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Biomedical subjects

N G Anderson

Publications and source records attributed to N G Anderson.

At least 19 recordsLinked to original sources
PubMed2006

Intrinsic measurement bias on computed tomography scout view is unpredictable: Computed tomography pelvimetry using a phantom.

Our aim was to determine the degree of bias in CT scanogram measurements. We obtained standard lateral and anteroposterior (AP) pelvimetry scanograms of a phantom pelvis after placing ball bearings or aluminium rods to mark bony landmarks. Computed tomography pelvimetry was carried out at the manufacturer-recommended table height on two commercial CT scanners and at 10-mm increments up to 50 mm above and below this height. The AP inlet, AP outlet, interspinous distance and transverse diameters were each measured three times for each scanogram. The true measurements were obtained directly from the disassembled phantom. Bias was defined as the difference between the CT measurement and the true measurement. Observer error was negligible. The transverse diameter was overestimated at high table positions and underestimated at low table positions on both scanners (+6 to -10 mm). After correcting for geometric distortion, up to 6 mm bias was still present. The point at which no bias occurred was different for each scanner and did not correspond to the manufacturers' recommended table height. The outlet was overestimated on both scanners by up to 5 mm. The true inlet measurement was overestimated by 1.2 mm. The interspinous distance was minimally underestimated on both scanners. The measurements on CT scanogram were underestimated or overestimated in an inconsistent and unpredictable fashion, varying from one type of measurement to another and from CT scanner to CT scanner. This has implications for the accuracy and clinical utility of measurements obtained from a CT scanogram.

Analysis of Variance↗
PubMed2006

Normal obstetric ultrasound reduces the risk of Down syndrome in fetuses of older mothers.

The objective of this study is to determine whether a normal fetal morphology ultrasound scan in women older than 35 years reduces the risk of aneuploidy. We reviewed the results of amniocentesis and second trimester sonogram in all women older than 35 years from 1991 to 1995. None had prior screening. We excluded fetuses with structural anomalies. We determined the sensitivity and specificity of minor markers in detecting Down syndrome and also determined the reduction in risk of a normal sonogram. Among the 2060 women older than 35 years giving birth during the study period, 16 (0.78%) delivered an infant with Down syndrome. Of the 16 fetuses, two had no prenatal testing or ultrasound, two had invasive testing but no second trimester sonogram, five had a normal sonogram and seven had one or more sonographic markers of Down syndrome. At least 17% of women older than 35 years did not participate in prenatal testing or ultrasound. Ultrasound detected Down syndrome with a sensitivity of 59% (95% confidence interval: 45-72%), a false-positive rate of 10.6% (9.4-11.8%) and a positive predictor value of 1 in 9. The likelihood of having normal karyotype if the sonogram was normal was 0.46 (0.31-0.61). In women older than 35 years, a normal second trimester sonogram reduces the risk of Down syndrome by more than 50%. At least 17% of women older than 35 years do not participate in prenatal testing or ultrasound.

Adult↗
PubMed2006

The ultrasound halo sign in angiolymphoid hyperplasia of the temporal artery.

An ultrasound halo sign surrounding the temporal artery is a well recognized feature associated with giant cell arteritis. We report a previously unreported case of this halo sign being present around the temporal artery due to angiolymphoid hyperplasia with eosinophilia (ALHE) in a young female patient.

Adult↗
PubMed2003

The parathyroid hormone-related protein receptor is expressed in breast cancer bone metastases and promotes autocrine proliferation in breast carcinoma cells.

Overproduction of parathyroid hormone-related protein (PTHRP) occurs in a high proportion of primary breast cancers (PBC) and is strongly implicated in their metastatic spread to bone. Although the PTHRP-receptor (PTHRP-R) is often coexpressed with PTHRP in PBC, its role in regulating breast cancer cell proliferation and metastases to bone remains unclear. The aims of this study were to determine the expression of the PTHRP-R in breast cancer bone metastases (BM) and to investigate the effects of PTHRP-R overexpression on breast cancer cell proliferation. PTHRP-R expression occurred in 85% (11 out of 13) of BM compared with 58% (39 out of 67) of PBC. Median expression was higher (P<0.05) in BM compared with PBC. PTHRP increased cAMP accumulation and DNA synthesis in MCF-7 cells stably overexpressing the PTHRP-R (MCF-7(WTR)) but not in MCF-7(VEC) control cells. The increase in DNA synthesis was mimicked by the cAMP pathway activator forskolin. The receptor antagonist PTHRP(7-34) reduced DNA synthesis in MCF-7(WTR) cells, but not MCF-7(VEC) cells, indicating that receptor overexpression promotes autocrine PTHRP activity. MCF-7(WTR) cells showed increased mitogenic responsiveness to fetal calf serum and reduced doubling times. PTHRP induced weak activation of ERK1 and ERK2 and potentiated their activation by serum growth factors. Collectively these results show that the PTHRP-R is frequently expressed in breast cancer BM and indicate that receptor overexpression drives proliferation via autocrine signals that are mediated via cAMP and ERK pathways.

Autocrine Communication↗
PubMed2003

The isoform-specific regulation of apoptosis by protein kinase C.

The process of apoptosis is regulated at several levels through phosphorylation by many different protein kinases. The protein kinase C (PKC) family, which comprises at least 10 isoforms with distinct means of regulation and tissue distribution patterns, have been shown to exert both inhibitory and stimulatory influences on apoptosis. This review details recent progress made in determining the roles played by individual PKC isoforms in the control of apoptosis, with reference to their target substrates and actions in different cell types. Although notable exceptions exist, the weight of evidence indicates that the alpha, beta, epsilon and atypical isoforms are anti-apoptotic in their action, whereas the delta and theta isoforms are usually involved in the promotion of apoptosis.

Animals↗
PubMed2003

Protein kinase C-epsilon promotes adipogenic commitment and is essential for terminal differentiation of 3T3-F442A preadipocytes.

The role of protein kinase C (PKC) isoforms in the commitment of multipotent fibroblasts to the adipocyte lineage and in their terminal differentiation into mature adipocytes was investigated. Ectopic overexpression of PKC-epsilon, but not other PKC isoforms, committed multipotent NIH-3T3 cells to adipogenic differentiation in the presence of hormonal inducers. In committed 3T3-F442A preadipocytes, PKC-epsilon protein expression increased during the course of terminal differentiation and cell-permeable PKC-epsilon inhibitory peptides, which prevent interaction with RACK (receptor for activated C-kinase) proteins, severely inhibited differentiation. PKC-epsilon accumulated in the nuclei of 3T3-F442A cells shortly after induction of differentiation and exhibited a distinctive punctate speckling immunocytochemical staining pattern. The spatiotemporal aspects of PKC-epsilon localization and expression coincided with that of C/EBP-beta, a transcription factor critically involved in promoting the early phase of adipogenesis. Collectively, these results demonstrate a role for PKC-epsilon in both adipogenic commitment and preadipocyte terminal differentiation.

3T3 Cells↗
PubMed2003

Autocrine signalling through erbB receptors promotes constitutive activation of protein kinase B/Akt in breast cancer cell lines.

The protein kinase PKB/Akt plays a pivotal role in promoting cell survival and proliferation. This study investigated the regulation of PKB/Akt activity in breast cancer cells. In primary invasive breast cancers PKB/Akt exhibited elevated phosphorylation at regulatory site Ser473 in 80% of cases, using immunohistochemistry. The degree of phospho-PKB/Akt immunoreactivity was positively correlated with the extent of its nuclear accumulation. Moderate/strong staining was seen in 31% of the samples but was absent in tumour-associated normal breast epithelia. To examine the mechanisms of PKB/Akt activation, we studied its phosphorylation in a panel of breast cancer cell lines. PKB/Akt was constitutively phosphorylated on both regulatory sites (Thr308 and Ser473) in the absence of serum growth factors in 7 of 8 lines but not in two cell lines derived from normal breast epithelia. Further analysis revealed that constitutive PKB/Akt phosphorylation was associated with loss of PTEN phosphatase expression (CAL51, MDA-MB-468, BT549 cells) and constitutive activation of erbB2 (SKBR3, BT474 cells). In two further breast cancer lines (T47D and HS578T) PKB/Akt phosphorylation was dependent upon autocrine factors acting primary through the epidermal growth factor receptor (EGFR) and erbB2. Conditioned medium from HS578T cells stimulated EGFR-dependent PKB/Akt phosphorylation in normal breast cells. These results demonstrate that PKB/Akt is frequently activated in breast cancer through diverse mechanisms, including autocrine signalling via erbB receptors.

Breast Neoplasms↗
PubMed2001

ZD1839 (Iressa), a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, potently inhibits the growth of EGFR-positive cancer cell lines with or without erbB2 overexpression.

Overexpression of the growth factor receptors EGFR and erbB2 occurs frequently in several human cancers and is associated with aggressive tumour behaviour and poor patient prognosis. We have investigated the effects of ZD1839 (Iressa), a novel EGFR tyrosine kinase inhibitor, on the growth, in vitro and in vivo, of human cancer cell lines expressing various levels of EGFR and erbB2. Proliferation of EGFR-overexpressing A431 and MDA-MB-231 cells in vitro was potently inhibited (50%-70%) by ZD1839 with half-maximally effective doses in the low nanomolar range. In parallel, ZD1839 blocked autophosphorylation of EGFR and prevented activation of PLC-gamma 1, ERK MAP kinases and PKB/Akt by EGF. It also inhibited proliferation in EGFR(+) cancer cell lines overexpressing erbB2 (SKBr3, SKOV3, BT474) by between 20% and 80%, effects which correlated with inhibition of EGF-dependent erbB2 phosphorylation and activation of ERK MAP kinase and PKB/Akt in SKOV3 cells. Oral administration of ZD1839 inhibited the growth of MDA-MB-231 and SKOV3 tumours, established as xenografts in athymic mice, by 71% and 32%, respectively. Growth inhibition coincided with reduced proliferation but no change in apoptotic index. Collectively, these results show that ZD1839, at the doses studied, is a potent inhibitor of proliferation not only in cells overexpressing EGFR but also in EGFR(+) cells that overexpress erbB2.

Cell Division↗
PubMed2001

Back to the future: the human protein index (HPI) and the agenda for post-proteomic biology.

The effort to produce an index of all human proteins (the human protein index, or HPI) began twenty years ago, before the initiation of the human genome program. Because DNA sequencing technology is inherently simpler and more scalable than protein analytical technology, and because the finiteness of genomes invited a spirit of rapid conquest, the notion of genome sequencing has displaced that of protein databases in the minds of most molecular biologists for the last decade. However, now that the human genome sequence is nearing completion, a major realignment is under way that brings proteins back to the center of biological thinking. Using an influx of new and improved protein technologies--from mass spectrometry to re-engineered two-dimensional (2-D) gel systems, the original objectives of the HPI have been expanded and the time frame for its execution radically shortened. Several additional large scale technology efforts flowing from the HPI are also described.

Biotechnology↗
PubMed2001

Studies of epidermal growth factor receptor inhibition in breast cancer.

Until recently, there has been little knowledge on the growth control of oestrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) and invasive breast cancer. The recent development of DCIS models, such as transgenic mice, cell-line xenograft models and, importantly, in vivo human DCIS xenograft models has facilitated the investigation and understanding of the control of growth of early pre-invasive breast lesions. Recent studies have shown that ER-negative DCIS, unlike ER-positive DCIS, is hormone independent and does not respond to anti-oestrogen treatment. Moreover, DCIS of the comedo type utilises type I tyrosine kinase growth factors, such as epidermal growth factor receptor (EGFR) and c-erbB-2, in receptor signalling for growth. New data underscore the importance of EGFR as the major modulating growth factor receptor in the control of proliferation in the breast. Pre-clinical studies performed on human DCIS xenografts in nude mice suggest a potential role for EGFR tyrosine kinase inhibitors (EGFR-TKIs). More specifically, ZD1839, a novel orally active and selective EGFR-TKI, has been shown to produce a response in DCIS through a decrease in epithelial proliferation. These findings have enhanced our knowledge of signal transduction pathways in cancer and indicate that tyrosine kinase blockade of EGFR has potential for the treatment and chemoprevention of DCIS. It is hoped that further advances in this area and evaluation of EGFR-TKIs in Phase II/III clinical trials will allow their therapeutic potential as anticancer agents to be appreciated.

Animals↗
PubMed2000

Outcome of primary vesicoureteric reflux detected following fetal renal pelvic dilatation.

OBJECTIVE: Postnatal investigation of mild degrees of fetal hydronephrosis has allowed subsequent detection of infants with vesicoureteric reflux (VUR). This study was designed to provide short to medium term information on such infants who had primary VUR, the rates of renal damage and progression over time, the risk factors for such damage and to compare the characteristics of those who had mild dilatation of the fetal renal pelvis (4-9 mm) with those who had moderate-severe dilatation (> or = 10 mm). METHODOLOGY: Since June 1989, infants whose antenatal sonography had identified a fetal renal pelvis with an anteroposterior diameter of > 4 mm were investigated postnatally with renal ultrasonography and micturating cystourethrogram (MCU), and placed on antimicrobial prophylaxis. Those with VUR received 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy. Infants were followed until discharge based on resolution of VUR, surgery, or low grade VUR. A 5.5 year cohort between June 1989 and December 1994 formed the study population. A review of notes and clinical review (if still under follow up) was undertaken. Vesicoureteric reflux on MCU was regraded according to the International Classification, and reflux nephropathy on DMSA scans was regraded according to criteria proposed by Goldraich. Regression analysis was used to assess risk factors for renal damage. RESULTS: There were 69 infants (37 girls, 32 boys) who were identified with primary VUR, with 37/69 having bilateral reflux. Eight had a urinary tract infection during the follow-up period. There was a broad distribution of grades of reflux detected (Grades I-3, Grades II-23, Grades III-19, Grades IV - 17, Grades V-7). 99m-Tc-dimercaptosuccinic acid scans on 57/69 (83%) demonstrated renal damage in eight infants (14%). This was predominantly global contraction of function. No progression of renal damage was seen over 2-7 years. Regression analysis showed a strong association between Grades IV, V reflux and the presence of renal damage (P < 0.001). Review of the degrees of fetal renal pelvic dilatation showed that 60/69 infants were detected because of mild (4-9 mm) dilatation. The majority (43/60) had lower grades of reflux (Grades I, II, 3), but there was no obvious cut-off between 4 and 9 mm that could predict high grade VUR (Grades IV, V). CONCLUSIONS: The use of 4 mm to define an abnormal fetal renal pelvis allows a much larger group of infants with high grade primary VUR to be detected than if a higher cut-off measurement is used. Although it also detects many more infants with low grade primary VUR, there is no obvious cut-off point at which this effect predominates. Progressive renal damage was not seen in follow up of up to 7 years of age. Renal damage on DMSA scanning in this group is almost exclusively a pattern of global contraction of function. The presence of high-grade VUR appears to be the only important factor in predicting the presence of renal damage.

Child↗
PubMed1999

Growth hormone-dependent differentiation of 3T3-F442A preadipocytes requires Janus kinase/signal transducer and activator of transcription but not mitogen-activated protein kinase or p70 S6 kinase signaling.

The signals mediating growth hormone (GH)-dependent differentiation of 3T3-F442A preadipocytes under serum-free conditions have been studied. GH priming of cells was required before the induction of terminal differentiation by a combination of epidermal growth factor, tri-iodothyronine, and insulin. Cellular depletion of Janus kinase-2 (JAK-2) using antisense oligodeoxynucleotides (ODNs) prevented GH-stimulated JAK-2 and signal transducer and activator of transcription (STAT)-5 tyrosine phosphorylation and severely attenuated the ability of GH to promote differentiation. Although p42(MAPK)/p44(MAPK) mitogen-activated protein kinases were activated during GH priming, treatment of cells with PD 098059, which prevented activation of these kinases, did not block GH priming. However, antisense ODN-mediated depletion of mitogen-activated protein kinases from the cells showed that their expression was necessary for terminal differentiation. Similarly, although p70(s6k) was activated during GH priming, pretreatment of cells with rapamycin, which prevented the activation of p70(s6k), had no effect on GH priming. However, rapamycin did partially block epidermal growth factor, tri-iodothyronine, and insulin-stimulated terminal differentiation. By contrast, cellular depletion of STAT-5 with antisense ODNs completely abolished the ability of GH to promote differentiation. These results indicate that JAK-2, acting specifically via STAT-5, is necessary for GH-dependent differentiation of 3T3-F442A preadipocytes. Activation of p42(MAPK)/p44(MAPK) and p70(s6k) is not essential for the promotion of differentiation by GH, although these signals are required for GH-independent terminal differentiation.

3T3 Cells↗
PubMed1999

Cerebellar vermis diameter at cranial sonography for assessing gestational age in low-birth-weight infants.

BACKGROUND: Clinical assessment of gestational age for very-low-birth-weight infants is often inaccurate. Survival rates are more dependent on gestational age than on the birth weight. OBJECTIVE: To assess whether cerebellar vermis diameter might predict gestational age in infants under 2,000 g and/or under 32 weeks' gestation. MATERIALS AND METHODS: We carried out a retrospective review of the hard-copy images of midline sagittal views of the cerebellum obtained at cranial sonography, performed via the anterior or posterior fontanelle, in 518 infants admitted to a regional neonatal intensive care unit between June 1991 and November 1996. The vermis diameter was measured from the base of the fourth ventricle to the junction of folium and tuber vermis. We generated regression equations for estimating gestational age from vermis diameter, and from vermis diameter and birth weight, for the 86 infants of known gestational age (less than 32 weeks), with birth weight under 2,000 g and who had scans carried out within 1 week of birth. RESULTS: Measurement of cerebellar vermis diameter alone allowed prediction of gestational age to +/- 1.53 weeks using a 68 % prediction interval, or +/- 3.0 weeks using a 95 % prediction interval. Gender was not significant in the regression analysis. CONCLUSION: Cerebellar vermis diameter predicts gestational age with slightly more precision than the new Ballard score.

Birth Weight↗
PubMed1998

Protein kinase C isoforms play differential roles in the regulation of adipocyte differentiation.

In this study we first established, by immunoblotting with specific antibodies, the temporal changes in cellular levels of protein kinase C (PKC) isoforms during differentiation of 3T3-F442A pre-adipocytes. Both pre-adipocyte and adipocyte 3T3-F442A cells were found to express PKC-alpha, -gamma, -delta, -epsilon, -zeta and -mu. However we were unable to detect PKC-beta, -eta or -theta. The same PKC isoform expression profile was found in rat adipocytes. The alpha, delta and gamma isoforms displayed similar temporal patterns of expression during differentiation of 3T3-F442A cells; all increased rapidly, peaking at day 2 of differentiation. Subsequently, the expression of these isoforms decreased, resulting in lower levels in fully differentiated adipocytes than in pre-adipocytes. The expression of PKC-epsilon increased steadily during differentiation, resulting in markedly elevated levels in adipocytes. Although expression of PKC-mu increased during differentiation, this was attributable to prolonged confluence rather than to the differentiation process itself. No change was observed in PKC-zeta levels during adipocyte development. Anti-sense oligodeoxynucleotides (ODNs) were used to deplete selectively the individual PKC subtypes. Each of the ODNs used effectively depleted the specific isoforms to undetectable levels and did not affect expression of the other PKC subtypes. This approach indicated that pre-adipocyte differentiation is not dependent upon PKC-zeta but that PKC-alpha,-delta and -mu each exert an inhibitory influence upon differentiation. Use of anti-sense ODNs to deplete PKC-epsilon and -gamma revealed that pre-adipocyte differentiation is dependent upon each of these isoforms. However, PKC-gamma, but not PKC-epsilon, appeared to be necessary for the clonal expansion of differentiating cells, suggesting that PKC-epsilon is required at a later phase in the differentiation process, when its expression is elevated, for the attainment and maintenance of the adipocyte phenotype.

3T3 Cells↗
PubMed1998

Cyclic AMP potentiates growth hormone-dependent differentiation of 3T3-F442A preadipocytes: possible involvement of the transcription factor CREB.

We have examined the effects of cyclic AMP on the differentiation of 3T3-F442A preadipocytes. High concentrations of intracellular cyclic AMP potently inhibited differentiation whereas low concentrations of intracellular cyclic AMP, induced by a number of different agents, promoted differentiation. To analyse these effects of cyclic AMP more closely, we developed a two-phase protocol for the differentiation of 3T3-F442A cells. Growth hormone (GH) was necessary to prime confluent cells during the first phase, following which, the addition of insulin and other adipogenic agents then promoted terminal differentiation. Cyclic AMP potentiated the priming action of GH but exerted an inhibitory effect on terminal differentiation when added to cells which had previously been primed with GH showing that the effects of cyclic AMP on preadipocyte differentiation are stage-dependent. We analysed the stimulatory effects of cyclic AMP during GH priming and found that cyclic AMP induced phosphorylation of the cyclic AMP response element (CRE) binding protein CREB and activated transcription of a CRE-linked reporter gene. Furthermore, GH also stimulated CREB phosphorylation and activation and this effect was potentiated by cyclic AMP. These results suggest a mechanism for the synergistic priming of preadipocytes for terminal differentiation by cyclic AMP and GH via the activation of differentiation genes containing CREs.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Proteome and proteomics: new technologies, new concepts, and new words.

The goal of proteomics is a comprehensive, quantitative description of protein expression and its changes under the influence of biological perturbations such as disease or drug treatment. Quantitative analysis of protein expression data obtained by high-throughput methods has led us to define the concept of "regulatory homology" and use it to begin to elucidate the basic structure of gene expression control in vivo. Such investigations lay the groundwork for construction of comprehensive databases of mechanisms (cataloguing possible biological outcomes), the next logical step after the soon to be completed cataloguing of genes and gene products. Mechanism databases provide a roadmap towards effective therapeutic intervention that is more direct than that offered by conventional genomics approaches.

Humans↗