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J Richmond

Publications and source records attributed to J Richmond.

At least 19 recordsLinked to original sources
PubMed2006

Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76.

AIMS/HYPOTHESIS: Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes. METHODS: We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and indices of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3,374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazards models, adjusted for sex, ethnicity and other known or putative risk factors. RESULTS: rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54-0.87], p=0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR=1.31 [95% CI 1.11-1.54], p=0.001) but less likely to double creatinine levels during follow-up (RR=0.49 [95% CI 0.27-0.89], p=0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus. CONCLUSIONS/INTERPRETATION: We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.

Albuminuria↗
PubMed2005

IHC for Her2 with CBE356 antibody is a more accurate predictor of Her2 gene amplification by FISH than HercepTest in breast carcinoma.

BACKGROUND: Her2 (c-erbB-2/neu) overexpression in breast carcinoma predicts response to the anti-Her2 monoclonal antibody, trastuzumab, and is associated with a poor prognosis. When considering patients for trastuzumab treatment, Her2 protein expression is measured by imunohistochemistry (IHC) and, where staining is equivocal, by fluorescence in situ hybridisation (FISH) detection of Her2 gene amplification. AIMS: To compare IHC using CBE356 with IHC using the Food and Drug Administration approved HercepTesttrade mark. METHODS: CBE356 and HercepTest were analysed using 167 FISH characterised breast carcinomas. Immunohistochemical expression of Her2 was measured semiquantitatively. Sensitivity, specificity, predictive values, and overall accuracy were calculated for both IHC methods using gene amplification by FISH as the end point, and IHC and FISH assays were tested in Kaplan-Meier survival analysis. RESULTS: The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CBE356 positive (2+ and 3+) cases were 94%, 89%, 95%, 84%, and 97%, respectively, and of HercepTest positive (2+ and 3+) cases were 91%, 66%, 98%, 92%, and 91%, respectively. A positive result with CBE356, HercepTest, or FISH was associated with significantly decreased overall survival (log rank p = 0.005, p = 0.0017, and p = 0.0005, respectively). CONCLUSIONS: Positive IHC staining for Her2 using CBE356 is 3% more accurate and 23% more sensitive at predicting Her2 gene amplification by FISH than positive staining with HercepTest. Negative IHC using CBE356 antibody is 6% more likely to represent a truly negative result than negative staining with HercepTest. Overall, CBE356 was a more accurate predictor of Her2 gene amplification by FISH than HercepTest.

Adult↗
PubMed2003

BMP signaling components are expressed in human fracture callus.

Of the various growth factors involved in the healing response after a fracture, bone morphogenetic proteins (BMPs) are emerging as key modulators. BMPs exert their effects by binding to a complex of type I and type II receptors leading to the phosphorylation of specific downstream effector proteins called Smads. The current study examined the presence of BMP signaling components in human callus obtained from five nascent malunions undergoing fracture fixation. These callus samples represented various stages of bone healing and a mixture of endochondral and intramembraneous bone healing. We performed immunohistochemistry on the callus, using antibodies for BMP (BMP-2,-3,-4,-7), their receptors (BMPR-IA, -IB, -II), and phosphorylated BMP receptor-regulated Smads (pBMP-R-Smads). Active osteoblasts showed fairly consistent positive staining for all BMPs that were examined, with the immunoreactivity most intense for BMP-7 and BMP-3. Immunostaining for BMPs in osteoblasts appeared to colocalize with the expression of BMPR-IA, -IB, and -II. Positive immunostaining for pBMP-R-Smads suggests that the BMP receptors expressed in these cells are activated. Staining for BMPs in cartilage cells was variable. The immunostaining appeared stronger in more mature cells, whereas staining for BMP receptors in cartilage cells was less ubiquitous. However, the expression of pBMP-R-Smads in cartilage cells suggests active signal transduction. Fibroblast-like cells also had a variable staining pattern. Overall, our findings indicate the presence of BMPs, their various receptors, and activated forms of receptor-regulated Smads in human fracture callus. To the best of our knowledge, this is the first study that documents the expression of these proteins in human fracture tissue. Complete elucidation of the roles of BMP in bone formation will hopefully lead to improved fracture healing care.

Adolescent↗
PubMed2001

Evaluating HER2 amplification and overexpression in breast cancer.

The development of Herceptin (Trazumatab) makes testing for HER2 status important for choosing optimal therapy in breast cancer. This study addresses the precision, accuracy, and reproducibility of HER2 assays. HER2 was assessed retrospectively by immunohistochemistry (IHC) with Dako 'Herceptest', by IHC with the monoclonal antibody CB11, and by fluorescence in situ hybridization (FISH, PathVysion), in a series of 216 formalin-fixed breast carcinomas including 191 for which quantitative HER2 data from radioimmunohistochemistry (Q-IHC) were available. All tests were scored independently by two observers. Positivity rates varied between Herceptest (12.6%), FISH (19.4%), and CB11 IHC (28.5%). Kappa values showed that IHC-based tests were more susceptible to inter-observer variation (kappa=0.67 and 0.74 for Herceptest and CB11, respectively) than FISH (kappa=0.973). Overall test accuracy (see the Materials and methods section) for CB11 IHC (83.8%) was lower than Herceptest (87.4%) or FISH (93.2%). FISH predicted p185 HER2 overexpression (determined by Q-IHC) better (concordance index C.Ind. 0.90) than CB11 IHC (C.Ind.=0.85) or Herceptest (C.Ind.=0.81). Of 42 cases with gene amplification by FISH, 67% were positive in the Herceptest (2+ or 3+) vs. 83% with CB11. Of 174 cases negative by FISH, 96% were negative in the Herceptest and 68% with CB11. In conclusion, FISH is the most accurate, reproducible, and precise predictor of HER2 overexpression in routine diagnostic laboratories.

Antibodies, Monoclonal↗
PubMed2000

CYP2D6 genotyping as an alternative to phenotyping for determination of metabolic status in a clinical trial setting.

The emerging application of pharmacogenomics in the clinical trial setting requires careful comparison with more traditional phenotyping methodologies, particularly in the drug metabolism area where phenotyping is used extensively. The research objectives of this study were 1) to assess the utility of cytochrome P450 2D6 (CYP2D6) genotyping as an alternative to traditional phenotyping as a predictor of poor metabolizer status; 2) to identify issues for consideration when implementing CYP2D6 genotyping in clinical trials; and 3) to outline the advantages and disadvantages of CYP2D6 genotyping compared with phenotyping. DNA samples obtained from 558 previously phenotyped individuals were blindly genotyped at the CYP2D6 locus, and the genotype-phenotype correlation was then determined. The CYP2D6 genotyping methodology successfully predicted all but 1 of the 46 poor metabolizer subjects, and it was determined that this 1 individual had a novel (presumably inactive) mutation within the coding region. In addition, we identified 2 subjects with CYP2D6 genotypes indicative of poor metabolizers who had extensive metabolizer phenotypes as determined by dextromethorphan/dextrorphan ratios. This finding suggests that traditional phenotyping methods do not always offer 100% specificity. Our results suggest that CYP2D6 genotyping is a valid alternative to traditional phenotyping in a clinical trial setting, and in some cases may be better. We also discuss some of the issues and considerations related to the use of genotyping in clinical trials and medical practice.

Cytochrome P-450 CYP2D6↗
PubMed1999

Noninvasive graft flow and patency assessment following minimally invasive direct coronary artery bypass (MIDCAB) grafting.

OBJECTIVE: Assessment of graft patency following minimally invasive direct coronary artery bypass (MIDCAB) surgery is essential in order to determine the efficacy of this technique. This study was conducted to evaluate the role of intraoperative and postoperative noninvasive flow and velocity measurements to follow and predict graft performance. METHODS: Between April 1996 and July 1997, 130 patients had 133 grafts placed using MIDCAB techniques. Intraoperative transit-time ultrasound was used to assess graft patency and flow prior to wound closure. Also, serial transcutaneous doppler examinations were performed to evaluate graft patency on the first postoperative day, at two weeks, and at three months. Peak values for systolic and diastolic waveforms were measured for both flow and velocity, and the diastolic-to-systolic ratio was calculated at each time interval. Recatheterization was performed selectively for inadequate ultrasound flow or doppler velocity, or for patient symptoms. RESULTS: Seven (5.3 %) grafts developed stenosis or occlusion. When compared to normal grafts, mean intraoperative flows, flow ratios, and velocity ratios were lower. Mean postoperative diastolic peak velocity (DPV) to systolic peak velocity (SPV) ratio remained stable over time for normal grafts; however, grafts with stenosis or occlusion demonstrated a diminished DPV/SPV ratio. CONCLUSIONS: Intraoperative transit-time ultrasound and outpatient transcutaneous doppler examinations did not reach a predictive value for graft stenosis or occlusion following MIDCAB surgery in this series of patients. However, these data demonstrate trends that may help identify patients at an increased risk for unfavorable events, guiding the use of postoperative recatheterization in such patients.

Aged↗
PubMed1998

Lipid vesicle size determines the Th1 or Th2 response to entrapped antigen.

Understanding the factors that control the differential induction of Th1 and Th2 responses is a key immunologic objective with profound implications for vaccination and immunotherapy of infectious and autoimmune diseases. Using Ag formulated in lipid vesicles prepared from nonionic surfactants, we describe a novel mechanism influencing the balance of the Th1 or Th2 response. Our results indicate that inoculation of BALB/c mice with vesicles with a mean diameter > or = 225 nm preferentially induces Th1 responses, as characterized by increased titers of IgG2a in plasma and elevated IFN-gamma production by lymph node cells. However, preparation of the same quantity of Ag in vesicles with mean diameter of < or = 155 nm induces a Th2 response, as identified by IgG1 in the absence of IgG2a production and increased lymph node IL-5 production. Although large (> or = 225 nm) vesicles could induce IL-12 production, smaller vesicles (< or = 155 nm) could not. However, small vesicles did induce higher levels of IL-1beta production by macrophages than larger vesicles. The role of IL-12 in this response was confirmed in IL-12-deficient mice, whose spleen cells failed to produce IFN-gamma following in vivo priming with Ag prepared in large vesicles. Our results therefore indicate that macrophages respond to endocytosis of large or small vesicles by producing different patterns of cytokines that can subsequently direct the immune response toward a Th1 or a Th2 phenotype.

Animals↗
PubMed1998

Fine-needle aspiration cytology of extranodal lymphoma.

The assessment of lymphoproliferative disorders using fine-needle aspiration (FNA) cytology may be problematic particularly when organs other than lymph node are involved. In this report we have reviewed 26 consecutive FNA specimens from superficial extranodal sites which were reported as diagnostic or suggestive of malignant lymphoma. The aspirates were obtained from skin or subcutaneous tissue (ten cases), thyroid (five cases), salivary gland (five cases), breast (four cases), neck, and pharynx (one case each). Ancillary studies including immunocytochemistry, in situ hybridisation to detect immunoglobulin light chain mRNA expression, and polymerase chain reaction for analysis of immunoglobulin heavy chain gene rearrangement were performed in 20, 12, and 7 cases, respectively. Clinicopathologic correlation confirmed the diagnosis of lymphoma in 25/26 aspirates. Nine of the 14 patients whose initial presentation was with an extranodal mass were considered to have primary lymphomas of mucosa-associated lymphoid tissue (MALT) type. In contrast, ten of 11 patients with recurrent extranodal disease had primary nodal type lymphomas. There was one false-positive diagnosis, a neck mass misinterpreted cytologically as B-cell lymphoma which was ultimately shown to be a branchial cyst. FNA cytology supported by appropriate ancillary investigations provides accurate diagnosis in most cases of extranodal lymphoma.

Adult↗
PubMed1998

Fine needle aspiration cytology diagnosis of malignant lymphoma and reactive lymphoid hyperplasia.

AIMS: To assess the diagnostic accuracy of lymph node fine needle aspiration (FNA) cytology to distinguish reactive lymphoid hyperplasia from malignant lymphoma, and to evaluate the contribution of ancillary techniques applied to cytological material. METHODS: Two hundred and seventy seven consecutive lymph node FNA specimens reported to be consistent with reactive lymphoid hyperplasia (n = 213) or suggestive/diagnostic of malignant lymphoma (n = 64) were reviewed. Follow up data were obtained by case record review or by histological correlation. The value of immunocytochemistry, in situ hybridisation for immunoglobulin light chain mRNA, and polymerase chain reaction (PCR) towards the final clinicopathological diagnosis was assessed in 92, 61, and 45 cases, respectively. RESULTS: Sixty one of 67 lymphomas and 207 of 209 reactive lymph nodes were accurately diagnosed by FNA cytology. There were six false negative aspirates including three cases of follicular lymphoma, two cases of Hodgkin's disease, and one chronic lymphocytic leukaemia. Two FNA specimens considered suspicious of lymphoma proved reactive on histology or clinical follow up. One metastatic small cell carcinoma was wrongly diagnosed as lymphoma. Ancillary studies contributed to the correct diagnosis in most cases although occasional misleading results were obtained, particularly with PCR. CONCLUSIONS: FNA cytology accurately distinguished reactive lymphoid hyperplasia from malignant lymphoma in 97% of cases. However, occasional wrong diagnoses occurred owing to sampling error or misinterpretation. Ancillary studies can be applied to cytological samples and contribute to the diagnosis in most cases.

Adult↗
PubMed1998

Measurement of vitamin D3 metabolites in smelter workers exposed to lead and cadmium.

OBJECTIVES: To investigate the effects of lead and cadmium on the metabolic pathway of vitamin D3. METHODS: Blood and urinary cadmium and urinary total proteins were measured in 59 smelter workers occupationally exposed to lead and cadmium. In 19 of these workers, the plasma vitamin D3 metabolites, (25-hydroxycholecalciferol (25 OHD3), 24R, 25-dihydroxycholecalciferol (24R,25(OH)2D3) and 1 alpha,25-dihydroxycholecalciferol (1 alpha, 25(OH)2D3)) were measured together with blood lead. Vitamin D3 metabolites were measured by radioimmunoassay, (RIA), lead and cadmium by atomic absorption spectrophotometry, and total proteins with a test kit. RESULTS: Ranges for plasma 25(OH)D3, 24R,25(OH)2D3 and 1 alpha,25(OH)2D3 were 1.0-51.9 ng/ml, 0.6-5.8 ng/ml, and 0.1-75.7 pg/ml, respectively. Ranges for blood lead were 1-3.7 mumol/l, (21-76 micrograms/dl), blood cadmium 6-145 nmol/l, and urinary cadmium 3-161 nmol/l. Total proteins in random urine samples were 2.1-32.6 mg/dl. Concentrations of lead and cadmium in blood showed no correlation (correlation coefficient -0.265) but there was a highly significant correlation between blood and urinary cadmium. Concentrations for 24R,25(OH)2D3 were depressed below the normal range as blood and urinary cadmium increased, irrespective of lead concentrations. High cadmium concentrations were associated with decreased plasma 1 alpha,25(OH)2D3 when lead concentrations were < 1.9 mumol/l and with above normal plasma 1 alpha,25(OH)2D3 when lead concentrations were > 1.9 mumol/l, Kruskal-Wallis analysis of variance (K-W ANOVA) chi 2 = 10.3, p = 0.006. Plasma 25(OH)D3 was negatively correlated with both urinary total proteins and urinary cadmium, but showed no correlation with plasma 24R,25(OH)2D3, 1 alpha,25(OH)2D3, blood lead, or blood cadmium. CONCLUSION: Continuous long term exposure to cadmium may result in a state of equilibrium between blood and urinary cadmium. Cadmium concentrations in blood could be predicted from the cadmium concentration of the urine, (regression coefficient +0.35 SE 0.077). Exposure to cadmium alone decreased the concentrations of 1 alpha,25(OH)2D3 and 24R,25(OH)2D3, whereas exposure to both cadmium and lead increased the concentrations of 1 alpha,25(OH)2D3. It has been suggested that cadmium and lead interact with renal mitochondrial hydroxylases of the vitamin D3 endocrine complex. Perturbation of the vitamin D metabolic pathway by cadmium may result in health effect, such as osteoporosis or osteomalacia, risks which are possibly increased in the presence of lead.

24,25-Dihydroxyvitamin D 3↗
PubMed1998

Blood lead in U.K. children--time for a lower action level?

1. Blood lead measurements in samples collected from 660 London schoolchildren during 1991 to 1992 suggest that the blood lead values in children in the U.K. are decreasing. 2. Geometric mean values for blood lead were 0.18 (range 0.05-0.71) micromol/l [3.7 (1. 0-15.0) microgram/dl]. Analysis of variance showed differences between ethnic groups, sex and schools. An age-matched subset of 148 children was compared with 136 children from an earlier study in 1986 and 1987. Trend analysis of the geometric mean lead values showed a negative slope (b=-0.484, P<0.0001), with maximum values of 0.81, 1.00, 0.71 and 0.43 micromol/l (17, 21, 15 and 9 microgram/dl) for the years 1986, 1987, 1991 and 1992 respectively. 3. It is recommended that children in the U.K. being investigated for anaemia, pica, recurrent abdominal pain or a high-risk environment should have blood lead values measured and that the action level for blood lead in children should be decreased from 1.19 micromol/l to 0.48 micromol/l (from 25 microgram/dl to 10 microgram/dl). 4. Guidance is offered to clinicians and other health professionals investigating excessive lead exposure.

Adolescent↗
PubMed1997

Non-Hodgkin's lymphomas complicating Sjögren's syndrome: can Epstein Barr virus be implicated?

We examined eight (6 parotid, 1 caecum, 1 lymph node) non Hodgkin's Lymphomas (NHL) complicating primary Sjögren's syndrome (SS), four parotid NHL, in patients without SS, and three salivary gland biopsies from SS patients and no NHL, for Epstein Barr virus (EBV), using immunohistochemistry for late membrane protein, in situ hybridisation (ISH) for EBER, and PCR for EBV DNA. Late membrane protein was not detected. In NHL's complicating SS, EBERs were detected in two parotid lymphomas by ISH. EBV DNA was detected in three SS parotid NHL. Cecal and lymph node SS NHL were negative for EBER and EBV DNA. EBV DNA was detected in two non SS NHLs, one expressed EBER. Despite positive EBV DNA results by PCR in three samples expression of EBER was noted in only one by ISH. This was a high grade NHL complicating SS. There was no evidence of EBV in low grade NHLs complicating SS.

DNA Primers↗
PubMed1996

Noradrenaline inhibition of Ca2+ channels and secretion in single patch-clamped insulinoma cells.

Noradrenaline effects on voltage-operated calcium channels and exocytosis were studied, for the first time, in single patch-clamped RINm5F insulin-secreting cells. Noradrenaline, despite small and variable inhibition of calcium currents, strongly inhibited the increase in membrane capacitance (a measure of exocytosis) stimulated by both step depolarizations and the calcium ionophore, ionomycin. Noradrenaline similarly inhibited KCl- and ionomycin-induced [3H]serotonin release from RINm5F cell populations. Noradrenaline effects were mediated by PTX-sensitive G proteins. Noradrenaline inhibitory effects on secretion are, therefore, mainly exerted downstream from Ca2+ influx.

Animals↗
PubMed1996

DNA vaccines.

Explore the source record for details and available documents.

Animals↗
PubMed1996

Expression of the human heat shock protein 60 in thyroid, pancreatic, hepatic and adrenal autoimmunity.

Heat shock proteins (hsps) have been proposed to play a role in autoimmune disease. Their highly conserved nature and role as a common antigenic determinant throughout phylogeny has raised the possibility that they may act as cellular targets of an autoimmune response when their expression is altered in stressed tissue cells. Using an antibody to human hsp60 we have demonstrated a wide tissue distribution in normal tissues, including thymus, the degree of staining reflecting the content of mitochondria in the cells, consistent with the known mitochondrial location of this protein. Enhanced staining was also demonstrated in oncocytes (deeply eosinophilic cells which have greatly increased numbers of mitochondria) in both thyroid and adrenal autoimmune disease and also in unrelated conditions where oncocytic change was identified. No enhancement was demonstrated in target cells in organ specific autoimmune diseases where oncocytic change was not seen, for example islet cells in diabetes and bile duct cells in primary biliary cirrhosis. Thus, no alteration of hsp60 expression was demonstrated which was specific to the autoimmune diseases studied.

Adrenal Glands↗
PubMed1995

The spirit of nursing and its healing art: a Jungian perspective.

Timely change is in the air as interest grows in the riches of nursing literature and other creative arts of nursing. Using Jungian and sociological concepts, this article takes a personal look at the literature's contribution to the profession. As the image of contemporary nursing is redefined, the power of the creative is evident, both in its grounding effect on individual practice and its unifying and strengthening potential for a changing profession.

Humans↗