Embedding routine health checks for adults with intellectual disabilities in primary care: practice nurse perceptions.

BACKGROUND: Adults with intellectual disabilities (IDs) have consistently poorer health outcomes than the general population. There is evidence that routine health checks in primary care may improve outcomes. We conducted a randomised controlled trial of practice nurse led health checks. Here, we report findings from the nested qualitative study. AIM: To explore practice nurse perceptions and experience of delivering an anticipatory health check for adults with IDs. DESIGN AND SETTING: Qualitative study in General Practices located in NHS Greater Glasgow and Clyde, Scotland, UK. METHOD: Eleven practice nurses from 11 intervention practices participated in a semi-structured interview. Analysis was guided by a framework approach. RESULTS: Practice nurses reported initially feeling 'swamped' and 'baffled' by the prospect of the intervention, but early misgivings were not realised. Health checks were incorporated into daily routines with relative ease, but this was largely contingent on existing patient engagement. The intervention was thought most successful with patients already well known to the practice. Chronic disease management models are commonly used by practice nurses and participants tailored health checks to existing practice. It emerged that few of the nurses utilised the breadth of the check instead modifying the check to respond to individual patients' needs. As such, already recognised 'problems' or issues dominated the health check process. Engaging with the health checks in this way appeared to increase the acceptability and feasibility of the check for nurses. There was universal support for the health check ethos, although some questioned whether all adults with IDs would access the health checks, and as a consequence, the long-term benefits of checks. CONCLUSION: While the trial found the intervention to be dominant over standard health care, the adjustments nurses made may not have maximised potential benefits to patients. Increasing training could further improve the benefits that health checks provide for people with IDs.

A numerical investigation of breast compression: a computer-aided design approach for prescribing boundary conditions.

Prior to performing an MRI-guided breast biopsy, the radiologist has to locate the suspect lesion with the breast compressed between rigid plates. However, the suspect lesion is typically identified from a diagnostic MRI exam with the breast hanging freely under the force of gravity. There are several challenges associated with localizing suspect lesions including, patient positioning, the visibility of the lesion may fade after contrast injection, menstrual cycles, and lesion deformation. Researchers have developed finite element analysis (FEA) methodologies that simulate breast compression with the intent of reducing these challenges. In this paper, we constructed a patient-specific finite element (FE) breast model from diagnostic MR images. In addition, we constructed surfaces corresponding to the biopsy MR volume and used them to deform the FE breast mesh. The predicted results suggest that the FE breast model, in its uncompressed configuration, can be compressed to replicate the perimeter of the biopsy MR volume. The simulated lesion displacement was within 3 mm of its actual position.

Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins.

Little axonal regeneration occurs after spinal cord injury in adult mammals. Regrowth of mature CNS axons can be induced, however, by altering the intrinsic capacity of the neurons for growth or by providing a permissive environment at the injury site. Fetal spinal cord transplants and neurotrophins were used to influence axonal regeneration in the adult rat after complete spinal cord transection at a midthoracic level. Transplants were placed into the lesion cavity either immediately after transection (acute injury) or after a 2-4 week delay (delayed or chronic transplants), and either vehicle or neurotrophic factors were administered exogenously via an implanted minipump. Host axons grew into the transplant in all groups. Surprisingly, regeneration from supraspinal pathways and recovery of motor function were dramatically increased when transplants and neurotrophins were delayed until 2-4 weeks after transection rather than applied acutely. Axonal growth back into the spinal cord below the lesion and transplants was seen only in the presence of neurotrophic factors. Furthermore, the restoration of anatomical connections across the injury site was associated with recovery of function with animals exhibiting plantar foot placement and weight-supported stepping. These findings suggest that the opportunity for intervention after spinal cord injury may be greater than originally envisioned and that CNS neurons with long-standing injuries can reinitiate growth, leading to improvement in motor function.

Descending modulation of opioid-containing nociceptive neurons in rats with peripheral inflammation and hyperalgesia.

Inflammation and hyperalgesia induce a dramatic up-regulation of opioid messenger RNA and peptide levels in nociceptive neurons of the spinal dorsal horn. Descending axons modulate nociceptive transmission at the spinal level during inflammatory pain, and may play a role in the development of persistent pain. The role of descending bulbospinal pathways in opioid-containing nociceptive neurons was examined. Removal of descending inputs to the spinal cord was performed by complete spinal transection at the midthoracic level. Seven days after spinal transection, rats received a unilateral hindpaw injection of complete Freund's adjuvant, a noxious stimulus that produces inflammation and hyperalgesia. Tissues from the L4 and L5 segments of the spinal cord were removed and analysed by northern blotting and immunocytochemistry. Spinal transection resulted in a further increase in both dynorphin and enkephalin messenger RNA content following complete Freund's adjuvant injection. There was a similar distribution and number of dynorphin-immunoreactive cells in transected rats compared to rats which received sham surgery. These data suggest that increased dynorphin messenger RNA ipsilateral to inflammation, in rats without descending axons, was due to increased expression within the same cells and not to recruitment of additional dynorphin-expressing cells. This reflects a greater dynamic response of nociceptive neurons to noxious stimuli in the absence of descending modulation. Therefore, the net effect of descending afferents on spinal nociceptive circuits may be to reduce the response of opioid-containing neurons to noxious stimulation from the periphery.

AP-1-related proteins bind to the enkephalin CRE-2 element in adrenal chromaffin cells.

Chromaffin cells of the adrenal medulla are neural crest-derived neuroendocrine cells that express neuropeptide genes in vivo and in vitro. As such these cells are useful for examining tissue- and cell-specific regulation of the enkephalin gene. We previously demonstrated that the chromatin configuration of the enkephalin gene correlated with its tissue-specific expression in the adrenal medulla and primary chromaffin cell cultures. In this study we examine and characterize binding of transcription factors to the enkephalin promoter/enhancer region. Gel shift analyses of this region with extracts from chromaffin cells and PC12 cells (a pheochromocytoma cell line that does not express the enkephalin gene) demonstrate that all detectable binding is to ENKCRE-2, a cyclic AMP response-like element, and that the binding is cell specific. Gel shift and supershift analyses show that, unlike reports demonstrating that binding activity in the CNS is composed of the cyclic AMP response element binding protein, CREB, the majority of protein binding in chromaffin cells is from the AP-1 family of transcription factors. This binding is composed of c-Jun, JunD, and possibly a novel Fos-related protein(s). These data suggest enkephalin gene expression in the adrenal gland is controlled by cell-specific binding of transcription factors from the Fos/Jun families to the enkephalin CRE-2 element. Furthermore, these data suggest at least two different modes of enkephalin gene regulation exist between endocrine and neuronal tissues.

Neuropeptide genes: targets of activity-dependent signal transduction.

Neuroendocrine cells respond to hormones and synaptic input by increasing or decreasing their own electrical activity and secretory output, and by changes in the repertoire of expression of neuronal genes. Neuropeptide genes are among those whose transcription rates can be dramatically up-and downregulated when neuronal activity is altered. In the last decade or so, our understanding of neuropeptide gene regulation has evolved from the concept of calcium-dependent coupling of neuropeptide secretion and biosynthesis to the current perspective of neuropeptide genes as the targets of multiple intracellular signaling pathways, entrained by intrinsic electrical activity and by transsynaptic influences. This review describes our current understanding of neuropeptide gene regulation in the adrenal gland as well as in the peripheral and central nervous systems. Particular emphasis is placed on the molecular mechanisms that allow unique patterns of expression of neuropeptide genes within specific types of neuroendocrine cells that contribute to the remarkable anatomical specificity of neuropeptide gene expression.

Identification of a TPA-responsive element mediating preferential transactivation of the galanin gene promoter in chromaffin cells.

The gene encoding the neuropeptide galanin is upregulated by second messenger signal transduction pathways in bovine chromaffin cells. To identify its transcriptional regulatory elements, 5'-flanking sequences of the galanin gene were transiently transfected into primary cultures of bovine chromaffin cells within reporter gene constructs. Multiple regions of the galanin 5' flank seem to be necessary for basal activity. The most promoter-proximal of these regions contains a sequence (TGACG) -66 to -62 nucleotides upstream from the transcriptional start site which mediates stimulation by 12-O-tetradecanoylphorbol-13-acetate (TPA), as demonstrated by site-directed mutagenesis and cis-activation experiments. This cis-regulatory element mediates preferential TPA stimulation of transcription from the galanin promoter in chromaffin cells compared with bovine endothelial or HeLa cells. DNA-protein binding assays indicate that an oligonucleotide that includes the galanin TPA-responsive element (GTRE) binds specifically to proteins from nuclear extracts of chromaffin cells. TPA treatment persistently increases this binding activity in chromaffin but not in endothelial cells. Mutation of the galanin promoter within the -66 to -62 region renders it unresponsive to transcriptional stimulation by TPA, and a correspondingly mutated oligonucleotide fails to bind chromaffin cell nuclear proteins in a gel-shift assay. Chromaffin cell nuclear extracts also contain proteins that bind consensus TPA-responsive (TRE) and cyclic AMP-responsive (CRE) elements. GTRE, TRE, and CRE oligonucleotides all compete more efficiently for protein binding to their labeled congeners than for protein binding to either of the other labeled oligonucleotides, suggesting that the GTRE, TRE, and CRE oligonucleotides, suggesting that the GTRE, TRE, and CRE oligonucleotides each bind unique as well as common proteins, likely to be members of the Jun/Fos and cAMP-responsive element-binding protein/activating transcription factors (CREB/ATF) families of transcription factors, in chromaffin cells.

Adrenal secretion of BAM-22P, a potent opioid peptide, is enhanced in rats with acute cholestasis.

The adrenal gland is known to produce and release endogenous opioids into the circulation. Bovine adrenal medulla docosapeptide (BAM-22P) is a potent opioid agonist, derived from the proenkephalin A gene, which is present in the adrenal medulla. This study was undertaken to determine whether BAM-22P is released into plasma during acute cholestatic liver injury, which increases plasma total opioid activity. Acute cholestasis was induced by bile duct ligation or administration of the hepatotoxin alpha-naphthylisothiocyanate. Plasma levels of BAM-22P were determined by a sensitive radioimmunoassay, and the specificity of the assay was confirmed using high-performance liquid chromatography. Plasma BAM-22P levels was cholestatic rats were significantly higher than those in control rats. This increase in plasma BAM-22P levels was completely prevented by adrenalectomy. Adrenal steady-state levels of proenkephalin mRNA, as determined by Northern blot hybridization analyses, were also increased significantly in cholestatic rats. These increases in proenkephalin mRNA levels were not paralleled by changes in adrenal BAM-22P peptide levels, which were similar in cholestatic rats and their respective controls. Similar levels of proenkephalin mRNA expression were observed in innervated and denervated adrenal glands from cholestatic rats, suggesting that the increase in adrenal proenkephalin mRNA levels in acute cholestasis is not due to splanchnic nerve activation. Thus acute cholestasis in the rat is associated with adrenal secretion and accumulation in plasma of the highly potent opioid peptide BAM-22P and an augmentation of adrenal proenkephalin mRNA expression. The increase in plasma BAM-22P levels may contribute substantially to the increase in total circulating opioid activity documented in cholestatic rats.

Enkephalin gene transcription in bovine chromaffin cells is regulated by calcium and protein kinase A signal transduction pathways: identification of DNase I-hypersensitive sites.

The bovine enkephalin gene is responsive to multiple signaling pathways in primary chromaffin cell cultures. We examined the effects of activation of the calcium and protein kinase A pathways on accumulation of enkephalin peptide and mRNA, gene transcription, and chromatin structure in the 5' region of the gene. We show here that the increase of enkephalin mRNA and peptide after depolarization of chromaffin cells with KCl or activation of adenylate cyclase with forskolin is preceded by an increase in enkephalin gene transcription. Both enkephalin peptide and mRNA were reduced by co-treatment of KCl- or forskolin-stimulated cultures with phorbol esters. Three enhancer sequences that were previously shown to be responsive to calcium, protein kinase A, and phorbol esters in the human gene in vitro were identified in the bovine enkephalin promoter, identifying a potential locus of control for these pathways in vivo. DNase I hypersensitivity mapping identified two tissue-specific sites that are associated with enkephalin gene expression in adrenal medulla and chromaffin cells; site 1 is in the promoter, which contains the three enhancer elements, and site 2 is in the first intron. These results suggest that regulation of the enkephalin gene in primary chromaffin cells by the calcium, protein kinase A, and protein kinase C signaling pathways occurs by modulation of transcription factor activity at several discrete loci on the enkephalin gene.

Tumor-suppressor function of muscarinic acetylcholine receptors is associated with activation of receptor-operated calcium influx.

Several members of the family of guanine nucleotide-binding protein (G protein)-coupled receptors have recently been shown to induce agonist-dependent foci development in NIH 3T3 cells and tumors in nude mice. We selected the five subtypes of the muscarinic acetylcholine receptor family to investigate their role in tumor suppression. When transfected and expressed in CHO-K1 Chinese hamster ovary cells, m1, m3, and m5 muscarinic acetylcholine receptor activation resulted in a morphology change. Receptor activation did not slow or inhibit monolayer growth of CHOm5 cells in culture but markedly inhibited density-independent growth in soft agar and suppressed tumor formation in nude mice. Receptor-mediated tumor suppression was found to be agonist-dependent and reversible and was blocked with a muscarinic receptor antagonist. Of the five signaling pathways associated with the m1, m3, and m5 receptors, only receptor-operated, and inositol trisphosphate-independent, calcium influx was found to correlate with inhibition of tumorigenicity. These data suggest a pivotal role for inositol trisphosphate-independent receptor-regulated calcium homeostasis in CHO-K1 tumor suppression.

Enkephalin biosynthesis is coupled to secretory activity via transcription of the proenkephalin A gene.

The molecular mechanisms regulating neuropeptide and secretory protein biosynthesis in neuroendocrine cells were examined using the prototype neuropeptide and secretory proteins enkephalin and chromogranin A (CGA). Treatment with the secretogogue nicotine results in the calcium-dependent secretion of enkephalin peptides from bovine chromaffin cells in primary culture and a concomitant increase in enkephalin peptide biosynthesis. Both secretion and biosynthesis are also stimulated by cell depolarization with elevated potassium. Elevation of intracellular cyclic AMP, on the other hand, results in stimulation of enkephalin biosynthesis and long-term, but not acute, secretion of enkephalin peptides. Coupling of enkephalin biosynthesis to calcium influx occurs at the level of transcription of the enkephalin gene. Thus, potassium depolarization causes a calcium-dependent elevation of enkephalin mRNA which is preceded by an increase in the rate of transcription of the enkephalin gene in the chromaffin cell. The accumulation of enkephalin message or peptide by potassium depolarization or treatment with nicotine is prevented by D600 or hexamethonium respectively, added 1 h after addition of nicotine or KCl and following acute release, suggesting that calcium acts as a continuous rather than triggering stimulus for enkephalin biosynthesis. Sequence analysis of the bovine enkephalin promoter identified sequence conservation of three enhancers previously reported in the human gene which are required for regulation of the gene by calcium, cAMP, and phorbol ester in vitro. In contrast to the regulation of the enkephalin system, no increase in either CGA or CGB mRNA or gene transcription attended depolarization-induced secretion from chromaffin cells. Since enkephalin and CGA are co-stored in and co-released from the same secretory vesicles in these cells, the results imply that a surplus of CGA is constitutively synthesized in chromaffin cells such that compensatory up-regulation during changes in the secretory state of the cell, such as occurs for enkephalin, is not required for the secretory proteins.

Malignant transformation of NIH 3T3 fibroblasts by human c-sis is dependent upon the level of oncogene expression.

High-level expression of the c-sis oncogene, which encodes the beta chain of platelet-derived growth factor, transforms immortalized rodent fibroblasts in vitro to a malignant phenotype. c-sis gene expression has been demonstrated in a variety of human tumors, although generally at levels much lower than those shown to transform cells in vitro. We examined the effect of lower levels of c-sis expression on the phenotype of NIH 3T3 fibroblasts. Clones with various levels of c-sis expression were generated by transfecting NIH 3T3 cells with a plasmid that expressed the human c-sis cDNA and the TN5 neomycin-resistance gene. G418-resistant clones, which expressed the c-sis cDNA, were selected and characterized. Alterations in the phenotype of the clones that expressed c-sis ranged from increased growth in soft agar to malignant tumor formation in nude and syngeneic mice. Increased levels of c-sis cDNA expression correlated with the acquisition of features of transformation in a dose-dependent manner and altered the cellular phenotype in a manner consistent with the progression of cells towards malignancy. These data support a model in which low levels of sis gene expression in tumors contribute to the acquisition of some features of transformation but require complementation by other genes or factors to produce a fully malignant phenotype.

Suppression of the chemically transformed phenotype of BHK cells by a human cDNA.

Transformation of the baby hamster kidney cell line BHK SN-10 by chemical carcinogens such as nitrosylmethylurea (NMU) is mediated by the loss of a gene product critical for the suppression of malignant transformation. Somatic cell hybrids between chemically transformed BHK SN-10 cells and either normal hamster kidney or human fibroblast cells are nontransformed; therefore, a recessive mechanism underlies the malignant transformation of BHK SN-10 cells after chemical carcinogenesis (A. Stoler and N. P. Bouck, Proc. Natl. Acad. Sci. USA 82:570-574, 1985). A human fibroblast cDNA library was constructed and introduced into NMU-transformed BHK SN-10 cells (NMU 34m) in order to identify a human cDNA capable of suppressing cellular transformation. NMU-transformed BHK cells were analyzed for reversion to an anchorage-dependent normal cellular phenotype after transfection with human cDNA. The human cDNA capable of inducing stable reversion of NMU 34m cells encodes the intermediate filament protein vimentin, which is apparently required for maintenance of the normal phenotype in BHK SN-10 cells.

Cytomegalovirus retinopathy as the initial manifestation of the acquired immunodeficiency syndrome.

Of 100 consecutive patients with human immunodeficiency virus infection and cytomegalovirus retinopathy, 15 did not have a previous diagnosis of the acquired immunodeficiency syndrome before the ocular infection. All had other HIV-related disorders that would place them in Group IV of the Centers for Disease Control hierarchical classification system for HIV infections. In nine patients, cytomegalovirus retinopathy was the only disorder that fulfilled the Centers for Disease Control criteria for diagnosis of AIDS. In the other six, examination disclosed additional preexistent or concurrent nonocular disorders that were also diagnostic of AIDS. No demographic, medical, or ophthalmic characteristics distinguished the nine patients for whom cytomegalovirus retinopathy was initially the only manifestation of AIDS. On the basis of published figures for the prevalence of cytomegalovirus retinopathy in patients with AIDS, and the incidence with which HIV-infected persons develop AIDS, it is estimated that approximately 1.8% of patients with AIDS have cytomegalovirus retinopathy as the first manifestation and that less than 1% of HIV-infected persons will develop cytomegalovirus retinopathy as the initial manifestation of AIDS during the first seven years after infection with HIV.