An ongoing challenge. Providing palliative care nursing in the community.
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Community Health Nursing↗
Biomedical subjects
M Davies
Publications and source records attributed to M Davies.
The definition and assessment of analytic process: can analysts agree?
Although analytic process (AP) is a core concept in psychoanalytic theory and practice and has emerged as an important variable in outcome studies, there is no consensus regarding its definition and operationalisation. This paper describes the development and validation of the Columbia Analytic Process Scale (CAPS), a rating scale developed to evaluate the presence or absence of AP in a single psychoanalytic session transcript for purposes of an outcome study. Definitions of interrater reliability and construct validity are reviewed and two studies designed to evaluate these important aspects of the CAPS are presented. The results demonstrate that the CAPS has adequate interrater reliability (kappa = .5). To establish construct validity the plan was to compare the CAPS rating of AP to clinical consensus. However, when a group of ten senior training and supervising analysts at Columbia were asked to rate five psychoanalytic session transcripts, no clinical consensus could be established. Statistical analysis of the pattern of the analysts' clinical ratings showed that the largest portion of the variance was accounted for by the error term of a two-way ANOVA. The implication of this finding is that the construct of AP itself is ill-defined. The results of this study suggest that the commonly used term AP has less consensually held meanings than analysts tend to believe; the impact of lack of definition of key terms on clinical and research pursuits within psychoanalysis is discussed.
Analysis of Variance↗
A steady-state labelling approach to the measurement of proteoglycan turnover in vivo and its application to glomerular proteoglycans.
Rats were implanted with mini osmotic pumps delivering sodium [35S]sulphate and their newly synthesized proteoglycans were labelled over a 146 h period (steady-state labelling). Proteoglycan turnover was measured in vivo using a chase protocol. Glomerular proteoglycans were recovered quantitatively and the perlecan present was isolated by immunoprecipitation. The procedure allows newly synthesized proteoglycans to be quantified in mass units (pmol of glycossminoglycan sulphate) after labelling and during the chase. Ultrastructural-immunogold experiments identified the location of perlecan as the glomerular basement membrane and mesangial matrix. Perlecan in the basement membrane was quantified using the ultrastructural-immunogold technique. Perlecan comprises about 10% of the total glomerular proteoglycans, which are otherwise associated with glomerular cells and the mesangium. Both the total glomerular heparan sulphate proteoglycans and perlecan turn over rapidly (t1/2 approximately 3-4 h and < 3 h respectively). In contrast, turnover of proteoglycans in other tissues was slow, except in the liver where the heparan sulphate and chondroitin sulphate t1/2 values were 16 h and 9 h respectively. Microalbuminuria was induced with a low-dose regimen of puromycin aminonucleoside. At the onset of microalbuminuria (5 days) there was no change in the level of newly synthesized perlecan, or in perlecan in the glomerular basement membrane detected by immunogold labelling. Newly synthesized perlecan had undergone a minimal change in turnover rate by day 5 in puromycin aminonucleoside-treated rats. In contrast, the total glomerular proteoglycan population showed a dramatic decrease in turnover by day 5. Since there was no evidence of accumulation of glomerular proteoglycans on either day 5 or day 6, it is likely that decreased turnover of cell-associated proteoglycans is accompanied by an equivalent decrease in their synthesis.
Albuminuria↗
A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
BACKGROUND: The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria. METHODS: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293). RESULTS: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor. CONCLUSIONS: Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.
Adolescent↗
Molecular biology of the GABA(A) receptor: functional domains implicated by mutational analysis.
GABA(A) receptors are the major inhibitory neurotransmitter receptors in mammalian brain. They belong to a family of ligand-gated ion channels that also includes the nicotinic acetylcholine receptors, glycine receptors and 5HT(3) receptors. Each receptor in the family is believed to be a pentamer of homologous subunits that assemble to form a central transmembrane ion pore which, in the case of the GABA(A) receptor, is anion-selective. For almost twenty years, there has been tremendous interest in the structure and function of GABA(A) receptors, not only because of their importance in regulating brain excitability but also because these proteins are the specific targets for a wide variety of therapeutic agents including the anxiolytic benzodiazepines and barbiturates. Molecular cloning has revealed that GABA(A) receptors are heterogeneous, being formed by combinations of different isoforms of several subunit classes (alpha, beta, gamma, delta). The physiological and pharmacological properties of individual GABAA receptor subtypes appear to depend on their precise subunit complement. In this review, we focus on the application of modern techniques in molecular biology, particularly mutational analysis, to identify structural domains of these receptors that are important for ligand recognition and receptor function.
Amino Acid Sequence↗
Creating a shared vision of out of hours care: using rapid appraisal methods to create an interagency, community oriented, approach to service development.
OBJECTIVES: To undertake a district wide review of out of hours primary health care services and identify the views of users and providers about current arrangements and options for development. DESIGN: A range of qualitative and quantitative survey methods based on rapid appraisal methods, modified to apply to an inner city district. SETTING: Socially deprived, multiethnic district in south east London with a population of over 700,000. MAIN OUTCOME MEASURES: Strengths and weaknesses of current out of hours services and suggestions for developments. RESULTS: Widespread dissatisfaction with current arrangements was identified, with specific problems relating to access, availability, demand for services, and interagency communication. Several areas for development were identified, including the establishment of an out of hours cooperative, multiagency primary care emergency centres, and telephone advice-triage. Many of these are now being planned or piloted. CONCLUSIONS: Rapid appraisal provided a helpful method, enabling partnerships to be established between local agencies and users in relation to service development. The shared understanding and commitment to improving services that resulted is now having a major impact on out of hours care in the district.
Attitude of Health Personnel↗
Developing a policy on osteoporosis. Clinical risk factors alone are insufficient in decision making.
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Decision Making↗
High school students who use crack and other drugs.
BACKGROUND: When it appeared in the 1980s, crack was thought to represent a completely new pathway of entry into drug use. Our objective was to identify the distinguishing characteristics of adolescents who have reached different stages of drug use, in particular the highest state represented by crack. METHODS: Adolescents (N = 7611) representative of students in grades 7 to 12 from 53 New York state schools were classified in the following six mutually exclusive, cumulative categories of drug use: nonusers; alcohol and/or cigarette users only; marijuana users only; users of illicit drugs other than marijuana but neither cocaine nor crack; cocaine but not crack users; and crack users. The groups were compared in level of psychosocial functioning. RESULTS: Students who use illicit drugs show deficits in school performance, quality of family relationships, and health and increased psychological symptoms. Compared with nonusers, they are more delinquent and more actively involved with their peers and live in social environments in which the perceived use of drugs by other adolescents and parents is more extensive. Delinquency and extent of perceived drug use consistently increase with each higher stage of use. Crack users exhibit the lowest level of psychosocial functioning of any drug-using group. CONCLUSIONS: There are stage-specific characteristics and common characteristics (delinquent participation, peer drug use) throughout the developmental sequence of drug use. Despite declines over the last two decades in the prevalence of the use of different drugs, young people who use drugs display characteristics over historical time similar to those of young drug users 20 years ago.
Adolescent↗
Adult height and diabetic nephropathy.
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Adult↗
Synthesis and characterization of segmented polyurethanes based on amphiphilic polyether diols.
Segmented polyurethanes (SPUs) based on polyethylene glycol (PEG), polypropylene glycol (PPG) and a series of Pluronics with different ethylene oxide/propylene oxide ratios (EO/PO) and molecular weights were prepared. Different diisocyanates were used for making SPUs: 4,4-diphenylmethane diisocyanate (MDI), 4,4-dicyclohexylmethane diisocyanate (MDCI), hexamethylene diisocyanate (HMDI) and isophorone diisocyanate (IPDI). 1,4-Butane diol (BD) and ethylene diamine (ED) were used as chain extenders. The polymers obtained were characterized by infrared spectroscopy (IR), nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC). The microphase morphology (phase separation and phase mixing) is discussed in more detail.
Biocompatible Materials↗
Burns in prisoners: an assessment of problems in handling prisoners in a burns unit.
All burns units look after members of the prison population at times. This can cause anxiety among the staff and unique problems with management. Four cases-were reviewed from Her Majesty's Prison (HMP) Perth, Scotland, all of whom required resuscitation, and a survey undertaken of the nursing staff in our unit to assess attitudes to caring for burns prisoners in particular. Despite a careful search of the literature, no reference to the problems of managing prisoners in a burns unit could be found. However, it was found that the handling of violent offenders can be a significant cause of anxiety for nursing staff, and the presence of prison officers a reassurance rather than a hindrance in the management of burned prisoners. It is therefore recommended that prison officers be present at all times while managing burned prisoners.
Adolescent↗
Vacuum ultrafiltration sampling for determination of plasma protein binding of drugs.
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Blood Proteins↗
Demonstration of vitamin D receptor transcripts in actively resorbing osteoclasts in bone sections.
The effects of the active metabolite of vitamin D, 1,25 dihydroxyvitamin D3 (1,25D), are mediated via the vitamin D receptor (VDR). 1,25D is known to have profound effects on bone resorption, but proof that the human osteoclast expresses VDR in vivo is absent. Receptors have been demonstrated in osteoblasts, and it has been generally accepted that the effects of 1,25D on formed osteoclasts are mediated via osteoblasts. Using conventional riboprobe in situ hybridization, VDR transcripts were readily detectable in osteoblasts within sections taken from normal bone and several actively remodelling bone tissues, namely, Paget's disease, renal hyperparathyroidism, and healing fracture callus. However, VDR transcripts also appeared to be present at low levels within osteoclasts from two pagetic samples and two hyperparathyroid samples. To examine this latter finding further, we have used the novel technique of in situ-reverse transcriptase-polymerase chain reaction (IS-RT-PCR) for specific amplification and detection of VDR mRNA within sections taken from the same conditions described above, and also from osteoclastoma samples. As expected, VDR transcripts were amplified and detected in osteoblasts and marrow cells, but were also prominently found in osteoclasts at approximately 50% of the level detected in osteoblasts in normal bone and at 60% in the active bone tissues. This suggests that in addition to effects on osteoclast precursors and those mediated via osteoblasts, 1,25D could exert direct effects on the active bone resorbing cells in vivo.
Bone Remodeling↗
Identification of domains in human recombinant GABAA receptors that are photoaffinity labelled by [3H]flunitrazepam and [3H]Ro15-4513.
We have used [3H]flunitrazepam and [3H]Ro15-4513 as photoaffinity labelling agents in combination with a chemical cleavage technique to localize the benzodiazepine recognition sites of specific human recombinant alpha 1 beta 1 gamma 2, alpha 1 beta 3 gamma 2 and alpha 6 beta 3 gamma 2 GABAA receptor subtypes. The chemical agent utilized was hydroxylamine, whose substrate is a relatively rare asparagine-glycine amide bond that occurs only in the alpha subunits of the receptors examined in this study. Cleavage products were resolved using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The results of these experiments show that, in the alpha 1 subunit-containing receptors, incorporation of [3H]flunitrazepam occurs within residues 1-103 of the alpha 1 subunit, while incorporation of [3H]Ro15-4513 occurs within the region of the alpha 1 subunit that lies between residue 104 and the C-terminus. Photolabelling of membranes prepared from the alpha 6 beta 3 gamma 2-expressing cell line with [3H]Ro15-4513 resulted in the incorporation of radiolabel into two major protein species of M(r) 56,000 and M(r) 48,000, indicating incorporation into the alpha 6 subunit and possibly also the gamma 2 subunit. Hydroxylamine cleavage of alpha 6-containing receptors labelled with [3H]Ro15-4513 produced a gel profile consistent with the incorporation of the label occurring between residue 125 and the C-terminal. Thus, we have shown that the recognition sites for the agonist [3H]flunitrazepam and the inverse agonist [3H]Ro15-4513 occur within distinct domains of the human GABAA receptor.
Affinity Labels↗
Dysregulation of autocrine TGF-beta isoform production and ligand responses in human tumour-derived and Ha-ras-transfected keratinocytes and fibroblasts.
This study examined the autocrine production of TGF-beta 1, -beta 2 and -beta 3 in culture supernatants from tumour-derived (H series, n = 7; BICR series, n = 5), Ha-ras-transfected (n = 4) and normal (n = 2) human keratinocytes using a sandwich enzyme-linked immunosorbent assay (ELISA). Detection limits were 39.0 pg ml-1 for TGF-beta 1, 78.0 pg ml-1 for TGF-beta 2 and 1.9 ng ml-1 for TGF-beta 3. Tumour-derived oral keratinocytes predominantly produced less TGF-beta 1 than normal oral epithelial cells; the expression of endogenous TGF-beta 2 was variable. In keratinocytes containing mutant Ha-ras, TGF-beta 1 production was enhanced and TGF-beta 2 was undetectable. TGF-beta 3 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) but the protein was not detected in conditioned media, most probably because of the low detection limits of the ELISA for this isoform. Neutralisation experiments indicated that the latent TGF-beta peptide was secreted in keratinocyte conditioned medium. Seven tumour-derived keratinocyte cell lines (H series) and fibroblasts separated from normal (n = 1) and tumour-derived (n = 2) keratinocyte cultures were examined for their response to exogenous TGF-beta 1, -beta 2 and -beta 3. Six of seven tumour-derived keratinocyte cell lines were inhibited by TGF-beta 1 and TGF-beta 2 (-beta 1 > -beta 2); one cell line was refractory to both TGF-beta 1 and TGF-beta 2. Keratinocytes were inhibited (4 of 7), stimulated (1 of 7) or failed to respond (2 of 7) to TGF-beta 3, TGF-beta 1, -beta 2 and -beta 3 stimulated both normal and tumour-associated fibroblasts, but the tumour-associated fibroblasts showed less response to the ligands than their normal counterparts following prolonged treatment with each isoform. The results demonstrate variable autocrine production of TGF-beta isoforms by malignant keratinocytes, with loss of TGF-beta 1 generally associated with the tumour-derived phenotype and modification of endogenous isoform production dependent on the genetic background of the tumour cells. Further, the variable response of the tumour-derived keratinocytes and contiguous fibroblasts to the TGF-beta isoforms suggests that dysregulation of TGF-beta autocrine and paracrine networks are common characteristics of squamous epithelial malignancy.
Cell Line↗
IL-1 beta, a major stimulator of hyaluronan synthesis in vitro of human peritoneal mesothelial cells: relevance to peritonitis in CAPD.
The effect of several different growth factors and cytokines on the synthesis of hyaluronan (HA) by human peritoneal mesothelial cells (HPMC) was investigated. Growth arrested HPMC synthesized low levels of HA, but co-culture with PDGF-bb, TGF-beta 1, TNF-alpha, and IL-6 at a concentration of 10 ng/ml all increased HA synthesis between two- to three-fold. At the same concentration IL-1 beta significantly increased the synthesis eight-fold (N = 3; P < 0.05). The effect of IL-1 beta was also dose- and time-dependent and could be totally negated with interleukin-1 receptor antagonist (IL-1 beta RcA). Non-infected and infected dialysate from patients receiving CAPD was also found to stimulate HA synthesis by HPMC. The levels found with non-infected fluid were 4 x 10(4) dpm/ml (N = 6) and 12.9 x 10(4) dpm/ml (N = 6; P < 0.002) and 8.7 x 10(4) dpm/ml (N = 6; P < 0.003) for infected fluid collected one and two days after the commencement of peritonitis. IL-1 beta RcA dramatically reduced the effect of infected but not non-infected dialysate. These results provide new insights into the manner in which HA synthesis is controlled in the mesothelium and suggest that IL-1 beta is a key cytokine in the inflammatory response in CAPD patients.
Adolescent↗
Calcium-sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis.
OBJECTIVE: Pancreatitis is an unusual complication of the benign disorder familial hypocalciuric hypercalcaemia (FHH) such that it could represent a distinct subgroup of FHH. In order to study this, we investigated three FHH kindreds with recurrent pancreatitis for mutations of the extracellular calcium-sensing receptor (CaR) to identify a possible common genetic aetiology for typical FHH and that associated with pancreatitis. PATIENTS AND METHODS: Three FHH kindreds (18 affected, 14 unaffected members) in which the proband had presented with recurrent pancreatitis were identified. The entire 3234bp coding region of the CaR gene was examined by direct DNA sequencing using fluorochrome labelled dideoxy-terminators. Mutations were confirmed and demonstrated to co-segregate with FHH by restriction enzyme analysis. RESULTS: Three novel heterozygous missense mutations (Asn178Asp, Arg220Gln and Pro221Ser) in the extracellular domain of the CaR were identified in each of the probands. These mutations, which co-segregated with the hypercalcaemia, were not detected as common polymorphisms in 55 unrelated normocalcaemic controls. CONCLUSIONS: Familial hypocalciuric hypercalcaemia with recurrent pancreatitis is associated with calcium-sensing receptor mutations, and thus this variant has the same genetic aetiology as typical familial hypocalciuric hypercalcaemia.
Adult↗