Sensation Seeking and Cortical Augmenting-Reducing

The experiment was designed to establish the relationship between the Sensation Seeking Scales (SSS) and cortical augmenting-reducing. Forty-nine male undergraduate Ss were used. Ss were presented with five intensities of light flashes in randomly presented blocks of trials at each intensity. Averaged evoked response (AER) amplitudes were measured at each intensity of light. Augmenting-reducing was measured for each S as the slope of the relationship between stimulus intensity and amplitude of response. This slope measure correlated very significantly (r= .59) with the Disinhibition subscale of the SSS and positively, but not significantly, with other subscales. Comparing the low and high scorers on the Disinhibition scale, a significant interaction between groups and stimulus intensities was found but no main effects of stimulus intensity or groups were found. The high Disinhibitors did not differ from the lows at the low stimulus intensities but did differ significantly at the highest intensity where the lows showed a marked reducing tendency. The results show an interesting convergence between the Disinhibition type of sensation seeking, manic tendencies, and the AER.     

Operation Everest II: Alterations in the immune system at high altitudes

We investigated the effects on immune function after progressive hypobaric hypoxia simulating an ascent to 25,000 ft (7620 m) over 4 weeks. Multiple simultaneousin vitro andin vivo immunologic variables were obtained from subjects at sea level, 7500 ft (2286 m), and 25,000 ft during a decompression chamber exposure. Phytohemag-glutinin-stimulated thymidine uptake and protein synthesis in mononuclear cells were reduced at extreme altitudes. Mononuclear-cell subset analysis by flow cytometry disclosed an increase in monocytes without changes in B cells or T-cell subsets. Plasma IgM and IgA but not IgG levels were increased at altitudes, whereas pokeweed mitogen-stimulatedin vitro IgG, IgA, and IgM secretion was unchanged. During exposure to 25,000 ft,in vitro phytohemagglutinin-stimulated interferon production and natural killer-cell cytotoxicity did not change statistically, but larger intersubject differences occurred. IgA and lysozyme levels (nasal wash) and serum antibodies to nuclear antigens were not influenced by altitude exposure. These results suggest that T-cell activation is blunted during exposure to severe hypoxemia, whereas B-cell function and mucosal immunity are not. Although the mechanism of alteredin vitro immune responsiveness after exposure to various environmental stressors has not been elucidated in humans, hypoxia may induce alterations in immune regulation as suggested byin vitro immune assays of effector-cell function.Some of this study's results were presented as an abstract at the FASEB meeting in St. Louis, Missouri, 1986.     

Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Among 80 women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (40 with the simple virilizing form and 40 with the salt-losing form), 40 reported having an adequate introitus and being heterosexually active. In 15 of 25 patients with the simple virilizing form, 25 pregnancies resulted in 20 normal children, whereas only 1 of 15 women with the salt-losing form became pregnant; this pregnancy was electively terminated. Several factors seem to be responsible for the low fertility rates: noncompliance with therapy was probably high, as suggested by hirsutism and poor endocrine follow-up in 25 percent of patients; whereas 49 patients had regular menstrual periods, 14 had irregular periods, 10 had amenorrhea, 5 had undergone hysterectomy, and 2 had entered menopause; 87 percent of patients with salt loss and 50 percent of those with simple virilization (P less than 0.001) had remained single; the vaginal introitus was reported to be inadequate for intercourse by 35 percent of patients (53 percent of those with salt loss and 18 percent of those with simple virilization; P less than 0.002); and heterosexual activity was reported less frequently among patients with an inadequate introitus. The status of the introitus seemed to have a more important role in the sexual activity reported than did the degree of prenatal exposure to androgen (which was higher among patients with salt loss than among those with simple virilization). However, our data did not rule out an effect of androgen exposure on female fetuses. Our experience indicates that improved surgical correction of the external genitalia and better compliance with therapy will be necessary to improve fertility rates among women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.     

Mutation of the gene encoding fibrillin-2 results in syndactyly in mice

Fibrillins are large, cysteine-rich glycoproteins that form microfibrils and play a central role in elastic fibrillogenesis. Fibrillin-1 and fibrillin-2, encoded by FBN1 on chromosome 15q21.1 and FBN2 on chromosome 5q23-q31, are highly similar proteins. The finding of mutations in FBN1 and FBN2 in the autosomal dominant microfibrillopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), respectively, has highlighted their essential role in the development and homeostasis of elastic fibres. MFS is characterized by cardiovascular, skeletal and ocular abnormalities, and CCA by long, thin, flexed digits, crumpled ears and mild joint contractures. Although mutations arise throughout FBN1, those clustering within exons 24-32 are associated with the most severe form of MFS, so-called neonatal MFS. All the mutations described in CCA occur in the "neonatal region" of FBN2. Both MFS and CCA are thought to arise via a dominant negative mechanism. The analysis of mouse mutations has demonstrated that fibrillin-1 microfibrils are mainly engaged in tissue homeostasis rather than elastic matrix assembly. In the current investigation, we have analysed the classical mouse mutant shaker-with-syndactylism using a positional candidate approach and demonstrated that loss-of-function mutations outside the "neonatal region" of Fbn2 cause syndactyly in mice. These results suggest that phenotypes distinct from CCA may result in man as a consequence of mutations outside the "neonatal region" of FBN2.     

Monoclonal antibodies to a rat nestin fusion protein recognize a 220-kDa polypeptide in subsets of fetal and adult human central nervous system neurons and in primitive neuroectodermal tumor cells.

Nestin is the major intermediate filament protein of embryonic central nervous system (CNS) progenitor cells. To identify proteins involved in early stages of lineage commitment in the developing human CNS we generated monoclonal antibodies to a TrpE-rat nestin fusion protein. This resulted in a monoclonal antibody (designated NST11) that did not recognize authentic human nestin, but did recognize a novel neuron-specific human polypeptide expressed in a subset of embryonic and adult CNS neurons as well as in medulloblastomas. NST11 immunoreactivity was abundant in developing spinal cord motor neurons, but was extinguished in these neurons by 17 weeks gestation. NST11 also labeled Purkinje cells at 17 weeks gestation, but Purkinje cells continued to express the NST11 antigen throughout gestation as well as in the adult cerebellum, and NST11 immunoreactivity was more abundant in Purkinje cells than in any other human CNS neurons. No NST11 immunoreactivity was detected in cells of the adult human peripheral nervous system or in a variety of adult non-neural human tissues. Further, NST11 almost exclusively stained cerebellar medulloblastomas. In Western blots of immature and mature human cerebral and cerebellar extracts, NST11 did not bind human nestin, but did detect an immunoband with a molecular weight of 220 kd. A similar immunoband was detected in medulloblastoma-derived cell lines with a neuron-like phenotype. These findings suggest that the NST11 monoclonal antibody recognizes a novel protein expressed by a subpopulation of immature and mature human CNS neurons, medulloblastomas, and medulloblastoma-derived cell lines.     

An ultrastructural study of normal human mammary epithelial cells in culture

The ultrastructure of normal human mammary cells cultured from post-weaning breast fluids is described. Cells from confluent monolayers in two week old cultures were studied. The epithelial nature of these cells was established by the demonstration of a well developed system of cell-to-cell interdigitation and numerous desmosomes. These cells also share with breast epithelial cells in vivo, polarity, with blunt short microvilli on the apical surface and an oriented arrangement of organelles in the basal and apical portions of the cells. The Golgi apparatus, which is the most highly developed organelle, is localized in the apical pole and contains substantial quantities of secretory material in the cisternae and vesicles. A variegated palisade of finely granular material mixed with tonofilaments is seen in the basal portion of the cells; many of these tonofilaments end in the terminal web of the desmosomes. The regular occurrence of these cells in breast fluids during the terminal phases of lactation suggests that their separation is a part of normal breast involution.     

Sensation Seeking, Trait and State Anxiety, and the Electrodermal Orienting Response

The relationship between sensation seeking and the orienting reflex (OR) using skin conductance change is investigated in two experiments. In Experiment I, high sensation seekers gave a greater initial OR In novel visual stimuli while not differing in habituation on subsequent trials. In Experiment II. the paradigm was extended to include auditory as well as visual stimuli. Again, high sensation seekers were found to be more arousable with respect to initial ORs while not differing in habituation rates. The results suggest that sensation seekers may be characterized as having strong excitatory CNS processes. In Experiment II, anxiety (trait and state) was also related to the OR. There were no effects due to trait anxiety but state anxiety did yield significant differences. The more highly anxious (state) subjects had weaker initial ORs than lows in both novel tones, but not to repeated tones. The findings with state anxiety are consistent with findings by others using anxiety neurotics as subjects.     

Cross-presentation: underlying mechanisms and role in immune surveillance

Summary: It was originally thought that a cell's major histocompatibility complex (MHC) class I molecules presented peptides derived exclusively from proteins synthesized by the cell itself. However, in some circumstances, antigens from the extracellular environment can be presented on MHC class I molecules and stimulate CD8⁺ T‐cell immunity, a process termed cross‐presentation. Cross‐presentation was originally discovered as an obscure phenomenon in transplantation immunity. However, it is now clear that it is a major mechanism by which the immune system monitors tissues and phagocytes for the presence of foreign antigen. Cross‐presentation is the only pathway by which the immune system can detect and respond to viral infections or mutations that exclusively occur in parenchymal cells rather than in bone marrow‐derived antigen‐presenting cells (APCs). Professional APCs, such as dendritic cells, are the principal cells endowed with the capacity to cross‐present antigens. In this process, the APCs acquire proteins from other tissue cells through endocytic mechanisms, especially phagocytosis or macropinocytosis. The internalized antigen can then be processed through at least two different mechanisms. In one pathway, the antigen is transferred from the phagosome into the cytosol, where it is hydrolyzed by proteasomes into oligopeptides that are then transported by the transporter associated with antigen processing to MHC class I molecules in the endoplasmic reticulum or phagosomes. In a second pathway, the antigen is cleaved into peptides by endosomal proteases, particularly cathepsin S, and bound by class I molecules probably in the endocytic compartment itself. Depending on the nature of the antigen, one or both of these pathways can contribute to cross‐presentation in vivo. The outcome of cross‐presentation can be either tolerance or immunity. Which of these outcomes occurs is thought to depend on whether antigens are acquired by themselves alone, leading to tolerance, or with immunostimulatory signals, leading to immunity. One source of such signals is from dying cells that release immunostimulatory ‘danger’ signals that promote the generation of immunity to their cellular antigens. In addition to the critical role of cross‐presentation in normal immune physiology, this pathway has considerable potential for being exploited for developing subunit vaccines that elicit both CD4⁺ and CD8⁺ T‐cell immunity.     

Apparent replication of suggestive linkage on chromosome 16 in the NIMH genetics initiative bipolar pedigrees

Analyses of a replication sample of families collected as part of the National Institute of Mental Health (NIMH) Genetics Initiative for bipolar disorder provide further evidence for linkage to a region of chromosome 16. Families who had a bipolar I (BPI) proband and at least one BPI or schizoaffective, bipolar type (SABP) first-degree relative were ascertained for the purpose of identifying genes involved in bipolar affective disorder. A series of hierarchical models of affected status was used in linkage analyses. Initial genetic analyses of chromosomes 3, 5, 15, 16, 17, and 22, completed at Indiana University in 540 subjects from 97 families, suggested evidence of linkage to chromosomes 5, 16, and 22 [Edenberg et al., 1997: Am J Med Genet 74:238-246]. Genotyping was subsequently performed on these chromosomes in a replication sample of 353 individuals from 56 families. Nonparametric linkage analyses were performed using both affected relative and sibling pair methods. Analyses in the new sample on chromosome 16, using the broadest model of affected status, corroborate previously reported suggestive linkage to the marker D16S2619. Combining the initial and replication samples further increased the evidence of linkage to this region, with a peak lod score of 2.8.     

Neutralizing antibodies to African swine fever virus proteins p30, p54, and p72 are not sufficient for antibody-mediated protection

Although antibody-mediated immune mechanisms have been shown to be important in immunity to ASF, it remains unclear what role virus neutralizing antibodies play in the protective response. Virus neutralizing epitopes have been identified on three viral proteins, p30, p54, and p72. To evaluate the role(s) of these proteins in protective immunity, pigs were immunized with baculovirus-expressed p30, p54, p72, and p22 from the pathogenic African swine fever virus (ASFV) isolate Pr4. ASFV specific neutralizing antibodies were detected in test group animals. Following immunization, animals were challenged with 10(4) TCID(50) of Pr4 virus. In comparison to the control group, test group animals exhibited a 2-day delay to onset of clinical disease and reduced viremia levels at 2 days postinfection (DPI); however, by 4 DPI, there was no significant difference between the two groups and all animals in both groups died between 7 and 10 DPI. These results indicate that neutralizing antibodies to these ASFV proteins are not sufficient for antibody-mediated protection.