Biomedical subjects
G Davies
Publications and source records attributed to G Davies.
L-Arginine in coronary atherosclerosis.
Nitric oxide is formed from the N-guanido terminal of the amino acid L-arginine and from molecular oxygen by nitric oxide synthase enzymes. L-arginine administration improves the coronary blood flow response to acetylcholine in patients with normal coronary arteries and hypercholesterolemia, reverses the defective endothelium-dependent vasodilation associated with an elevated plasma low-density lipoprotein level or hypercholesterolemia, dilates coronary epicardial arteries and stenoses, enhances nitric oxide generation, and inhibits lesion formation after balloon angioplasty. Stimulation of endogenous nitric oxide production could inhibit atherogenesis, and therefore may be of benefit in patients with risk factors for atherosclerosis.
Nonmyeloablative stem cell transplantation for congenital immunodeficiencies.
The optimal approach for stem cell transplantation in children with immunodeficiency has yet to be determined. Conditioning therapy is necessary for reliable engraftment and full immune reconstitution; however, the beneficial effect of cytoreductive conditioning is counterbalanced by increased short- and long-term treatment-related toxicity. Whether bone marrow transplantation with a nonmyeloablative preparative regimen was sufficient for the establishment of donor immune reconstitution, with the resultant correction of disease phenotype, was investigated. Eight patients with severe immunodeficiency states underwent T-cell replete bone marrow transplantation from a human leukocyte antigen-matched unrelated (n = 6) or sibling (n = 2) donor with nonmyeloablative conditioning using a fludarabine-melphalan-anti-lymphocyte globulin-based regimen. All patients had severe organ dysfunction that precluded transplantation with conventional conditioning. All patients were engrafted with predominantly donor hematopoiesis, and the duration of neutropenia was brief. Significant acute graft-versus-host disease (GVHD) did not develop, but one patient had limited chronic GVHD. One patient died of disease recurrence, and 3 have stable, mixed chimerism. At a median follow-up of 1 year, all patients have had good recovery of CD3(+) T-cell numbers, and 6 of 7 evaluable patients have normal phytohemagglutinin stimulation indices. The rate of immune reconstitution is comparable with that of historical controls undergoing standard myeloablative protocols. Two patients with CD40 ligand deficiency now show significant expression, and a patient with adenosine deaminase deficiency has improved deoxy adenosine triphosphate metabolites. In summary, it has been demonstrated that nonmyeloablative stem cell transplantation permits rapid engraftment from both sibling and unrelated donors with minimal toxicity even in the presence of severe organ dysfunction. If long-term immune reconstitution of patients treated with this protocol is demonstrated, it is believed this approach might offer significant advantages compared with standard protocols by combining adequate immune reconstitution with reduced short- and long-term toxicity. (Blood. 2000;96:1239-1246)
The carvedilol hibernation reversible ischaemia trial, marker of success (CHRISTMAS) study. Methodology of a randomised, placebo controlled, multicentre study of carvedilol in hibernation and heart failure.
BACKGROUND: Carvedilol reduces mortality and improves symptoms and ejection fraction in ischemic heart failure, but its mode of action is not well defined and not all patients respond to treatment. The aim of the CHRISTMAS (Carvedilol Hibernation Reversible Ischaemia Trial, Marker of Success) study is to examine whether hibernation may be a significant factor determining this response. This paper describes the methodology and the rationale for the choice of the nuclear cardiology and echocardiography imaging techniques used in the study. METHODS AND RESULTS: The CHRISTMAS study is a double-blind, randomised, parallel group, multinational study of oral carvedilol versus placebo in patients with chronic stable heart failure due to left ventricular systolic dysfunction from coronary artery disease. The study aims to randomise 400 patients who are on optimal treatment. Two parallel groups will be randomised to carvedilol or placebo, namely 200 with hibernating myocardium at baseline and 200 matched patients without. The presence of hibernation is defined from a mismatch between regional contractile function and regional viability, measured by echocardiography (severe segmental asynergy) and nitrate prepared resting Tc99m-MIBI myocardial perfusion imaging (segmental activity >60%). The primary treatment-related end-point of the study is the comparison of the mean change, from baseline to the final visit, in radionuclide-determined left ventricular ejection fraction in patients on placebo with those on carvedilol, between the groups designated as hibernating and non-hibernating. Other end-points being examined include the prevalence of hibernation in heart failure, the relationship between the volume of hibernating myocardium and the ejection fraction response, the prevalence of reversible ischemia in heart failure, and the comparison of echo with gated SPECT. To date, 303 patients have been screened and 251 patients randomised in the study. The study aims to report in 2000. CONCLUSIONS: The CHRISTMAS study addresses the issue of whether the presence of hibernation is a predictor of the ejection fraction response to carvedilol in heart failure. It also examines the potential role of medical therapy in hibernation as well as a number of other end-points. The study may potentially lead to an important new role for nuclear cardiology in heart failure, and demonstrates important synergy between cardiac imaging and the pharmaceutical industry.
Seasonality of first admissions for schizophrenia in the Southern Hemisphere.
Northern Hemisphere studies of first admissions for schizophrenia have shown an excess of summer admissions (June, July and August) compared to other times of the year. The within-year fluctuations in first admissions could be related to meteorological factors that fluctuate between seasons (e.g. temperature, photoperiod) and/or social factors (e.g. holidays, religious events). If meteorological factors were primarily responsible for the fluctuation, then Southern Hemisphere studies should find excess first admissions in December, January and February. This paper presents the first season of first admission study of schizophrenia in the Southern Hemisphere. The month and year of first admission for schizophrenia (ICD 8/9) for 4487 male and 3252 female, Australian-born individuals were extracted from a Queensland mental health register. Spectral analysis showed a strong annual periodicity of first admissions for males with the peak in August (Southern Hemisphere winter) and a trough in the summer months (December to February). The pattern for females also displayed annual periodicity. These results correspond to the Northern Hemisphere reports of excess of schizophrenia first admissions in terms of the month of the year but not the season of excess. Further work is needed in order to clarify the impact of latitude and meteorological factors on the month of first admission for schizophrenia.
Nutritionally independent B12 deficiency and Alzheimer disease.
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Expression of MHC class II molecules contributes to lipopolysaccharide responsiveness.
Activation of phagocytes by lipopolysaccharide (LPS) causes synthesis and secretion of various mediators of inflammation. CD14, a glycosylphosphatidylinositol-anchored monocytic antigen serving as receptor for LPS, and members of the family of Toll-like receptors mediate cellular activation in response to LPS. Here we investigated whether expression of MHC class II molecules modified the response to LPS. Comparing LPS responsiveness of human and murine cells differing for expression of MHC class II molecules, we found that lack or a low level of expression of MHC class II molecules resulted in diminished secretion of pro-inflammatory cytokines following stimulation with LPS. Thus, expression of MHC class II molecules modifies LPS responsiveness, a finding suggesting that these molecules contribute to the pathogenesis not only of exotoxin-triggered toxic shock but also of endotoxin-triggered septic shock. Additionally to their role in antigen-specific immunity MHC class II molecules may influence the inflammatory response triggered by microbial constituents.
Can angiography predict the vulnerable lesion that progresses to myocardial infarction?
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Facial composite production: a comparison of mechanical and computer-driven systems.
Computer-driven systems for constructing composite faces of suspects (E-fit; Mac-a-Mug) have largely replaced mechanical systems (Photofit; the Identikit) in police use, yet little is known of their comparative effectiveness in rendering an accurate likeness. Participants (N = 24) constructed 2 of 4 familiar or unfamiliar faces, for one of which they used Photofit and for the other, E-fit. A likeness of each face was made first under target-absent conditions and then with photographs of the target present. The accuracy of the resulting composites was assessed by familiarity ratings, names elicited, and matching accuracy. The computer-driven system showed consistent superiority only when a familiar face was constructed in the presence of photographs; when participants worked from memory, E-fit was no better than Photofit. The implications of these findings for theories of face retrieval and the operational use of composites are discussed.
Endoscopic ultrasound guided biopsy of sub-carinal lymph nodes.
AIM/METHODS: Endoscopic ultrasound (EUS) guided biopsy is not widely available in the U.K., and sub-carinal nodes can be difficult to biopsy percutaneously. Tissue obtained from these nodes can influence patient management. We describe our initial experience with EUS guided transoesophageal biopsy of sub-carinal nodes using a Pentax FG-34 EUS probe and a 22 G Hancke-Villman or Echotip needle in 20 patients. RESULTS: Malignant cells were obtained from the nodes in 13 patients, and in another patient in whom the node biopsy was negative, small cell carcinoma cells were obtained from a lesion in the liver. There were no complications. CONCLUSIONS: Mediastinoscopy to obtain tissue, or the blind treatment of presumed malignancy was avoided in all the patients in whom a positive biopsy was obtained. In many of these patients, more conventional methods to obtain a tissue diagnosis had already failed. The problem solving capability of this safe, well-tolerated technique is discussed.Roberts, S. A. Clinical Radiology55, 832-836.
Validation of a pediatric asthma caregiver diary.
BACKGROUND: Young children are generally not able to consistently and reliably perform tests of airway function, and normative values are not available. Reliable and valid measures of parental reporting of asthma symptoms and functioning are needed to determine the efficacy of asthma interventions. OBJECTIVE: A pediatric asthma caregiver diary was developed and validated for use in interventional asthma studies. METHODS: A 3-week prospective study of 125 caregiver parents and their children, aged 2 to 5 years, with persistent asthma was conducted. At baseline, children were classified as either stable (no change to anti-inflammatory therapy) or unstable (anti-inflammatory therapy added or increased). RESULTS: A symptom scale and day without asthma symptoms (DWAS) were defined from pediatric asthma caregiver diary questions. The scale and DWAS statistically differentiated between the stable and unstable groups at week 1 and detected change between the 2 groups (P <.01). On average, caregivers reported low symptom scores. However, the frequency of DWAS was only 43% of days in the stable group and 22% in the unstable group. CONCLUSION: The pediatric asthma caregiver diary scale and DWAS have acceptable measurement characteristics for use in clinical trials of children with asthma symptoms. The DWAS indicates an opportunity for improvement in asthma control in this population.
Complex stenosis morphology and vasomotor responses to inhibition of nitric oxide synthesis.
OBJECTIVE: To assess the relation between coronary vasomotor effects of N(G)-monomethyl-L-arginine (LNMMA) administration and coronary stenosis morphology, length, and severity in patients with stable angina. DESIGN: In 28 patients (24 male, four female) with coronary artery disease and chronic stable angina, intracoronary normal saline and 4 micromol/min LNMMA were infused for four minutes each, followed by an intracoronary bolus of 250 microg glyceryl trinitrate. Coronary stenoses were classified as concentric (smooth), eccentric (smooth), or complicated (irregular). The diameters of these stenoses and their adjacent reference proximal segments were measured by quantitative angiography. RESULTS: During LNMMA infusion a significantly larger proportion of complicated stenoses than concentric and eccentric stenoses constricted by >/= 5% (p < 0.01) and the magnitude of vasoconstriction was greater in complicated than in concentric and eccentric stenoses (p < 0.05). For complicated stenoses the magnitude of constriction (in mm) with reference to normal saline was greater than that of the concentric and eccentric stenoses (p < 0.05), whereas concentric and eccentric stenoses constricted similarly. Irrespective of the type of morphology, there was a correlation (p < 0.05) between both the severity and the length of stenoses and the magnitude of vasoconstriction to LNMMA. A similar proportion of concentric, eccentric, and complicated stenoses showed >/= 5% increase in diameter with glyceryl trinitrate, and the magnitude of the response was similar in the three groups. CONCLUSIONS: In patients with coronary artery disease, the response to LNMMA is greater when stenosis morphology is complex, indicating greater nitric oxide activity. This provides further evidence that plaques with complex morphology are in an active state.
The impact of risk factors for atherosclerosis on the vasomotor effects of inhibition of nitric oxide synthesis in patients with normal angiograms.
We assessed the impact of systematic risk factors on the vasomotor effects of inhibition of nitric oxide synthesis. N(G)-monomethyl-L-arginine (LNMMA) was infused intracoronarily at 4, 8 and 16 micromol/min followed by intracoronary bolus administration of 250 microg nitroglycerin. Computerized angiography was used to assess the changes in the diameter of coronary segments. During the LNMMA infusions there was no significant difference in LNMMA response between smokers and non-smokers (-5.5+/-0.8 and -6.6+/-0.6%, respectively) or between hypertensives and normotensives (-6.4+/-1.1 and -6.1+/-0.6%, respectively), but the response was less in hypercholesterolaemic patients (-4.5+/-0.7 vs. -8.0+/-0.6%, p<0.05). Thus, the reduced nitric oxide activity is related to hypercholesterolaemia but not to smoking and hypertension.
Closed-circuit television: how effective an identification aid?
Two experiments simulated identification of suspects from CCTV recordings: Expt 1 simulated identification from whole body shots while Expt 2 showed close-up pictures of targets' faces. The results are consistent with those of Bruce el al. (1999) and Kemp, Towell, and Pike (1997) in showing surprisingly high rates of error in person identification from CCTV material. In Expt 1, participants (N = 80) searched for a suspicious incident in a 25-minute surveillance film which was shown either in colour or monochrome. They then attempted to describe and identify the persons involved. Accuracy of identification was just 15% from memory with a 60% false alarm rate. When judgments were made with access to a still frame image of the target, accuracy rose to 30%, with a 65% false alarm rate. Colour did not improve identification, but did prompt more description of the targets' clothing. In Expt 2, participants (N = 80) observed video-clips which included close-up pictures, of four targets before identifying each in target present or absent arrays. Identification errors were lower on this occasion, averaging 21% when judgements were made from memory and 13% with continuous reference to the recording. The theoretical and practical implications of these findings are discussed.
Outcome variables in periodontal research: means and threshold-based site changes.
BACKGROUND: The exclusive use of mean measurements in periodontal research might at times be misleading, as changes in different sites in the same individual might nullify each other. The purpose of the present study was to compare disease progression and response to periodontal therapy using both individual site activity with thresholds and mean patient changes. METHODS: Seventy-nine (79) subjects with established periodontitis were monitored for 1 year (no treatment [NTx] group); 108 subjects who received scaling, root planing, and quarterly prophylaxis were observed in a similar time interval (treatment [Tx] group). Probing depth (PD), attachment level (AL) and alveolar crestal height (ACH) were measured at baseline and 1 year using pressure-sensitive probes and computer-assisted image analysis of radiographs. RESULTS: Mean reduction in PD (0.50 mm) was observed in the Tx group compared to a small increase (-0.04 mm) in the NTx group (P= 0.0001). Treatment resulted in mean AL gain (0.44 mm) compared to net AL loss (-0.21 mm) in the NTx group (P= 0.0001). Subjects in the Tx group had twice as many sites with AL gain (beyond the threshold) compared to NTx subjects (16.64+/-1.07% versus 8.11+/-0.68%) which was highly significant (P = 0.0001, Student t test). Similarly, although in the opposite direction, percentage of sites with AL loss beyond threshold was 6.21+/-0.47% (Tx group) and 14.02+/-1.15% (NTx group) which was also highly significant (P = 0.0001, Student t test). Change in ACH was minimal for the Tx group (-0.07+/-0.03 mm) while NTx subjects experienced greater bone loss throughout the year (-0.16+/-0.02 mm); percentage of sites with ACH loss was similar for both groups, while the Tx group had 3 times the number of sites with ACH gain (11.76% versus 3.42%), suggesting that the reduction in mean bone loss in the Tx group did not result from a reduction in losing sites, but rather from an increase in gaining sites. The use of both means and binary data seems to supplement the information regarding the nature and mechanism of disease progression and arrest. CONCLUSIONS: The characteristics of periodontal disease with its multifactorial patient, local, and site-related etiology support the use of both mean and site-based changes in clinical studies of periodontal disease and treatment.
Cell-cell adhesion molecules and signaling intermediates and their role in the invasive potential of prostate cancer cells.
PURPOSE: The highly variable natural history of prostate carcinoma may be reflected in heterogeneity of invasive potential between tumors. MATERIALS AND METHODS: We have examined two prostate cancer cell lines of low invasive potential (CAHPV10 and PZHPV7) and three cell lines of high invasive potential (DU-145, PC-3, LNCapFGC), to determine whether specific adhesion molecule profiles correlated with their invasive behavior. RESULTS: Using an in vitro invasion assay, we demonstrated that DU-145, LNCapFGC and PC-3 cells were highly invasive compared with CA-HPV-10 and PZ-HPV-7 cells. LNCapFGC cells expressed high levels of E-cadherin, alpha-, beta- and gamma-catenin, desmoglein, desmoplakin and GSK3beta using immunoblotting. This was, in general, comparable to immunohistochemical staining. PC-3 cells had no E-cadherin or alpha-catenin, but expressed a high level of the HGF/SF receptor c-Met. In contrast, DU-145 cells were found to express E-cadherin and low levels for all other protein molecules, except c-Met. The DU-145 cell line also lacked alpha-catenin expression. In CA-HPV-10 and PZ-HPV-7 cells, there was no detection of APC, PECAM-1, P-cadherin or Wnt-1. DU-145, LNCapFGC and PC-3 cells formed cell-cell aggregates, which were reduced by inclusion of anti-E-cadherin antibody and the motogen HGF/SF. CONCLUSION: These results show that prostate cancer cells exhibit a diverse expression of cell-cell adhesion molecules and their signaling intermediates. The expression of these adhesion molecules bears an important relationship with the invasive phenotype of these cells.
Heterogeneity in schizophrenia; mixture modelling of age-at-first-admission, gender and diagnosis.
OBJECTIVE: Identifying and explaining sources of heterogeneity in schizophrenia would help elucidate its aetiology and course. In this paper we examine heterogeneity in terms of age-at-first-admission, diagnosis and gender by decomposing a large dataset using mixture modelling. METHOD: Using the Queensland Mental Health Statistics System, we first extracted age-at-first-admission data for schizophrenia (ICD8/9 295) to represent a 'narrow' definition of schizophrenia (N= 7651); we then added paraphrenia (297) and other non-organic psychoses (298) for a 'broad' definition (N= 10 199). Mixture models were fitted to these narrowly and broadly defined distributions for both males and females. RESULTS: For narrowly defined schizophrenia a three-component model best fitted both male and female distributions. While the mean ages of these components were very similar for both males and females, the ratios of males to females crossed from an excess of males in the 'youngest' component to an excess of females in the 'oldest' component. When using the broad definition, four components best fitted the underlying distributions. While the first three were similar to those found for narrowly defined schizophrenia, the additional fourth component reverted to a male excess; however, the mean age for males was 10 years younger than for females. CONCLUSION: Our findings suggest that subtypes based on age-at-first-admission can be identified, although the number identified depends on how inclusively schizophrenia is defined. While there appear to be the same number with similar mean ages for both genders, there are differences in the proportions of males to females. Further work to fully characterize their nature is warranted.