bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of valine 106 on structure–function relation of cytosolic human thymidine kinase
Authors: Frederiksen Hanne , Berenstein Dvora , Munch‐Petersen Birgitte
Published: May 2004

Information on the regulation and structure–function relation of enzymes involved in DNA precursor synthesis is pivotal, as defects in several of these enzymes have been found to cause depletion or deletion of mitochondrial DNA resulting in severe diseases. Here, the effect of amino acid 106 on the enzymatic properties of the cell‐cycle‐regulated human cytosolic thymidine kinase 1 (TK1) is investigated. On the basis of the previously observed profound differences between recombinant TK1 with Val106 (V106WT) and Met106 (V106M) in catalytic activity and oligomerization pattern, we designed and characterized nine mutants of amino acid 106 differing in size, conformation and polarity. According to their oligomerization pattern and thymidine kinetics, the TK1 mutants can be divided into two groups. Group I (V106A, V106I and V106T) behaves like V106WT, in that pre‐assay exposure to ATP induces reversible transition from a dimer with low catalytic activity to a tetramer with high catalytic activity. Group II (V106G, V106H, V106K, V106L and V106Q) behaves like V106M in that they are permanently high activity tetramers, irrespective of ATP exposure. We conclude that size and conformation of amino acid 106 are more important than polarity for the catalytic activity and oligomerization of TK1. The role of amino acid 106 and the sequence surrounding it for dimer–tetramer transition was confirmed by cloning the putative interface fragment of human TK1 and investigating its oligomerization pattern.
K8 and K12 are biotinylated in human histone H4
Authors: Camporeale Gabriela , Shubert Elizabeth E. , Sarath Gautam , Cerny Ronald , Zempleni Janos
Published: May 2004

Folding of DNA into chromatin is mediated by binding to histones such as H4; association of DNA with histones is regulated by covalent histone modifications, e.g. acetylation, methylation, and biotinylation. We sought to identify amino‐acid residues that are biotinylated in histone H4, and to determine whether acetylation and methylation of histones affect biotinylation. Synthetic peptides spanning fragments of human histone H4 were biotinylated enzymatically using biotinidase. Peptide‐bound biotin was probed with streptavidin–peroxidase. Peptides based on the N‐terminal sequence of histone H4 were effectively recognized by biotinidase as substrates for biotinylation; in contrast, peptides based on the C‐terminal sequences were not biotinylated. Substitution of K8 or K12 with alanine or arginine decreased biotinylation, suggesting that these lysines are targets for biotinylation; K8 and K12 are also known targets for acetylation. Chemical acetylation or methylation of a given lysine decreased subsequent enzymatic biotinylation of neighboring lysines, consistent with cross‐talk among histone modifications. Substitution of a given lysine (positive charge) with glutamate (negative charge) abolished biotinylation of neighboring lysines, providing evidence that the net charge of histones has a role in biotinylation. An antibody was generated that specifically recognized histone H4 biotinylated at K12. This antibody was used to detect biotinylated histone H4 in nuclear extracts from human cells. These studies suggest that K8 and K12 in histone H4 are targets for biotinylation, that acetylation and biotinylation compete for the same binding sites, and that acetylation and methylation of histones affect biotinylation of neighboring lysines.
Modeling the Qo site of crop pathogens in Saccharomyces cerevisiae cytochrome b
Authors: Fisher Nicholas , Brown Amanda C. , Sexton Graham , Cook Alison , Windass John , Meunier Brigitte
Published: May 2004

Saccharomyces cerevisiae has been used as a model system to characterize the effect of cytochrome b mutations found in fungal and oomycete plant pathogens resistant to Qo inhibitors (QoIs), including the strobilurins, now widely employed in agriculture to control such diseases. Specific residues in the Qo site of yeast cytochrome b were modified to obtain four new forms mimicking the Qo binding site of Erysiphe graminis, Venturia inaequalis, Sphaerotheca fuliginea and Phytophthora megasperma. These modified versions of cytochrome b were then used to study the impact of the introduction of the G143A mutation on bc1 complex activity. In addition, the effects of two other mutations F129L and L275F, which also confer levels of QoI insensitivity, were also studied. The G143A mutation caused a high level of resistance to QoI compounds such as myxothiazol, axoxystrobin and pyraclostrobin, but not to stigmatellin. The pattern of resistance conferred by F129L and L275F was different. Interestingly G143A had a slightly deleterious effect on the bc1 function in V. inaequalis, S. fuliginea and P. megasperma Qo site mimics but not in that for E. graminis. Thus small variations in the Qo site seem to affect the impact of the G143A mutation on bc1 activity. Based on this observation in the yeast model, it might be anticipated that the G143A mutation might affect the fitness of pathogens differentially. If so, this could contribute to observed differences in the rates of evolution of QoI resistance in fungal and oomycete pathogens.
Binding of the potential antitumour agent indirubin‐5‐sulphonate at the inhibitor site of rabbit muscle glycogen phosphorylase b
Authors: Kosmopoulou Magda N. , Leonidas Demetres D. , Chrysina Evangelia D. , Bischler Nicolas , Eisenbrand Gerhard , Sakarellos Constantinos E. , Pauptit Richard , Oikonomakos Nikos G.
Published: May 2004

The binding of indirubin‐5‐sulphonate (E226), a potential anti‐tumour agent and a potent inhibitor (IC50 = 35 nm) of cyclin‐dependent kinase 2 (CDK2) and glycogen phosphorylase (GP) has been studied by kinetic and crystallographic methods. Kinetic analysis revealed that E226 is a moderate inhibitor of GPb (Ki = 13.8 ± 0.2 µm) and GPa (Ki = 57.8 ± 7.1 µm) and acts synergistically with glucose. To explore the molecular basis of E226 binding we have determined the crystal structure of the GPb/E226 complex at 2.3 Å resolution. Structure analysis shows clearly that E226 binds at the purine inhibitor site, where caffeine and flavopiridol also bind [Oikonomakos, N.G., Schnier, J.B., Zographos, S.E., Skamnaki, V.T., Tsitsanou, K.E. & Johnson, L.N. (2000) J. Biol. Chem.275, 34566–34573], by intercalating between the two aromatic rings of Phe285 and Tyr613. The mode of binding of E226 to GPb is similar, but not identical, to that of caffeine and flavopiridol. Comparative structural analyses of the GPb–E226, GPb–caffeine and GPb–flavopiridol complex structures reveal the structural basis of the differences in the potencies of the three inhibitors and indicate binding residues in the inhibitor site that can be exploited to obtain more potent inhibitors. Structural comparison of the GPb–E226 complex structure with the active pCDK2–cyclin A–E226 complex structure clearly shows the different binding modes of the ligand to GPb and CDK2; the more extensive interactions of E226 with the active site of CDK2 may explain its higher affinity towards the latter enzyme.
Effects of white and red wine on endothelial function in subjects with coronary artery disease
Authors: Whelan A. P. , Sutherland W. H. F. , McCormick M. P. , Yeoman D. J. , De Jong S. A. , Williams M. J. A.
Published: May 2004

Abstract

Background : Levels of anti‐oxidant polyphenols are higher in red than in white wine and are thought to contribute to the reduced cardiovascular risk associated with moderate consumption of wine observed in epidemiological studies.

Aim : To compare the acute effects of acute ingestion of white and red wine on endothelial function in subjects with coronary artery disease (CAD).

Methods : Fourteen subjects with proven CAD were randomised to consume white and red wine with a light meal in a single blind cross‐over study. Flow‐mediated dilatation (FMD) of the brachial artery was measured using high‐resolution ultrasonography. Endothelial function, lipid profile, plasma alcohol and polyphenols were measured at baseline, 60 and 360 min after wine consumption.

Results : At baseline, FMD was similar (white wine 1.6 ± 1.9%, red wine 1.8 ± 1.7%). At 360 min after ingestion of wine there was no difference in FMD, which improved nearly threefold after both wines (white wine 4.7 ± 2.2%, red wine 3.4 ± 2.9%; P = 0.002). There was no detectable change in plasma polyphenol levels after either wine.

Conclusions : These data suggest that wine acutely improves endothelial function in patients with CAD. This improved endothelial function might contribute to a reduced risk of cardiovascular events. (Intern Med J 2004; 34: 224−228)
Tackling Australia's future health problems: developing strategies to combat sarcopenia − age‐related muscle wasting and weakness
Authors: Lynch G. S.
Published: May 2004

Abstract

Some of the most serious consequences of ageing are its effects on skeletal muscle structure and function. Ageing is associated with a progressive loss of muscle mass (sarcopenia), a slowing of movement, and a decline in strength; factors that increase the risk of injury from sudden falls and a reliance on the frail elderly for assistance in accomplishing even the most basic tasks required for independent living. From a public health perspective, sarcopenia has widespread clinical implications. As the proportion of older persons in the popu­lation continues to grow, sarcopenia will have a dramatic impact on the lives of Australians and place increasing demands on health care. Although it is generally agreed that the deleterious effects of ageing on skeletal muscle are inevitable, debate exists as to whether these intrinsic changes are immutable or reversible. There is clearly a profound need for therapeutic strategies that can slow the effects of ageing on muscle function, and restore muscle size and strength in the frail elderly so that their quality of life can be maintained or improved. Physical activity plays an important role in slowing the effects of ageing, but exercise alone will not prevent the gradual decline in skeletal muscle function. Other factors, such as age‐related changes in circulating levels of muscle anabolic hormones and growth factors, must also be considered when developing strategies to combat sarcopenia. Much research is needed to test the safety and efficacy of these exciting experimental strategies before they can be recommended for clinical application. (Intern Med J 2004; 34: 294−296)
Management of brain metastases
Authors: Lim L. C. , Rosenthal M. A. , Maartens N. , Ryan G.
Published: May 2004

Abstract

Solid tumour brain metastases are a frequent clinical dilemma for oncologists and general physicians. The sound management of brain metastases requires a multidisciplinary approach. In this review we discuss the diagnosis and management of brain metastases including the role of surgery, radiotherapy, and chemotherapy. The standard approaches of surgical excision and primary radiotherapy have evolved from randomised studies. However, controversies remain regarding post‐surgery irradiation in the setting of a solitary metastasis and the role of palliative chemotherapy. (Intern Med J 2004; 34: 270−278)
Arm position and blood pressure: an audit
Authors: Mourad A. , Carney S.
Published: May 2004

Abstract

Although arm position significantly alters blood pressure, this aspect of clinical behaviour has not been evaluated. Consequently, an audit of arm position preference involving 182 clinicians including physicians, general practitioners and nurses was performed. A marked variation in standing and sitting arm position preference, both between and within the three groups, was recorded, although approximately two‐thirds of clinicians preferred the same arm position in the standing and sitting position. In particular, only 8 and 4% of clinicians chose the horizontal arm position in sitting and standing subjects, respectively. Choosing the dependent arm is a behaviour likely to lead to the overdiagnosis of hyper­tension and inappropriate treatment of hypertension because the dependent arm falsely elevates both systolic and diastolic blood pressure. These results should encourage national and international organizations to reaffirm the importance of the horizontal arm in the measurement of blood pressure. (Intern Med J 2004; 34: 290−291)
Left ventricular dysfunction in normotensive Type 1 diabetic patients: the impact of autonomic neuropathy
Authors: Taskiran M. , Rasmussen V. , Rasmussen B. , Fritz‐Hansen T. , Larsson H. B. W. , Jensen G. B. , Hilsted J.
Published: May 2004

Aims  The pathophysiological mechanisms responsible for increased cardiovascular mortality in diabetic autonomic neuropathy (AN) are largely unknown. The aim was to determine the relative role of AN in the pathogenesis of cardiac diastolic dysfunction and left ventricular hypertrophy in Type 1 diabetes.

Methods  Ten Type 1 diabetic patients with AN, defined by cardiovascular tests (AN+) and 10 age‐ and sex‐matched patients without neuropathy (AN–) as well as 10 healthy subjects (C) participated in the study. Left ventricular diastolic function was assessed by Doppler echocardiography, whilst systolic function was evaluated by cine magnetic resonance (MR) imaging.

Results  Doppler echocardiography showed a significant decrease in E/A ratio, i.e. the ratio between peak Early transmitral filling velocity during early diastole (E‐wave) and peak transmitral Atrial filling velocity during late diastole (A‐wave), in AN+ compared with C (P < 0.01) [0.95 ± 0.08 (mean ± sem) (AN+); 1.19 ± 0.09 (AN–); 1.33 ± 0.10 (C)]. The E‐wave deceleration time was significantly shorter in AN+ compared with AN– and C (P < 0.02) [178 ± 7 ms (AN+); 203 ± 9 ms (AN–); 205 ± 9 ms (C)]. Cine MR imaging showed a significantly greater left ventricular mass index in AN+ compared with C [103 ± 4 g/m2 (AN+) vs. 98 ± 7 (AN–) and 92 ± 4 g/m2 (C), P < 0.05].

Conclusion  Autonomic neuropathy is associated with left ventricular hypertrophy and diastolic dysfunction in Type 1 diabetic patients.
Post‐challenge hyperglycaemia is an independent risk factor for arterial stiffness in Japanese men
Authors: Ohshita K. , Yamane K. , Ishida K. , Watanabe H. , Okubo M. , Kohno N.
Published: May 2004

Aims  Arterial stiffness is an independent predictor of cardiovascular disease, but the impact of post‐challenge hyperglycaemia on arterial stiffness is unknown. To investigate the association between arterial stiffness and post‐challenge hyperglycaemia, we measured the second derivative of photoplethysmogram as an indicator of arterial stiffness.

Methods  This study was done in 159 asymptomatic Japanese men aged 50.7 ± 13.0 years. All subjects underwent a 75‐g oral glucose tolerance test and measurement of the second derivative of photoplethysmogram.

Results  According to the World Health Organization criteria (1998), 110 subjects had normal glucose tolerance, 10 had impaired fasting glucose, 30 had impaired glucose tolerance, and nine had diabetes. The b/a ratio (an index of arterial stiffness) showed a significant relationship with age (r = 0.58, P < 0.0001), height (r = −0.33, P < 0.0001), 2‐h post‐challenge glucose (r = 0.32, P < 0.0001), systolic blood pressure (r = 0.22, P = 0.006), and diastolic blood pressure (r = 0.21, P = 0.009). After adjustment for age and height, there were significant correlations between the b/a ratio and diastolic blood pressure (r = 0.18, P = 0.02), fasting glucose (r = 0.16, P = 0.049), and 2‐h post‐challenge glucose (r = 0.21, P = 0.009). Stepwise multiple regression analysis showed that only age (β= 0.006, se = 0.0007, P < 0.001) and 2‐h post‐challenge glucose (β = 0.0005, se = 0.0002, P < 0.05) contributed significantly to the b/a ratio (adjusted R2 = 0.38).

Conclusions  These results indicate that post‐challenge hyperglycaemia is an independent risk factor for arterial stiffness.
Diabetes mellitus as a risk factor for primary open‐angle glaucoma: a meta‐analysis
Authors: Bonovas S. , Peponis V. , Filioussi K.
Published: May 2004

Aim  The association of diabetes mellitus with primary open‐angle glaucoma has been controversial. The study aimed to examine the strength of this association through a detailed meta‐analysis of studies published in peer‐reviewed journals.

Methods  A comprehensive search for articles published through 2002 was performed and data were abstracted. Prior to meta‐analysis, all studies were evaluated for publication bias and heterogeneity. Pooled odds ratio (OR) was calculated using the random and the fixed‐effects model.

Results  Twelve studies published between 1987 and 2001 were included (five case–control studies and seven cross‐sectional studies). Significant heterogeneity among the studies was detected (P = 0.023). No evidence of publication bias was found (P = 0.37). The association of diabetes mellitus with primary open‐angle glaucoma was statistically significant assuming either a random effects [OR = 1.50, 95% confidence interval (CI) 1.16, 1.93], or a fixed‐effects model (OR = 1.27, 95% CI 1.10, 1.45).

Conclusions  Our meta‐analysis results suggest that diabetic patients are at significantly increased risk of developing primary open‐angle glaucoma. Clinicians should be aware of this possibility.

Diabet. Med. (2004)
Childhood diabetes: parents’ experience of home management and the first year following diagnosis
Authors: Lowes L. , Lyne P. , Gregory J. W.
Published: May 2004

Aims  To explore parents’ experience of having a child diagnosed with Type 1 diabetes, managed at home, and their first year following diagnosis.

Methods  A qualitative, longitudinal study based on 40 in‐depth interviews with parents of 20 children with newly diagnosed Type 1 diabetes managed at home from diagnosis in South Wales.

Results  Many parents were alarmed by the speed of diagnosis following the gradual progress of their child's symptoms. The provision of timely, adequate information was important to all parents. Although five parents had initial concerns about going home, all parents were subsequently pleased their children had not been hospitalized. Home management enabled parents to integrate diabetes management into the family's normal lifestyle from diagnosis. Professional support, particularly accessible telephone advice, was valued by and reassured parents. Parents experienced a loss of spontaneity, a continuing fear of hypoglycaemia and did not want their child to feel different to other children. Acutely aware of the seriousness of diabetes, they did their utmost to achieve optimal glycaemic control but felt that diabetes could not ‘dominate’ if they were to lead a ‘normal’ life.

Conclusions  The experience of parents in this study suggests that parents of children with newly diagnosed diabetes are able to cope successfully when given the opportunity to start treatment at home. Therefore, if children with diabetes are clinically well at diagnosis, this study supports home management as a system of care from the parents’ point of view. These findings are relevant to clinicians, policy makers and health service managers involved in planning and providing paediatric diabetes care.
An assessment of the adequacy of suspension of insulin in pen injectors
Authors: Brown A. , Steel J. M. , Duncan C. , Duncan A. , McBain A. M.
Published: May 2004

Aims  To evaluate the completeness of insulin resuspension by users of neutral Hagedorn (NPH) insulin pens and premixed insulin pens and to relate this to how patients mix insulin before injecting.

Methods  Patients (n = 180) administering a medium duration or premixed insulin in cartridges in disposable pens were asked questions about mixing insulin, injection technique and storing insulin. They were also asked to demonstrate how they mixed their insulin and to send in a half‐used pen. The cloudy component equates to the complexed insulin, while the clear component is the diluting fluid or soluble insulin, depending on the type of insulin used. The optical density, a simple way of measuring cloudiness, was measured in each cartridge or disposable pen and was compared with the range obtained from a series of unused control pens. The results for 146 pens containing the most commonly used insulin were included. The 21 patients whose residual pen insulins showed optical densities > 5 sd from the mean were re‐interviewed and their medical records were examined in detail. Insulin in the pens was also measured by immunoassay to confirm the utility of optical density measurements.

Results  Only one patient mixed the insulin as the manufacturers recommended. In 58 out of 146 pens or cartridges (40%) the opacity of the insulin varied significantly from the expected value.

Conclusions  Most patients in Kirkcaldy do not mix insulin adequately. This may result in their giving different incorrect doses of insulin during the use of each pen. More emphasis should be given to teaching patients to mix correctly.
Improving glycaemic control of patients with Type 2 diabetes in a primary care setting: a French application of the Staged Diabetes Management programme
Authors: Varroud‐Vial M. , Simon D. , Attali J. , Durand‐Zaleski I. , Bera L. , Attali C. , Letondeur C. , Strauss K. , Petit C. , Charpentier G.
Published: May 2004

Aims  To assess the impact of a French adaptation of the Staged Diabetes Management (SDM) programme on glycaemic control of people with Type 2 diabetes in primary care. Secondary endpoints were blood pressure, blood lipids, healthcare costs and quality of life.

Methods  Prospective, randomized controlled study, of 1 years’ duration. General practitioners (GPs) were recruited in four separate districts of a French region. They enrolled consecutive patients with Type 2 diabetes. GPs in the intervention group were educated in the SDM programme. GPs in the control group were asked to provide usual care. Healthcare costs were collected by medical departments of the Health Insurance systems. Quality of life was assessed with the Duke Health Profile.

Results  Three hundred and forty patients enrolled by 57 GPs completed the study, 192 in the intervention group and 148 in the control group. Patients in the intervention group were managed more adequately in accordance with the guidelines (P < 0.05 for nine out of 10 items). HbA1c decreased by 0.31% in the intervention group and increased by 0.56% in the control group, resulting in a difference of 0.87% by the end of the study (P = 0.001). Blood pressure and blood lipids did not differ between groups. Occurrence of major complications was low and identical in both groups. Incremental costs during the study in the intervention group were 35 euros per patient per month, and this was not significantly different in comparison with the control group. Quality of life was not affected by the intervention.

Conclusions  Educating GPs in the French adaptation of the SDM programme improves glycaemic control in a primary care setting, without significantly increasing healthcare costs.
Educational outreach in diabetes to encourage practice nurses to use primary care hypertension and hyperlipidaemia guidelines (EDEN): a randomized controlled trial
Authors: New J. P. , Mason J. M. , Freemantle N. , Teasdale S. , Wong L. , Bruce N. J. , Burns J. A. , Gibson J. M.
Published: May 2004

Objective  To determine the effectiveness of specialist nurse delivered education in primary care to improve control of hypertension and hyperlipidaemia in patients with diabetes.

Design and setting  Practice‐level randomized controlled trial, Salford, England.

Subjects  From 44 practices, 10 303 subjects presenting in general practice with raised blood pressure (= 140/80 mmHg), raised total cholesterol (= 5.0 mmol/l) or both.

Interventions  Practices were randomized to receive either the intervention for hyperlipidaemia or for hypertension; practices acted as control for the intervention not received. Specialist nurses arranged a schedule of visits with general practitioners and general practice nurses, reminding them of diabetes protocols and clinical targets. They provided educational materials and protocols used in secondary care for nurse and doctor interventions including stepping up pharmacotherapy when necessary. Practices received a list of patients in their practice who were poorly controlled at their last annual review; new and recalled patients were targeted.

Outcome measures  At subsequent annual review, blood pressure and total cholesterol values were obtained from the Salford electronic diabetes register for patients from participating practices.

Results  Overall, specialist nurse‐led educational outreach to primary care was associated with no improvement in patients achieving target after 1 year—odds ratio (OR): 1.03 (95% CI 0.95–1.11; P = 0.52). Similar results were achieved with hyperlipidaemia OR: 1.04 (95% CI 0.88–1.23; P = 0.62) and hypertension OR: 1.01 (95% CI 0.80–1.27; P = 0.93).

Conclusion  This study provides evidence that the use of specialist nurses to perform educational outreach to improve target adherence to patients with diabetes in primary care is not effective.
An increase in insulin sensitivity and basal beta‐cell function in diabetic subjects treated with pioglitazone in a placebo‐controlled randomized study
Authors: Wallace T. M. , Levy J. C. , Matthews D. R.
Published: May 2004

Aims  To investigate the effect of treatment with pioglitazone on beta‐cell function and insulin sensitivity in Type 2 diabetes.

Methods  Thirty subjects with diet‐controlled Type 2 diabetes were randomized to 3 months treatment with pioglitazone (n = 19) or placebo (n = 11). All subjects underwent basal sampling for homeostatic model assessment (HOMA), followed by an intravenous glucose tolerance test and hyperglycaemic clamp, followed by an euglycaemic hyperinsulinaemic clamp; at baseline and after treatment.

Results  All results are expressed as mean (sem). Pioglitazone increased basal insulin sensitivity by 24.7% (7.8) HOMA‐%S vs. 2.1% (5.9) in the placebo group (P = 0.02). Stimulated insulin sensitivity, M/I, increased in the pioglitazone group compared with placebo: +15.1 (2.8) l kg−1 min−1 vs. +3.2 (2.9) l kg−1 min−1, respectively (P = 0.009). Pioglitazone increased adiponectin by 39.3 (6.3), ng/ml compared with a decrease of 0.8 (1.3) ng/ml with placebo (P = 0.00004). HOMA‐%B increased with pioglitazone, +11.5% (4.8) vs. −2.0% (4.8) with placebo (P = 0.049), but there was no change in stimulated beta‐cell function as determined by hyperglycaemic clamps. There was a significant reduction in the proinsulin/insulin ratio in the pioglitazone group, −0.057 (0.02) compared with placebo, +0.004 (0.02) (P = 0.03). There was a significant reduction in HbA1c of 0.6% (0.1) in the pioglitazone group compared with placebo (P = 0.003). There was no significant weight gain associated with pioglitazone therapy: +0.7 (sem 0.6) kg vs. +1.1 (sem 0.5) kg in placebo group (P = NS).

Conclusions  Basal beta‐cell function and insulin sensitivity improved following pioglitazone therapy. The improvement in proinsulin to insulin ratio suggests that beta‐cells are under less stress.
Familial hyperinsulinaemia associated with epilepsy and mental retardation—a syndrome of familial insulin resistance
Authors: Idris I. , Miller D. , Page S. R.
Published: May 2004

Background  Variants of type A insulin resistance, characterized by female hyperandrogenism and ‘acromegaloid’ features, have been ascribed to genetic defects of the insulin receptor or post‐receptor pathways via autosomal dominant or recessive inheritance patterns. Whilst a variety of congenital syndromes of insulin resistance are identified by their characteristic clinical phenotypes, an association with epilepsy and mental retardation has not previously been reported.

Case report  We describe three female siblings (aged 12, 19 and 21) with fasting hyperinsulinaemia (116–443 pmol/l; normal range < 80 pmol/l) and mental retardation. Two siblings also have epilepsy. The eldest has features of severe insulin resistance with dyslipidaemia, acanthosis nigricans, ‘acromegaloid features’ and diabetes requiring high dose insulin therapy in combination with a glitazone. Their mother has fasting hyperinsulinaemia (113 pmol/l), mental retardation and epilepsy. None had clinical or biochemical features of hyperandrogenism or evidence of pigmentory retinopathy, deafness or renal insufficiency. Autoantibody screens were negative. Interestingly, there is no evidence of mental retardation or epilepsy among males in the family.

Conclusion  This family suggests the presence of a yet‐undefined syndrome of familial insulin resistance affecting female kindred. Further studies are being undertaken to clarify the genetic defects and mode of inheritance.
Catching the Celtic Tiger by Its Tail
Authors: FERREIRA M. LUISA , VANHOUDT PATRICK
Published: May 2004

The article attempts to assess the major sources behind the exceptional Irish growth performance in the 1990s. Unlike other Tigers, Ireland's growth is due to efficiency gains, rather than capital deepening, but the causes for the swift growth in total factor productivity cannot be pinned down to a single factor. Human capital, foreign direct investment, social partnership agreements, sound budget and economic policies since the late 1980s, EU membership, all seemed to have interacted to produce this high‐growth economy. This article focuses on the two mostly quoted catalysts, i.e. FDI and human capital. It provides evidence that — although crucial as enablers for the Irish economic performance — neither the rapid expansion of the compulsory education system in the 1970s and 1980s nor the sheer volume of FDI inflows can by themselves explain why Ireland has grown so much faster than other world economies. Instead, it argues that higher education, especially the vocational/technical stream of educational provision, and the sector composition of FDI in favour of high‐tech industries, were self‐reinforcing factors and have been decisive for the Republic's extraordinary boom.

Is fearr lán doirn de cheird ná lán mála d’ór  (A handful of skill is better than a bagful of gold)

Irish proverb
All Invariant Moments of the Wishart Distribution
Authors: Letac Gérard , Massam Hélène
Published: May 2004

Abstract.  In this paper, we compute moments of a Wishart matrix variate U of the form 𝔼(Q(U)) where Q(u) is a polynomial with respect to the entries of the symmetric matrix u, invariant in the sense that it depends only on the eigenvalues of the matrix u. This gives us in particular the expected value of any power of the Wishart matrix U or its inverse U− 1. For our proofs, we do not rely on traditional combinatorial methods but rather on the interplay between two bases of the space of invariant polynomials in U. This means that all moments can be obtained through the multiplication of three matrices with known entries. Practically, the moments are obtained by computer with an extremely simple Maple program.
Statistical Modelling and Deconvolution of Yield Meter Data
Authors: Tøgersen Frede Aakmann , Waagepetersen Rasmus
Published: May 2004

Abstract. This paper considers the problem of mapping spatial variation of yield in a field using data from a yield monitoring system on a combine harvester. The unobserved yield is assumed to be a Gaussian random field and the yield monitoring system data is modelled as a convolution of the yield and an impulse response function. This results in an unusual spatial covariance structure (depending on the driving pattern of the combine harvester) for the yield monitoring system data. Parameters of the impulse response function and the spatial covariance function of the yield are estimated using maximum likelihood methods. The fitted model is assessed using certain empirical directional covariograms and the yield is finally predicted using the inferred statistical model.
Maximum Likelihood Estimation for Cox's Regression Model Under Case–Cohort Sampling
Authors: Scheike Thomas H. , Martinussen Torben
Published: May 2004

Abstract. Case–cohort sampling aims at reducing the data sampling and costs of large cohort studies. It is therefore important to estimate the parameters of interest as efficiently as possible. We present a maximum likelihood estimator (MLE) for a case–cohort study based on the proportional hazards assumption. The estimator shows finite sample properties that improve on those by the Self & Prentice [Ann. Statist. 16 (1988)] estimator. The size of the gain by the MLE varies with the level of the disease incidence and the variability of the relative risk over the considered population. The gain tends to be small when the disease incidence is low. The MLE is found by a simple EM algorithm that is easy to implement. Standard errors are estimated by a profile likelihood approach based on EM‐aided differentiation.
Statistical and Combinatorial Aspects of Comparative Genomics*
Authors: Eriksson Kimmo
Published: May 2004

Abstract.  This document presents a survey of the statistical and combinatorial aspects of four areas of comparative genomics: gene order based measures of evolutionary distances between species, construction of phylogenetic trees, detection of horizontal transfer of genes, and detection of ancient whole genome duplications.
Exact Non‐Parametric Confidence, Prediction and Tolerance Intervals with Progressive Type‐II Censoring
Authors: Guilbaud Olivier
Published: May 2004

Abstract.  This article extends recent results [Scand. J. Statist. 28 (2001) 699] about exact non‐parametric inferences based on order statistics with progressive type‐II censoring. The extension lies in that non‐parametric inferences are now covered where the dependence between involved order statistics cannot be circumvented. These inferences include: (a) tolerance intervals containing at least a specified proportion of the parent distribution, (b) prediction intervals containing at least a specified number of observations in a future sample, and (c) outer and/or inner confidence intervals for a quantile interval of the parent distribution. The inferences are valid for any parent distribution with continuous distribution function. The key result shows how the probability of an event involving k dependent order statistics that are observable/uncensored with progressive type‐II censoring can be represented as a mixture with known weights of corresponding probabilities involving k dependent ordinary order statistics. Further applications/developments concerning exact Kolmogorov‐type confidence regions are indicated.
Direct and Indirect Causal Effects via Potential Outcomes*
Authors: Rubin Donald B.
Published: May 2004

Abstract. The use of the concept of ‘direct’ versus ‘indirect’ causal effects is common, not only in statistics but also in many areas of social and economic sciences. The related terms of ‘biomarkers’ and ‘surrogates’ are common in pharmacological and biomedical sciences. Sometimes this concept is represented by graphical displays of various kinds. The view here is that there is a great deal of imprecise discussion surrounding this topic and, moreover, that the most straightforward way to clarify the situation is by using potential outcomes to define causal effects. In particular, I suggest that the use of principal stratification is key to understanding the meaning of direct and indirect causal effects. A current study of anthrax vaccine will be used to illustrate ideas.
Antiangiogenic effect of metronomic paclitaxel treatment in prostate cancer and non‐tumor tissue in the same animals: a quantitative study
Authors: LENNERNÄS BO , ALBERTSSON PER , DAMBER JAN‐ERIK , NORRBY KLAS
Published: May 2004

Well‐tolerated continuous or metronomic chemotherapy can exert a marked antiangiogenic and thus superior antitumor effect compared with conventional high‐dose, temporarily spaced‐out chemotherapy, as shown in preclinical studies. There is, however, no means of directly assessing the antiangiogenic effect in a tumor, a serious impediment to assessing the effects of putative antiangiogenic chemotherapeutics or treatments. In an attempt to circumvent or minimize this impediment we studied the antiangiogenic effect of well‐tolerated metronomic paclitaxel therapy in a surrogate tumor‐free tissue that allows true quantitative analysis as well as in syngeneic At‐1 prostate cancer in the same rat. This novel model allows an accurate comparison of the angiogenesis‐modulating effect of chemotherapy in the two tissues to be made. The effect of chemotherapy on VEGF‐A‐mediated angiogenesis, a characteristic of most tumors, was assessed truly quantitatively by microscopic morphometry and image analysis in the tumor‐free mesentery. The chemotherapy significantly suppressed VEGF‐A‐mediated angiogenesis in the mesentery to an extent that closely mirrored the significant increase in tumor necrosis measured morphometrically and the significant decrease in tumor growth rate. This finding opens an avenue to study quantitatively and systematically the antiangiogenic effect of chemotherapeutic modalities and treatments that approximately mirror their antiangiogenic effect in the At‐1 tumor.
A hospital‐associated outbreak of Legionnaires' disease caused by Legionella pneumophila serogroups 4 and 10 with a common genetic fingerprinting pattern
Authors: BERNANDER SVERKER , JACOBSON KERSTIN , LUNDHOLM MONICA
Published: May 2004

An outbreak of eight cases of pneumonia caused by Legionella pneumophila non‐serogroup 1 (non‐sg 1) occurred at a Swedish university hospital in 1993. Including previous and subsequent sporadic cases, the total number of culture‐positive patients was 13. Twelve available non‐sg1 isolates from patients were compared to 50 environmental water isolates using a monoclonal antibody test for serogrouping and amplified fragment length polymorphism analysis (AFLP). Of the 12 hospital‐associated Legionella non‐sg 1 patient isolates, 4 were serogrouped as sg 4, 7 as sg 10, and one as sg 6. Using AFLP fingerprinting all serogroup (sg) 4 and 10 isolates were genetically related except for minor variations. Furthermore, sg 4 isolates were identical in AFLP to sg 10 isolates. Patient isolates were also identical to isolates found in the water system of several hospital buildings, but quite unrelated to isolates obtained in a subsequent outbreak at the same hospital caused by L. pneumophila sg 1. Serogroup variations in outbreaks may occur despite a common molecular fingerprinting pattern. Evidently, the L. pneumophila sg 4 and 10 strains were closely related genetically, which raises the question whether this variation in phenotype is due to a genetic event or to a variable phenotypic expression. Genetic fingerprinting should be used in conjunction with serogrouping in epidemiological investigations.
Localized peribronchial adenomyomatous hyperplasia arising from an ectatic bronchus with aspergilloma
Authors: MITO KATSUHIKO , KASHIMA KENJI , DAA TSUTOMU , MIURA TAKASHI , NAKAYAMA IWAO , YOKOYAMA SHIGEO
Published: May 2004

A cavitary lesion containing a mobile nodule was found in the right lower lung of a 68‐year‐old woman. Suspecting bronchiectasis with a fungus ball, we performed wedge resection of the right lower lobe. Light microscopy revealed that a uniformly thickened muscular layer around the ectatic bronchus with aspergilloma had formed a focally protruding mass. It was composed of bundles of hyperplastic smooth muscle and entrapped glandular structures. Given the histological similarity between the lesion and adenomyomatous hyperplasia of the gallbladder, we diagnosed the previously undescribed lesion as “localized peribronchial adenomyomatous hyperplasia”. This condition should be recognized as a tumor‐like form of smooth muscle hyperplasia induced by bronchiectasis and inflammation.
Self‐care intervention to reduce oral candidiasis recurrences in HIV‐seropositive persons: a pilot study
Authors: Hilton Joan F. , MacPhail Laurie A. , Pascasio Laura , Sroussi Hervé Y. , Cheikh Behnaz , LaBao Maria E. , Malvin Katherine , Greenspan Deborah , Dodd Marylin J.
Published: May 2004

Abstract –  Objectives: This single‐blind randomized controlled pilot study evaluated the efficacy of a behavioral intervention program, PRO‐SELF: Candidiasis, to reduce time to recurrence of oral candidiasis over 6 months in susceptible HIV‐seropositive persons. The intervention involved instruction by dentists on improving oral hygiene, minimizing sugar intake, and self‐diagnosing candidiasis. Methods: Participants were adults with oral candidiasis responsive to antifungals who presented to the UCSF Stomatology Clinic between 1997 and 2000. At 2–3 weeks of follow‐up visits, a dentist ‘examiner’, masked to group assignment, quizzed participants as to the presence of candidiasis, and assessed candidiasis status. A second, unmasked dentist ‘instructor’ then delivered the program to intervention participants. Participants recorded dietary and oral hygiene practices in 24‐h recall diaries: intervention participants at each visit and controls at initial and final visits. Results: At randomization, CD4+ cell counts (cells/mm3) were 298 ± 188 among 18 intervention participants and 396 ± 228 among 17 controls. The candidiasis recurrence rates at 6 months were 78% among intervention compared with 88% among control participants (hazard ratio 0.72; 95% CI 0.35–1.50). Performing oral hygiene after meals/snacks showed the largest relative improvement: intervention–control difference in proportion of meals/snacks affected was 24% (95% CI −1 to 48%). Self‐diagnoses of candidiasis were inaccurate, possibly because of mild episodes. Conclusions: The results weakly indicate that regular instruction from healthcare professionals helps patients delay candidiasis recurrence by improving oral hygiene. Among HIV‐seropositive persons, those with poor oral hygiene, and high‐sugar diets are most likely to benefit.
The utility of the zero‐inflated Poisson and zero‐inflated negative binomial models: a case study of cross‐sectional and longitudinal DMF data examining the effect of socio‐economic status
Authors: Lewsey J. D. , Thomson W. M.
Published: May 2004

Abstract – Objectives: To examine the utility of the zero‐inflated Poisson (ZIP) and zero‐inflated negative binomial (ZINB) modelling approaches for modelling four sets of dental caries data from the same cohort study [with particular attention to the influence of childhood socioeconomic status (SES)]: cross‐sectional data on the deciduous dentition at age 5 years; cross‐sectional data on the permanent dentition at age 18 and 26 years; and longitudinal data on caries increment between ages 18 and 26 years.Methods: Data on dental caries occurrence at ages 5, 18 and 26 years were obtained from the Dunedin Multidisciplinary Health and Development Study (DMHDS). ZIP and ZINB models were fitted to the cross‐sectional (n = 745) and longitudinal (n = 809) data sets using Stata (Intercooled Stata 7.0). The dependent variables for the three cross‐sectional analyses were the DMFS indices at age 5, 18, and 26 years, and net DFS increment (NETDFS) was the dependent variable for the longitudinal analysis.Results: The empty ZIP model was a poor fit for all four data sets, whereas the empty ZINB model showed good fit; consequently both the cross‐sectional and longitudinal analyses were conducted using ZINB modelling. Being in the high‐SES group during childhood was associated with a greater probability of being caries‐free by age 18 years, over and above that which would be expected from the negative binomial process. Low childhood SES also had the largest coefficient in the modelling of the negative binomial process, but at age 5 years, where the adjusted mean dmfs score in the low‐SES group was 6.8 (compared with 4.7 and 2.9 in the medium‐ and high‐SES groups, respectively). The substantial SES differences which existed at age 5 years (in the deciduous dentition) had reduced somewhat by age 18 years, and had widened again by age 26 years. In the longitudinal analysis, ‘baseline’ caries experience (age 18‐year DMFS) was a predictor both of being an extra zero and of caries severity.Conclusion: This investigation of the utility of the zero‐inflated approach for modelling both cross‐sectional and longitudinal caries data has shown that ZIP/ZINB models can provide new insight into disease patterns. It is anticipated that they will become increasingly useful in epidemiological studies that use the DMF index as the outcome measure.
Willingness to pay for dentin regeneration in a sample of dentate adults
Authors: Birch Stephen , Sohn Woosung , Ismail Amid I. , Lepkowski James M. , Belli Robert F.
Published: May 2004

Abstract – Objectives: Measurement of individuals’ valuation of dental treatments is important in the evaluation of new technologies. In this paper the value of dentin regeneration, a new treatment for teeth with reversible pulpitis, is measured based on what individuals say they would be willing to pay to receive the treatment.Methods: A total of 611 randomly selected dentate adults answered willingness to pay (WTP) and dental insurance questions. Detailed descriptions of the process and expected outcomes for dentin regeneration were presented to subjects as part of a larger study measuring preferences for different treatments. WTP was determined for two different levels of success for dentin regeneration.Results: At a success rate of 95%, the mean WTP for dentin regeneration was $262.70 (noninsured) and $11.00 per month (insured subjects). For success rate of 75%, the corresponding values were $210.90 and $9.20 per month. Multivariate analyses were used to identify any significant relationships between WTP and a range of variables covering socio‐demographic, socio‐economic, dental experience and oral health status variables. The findings indicate that individuals’ valuations of treatments involve substantial unexplained variation. About half of the noninsured subjects would pay for dentin regeneration if it cost $200 per tooth.Conclusions: The data on the WTP for dentin regeneration indicate that a substantial percentage of adults will pay for this new technology. This study provides for the first time an estimate of WTP for dentin regeneration among the population.
A meta‐analysis of the prevalence of dental agenesis of permanent teeth
Authors: Polder Bart J. , Van’t Hof Martin A. , Van der Linden Frans P. G. M. , Kuijpers‐Jagtman Anne M.
Published: May 2004

Abstract –  Objective: To gain more insight into the prevalence of dental agenesis. Methods: Data from Caucasian populations in North America, Australia and Europe were included in a meta‐analysis. For the prevalence of African American, Chinese and Arab groups only indications could be reported because of a limited number of studies. Results: Agenesis differs by continent and gender: the prevalence for both sexes was higher in Europe (males 4.6%; females 6.3%) and Australia (males 5.5%; females 7.6%) than for North American Caucasians (males 3.2%; females 4.6%). In addition, the prevalence of dental agenesis in females was 1.37 times higher than in males. The mandibular second premolar was the most affected tooth, followed by the maxillary lateral incisor and the maxillary second premolar. The occurrence of dental agenesis was divided into three main groups: common (P2i > I2s > P2s), less common (I1i > I2i & P1s > Cs & M2i) and rare (M2s & M1s > Ci > M1i & I1s). Unilateral occurrence of dental agenesis is more common than bilateral occurrence. However, bilateral agenesis of maxillary lateral incisors is more common than unilateral agenesis. The overall prevalence of agenesis in the maxilla is comparable with that in the mandible, but a marked difference was found between both jaws regarding tooth type. Absence of one or two permanent teeth is found in 83% of the subjects with dental agenesis. A practical application of the results of the meta‐analysis is the estimation of dental treatment need.