bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin pump therapy vs. multiple daily injections in obese Type 2 diabetic patients
Authors: Wainstein J. , Metzger M. , Boaz M. , Minuchin O. , Cohen Y. , Yaffe A. , Yerushalmy Y. , Raz I. , Harman‐Boehm I.
Published: September 2005

Aims  To compare the efficacy of insulin pump treatment with multiple daily injections in the treatment of poorly controlled obese Type 2 diabetic patients already receiving two or more daily injections of insulin plus metformin.

Methods  Forty obese Type 2 diabetic subjects (using insulin) were randomized to treatment with continuous subcutaneous infusion pump (CSII) (Minimed®) or multiple daily insulin injections (MDI). At the end of the first 18‐week treatment period, patients underwent a 12‐week washout period during which they were treated with MDI plus metformin. They were then crossed‐over to the other treatment for an 18‐week follow‐up period. Patients performed 4‐point daily self blood‐glucose monitoring (SBGM) on a regular basis and 7‐point monitoring prior to visits 2, 8, 10 and 16. A subset of patients underwent continuous glucose monitoring using the Minimed® continuous glucose monitoring system (CGMS) at visits 2, 8, 10 and 16. A standard meal test was performed in which serum glucose was tested at fasting and once each hour for 6 h following a test meal. Glucose levels were plotted against time and the area under the curve (AUC) was calculated. HbA1c, weight, daily insulin dose and hypoglycaemic episodes were recorded.

Results  In obese Type 2 diabetic patients already treated with insulin, treatment with CSII significantly reduced HbA1c levels compared with treatment with MDI. An additional CSII treatment benefit was demonstrated by reduced meal‐test glucose AUC. Initial reduction of daily insulin requirement observed in CSII‐treated subjects during the first treatment period was attributable to a period effect and did not persist over time.

Conclusions  In the intent‐to‐treat analysis, CSII appeared to be superior to MDI in reducing HbA1c and glucose AUC values without significant change in weight or insulin dose in obese, uncontrolled, insulin‐treated Type 2 diabetic subjects.
Socio‐economic inequalities in the prevalence of Type 2 diabetes, cardiovascular risk factors and chronic diabetic complications in the Basque Country, Spain
Authors: Larrañaga I. , Arteagoitia J. M. , Rodriguez J. L. , Gonzalez F. , Esnaola S. , Piniés J. A. ,   the Sentinel Practice Network of the Basque Country
Published: September 2005

Aims  To establish the relationship between socio‐economic status and the prevalence of known Type 2 diabetes, cardiovascular risk factors and chronic diabetic complications.

Methods  In 2000, a cross‐sectional survey was conducted among 61 general practitioners (GPs) who studied 65 651 people older than 24 years. Of those, 2985 known Type 2 diabetic patients were registered. The main outcome measures were: diabetes prevalence, major cardiovascular risk factors, chronic diabetic complications and primary care services utilization in Type 2 diabetic patients. Socio‐economic status was based on area‐based socio‐economic measures.

Results  The prevalence of known Type 2 diabetes was higher in patients of lower socio‐economic status (OR: 2.17, 95% CI: 1.77–2.28), especially among women (OR: 2.28, 95% CI: 1.91–2.73). In Type 2 diabetes patients, obesity, sedentary lifestyle, and abnormal levels of low‐density lipoprotein (LDL) cholesterol and HbA1c were more prevalent among those from lower socio‐economic status. Macroangiopathy was inversely associated with socio‐economic status after adjustment for clinical and demographic variables. Patients of lower socio‐economic status more frequently visited primary care services than those of higher status.

Conclusions  This study shows an association between deprivation and Type 2 diabetes prevalence, cardiovascular risk factors and chronic diabetic complications in Type 2 diabetes patients. Despite a greater use of health services by less wealthy patients, they showed worse glycaemic control and more chronic complications. Besides clinical variables, socio‐economic status and environmental information need to be considered in the assessment of risk profile of diabetic patients by health professionals and by health service planners.
Association of angiotensin‐converting enzyme DD genotype with 24‐h blood pressure abnormalities in normoalbuminuric children and adolescents with Type 1 diabetes
Authors: Barkai L. , Soós A. , Vámosi I.
Published: September 2005

Aims  To assess the distribution of the insertion/deletion (I/D) polymorphism of the angiotensin‐converting enzyme (ACE) gene in children and adolescents with Type 1 diabetes and to evaluate the association between ACE genotype and blood pressure (BP).

Methods  ACE genotypes were assessed in 124 normoalbuminuric, clinically normotensive Type 1 diabetic children and adolescents and 120 non‐diabetic controls using polymerase chain reaction. Twenty‐four‐hour ambulatory BP monitoring was undertaken in all patients.

Results  ACE genotypes distributed in patients as follows: 34 (27%) DD, 57 (46%) ID, 33 (27%) II. The distribution was similar in the control group: DD in 28% (33), ID in 45% (54), and II in 27% (33). Patients with DD genotype had higher mean 24‐h diastolic BP (73.8 ± 6.2 vs. 70.2 ± 5.0 and 69.7 ± 6.3 mmHg; P = 0.005) and lower diurnal variation in BP (11.8 ± 4.6 vs. 14.2 ± 4.2 and 14.8 ± 4.3%; P = 0.011) compared with ID and II groups. Four patients in the DD group proved to be non‐dipper compared with one in the ID and none in the II group (P = 0.026). Twenty‐four‐hour diastolic blood pressure was independently predictive for AER as dependent variable in the DD genotype patient group (r2 = 0.12, P = 0.03).

Conclusions  Children and adolescents with Type 1 diabetes do not differ from the non‐diabetic population regarding the I/D polymorphism of the ACE gene. ACE gene polymorphism is associated with BP abnormalities in normotensive and normoalbuminuric children and adolescents with Type 1 diabetes.
Does close glycaemic control promote healing in diabetic foot ulcers? Report of a feasibility study
Authors: Idris I. , Game F. , Jeffcoate W.
Published: September 2005

Aim  To undertake a pilot study to determine the feasibility of a definitive trial of the effect of close glycaemic control on healing of foot ulcers in diabetes.

Methods  All patients attending a dedicated multidisciplinary clinic for the management of established ulcers over a 20‐week period were systematically screened for inclusion in a randomised, single‐blinded study.

Findings  Two hundred individuals with foot ulcers attended the clinic during the recruitment period, but only nine met the predefined inclusion and exclusion criteria. One of these was withdrawn because of an adverse event immediately before recruitment, two proved incapable of administering insulin injections and were withdrawn prior to randomization. Four withheld consent, and one was advised to withhold consent by his community nurse. One was randomised and completed the 3‐month study. The study was abandoned at 20 weeks when it was decided that it would be unlikely that a sufficient number of suitable patients would ever be recruited, and that it would therefore be unethical to approach further subjects.

Conclusions  It was concluded that although evidence is required to guide future practice in this field, the study design chosen was not feasible.
Coeliac disease in children with Type 1 diabetes mellitus: the effect of the gluten‐free diet
Authors: Sanchez‐Albisua I. , Wolf J. , Neu A. , Geiger H. , Wäscher I. , Stern M.
Published: September 2005

Patients and methods  We assessed the frequency of coeliac disease in 281 children with Type 1 diabetes and the effect of gluten‐free diet (GFD) in newly diagnosed cases. Serological screening was performed using anti‐gliadin and anti‐endomysium antibodies. Data were obtained about clinical symptoms, height and weight‐for‐height.

Results  A small intestinal biopsy was recommended to 18 patients (6.4%) with positive serological results and 12 children agreed. Nine of them had coeliac disease. Three out of nine coeliac children complained about gastrointestinal symptoms. On a GFD, the symptoms disappeared in two patients. Iron‐deficiency anaemia was present in four subjects and disappeared in the three patients who accepted the GFD. In three patients (33%), coeliac disease was asymptomatic. Height and weight‐for‐height were in the normal range for all patients. For well‐complying patients, there was a significant increase in height standard deviation at diagnosis and on follow‐up (−0.28 vs. +0.35) (P = 0.03). Changes in weight‐for‐height were not significant (−4.0% vs. +1.4%) (P = 0.28). There was a trend to an improvement in HbA1c (8.0 vs. 7.3%) (P = 0.05).

Conclusions  Serological screening is effective. There is a therapeutic benefit for some screening‐detected patients, but confirmatory studies are needed.
Long‐term effects of pioglitazone and metformin on insulin sensitivity in patients with Type 2 diabetes mellitus
Authors: Roden M. , Laakso M. , Johns D. , Widel M. , Urquhart R. , Richardson C. , Mariz S. , Tan M. H.
Published: September 2005

Aim  Despite their comparable glycaemic effects in patients with Type 2 diabetes mellitus (T2DM), pioglitazone and metformin may have different effects on insulin sensitivity because they have different mechanisms of action. We studied the changes in insulin sensitivity, as assessed by the Quantitative Insulin Sensitivity Check Index (QUICKI), in patients with T2DM who used metformin or pioglitazone as monotherapy or in combination therapy with sulphonylurea.

Methods  Data in this report are from two multicentre, randomized, double‐blind, double‐dummy studies conducted in Europe (monotherapy) or in Europe and Canada (combination therapy study). Patients were randomized to 52 weeks of treatment consisting of a 12‐week forced titration period and a 40‐week maintenance period. HbA1c, fasting plasma glucose (FPG) and fasting serum insulin (FSI) were quantified from a single blood sample at weeks 0, 8, 16, 24, 32, 42 and 52. Insulin sensitivity was assessed with QUICKI, which is calculated from FSI and fasting blood glucose (FBG) concentrations using the formula 1/(log10 FSI + log10 FBG). Time course effects of the treatments were compared by repeated measures analysis of covariance.

Results  As monotherapy, pioglitazone and metformin increased QUICKI compared with baseline (baseline vs. end point [mean ± sem]; pioglitazone [0.303 ± 0.001 vs. 0.321 ± 0.001; P < 0.001] and metformin [0.304 ± 0.001 vs. 0.315 ± 0.001; P < 0.001]). Pioglitazone increased insulin sensitivity more than metformin from week 4 through week 52. There were significant increases in QUICKI from baseline in both combination therapy groups (baseline vs. end point; pioglitazone + sulphonylurea [0.305 ± 0.001 vs. 0.319 ± 0.001; P < 0.001] and metformin + sulphonylurea [0.306 ± 0.001 vs. 0.317 ± 0.001; P < 0.001]). Overall, pioglitazone + sulphonylurea significantly increased insulin sensitivity more than metformin + sulphonylurea.

Conclusion  Pioglitazone differed from metformin in its effects on insulin sensitivity despite both drugs having comparable glycaemic effects.
Comparison of metabolic effects of pioglitazone, metformin, and glimepiride over 1 year in Japanese patients with newly diagnosed Type 2 diabetes
Authors: Yamanouchi T. , Sakai T. , Igarashi K. , Ichiyanagi K. , Watanabe H. , Kawasaki T.
Published: September 2005

Aims  To compare the metabolic effects of pioglitazone, metformin, and glimepiride in the treatment of Japanese patients with newly diagnosed Type 2 diabetes.

Methods  A total of 114 patients with Type 2 diabetes who had never used oral hypoglycaemic drugs were studied for 12 months. Patients were randomly assigned to pioglitazone (30–45 mg/day, n = 38), metformin (750 mg/day, n = 39), or glimepiride (1.0–2.0 mg/day, n = 37). The effect of treatment on fasting plasma glucose (FPG), glycated haemoglobin (HbA1c), 1,5‐anhydroglucitol (1,5AG), total cholesterol, high‐density lipoprotein (HDL)‐cholesterol, triglycerides, free fatty acids (FFA), and fasting plasma insulin levels was monitored monthly. Body weight and safety data were also collected.

Results  Eight patients withdrew from the study (three in the pioglitazone group, two in the metformin group, and three in the glimepiride group). The rate of reduction of HbA1c was fastest in patients receiving glimepiride and slowest in patients receiving pioglitazone. Although there were no significant differences among the three groups in HbA1c levels at the end of the study, patients taking pioglitazone had relatively lower FPG and 1,5AG levels than patients taking the other two drugs. These results suggest that pioglitazone acts predominantly on nocturnal metabolism rather than at mealtimes. FFA were reduced significantly in those taking pioglitazone (542.2 µEq/l vs. 237.3 µEq/l; P < 0.01) before a decrease in HbA1c was apparent. The change in FFA levels correlated with the change in HbA1c (r = 0.409, P < 0.01). There were no significant differences in other lipid parameters among the groups.

Conclusions  Pioglitazone, metformin, and glimepiride are equally effective in reducing blood glucose in patients with newly diagnosed Type 2 diabetes. However, their specific characteristics, such as the rapid action on blood glucose levels of glimepiride and the favourable action on FPG and FFA of pioglitazone, should be considered when choosing an appropriate agent.
Patterns of care as a risk factor for the development of vision‐threatening diabetic retinopathy: a population‐based matched case–control study using insurance claims (Medicare) data
Authors: Orr N. J. , Boyages S. C.
Published: September 2005

Objectives  To evaluate systematically the effectiveness of the primary healthcare system in Australia in preventing the development of advanced diabetes complications.

Methods  Diabetes patients (n = 4632) who had received their first laser photocoagulation treatment in 2000 were compared with a random sample of diabetes patients who had never received this treatment (n = 4632). Patterns of health care utilization were compared over a 7‐year period (1993–1999) using the Australian Medicare database.

Results  There were significant differences in levels of healthcare utilization: cases were less likely to attend a general practitioner, from odds ratio (OR) = 0.21 (P < 0.0001) in 1993 to 0.53 (P < 0.0001) in 1999; less likely to be tested for HbA1c, from OR = 0.24 in 1997 (P < 0.0001) to 0.38 in 1999 (P < 0.0001); for HDL‐cholesterol, from OR = 0.017 (P < 0.0001) in 1999 to 0.04 (P < 0.0001) in 1993; and to attend specialists and consultant physicians, from OR = 0.25 (P < 0.0001) in 1994 to 0.44 (P < 0.0001) in 1999. The multivariate analysis emphasized the importance of timely diagnosis, HDL‐cholesterol testing and optometry attendances in the prevention of advanced diabetes complications.

Conclusions  The study supports the contention that healthcare utilization may be as important a determinant of health outcomes as clinical risk factors such as blood glucose control. This highlights the importance of early diagnosis and the need to address systemic barriers so as to increase primary care utilization for people at risk of advanced diabetes complications.
ECONOMIC IMPORTANCE OF THE SUGAR INDUSTRY FOR FIJI
Authors: Narayan Paresh Kumar , Prasad Biman Chand
Published: September 2005

For more than a century, the sugar industry has been perceived as the backbone of the Fijian economy, given its contributions to gross domestic product (GDP) and employment generation. However, because of the non‐renewal of land leases and the gradual withdrawal of preferential prices by the European Union, the industry is on the verge of collapse. We use the Fiji computable general equilibrium model to simulate the economy‐wide impact of a 30% reduction in sugar production. Among our key results, we find that in the long run a 30% reduction in sugar production leads to a 2.1% fall in exports, and government expenditure and real consumption fall by 1.9% and 1.6%, respectively. These declines in the aggregate demand components are reflected in a fall of approximately 1.8% in Fiji's GDP. The negative repercussion of declining economic growth is reflected in a 1.5% decline in real national welfare.
MULTIPLE LABOR GROUPS AND THEIR EFFECTS ON SMALL CITY AND TOWN SAMS AND CGE MODELS
Authors: Schwarm Walter , Cutler Harvey
Published: September 2005

This paper extends Schwarm and Cutler (2003) by incorporating three labor groups while using their methods to source data and provide an organizational framework that allows effective and straightforward creation of social accounting matrices (SAMs) and regional computable general equilibrium (CGE) models. While CGE models typically describe relatively large geographical areas and are therefore not able to capture the uniqueness of individual cities or towns within the region, our model allows simulations of small cities and towns that highlight regional similarities or differences. The differing effects of both an increase in manufacturing and a change in the sales tax are examined to demonstrate the insights and regional characteristics that such methods allow a researcher to obtain.
EFFECT OF PUBLIC INVESTMENT ON THE REGIONAL ECONOMIES IN POSTWAR JAPAN
Authors: Kataoka Mitsuhiko
Published: September 2005

This paper examines the effect of public investment on the regional economies of postwar Japan. It evaluates the effects of efficiency‐verses‐equity‐oriented allocation policies by estimating the aggregate regional production function and calculating the marginal productivity of public capital for each region, using panel data covering the 47 prefectures over the period from 1955 to 2000. The empirical results show that public capital investment has alternated between an allocation policy based on efficiency and one that is based on equity, and, in fact, such investment was used as a policy tool for adjusting income distribution and accelerating economic growth. Numerical simulations are used to analyze the trade‐offs between economic efficiency and inter‐prefectural equity. The results indicate that in the case of income‐elastic labor mobility, an efficiency‐oriented allocation policy leads to larger aggregate gross domestic product by promoting both growth and equity simultaneously.
EXAMINING THE RELATIONSHIP BETWEEN QUALITY OF LIFE AMENITIES AND ECONOMIC DEVELOPMENT IN THE SOUTHEAST USA
Authors: Nzaku Kilungu , Bukenya James O.
Published: September 2005

This paper contributes to the ongoing discussion about amenity‐driven rural development strategies by examining the relationship between quality of life amenities and rural economic development in the Southeast USA. The premise is that what is true at a national level may provide a partial or misleading picture when we look at particular areas. Additionally, data available at the county level can often provide richer and more precise information than what is found at the national level. The paper estimates spatial regression models using county‐level data. For the most part, the results suggest that the differences in quality of life and amenities factors can explain a large portion of the trend in per capita income, employment and population change across counties in the Southeast USA.
Differential monoaminergic, neuroendocrine and behavioural responses after central administration of corticotropin‐releasing factor receptor type 1 and type 2 agonists
Authors: De Groote Lotte , Peñalva Rosana G. , Flachskamm Cornelia , Reul Johannes M. H. M. , Linthorst Astrid C. E.
Published: September 2005

Corticotropin‐releasing factor (CRF) mediates various aspects of the stress response. To differentiate between the roles of CRF1 and CRF2 receptor subtypes in monoaminergic neurotransmission, hypothalamic–pituitary–adrenocortical axis activity and behaviour we compared the effects of CRF and urocortin 1 with those of the selective CRF2 receptor ligands urocortin 2 and urocortin 3. In vivo microdialysis in the rat hippocampus was used to assess free corticosterone, extracellular levels of serotonin (5‐HT) and noradrenaline (NA), and their metabolites 5‐hydroxyindoleacetic acid (5‐HIAA) and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG), respectively. Intracerebroventricular (i.c.v.) injection of CRF and urocortin 1, 2 and 3 (1.0 µg) increased hippocampal levels of 5‐HT and 5‐HIAA. CRF and urocortin 1 increased NA and MHPG, whereas urocortin 2 and urocortin 3 elevated MHPG, but not NA levels. CRF and the urocortins induced an immediate increase in behavioural activity. CRF and urocortin 1 mainly caused grooming and exploratory behaviour. In contrast, urocortin 2 and urocortin 3 both induced exploratory behaviour, but not grooming, and increased time spent eating food pellets. All urocortins, but not CRF, suppressed food intake 4–6 h after injection. Hippocampal free corticosterone levels were elevated by CRF, urocortin 1 and 3, but not by urocortin 2. The time courses of the CRF‐ and urocortin 1‐induced responses were significantly prolonged as compared to those of the CRF2 receptor ligands. The stimulatory changes evoked by CRF and urocortin 1 were present up to 4–6 h after injection, whereas the effects of urocortin 2 and urocortin 3 returned to baseline within 2.5 h after injection. Pre‐treatment with the selective antagonist antisauvagine‐30 (5.0 µg, i.c.v.) confirmed that the effects of urocortin 3 were CRF2 receptor‐mediated. The differential time course of the monoaminergic, neuroendocrine and behavioural effects of CRF and urocortin 1, as compared to urocortin 2 and urocortin 3, and the specific behavioural pattern induced by the CRF2 receptor ligands, suggest a distinct role for CRF2 receptors in the stress response.
Length and overall sequence of the PEN‐2 C‐terminal domain determines its function in the stabilization of presenilin fragments
Authors: Prokop Stefan , Haass Christian , Steiner Harald
Published: September 2005

γ‐Secretase is an aspartyl protease complex that catalyzes the intramembrane cleavage of a subset of type I transmembrane proteins including the β‐amyloid precursor protein (APP) implicated in Alzheimer's disease. Presenilin (PS), nicastrin (NCT), anterior pharynx defective (APH‐1) and presenilin enhancer‐2 (PEN‐2) constitute the active γ‐secretase complex. PEN‐2, the smallest subunit, is required for triggering PS endoproteolysis. Stabilization of the resultant N‐ and C‐terminal fragments, which carry the catalytically active site aspartates, but not endoproteolysis itself, requires the C‐terminal domain of PEN‐2. To functionally dissect the C‐terminal domain we created C‐terminal deletion mutants and mutagenized several evolutionary highly conserved residues. The PEN‐2 mutants were then probed for functional complementation of a PEN‐2 knockdown, which displays deficient PS1 endoproteolysis and impaired NCT maturation. Progressive truncation of the C‐terminus caused increasing loss of function. This was also observed for an internal deletion mutant as well as for C‐terminally tagged PEN‐2 with a twofold elongated C‐terminal domain. Interestingly, only simultaneous, but not individual substitution of the highly conserved D90, F94, P97 and G99 residues with alanine interfered with PEN‐2 function. All loss of function mutants identified allowed PS1 endoproteolysis, but failed to stably associate with the resultant PS1 fragments, which like the PEN‐2 loss of function mutants underwent proteasomal degradation. However, complex formation of the PEN‐2 mutants with PS1 fragments could be recovered when proteasomal degradation was blocked. Taken together, our data suggest that the PS‐subunit stabilizing function of PEN‐2 depends on length and overall sequence of its C‐terminal domain.
Constitutive high‐affinity choline transporter endocytosis is determined by a carboxyl‐terminal tail dileucine motif
Authors: Ribeiro Fabiola M. , Black Stefanie A. G. , Cregan Sean P. , Prado Vania F. , Prado Marco A. M. , Rylett R. Jane , Ferguson Stephen S. G.
Published: September 2005

Maintenance of acetylcholine synthesis depends on the effective functioning of a high‐affinity sodium‐dependent choline transporter (CHT1). Recent studies have shown that this transporter is predominantly localized inside the cell, unlike other neurotransmitter transporters, suggesting that the trafficking of CHT1 to and from the plasma membrane may play a crucial role in regulating choline uptake. Here we found that CHT1 is rapidly and constitutively internalized in clathrin‐coated vesicles to Rab5‐positive early endosomes. CHT1 internalization is controlled by an atypical carboxyl‐terminal dileucine‐like motif (L531, V532) which, upon replacement by alanine residues, blocks CHT1 internalization in both human embryonic kidney 293 cells and primary cortical neurons and results in both increased CHT1 cell surface expression and choline transport activity. Perturbation of clathrin‐mediated endocytosis with dynamin‐I K44A increases cell surface expression and transport activity to a similar extent as mutating the dileucine motif, suggesting that we have identified the motif responsible for constitutive CHT1 internalization. Based on the observation that the localization of CHT1 to the plasma membrane is transient, we propose that acetylcholine synthesis may be influenced by processes that lead to the attenuation of constitutive CHT1 endocytosis.
Caspase 7: increased expression and activation after traumatic brain injury in rats
Authors: Larner Stephen F. , McKinsey Deborah M. , Hayes Ronald L. , W. Wang Kevin K.
Published: September 2005

Caspases, a cysteine proteinase family, are required for the initiation and execution phases of apoptosis. It has been suggested that caspase 7, an apoptosis executioner implicated in cell death proteolysis, is redundant to the main executioner caspase 3 and it is generally believed that it is not present in the brain or present in only minute amounts with highly restricted activity. Here we report evidence that caspase 7 is up‐regulated and activated after traumatic brain injury (TBI) in rats. TBI disrupts homeostasis resulting in pathological apoptotic activation. After controlled cortical impact TBI of adult male rats we observed, by semiquantitative real‐time PCR, increased mRNA levels within the traumatized cortex and hippocampus peaking in the former about 5 days post‐injury and in the latter within 6–24 h of trauma. The activation of caspase 7 protein after TBI, demonstrated by immunoblot by the increase of the active form of caspase 7 peaking 5 days post‐injury in the cortex and hippocampus, was found to be up‐regulated in both neurons and astrocytes by immunohistochemistry. These findings, the first to document the up‐regulation of caspase 7 in the brain after acute brain injury in rats, suggest that caspase 7 activation could contribute to neuronal cell death on a scale not previously recognized.
Nuclear translocation of the SRF co‐activator MAL in cortical neurons: role of RhoA signalling
Authors: Tabuchi Akiko , Estevez Marcel , Henderson Jennifer A. , Marx Ruth , Shiota Jun , Nakano Hiroyasu , Baraban Jay M.
Published: September 2005

Although it is well established that RhoA signaling pathways play key roles in regulating neuronal morphology, their involvement in other aspects of neuronal function has received little attention. Recent studies have elucidated a novel intracellular signaling pathway used by RhoA to elicit activation of serum response factor (SRF)‐mediated transcription. In this pathway, activation of RhoA triggers nuclear translocation of the SRF co‐activator, megakaryocytic acute leukemia (MAL). In assessing whether RhoA regulates transcription in neurons via this pathway, we have found that a constitutively active form of Tech (transcript‐enriched in cortex and hippocampus), a RhoA guanine nucleotide exchange factor (GEF) that is expressed in forebrain neurons, stimulates SRF reporter activity in extracts of primary cortical cultures and induces nuclear translocation of MAL in cortical neurons. Both of these responses appear to be mediated by Tech's activation of RhoA as they are not mimicked by a mutant Tech construct lacking RhoA GEF activity and are blocked by C3 transferase, a selective inhibitor of RhoA. Furthermore, Tech‐induced increases in SRF activity are suppressed by a dominant negative MAL construct. These findings demonstrate that RhoA signaling pathways are able to regulate transcription in neurons by triggering translocation of the SRF co‐activator MAL.
Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation
Authors: Babu Jeganathan Ramesh , Geetha Thangiah , Wooten Marie W.
Published: September 2005

Inclusions isolated from several neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by ubiquitin‐positive proteinaceous aggregates. Employing confocal and immunoelectron microscopy, we find that the ubiquitin‐associating protein sequestosome1/p62, co‐localizes to aggregates isolated from AD but not control brain, along with the E3 ubiquitin ligase, TRAF6. This interaction could be recapitulated by co‐transfection in HEK293 cells. Employing both in vitro and in vivo approaches, tau was found to be a substrate of the TRAF6, possessing lysine 63 polyubiquitin chains. Moreover, tau recovered from brain of TRAF6 knockout mice, compared with wild type, was not ubiquitinated. Tau degradation took place through the ubiquitin–proteasome pathway and was dependent upon either the K63‐polyubiquitin chains or upon p62. In brain lysates of p62 knockout mice, tau fails to co‐interact with Rpt1, a proteasomal subunit, thereby indicating a requirement for p62 shuttling of tau to the proteasome. Our results demonstrate that p62 interacts with K63‐polyubiquitinated tau through its UBA domain and serves a novel role in regulating tau proteasomal degradation. We propose a model whereby either a decline in p62 expression or a decrease in proteasome activity may contribute to accumulation of insoluble/aggregated K63‐polyubiquitinated tau.
Excitotoxic and apoptotic neuronal death induce different patterns of glial activation in vitro
Authors: Pérez‐Capote Kamil , Serratosa Joan , Solà Carme
Published: September 2005

We have studied glial activation in rat cerebellar neuronal‐glial cultures after inducing neuronal death using various stimuli. Cultures were exposed to 100 µm glutamate for 20 min, which induces excitotoxic neuronal death, or to potassium/serum deprivation, which induces apoptosis of granule neurons. We evaluated alterations in several parameters related to glial activation: nuclear factor‐κB activation, nitric oxide and tumour necrosis factor‐α production, which are associated with a pro‐inflammatory response, glial proliferation and phagocytic activity. Although the two experimental models of neuronal damage resulted in the death of most neuronal cells within 24 h, differences were observed in the response of the various glial parameters evaluated. While nitric oxide production was not detected in any case, tumour necrosis factor‐α production, nuclear factor‐κB activation and glial proliferation were only induced in the presence of excitotoxic neuronal death. However, phagocytosis was induced in both cases, although earlier in the case of apoptotic neuronal death. These results show that glial cells respond to excitotoxic neuronal death with an inflammatory response associated with proliferation and phagocytosis. In contrast, whilst glial cells do not produce pro‐inflammatory molecules in the presence of apoptotic neuronal death, phagocytic activity is rapidly induced.
ALS‐IgG‐induced selective motor neurone apoptosis in rat mixed primary spinal cord cultures
Authors: Demestre M. , Pullen A. , Orrell R. W. , Orth M.
Published: September 2005

There is evidence that in sporadic amyotrophic lateral sclerosis (ALS) immunological mechanisms may be involved in the pathophysiology of the disease. We tested whether purified IgG from ALS patients induce cell death in rat mixed primary spinal cord cultures and compared this with the effect of IgG purified from patients with Guillain–Barré syndrome (GBS) or from healthy donors. Treatment with ALS‐IgG increases caspase‐3 apoptosis when compared with control IgG or with GBS‐IgG, but does not induce death by necrosis. Because ALS is characterized by the selective loss of motor neurones, we next assessed the differential effect of ALS‐IgG on motor neurones or astrocytes. We showed, semiquantitatively, that motor neurones are more susceptible to apoptosis when cultures were treated with ALS‐IgG compared with control‐IgG. In conclusion, we have demonstrated in primary spinal cord cultures that IgG from patients with ALS induces apoptosis selectively in motor neurones, and that the caspase‐3 pathway is involved. This suggests that immunological mechanisms may contribute to the selective loss of motor neurones in ALS.
Acute and long‐term effects of IL‐6 on cultured dorsal root ganglion neurones from adult rat
Authors: Segond von Banchet Gisela , Kiehl Michaela , Schaible Hans‐Georg
Published: September 2005

IL‐6 contributes to pain and hyperalgesia in inflamed tissue. We have investigated short‐ and long‐term effects of IL‐6 on dorsal root ganglion (DRG) neurones. Glycoprotein 130‐like immunoreactivity (the signal transduction receptor subunit) was found in almost all neurones in DRG sections and in cultured DRG neurones from adult rat. In calcium‐imaging studies bath application of IL‐6 caused an increase of intracellular calcium in about one‐third of the DRG neurones suggesting functional IL‐6 receptors in a proportion of neurones. Long‐term but not short‐term exposure of DRG neurones to IL‐6 in vitro significantly enhanced the proportion of DRG neurones expressing neurokinin 1 receptor‐like immunoreactivity from 10% to up to 40%. This up‐regulation was dependent on the activation of mitogen‐activated protein kinase kinase (MEK) in the neurones, suggesting that the mitogen‐activated protein kinase (MAPK) pathway is important for this effects of IL‐6. Calcium‐imaging studies demonstrated that previous exposure of DRG neurones to IL‐6 enhanced the proportion of neurones that exhibit a substance P‐induced rise in intracellular calcium. These data show that IL‐6 has short‐ and long‐term effects on a proportion of DRG neurones. These effects are likely to contribute to pro‐nociceptive effects of IL‐6.
Proline mutations induce negative‐dosage effects on uptake velocity of the dopamine transporter
Authors: Lin Zhicheng , Uhl George R.
Published: September 2005

Ala and Gly substitutions for Pro 101 (P101) located in transmembrane domain 2 of the dopamine transporter (DAT) abolished transport activity but did not disrupt plasma membrane expression. Due to the high conservation of P101 in all neurotransmitter transporters and the capability of Pro to add flexibility to helices, we hypothesized that P101 contributes to the dynamic feature of substrate translocation. To test this hypothesis, here we analysed transport activity for DAT mutants where this Pro was mutated into different amino acids, including Ser, Val, Leu and Phe. The transmembrane domain 2 helix of P101F, unlike the other mutants, was computationally predicted to have a Van der Waals energy threefold higher than the wild‐type helix. P101F mutant expression was consistently disrupted in COS cells. Among all the other mutants that express normally, P101V, with a side‐chain size close to that of Pro, restores the transport activity of P101A by sevenfold. Most importantly, P101V, P101L and P101S display negative‐dosage effects on dopamine (DA) transport, i.e. the velocity–concentration curve for DA uptake does not show a plateau with increasing [DA] but rather peaks and then goes down. These data support the view that P101 of DAT plays an essential role in DA translocation.
The membrane environment of endogenous cellular prion protein in primary rat cerebellar neurons
Authors: Loberto Nicoletta , Prioni Simona , Bettiga Arianna , Chigorno Vanna , Prinetti Alessandro , Sonnino Sandro
Published: September 2005

We studied the membrane environment of cellular prion protein in primary cultured rat cerebellar neurons differentiated in vitro. In these cells, about 45% of total cellular prion protein (corresponding to a 35‐fold enrichment) is associated with a low‐density, sphingolipid‐ and cholesterol‐enriched membrane fraction, that can be separated by flotation on sucrose gradient. Biotinylation experiments indicated that almost all prion protein recovered in this fraction was exposed at the cell surface. Prion protein was efficiently separated from this fraction by a monoclonal antibody immunoseparation procedure. Under conditions designed to preserve lipid‐mediated membrane organization, several proteins were found in the prion protein‐enriched membrane domains (i.e. the non‐receptor tyrosine kinases Lyn and Fyn and the neuronal glycosylphosphatidylinositol‐anchored protein Thy‐1). The prion protein‐rich membrane domains contained, as well, about 50% of the sphingolipids, cholesterol and phosphatidylcholine present in the sphingolipid‐enriched membrane fraction. All main sphingolipids, including sphingomyelin, neutral glycosphingolipids and gangliosides, were similarly enriched in the prion protein‐rich membrane domains. Thus, prion protein plasma membrane environment in differentiated neurons resulted to be a complex entity, whose integrity requires a network of lipid‐mediated non‐covalent interactions.
Cumulative irritation patch test of sanitary pads on sensitive skin
Authors: Farage Miranda , Stadler Angela
Published: September 2005

Background  Tools are needed to assess the effects of various products on sensitive skin.

Aim  To investigate the cutaneous compatibility of various sanitary pads in people with self‐declared sensitive skin.

Patients/methods  Eight subjects, who considered their skin to be sensitive and who reported adverse skin responses to everyday products or clothing, were patch tested on the arm with two, low‐irritancy sanitary pads for four consecutive 24‐hour periods. Test products differed only in their surface covering. Sodium lauryl sulfate solution (0.1% w/v) and physiological saline served as standard irritant and nonirritant controls, respectively. Skin irritation (erythema) was graded after each 24‐hour period.

Results  No significant difference in skin erythema scores was observed between groups (scores on day 4: 1.06 ± 0.11 vs. 1.25 ± 0.13, on a five‐point scale, P < 0.05). The temporal development of cumulative irritation associated with the pads was comparable to that observed with the nonirritant control (a plateau in maximal group scores) and distinct from that of the irritant control (continuously rising scores).

Conclusion  Sanitary pads under investigation elicited negligible cumulative irritation in a four‐day patch test on subjects with self‐declared sensitive skin. The temporal pattern of cumulative response was consistent with the inherently low irritation potential of the products.
An evaluation of topical 3% salicylic acid and 1% hydrocortisone in the maintenance of scalp pruritus
Authors: Draelos Zoe Diana
Published: September 2005

Background  Scalp pruritus is a common condition causing dermatologic distress. The presence of skin scale on clothing is cosmetically undesirable and scalp scratching in public is socially embarrassing. Scratching can also result in removal of the cuticle and premature hair shaft fracture.

Objective  To demonstrate the efficacy of 3% salicylic acid in combination with 1% hydrocortisone in the treatment of scalp pruritus.

Methods  Sixty subjects with moderate scalp scaling and scalp pruritus were enrolled in a three‐arm double blind 2‐week study. The 20 subjects in arm 1 applied a topical 1% hydrocortisone product twice daily. The 20 subjects in arm 2 applied a topical 3% salicylic acid product twice daily. Lastly, the 20 subjects in arm 3 applied a topical 3% salicylic acid product in the morning and a topical 1% hydrocortisone product in the evening. Evaluations were performed at baseline, after 1 week of treatment, and after 2 weeks of treatment. The study investigator evaluated the subjects for scalp scale, erythema, excoriation, and overall assessment. In addition, scalp scale scrapings were collected and analyzed to gain further insight into scalp scale morphology. Subject assessments and scalp photography was also performed.

Results  The investigator assessments revealed less excoriation in the hydrocortisone twice daily arm over the salicylic acid twice daily arm (P = 0.03), which might be expected because of its anti‐inflammatory effect. The morning salicylic acid application and evening hydrocortisone application arm performed better than the salicylic acid twice daily group at week 2 in terms of erythema (P = 0.02), excoriation (P = 0.03), and overall assessment (P = 0.01). Scalp scale scrapings revealed the least amount of retained skin scale in the combination salicylic acid/hydrocortisone group.

Conclusion  The combination of a 3% salicylic acid keratolytic combined with a 1% hydrocortisone anti‐inflammatory provides the best relief of scalp pruritus.
Changes to Category C of the British List†
Authors: DUDLEY STEVE P.
Published: September 2005

In its maintenance of the British List, the British Ornithologists’ Union Records Committee (BOURC) is responsible for assigning species to categories to indicate their status on the List. In 1995, the British Ornithologists’ Union (BOU) and the Joint Nature Conservation Committee (JNCC) held a conference on naturalized and introduced birds in Britain (Holmes & Simons 1996). This led to a review of the process of establishment of such species and the terms that best describe their status (Holmes & Stroud 1995) as well as a major review of the categorization of species on the British List (Holmes et al. 1998). The BOURC continues to review the occurrence and establishment of birds of captive origin in Britain. This paper summarizes the status of naturalized and introduced birds in Britain and announces changes to the categorization of many on the British List or its associated appendices (Categories D and E):

Mute Swan Cygnus olor Categories AC change to AC2

Black Swan Cygnus atratus Category E* – no change

Greylag Goose Anser anser Categories ACE* change to AC2C4E*

Snow Goose Anser caerulescens Categories AE* change to AC2E*

Greater Canada Goose Branta canadensis Categories ACE* change to C2E*

Barnacle Goose Branta leucopsis Categories AE* change to AC2E*

Egyptian Goose Alopochen aegyptiacus Categories CE* change to C1E*

Ruddy Shelduck Tadorna ferruginea Categories BDE* – no change

Muscovy Duck Cairina moschata Category E* – alert JNCC

Wood Duck Aix sponsa Category E* – no change

Mandarin Duck Aix galericulata Categories CE* change to C1E*

Gadwall Anas strepera Category A change to AC2

Mallard Anas platyrhynchos Categories AE* change to AC2C4E*

Red‐crested Pochard Netta rufina Categories AE* change to AC2E*

Ruddy Duck Oxyura jamaicensis Categories CE* change to C1E*

Black Grouse Tetrao tetrix Categories AE – no change

Western Capercaillie Tetrao urogallus Categories BC change BC3

Red‐legged Partridge Alectoris rufa Categories CE* change to C1E*

Grey Partridge Perdix perdix Categories ACE change to AC2E

Common Pheasant Phasianus colchicus Categories CE* change to C1E*

Golden Pheasant Chrysolophus pictus Categories CE* change to C1E*

Lady Amherst's Pheasant Chrysolophus amherstiae Categories CE* change to C6E*

Black‐crowned Night Heron Nycticorax nycticorax Categories AE* – no change

Sacred Ibis Threskiornis aethiopicus Category E – no change

Red Kite Milvus milvus Categories AC change to AC3

White‐tailed Eagle Haliaeetus albicilla Categories ACE change to AC3E

Northern Goshawk Accipiter gentilis Categories AE* change to AC3E*

Rock/Feral Pigeon Columbia livia Categories AE* change to AC4E*

Rose‐ringed Parakeet Psittacula krameri Categories CE* change to C1E*

Barn Owl Tyto alba Categories AE* – no change

Little Owl Athene noctua Category C change to C1
Host range in solitary versus gregarious parasitoids: a laboratory experiment
Authors: Traynor Ruth E. , Mayhew Peter J.
Published: September 2005

Behavioural interactions among relatives may have consequences for many other traits. We tested the hypothesis that solitary parasitoids (displaying siblicidal behaviour in their larvae) have narrower host ranges than gregarious parasitoids (with tolerant larvae). In laboratory experiments, we compared parasitization success in two sister species of braconid wasp [Aphaereta genevensis(Fischer), solitary, andAphaereta pallipes(Say), gregarious (Hymenoptera: Braconidae: Alysiini)] on eightDrosophilaspecies or strains. Host species or strain was the most important factor affecting parasitization success, and some of this variation was accountable to host physiological defences. Although two hosts were more suitable for the solitary species, and one more suitable for the gregarious species, these differences were small, and there was no consistent difference across all hosts. Wasp body size was positively correlated with parasitization success in both wasp species. This may be because body size increases oviposition success, or the motivation to oviposit. InA. pallipesparasitization success peaked after 3–4 days, but later inA. genevensis. This is likely due to low life expectancy and high egg loads increasing oviposition tendency in youngA. pallipes, and egg limitation decreasing oviposition tendency in oldA. pallipes. These data suggest that interactions among wasp larvae do not greatly affect the size of the fundamental niche examined here. However, they show the potential for life history traits, which differ between the species as a likely consequence of larval interactions, to affect the extent of the realized niche.
Influence of mineral fertilization on food quality of oak leaves and utilization efficiency of food components by the gypsy moth
Authors: Giertych M.J. , Bąkowski M. , Karolewski P. , Zytkowiak R. , Grzebyta J.
Published: September 2005

Host plant quality is a key determinant of the performance of larvae of herbivorous insects. The effects of nitrogen and dolomite fertilization on the quality of pedunculate oak, Quercus robur L. (Fagaceae) foliage, as a food for gypsy moth, Lymantria dispar L. (Lepidoptera: Lymantriidae) larvae were evaluated. The seedlings were divided into five fertilization treatments (nonfertilized control, commercial nutrient solution, commercial nutrient solution + (NH4)2SO4, commercial nutrient solution + KNO3, and commercial nutrient solution + dolomite). The experiment was performed in Petri dishes, in each of which a fresh leaf from one treatment and one larva were placed. Insect performance assays, survival, development, growth, and food utilization were evaluated for each fertilization treatment. Leaf samples were assayed for nitrogen and other main nutrients, soluble carbohydrates, and phenolic compounds. The fertilizer treatment with added ammonium improved gypsy moth performance, and the amount of food eaten was the lowest in this treatment. Utilization of elements from the food depended on the element and on the fertilization treatment. The insect bodies retained 50–64% of the nitrogen and 55–79% of the phosphorus. The results show that the efficiency of conversion of ingested food (ECI) and the efficiency of conversion of digested food (ECD) differ among the fertilization treatments, but it is not possible to define a general trend. Our results suggest that fertilization (especially ammonium) of host plants can increase herbivore performance, decrease the amount of food needed, and increase its utilization efficiency.