The influence of nursery school on social interactions.
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Sexual activities and attitudes of a group of adolescents, who have been followed from early infancy as a part of the New York Longitudinal Study, are reported. Adolescents in the study evince a more matter-of-fact, less fearful attitude than that of previous generations, but do not seem more prone to casual sexual encounters. Sexual conflicts are seen to occur only in relation to overall psychological conflict.
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Chronic catecholamine depletion induced by reserpine pretreatment of rats, or 6-hydroxydopamine pretreatment of guinea-pigs, resulted in an enhanced sensitivity of isolated papillary muscles to isoprenaline. This hypersensitivity was accompanied by 1.41-(rats) and 1.52-fold (guinea-pigs) increases in the number of [3H]dihydroalprenolol binding sites, without changes in binding affinity. An equation was derived for calculation of increases in receptor number. Application of this showed that substantially greater increases in receptor number were required (2.32- to 4.04-fold) to account for the degree of supersensitivity observed.
The alpha 1-adrenoceptor-mediated responses of the rat prostate to phenylephrine have been examined in-vitro. Phenylephrine induced concentration-dependent contractions of the isolated prostate gland which were antagonized by WB4101 (1-30 nM). Schild plot analysis of the antagonism yielded a straight line with a slope not significantly different from unity. The pKB value of 9.2 was similar to that obtained for WB4101 on the rat vas deferens (9.4) but was greater than that obtained on the rat spleen (8.4). Chloroethylclonidine depressed responses to phenylephrine of the rat spleen but not the prostate or the vas deferens. These results indicate that the rat prostate gland possesses a typical alpha 1A-adrenoceptor similar to that found in the vas deferens.
This study demonstrates that in-vitro incubation with insulin results in a reduction of the sensitivity of cardiac tissues from streptozotocin-diabetic rats to isoprenaline. Following incubation with insulin, the sensitivity of left atria and papillary muscles from diabetic animals was not significantly different from those of control animals. Insulin incubation had no effect on the sensitivity of diabetic tissues to forskolin or on ventricular beta-adrenoceptor number. Reduction of blood glucose in the absence of insulin by fasting, did not affect the sensitivity of tissues from diabetic animals to isoprenaline. These results suggest that insulin itself can directly reduce beta-adrenoceptor sensitivity without altering receptor number.
The effect of 17 beta-oestradiol pretreatment and the natural oestrous cycle on responses of rat cardiac and vascular alpha-adrenoceptors was investigated. It was found that treatment with the oestrogen had no effect on cardiac adrenoceptor sensitivity, while pretreatment with the hormone caused a significant increase in vascular alpha 2-, but not vascular alpha 1-adrenoceptor responsiveness. Pressor responses of pithed rats to selective alpha 1- or alpha 2-adrenoceptor agonists did not alter, however, during the natural oestrous cycle. These findings suggest that changes in oestrogen levels are capable of altering alpha-adrenoceptor-mediated vascular responses but that the relatively small changes in oestrogen which may occur throughout the natural oestrous cycle do not appear to alter the responses of these vascular alpha-adrenoceptors.
Chemical sympathectomy of guinea-pigs was induced by chronic pretreatment with 6-hydroxydopamine over a 20 day period. Control animals were sham injected with vehicle at the same times. Isolated tissues were removed from the animals and beta-adrenoceptor sensitivity assessed from cumulative concentration-response curves for isoprenaline, followed after wash-out by a partial agonist (salbutamol, ritodrine or prenalterol). The following responses were measured: increases in force and rate of contraction of left and right atria respectively, inhibition of carbachol-induced ileal contractions, relaxation of intrinsic tone of lung strips and tracheal spirals, inhibition of contractions of vas deferens and soleus muscle induced by field stimulation. Left and right atria and ileum from 6-hydroxydopamine-pretreated guinea-pigs exhibited supersensitivity to beta-adrenoceptor stimulation. This was measured as a leftwards shift of the concentration-response curve for isoprenaline and as an elevation of the partial agonist maximum response (relative to isoprenaline), when compared with tissues from sham-injected controls. The supersensitivity was assumed to be due to the loss of endogenous neurotransmitter release by chemical sympathectomy and specific for the beta-adrenoceptor. In contrast, lung strips, vas deferens and soleus muscle were not supersensitive. The responses of these tissues are thought to be mediated via beta 2-adrenoceptors whereas cardiac and ileal responses are beta 1-adrenoceptor mediated. The latter receptor subtype would therefore appear to be under the influence of sympathetic innervation, but since no supersensitivity occurred at beta 2-adrenoceptors these were presumed to be non-innervated but stimulated by circulating adrenaline. These results obtained by use of chemical sympathectomy with 6-hydroxydopamine support the contention that the physiological basis of beta-adrenoceptor subclassification is that the beta 1-subtype are innervated whereas the beta 2-subtype are non-innervated.
An unconstrained loading system was developed to measure the passive envelope of joint motion in an animal model commonly used to study ligament healing and joint arthritis. The design of the five-degree-of-freedom system allowed for unconstrained knee joint loading throughout flexion with repeated removal and reapplication of the device to a specimen. Seven New Zealand White rabbit knees were subjected to varus, valgus, internal and external loads, and the resulting envelopes of motion were recorded using an electromagnetic tracking device. Intra-specimen reproducibility was excellent when measured in one specimen, with maximal rotational differences of 0.6 and 0.3 deg between the fourth and fifth testing cycles for the varus (VR) and valgus (VL) envelopes, respectively. Similarly, the maximal internal (INT) and external (EXT) envelope differences were 0.5 and 0.4 deg, respectively, between the fourth and fifth cycles. Good inter-animal envelope reproducibility was also observed with consistent motion pathways for each loading condition. A maximal VR-VL laxity of 17.9 +/- 2.3 deg was recorded at 95 deg flexion for the seven knees tested. The maximal INT-EXT laxity of 75.2 +/- 4.8 deg occurred at 50 deg flexion. Studies on measurement reproducibility of re-applying individual testing components demonstrated a maximal error of 1.2 +/- 0.7 deg. Serial removal and re-application (test-retest) of the complete measuring system to one cadaveric knee demonstrated maximal envelope differences of less than 0.7 deg for VR-VL rotation and 2.1 deg for INT-EXT rotation. Our results demonstrate that the measuring system is reproducible and capable of accurate evaluation of knee joint motion. Baseline in vitro data were generated on normal joint kinematics for future in-vivo studies with this system, evaluating ligament healing and disease progression in arthritis models.
Alterations in the myogenic activity of the bladder smooth muscle are thought to serve as a basis for the involuntary detrusor contractions associated with the overactive bladder. Activation of ATP-sensitive K(+) (K(ATP)) channels has been recognized as a potentially viable mechanism to modulate membrane excitability in bladder smooth muscle. In this study, we describe the preclinical pharmacology of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel 1,4-dihydropyridine K(ATP) channel opener (KCO) that demonstrates enhanced bladder selectivity for the suppression of unstable bladder contractions in vivo relative to other reference KCOs. A-278637 activated K(ATP) channels in bladder smooth muscle cells in a glyburide (glibenclamide)-sensitive manner as assessed by fluorescence membrane potential assays using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (EC(50) = 102 nM) and by whole cell patch clamp. Spontaneous (myogenic) phasic activity of pig bladder strips was suppressed (IC(50) = 23 nM) in a glyburide-sensitive manner by A-278637. A-278637 also inhibited carbachol- and electrical field-stimulated contractions of bladder strips, although the respective potencies were 8- and 13-fold lower compared with inhibition of spontaneous phasic activity. As shown in the accompanying article [Brune ME, Fey TA, Brioni JD, Sullivan JP, Williams M, Carroll WA, Coghlan MJ, and Gopalakrishnan M (2002) J Pharmacol Exp Ther 303:387-394], A-278637 suppressed myogenic contractions in vivo in a model of bladder instability with superior selectivity compared with other KCOs, WAY-133537 [(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)cyclobut-1-enylamino]-3-ethyl-benzonitrile] and ZD6169 [(S)-N-(4-benzoylphenyl)3,3,3-trifluro-2hydroxy-2-methyl-priopionamide]. A-278637 did not interact with other ion channels, including L-type calcium channels or other neurotransmitter receptor systems. The pharmacological profile of A-278637 represents an attractive basis for further investigations of selective K(ATP) channel openers for the treatment of overactive bladder via myogenic etiology.
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The ability of Trypanosoma cruzi, the etiological agent of Chagas' disease to acquire host cell surface antigen was tested. Parasites emerging after intracellular replication in WOS sarcoma monolayers expressed a sarcoma-associated surface antigen. This antigen was deleted from these parasites after replication in the MNS control monolayer, which does not express WOS sarcoma-associated surface antigen, or by replication in cell-free medium. This type of reversible acquisition of host surface antigen has not been previously described in T. cruzi or other intracellular protozoan parasites.
Recent studies have demonstrated that the beta-chemokines RANTES, MIP-1alpha, and MIP-1beta suppress human immunodeficiency virus type 1 (HIV-1) replication in vitro and may play an important role in protecting exposed but uninfected individuals from HIV-1 infection. However, levels of beta-chemokines in AIDS patients are comparable to and can exceed levels in nonprogressing individuals, indicating that global beta-chemokine production may have little effect on HIV-1 disease progression. We sought to clarify the role of beta-chemokines in nonprogressors and AIDS patients by examination of beta-chemokine production and HIV-1 infection in patient T-lymphocyte clones established by herpesvirus saimiri immortalization. Both CD4+ and CD8+ clones were established, and they resembled primary T cells in their phenotypes and expression of activated T-cell markers. CD4+ T-cell clones from all patients had normal levels of mRNA-encoding CCR5, a coreceptor for non-syncytium-inducing (NSI) HIV-1. CD4+ clones from nonprogressors and CD8+ clones from AIDS patients secreted high levels of RANTES, MIP1alpha, and MIP-1beta. In contrast, CD4+ clones from AIDS patients produced no RANTES and little or no MIP-1alpha or MIP-1beta. The infection of CD4+ clones with the NSI HIV-1 strain ADA revealed an inverse correlation to beta-chemokine production; clones from nonprogressors were poorly susceptible to ADA replication, but clones from AIDS patients were highly infectable. The resistance to ADA infection in CD4+ clones from nonprogressors could be partially reversed by treatment with anti-beta-chemokine antibodies. These results indicate that CD4+ cells can be protected against NSI-HIV-1 infection in culture through endogenously produced factors, including beta-chemokines, and that beta-chemokine production by CD4+, but not CD8+, T cells may constitute one mechanism of disease-free survival for HIV-1-infected individuals.
Drosophila N-cadherin (CadN) is an evolutionarily conserved classic cadherin which has a large, complex extracellular domain and a catenin-binding cytoplasmic domain. The CadN locus contains three modules of alternative exons (7a/b, 13a/b, and 18a/b) and undergoes alternative splicing to generate multiple isoforms. Using quantitative transcript analyses and green fluorescent protein-based cell sorting, we found that during development CadN alternative splicing is regulated in a temporal but not cell-type-specific fashion. In particular, exon 18b is predominantly expressed during early developmental stages, while exon 18a is prevalent at the late developmental and adult stages. All CadN isoforms share the same molecular architecture but have different sequences in their extracellular and transmembrane domains, suggesting functional diversity. In vitro quantitative cell aggregation assays revealed that all CadN isoforms mediate homophilic interactions, but the isoforms encoded by exon 18b have a higher adhesive activity than those by its alternative, 18a. Domain-swapping experiments further revealed that the different sequences in the transmembrane domains of isoforms are responsible for their differential adhesive activities. CadN alternative splicing might provide a novel mechanism to fine-tune its adhesive activity at different developmental stages or to restrict the use of high-affinity 18b-type isoforms at the adult stage.
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The ophthalmic histopathology is detailed in a case of trisomy 18 (Edwards's syndrome). In addition to the ocular pathology already reported, previously unreported findings of iris stromal hypoplasia, abnormal lens shape, and decreased ganglion cells in the retina are noted. The ophthalmic histopathology associated with this syndrome and the relationship of several genetic disorders to their ocular manifestations are discussed.