bluuebunny/crossref_metadata_2025_split huggingface dataset:
Islet autoimmunity and genetic mutations in Chinese subjects initially thought to have Type 1B diabetes
Authors: Zhang D. , Zhou Z. , Li L. , Weng J. , Huang G. , Jing P. , Zhang C. , Peng J. , Xiu L. 
Published: August 2005

AbstractAims  To explore the contribution of islet autoimmunity and genetic mutations in Chinese patients initially thought to have Type 1B diabetes.Methods  A group of 33 Chinese patients with newly diagnosed Type 1B diabetes, were identified by the absence of autoantibodies to glutamic acid decarboxylase (GAD), IA‐2, insulin, thyroid globulin or thyroid peroxidase, or high‐risk HLA‐DQ haplotypes. The cohort was further characterized by measurement of autoantibodies to carboxypeptidase H (CPH) and SOX13 using radioligand assays, and testing for genetic mutations associated with MODY3/MODY6 and mitochondrial diabetes. Mutations of HNF‐1α (MODY3) and neuroD1/β2 (MODY6) genes were screened using the single‐strand conformation polymorphism (SSCP) technique and sequencing. Mitochondrial DNA mutations were analysed with polymerase chain reaction—restriction fragment length polymorphism (PCR‐RFLP).Results  Within the cohort, we found one patient with a novel mutation, R321H (CGC→CAC) in exon 5 of the HNF‐1α gene, one with ND1 mt3316 G→A mutation in mitochondrial DNA, five with Ala45Thr polymorphisms in the neuroD1/β2 gene, and two patients with autoantibodies to SOX13.Conclusions  Some of the Chinese patients originally thought to have Type 1B diabetes do have other evidence of islet autoimmunity and genetic mutations involved in the underlying aetiology. This suggests that more rigorous screening for these conditions is needed before classifying subjects as having Type 1B diabetes.
Orlistat in the treatment of overweight or obese Chinese patients with newly diagnosed Type 2 diabetes
Authors: Shi Y.‐F. , Pan C.‐Y. , Hill J. , Gao Y. 
Published: August 2005

AbstractAims  Orlistat promotes weight loss in overweight and obese patients with Type 2 diabetes receiving hypoglycaemic treatment, but has not been investigated in patients with newly diagnosed and previously untreated Type 2 diabetes. We evaluated the efficacy of 24 weeks’ treatment with orlistat, combined with a mildly reduced‐calorie diet, on weight loss and glycaemic control in overweight and obese patients with newly diagnosed and previously untreated Type 2 diabetes.Methods  A total of 249 Chinese patients (body mass index 25–40 kg/m2) with recently diagnosed Type 2 diabetes were randomized to placebo (n = 124) or orlistat 120 mg (n = 125) three times daily; all patients followed a mildly reduced‐calorie diet. Patients had HbA1c 6.5–8.5% (mean 7.3%) and had never received any glucose‐lowering medication.Results  Orlistat‐treated patients achieved significantly greater weight loss at the study end than placebo‐treated patients (−5.4 vs. −2.4 kg; P < 0.0001). More orlistat than placebo patients lost ≥ 5% (60.5 vs. 26.8%; P < 0.0001) and ≥ 10% of their body weight (20.2 vs. 4.9%; P = 0.0002). A significantly greater decrease in HbA1c from baseline was obtained with orlistat than placebo (−1.0 vs. −0.6%; P = 0.0008). Orlistat‐treated patients achieved a significantly greater decrease in fasting plasma glucose (−1.3 vs. −0.5 mmol/l; P = 0.0003) and in the 2‐h oral glucose tolerance test (−4.1 vs. −1.4 mmol/l; P < 0.0001) than placebo recipients. Also, more orlistat‐ than placebo‐treated patients improved from diabetic status to normal or impaired glucose tolerance (44.3 vs. 32.5%; P = 0.0763) after 24 weeks. Orlistat also produced improvements in lipid profiles and waist circumference.Conclusions  In combination with a mildly reduced‐calorie diet, orlistat significantly reduces body weight, and improves glycaemic control and several cardiovascular risk factors in overweight and obese Chinese patients with newly diagnosed Type 2 diabetes.
Factors associated with insulin discontinuation in subjects with ketosis‐prone diabetes but preserved β‐cell function
Authors: Maldonado M. R. , Otiniano M. E. , Cheema F. , Rodriguez L. , Balasubramanyam A. 
Published: August 2005

AbstractAim  To evaluate factors predictive of insulin discontinuation in subjects with ketosis‐prone Type 2 diabetes.Methods  One hundred and six subjects with ketosis‐prone Type 2 diabetes were recruited during the index episode of diabetic ketoacidosis (DKA). All subjects were followed in a special clinic for at least 6 months. If the subject's glycaemic control reached specified glycaemic goals, exogenous insulin was gradually decreased until discontinuation. Baseline and follow‐up characteristics were compared between the off‐insulin and the on‐insulin groups.Results  At the end of the follow‐up period (915 ± 375 days) insulin was discontinued in 47% subjects. Subjects in the off‐insulin group were significantly older at the time of diagnosis of diabetes. In the off‐insulin group the majority of subjects were newly diagnosed with diabetes. After 6 months of follow‐up, subjects in the off‐insulin group had significantly lower mean HbA1c, higher mean C‐peptide‐to‐glucose ratio and had more clinic visits per year. In the proportional hazard analysis, new‐onset diabetes [hazard ratio (HR) 1.54; 95% confidence interval (CI) 1.02–2.45], and a higher C‐peptide‐to‐glucose ratio at 6 months of follow‐up (HR 1.77; 95% CI 1.22–2.63) were significant predictors of insulin discontinuation.Conclusions  In subjects with ketosis‐prone Type 2 diabetes, the best predictors of insulin discontinuation are having new‐onset diabetes, and higher β‐cell functional reserve (as measured by the C‐peptide‐to‐glucose ratio).
Optimal timing of injection of once‐daily insulin glargine in people with Type 1 diabetes using insulin lispro at meal‐times
Authors: Ashwell S. G. , Gebbie J. , Home P. D. 
Published: August 2005

AbstractAims  To compare blood glucose control when insulin glargine is given at lunch‐time, dinner‐time, and bed‐time in people with Type 1 diabetes using insulin lispro at meal‐times.Methods  In this 16‐week, three‐way, cross‐over study, 23 people with Type 1 diabetes were randomized to insulin glargine injection at lunch‐time (L) [mean 12.37 ± 00.34 (± sd) h], dinner‐time (D) (18.12 ± 00.40 h), or bed‐time (B) (22.29 ± 00.40 h), each plus meal‐time insulin lispro. Each 4‐week treatment period concluded with a 24‐h inpatient metabolic profile.Results  Insulin doses, HbA1c, and fructosamine concentration did not differ between treatment periods. Pre‐breakfast self‐monitored blood glucose (SMBG) concentration was higher with injection of glargine at lunch‐time than at other times [L: 9.2 ± 0.3 (± se) vs. D: 8.2 ± 0.3 or B: 8.0 ± 0.3 mmol/l, P = 0.016], as probably was pre‐lunch SMBG (L: 8.6 ± 0.7 vs. D: 6.4 ± 0.7 or B: 6.4 ± 0.8 mmol/l, P = 0.051). Pre‐dinner SMBG level was higher with dinner‐time glargine than other injection times (D: 9.4 ± 0.9 vs. L: 4.9 ± 0.9 or B: 7.4 ± 1.1 mmol/l, P = 0.007). For 22.00 to 02.00 h, mean inpatient plasma glucose concentration was higher with injection of glargine at bed‐time than other times (B: 9.1 ± 0.6 vs. L: 7.8 ± 0.6 or D: 6.7 ± 0.6 mmol/l, P = 0.023). Plasma free insulin concentration was lower at the end of the afternoon with dinner‐time glargine than other injection times (D: 11.5 ± 1.4 vs. L: 20.2 ± 1.3 or B: 16.5 ± 1.3 mU/l, P < 0.001). Frequency of hypoglycaemia was not different, but timing of hypoglycaemia differed between treatment periods.Conclusions  Blood glucose levels rise around the time of injection of insulin glargine whether given at lunch‐time, dinner‐time or bed‐time. Bed‐time injection leads to hyperglycaemia in the early part of the night which is improved by giving insulin glargine at lunch‐time or dinner‐time.
Angiotensin II does not affect endothelial tone in Type 1 diabetes—results of a double‐blind placebo controlled trial
Authors: Browne D. L. , Meeking D. R. , Allard S. E. , Munday J. L. , Shaw K. M. , Cummings M. H. 
Published: August 2005

AbstractAims  Previously, we have demonstrated that patients with normoalbuminuric Type 1 diabetes are characterized by impaired nitric oxide bioavailability compensated for by increased vasodilatory prostanoid‐mediated vasodilation. Experimental evidence suggests vascular responses to endogenous angiotensin II involve the nitric oxide and prostaglandin pathways. We examined whether selective blockade of angiotensin II influences endothelial tone with particular reference to the nitric oxide/prostaglandin pathways in patients with Type 1 diabetes free from vascular complications.Methods  At baseline, we studied changes in forearm blood flow in response to brachial arterial infusions of acetylcholine, l‐NMMA, a combination of l‐NMMA and the cyclo‐oxygenase inhibitor indomethacin and nitroprusside in 30 patients with normoalbuminuric Type 1 diabetes [21 male, 9 female; age 38.5 ± 1.9 years (mean ± sem)]. Patients were randomized to 2 weeks’ treatment with placebo or the selective angiotensin II receptor blocking agent irbesartan, 300 mg, prior to forearm vasoactive responses being re‐examined.Results  The forearm responses to nitroprusside and acetylcholine were unchanged by both placebo (P = 0.23 and P = 0.36, respectively) and irbesartan (P = 0.41 and P = 0.36). Similarily, dose–response curves to acetylcholine in the presense of l‐NMMA alone (P = 0.42) and a combination of l‐NMMA and indomethacin (P = 0.44) were not altered by angiotensin II blockade.Conclusion  This study demonstrated that physiological blockade of endogenous angiotensin II in Type 1 diabetes does not augment agonist‐evoked vasodilation or the contribution of nitric oxides and prostanoids to endothelial tone.
Diabetes mellitus and impaired glucose regulation in the Canary Islands (Spain): prevalence and associated factors in the adult population of Telde, Gran Canaria1
Authors: Boronat M. , Varillas V. F. , Saavedra P. , Suárez V. , Bosch E. , Carrillo A. , Nóvoa F. J. 
Published: August 2005

AbstractAims  To estimate the prevalence and the determinants of diabetes mellitus and impaired glucose regulation (IGR) in an adult Canarian population.Methods  Cross‐sectional study. One thousand and thirty subjects aged 30–82 years were randomly selected. Participants completed a survey questionnaire and underwent blood pressure measurements, anthropometry, blood samples, and a 75‐g standardized oral glucose tolerance test.Results  The age‐standardized prevalence of diabetes was 15.8% (95% confidence interval: 11.8–19.8) in men and 10.6% (7.1–14.1) in women. Total prevalence was 13.2% (11.1–15.2). Among individuals with diabetes, 55.4% of men and 38.2% of women were not previously diagnosed. The age‐standardized prevalences of impaired glucose tolerance and impaired fasting glycaemia were 11.4% (9.5–13.4) and 2.8% (1.8–3.8), respectively. In multivariate analyses, age, waist circumference, serum triglycerides, and familial history of diabetes were independently associated with diabetes in both sexes, while a value of C‐reactive protein (CRP) ≥ 1 mg/l showed an association with diabetes, but only in men. Age and triglycerides were related to impaired glucose regulation (IGR) in both sexes, waist circumference was related to IGR exclusively in men, and familial diabetes exclusively in women. Statistically significant interactions between gender and both CRP and triglycerides were found with respect to diabetes, and between gender and both waist circumference and triglycerides for IGR.Conclusions  Compared with the rest of Spain, the prevalence of diabetes is moderately increased in this area of the Canary Islands. Along with other well‐established risk factors, CRP was independently associated with diabetes, but only in the male population.
Altered chemokine levels in individuals at risk of Type 1 diabetes mellitus
Authors: Hanifi‐Moghaddam P. , Kappler S. , Seissler J. , Müller‐Scholze S. , Martin S. , Roep B. O. , Strassburger K. , Kolb H. , Schloot N. C. 
Published: August 2005

AbstractAims  The hypothesis was tested in an exploratory study that individuals at high risk of developing Type 1 diabetes mellitus have altered systemic levels of cytokines and chemokines.Subjects and methods  Forty‐two non‐diabetic first‐degree relatives of patients with Type 1 diabetes mellitus were recruited. Of these, 18 had multiple islet autoantibodies (islet cell antibody, glutamic acid decarboxylase antibody, IA‐2 antibody). Follow‐up for 9–11 years confirmed high vs. moderate diabetes risk in islet autoantibody‐positive vs. ‐negative relatives. Cytokines and chemokines were determined by enzyme‐linked immunosorbent assay (ELISA).Results  Serum concentrations of classic Th1‐associated cytokines (IFN‐γ, IL‐12, IL‐18) or Th2/Treg‐associated cytokines (IL‐5, IL‐10, IL‐13) did not significantly differ in high vs. moderate diabetes risk group. However, of six chemokines analysed, levels of CCL3 and CCL4 were increased (P = 0.0442 and P = 0.0334) while CCL2 was decreased (P = 0.0318) in the multiple islet autoantibody‐positive group. No significant differences were seen for CCL5, CCL11, CXCL10. There was a significant correlation between the two closely related chemokines CCL3 and CCL4 in individuals at risk (r = 0.84, P = 0.00005), but not in the autoantibody‐negative group.Conclusion  Relatives at high risk of developing Type 1 diabetes mellitus have abnormal cellular immune regulation at the level of systemic chemokines. The up‐regulation of CCL3 and CCL4 vs. down‐regulation of CCL2 suggests opposed functions of these chemokines in the disease process. These findings need to be confirmed by independent studies.
NONIDENTITY, WRONGFUL CONCEPTION AND HARMLESS WRONGS
Authors: Markie P. J. 
Published: August 2005

AbstractJoel Feinberg and Dan Brock have independently developed a solution to the Problem of Nonidentity as it occurs in cases where a mother's negligent act of conception causes her child to be born with a severe disability. I display three problems in the Feinberg‐Brock proposal and develop an alternative view that explains both cases of wrongful conception and additional instances of the Problem of Nonidentity presented by Derek Parfit and others.
BLOCKING THE PATH FROM VAGUENESS TO FOUR DIMENSIONALISM*
Authors: Miller Kristie 
Published: August 2005

AbstractThere is a general form of an argument which I call the ‘argument from vagueness’ which attempts to show that objects persist by perduring, via the claim that vagueness is never ontological in nature and thus that composition is unrestricted. I argue that even if we grant that vagueness is always the result of semantic indeterminacy rather than ontological vagueness, and thus also grant that composition is unrestricted, it does not follow that objects persist by perduring. Unrestricted mereological composition lacks the power to ensure that there exist instantaneous objects that wholly overlap persisting objects at times, and thus lacks the power to ensure that there exists anything that could be called a temporal part. Even if we grant that such instantaneous objects exist, however, I argue that it does not follow that objects perdure. To show this I briefly outline a coherent version of three dimensionalism that grants just such an assumption. Thus considerations pertaining to the nature of vagueness need not lead us inevitably to accept perdurantism.
Activation of latent cyclin‐dependent kinase 5 (Cdk5)–p35 complexes by membrane dissociation
Authors: Zhu Ying‐Shan , Saito Taro , Asada Akiko , Maekawa Shohei , Hisanaga Shin‐ichi 
Published: August 2005

AbstractCyclin‐dependent kinase 5 (Cdk5) is a Ser/Thr kinase of increasingly recognized importance in a large number of fields, ranging from neuronal migration to synaptic plasticity and neurodegeneration. However, little is known about its mechanism of activation beyond its requirement for binding to p35 or p39. We have examined membrane interactions as one method of regulating the Cdk5–p35 complex. The kinase activity of Cdk5–p35 is low when it is bound to membranes. The Cdk5–p35 found in rat brain extract associates with membranes in two ways. Approximately 75% of complexes associate with membranes via ionic interactions only, and the remaining 25% associate with membranes via ionic interactions together with lipidic interactions. Solubilization with detergent or high‐salt solution activates Cdk5–p35 several fold, and this activation is reversible. Therefore, membrane interactions represent a novel mechanism for the regulation of Cdk5–p35 kinase activity.
Microglia‐specific expression of microsomal prostaglandin E2 synthase‐1 contributes to lipopolysaccharide‐induced prostaglandin E2 production
Authors: Ikeda‐Matsuo Yuri , Ikegaya Yuji , Matsuki Norio , Uematsu Satoshi , Akira Shizuo , Sasaki Yasuharu 
Published: August 2005

AbstractMicrosomal prostaglandin E2 synthase (mPGES)‐1 is an inducible protein recently shown to be an important enzyme in inflammatory prostaglandin E2 (PGE2) production in some peripheral inflammatory lesions. However, in inflammatory sites in the brain, the induction of mPGES‐1 is poorly understood. In this study, we demonstrated the expression of mPGES‐1 in the brain parenchyma in a lipopolysaccharide (LPS)‐induced inflammation model. A local injection of LPS into the rat substantia nigra led to the induction of mPGES‐1 in activated microglia. In neuron‐glial mixed cultures, mPGES‐1 was co‐induced with cyclooxygenase‐2 (COX‐2) specifically in microglia, but not in astrocytes, oligodendrocytes or neurons. In microglia‐enriched cultures, the induction of mPGES‐1, the activity of PGES and the production of PGE2 were preceded by the induction of mPGES‐1 mRNA and almost completely inhibited by the synthetic glucocorticoid dexamethasone. The induction of mPGES‐1 and production of PGE2 were also either attenuated or absent in microglia treated with mPGES‐1 antisense oligonucleotide or microglia from mPGES‐1 knockout (KO) mice, respectively, suggesting the necessity of mPGES‐1 for microglial PGE2 production. These results suggest that the activation of microglia contributes to PGE2 production through the concerted de novo synthesis of mPGES‐1 and COX‐2 at sites of inflammation of the brain parenchyma.
Expression and function of α2‐adrenoceptors in zebrafish: drug effects, mRNA and receptor distributions
Authors: Ruuskanen Jori O. , Peitsaro Nina , Kaslin Jan V. M. , Panula Pertti , Scheinin Mika 
Published: August 2005

AbstractThe α2‐adrenoceptors are G‐protein‐coupled receptors that mediate many of the physiological effects of norepinephrine and epinephrine. Mammals have three subtypes of α2‐adrenoceptors, α2A, α2B and α2C. Zebrafish, a teleost fish used widely as a model organism, has five distinct α2‐adrenoceptor genes. The zebrafish has emerged as a powerful tool to study development and genetics, with many mutations causing diseases reminiscent of human diseases. Three of the zebrafish adra2 genes code for orthologues of the mammalian α2‐adrenoceptors, while two genes code for α2Da‐ and α2Db‐ adrenoceptors, representing a duplicated, fourth α2‐adrenoceptor subtype. The three different mammalian α2‐adrenoceptor subtypes have distinct expression patterns in different organs and tissues, and mediate different physiological functions. The zebrafish α2‐adrenergic system, with five different α2‐adrenoceptors, appears more complicated. In order to deduce the physiological functions of the zebrafish α2‐adrenoceptors, we localized the expression of the five different α2‐adrenoceptor subtypes using RT–PCR, mRNA in situ hybridization, and receptor autoradiography using the radiolabelled α2‐adrenoceptor antagonist [ethyl‐3H]RS‐79948–197. Localization of the α2A‐, α2B‐ and α2C‐adrenoceptors in zebrafish shows marked conservation when compared with mammals. The zebrafish α2A, α2Da, and α2Db each partially follow the distribution pattern of the mammalian α2A: a possible indication of subfunction partitioning between these subtypes. The α2‐adrenergic system is functional in zebrafish also in vivo, as demonstrated by marked locomotor inhibition, similarly to mammals, and lightening of skin colour induced by the specific α2‐adrenoceptor agonist, dexmedetomidine. Both effects were antagonized by the specific α2‐adrenoceptor antagonist atipamezole.
Impairment of blood–cerebrospinal fluid barrier properties by retrovirus‐activated T lymphocytes: reduction in cerebrospinal fluid‐to‐blood efflux of prostaglandin E2
Authors: Khuth Seng Thuon , Strazielle Nathalie , Giraudon Pascale , Belin Marie‐Françoise , Ghersi‐Egea Jean‐François 
Published: August 2005

AbstractThe choroid plexus epithelium forms the interface between the blood and the CSF. In conjunction with the tight junctions restricting the paracellular pathway, polarized specific transport systems in the choroidal epithelium allow a fine regulation of CSF‐borne biologically active mediators. The highly vascularized stroma delimited by the choroidal epithelium can be a reservoir for retrovirus‐infected or activated immune cells. In this work, new insight in the implication of the blood–CSF barrier in neuroinfectious and inflammatory diseases is provided by using a differentiated cellular model of the choroidal epithelium, exposed to infected T lymphocytes. We demonstrate that T cells activated by a retroviral infection, but not non‐infected cells, reduce the transporter‐mediated CSF‐to‐blood efflux of organic anions, in particular that of the potent pro‐inflammatory prostaglandin PGE2, via the release of soluble factors. A moderate alteration of the paracellular permeability also occurs. We identified the viral protein Tax, oxygenated free radicals, matrix‐metalloproteinases and pro‐inflammatory cytokines as active molecules released during the exposure of the epithelium to infected T cells. Among them, tumour necrosis factor and interleukin 1 are directly involved in the mechanism underlying the decrease in some choroidal organic anion efflux. Given the strong involvement of CSF‐borne PGE2 in sickness behaviour syndrome, these data suggest that the blood–CSF barrier plays an important role in the pathophysiology of neuroinflammation and neuroinfection, via changes in the transport processes controlling the CSF biodisposition of PGE2.
Effect of neurosteroids on the retinal gabaergic system and electroretinographic activity in the golden hamster
Authors: Jaliffa Carolina O. , Howard Sarah , Hoijman Esteban , Salido Ezequiel , Sarmiento María I. Keller , Arias Pablo , Rosenstein Ruth E. 
Published: August 2005

AbstractIt has been established that neurosteroids can either inhibit or enhance GABAA receptor activity. Although GABA is the main inhibitory neurotransmitter in the mammalian retina, the effects of neurosteroids on retinal GABAergic activity have not been investigated. The aim of this work was to study the neurochemical and electroretinographic effects of neurosteroids in the golden hamster. On one hand, pregnenolone sulfate inhibited and allotetrahydrodeoxycorticosterone increased GABA‐induced [36Cl]– uptake in neurosynaptosomes. On the other hand, in whole retinas, pregnenolone sulfate increased, whereas allotetrahydrodeoxycorticosterone decreased high potassium‐induced [3H]GABA release. The effect of both neurosteroids on GABA release was Ca2+‐dependent, as in its absence release was not altered. The intravitreal injection of pregnenolone sulfate or vigabatrin (an irreversible inhibitor of GABA degradation) significantly decreased scotopic b‐wave amplitude, whereas the opposite effect was evident when bicuculline or allotetrahydrodeoxycorticosterone were injected. A protein with a molecular weight close to that of hamster adrenal cytochrome P450 side‐chain cleavage (P450scc) was detected in the hamster retina. P450scc‐like immunoreactivity was localized in the inner nuclear and the ganglion cell layers. These results indicate that neurosteroids significantly modulate retinal GABAergic neurotransmission and electroretinographic activity. In addition, the selective localization of P450scc suggests that neurosteroid biosynthesis might occur only in some layers of the hamster retina.