bluuebunny/crossref_metadata_2025 huggingface dataset:
The combined action of 9 lipoxygenase and galactolipase is sufficient to bring about programmed cell death during tobacco hypersensitive response
Authors: CACAS JEAN‐LUC , VAILLEAU FABIENNE , DAVOINE CELINE , ENNAR NAJLA , AGNEL JEAN‐PIERRE , TRONCHET MAURICE , PONCHET MICHEL , BLEIN JEAN‐PIERRE , ROBY DOMINIQUE , TRIANTAPHYLIDES CHRISTIAN , MONTILLET JEAN‐LUC
Published: September 2005

Oxylipins, derived from fatty acid hydroperoxides (FAHs), are thought to play different roles during plant pathogen interactions. During hypersensitive response (HR) some of them serve as signals necessary for defence gene activation whereas others could contribute to pathogen killing or could participate in the execution of plant programmed cell death (PCD) associated with this resistance. In order to address the role of these compounds in the latter process, we have closely observed lipid peroxidation, the first step of this metabolic pathway, under different situations which led either to accelerated or inhibited HR cell death. The oxidative process has been studied in cryptogein‐elicited tobacco leaves and during Ralstonia solanacearum‐induced HR. It was shown that FAH accumulation was preceded by the co‐ordinated rise in 9 lipoxygenase (9 LOX) and galactolipase activities in addition to the transcription of a set of four genes encoding 9 LOX and patatin‐like proteins, NtPAT1‐3. The latter gene expression was at the origin of a metabolic pathway allowing the release of poly‐unsaturated fatty acids from plastid galactolipids and their oxidation into free 9 FAHs. This 9 LOX‐dependent lipid peroxidation was found to be sufficient to lead to HR cell death. Finally, during the bacterial‐induced HR, lipid peroxidation appeared as a composite of metabolites of enzymatic and non‐enzymatic origins and suggested the role of H2O2 as an important source of oxidant that might, in synergy with 9 FAHs, contribute to cell death execution.
Microelectrode and 133Cs nuclear magnetic resonance evidence for variable cytosolic and cytoplasmic nitrate pools in maize root tips
Authors: RADCLIFFE S. A. , MILLER A. J. , RATCLIFFE R. G.
Published: September 2005

The effect of nitrate uptake on the subcellular distribution of tissue nitrate in 2–5 mm maize root tips was investigated by two complementary methods. First a novel in vivo analysis using 133Cs nuclear magnetic resonance (NMR) was used to demonstrate changes in the cytoplasmic and vacuolar pools during caesium nitrate uptake. This method depended on interpreting the nitrate‐induced changes in the positions of the cytoplasmic and vacuolar caesium signals. The assignment of the signals was confirmed by using in vivo39K NMR to observe the displacement of cytoplasmic potassium into the vacuole during caesium uptake, and in vivo133Cs NMR to observe the displacement of cytoplasmic caesium into the vacuole during potassium uptake. Secondly nitrate‐selective microelectrodes were used to quantify the change in the cytosolic nitrate activity that occurred in the outermost cells of root tips under the same conditions. Both methods showed that the detected nitrate pool increased over a period of 8–10 h in the presence of 10 m m nitrate and it is concluded that the data provide support for the view that homeostasis in the cytosolic and cytoplasmic nitrate pools is not necessarily an invariant characteristic of root tips.
Nitrogen acquisition, PEP carboxylase, and cellular pH homeostasis: new views on old paradigms
Authors: BRITTO DEV T. , KRONZUCKER HERBERT J.
Published: September 2005

The classic biochemical pH‐stat model of cytosolic pH regulation in plant cells presupposes a pH‐dependent biosynthesis and degradation of organic acids, specifically malic acid, in the cytosol. This model has been used to explain the higher tissue accumulation of organic acids in nitrate (NO3–)‐grown, relative to ammonium (NH4+)‐grown, plants, the result of proposed cytosolic alkalinization by NO3–metabolism, and acidification by NH4+metabolism. Here, a critical examination of the model shows that its key assumptions are fundamentally problematic, particularly in the context of the effects on cellular pH of nitrogen source differences. Specifically, the model fails to account for proton transport accompanying inorganic nitrogen transport, which, if considered, renders the H+production of combined transport and assimilation (although not the accumulation) to be equal for NO3–and NH4+as externally provided N sources. We show that the model's evidentiary basis in total‐tissue mineral ion and organic acid analysis is not directly relevant to subcellular (cytosolic) pH homeostasis, while the analysis of the ionic components of the cytosol is relevant to this process. A literature analysis further shows that the assumed greater activity of the enzyme phosphoenolpyruvate (PEP) carboxylase under nitrate nutrition, which is a key characteristic of the biochemical pH‐stat model as it applies to nitrogen source, is not borne out in numerous instances. We conclude that this model is not tenable in its current state, and propose an alternative model that reaffirms the anaplerotic role of PEP carboxylase within the context of N nutrition, in the production of carbon skeletons for amino acid synthesis.
A unique mode of parasitism in the conifer coral treeParasitaxus ustus(Podocarpaceae)
Authors: FEILD TAYLOR S. , BRODRIBB TIM J.
Published: September 2005

Almost all parasitic plants, including more than 3000 species, are angiosperms. The only suggested gymnosperm exception is the New Caledonian conifer,Parasitaxus ustus, which forms a bizarre graft‐like attachment to the roots of another coniferFalcatifolium taxoides. Yet, the degree of resource dependence ofParasitaxusonFalcatifoliumhas remained speculative. Here we show thatParasitaxusis definitively parasitic, but it displays a physiological habit unlike any known angiosperm parasite. Despite possessing chloroplasts, it was found that the burgundy red shoots ofParasitaxuslack significant photosynthetic electron transport. However unlike non‐photosynthetic angiosperm parasites (holoparasites), tissues ofParasitaxusare considerably enriched in13carbon relative to its host. In line with anatomical observations of fungal hyphae embedded in the parasite/host union, stable carbon isotopic measurements indicate that carbon transport from the host toParasitaxusmost likely involves a fungal partner. Therefore,Parasitaxusparallels fungus‐feeding angiosperms (mycoheterotrophs) that steal carbon from soil mycorrhizal fungi. Yet with its tree‐like habit, association with fungi residing within the host union, high stomatal conductance, and low water potential, it is demonstrated thatParasitaxusfunctions unlike any known angiosperm mycoheterotroph or holoparasite.Parasitaxusappears to present a unique physiological chimera of mistletoe‐like water relations and fungal‐mediated carbon trafficking from the host.
Light‐dependent conversion of carotenoids in the parasitic angiosperm Cuscuta reflexa L.
Authors: SNYDER ALISON M. , CLARK BRUCE M. , BUNGARD RALPH A.
Published: September 2005

The parasitic angiosperm Cuscuta reflexa contains unusually high amounts of the carotenoids lutein‐5,6‐epoxide and 9‐cis‐violaxanthin. In this study the light‐dependent conversions of these carotenoids in entire plant tissue and purified LHCIIb was compared with that of the xanthophyll cycle carotenoid violaxanthin when plants are exposed to high irradiance followed by low irradiance. In entire tissue under high irradiance, similar conversion kinetics and stoichiometry with de‐epoxidation products suggest that both lutein‐5,6‐epoxide and all‐trans‐violaxanthin are equally suitable substrates for de‐epoxidase. This is not the case under low irradiance as, although epoxidation of zeaxanthin and antheraxanthin rapidly restores the violaxanthin pool, the recovery of the lutein‐5,6‐epoxide pool is comparatively slow and has no stoichiometric relationship with its de‐epoxidation product, lutein. Light‐dependent changes in the concentration of 9‐cis‐violaxanthin mimic violaxanthin. However, the inability to detect de‐epoxidation products or to de‐epoxidize 9‐cis‐violaxanthin in vitro suggests that it is not subject to de‐epoxidation and, instead, its concentration changes may reflect the equilibrium between isomers of violaxanthin. Light exposure did not affect the composition of carotenoids bound to purified LHCIIb, indicating that these bound carotenoids are not subject to de‐epoxidation and do not contribute to the isomer pool equilibrium. The biosynthetic origins of lutein‐5,6‐epoxide and the potential role of these carotenoid cycles in photoprotection are discussed.
Citrus abscission and Arabidopsis plant decline in response to 5‐chloro‐3‐methyl‐4‐nitro‐1H‐pyrazole are mediated by lipid signalling
Authors: ALFEREZ FERNANDO , SINGH SHILA , UMBACH ANN L. , HOCKEMA BRANDON , BURNS JACQUELINE K.
Published: September 2005

The compound 5‐chloro‐3‐methyl‐4‐nitro‐1H‐pyrazole (CMNP) is a pyrazole‐derivative that induces abscission selectively in mature citrus (Citrus sinensis) fruit when applied to the canopy and has herbicidal activity on plants when applied to roots. Despite the favourable efficacy of this compound, the mode of action remains unknown. To gain information about the mode of action of CMNP, the effect of application to mature citrus fruit and Arabidopsis thaliana roots was explored. Peel contact was essential for mature fruit abscission in citrus, whereas root drenching was essential for symptom development and plant decline in Arabidopsis. CMNP was identified as an uncoupler in isolated soybean (Glycine max) mitochondria and pea (Pisum sativum) chloroplasts and an inhibitor of alcohol dehydrogenase in citrus peel, but not an inhibitor of protoporphyrinogen IX oxidase. CMNP treatment reduced ATP content in citrus peel and Arabidopsis leaves. Phospholipase A2 (PLA2) and lipoxygenase (LOX) activities, and lipid hydroperoxide (LPO) levels increased in flavedo of citrus fruit peel and leaves of Arabidopsis plants treated with CMNP. An inhibitor of PLA2 activity, aristolochic acid (AT), reduced CMNP‐induced increases in PLA2 and LOX activities and LPO levels in citrus flavedo and Arabidopsis leaves and greatly reduced abscission in citrus and delayed symptoms of plant decline in Arabidopsis. However, AT treatment failed to halt the reduction in ATP content. Reduction in ATP content preceded the increase in PLA2 and LOX activities, LPO content and the biological response. The results indicate a link between lipid signalling, abscission in citrus and herbicidal damage in Arabidopsis.
Ozone induced emissions of biogenic VOC from tobacco: relationships between ozone uptake and emission of LOX products
Authors: BEAUCHAMP JONATHAN , WISTHALER ARMIN , HANSEL ARMIN , KLEIST EINHARD , MIEBACH MARCO , NIINEMETS ÜLO , SCHURR ULI , WILDT JÜRGEN
Published: September 2005

Volatile organic compound (VOC) emissions from tobacco (Nicotiana tabacum L. var. Bel W3) plants exposed to ozone (O3) were investigated using proton‐transfer‐reaction mass‐spectrometry (PTR‐MS) and gas chromatography mass‐spectrometry (GC‐MS) to find a quantitative reference for plants’ responses to O3 stress. O3 exposures to illuminated plants induced post‐exposure VOC emission bursts. The lag time for the onset of volatile C6 emissions produced within the octadecanoid pathway was found to be inversely proportional to O3 uptake, or more precisely, to the O3 flux density into the plants. In cases of short O3 pulses of identical duration the total amount of these emitted C6 VOC was related to the O3 flux density into the plants, and not to ozone concentrations or dose–response relationships such as AOT 40 values. Approximately one C6 product was emitted per five O3 molecules taken up by the plant. A threshold flux density of O3 inducing emissions of C6 products was found to be (1.6 ± 0.7) × 10−8 mol m−2 s−1.
The determination of membrane transport parameters with the cell pressure probe: theory suggests that unstirred layers have significant impact
Authors: TYREE MELVIN T. , KOH SHARON , SANDS PETER
Published: September 2005

A simulation model was written to compute the time‐kinetics of turgor pressure, P, change in Chara corallina during cell pressure probe experiments. The model allowed for the contribution of a membrane plus zero, one, or two unstirred layers of any desired thickness. The hypothesis that a cell with an unstirred layer is a composite membrane that will follow the same kind of kinetics with or without unstirred layers was tested. Typical ‘osmotic pulse’ experiments yield biphasic curves with minimum or maximum pressures, Pmin(max), at time tmin(max) and a solute exponential decay with halftime . These observed data were then used to compute composite membrane properties, namely the parameters Lp = the hydraulic conductance, σ = reflection coefficient and Ps = solute permeability using theoretical equations. Using the simulation model, it was possible to fit an experimental data set to the same values of Pmin(max), tmin(max) and incorporating different, likely values of unstirred layer thickness, where each thickness requires a unique set of plasmalemma membrane values of Lp, σ and Ps. We conclude that it is not possible to compute plasmalemma membrane properties from cell pressure probe experiments without independent knowledge of the unstirred layer thickness.
CO2 enrichment predisposes foliage of a eucalypt to freezing injury and reduces spring growth
Authors: BARKER DAVID H. , LOVEYS BETH R. , EGERTON JOHN J. G. , GORTON HOLLY , WILLIAMS WILLIAM E. , BALL MARILYN C.
Published: September 2005

Seedlings of Eucalyptus pauciflora, were grown in open‐top chambers fumigated with ambient and elevated [CO2], and were divided into two populations using 10% light transmittance screens. The aim was to separate the effects of timing of light interception, temperature and [CO2] on plant growth. The orientation of the screens exposed plants to a similar total irradiance, but incident during either cold mornings (east‐facing) or warm afternoons (west‐facing). Following the first autumn freezing event elevated CO2‐grown plants had 10 times more necrotic leaf area than ambient CO2 plants. West‐facing plants had significantly greater (25% more) leaf damage and lower photochemical efficiency (Fv/Fm) in comparison with east‐facing plants. Following a late spring freezing event east‐facing elevated CO2 plants suffered a greater sustained loss in Fv/Fm than west‐facing elevated CO2‐ and ambient CO2‐grown plants. Stomatal conductance was lower under elevated CO2 than ambient CO2 except during late spring, with the highest leaf temperatures occurring in west‐facing plants under elevated CO2. These higher leaf temperatures apparently interfered with cold acclimation thereby enhancing frost damage and reducing the ability to take advantage of optimal growing conditions under elevated CO2.
Defoliation alters the relative contributions of recent and non‐recent assimilate to root exudation from Festuca rubra
Authors: PATERSON ERIC , THORNTON BARRY , MIDWOOD ANDREW J. , SIM ALLAN
Published: September 2005

The deposition of organic compounds from plant roots is a key determinant of rhizosphere microbial activity and community structure. Consequently, C‐flow from roots to soil is an important process in coupling plant and microbial productivity, via impacts on microbial nutrient cycling in soil. Experimentally, isotopic tracers (13C or 14C) are used to track C inputs to soil and microbial communities. However, in many such studies the relationship between labelled C‐flows and total C‐flows are not established, limiting the interpretative value of the results. In this study, we applied steady‐state near natural abundance 13CO2 labelling to determine the impact of partial defoliation of Festuca rubra on root exudation. This approach in axenic culture facilitated determination of the contribution of pre‐ and post‐defoliation assimilates both to root C‐flow and plant tissues. The results demonstrated that total root exudation was increased in the two days following defoliation. This was concurrent with reduced net CO2 assimilation and reduced allocation of post‐defoliation assimilates below‐ground and to active root meristems. Through determination of the δ13C of root exudates, it was established that the source of the increased root exudation was pre‐defoliation assimilate. However, this response was transient, with reduced deposition of pre‐ and post‐defoliation assimilates from roots during the period 2–4 d following defoliation. The results highlight the limitations of pulse‐labelling approaches as a means of quantifying impacts of treatments on root exudation, particularly where the treatment is likely to affect plant C‐partitioning or the balance between deposition to, and re‐mobilization from, C‐storage pools.
The Arabidopsis csb3 mutant reveals a regulatory link between salicylic acid‐mediated disease resistance and the methyl‐erythritol 4‐phosphate pathway
Authors: Gil Ma José , Coego Alberto , Mauch‐Mani Brigitte , Jordá Lucia , Vera Pablo
Published: September 2005

We report on constitutive subtilisin3 (csb3), an Arabidopsis mutant showing strikingly enhanced resistance to biotrophic pathogens. Epistasis analyses with pad4, sid2, eds5, NahG, npr1, dth9 and cpr1 mutants revealed that the enhanced resistance of csb3 plants requires intact salicylic acid (SA) synthesis and perception. CSB3 encodes a 1‐hydroxy‐2‐methyl‐2‐butenyl 4‐diphosphate synthase, the enzyme controlling the penultimate step of the biosynthesis of isopentenyl diphosphate via the 2‐C‐methyl‐d‐erythritol‐4‐phosphate (MEP) pathway in the chloroplast. CSB3 is expressed constitutively in healthy plants, and shows repression in response to bacterial infection. We also show the pharmacological complementation of the enhanced‐resistance phenotype of csb3 plants with fosmidomycin, an inhibitor of the MEP pathway, and propose that CSB3 represents a point of metabolic convergence modulating the magnitude of SA‐mediated disease resistance to biotrophic pathogens.
hca: an Arabidopsis mutant exhibiting unusual cambial activity and altered vascular patterning
Authors: Pineau Christophe , Freydier Amandine , Ranocha Philippe , Jauneau Alain , Turner Simon , Lemonnier Gaëtan , Renou Jean‐Pierre , Tarkowski Petr , Sandberg Göran , Jouanin Lise , Sundberg Björn , Boudet Alain‐Michel , Goffner Deborah , Pichon Magalie
Published: September 2005

By screening a T‐DNA population of Arabidopsis mutants for alterations in inflorescence stem vasculature, we have isolated a mutant with a dramatic increase in vascular tissue development, characterized by a continuous ring of xylem/phloem. This phenotype is the consequence of premature and numerous cambial cell divisions in both the fascicular and interfascicular regions that result in the loss of the alternate vascular bundle/fiber organization typically observed in Arabidopsis stems. The mutant was therefore designated high cambial activity (hca). The hca mutation also resulted in pleiotropic effects including stunting and a delay in developmental events such as flowering and senescence. The physiological characterization of hca seedlings in vitro revealed an altered auxin and cytokinin response and, most strikingly, an enhanced sensitivity to cytokinin. These results were substantiated by comparative microarray analysis between hca and wild‐type plants. The genetic analysis of hca indicated that the mutant phenotype was not tagged by the T‐DNA and that the hca mutation segregated as a single recessive locus, mapping to the long arm of chromosome 4. We propose that hca is involved in mechanisms controlling the arrangement of vascular bundles throughout the plant by regulating the auxin–cytokinin sensitivity of vascular cambial cells. Thus, the hca mutant is a useful model for examining the genetic and hormonal control of cambial growth and differentiation.
LORE1, an active low‐copy‐number TY3‐gypsy retrotransposon family in the model legume Lotus japonicus
Authors: Madsen Lene Heegaard , Fukai Eigo , Radutoiu Simona , Yost Christopher Karl , Sandal Niels , Schauser Leif , Stougaard Jens
Published: September 2005

We have identified a low‐copy‐number retrotransposon family present in nine to 10 copies in the Lotus japonicus model legume genome, and characterized its activity. LORE1 (Lotus retrotransposon 1) belongs to the Ty3‐gypsy group of elements, and is a long terminal repeat (LTR) retrotransposon. Genetic mapping located LORE1 elements in gene‐rich regions of Lotus chromosomes, and analysis of native as well as new insertion sites revealed integration outside the highly repetitive sequences of centromeres and telomeres. Sequencing of individual LORE1 family members identified several intact elements, and analysis of new insertions showed that at least one member is active and reinserts into functional genes, creating gene‐disruption mutations. Southern blot analysis and SSAP on a selection of symbiotic mutants revealed up to 12 new insertion sites in individual mutant lines and a Mendelian segregation of new inserts. Expression analysis showed that LORE1 elements are transcribed in all organs analysed and, in contrast to other active retrotransposons, LORE1 appears not to be transcriptionally upregulated during in vitro tissue culture. Activity of LORE1 in callus and whole plants suggests that a simple insertion mutagenesis based on endogenous LORE1 elements can be established for Lotus.
Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney
Authors: HA HUNJOO , LEE HI BAHL
Published: September 2005

SUMMARY:  Diabetic nephropathy is characterized by excessive accumulation of extracellular matrix (ECM) in the kidney. Reactive oxygen species (ROS) play a central role in the ECM synthesis and degradation in the glomeruli and tubulointerstitium leading to renal fibrosis. High glucose (HG) induces cellular ROS through protein kinase C (PKC)‐dependent activation of NADPH oxidase and through mitochondrial metabolism. ROS thus generated activate signal transduction cascade (PKC, mitogen‐activated protein kinases, and janus kinase/signal transducers and activators of transcription) and transcription factors (nuclear factor‐κB, activated protein‐1, and specificity protein‐1), up‐regulate transforming growth factor‐β1 (TGF‐β1), angiotensin II (Ang II), monocyte chemoattractant protein‐1 (MCP‐1), and plasminogen activator inhibitor‐1 (PAI‐1) gene and protein expression, and promote formation of advanced glycation end‐products (AGE). PKC, TGF‐β1, Ang II, and AGE also induce cellular ROS and signal through ROS leading to enhanced ECM synthesis. NF‐κB‐MCP‐1 pathway is activated by ROS and promotes monocyte recruitment and profibrotic process in the kidney. HG‐ and TGF‐β1‐induced PAI‐1 up‐regulation is mediated by ROS and contribute to ECM accumulation via suppression of plasmin ativity. TGF‐β1‐induced myofibroblast transformation of renal tubular epithelial cells (epithelial‐mesenchymal transition) is also mediated by ROS and contribute to tubulointerstitial fibrosis. In summary, ROS transduce and amplify glucose signalling in renal cells under high glucose environment and play a critical role in excessive ECM deposition in the diabetic kidney. A better understanding of ROS production and removal will allow more effective therapeutic strategies in diabetic renal and other vascular complications.
Protective effect of peroxisome proliferator activated receptor gamma agonists on diabetic and non‐diabetic renal diseases
Authors: CHUNG BYUNG HA , LIM SUN WOO , AHN KYUNG OHK , SUGAWARA AKIRA , ITO SADAYOSHI , CHOI BUM SOON , KIM YONG SOO , BANG BYUNG KEE , YANG CHUL WOO
Published: September 2005

SUMMARY:  Peroxisome proliferator activated receptor gamma (PPARγ) agonist has not only antidiabetic effect but also a protective effect against various types of injury of the kidney. The protective effects of PPARγ agonists are observed in diabetic nephropathy and non‐diabetic renal diseases such as 5/6 ablation model of renal failure, experimental glomerulonephritis, ischemia‐reperfusion injury, hypertensive nephropathy and cyclosporin‐induced renal injury. The mechanism of renoprotection by PPARγ agonist is multifactorial. Anti‐fibrotic and anti‐inflammatory effects, suppression of renin‐angiotensin system, vascular protective effect and antiapoptotic effect were proposed.
Cerebral cortical laminar necrosis on diffusion‐weighted MRI in hypoglycaemic encephalopathy
Authors: Yoneda Y. , Yamamoto S.
Published: September 2005

Background  Laminar necrosis of the cerebral cortex characterized neuropathologically by delayed selective neuronal necrosis occurs in hypoglycaemic encephalopathy and other brain diseases.

Case report  A 37‐year‐old male with insulin‐treated Type 1 diabetes mellitus developed hypoglycaemic encephalopathy associated with respiratory failure. Brain diffusion‐weighted MRI during the subacute period demonstrated high signals along the cerebral cortex. Brain single‐photon emission computed tomography showed diffuse, severe cerebral hypoperfusion. The patient remained comatose and died 1 month later.

Conclusions  High signals along the cortical bands on diffusion‐weighted MRI suggest cortical laminar necrosis, although a postmortem examination was unavailable. Sustained hypoglycaemic brain injury, possibly associated with respiratory hypoxia, may be the underlying mechanism.
Reporting of diabetes on death certificates using data from the UK Prospective Diabetes Study
Authors: Thomason M. J. , Biddulph J. P. , Cull C. A. , Holman R. R.
Published: September 2005

Aims  To study the effect of age at death, sex, ethnic group, date of death, underlying cause of death and social class on the frequency of reporting diabetes on death certificates in known cases of diabetes.

Methods  Data were extracted from certificates recording 981 deaths which occurred between 1985 and 1999 in people aged 45 years or more who participated in the UK Prospective Diabetes Study, to which 23 English, Scottish and Northern Ireland centres contributed. Diabetes (9th revision of the International Classification of Diseases; ICD‐9 250) entered on parts 1A−1C or 2A−2C of the death certificate was considered as reporting diabetes. Logistic regression analyses were used to determine independent factors associated with the reporting of diabetes.

Results  Diabetes was reported on 42% (419/981) of all death certificates and on 46% (249/546) of those with underlying cardiovascular disease causes. Reporting of diabetes was independently associated on all death certificates with per year of age increase (OR 1.02; 95% CI 1.001–1.04, P = 0.037), underlying cause of death (non‐cardiovascular causes OR 0.76; 95% CI 0.59–0.98, P = 0.035) and social class (classes I–II OR 1.00; class III OR 1.35; 95% CI 0.96–1.89, P = 0.084, classes IV–V OR 1.48; 95% CI 1.05–2.10, P = 0.027). Stratification by age, sex, and underlying cause of death also revealed significant differences in the frequency of reporting diabetes over time.

Conclusions  The rate of reporting of diabetes on cardiovascular disease death certificates remains poor. This may indicate a lack of awareness of the importance of diabetes as a risk factor for cardiovascular disease.
Changes in liver tests during 1‐year treatment of patients with Type 2 diabetes with pioglitazone, metformin or gliclazide
Authors: Belcher G. , Schernthaner G.
Published: September 2005

Aims  Patients with Type 2 diabetes are at increased risk of liver damage. Therefore, it is of particular importance to investigate the hepatic effects of drugs used to treat such patients.

Methods  Liver testing results performed in four 1‐year, randomized, double‐blind studies comparing effects of pioglitazone, metformin or a sulphonylurea, gliclazide, in the treatment of over 3700 patients with Type 2 diabetes have been analysed.

Results  Pioglitazone caused reductions in mean levels of hepatic enzymes of between 3 and 18%, whilst gliclazide caused small increases of between 3 and 13%. Metformin treatment showed either small mean increases or decreases. More patients receiving pioglitazone had liver tests within the normal range at the end of treatment (≥ 87%) compared with patients receiving metformin (≥ 80%) or gliclazide (≥ 75%). Slightly fewer patients with pioglitazone than with comparators showed a large increase (> 3 upper limit of normal) in alanine aminotransferase levels at any time during treatment (pioglitazone 0.9%, metformin 1.9%, gliclazide 1.9%).

Conclusions  During pioglitazone treatment there is a reduction in liver enzyme levels. Although the mechanism of this effect is not clear, the results demonstrate potential beneficial effects on the liver during treatment of patients with Type 2 diabetes with pioglitazone.
Increases in body mass index, even within non‐obese levels, raise the risk for Type 2 diabetes mellitus: a follow‐up study in a Japanese population
Authors: Nagaya T. , Yoshida H. , Takahashi H. , Kawai M.
Published: September 2005

Aims  Obesity, the strongest risk factor for Type 2 diabetes mellitus, is less prevalent in Japanese than in other populations. We investigated the effects of body mass index (BMI, kg/m2) on the incidence of diabetes mellitus in a Japanese population.

Methods  A follow‐up study in 16 829 men and 8370 women who were apparently healthy at baseline (age 30–59 years, BMI 14.9–43.2 kg/m2). Incident diabetes mellitus was identified by ‘fasting serum glucose ≥ 7.00 mmol/l (126 mg/dl)’ and/or ‘under medical treatment for diabetes mellitus’. Hazard ratio, as an index for risk ratio, for incident diabetes mellitus according to BMI was estimated using Cox's proportional hazard models. Baseline age, smoking, drinking, exercise and education were computed as confounders.

Results  During mean follow‐up periods of 7.4 years for men and 7.1 years for women, 869 men and 224 women had incident diabetes mellitus. Although the subjects were averagely non‐obese [mean (sd) BMI 23.1 (2.6) kg/m2 for men, 22.3 (2.7) kg/m2 for women], hazard ratio for incident diabetes mellitus increased in parallel with increases in BMI. Multivariate‐adjusted hazard ratios (95% confidence intervals) for increases in BMI of 1 kg/m2 were 1.26 (1.24, 1.29) for men and 1.24 (1.20, 1.29) for women.

Conclusion  BMI, even within the non‐obese level, is a dose‐dependent risk factor for diabetes mellitus in middle‐aged Japanese. Increases in BMI of 1 kg/m2 (= body‐weight gain of 2.4–2.9 kg) may raise the risk by about 25%.
Nurse case manager effectiveness and case load in a large clinical practice: implications for workforce development
Authors: Wilson C. , Curtis J. , Lipke S. , Bochenski C. , Gilliland S.
Published: September 2005

Aims  Description of nurse case management experiences across different settings and patient populations is needed to define critical elements of the intervention and to help develop a workforce capable of responding to the growing diabetic population.

Methods  In a clinic providing services to American Indian and Alaska Native people, a retrospective cohort design was used to assess outcomes of patients who did and did not receive case management services and to quantify the case load of a team of four nurse case managers.

Results  Patients with nurse case managers were more likely to have an eye examination [OR 2.9, 95% CI (2.1, 3.8)], diet and exercise instruction by a registered dietitian [OR 2.8, 95% CI (1.9, 4.1)], self monitor blood glucose [OR 2.1, 95% CI (1.5, 3.1)], dental examination [OR 1.7, 95% CI (1.3, 2.3)], foot examination [OR 1.6, 95% CI (1.2, 2.1)], and nephropathy screening [OR 1.6, 95% CI (1.2, 2.1)]. After adjustment for type of treatment, initial HbA1c, and diet instruction by a registered dietitian, the change in HbA1c remained significantly greater among those patients with a case manager than in those without (−0.52 units with vs. −0.17 units without, P < 0.006). The case load used to achieve this outcome averaged one nurse case manager per 365 patients.

Conclusions  In this setting, a case management team comprised of four nurses with varying degrees of clinical experience was effective in improving adherence with diabetes services and had a favourable effect on short‐term glucose control trends.
β‐cell preservation: a potential role for thiazolidinediones to improve clinical care in Type 2 diabetes
Authors: Leiter L. A.
Published: September 2005

Type 2 diabetes is caused by progressively increasing insulin resistance coupled with deteriorating β‐cell function, and there is a growing body of evidence to suggest that both of these defects precede hyperglycaemia by many years. Several studies have demonstrated the importance of maintaining β‐cell function in patients with Type 2 diabetes. This review explores parameters used to indicate β‐cell dysfunction, in Type 2 diabetes and in individuals with a predisposition to the disease. A genetic element undoubtedly underlies β‐cell dysfunction; however, a number of modifiable components are also associated with β‐cell deterioration, such as chronic hyperglycaemia and elevated free fatty acids. There is also evidence for a link between pro‐inflammatory cytokines and impairment of insulin‐signalling pathways in the β‐cell, and the potential role of islet amyloid deposition in β‐cell deterioration continues to be a subject for debate. The thiazolidinediones are a class of agents that have demonstrated clinical improvements in indices of β‐cell dysfunction and have the potential to improve β‐cell function. Data are accumulating to show that this therapeutic group offers a number of advantages over traditionally employed oral agents, and these data demonstrate the growing importance of thiazolidinediones in Type 2 diabetes management.
The effect of manipulation of basal pulsatile insulin on insulin action in Type 2 diabetes
Authors: Au S. , Courtney C. H. , Ennis C. N. , Sheridan B. , Atkinson A. B. , Bell P. M.
Published: September 2005

Aim  Disordered insulin pulsatility is associated with insulin resistant states including Type 2 diabetes. However, whether abnormal basal insulin pulses play a role in the pathogenesis of insulin resistance or are simply an associated feature remains undetermined. We investigated this relationship further by studying the effect of overnight (10 h) pulsatile insulin infusion on subsequent insulin sensitivity.

Methods  We studied 17 Type 2 diabetic patients who underwent one of two protocols. In protocol A (10 patients) on two separate nights we infused insulin 0.1 mU/kg/min either in a constant infusion or in pulses every 13 min. Octreotide (0.43 µg/kg/h) was given to suppress endogenous insulin secretion and physiological replacement of glucagon (30 ng/kg/h) administered. Insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp (2 mU/kg/min) next morning. In protocol B (seven patients), we employed the same experimental procedure but used a basal insulin infusion rate of 0.09 mU/kg/min in 7‐min or 13‐min pulses.

Results  Appropriate pulse patterns were confirmed in each protocol. In protocol A, after overnight infusions, glucose infusion rates required to maintain euglycaemia at steady state hyperinsulinaemia were similar (33.9 ± 5.2 vs. 31.2 ± 4.1 µmol/kg/min; P = NS). In protocol B, after overnight infusions the glucose infusion rates required during hyperinsulinaemia were significantly lower during 7‐min pulses (39.9 ± 5.7 vs. 44.7 ± 5.6 µmol/kg/min; P < 0.05).

Conclusion  There was no demonstrable priming effect derived from overnight pulsatile insulin compared with constant insulin infusion on subsequent insulin sensitivity in Type 2 diabetic subjects. The failure of 7‐min pulses to exhibit an advantageous effect over 13‐min pulses raises questions about the natural frequency of basal insulin pulses and their biological effect.
High prevalence and severity of cardiac autonomic neuropathy in Vietnamese diabetic patients
Authors: N’Guyen Thi N. , Paries J. , Attali J. R. , Valensi P.
Published: September 2005

Aims  Malnutrition is frequent in Vietnamese people and may influence cardiac autonomic neuropathy (CAN). The aim of the present study was to investigate cardiac autonomic function in healthy subjects living in Vietnam and the prevalence of CAN in Vietnamese diabetic patients.

Methods  One hundred and five diabetic patients (BMI = 19.8 ± 0.3 kg/m2), 50 Type 1 and 55 Type 2, living in Hué (Vietnam) were selected and compared with 60 non‐diabetic healthy Vietnamese controls (BMI = 20.8 ± 0.2 kg/m2) and also European controls. CAN function was evaluated by five standardized tests: three tests for heart rate variations (HRV) which depend mainly on parasympathetic activity, and two tests for blood pressure (BP) response which depend mainly on sympathetic activity.

Results  With age taken into account, 41 of the 60 Vietnamese controls had at least mild CAN, as defined by one abnormal test for HRV when compared with the European control series, and 11 of them had two or three abnormal tests. Among the Vietnamese control men, those with abnormal HRV had lower BMI than those without (P = 0.036). Seven Vietnamese controls had postural hypotension and 16 had an abnormal BP response to the handgrip test. Compared with the Vietnamese controls, 71 diabetic patients (67.6%), 40 Type 1 and 31 Type 2, had at least mild CAN, 37 of them had two or three abnormal HRV tests, and 56 diabetic patients (53.3%) had an abnormal BP response to the sympathetic tests. Abnormal HRV were associated with significantly lower BMI, waist and hip circumferences, longer diabetes duration and higher fasting blood glucose. In the logistic regression analyses, abnormal HRV were associated significantly with duration of diabetes and BMI in patients with Type 2 diabetes.

Conclusions  Cardiac autonomic dysfunction is frequent in normal Vietnamese subjects. CAN appears to be a more frequent complication of diabetes in Vietnam than in Western countries and diabetic parasympathetic dysfunction is frequently associated with sympathetic disorders. This confirms the deleterious effect a poor nutritional state has on cardiac autonomic function.
Pioglitazone initiation and subsequent hospitalization for congestive heart failure
Authors: Karter A. J. , Ahmed A. T. , Liu J. , Moffet H. H. , Parker M. M.
Published: September 2005

Aims  Thiazolidinediones (TZD) have been associated with an expansion in plasma volume and the development of peripheral oedema. A recent study reported an association between the use of TZDs and development of congestive heart failure (CHF). The objective of this study was to determine if short‐term use of pioglitazone, a TZD, is associated with increased risk of admission to hospital because of CHF in a well‐characterized, community‐based cohort of Type 2 diabetic patients without prevalent CHF.

Methods  A cohort study of all patients in the Kaiser Permanente Medical Care Program with Type 2 diabetes (Kaiser Permanente Northern California Diabetes Registry) who initiated any diabetes pharmacotherapy (n = 23 440) between October 1999 and November 2001. Only patients initiating single new therapies (‘new users’) were included to reduce confounding and create mutually exclusive exposure groups. We constructed Cox proportional hazards models (with sulphonylureas initiators specified as the reference group) to evaluate the impact of initiating new diabetes therapies on time‐to‐incident admission to hospital because of CHF, defined by primary hospital discharge diagnosis.

Results  Patients initiated pioglitazone (15.2%), sulphonylureas (25.3%), metformin (50.9%), and insulin (8.6%) alone, or as additions to pre‐existing or maintained therapies. Three hundred and twenty admissions for CHF were observed during the follow‐up (mean 10.2 months) after drug initiation. Relative to patients initiating sulphonylureas, there were no significant increases in the incidence of hospitalization for CHF in those initiating pioglitazone [hazard ratio (HR) = 1.28; 95% confidence interval (CI): 0.85–1.92] after adjusting for demographic, behavioural and clinical factors. There was a significantly higher incidence among those initiating insulin (HR = 1.56; 95% CI: 1.00–2.45) and lower incidence among those initiating metformin (HR = 0.70; 95% CI: 0.49–0.99).

Conclusions  This study of patients with Type 2 diabetes failed to find evidence that short‐term pioglitazone use was associated with an elevated risk of hospitalization for CHF relative to the standard, first‐line diabetes therapy.
HOUSING POLICY ISSUES IN A RICH COUNTRY WITH HIGH POPULATION GROWTH: THE CASE OF RIYADH, SAUDI ARABIA
Authors: Struyk Raymond J.
Published: September 2005

Riyadh is a dynamic city characterized by extremely rapid growth over the past quarter of a century. Nevertheless, its housing stock is generally of high quality. This article explores the city's current and future housing issues. It does so in the context of projecting Riyadh's housing needs, both physical units and corresponding investment, over the 20‐year period beginning in 2004. The analysis was carried out using the Housing Needs Assessment Model developed by the Urban Institute and applied in a number of countries. The results show that the great majority of Riyadh's residents will continue to have very favorable housing conditions. Still, several percent of all households (more than 50 000 in the middle of the projection period) will face housing affordability problems. We argue for implementation of a rental housing allowance program to address this issue. Additionally, it is an open question as to whether the Kingdom of Saudi Arabia will be able to continue to provide housing consistent with the aspirations of middle class families. The analysis pays particular attention to the presence of a large number of guest workers and of the practice of employer‐provided housing.
Learning from the experts: people with learning difficulties training and learning from each other*
Authors: Weeks Louise , Shane Chris , MacDonald Fiona , Hart Craig , Smith Roger
Published: September 2005

This article is about a training project run by Central England People First (CEPF). CEPF has been doing workshops, conferences and other training for over 10 years. It seemed like a good idea to help other people with learning difficulties to learn how to be trainers. This would help them to speak out about their lives and the services they want. CEPF asked the Department of Health for some money to design a ‘training for trainers’ programme, and try it out. The Department of Health agreed, and CEPF set up the National User Training Development Project. The training team designed a 2‐day programme, and asked people in different parts of the country to try it out. Eight organizations agreed, including a care village, another People First group and two social services departments. Eighty people with learning difficulties and support people took part. The project team told them about what training is for, and how to organize it. They also had the chance to try out their own ideas. They practiced ‘role plays’, ‘speaking up’, doing quizzes and using video recorders. At the end, the people who took part filled in evaluation sheets, so that the team could find out if the training was useful. Most people said that they had enjoyed it, and that they had learned something. At the end of this project, we think we have learnt two things:

1.  People with learning difficulties can be good trainers, because they are experts about services and the things that are important in their lives.

2. Using training can be a good way of helping people with learning difficulties to speak out about how they want to be treated.
Distinct mechanisms of neuronal apoptosis are triggered by antagonism of Bcl‐2/Bcl‐x(L) versus induction of the BH3‐only protein Bim
Authors: Zimmermann Angela K. , Loucks F. Alexandra , Le Shoshona S. , Butts Brent D. , Florez‐McClure Maria L. , Bouchard Ron J. , Heidenreich Kim A. , Linseman Daniel A.
Published: September 2005

Primary cerebellar granule neurons (CGNs) require depolarizing extracellular potassium for their survival. Removal of depolarizing potassium triggers CGN apoptosis that requires induction of Bim, a BH3‐only Bcl‐2 family member. Bim is classically thought to promote apoptosis by neutralizing pro‐survival Bcl‐2 proteins. To determine if this is the principal function of Bim in CGNs, we contrasted Bim‐mediated apoptosis to neuronal death induced by HA14‐1, a BH3‐domain mimetic that antagonizes Bcl‐2 and Bcl‐x(L). HA14‐1 elicited CGN apoptosis characterized by caspase 3 and 9 activation, cytochrome c release, conformational activation of Bax, and mitochondrial depolarization. HA14‐1 provoked CGN apoptosis in the absence of Bim induction and negative regulators of Bim transcription did not prevent HA14‐1‐induced cell death. However, the antioxidant glutathione and its precursor, N‐acetyl‐l‐cysteine, suppressed HA14‐1‐induced apoptosis. Similarly, apoptosis induced by either a structurally distinct Bcl‐2/Bcl‐x(L) inhibitor (compound 6) or Bcl‐2 antisense oligonucleotides was diminished by glutathione. In contrast, antioxidants had no effect on CGN apoptosis provoked by either removal of depolarizing potassium or overexpression of a GFP–Bim fusion protein, two models of Bim‐dependent death. These data show that antagonism of Bcl‐2/Bcl‐x(L) function elicits oxidative stress‐dependent CGN apoptosis that is mechanistically distinct from Bim‐mediated cell death. These results further indicate that, although Bcl‐2/Bcl‐x(L) antagonism is sufficient to induce neuronal apoptosis, Bim likely promotes neuronal death by interacting with additional proteins besides Bcl‐2/Bcl‐x(L).
Dopaminergic transmission in STOP null mice
Authors: Brun Philippe , Bégou Mélina , Andrieux Annie , Mouly‐Badina Laurence , Clerget Magali , Schweitzer Annie , Scarna Hélène , Renaud Bernard , Job Didier , Suaud‐Chagny Marie‐Françoise
Published: September 2005

Neuroleptics are thought to exert their anti‐psychotic effects by counteracting a hyper‐dopaminergic transmission. Here, we have examined the dopaminergic status of STOP (stable tubule only polypeptide) null mice, which lack a microtubule‐stabilizing protein and which display neuroleptic‐sensitive behavioural disorders. Dopamine transmission was investigated using both behavioural analysis and measurements of dopamine efflux in different conditions. Compared to wild‐type mice in basal conditions or following mild stress, STOP null mice showed a hyper‐locomotor activity, which was erased by neuroleptic treatment, and an increased locomotor reactivity to amphetamine. Such a behavioural profile is indicative of an increased dopaminergic transmission. In STOP null mice, the basal dopamine concentrations, measured by quantitative microdialysis, were normal in both the nucleus accumbens and the striatum. When measured by electrochemical techniques, the dopamine efflux evoked by electrical stimulations mimicking physiological stimuli was dramatically increased in the nucleus accumbens of STOP null mice, apparently due to an increased dopamine release, whereas dopaminergic uptake and auto‐inhibition mechanisms were normal. In contrast, dopamine effluxes were slightly diminished in the striatum. Together with previous results, the present study indicates the association in STOP null mice of hippocampal hypo‐glutamatergy and of limbic hyper‐dopaminergy. Such neurotransmission defects are thought to be central to mental diseases such as schizophrenia.