bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type 1 diabetes in Yorkshire, UK: time trends in 0–14 and 15–29‐year‐olds, age at onset and age‐period‐cohort modelling
Authors: Feltbower R. G. , McKinney P. A. , Parslow R. C. , Stephenson C. R. , Bodansky H. J. 
Published: May 2003

AbstractAims To investigate whether the rising incidence of Type 1 diabetes in children is evident in young adults and determine whether age at onset has decreased over time.Methods Two geographically defined datasets from the population‐based Yorkshire Diabetes Register were analysed: (i) 2718 children diagnosed under 15 years with Type 1 diabetes from 1978 to 2000 in Yorkshire; (ii) 631 young adults (15–29 years) diagnosed from 1991 to 1999 in West Yorkshire. Log‐linear regression and age‐period‐cohort modelling evaluated changes in incidence over time and age at onset.Results Incidence rose steadily for 0–14‐year‐olds in Yorkshire with an average annual increase of 2.9%[95% confidence interval (CI) 2.0, 3.8]. In West Yorkshire between 1991 and 1999, the time trends for 0–14 and 15–29‐year‐olds were significantly different (P = 0.014). Stable rates in 15–29‐year‐olds contrasted with an average annual increase of 5.9% (95% CI 2.7, 9.2) for 0–14‐year‐olds. The mean age at onset fell from 9.2 to 8.4 years for 0–14‐year‐olds and from 16.0 to 14.6 years for 0–29‐year‐olds. Age‐period‐cohort modelling showed a statistically significant (P < 0.001) increased risk of developing diabetes was associated with decreasing age for those diagnosed more recently.Conclusions A steady and continuing rise in the incidence of Type 1 diabetes over time is observed for children but not for young adults. In parallel, the age at onset is gradually decreasing and more recent birth cohorts are at increased risk. This overall pattern is consistent with the influence of an environmental agent that is gradually affecting children at younger and younger ages.Diabet. Med. 20, 437–441 (2003)
Adolescent onset Type 2 diabetes in a non‐obese Caucasian patient with an unbalanced translocation
Authors: Owen K. R. , Roland J. , Smith K. , Hattersley A. T. 
Published: May 2003

AbstractBackground Childhood onset Type 2 diabetes in the UK has been reported in obese, insulin‐resistant subjects. Investigation is necessary to exclude other aetiologies including genetic causes. The co‐existence of diabetes and a chromosomal breakpoint may indicate the position of novel diabetes genes.Case report We describe a novel unbalanced translocation between Xq and 10p associated with amenorrhoea and onset of Type 2 diabetes in a non‐obese Caucasian adolescent. There was no evidence of an autoimmune or known genetic aetiology for the diabetes and the phenotype was not typical of youth‐onset Type 2. We therefore hypothesize that the translocation is implicated in the aetiology of the diabetes. This is supported by previous reports of diabetes as a feature of Xq deletions and Turner's syndrome and linkage to the Xq region in a genome‐wide scan for Type 2 genes.Conclusion That this region may harbour a gene predisposing to Type 2 diabetes and that cytogenetic studies may be useful in investigating diabetes in children and young adults.Diabet. Med. 20, 483–485 (2003)
The vitamin D receptor gene variant and physical activity predicts fasting glucose levels in healthy young men
Authors: Ortlepp J. R. , Metrikat J. , Albrecht M. , Von Korff A. , Hanrath P. , Hoffmann R. 
Published: May 2003

AbstractAims Vitamin D can influence lipolysis and insulin secretion. A common genetic polymorphism of the vitamin D receptor (VDR), which has been found to be associated with bone mineral density, has been reported to be also associated with Type 2 diabetes mellitus (DM). To test the influence of the VDR polymorphism on fasting glucose in healthy young men before the onset of Type 2 DM, we studied a homogeneous population of aircrew members.Methods A total of 1539 individuals were recruited during routine medical qualification for flying duty. Physical activity was assessed in all individuals and categorized into low physical activity (≤ 3 h per week) and high physical activity (> 3 h per week). The BsmI VDR polymorphism was analysed by polymerase chain reaction. On the day of blood testing the individuals were fasting for at least 8 h overnight. Serum glucose was measured within 60 min after sampling venous blood.Results In young males with low physical activity (n = 752) gene carriers with the VDR genotype BB (n = 137) have significantly (P < 0.001) higher levels of fasting glucose (5.61 ± 0.49 mmol/l) than gene carriers with the genotype Bb (n = 370; 5.44 ± 0.44 mmol/l) or bb (n = 245; 5.38 ± 0.44 mmol/l). Of BB gene carriers, 47% had fasting glucose levels > 5.55 mmol/l compared with 36% of Bb gene carriers and 34% of bb gene carriers (P = 0.018). This effect is absent in gene carriers with high physical activity (n = 787).Conclusions The VDR genotype is associated with altered fasting glucose levels in young men with low physical activity. If this association is confirmed in other populations it might be worthwhile studying the particular benefits of an exercise programme in dependents of the VDR genotype.Diabet. Med. 20, 451–454 (2003)
Relationship of lipoprotein(a) with intimal medial thickness of the carotid artery in Type 2 diabetic patients in south India
Authors: Velmurugan K. , Deepa R. , Ravikumar R. , Lawrence J. B. , Anshoo H. , Senthilvelmurugan M. , Enas E. A. , Mohan V. 
Published: May 2003

AbstractObjective The objective of this study was to investigate the association of lipoprotein(a) [Lp(a)] levels with intimal medial thickness (IMT) in Type 2 diabetic patients in south India.Study design We studied 587 consecutive Type 2 diabetic patients at the M.V. Diabetes Specialities Centre, Chennai. The mean age of the study group was 55 ± 10 years and 71.2% were males. IMT of the right common carotid artery was determined using high‐resolution B mode ultrasonography. Lp(a) levels were measured using ELISA. Since the frequency distribution of Lp(a) was skewed, Lp(a) values were log transformed and the geometric mean was used for statistical analysis. The tertiles of IMT were determined to analyse the association of Lp(a) and other factors with IMT.Result The mean Lp(a) level in the study patients was 18.9 ± 3.1 mg/dl (geometric mean ± sd) and the mean IMT of the study subjects was 0.93 ± 0.19 mm (mean ± sd). The prevalence of carotid atherosclerosis (defined as IMT > 1.1 mm) among subjects with elevated Lp(a) levels > 20 mg/dl was significantly higher compared with those with Lp(a) levels ≤ 20 mg/dl (26.9% vs. 16.3%, P = 0.003). Lp(a) levels increased with increase in tertiles of IMT (anova, P < 0.05). Pearson correlation analysis of carotid IMT with other cardiovascular risk factors revealed strong correlation of IMT with age (P < 0.0001), duration of diabetes (P < 0.0001), systolic blood pressure (P < 0.0001), diastolic blood pressure (P = 0.006), LDL‐cholesterol (P = 0.023), HbA1c (P = 0.017) and Lp(a) (P < 0.0001). Multiple logistic regression analysis showed age (P = 0.010), LDL‐cholesterol (P = 0.032) and Lp(a) (P = 0.021) to be associated with carotid atherosclerosis.Conclusion The results suggest that Lp(a) has a strong association with IMT of carotid arteries in Type 2 diabetic subjects in south India.Diabet. Med. 20, 455–461 (2003)
Insulin resistance Type A and short 5th metacarpals
Authors: Patel Vinod K. , Davies Huw Alban 
Published: May 2003

AbstractBackground/aims Insulin resistance is associated with a number genetic syndromes and a variety of defects of insulin action.Methods We describe three members of an extended family spanning two generations with insulin resistance Type A and short 5th metacarpals. The proband had secondary amenorrhoea, male pattern hair distribution, acne, hirsutism, deep voice, acanthosis nigricans, polycystic ovaries, diabetes, features of acromegaly, raised creatine kinase and triglyceride levels and short 5th metacarpals. Her growth hormone, adrenal steroid and testosterone levels were normal. The proband's daughter had severe acne, hirsutism, acanthosis nigricans, polycystic ovaries, raised triglyceride, glucose and testosterone level short metacarpals and normal insulin receptor gene. The proband's son had a muscular build, raised creatine kinase, hypertriglyceridaemia and short 5th metacarpals. His fasting insulin levels were normal but pro‐insulin was raised.Result/conclusion There are many familial and genetic syndromes associated with insulin resistance. This family was diagnosed as having insulin resistance Type A. This family does not conform entirely to any of the previously described syndromes and a number of family members have the phenotype of short 5th metacarpals, which appears to be associated with the features of insulin resistance Type A.Diabet. Med. 20, 500–504 (2003)
Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice
Authors: Dedeoglu Alpaslan , Kubilus James K. , Yang Lichuan , Ferrante Kimberly L. , Hersch Steven M. , Beal M. Flint , Ferrante And Robert J. 
Published: June 2003

AbstractWhile there have been enormous strides in the understanding of Huntington's disease (HD) pathogenesis, treatment to slow or prevent disease progression remains elusive. We previously reported that dietary creatine supplementation significantly improves the clinical and neuropathological phenotype in transgenic HD mice lines starting at weaning, before clinical symptoms appear. We now report that creatine administration started after onset of clinical symptoms significantly extends survival in the R6/2 transgenic mouse model of HD. Creatine treatment started at 6, 8, and 10 weeks of age, analogous to early, middle, and late stages of human HD, significantly extended survival at both the 6‐ and 8‐week starting points. Significantly improved motor performance was present in both the 6‐ and 8‐week treatment paradigms, while reduced body weight loss was only observed in creatine‐supplemented R6/2 mice started at 6 weeks. Neuropathological sequelae of gross brain and neuronal atrophy and huntingtin aggregates were delayed in creatine‐treated R6/2 mice started at 6 weeks. We show significantly reduced brain levels of both creatine and ATP in R6/2 mice, consistent with a bioenergetic defect. Oral creatine supplementation significantly increased brain concentrations of creatine and ATP to wild‐type control levels, exerting a neuroprotective effect. These findings have important therapeutic implications, suggesting that creatine therapy initiated after diagnosis may provide significant clinical benefits to HD patients.
Brain edema induced by in vitro ischemia: causal factors and neuroprotection
Authors: MacGregor Duncan G. , Avshalumov Marat V. , Rice Margaret E. 
Published: June 2003

AbstractDecreased cerebral blood flow, hence decreased oxygen and glucose, leads to ischemic brain injury via complex pathophysiological events, including excitotoxicity, mitochondrial dysfunction, increased intracellular Ca2+, and reactive oxygen species (ROS) generation. Each of these could also contribute to cerebral edema, which is the primary cause of patient mortality after stroke. In vitro brain slices are widely used to study ischemia. Here we introduce a slice model to investigate ischemia‐induced edema. Significant water gain was induced in coronal slices of rat brain by 5 min of oxygen and glucose deprivation (OGD) at 35°C, with progressive edema formation after return to normoxic, normoglycemic medium. Edema increased with increasing injury severity, determined by OGD duration (5–30 min). Underlying factors were assessed using glutamate‐receptor antagonists (AP5/CNQX), blockade of mitochondrial permeability transition [cyclosporin A (CsA) versus FK506], inhibition of Na+/Ca2+ exchange (KB‐R7943), and ROS scavengers (ascorbate, Trolox®, dimethylthiourea, Tempol®). All agents except KB‐R7943 and FK506 significantly attenuated edema when applied after OGD; KB‐R7943 was effective when applied before OGD. Significantly, complete prevention of ischemia‐induced edema was achieved with a cocktail of AP5/CNQX, CsA and Tempol® applied after OGD, which demonstrates the involvement of multiple, additive mechanisms. The efficacy of this cocktail further shows the potential value of combination therapies for the treatment of cerebral ischemia.
Dopaminergic neuronal differentiation from rat embryonic neural precursors by Nurr1 overexpression
Authors: Kim Ju‐Yeon , Koh Hyun Chul , Lee Ji‐Yeon , Chang Mi‐Yoon , Kim You‐Chan , Chung Hee‐Yong , Son Hyeon , Lee Yong‐Sung , Studer Lorenz , McKay Ron , Lee Sang‐Hun 
Published: June 2003

AbstractIn vitroexpanded CNS precursors could provide a renewable source of dopamine (DA) neurons for cell therapy in Parkinson's disease. Functional DA neurons have been derived previously from early midbrain precursors. Here we demonstrate the ability of Nurr1, a nuclear orphan receptor essential for midbrain DA neuron developmentin vivo, to induce dopaminergic differentiation in naïve CNS precursorsin vitro. Independent of gestational age or brain region of origin, Nurr1‐induced precursors expressed dopaminergic markers and exhibited depolarization‐evoked DA releasein vitro. However, these cells were less mature and secreted lower levels of DA than those derived from mesencephalic precursors. Transplantation of Nurr1‐induced DA neuron precursors resulted in limited survival andin vivodifferentiation. No behavioral improvement in apomorphine‐induced rotation scores was observed. These results demonstrate that Nurr1 induces dopaminergic features in naïve CNS precursorsin vitro. However, additional factors will be required to achievein vivofunction and to unravel the full potential of neural precursors for cell therapy in Parkinson's disease.
Use of Arc expression as a molecular marker of increased postsynaptic 5‐HT function after SSRI/5‐HT1A receptor antagonist co‐administration
Authors: Castro Elena , Tordera Rosa M. , Hughes Zoe A. , Pei Qi , Sharp Trevor 
Published: June 2003

AbstractAn increase in central postsynaptic 5‐hydroxytryptamine (5‐HT) function activates expression of activity‐related cytoskeletal protein (Arc). Here, Arc expression was used to test whether, in rats, co‐administration of a 5‐HT re‐uptake inhibitor (paroxetine) and a 5‐HT1A receptor antagonist (WAY 100635) increases postsynaptic 5‐HT function. After pre‐treatment with WAY 100635 (0.3 mg/kg s.c.), paroxetine (5 mg/kg s.c.) caused a threefold increase in 5‐HT in prefrontal cortex microdialysates. In situ hybridization studies found that neither paroxetine (5 mg/kg s.c.) nor WAY 1000635 (0.3 mg/kg s.c.) altered Arc mRNA abundance in any region examined. In contrast, paroxetine (5 mg/kg s.c.) increased Arc mRNA after pre‐treatment with WAY 100635 (0.3 mg/kg s.c.). This increase was apparent in cortical regions (frontal, parietal and cingulate) and caudate nucleus but was absent in hippocampus (CA1). Increases in Arc mRNA were accompanied by an increase in c‐fos mRNA. The increase in Arc expression induced by paroxetine/WAY 100635 was abolished by the 5‐HT synthesis inhibitor, p‐chlorophenylalanine (300 mg/kg i.p., daily for two days). In conclusion, paroxetine and WAY 100635 injected in combination (but not alone) caused a region‐specific, 5‐HT‐mediated increase in Arc expression. These data provide molecular evidence that co‐administration of a 5‐HT re‐uptake inhibitor and 5‐HT1A receptor antagonist increases 5‐HT function at the postsynaptic level.
Proteomic identification of nitrated proteins in Alzheimer's disease brain
Authors: Castegna Alessandra , Thongboonkerd Visith , Klein Jon B. , Lynn Bert , Markesbery William R. , Butterfield D. Allan 
Published: June 2003

AbstractNitration of tyrosine in biological conditions represents a pathological event that is associated with several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease (AD). Increased levels of nitrated proteins have been reported in AD brain and CSF, demonstrating the potential involvement of reactive nitrogen species (RNS) in neurodegeneration associated with this disease. Reaction of NO with leads to formation of peroxynitrite ONOO–, which following protonation, generates cytotoxic species that oxidize and nitrate proteins. Several findings suggest an important role of protein nitration in modulating the activity of key enzymes in neurodegenerative disorders, although extensive studies on specific targets of protein nitration in disease are still missing.The present investigation represents a further step in understanding the relationship between oxidative modification of protein and neuronal death in AD. We previously applied a proteomics approach to determine specific targets of protein oxidation in AD brain, by successfully coupling immunochemical detection of protein carbonyls with two‐dimensional polyacrylamide gel electrophoresis and mass spectrometry analysis. In the present study, we extend our investigation of protein oxidative modification in AD brain to targets of protein nitration. The identification of six targets of protein nitration in AD brain provides evidence to the importance of oxidative stress in the progression of this dementing disease and potentially establishes a link between RNS‐related protein modification and neurodegeneration.
Interleukin‐18 induces expression and release of cytokines from murine glial cells: interactions with interleukin‐1β
Authors: Wheeler Rachel D. , Brough David , Le Feuvre Rosalind A. , Takeda Kiyoshi , Iwakura Yoichiro , Luheshi Giamal N. , Rothwell Nancy J. 
Published: June 2003

AbstractInterleukin (IL)‐18, a member of the IL‐1 cytokine family, is an important mediator of peripheral inflammation and host defence responses. IL‐1 is a key proinflammatory cytokine in the brain, but the role of IL‐18 in the CNS is not yet clear. The objective of this study was to investigate the actions of IL‐18 on mouse glial cells. IL‐18 induced intracellular expression of IL‐1α and proIL‐1β, and release of IL‐6 from mixed glia. Treatment of lipopolysaccharide‐primed microglia with adenosine triphosphate (ATP), an endogenous secondary stimulus, induced IL‐1β and IL‐18 release. Although deletion of the IL‐18 gene did not affect IL‐1β expression or release in this experimental paradigm, IL‐1β knockout microglia released significantly less IL‐18 compared to wild‐type microglia. In addition, ATP induced release of mature IL‐1β from IL‐18‐primed microglia. These data suggest that IL‐18 may contribute to inflammatory responses in the brain, and demonstrate that, in spite of several common features, IL‐18 and IL‐1β differ in their regulation and actions.
Functional consequences of homo‐ but not hetero‐oligomerization between transporters for the biogenic amine neurotransmitters
Authors: Kocabas A. M. , Rudnick G. , Kilic F. 
Published: June 2003

AbstractBefore this study, the human norepinephrine transporter (hNET) was the only member of the biogenic amine neurotransmitter transporter family that had not been demonstrated to be a functional homo‐oligomer. Here, using two forms of the transporter, I155C and hNET‐myc, with distinct antigenicity and inhibitor sensitivity, we demonstrated that hNET exists as a homo‐oligomer. hNET I155C is a functional mutant and is sensitive to inactivation by the sulfhydryl reagent [2‐(trimethylammonium)ethyl]methanethiosulfonate, while hNET‐myc is resistant to inactivation by this reagent. Coimmunoprecipitation of these two forms demonstrated that a physical interaction exists between norepinephrine transporter monomers. Further characterization of this physical interaction has revealed that the activity of norepinephrine transporters depends on interactions between monomers. Because norepinephrine transporters and serotonin transporters are the only two members of the neurotransmitter transporter family endogenously expressed in the cell membrane of the same cells, placental syncytiotrophoblasts, we tested the ability of norepinephrine transporters and serotonin transporters to associate and function in a hetero‐oligomeric form. Similarly, coexpression of hNET‐myc with serotonin transporter‐FLAG showed a physical interaction in coimmunoprecipitation assays. However, coexpression of serotonin and norepinephrine transporters did not sensitize norepinephrine transporter activity to inhibition by citalopram, a selective serotonin transport inhibitor. Thus, the norepinephrine transporter–serotonin transporter physical association did not produce functional consequences. Based on this, we propose that the transporters for biogenic amine neurotransmitters interact functionally in homo‐ but not hetero‐oligomeric forms.
Two serine residues distinctly regulate the rescue function of Humanin, an inhibiting factor of Alzheimer's disease‐related neurotoxicity: functional potentiation by isomerization and dimerization
Authors: Terashita Kenzo , Hashimoto Yuichi , Niikura Takako , Tajima Hirohisa , Yamagishi Yohichi , Ishizaka Miho , Kawasumi Masaoki , Chiba Tomohiro , Kanekura Kohsuke , Yamada Marina , Nawa Mikiro , Kita Yoshiko , Aiso Sadakazu , Nishimoto Ikuo 
Published: June 2003

AbstractThe 24‐residue peptide Humanin (HN), containing two Ser residues at positions 7 and 14, protects neuronal cells from insults of various Alzheimer's disease (AD) genes and Aβ. It was not known why the rescue function of (S14G)HN is more potent than HN by two to three orders of magnitude. Investigating the possibility that the post‐translational modification of Ser14 might play a role, we found that HN with d‐Ser at position 14 exerts neuroprotection more potently than HN by two to three orders of magnitude, whereas d‐Ser7 substitution does not affect the rescue function of HN. On the other hand, S7A substitution nullified the HN function. Multiple series of experiments indicated that Ser7 is necessary for self‐dimerization of HN, which is essential for neuroprotection by this factor. These findings indicate that the rescue function of HN is quantitatively modulated by d‐isomerization of Ser14 and Ser7‐relevant dimerization, allowing for the construction of a very potent HN derivative that was fully neuroprotective at 10 pm against 25 µm Aβ1–43. This study provides important clues to the understanding of the neuroprotective mechanism of HN, as well as to the development of novel AD therapeutics.
Cystatin C colocalizes with amyloid‐β and coimmunoprecipitates with amyloid‐β precursor protein in sporadic inclusion‐body myositis muscles
Authors: Vattemi Gaetano , King Engel W. , McFerrin Janis , Askanas Valerie 
Published: June 2003

AbstractCystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated within amyloid‐β (Aβ) amyloid deposits in Alzheimer's disease (AD) brain and was proposed to play a role in the AD pathogenesis. Because the chemo‐morphologic muscle phenotype of sporadic inclusion‐body myositis (s‐IBM) has several similarities with the phenotype of AD brain, including abnormal accumulation of Aβ deposits, we studied expression and localization of CC in muscle biopsies of 10 s‐IBM, and 16 disease‐ and five normal‐control muscle biopsies. Physical interaction of CC with amyloid‐β precursor protein (AβPP) was studied by a combined immunoprecipitation/immunoblotting technique in the s‐IBM muscle biopsies and in AβPP‐overexpressing cultured human muscle fibers. In all s‐IBM muscle biopsies, CC‐immunoreactivity either colocalized with, or was adjacent to, the Aβ‐immunoreactive inclusions in 80–90% of the vacuolated muscle fibers, mostly in non‐vacuolated regions of their cytoplasm. Ultrastructurally, CC immunoreactivity‐colocalized with Aβ on 6–10 nm amyloid‐like fibrils and floccular material. By immunoblotting, CC expression was strongly increased in IBM muscle as compared to the controls. By immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with AβPP, both in s‐IBM muscle and in AβPP‐overexpressing cultured normal human muscle fibers. Our studies (i) demonstrate for the first time that CC physically associates with AβPP, and (ii) suggest that CC may play a novel role in the s‐IBM pathogenesis, possibly by influencing AβPP processing and Aβ deposition.