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Biomedical subjects

R P Hart

Publications and source records attributed to R P Hart.

At least 19 recordsLinked to original sources
PubMed1999

Motoric encoding and retention of pictures in Alzheimer's disease.

20 patients with Alzheimer's disease were shown line drawings of common objects on two trials. During the second trial they were asked to pantomime an action for the object and then provided a standard motoric cue or were asked to name it and then provided a standard semantic cue. Semantic cueing served as a stimulus-processing control condition. Memory for pictures was assessed at a 48-hr. delay interval using a yes-no recognition-memory procedure. Discrimination of stimulus pictures from distractors at 48 hours was similar for the motoric and control (semantic) encoding condition. These findings suggest that motoric encoding does not enhance long-term retention of episodic memories for pictures in such patients.

Aged↗
PubMed1998

Cultured sympathetic neurons express functional interleukin-1 receptors.

Since recent work has identified an apoptotic pathway in sympathetic neurons that is mediated by autocrine interleukin-1 (IL-1), we investigated whether cultured sympathetic neurons possess functional IL-1 receptors. Cultured sympathetic neurons express levels of IL-1RI and IL-1RAcP mRNAs consistent with signal transduction. Neurons stimulated with IL-1 demonstrate enhanced p65 NF-kappaB nuclear translocation and enhanced NF-kappaB DNA binding activity, with at least p65 and p50 subunits participating in the DNA binding activity. RNA differential display identified several neuronal mRNAs regulated by IL-1, including a member of the reticulon family. We conclude that IL-1 stimulates a potential component of a neuronal secretory pathway.

Animals↗
PubMed1998

Vigilance performance in Parkinson's disease and depression.

Patients with Parkinson's disease (PD), patients with Major Depression (MD) and normal control (NC) subjects were administered a continuous performance test (CPT) under neutral and incentive conditions. Patients made more errors than NC subjects with the MD group making a disproportionately large number of omission errors and the PD group tending to make commission errors. Incentive reduced errors across groups. Reaction times were slowest in the MD group. The pattern of findings in patients with MD is consistent with a failure of effort-demanding cognitive processes. In contrast, nondemented patients with PD appeared to have deficiencies in executive control. A previously reported paradoxical effect of incentive on recognition memory performance in depressed patients did not generalize to a vigilance task.

Aged↗
PubMed1997

Abbreviated cognitive test for delirium.

The cognitive test for delirium (CTD) was recently developed to identify delirium in an intensive care unit (ICU) setting. Stepwise discriminant analyses using the original validation sample indicated that a total score formed by summing only two of the nine content scores (visual attention span and recognition memory for pictures) maintained good reliability (coefficient alpha = 0.79) and the ability to discriminate delirium from dementia, schizophrenia, and depression (p < 0.0001) and delirium from moderate to severe dementia (p < 0.0002). This abbreviated version of the CTD is more practical for use by ICU clinicians.

Adult↗
PubMed1997

Localisation of mRNA for interleukin-1 receptor and interleukin-1 receptor antagonist in the rat ovary.

Interleukin-1 (IL-1) is a multifunctional cytokine with profound effects on ovarian function. The effects of IL-1 on ovarian steroidogenesis have been demonstrated in several species. IL-1 mRNA levels are increased in the thecal layer of the ovulating follicle and IL-1 beta has been shown to induce ovulations in vitro. In this study we have investigated the presence and distribution of the mRNAs for type I IL-1 receptor (IL-1RtI) and for the naturally occurring IL-1 receptor antagonist (IL-1ra) in ovaries of adult cycling rats, to elucidate the target cells for IL-1 action. We have demonstrated the presence of mRNA for both substance by in situ hybridisation and reverse transcription PCR. mRNA for IL-1RtI was not found in primordial follicles but was abundant in the granulosa and thecal layer in developing follicles with stronger signals in the granulosa layer. In the preovulatory and ovulatory follicles, there was a further increase in the signal for IL-1RtI mRNA in the thecal layer compared with the granulosa layer. Corpora lutea were weakly positive at all stages and atretic follicles were largely negative. No mRNA was detected in oocytes of any stage mRNA for IL-1ra showed a similar distribution to that of IL-1RtI. The changes in distribution suggest an action of IL-1 on rat granulosa cells during follicular development and on thecal cells during ovulation.

Animals↗
PubMed1996

Cloning and characterization of an alternatively processed human type II interleukin-1 receptor mRNA.

Two types of interleukin (IL)-1 receptors with three extracellular immunoglobulin-like domains, limited homology (28%), and different pharmacological characteristics termed type I and type II have been cloned from mouse and human cell lines. Both receptors exist in transmembrane and soluble forms; the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors. In preliminary cross-linking studies with radiolabeled IL-1, we found that monkey kidney COS1 cells express a soluble receptor with molecular mass of approximately 55-60 kDa, which is different from previously reported soluble IL-1 receptors. This soluble IL-1 receptor protein from COS1 cells was purified to homogeneity by affinity chromatography using recombinant IL-1beta as the ligand and shown to have an affinity for human 125I-IL-1beta (KD approximately 2-3 nM) comparable to the human type II IL-1 receptor (IL-1RII). The purified protein was microsequenced, and the sequence information was used to design primers to clone the COS1 IL-1RII using reverse transcription-coupled polymerase chain reaction; the DNA comparison with monkey COS1 and human IL-1RII indicate that they are 95% identical at the nucleic acid and amino acid levels. In addition, another cDNA, which represents an alternatively processed mRNA of the IL-1RII gene, was also cloned both from monkey COS1 and human Raji cells and was shown to have approximately 95% sequence identity between these species. While the cDNA of the novel alternatively processed gene has a 5' end identical to the IL-1RII, the 200 base pairs at the 3' end are different and the sequence predicts a soluble IL-1 receptor protein of 296 amino acids. Radioligand binding studies of the alternatively processed IL-1RII mRNA demonstrated kinetic and pharmacological characteristics similar to the known type II IL-1 receptor. COS7 cells (which lack IL-1 receptor) transfected with the transmembrane form of the human IL-1RII cDNA showed 125I-IL-1beta binding in both the membrane fractions and supernatant. In contrast, COS7 cells transfected with the alternatively processed human IL-1RII cDNA showed high affinity 125I-IL-1beta binding (Ki approximately 1.2 nM) predominantly in the supernatant; a very small amount of detectable membrane IL-1 binding activity was also observed presumably due to association of the soluble IL-1 receptor and membrane-integrated proteins. In cross-linking and ligand blot studies, the alternatively processed human IL-1RII cDNA-transfected COS7 cells expressed a soluble IL-1 receptor with molecular masses ranging from 60 to 160 kDa, further indicating the association between this soluble IL-1 receptor and other soluble proteins. In summary, we report the purification and characterization of a soluble IL-1 receptor expressed by COS1 cells and the cloning of an alternatively processed type II IL-1 receptor mRNA from both human and COS1 cells. The alternative splicing of a primary transcript leading to a secreted protein provides a potentially important mechanism by which soluble IL-1RII can be produced.

Alternative Splicing↗
PubMed1996

Activation of acidic sphingomyelinase and protein kinase C zeta is required for IL-1 induction of LIF mRNA in a Schwann cell line.

Axotomy of sympathetic superior cervical ganglia (SCG) causes Schwann cells to induce mRNA encoding leukemia inhibitory factor (LIF), a neuropoietic cytokine that has been shown to promote sympathetic neuron survival and peptide gene regulation. LIF mRNA is virtually undetectable in uninjured SCG, but is induced by the inflammatory cytokine interleukin-1 (IL-1). The SC1 Schwann cell line was used to study this regulatory mechanism. LIF mRNA increased five-to-tenfold in SC1 cells when IL-1 receptors were stimulated with IL-1. The action of IL-1 is thought to be mediated by the type I IL-1 receptor (IL-1RI), which has been suggested to stimulate a ceramide-dependent protein kinase pathway, much like tumor necrosis factor-alpha. However, stimulation of the ceramide-dependent protein kinase pathways in SC1 cells with either 2-acetylceramide or sphingomyelinase treatment does not induce LIF mRNA accumulation, but 2-acetylceramide addition induces cyclooxygenase-2 mRNA in parallel experiments. Inhibition of phosphotidylcholine-phospholipase C activity, endosomal acidification, or activity of atypical protein kinase C reduce LIF induction by IL-1. These results are consistent with IL-1 regulation of LIF mRNA through stimulation of the endosomal, acidic sphingomyelinase pathway, leading to ceramide activation of protein kinase C zeta. Utilization of this branch of the ceramide signaling pathway may be cell type specific or may be specific for the LIF mRNA response.

Animals↗
PubMed1996

Interleukin-1 beta increases leukemia inhibitory factor mRNA levels through transient stimulation of transcription rate.

Interleukin-1 beta (IL-1 beta) induces leukemia inhibitor factor (LIF) expression in a number of cell types including non-neuronal cells of the sympathetic superior cervical ganglion (SCG). Upregulation of LIF by inflammatory cytokines is usually associated with injury response. We characterized the molecular mechanism of LIF mRNA regulation by IL-1 beta in explanted neonatal rat SCG and a Schwann cell line. IL-1 beta increases LIF mRNA levels by interacting with IL-1 receptors in SCG, since this induction could be diminished by inclusion of either soluble IL-1 receptors or IL-1 receptor antagonist. The antiinflammatory glucocorticoid dexamethasone also inhibits LIF mRNA induction by IL-1 beta. LIF mRNA encodes a 3' AU-rich mRNA stability control sequence, but IL-1 beta does not appear to regulate the decay of LIF mRNA by this mechanism. IL-1 beta does not raise LIF gene transcription rate in cultured SCG 6 or 24 h after addition of IL-1 beta as measured by nuclear run-on assays. LIF gene transcription is induced repidly and transiently in an immortalized Schwann cell line, returning to uninduced rates by 1 h after induction. These results suggest that the IL-1 beta induction of LIF gene expression is at least partially transcriptional, but that LIF mRNA increases to a greater extent than LIF transcription, suggesting the possibility of posttranscriptional regulation as well.

Animals↗
PubMed1996

Interleukin-1 involvement in the induction of leukemia inhibitory factor mRNA expression following axotomy of sympathetic ganglia.

Axotomy of superior cervical (sympathetic) ganglia (SCG) results in increased neuropeptide gene expression. In vitro, neuropeptide gene expression is similarly increased by exposure to the inflammatory cytokine interleukin-1 (IL-1). The effect of IL-1 in-vitro has been shown to be mediated by leukemia inhibitory factor (LIF). Since IL-1 regulates neuropeptide expression via LIF in vitro, we asked whether axotomy in vivo produces an increase in LIF mRNA, and whether that increase is regulated by IL-1 activity. Within 6 h following axotomy, ganglionic LIF mRNA is substantially elevated. Moreover, axotomy produces a rapid and transient increase in intraganglionic IL-1 beta mRNA, followed rapidly by an increase in ICAM-1 mRNA, thereby suggesting a local source of IL-1 activity. Pretreatment with the anti-inflammatory agent dexamethasone (DEX) reduces the increases of both IL-1 beta and LIF mRNAs following axotomy. mRNA encoding the specific signal-transducing Type I IL-1 receptor is present in unlesioned SCG in vivo, and increases following axotomy. Local application of IL-1 beta in vivo induces LIF mRNA even in uninjured ganglia, though not to the extent seen with axotomy. DEX treatment blocks this IL-1 beta-mediated increase in LIF mRNA. Therefore, DEX blocks the induction of LIF mRNA by inhibiting both the production of IL-1 and its action on LIF gene expression. Axotomy of a homozygous IL-1 receptor type I gene knockout mouse leads to a delayed and/or diminished induction of LIF mRNA in SCG, but does not prevent LIF mRNA expression. We conclude that while IL-1 is likely to be involved in the cascade of gene expression that follows axotomy, it alone is not sufficient to mediate the full induction of LIF mRNA by axotomy.

Animals↗
PubMed1995

Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1-induced cellular activation.

Systemic interleukin-1 (IL-1) activates the hypothalamo-pituitary-adrenal (HPA) axis, an effect exerted through increased synthesis and secretion of corticotropin-releasing factor (CRF) by parvicellular neurosecretory neurons. The site(s) and mechanism(s) through which circulating IL-1 may access central systems governing HPA axis output remain obscure. To identify potential cellular targets for blood-borne IL-1, we analyzed the distribution of mRNA encoding the rat type 1 IL-1 receptor (IL-1R1) in rat brain. Regional ribonuclease protection assays detected a single protected fragment corresponding to the membrane-bound form of the IL-1R1 mRNA in all areas analyzed. In situ hybridization revealed labeling predominantly over barrier-related cells, including the leptomeninges, non-tanycytic portions of the ependyma, the choroid plexus, and vascular endothelium. Low to moderate levels of the IL-1R1 mRNA were detected in just a few neuronal cell groups, including the basolateral nucleus of the amygdala, the arcuate nucleus of the hypothalamus, the trigeminal and hypoglossal motor nuclei, and the area postrema. No specific labeling for IL-1R1 mRNA was detected over neurons that respond to intravenous IL-1 beta by induction of transcription factor Fos, including hypophysiotropic CRF cells and brainstem catecholamine neurons. Injection of IL-1 beta did, however, provoke induction of mRNA encoding the immediate-early gene, NGFI-B, but not c-fos, in two major loci of IL-1R1 expression, vascular endothelial cells, and the area postrema. Intravenous injection of IL-1 beta acutely down-regulated IL-1R1 mRNA in perivascular cells, but not in neuronal cell groups. These results suggest the parenchymal sites of IL-1R1 expression in rat to be distinct from those reported previously in mouse. The common expression in both species of an IL-1R in non-neuronal elements highlights the possibility that IL-1-mediated activation of CRF neurons may result from cytokine-receptor interaction at vascular, and/or other barrier-related, sites to trigger release of secondary signalling molecules in a position to interact with components of HPA control circuitry.

Animals↗
PubMed1995

Tumor necrosis factor-alpha induces substance P in sympathetic ganglia through sequential induction of interleukin-1 and leukemia inhibitory factor.

The present study establishes that tumor necrosis factor-alpha (TNF-alpha) induction of sympathetic substance P (SP) requires sequential induction of both interleukin (IL-1) and leukemia inhibitory factor (LIF). TNF-alpha dose-dependently induces SP, an induction that is secondary to an increase in the SP precursor, preprotachykinin (PPT), mRNA. Since TNF-alpha conditioned medium (CM) mimics the effect of TNF-alpha by raising SP, actions that are not antagonized by a neutralizing TNF-alpha antibody, TNF-alpha induction of SP is mediated by a soluble intermediate or intermediates. The blockade of TNF-alpha action by a specific IL-1 receptor antagonist and the induction of IL-1 mRNA by TNF-alpha suggest that IL-1 is one of the intermediates. Moreover, because immunoprecipitation with LIF antibodies decreases SP-inducing activity of TNF-alpha CM, and because LIF mRNA is also induced by TNF-alpha, LIF is a second intermediate. Furthermore, TNF-alpha-induced LIF mRNA is blocked by the IL-1 receptor antagonist, whereas IL-1-induced LIF mRNA is not affected by TNF-alpha antibodies, suggesting that TNF-alpha first induces IL-1, and IL-1 subsequently induces LIF. These data suggest that TNF-alpha induces SP in sympathetic ganglia through the sequential inductions of IL-1 and LIF.

Animals↗
PubMed1995

Species-specific activity of rat recombinant interleukin-1 beta.

We have constructed expression clones for mature rat interleukin-1 beta (IL-1 beta). Using these clones, rat recombinant IL-1 beta (rrIL-1 beta) was prepared and purified by a single-step cation-exchange chromatography method. In addition, synthetic rrIL-1 beta mRNA was transcribed and used to synthesize radiolabeled 35S-rrIL-1 beta for binding studies. The rrIL-1 beta produced was demonstrated to have IL-1 bioactivity in a mouse thymocyte proliferation assay, in which it could be blocked by inclusion of human recombinant IL-1 receptor antagonist (hrIL-1Ra). Similarly, rrIL-1 beta induced LIF mRNA expression in cultured rat sympathetic ganglia. In each case, the maximal dose of rrIL-1 beta was similar to that of human IL-1 beta. However, the peak response in rat tissue was twofold higher with rat IL-1 beta than with human IL-1 beta. The expression of rrIL-1 beta provides a useful tool for studying IL-1 receptors in rat, in which human and mouse IL-1 beta have been found to bind poorly. Species-specific activity of rat IL-1 beta may correlate with compensatory ionic properties of rat IL-1 receptor.

Amino Acid Sequence↗
PubMed1994

The interleukin-1-induced increase of substance P in sympathetic ganglia is not mediated by ciliary neurotrophic factor.

Interleukin-1 (IL-1) induction of substance P (SP) in cultured sympathetic ganglia requires a soluble intermediate molecule that is present in IL-1 conditioned medium (IL-1CM). One of the required intermediates is leukemia inhibitory factor (LIF; Shadiack et al., J Neurosci 13:2601-2609, 1993). In the present study we have examined the possibility that ciliary neurotrophic factor (CNTF) is another intermediate involved in the IL-1 induction of sympathetic SP. CNTF mimics the action of IL-1CM by raising both SP and choline acetyltransferase activity--actions that are blocked by a specific neutralizing antiserum for CNTF. However, IL-1CM and CNTF differ in their response to depolarizing agents: while KCl (40 mM) blocks the action of IL-1CM (and LIF), it enhances the action of CNTF. Furthermore, neither CNTF bioactivity nor CNTF protein is detected in IL-1CM. Neutralizing antiserum to CNTF fails to block the action of either IL-1 or IL-1CM, suggesting that neither a soluble nor a membrane-bound form of the molecule is active in direct response to IL-1 action. While Northern blots confirm the presence of both CNTF and CNTF receptor mRNA in neonatal ganglia, neither culturing nor IL-1 treatment alters these mRNA levels. These data taken together suggest that while CNTF is present and possibly active in sympathetic ganglia, it is not a mediator of the IL-1 induction of SP.

Animals↗
PubMed1994

Lipopolysaccharide induces substance P in sympathetic ganglia via ganglionic interleukin-1 production.

The immune cytokine interleukin-1 (IL-1) causes a pronounced elevation in substance P (SP) immunoreactivity and the mRNA coding for its preprotachykinin precursor in cultured superior cervical (sympathetic) ganglia (SCG; Jonakait and Schotland, 1990; Freidin and Kessler, 1991; Hart et al., 1991). In this study we have investigated the possibility that the SCG can respond to other immune stimulators, notably lipopolysaccharide (LPS), a product of bacterial cell walls. LPS treatment of cultured SCG resulted in a dose-dependent increase in SP. However, LPS did not induce SP in the absence of non-neuronal cells, suggesting the necessity of a non-neuronal cell-derived intermediate. Since the LPS induction of SP was partially blocked by a specific IL-1 receptor antagonist (IL-1ra) and since LPS induced approximately an 8-fold increase in mRNA coding for IL-1 itself, we concluded that IL-1 is at least one of these LPS-induced intermediates. TNF-alpha, which also raises SP levels, may be another. IL-6, which may also be increased by LPS, does not increase levels of SP. The synthetic glucocorticoid hormone dexamethasone (DEX) blocks the LPS induction of SP with a Ki approximating 8 x 10(-11) M. The inhibition is due in part to the blockade of the LPS induction of ganglionic IL-1 mRNA. Moreover, inhibition of the LPS induction of SP by indomethacin implies mediation of the effect through prostaglandins. The inhibition by indomethacin suggests a non-monocytic cell source since prostaglandins are thought to restrict the LPS induction of monocytic IL-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Interferon-gamma promotes cholinergic differentiation of embryonic septal nuclei and adjacent basal forebrain.

In cultured rat embryonic septal nuclei with adjacent basal forebrain, murine interferon-gamma (IFN gamma) produces a striking increase in choline acetyltransferase (ChAT) activity and mRNA. The effect of IFN gamma on cholinergic differentiation is more potent in E14 cultures than in older cultures. IFN gamma does not cause a change in the affinity of ChAT for choline, nor does it affect cell proliferation. Whereas IFN gamma doubles neuronal cell number, the cholinergic cell number increases more than 7-fold. Ameboid microglia respond to IFN gamma with the translocation of p91 to the nucleus. The action of IFN gamma is not mediated by NGF or bFGF. The enhancement of cholinergic expression that occurs with increased cell density may be partly attributable to an endogenous IFN gamma-like molecule, since antibodies to IFN gamma offset the effects of increased cell density.

Animals↗
PubMed1994

Neuropsychological functioning in older insomniacs with or without obstructive sleep apnea.

The relationships between neuropsychological functioning and sleep loss, sleep apnea, and hypoxemia were examined. Forty-five older insomniacs (M age = 64.6 years) with or without sleep apnea were administered neuropsychological tests after 1 night of nocturnal monitoring in a sleep laboratory. The results showed few differences on cognitive and psychomotor performance between individuals with sleep disruptions alone compared with those whose insomnia was associated with sleep apnea and hypoxemia. There were no significant relationships between nocturnal sleep and respiratory variables and daytime functioning. Furthermore, cognitive and psychomotor performance in older insomniacs with or without sleep apnea revealed minimal impairment compared with age-matched normative data. The results suggest that when the severity of sleep disruptions is controlled, there are minimal differences in neuropsychological functioning of older adults with mild to moderate sleep apnea compared with those without apnea.

Aged↗
PubMed1993

Factors related to the severity of tardive dyskinesia.

This study was undertaken to clarify factors associated with severity of tardive dyskinesia (TD). It was hypothesized that dopaminergic changes associated with neuroleptic medication may interact with unknown vulnerabilities contributing to the manifestation of TD. Fifty-four psychiatric patients residing on the acute and intermediate care wards of a Veterans Administration hospital participated. Thirty schizophrenic and 24 manic patients, under 60 years of age, were assessed for TD using the Abnormal Involuntary Movement Scale. Cognitive tests were used to form verbal and nonverbal composite indices. The results of multiple regression analyses revealed a modest linear relationship between TD and nonverbal function (p < .03) after controlling for duration of hospitalization, years of illness, motor speed, and age. This relationship was noted for both manic and schizophrenic patients. The results of this study suggest that nonverbal dysfunction is related to severity of TD.

Adult↗