     

Neuropeptides and neurotransmitter-synthesizing enzymes in intrinsic neurons of the human urinary bladder

Summary The expression of neuropeptides, and the enzymes nitric oxide synthase and tyrosine hydroxylase were examined in intramural ganglia of human urinary bladder using single label immunocytochemistry. Scattered ganglia composed of between 1–36 neurons (median 4) were observed in all layers of the lateral wall of the bladder. These contained immunoreactivity to vasoactive intestinal peptide, nitric oxide synthase, neuropeptide Y, and galanin. Neurons within the bladder were heterogeneous with regard to their content of these antigens, with the proportion of immunopositive cells ranging from 58–84%. Occasional neurons with immunoreactivity to the catecholamine-synthesizing enzyme, tyrosine hydroxylase, were also observed. No cell somata, however, were immunoreactive for enkephalin, substance P, calcitonin generelated peptide or somatostatin. Varicose terminals entering the ganglia were seen to form pericellular baskets surrounding some of the principal ganglion cells. The most prominent pericellular varicosities were those containing calcitonin gene-related peptide- or vasoactive intestinal peptide-immunoreactivity, followed by those with immunoreactivity for enkephalin, neuropeptide Y, or galanin. Less common were pericellular varicosities with substance P-immunoreactivity, which may represent collateral processes of unmyelinated primary sensory fibres, and presumptive noradrenergic processes containing tyrosine hydroxylase. Some calcitonin gene-related peptide-immunoreactive varicosities constituted a distinct type, terminating as large pericellular boutons 2–4 m in diameter. Fibres containing nitric oxide synthase- or somatostatin-immunoreactivity were not associated with the intramural neurons. The results demonstrate that intrinsic neurons within the human urinary bladder express a number of neuroactive chemicals, and could in principle form circuits with the potential to support integrative activity.     

Food allergy,asthma bronchiale,and rhinitis in atopic dermatitis patients with total immunoglobulin E under and above 200 IU/ml

The objective of this study is to evaluate if there is a difference in the occurrence of asthma bronchiale, rhinitis, pollen allergy, food allergy and sensitization to basic food allergens, onset of atopic dermatitis (AD), family history about atopy, and duration of eczematic lesions in AD patients with the level of total immunoglobulin E (IgE) under or above 200 IU/ml. Complete allergological and dermatological examination was performed and the statistical evaluation of the relations among the patients with the level of IgE under 200 IU/ml and above 200 IU/ml was performed. Out of 277 patients suffering from AD, we included 87 men and 190 women; the average age was 25.9 years. From 277 patients, 92 patients (33%) have IgE under 200 IU/ml; in these patients, the occurrence of tested parameters is significantly lower in comparison to patients with IgE above 200 IU/ml.     

Surfactant protein A and B genetic variants in respiratory distress syndrome in singletons and twins

Interactive genetic and environmental factors may influence the differentiation of surfactant and the risk of respiratory distress syndrome (RDS). DNA samples from 441 premature singleton infants and 480 twin or multiple infants were genotyped for surfactant-specific protein (SP)-A1, SP-A2, and SP-B exon 4 polymorphisms and intron 4 size variants in a homogeneous white population. Distributions of the SP-A and SP-B gene variants between RDS and no-RDS infants were determined alone and in combination. SP-A1 allele 6A2 (p = 0.009) and the homozygous genotype 6A2/6A2 (p = 0.003) were overrepresented in RDS of singletons when the SP-B exon 4 genotype was Thr/Thr, and underrepresented in RDS of multiples when the SP-B genotype was Ile/Thr (p = 0.012 for 6A2 and p = 0.03 for 6A2/6A2) or Thr/Thr (p = 0.12 for 6A2 and p = 0.018 for 6A2/6A2, respectively). The SP-A 6A2 allele in the SP-B Thr131 background predisposed the smallest singleton infants to RDS, whereas near-term multiples were protected from RDS. There was a continuous association between fetal mass and risk of RDS, defined by the SP-A and SP-B variants. Labeled lung explants with the Thr/Thr genotype showed proSP-B amino-terminal glycosylation, which was absent in Ile/Ile samples. Genetic and environmental variation may influence intracellular processing of surfactant complex and the susceptibility to RDS.