bluuebunny/crossref_metadata_2025 huggingface dataset:
The Hollowing-out of Hong Kong Electronics: Organizational Inertia and Industrial Restructuring in the 1990s
Authors: Chiu Stephen , Wong Ka -Chung
Published: August 2004

This paper aims to enrich the literature on East Asian development by focusing on one critical difference between Hong Kong and the other NIEs – Hong Kong's rapid deindustrialization since the mid-1980s. We shall argue that while global restructuring gives rise to upgrading opportunities for various localities, it is the process of capability formation associated with the local business model that determines whether or not a locality is likely to benefit from these opportunities. We focus on the electronics industry as a crucial case and based on archival data and case interviews. We show that a strategic inertia associated with the "subcontractor model" locks Hong Kong firms in the OEM role within the buyer-driven global chain. Analyzing the evolution of local firms clearly illustrates the "imprinting" effect of the start-up environment on internal organizational structure and subsequent strategic choice. We conclude from this restructuring experience that sustainability
Expression and release patterns of neuropeptides during embryonic development and hatching of the green shore crab, Carcinus maenas
Authors: Chung J. Sook , Webster Simon G.
Published: August 2004

Crustacean ecdysis is controlled by at least three neuropeptides:moult-inhibiting hormone (MIH), which represses ecdysteroid synthesis;crustacean hyperglycaemic hormone (CHH), which not only influences ecdysteroid synthesis but also water uptake during moulting; and crustacean cardioactive peptide (CCAP), which is involved in stereotyped ecdysis behaviour. During embryonic development, moulting takes place in the egg, but there is little information regarding developmental expression of these neuropeptides during this period or during hatching – an event that is analogous to eclosion in insects. To address this problem, we determined expression profiles of MIH and CHH mRNA by quantitative RT-PCR, together with developmental peptide expression studies [confocal immunocytochemistry (ICC) and radioimmunoassay(RIA)]. Likely homologous events relating to neuropeptide surges of both CHH and CCAP were seen during larval hatching, when compared to the adult moult,and cell-specific copy concentration of both MIH and CHH mRNAs was identical to that of the adult during late embryonic development. We measured parallel mRNA and peptide expression of two neuropeptides (red pigment-concentrating hormone RPCH) and pigment-dispersing hormone (PDH) during development, as these have roles as neuromodulators and as classical neurohormonal roles. For MIH and CHH, gene expression was in accordance with peptide expression, but novel sites of CHH expression were found (abdominal peripheral neurones), the expression and release patterns of which may be related to larval eclosion and water uptake necessary for eggshell rupture and hatching. For RPCH and PDH,gene transcription and peptide expression were not in accordance. A significant contribution of maternally derived (non-translated) PDH mRNA to the embryo was seen, and for RPCH, high-level mRNA and peptide expression during late embryogenesis is related to a long ignored, but potentially important release site – the enigmatic post-commissural organs –which are the most prominent structures expressing RPCH during late embryogenesis.
SMAD-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA4/5/6-dependent chickNkx2.5enhancer
Authors: Lee Kyu-Ho , Evans Samuel , Ruan Todd Y. , Lassar Andrew B.
Published: August 2004

Prior work has indicated that BMP signals act in concert with FGF8, WNT11 and WNT antagonists to induce the formation of cardiac tissue in the vertebrate embryo. In an effort to understand how these signaling pathways control the expression of key cardiac regulators, we have characterized the cis-regulatory elements of the chick tinman homolog chick Nkx2.5. We find that at least three distinct cardiac activating regions (CARs) of chick Nkx2.5 cooperate to regulate early expression in the cardiac crescent and later segmental expression in the developing heart. In this report, we focus our attention on a 3′ BMP-responsive enhancer, termed CAR3, which directs robust cardiac transgene expression. By systematic mutagenesis and gel shift analysis of this enhancer, we demonstrate that GATA4/5/6, YY1 and SMAD1/4 are all necessary for BMP-mediated induction and heart-specific expression of CAR3. Adjacent YY1 and SMAD-binding sites within CAR3 constitute a minimal BMP response element, and interaction of SMAD1/4 with the N terminus of YY1 is required for BMP-mediated induction of CAR3. Our data suggest that BMP-mediated activation of this regulatory region reflects both the induction of GATA genes by BMP signals, as well as modulation of the transcriptional activity of YY1 by direct interaction of this transcription factor with BMP-activated SMADs.
Coordination of chondrocyte differentiation and joint formation byα5β1 integrin in the developing appendicular skeleton
Authors: Garciadiego-Cázares David , Rosales Carlos , Katoh Masaru , Chimal-Monroy Jesús
Published: August 2004

The control point by which chondrocytes take the decision between the cartilage differentiation program or the joint formation program is unknown. Here, we have investigated the effect of α5β1 integrin inhibitors and bone morphogenetic protein (BMP) on joint formation. Blocking ofα5β1 integrin by specific antibodies or RGD peptide(arginine-glycine-aspartic acid) induced inhibition of pre-hypertrophic chondrocyte differentiation and ectopic joint formation between proliferating chondrocytes and hypertrophic chondrocytes. Ectopic joint expressed Wnt14,Gdf5, chordin, autotaxin, type I collagen and CD44, while expression of Indian hedgehog and type II collagen was downregulated in cartilage. Expression of these interzone markers confirmed that the new structure is a new joint being formed. In the presence of BMP7, inhibition of α5β1 integrin function still induced the formation of the ectopic joint between proliferating chondrocytes and hypertrophic chondrocytes. By contrast,misexpression of α5β1 integrin resulted in fusion of joints and formation of pre-hypertrophic chondrocytes. These facts indicate that the decision of which cell fate to make pre-joint or pre-hypertrophic is made on the basis of the presence or absence of α5β1 integrin on chondrocytes.
Mitogen-activated protein kinase regulates neurofilament axonal transport
Authors: Chan Walter Kong-Ho , Dickerson Angelo , Ortiz Daniela , Pimenta Aurea F. , Moran Catherine M. , Motil Jennifer , Snyder Scotti J. , Malik Kafaid , Pant Harish C. , Shea Thomas B.
Published: August 2004

Mitogen-activated protein kinase (MAP) kinase plays a pivotal role in the development of the nervous system by mediating both neurogenesis and neuronal differentiation. Here we examined whether p42/44 MAP kinase plays a role in axonal transport and the organization of neurofilaments (NFs) in axonal neurites. Dominant-negative p42/44 MAP kinase, anti-MAP kinase antisense oligonucleotides and the MAP kinase inhibitor PD98059 all reduced NF phospho-epitopes and inhibited anterograde NF axonal transport of GFP-tagged NF subunits in differentiated NB2a/d1 neuroblastoma cells. Expression of constitutively active MAP kinase and intracellular delivery of active enzyme increased NF phospho-epitopes and increased NF axonal transport. Longer treatment with PD98059 shifted NF transport from anterograde to retrograde. PD98059 did not inhibit overall axonal transport nor compromise overall axonal architecture or composition. The p38 MAP kinase inhibitor SB202190 did not inhibit NF transport whereas the kinase inhibitor olomoucine inhibited both NF and mitochondrial transport. Axonal transport of NFs containing NF-H whose C-terminal region was mutated to mimic extensive phosphorylation was substantially less affected by PD98059 compared to a wild-type construct. These data suggest that p42/44 MAP kinase regulates NF anterograde transport by NF C-terminal phosphorylation. MAP kinase may therefore stabilize developing axons by promoting the accumulation of NFs within growing axonal neurites.
Intramolecular protein-protein and protein-lipid interactions control the conformation and subcellular targeting of neuronal Ykt6
Authors: Hasegawa Haruki , Yang Zhifen , Oltedal Leif , Davanger Svend , Hay Jesse C.
Published: August 2004

Although the membrane-trafficking functions of most SNAREs are conserved from yeast to humans, some mammalian SNAREs have evolved specialized functions unique to multicellular life. The mammalian homolog of the prenylated yeast SNARE Ykt6p might be one such example, because rat Ykt6 is highly expressed only in brain neurons. Furthermore, neuronal Ykt6 displayed a remarkably specialized, punctate localization that did not overlap appreciably with conventional compartments of the endomembrane system, suggesting that Ykt6 might be involved in a pathway unique to or specifically modified for neuronal function. Targeting of Ykt6 to its unique subcellular location was directed by its profilin-like longin domain. We have taken advantage of high-resolution structural data available for the yeast Ykt6p longin domain to examine mechanisms by which the mammalian longin domain controls Ykt6 conformation and subcellular targeting. We found that the overall tertiary structure of the longin domain, not sequence-specific surface features, drives direct targeting to the Ykt6 punctate structures. However, several sequence-specific surface features of the longin domain indirectly regulate Ykt6 localization through intramolecular interactions that mask otherwise-dominant targeting signals on the SNARE motif and lipid groups. Specifically, two hydrophobic binding pockets, one on each face of the longin domain, and one mixed hydrophobic/charged surface, participate in protein-protein interactions with the SNARE motif and protein-lipid interactions with the lipid group(s) at the molecule's C-terminus. One of the hydrophobic pockets suppresses protein-palmitoylation-dependent mislocalization of Ykt6 to the plasma membrane. The Ykt6 intramolecular interactions would be predicted to create a compact, closed conformation of the SNARE that prevents promiscuous targeting interactions and premature insertion into membranes. Interestingly, both protein-protein and protein-lipid interactions are required for a tightly closed conformation and normal targeting.
A key role for stress-induced satellite III transcripts in the relocalization of splicing factors into nuclear stress granules
Authors: Metz Alexandra , Soret Johann , Vourc'h Claire , Tazi Jamal , Jolly Caroline
Published: August 2004

Exposure of cells to stressful conditions results in the rapid synthesis of a subset of specialized proteins termed heat shock proteins (HSPs) which function in protecting the cell against damage. The stress-induced activation of hsp genes is controlled by the heat shock transcription factor 1 (HSF1). At the cellular level, one of the most striking effects of stress is the rapid and reversible redistribution of HSF1 into a few nuclear structures termed nuclear stress granules which form primarily on the 9q12 locus in humans. Within these structures, HSF1 binds to satellite III repeated elements and drives the RNA polymerase II-dependent transcription of these sequences into stable RNAs which remain associated with the 9q12 locus for a certain time after synthesis. Other proteins, in particular splicing factors, were also shown to relocalize to the granules upon stress. Here, we investigated the role of stress-induced satellite III transcripts in the relocalization of splicing factors to the granules. We show that the recruitment of the two serine/arginine-rich (SR) proteins SF2/ASF and SRp30c requires the presence of stress-induced satellite III transcripts. In agreement with these findings, we identified the second RNA-recognition motif (RRM2) of hSF2/ASF as the motif required for the targeting to the granules, and we showed by immunoprecipitation that the endogenous hSF2/ASF protein is present in a complex with satellite III transcripts in stressed cells in vivo. Interestingly, satellite III transcripts also immunoprecipitate together with small nuclear ribonucleoproteins (snRNPs) in vivo whereas the intronless hsp70 transcripts do not, supporting the proposal that these transcripts are subject to splicing. Altogether, these data highlight the central role for satellite III transcripts in the targeting and/or retention of splicing factors into the granules upon stress.
Cdk5 and Trio modulate endocrine cell exocytosis
Authors: Xin Xiaonan , Ferraro Francesco , Bäck Nils , Eipper Betty A. , Mains Richard E.
Published: August 2004

Hormone secretion by pituitary cells is decreased by roscovitine, an inhibitor of cyclin-dependent kinase 5 (Cdk5). Roscovitine treatment reorganizes cortical actin and ultrastructural analysis demonstrates that roscovitine limits the ability of secretory granules to approach the plasma membrane or one another. Trio, a multifunctional RhoGEF expressed in pituitary cells, interacts with peptidylglycine α-amidating monooxygenase, a secretory granule membrane protein known to affect the actin cytoskeleton. Roscovitine inhibits the ability of Trio to activate Rac, and peptides corresponding to the Cdk5 consensus sites in Trio are phosphorylated by Cdk5. Together, these data suggest that control of the cortical actin cytoskeleton, long known to modulate hormone exocytosis and subsequent endocytosis, involves Cdk5-mediated activation of Trio.
A genetic algorithm-based model predictive control autopilot design and its implementation in an autonomous underwater vehicle
Authors: Naeem W , Sutton R , Chudley J , Dalgleish F R , Tetlow S
Published: August 2004

The control of any underwater vehicle has always been a challenging task and is certainly an important and necessary feature of an autonomous underwater vehicle (AUV). This paper describes the implementation of a genetic algorithm (GA)-based model predictive controller for an AUV named Hammerhead which is being developed jointly by the Universities of Plymouth and Cranfield. To the present authors' knowledge, this is the first successful application of a GA in realtime optimization for controller tuning in the marine sector and thus the paper makes an extremely novel and useful contribution to control system design. The advantages of using model predictive control (MPC) include its constraint handling and disturbance rejection properties commonly present in an underwater environment. The use of GAs generalizes MPC to employ linear as well as nonlinear process models. Furthermore, it supports the inclusion of various types of objective function without having to change the controller structure. The model required for MPC is extracted using system identification techniques on actual AUV data obtained from full-scale in-water tests. A description of Hammerhead AUV is outlined and simulation and experiment data are shown which were obtained by optimizing the cost function online using the GA. Results demonstrate good tracking behaviour despite the presence of disturbances and ever-present modelling uncertainty.
An improved matching method to solve the diffraction—radiation problem of a ship moving in waves
Authors: Du S X , Hudson D A , Price W G , Temarel P
Published: August 2004

On the underlying assumption that the disturbance of the far-field velocity potential caused by the motion of a ship is small and may be linearized, an improved matching method is developed. Two arrays of fundamental singularities are placed inside the ship hull, which satisfy the linear free surface condition outside the truncated fluid domain and the far-field radiation condition. The choice of fundamental singularity depends on the problem under investigation (e.g. pulsating, translating or translating and pulsating source). The unknown strength of these singularities and the near-field velocity potential are determined in a coupled manner. It is shown from numerical examples that the present method provides a more efficient and accurate representation of waves in the far field than conventional matching methods.
Experimental investigation versus numerical simulation of the dynamic response of a moored floating structure to waves
Authors: Dessi D , Carcaterra A , Diodati G
Published: August 2004

A combined experimental/numerical investigation of a moored floating structure response to incoming waves is presented. The floating structure consists of three bodies, equipped with fenders, joined by elastic cables. The system is also moored to the seabed with eight mooring lines. This corresponds to an actual configuration of a floating structure used for ships and submarines in special docking operations. The dynamic wave response is investigated by performing experiments in a towing tank equipped with a wave maker. Experimental results are compared with numerical simulations in regular and irregular waves, showing a good agreement. The predicted time histories of pitch, heave and surge motions of the three-body structure and of the mooring line forces bear very satisfactorily the experimental results in regular head waves. The case of irregular waves is also encouraging, since the statistics of the response is correctly kept up to the fourth-order statistical moments. This confirms that the theoretical model proposed in this paper is a suitable tool to predict the actual behaviour of a complex moored structure at sea.
A simplified modular approach for the prediction of the roll motion due to the combined action of wind and waves
Authors: Bulian G , Francescutto A
Published: August 2004

In this work a combined analytical-numerical approach is proposed to address the problem of the ship roll motion under the combined action of wind and waves. Roll motion is modelled as a one-degree-of-freedom system non-linear in both damping and restoring. The approach is modular, allowing an easy update of the methodology on the basis of new research outcomes. Realistic environmental conditions regarding the effects of both wind and waves are taken into account and can be easily changed. The spatial correlation of wind gusts is taken into account by means of an ‘aerodynamic admittance’ function, whereas the moment due to waves is obtained from the sea slope spectrum using the concept of effective wave slope, leading to a ‘hydrodynamic admittance’ function. Both static and dynamic aspects of the problems are taken into account. The proposed analytical procedure, based on statistical linearization technique, allows approximate statistical averages of the roll motion, assumed to be Gaussian, to be obtained without necessarily resorting to time-consuming Monte Carlo simulations. On the basis of the results obtained, an estimation of the capsize probability can be carried out. It seems that the effect of wind gustiness could be considered very small when compared with the effects of waves and mean wind speed when the metacentric height is sufficiently large. Finally, the presented approach moves towards the concept of ‘performance-based analysis’, recently introduced at the International Maritime Organization as the basis for future developments of intact stability, in a clear and formal way.
Hysteretic characteristics of the Wells turbine in a deep stall condition
Authors: Kinoue Y , Setoguchi T , Kim T H , Mamum M , Kaneko K , Inoue M
Published: August 2004

In order to make clear the hysteresis behaviour of Wells turbine performance in a deep stall condition, experimental and numerical investigations were made for the hysteretic characteristics of such a turbine in such conditions. The experimental investigation was made by the use of turbine equipment in which a sinusoidal flow condition was simulated. The numerical investigation was made using an unsteady three-dimensional Navier-Stokes numerical simulation. The experimental and calculated turbine unsteady performances show two characteristic hysteretic loops. The counter-clockwise hysteresis loop in the unstalled condition can be associated with the separation on the suction surface near the hub, whereas the clockwise hysteresis loop in the deep stall condition can be associated with the separation on the suction surface near the tip.
Evidence for the clinical use of tumour markers
Authors: Duffy Michael J
Published: August 2004

Testing for tumour markers should only be performed if it results in a better patient outcome, increased quality of life or reduced overall cost of care. Ideally, the clinical value of a tumour marker should be validated in a large prospective study or a meta-analysis of small-scale retrospective/prospective studies (i.e. a level 1 evidence study) prior to routine use. Markers that have been validated in such a level 1 evidence study include carcinoembryonic antigen in the surveillance of patients with diagnosed colorectal cancer, alphafetoprotein, human chorionic gonadotrophin and lactate dehydrogenase for evaluating prognosis in patients non-seminomatous germ cell tumours, CA 125 for monitoring therapy in patients with ovarian cancer, oestrogen receptors for predicting response to hormone therapy in breast cancer, HER-2 for predicting response to trastuzumab in patients with advanced breast cancer and urokinase plasminogen activator/plasminogen activator inhibitor type 1 for determining prognosis in breast cancer. Although currently in widespread use, the value of prostate-specific antigen in screening for prostate cancer has yet to be validated in a large prospective randomized trial.
A prospective randomized controlled trial of point-of-care testing on the coronary care unit
Authors: Collinson PO , John C , Lynch S , Rao A , Canepa-Anson R , Carson E , Cramp D
Published: August 2004

Background: We report the results of a prospective randomized controlled trial comparing point-of-care testing (POCT) with central laboratory testing (CLT) in a six-bed coronary care unit in a district general hospital.

Methods: 263 consecutive admissions with chest pain and suspected acute coronary syndrome were randomized to measurement of cardiac troponin T by POCT or CLT only. Patient management was according to a pre-specified protocol utilizing clinical features, electrocardiographic changes and cardiac biomarkers (creatine kinase and cardiac troponin T) to define management. Outcome measures were diagnostic accuracy compared with CLT as 'gold standard', result turnaround time, mortality and length of stay in all patients and those with a protocol-driven early discharge policy.

Results: Diagnostic accuracy and mortality was equivalent in the POCT and CLT arm. Overall there was no difference in length of stay. In the pre-specified early discharge group ( n = 64) there was a significant reduction in median length of non-coronary care unit stay (145.3 h versus 79.5 h) and overall hospital stay (209.3 h versus 149.9 h) in those randomized to POCT.

Conclusion: A combination of rapid biochemical diagnosis and structured decisionmaking reduces length of hospital stay.
Iatrogenic copper deficiency causing anaemia and neutropenia
Authors: Todd Louise M , Godber Ian M , Gunn Ian R
Published: August 2004

A 79-year-old woman presented with an obstructed femoral hernia and had a wedge resection of the small intestine. Post-operatively she developed wound dehiscence and spent 3 days in the adult critical care unit. Good recovery followed and she was allowed home after 2 months in hospital. Six months later she presented with anaemia, neutropenia and a very low serum copper concentration. Review of her notes revealed that she had been given oral zinc therapy while in the critical care unit and this treatment had been continued on discharge from hospital. Serum copper, haemoglobin and white cell count recovered after oral zinc was discontinued. Oral zinc treatment can lead to symptomatic copper deficiency in susceptible patients.
Diagnostic value of heart fatty acid binding protein and myoglobin in patients admitted with chest pain
Authors: Alansari Salwa E , Croal Bernard L
Published: August 2004

Introduction: Patients presenting with chest pain do so at varying times following its onset. In addition, their histories can be unreliable, making the interpretation of time-dependent biochemical markers difficult. Patients are therefore subsequently managed according to measurements of specific markers, such as troponin, taken many hours following their admission. Earlier markers such as myoglobin and heart fatty acid binding protein (hFABP) may provide information earlier; however, the true role of such markers remains unclear when applied to real life patient cohorts. We aimed to evaluate and compare the diagnostic accuracy of the early markers hFABP and myoglobin (in terms of area under ROC curves, sensitivity and specificity) to troponin I (cTnI) in a pragmatic group of patients presenting with chest pain.

Methods: 302 patients presenting with chest pain had blood samples withdrawn both on admission and 12 h later. These were analysed for cTnI, myoglobin and hFABP. Standard clinical and electrocardiographic data were also obtained. Only the cTnI results were reported back to the clinicians and hence only they would have affected clinical care. Patients were grouped clinically according to both the American College of Cardiology/European Society of Cardiology new definition of myocardial infarction (MI) and by clinicians' diagnosis of MI.

Results: Median time from onset of symptoms to admission was 5.0 h (IQR 3.0-12 h). Greater ROC curve areas for the diagnosis of MI by both sets of criteria were obtained for cTnI over both myoglobin and hFABP. ROC curve areas for myoglobin and hFABP were also no better than that for cTnI in those patients presenting less than 4 h after the onset of chest pain. Both myoglobin and hFABP also performed poorly in those patients who were cTnI negative on admission.

Conclusion: Myoglobin and hFABP provide little clinical value when measured on admission in patients presenting with chest pain.
Iatrogenic copper deficiency following information and drugs obtained over the internet
Authors: Lang TF , Glynne-Jones R , Blake S , Taylor A , Kay JDS
Published: August 2004

We report the case of a 56-year-old woman with a 7-year history of metastatic cancer who presented with severe copper deficiency following self-treatment with the copper-chelating agent tetrathiomolybdate. This compound was used with the aim of inhibiting tumour angiogenesis and was obtained from the USA by placing an order on the internet. The patient exhibited severe neutropenia as her serum copper concentration fell from 19.8 μmol/L to 3.3 μmol/L and her caeruloplasmin concentration from 35 mg/dL to 4 mg/dL.
Objective determination of appropriate reporting intervals
Authors: Badrick Tony , Wilson Susan R , Dimeski Goce , Hickman Peter E
Published: August 2004

Background: The reporting interval is the incremental value chosen in reporting analyte concentration. Reporting intervals for different analytes are often inappropriately narrow, when analytical imprecision and biological variability are considered.

Methods: We have used statistical techniques to determine intervals for individual analytes at which there is 50% or 95% confidence that two results are analytically different, and compared these with the reporting intervals in use for a range of general chemistry analytes and analytes usually measured by immunoassay.

Results: No analytes met the criteria for 95% confidence that the results are analytically different. Even at the 50% confidence level, 24 of 46 analytes failed at all concentrations examined. For some analytes, particularly hormones at high concentration, the reporting interval increment should be increased by a factor of at least ten.

Conclusions: The majority of analytes are inappropriately reported when analytical precision alone is considered. The concept of the 'uncertainty of measurement' has not been adequately addressed. A consensus should be reached and implemented on appropriate reporting intervals for all analytes.
Detection and quantitation of normal and variant haemoglobins: an analytical review
Authors: Wild Barbara J , Bain Barbara J
Published: August 2004

As well as six 'normal' haemoglobins that occur at various stages of development, more than 800 abnormal or variant haemoglobins have been described. Many of these variant haemoglobins have no significant clinical consequences apart from causing confusion to clinicians and in laboratories; however, some of the variant haemoglobins result in major morbidity or mortality. The laboratory challenge is to detect these clinically significant haemoglobins and to identify them with sufficient accuracy for clinical purposes, as well as to quantitate both these and the 'normal' haemoglobins. The techniques used to detect and quantitate these haemoglobins in routine service laboratories are discussed in detail. Methods used by referral laboratories, such as mass spectrometry and DNA analysis, are briefly discussed. Haemoglobin analysis is most often undertaken as part of neonatal, antenatal or pre-anaesthetic screening; these programmes are reviewed, together with possible changes to neonatal screening and antenatal screening that may occur as part of the NHS National Plan.
Vitamin D deficiency masking primary hyperparathyroidism
Authors: Hannan FM , Fairney A , Johnston DG
Published: August 2004

Vitamin D deficiency and primary hyperparathyroidism (PHPT) are relatively common disorders. The coexistence of these conditions should be considered, as depletion of vitamin D may alter the clinical expression of autonomous parathyroid disease. We report details of a vitamin D deficient patient in whom replacement therapy led to the unmasking of occult PHPT.
Point-of-care test to monitor adherence to anti-tuberculous treatment
Authors: Whitfield Ruth , Cope Graham F
Published: August 2004

Background: In the fight against the global tuberculosis epidemic, it is essential to ensure that patients adhere to the treatment prescribed. As the treatment is given for a minimum of 6 months it is common for patients not to take their drugs regularly. Strategies are therefore needed to assess adherence to treatment. One established method is to examine the patient's urine for the presence of drug metabolites. A rapid point-of-care test would overcome some of the drawbacks associated with currently available methods.

Method: A rapid, safe point-of-care test for isoniazid metabolites (IsoScreen, Surescreen Diagnostics Limited, Derby, UK) has been developed and used to help assess adherence to treatment in a busy clinic for tuberculosis patients in South London.

Results: Urine samples were examined from 191 patients receiving isoniazid, usually in combination with rifampicin and other anti-tuberculous drugs. Isoscreen was positive in 93.2% of patients, suggesting that 6.8% might be poorly adhering to treatment. By contrast, examining the same urine samples for evidence of rifampicin ingestion gave positive results in only 43.5%, due to the fact that this test is only positive for a few hours after drug ingestion.

Conclusion: IsoScreen has been shown to provide a rapid and safe point-of-care test, which contributes to the detection of non-adherence in patients with tuberculosis.
Morning salivary cortisol versus short Synacthen test as a test of adrenal suppression
Authors: Patel Rajan S , Shaw Steve R , McIntyre Halena E , McGarry Gerald W , Wallace A Michael
Published: August 2004

Background: The short Synacthen test (SST) is the most commonly used test for the assessment of adrenal suppression. We investigated the potential of a simpler and more cost-effective procedure [morning salivary cortisol (MSC)] as an outpatient screening tool to detect adrenal suppression in patients using topical intranasal corticosteroids for rhinosinusitis.

Method: Forty-eight patients who were using topical corticosteroids underwent adrenal function assessment by way of SST and MSC measurement.

Results: Sixteen of the 48 patients had impaired MSCs. Of these 16 patients, 15 had an impaired SST (sensitivity 100%) and one had a normal SST. All patients with normal MSCs also had normal SSTs (specificity 97%).

Conclusion: The morning salivary cortisol measurement is a useful screening tool for adrenal suppression in this setting.
An audit of tumour marker requests in Northern Ireland
Authors: McDonnell Margaret
Published: August 2004

Background: An audit of tumour marker requests was carried out in Northern Ireland. The aims were to establish the extent of inappropriate requesting, to effect change in request practice if required, and to standardize laboratory reports for tumour markers.

Methods: A baseline audit was conducted to investigate the appropriateness of tumour marker requesting patterns in Northern Ireland. Information booklets containing guidelines for tumour markers were then distributed to all clinicians and a post-intervention audit was carried out.

Results: At baseline, 80% of requests for tumour markers were appropriate for the source of the tumour; however, 54% of clinicians used tumour markers to screen for malignancy and there was a low index of suspicion in 35% of these. Requests for more than two tumour markers were received for 5% of request forms. The postintervention survey showed no change in requesting practice. Comments were returned by requestors for 55% of questionnaires. They appeared to be appropriate in 72% of cases.

Conclusions: There is a low level of inappropriate requesting of tumour markers in Northern Ireland. Audit and feedback combined with circulation of guidelines were unsuccessful interventions in improving the appropriateness of request practice for these tests.
A population-based study of primary care predictors of non-attendance for cervical screening
Authors: Webb R , Richardson J , Pickles A
Published: August 2004

Objective: To identify and estimate the population impact of primary care service delivery factors that independently predict non-attendance for cervical screening.

Setting: Screening records of all eligible women aged 30 years and over and resident in the former Manchester Health Authority area were analysed (n=72,613).

Methods: Practice-level and GP-level explanatory variables, along with area-level covariates, were obtained and merged to the study data set. Logistic regression models were used to identify factors associated with having no recorded history of attending NHS cervical screening services. A multivariate model was created to identify independent predictors of non-attendance with comprehensive adjustment for women's age, area-level socio-demographic factors, and other primary care factors. Attributable fraction estimates were used to assess the population impact of the independent predictors.

Results: Large practice size (>4,000 patients), single-handed practice, South Asian male GP, part-time GP employment status, older age and birthplace overseas, and area-level measures of deprivation and transience independently predicted non-attendance. Women born overseas and registered at larger practices were especially unlikely to have ever attended. The combined population attributable fraction estimate for the independent predictors reflecting primary care service delivery was almost 40%, and that for all variables in the final model was over 70%.

Conclusions: Independent predictors of non-attendance reflecting general practice structure, workload and GP characteristics were identified. Although relative risks were modest, the collective population impact of these factors was considerable, which has implications for the implementation of informed targeting and the development of new screening services by Primary Care Trusts.
Number needed to screen: lives saved over 20 years of follow-up in mammographic screening
Authors: Tabar L , Vitak B , Yen MFA , Chen HHT , Smith RA , Duffy SW
Published: August 2004

Objective: To estimate the number needed to screen with mammography to save one life, based on a stated amount of screening activity and long-term follow-up for breast cancer death.

Setting: A randomised controlled trial of mammographic screening for breast cancer, with 77,080 women invited to screening and 55,985 not invited. The invited group was offered screening for seven years. Follow-up continued for a total of just over 20 years.

Methods: Number needed to screen for seven years to save one life over 20 years was calculated by dividing the number screened (not the number invited) by the total number of lives saved. Similarly, we calculated the number of mammographic examinations required to save one life.

Results: We estimate that the number of women needed to screen for seven years to save one life over 20 years is 465 (95% CI 324–819). The number of mammographic examinations needed to save one life was 1499 (95% CI 1046–2642).

Conclusions: The number needed to screen to save one life is smaller than has been reported in the past. Mammographic screening is effective in absolute terms as well as relative. Long-term follow-up allowed us to estimate the absolute benefit with greater accuracy.
Meta-analysis on the validity of pepsinogen test for gastric carcinoma, dysplasia or chronic atrophic gastritis screening
Authors: Dinis-Ribeiro M , Yamaki G , Miki K , Costa-Pereira A , Matsukawa M , Kurihara M
Published: August 2004

Aim: To assess the validity of the measurement of pepsinogen I and II as a screening test for gastric cancer and pre-malignant lesions, namely low-grade dysplasia, both in the general population and in selected groups of patients.

Methods: A meta-analysis of sensitivity and specificity results from individual papers on the use of the pepsinogen test. An intrinsic cut-off effect was assumed and a random effect model was used for pooling.

Results: Forty-two data sets were included: 27 (64%) population-based screening studies (n=296,553) and 15 (36%) sets of selected individuals (n=4385). Homogenous sensitivity and diagnostic odds ratio (DOR) estimates were found in studies using both pepsinogen I levels and pepsinogen I/II ratio calculations. Pooled pairs of sensitivity and false positive rates (FPr) for pepsinogen I ≤ 70; pepsinogen I/II ratio ≤ 3, pepsinogen I ≤50; pepsinogen I/II ratio ≤ 3, and pepsinogen I ≤ 30; pepsinogen I/II ratio ≤ 2, were sensitivity 77%/FPr 27%, sensitivity 68%/FPr 31%, and sensitivity 52%/FPr 84%, respectively. Positive predictive values (PPV) varied between 0.77% and 1.25%, and negative predictive values (NPV) varied between 99.08% and 99.90%. In selected groups, pooling was only possible when considering pepsinogen I ≤ 70; pepsinogen I/II ratio ≤ 3: giving sensitivity 57%, specificity 80%, PPV 15% and NPV 83%. As for the diagnosis of dysplasia, studies considering pepsinogen I <50; pepsinogen I/II ratio <3 obtained sensitivity 65% and specificity ranging from 74%–85%, both with NPV >95%.

Conclusion: Pepsinogen test definition should include pepsinogen I/II ratio as consistency was obtained, both in population based studies and in selected groups for those studies that used pepsinogen I serum levels together with pepsinogen I/II ratio for screening for gastric cancer in high-incidence regions other than Japan. Further studies of this test in the management of high-risk patients seem to be worthwhile.
Screening for physical and psychological illness in the British Armed Forces: I: The acceptability of the programme
Authors: Rona RJ , Jones M , French C , Hooper R , Wessely S
Published: August 2004

Objectives: To assess the response to a self-administered questionnaire and attendance of a medical centre for physical and psychological health screening.

Methods: 4500 men and women from the three services were randomly selected to receive either a full or abridged screening questionnaire. The full questionnaire included the General Health Questionnaire-12 (GHQ-12) and Post-traumatic Stress Disorder (PTSD) checklist, 15 symptoms, a self-assessed health status question and three questions on alcohol behaviour (WHO Audit). The abridged questionnaire included GHQ-4, a slightly shortened PTSD checklist and five symptoms, but excluded questions on alcohol behaviour. All 'screen-positive' and a random 'screen-negative' sample were invited to attend a medical centre.

Results: 67.1% of the servicemen completed a questionnaire; slightly but significantly more the abridged than the full questionnaire (4.9%, 95% confidence interval 2.3–7.4%). Of those receiving a full or abridged questionnaire, 32% and 22.5% respectively were 'screen-positives', most of the difference (7.5%) attributable to alcohol behaviour. Less than 30% of the servicemen invited to attend a medical centre accepted the invitation, even fewer during the preparation for deployment to Iraq. Those who fulfilled the criteria for PTSD, alcohol behaviour or multi-criteria 'screen-positive' were more reluctant than controls to attend.

Conclusions: Screening for psychological illness has little support among servicemen, perhaps because they may not wish to share concerns with a military doctor. Avoidance behaviour among those with a psychological condition may also selectively reduce willingness to attend a medical centre. Screening during pre-deployment periods has even less support than at other times.
Modelling the impact of detecting and treating ductal carcinoma in situ in a breast screening programme
Authors: McCann Jenny , Treasure Peter , Duffy Stephen
Published: August 2004

Objectives: Screening has substantially increased the detection of carcinoma in situ of the breast (CIS). Opinions vary as to whether this constitutes over-diagnosis or an opportunity to interrupt breast cancer's natural history. In England, incidence of invasive cancer and CIS increased in women of screening age (50–64 years), leading to a subsequent deficit in invasive incidence in women aged 65–69 years immediately beyond the invited age range. We aimed to model underlying incidence of invasive cancer and CIS expected in the absence of screening, and to quantify the likely relative contributions of their early detection to the observed reduction in invasive cancer in women of postscreening age.

Setting: UK NHS breast screening programme in England.

Methods: Poisson regression modelling was used to establish the underlying incidence of invasive and in situ cancers in the absence of screening. We then estimated age- and year-specific excess detection rates attributable to screening. Applying these to population figures we estimated conservatively the relative contributions of early diagnosis of CIS and invasive cancer at 50–64 years of age to the subsequent deficit in invasive cancer in women beyond invitation age (65–69 years), for screening early in the programme and at steady state.

Results: Our model estimated a 1.6% annual increase in incidence, giving an estimated deficit of 4.22 invasive cancers per 10,000 women aged 65–69 years in 1996. Carcinoma in situ contributed 13–17% to the deficit, assuming a mean six year lead time and 75–100% progression to invasive cancer. At steady state, with current screening performance and with lead times of 3–4 years (invasive cancer) and 6–9 years (CIS), invasive incidence might be reduced by 5–6 cancers per 10,000 women aged 65–69 years in 2010 (15–20% of underlying incidence), CIS contributing 20–40%.

Discussion: The longer lead time associated with CIS attenuates the impact its early detection has on subsequent invasive incidence. At steady state screening, its detection contributes significantly to the deficit in invasive incidence. Our results suggest that, cancer for cancer, there may be just as much benefit in detecting and treating a case of CIS as there is in treating a case of invasive cancer.
Screening for physical and psychological illness in the British Armed Forces: III: The value of a questionnaire to assist a Medical Officer to decide who needs help
Authors: Rona RJ , Hooper R , Jones M , French C , Wessely S
Published: August 2004

Objectives: To estimate the positive and negative predictive values (PPVT and NPVT), sensitivity and specificity of a full and abridged screening questionnaire of physical and psychological health, using primary care doctors' (medical officers [MOs]) assessments as to whether the servicemen needed medical help as a gold standard.

Methods: From a tri-service random sample of those who completed a questionnaire, all 'screen-positive' and an equal random sample of 'screen-negative' were selected to attend their medical centre. MOs were aware that the screening was aimed at detecting psychological illness, but were blind as to the 'screen-positivity' of any serviceman. The MO completed a questionnaire that asked whether the patient needed medical help and whether s/he was previously aware of this need.

Results: 314 subjects were available for analysis. The PPVT was 47% (95% confidence interval [CI] 36–59%) for the full questionnaire and 48% (95% CI 36–60%) for the abridged questionnaire. Of those 'screen-positive' subjects whom the MO rated as needing help, one third had problems already known to the MO, regardless of the length of the questionnaire. The sensitivity and specificity of the full and abridge questionnaires were 43% and 74%, and 36% and 83% respectively. The PPVT did not vary greatly between health dimensions nor did selection of servicemen with very high scores.

Conclusions: The use of MOs as a gold standard is important because of their central role in initiating the management of any condition uncovered by a screening programme. Using MOs as a gold standard, the validity of the screening questionnaires for physical and psychological health in the military was mediocre.
A cluster-randomised trial of screening for language disorders in toddlers
Authors: de Koning HJ , de Ridder-Sluiter JG , van Agt HME , Reep-van den Bergh CMM , van der Stege HA , Korfage IJ , Polder JJ , van der Maas PJ
Published: August 2004

Objective: To assess the screening performance of a specific language-screening instrument at 18 and 24 months of age and to assess its effect on the early detection and prognosis of language delay.

Design: Child health care physicians were randomised to the intervention group, in which specific language screening was conducted twice (at age 18 months and 24 months), or to the control group (usual care). The specific screening instrument consisted of a uniform set of questions for the parents and test elements for the child, with scaled scores to assess responses.

Setting: Child health care in the Netherlands and referral of screen-positive children.

Subjects: 5734 children in the intervention group and 4621 in the control group.

Main outcome measures: Test characteristics and disorders at 24 months, and confirmed diagnoses of a language disorder before 36 months in both groups. Gold standard based on reports of parents, specialists and expert panel. Prognosis estimated from two diagnostic language development performance scores at 36 months (in questionnaire).

Results: In the intervention group, 3147 of the 5734 children (55%) were screened with the specific screening instrument and 73 of the screened children (2.3%) were screen-positive. Of the screen-positive children, 41 (55%) had confirmed language delay (diagnostic assessment and/or reported treatment). The estimated sensitivity of the test ranged between 24–52% depending on the severity of language disorders. The prevalence of language disorders in three-year olds was estimated to be 2.4–5.3%. In the intervention group, 1.25–2 times more children with language delay had been diagnosed before 36 months. The assessment of language development at 36 months showed no statistically significant differences between the intervention and the control groups.

Conclusions: The inclusion of a specific language-screening instrument in child health centre activities resulted in the earlier detection of children with language delay. Short-term health benefits could not be demonstrated. Large-scale introduction cannot be recommended on the basis of this information alone.