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The synaptic responses of turtle cerebellar Purkinje cells to stimulation of localized mossy fibre systems have been studied by use of intrasomatic and intradendritic recordings in a brainstem-cerebellum preparation in vitro. Activation of mossy fibre inputs from the spinocerebellar pathway evoked fast, disynaptic postsynaptic potentials which were graded in amplitude with stimulus intensity and elicited at latencies consistent with those reported for peripheral nerve stimulation. Repetitive activation (50-100 Hz, 2-10 stimuli) of both spinocerebellar and trigeminocerebellar pathways evoked a slow, long-lasting excitatory postsynaptic potential regardless of whether single stimuli resulted in excitatory, inhibitory, or no postsynaptic responses. This slow potential was capable of triggering dendritic pacemaker discharges in recorded Purkinje cells in addition to volleys of simple spikes when activated at or near resting membrane potential. The fast excitatory synaptic potentials evoked by spinocerebellar stimulation were blocked by the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, consistent with the hypothesis that they are mediated by activation of ionotropic glutamate receptors of the alpha-amino-3-hydroxy-5-methylisox-azole-4-proprionic acid subtype at the mossy fibre-granule cell synapse and the subsequent parallel fibre-Purkinje cell synapse. The slow excitatory synaptic potential evoked by repetitive stimulation of either the spinocerebellar tract or trigeminal nerve was blocked by DL-2-amino-5-phosphonvalerate, indicating that this potential is primarily dependent upon N-methyl-D-aspartate receptors at the mossy fibre-granule cell synapse for its expression. This slow potential was reversibly potentiated by L-2-amino-4-phosphonobutyrate and bicuculline; the metabotropic glutamate antagonist (+)-alpha-methyl-4-carboxyphenylglycine did not block this potentiation. The ability of mossy fibre inputs to drive long, slow excitatory events in Purkinje cells adds another dimension to the mechanisms by which various sensory modalities can be processed interactively in the cerebellar cortex. The ability of incoming systems to access a second, longer duration response of the cerebellar output neuron may be of significant consequence to our understanding of the manner in which this neural centre integrates sensory information from multiple sources.

Previous studies have shown that neonatal, but not adult, murine thymic T cells proliferate when co-cultured with syngeneic, adult splenic B cells. Evidence suggests that expansion of such self-reactive T cells precedes their clonal deletion or functional inactivation (anergy). This mechanism may be of particular significance for establishing peripheral (extrathymic) tolerance. In order to assess the autostimulatory capacity of B cells present in a variety of lymphoid tissues, neonatal T cells were cultured with Peyer's patch and peritoneal cavity cells. The results indicate that B cells in these tissues readily induce T cell proliferation. Evidence suggests that the B-1 B cell subpopulation is not obligatory for this process. Self-reactive T cells were evident in the spleen of young mice, substantiating a role for B cells in maintaining peripheral tolerance. The results suggest that B cells involved in this process are distributed in a variety of lymphoid organs.

The primary method employed to correct immune deficiency is bone marrow transfer. Depending upon the exact nature of the immune deficiency, however, alternative cell sources may be used to provide a more rapid reconstitution of immune function. In this report, peritoneal cavity (PerC) B cells are shown to be effective in the rapid emendation of the B-cell defect exhibited by XID mice. Restoration of normal numbers of splenic IgM antibody-secreting cells (ASC) and serum IgM levels were observed 4 and 7 days, respectively, after the i.v. transfer of 3 x 10(6) PerC. This regimen also restored responsiveness to thymus-independent type 2 (TI-2) antigens in XID recipients. Transfer of 30 x 10(6) spleen (SP) cells restored these functions in XID recipients but at a considerably slower rate. The data indicate that introducing a small number of PerC B cells into systemic circulation results in the rapid restoration of serum IgM levels in unirradiated XID mice.

The autologous mixed lymphocyte response (AMLR) is characterized by the proliferation of neonatal, but not adult, thymic T cells when cocultured with adult syngeneic B cells. Studies of the AMLR have revealed a temporal correlation between loss of T cell self-reactivity and development of stimulatory B cells. Such observations impart a role for B cells in the development of T cell tolerance. To test this hypothesis, we studied the AMLR in X-chromosome-linked immune-defective (XID) mice. As B cell maturation is delayed in this strain, we postulated that the AMLR-stimulatory capacity of B cells from XID mice might be impaired and lead to delayed acquisition of T cell tolerance. This report provides evidence that T cell tolerance to self-B cells is delayed in XID mice. Normal mice possess tolerant thymic T cells by 1 week of age, whereas thymic T cells in the XID mouse remain self-reactive through 4 weeks of age. These results reinforce a role for B cells in the development of T cell tolerance to self.

We describe different single-amino acid aberrations in the DNA-binding domain (DBD) of the human androgen receptor (hAR) in three families with complete androgen insensitivity. No additional alteration was found in the translated portion of each mutant gene. In one family, an in-frame 3 nt deletion removes codon 581-(or 582) and, thereby, one of two phenylalanines that invariably occupy adjacent positions in the N-terminal alpha-helical region of the DBD in the steroid/thyroid/vitamin D receptor superfamily. In the second, an in-frame 3 nt loss deletes Arg614, an invariant residue in the C-terminal alpha-helix of the DBD. In the third, a G-->A transition causes Arg614His. Following transient transfection of COS cells with each mutant AR plasmid, there is a normal concentration of specific androgen-binding activity that has a reduced ability to bind two types of androgen response element (ARE), and to transregulate an androgen-responsive human growth hormone reporter gene. In genital skin fibroblasts with delta Phe581 or Arg614His, androgen-binding, AR protein and AR mRNA are markedly reduced; in gonadal fibroblasts with delta Arg614, AR mRNA may be reduced. Our data substantiate the primary contributions of Phe581 and Arg614 to normal hAR-ARE binding, and expose important secondary effects of the mutations affecting each residue.

We have discovered two different point mutations in a single codon of the X-linked androgen-receptor (AR) gene in two pairs of unrelated families who have complete androgen insensitivity (resistance) associated with different AR phenotypes in their genital skin fibroblasts. One mutation is a C-to-T transition at a CpG sequence near the 5' terminus of exon 6; it changes the sense of codon 773 from arginine to cysteine, ablates specific androgen-binding activity at 37 degrees C, and eliminates a unique KpnI site at the intron-exon boundary. The other mutation is a G-to-A transition that changes amino acid 773 to histidine and eliminates an SphI site. This mutant AR has a normal androgen-binding capacity at 37 degrees C but has a reduced affinity for androgens and is thermolabile in their presence. Transient transfection of COS cells with cDNA expression vectors yielded little androgen-binding activity at 37 degrees C from Arg773Cys and abundant activity with abnormal properties from Arg773His, thereby providing the pathogenicity of both sequence alterations. This conclusion coincides with the following facts about evolutionary preservation of the position homologous to Arg773 in the AR: it is occupied by Arg or lysine in the progesterone, glucocorticoid, and mineralocorticoid receptors, and it is within a 14-amino-acid region of their steroid-binding domains that share approximately 85% amino acid identity.

Movement control in vertebrates is a complex function that is known to involve several parallel systems. In amphibians, which lack the isocortical structures shown in mammals to initiate and control voluntary movements, supraspinal motor control systems have received surprisingly little attention. Because amphibians lack a corticospinal equivalent, coordination and control of all movement strategies must take place in non-cortical, supraspinal integrating centers. The rubro-cerebello-rubrospinal circuit is likely to represent a major motor control system in such vertebrates. In this anatomical investigation four mesencephalic tegmentospinal projection nuclei are described in ranid amphibians (Rana catesbiana and Rana pipiens): reticular formation, accessory optic complex, interstitial nucleus of Cajal, and the red nucleus. The red nucleus, which shows no distinct somatotopic organization, can be distinguished because it is the only one of the four that is predominantly contralateral in its projections. Horseradish peroxidase injections into the tegmentum and the cerebellum demonstrated that the red nucleus also maintains reciprocal connections with the cerebellum via the deep cerebellar nucleus. These connections could not be localized to any distinct region in the deep cerebellar nuclear mass, suggesting that this represents a single cerebellar recipient nucleus. Thus, anuran amphibians are shown to possess the major pathways that comprise the rubro-cerebello-rubrospinal circuitry in mammals.

1. A preparation of turtle (Chrysemys picta and Pseudemys scripta) brain in which the integrity of the intracortical and geniculocortical pathways in visual cortex are maintained in vitro has been used to differentiate the excitatory amino acid (EAA) receptor subtypes involved in geniculocortical and intracortical synapses. 2. Stimulation of the geniculocortical fibers at subcortical loci produces monosynaptic excitatory postsynaptic potentials (EPSPs) in visual cortical neurons. These EPSPs are blocked by the broad-spectrum EAA receptor antagonist kynurenate (1-2 mM) and the non-N-methyl-D-aspartate (NMDA) antagonist 6, 7-dinitroquinoxaline-2,3-dione (DNQX, 10 microM), but not by the NMDA antagonist D,L-2-amino-5-phosphonovalerate (D,L-AP-5, 100 microM). These results indicate that the geniculocortical EPSP is mediated by EAAs that access principally, if not exclusively, EAA receptors of the non-NMDA subtypes. 3. Stimulation of intracortical fibers evokes compound EPSPs that could be resolved into three components differing in latency to peak. The component with the shortest latency was not affected by any of the EAA-receptor antagonists tested. The second component, of intermediate latency, was blocked by kyurenate and DNQX but not by D,L-AP-5. The component of longest latency was blocked by kynurenate and D,L-AP-5, but not by DNQX. These results indicate that the compound intracortical EPSP is comprised of three pharmacologically distinct components that are mediated by an unknown receptor, by quisqualate/kainate, and by NMDA receptors, respectively. 4. Repetitive stimulation of intracortical pathways at 0.33 Hz produces a dramatic potentiation of the late, D,L-AP-5-sensitive component of the intracortical EPSP. 5. These experiments lead to a hypothesis about the subtypes of EAA receptors that are accessed by the geniculocortical and intracortical pathways within visual cortex.

Human genital skin fibroblasts (GSF) make a relatively abundant 56/58 kDa protein that binds androgens. The protein shares many properties with the approximately 100 kDa androgen receptor that is encoded by a locus in the q12 region of the X chromosome. It does not appear to be androgen-induced, yet is absent in GSF of most patients with complete androgen insensitivity (CAI). A precursor-product relation with the androgen receptor (AR) protein has been largely excluded; that it may be an unorthodox product of the AR gene has not. The 56/58 kDa protein is made by the GSF of a mentally retarded subject who has CAI because of a complete deletion of the coding portion of the AR gene. Hence, the strong constitutional and statistical correlations that have been demonstrated between the two proteins cannot arise because they share the same gene. The subject's genomic DNA hybridizes normally with 11 single-copy probes from Xq11-Xq13. Therefore, we cannot attribute her mental retardation to a contiguous gene syndrome.

The movement away from hospital-based schemes of care for those with a psychiatric disability in favour of community-based schemes of care constitutes a turning point in the history of psychiatric provision in most Western European societies. The origins and rationale of this movement have sometimes been explained by reference to extra-discursive (economic) interests, and sometimes by reference to a form of technological or scientific determinism in which the discovery of such things as the neuroleptic drugs during the 1950s is said to have played a major role. This paper argues that the impetus for community as against hospital-based care can only be understood in terms of a changing discourse of psychiatry and psychiatric nursing, and especially those forms of thought which have tended to place 'illness' in the wings and set its primary sights on behavioural and social 'deficits'. There is a sense, therefore, in which hospital-based practices of psychiatrists and nurses have constituted the source and origin of their own transformation--a transformation in which the rationale of the psychiatric hospital has been eroded. The arguments in this paper are substantiated by reference to a current study of the forms of knowledge and daily practice which are drawn upon by nurses and psychiatrists in the psychiatric wards of a large Northern Irish hospital.

1. The excitatory synaptic responses of turtle Purkinje cells to climbing and parallel fiber (CF and PF) stimulation have been studied by the use of intrasomatic and intradendritic recordings in intact cerebellum and brain stem-cerebellum preparations in vitro. 2. Activation of CF inputs from the cerebellar peduncle or the region of the inferior olive evoked complex spikes followed by slow excitatory postsynaptic potentials (EPSPs), both of which were evoked in an all-or-none fashion. 3. Single stimuli applied to the cerebellar molecular layer activated fast PF-mediated EPSPs; brief trains of PF stimuli (2-5 stimuli, 50-100 Hz) evoked volleys of fast EPSPs followed by a slow, long-lasting EPSP. The amplitude of the fast and slow PF-mediated EPSPs were both graded with stimulus intensity. 4. Slow EPSPs evoked both by CF and PF stimulation were associated with an increase in membrane conductance and were increased in amplitude by hyperpolarization. 5. The CF-evoked slow EPSP was profoundly attenuated by repetitive activation at interstimulus intervals of less than 15-20 s, whereas the PF-evoked slow EPSP was not reduced by repetitive activation. 6. The PF-evoked slow EPSP readily triggered dendritic pacemaker discharges when activated at or near resting membrane potential. The activation of this potential by phasic PF volleys may, therefore, provide an appropriate synaptic drive to cerebellar Purkinje cells to entrain the intrinsic pacemaker properties of these cells to cycles of motor activity. 7. Both slow synaptic potentials were blocked by the excitatory amino acid antagonists kynurenate and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but not by DL-2-amino-5-phosphonovalerate (DL-AP5) or L-serine-O-phosphate (L-SOP). The PF-evoked slow EPSP was selectively antagonized by L-2-amino-4-phosphonobutyrate (L-AP4; 20-100 microM). 8. It is suggested that the CF- and PF-evoked slow EPSPs observed in this study represent a novel class of excitatory amino acid receptor-mediated slow synaptic potentials activated by Purkinje cell afferents, which may play a role in synaptic integration and motor pattern generation in the cerebellum.

This paper focuses upon the collection and processing of government mortality statistics, and especially upon the organisational and theoretical contexts within which such statistics are assembled. Two items of mortality data in particular are examined with a view to illustrating the broader issues: medical cause of death, and social class of deceased. Using a 10 per cent sample of 1981 Belfast death certificates as a base, the paper attempts to trace the specific stages through which the cause of death and social class data have to pass prior to their incorporation into mortality reports. The paper indicates that there are numerous grounds for believing that both kinds of data are flawed at their points of origin, and that the transformations which the data undergo during coding procedures leads to further distortions of our image of mortality and its social base. It is argued that these flaws and distortions are only partly due to technical and organisational shortcomings, and more likely due to weaknesses in the theoretical frameworks through which the data are sifted. The paper concludes by suggesting that the existing arrangements for registering deaths, dominated as they are by the principles of forensic medicine, are more properly viewed as a system for policing the dead, than as a mechanism for generating worthwhile data about diseases and their social distribution.

Rates of sexual-partner change and patterns of high-risk behaviour are important determinants of the spread of HIV. We carried out a survey to assess the feasibility of studying sexual lifestyle in a random sample of the British population, aged 16-64 years, in November 1987. Two thousand and seventy-seven households were selected using a multi-stage probability sampling procedure. Seven hundred and eight-five adults participated in a structured interview. The schedule included demographic details, attitudes to AIDS, numbers of sexual partners in different time periods, history of homosexuality and contact with prostitutes. An interview was obtained in 61% of households where contact was made, but the overall response rate was low (48%). There was marked variability between individuals in numbers of sexual partners in given time intervals. Men and women in younger cohorts had experienced first sexual intercourse earlier and had higher numbers of sexual partners than people in older cohorts. Surprisingly few reported high-risk behaviour such as homosexuality and use of prostitution. The methodological problems in trying to obtain unbiased and valid data on sexual behaviour are discussed. Further work is necessary to improve the response rate and questionnaire design.

Artefact explanations seek to account for inequalities in health as a construct of the measurement process. The Black Report believed that the artefact explanation was relatively unimportant in accounting for the persistence of class inequalities in health. This paper reviews the evidence on artefact explanations of class differentials in specific-cause and all-cause mortality data, and also of differentials by occupation, by geography, and by gender. It is concluded that the role of artefact explanations in mortality differentials is larger, more pervasive, and more complex than Black and his colleagues believed.

In the isolated turtle cerebellum intracellular recordings from Purkinje cell dendrites and somata reveal novel slow excitatory synaptic potentials evoked by activation of climbing fiber (CF) or parallel fiber (PF) inputs. Classical fast excitatory synaptic responses to CF and PF stimulation are followed by large, slow excitatory postsynaptic potentials (sEPSPs) which are associated with an increase in conductance and are enhanced by hyperpolarization. Both sEPSPs are blocked by the excitatory amino acid (EAA) antagonist kynurenate, but not by DL-2-amino-5-phosphonovalerate (AP-5). The EAA receptor antagonist L-amino-4-phosphonobutyric acid (L-AP-4) reversibly blocked the PF-sEPSP without affecting the CF-sEPSP. Two novel slow synaptic potentials mediated by excitatory amino acid receptors can therefore be observed in turtle cerebellum which may play an important role in synaptic integration.

The effects of excitatory amino acid (EAA) receptor antagonists were examined on intracellularly recorded epileptiform discharges in turtle hippocampal (ventromedial cortical) pyramidal neurons in vitro. Afferent synaptic activation of turtle hippocampal neurons evoked monophasic or biphasic GABAergic inhibitory postsynaptic potentials (IPSPs). In the presence of bicuculline (5 microM) or picrotoxin (100 microM) IPSPs were reduced, and long-lasting ictal-like discharges were transiently observed prior to the establishment of a regular rhythm of discharge of spontaneous paroxysmal depolarization shifts (PDSs). Bicuculline-induced PDSs were reversibly reduced in amplitude and duration, but not abolished by the EAA receptor antagonists kynurenic acid (1 mM), cis-2,3-piperidine dicarboxylic acid (cis-2,3-PDA) (1 mM), or DL-2-amino-5-phosphonovalerate (DL-AP-5) (100 microM), revealing a long-lasting hyperpolarizing afterpotential. These results indicate that the blockade of GABAergic inhibition leads to the genesis of epileptiform discharges, and EAA receptor antagonists (particularly those of the N-methyl-D-aspartate (NMDA) receptor subtype) block the maintained depolarization underlying PDSs, but do not prevent their spontaneous discharge in turtle hippocampus.