bluuebunny/crossref_metadata_2025 huggingface dataset:
Amyloid Precursor Protein and Presenilin Involvement in Cell Signaling
Authors: Venezia Valentina , Nizzari Mario , Carlo Pia , Corsaro Alessandro , Florio Tullio , Russo Claudio
Published: June 2007

To date the most relevant role for the amyloid precursor protein (APP) and for the presenilins (PSs) on Alzheimer’s disease (AD) genesis is linked to the ‘amyloid hypothesis’, which considers an aberrant formation of amyloid-β peptides the cause of neurodegeneration. In this view, APP is merely a substrate, cleaved by the γ-secretase complex to form toxic amyloid peptides, PSs are key players in γ-secretase complex, and corollary or secondary events are Tau-linked pathology and gliosis. A second theory, complementary to the amyloid hypothesis, proposes that APP and PSs may modulate a yet unclear cell signal, the disruption of which may induce cell-cycle abnormalities, neuronal death, eventually amyloid formation and finally dementia. This hypothesis is supported by the presence of a complex network of proteins, with a clear relevance for signal transduction mechanisms, which interact with APP or PSs. In this scenario, the C-terminal domain of APP has a pivotal role due to the presence of the 682YENPTY687 motif that represents the docking site for multiple interacting proteins involved in cell signaling. In this review we discuss the significance of novel findings related to cell signaling events modulated by APP and PSs for AD development.
Development of a Novel Yeast Cell-Based System for Studying the Aggregation of Alzheimer’s Disease-Associated Aβ Peptides in vivo
Authors: von der Haar Tobias , Jossé Lyne , Wright Paul , Zenthon Jo , Tuite Mick F.
Published: June 2007

Alzheimer’s disease is the most common neurodegenerative disease, affecting ∼50% of humans by age 85. The disease process is associated with aggregation of the Aβ peptides, short 39–43 residue peptides generated through endoproteolytic cleavage of the Alzheimer’s precursor protein. While the process of aggregation of purified Aβ peptides in vitro is beginning to be well understood, little is known about this process in vivo. In the present study, we use the yeast Saccharomyces cerevisiae as a model system for studying Aβ-mediated aggregation in an organism in vivo. One ofthis yeast’s endogenous prions, Sup35/[PSI+], loses the ability to aggregate when the prion-forming domain of this protein is deleted. We show that insertion of Aβ peptide sequences in place of the original prion domain of this protein restores its ability to aggregate. However, the aggregates are qualitatively different from [PSI+] prions in their sensitivity to detergents and in their requirements on trans-acting factors that are normally needed for [PSI+] propagation. We conclude that we have established a useful new tool for studying the aggregation of Aβ peptides in an organism in vivo.
Novel Processing of Notch 1 within Its Intracellular Domain by a Cysteine Protease
Authors: Fassa Angeliki , Parisiadou Loukia , Robakis Nikolaos K. , Efthimiopoulos Spiros
Published: June 2007

In order to study N1 processing, we expressed human N1 (hN1) in HEK293 cells (293-hN1). Following Western blot analysis of 293-hN1 extracts, we detected, in addition to full-length hN1 and the N1 extracellular domain truncated form (N1-TM), a novel extracellular domain truncated form of hN1 with a COOH-terminal deletion, designated hN1-TMΔCT. Treatment of cells with the γ-secretase inhibitor L-685,458 resulted in an accumulation of hN1-TMΔCT suggesting that this fragment is a γ-secretase substrate. To identify the proteolytic activity(ies) that generates hN1-TMΔCT, we treated 293-hN1 cells with inhibitors of proteasome, calpains, caspases, serine and cysteine proteases. Despite the presence of a caspase-3 cleavage site within hN1 intracellular domain, none of the caspase inhibitors inhibited hN1-TMΔCT production. The proteasomal inhibitors used had also no effect. Incubation of cells with the cysteine protease inhibitor E64d resulted in the accumulation of hN1-TM and the inhibition of hN1-TMΔCT production suggesting a precursor-product relationship and that a cysteine protease is involved. Similarly, treatment of cells expressing amyloid precursor protein or E-cadherin with E-64d resulted in the accumulation of COOH-terminal fragments suggesting that these proteins are also processed within their intracellular domain by a cysteine protease. Processing towards hN1-TMΔCT requires maturation and transport of hN1 to the cell surface since treatment with brefeldin A inhibited its production and resulted in accumulation of hN1. Processing of hN1 within its intracellular domain could generate fragments that can exert novel functions and/or interfere with the function of hN1 intracellular domain.
Study on the Putative Contribution of Caspases and the Proteasome to the Degradation of Aph-1a and Pen-2
Authors: Dunys Julie , Kawarai Toshitaka , Giaime Emilie , Wilk Sherwin , Herrant M. , Auberger P. , St. George-Hyslop Peter , Alves da Costa Cristine , Checler Frédéric
Published: June 2007

The presenilin-dependent γ-secretase complex is mainly composed of four distinct proteins, namely presenilin 1 or presenilin 2, nicastrin, anterior pharynx defective-1 (Aph-1) and presenilin enhancer (Pen-2). The mechanisms by which the complex is assembled, how its stochiometry is controlled and how its catalytic activity is regulated are poorly understood. Recent studies indicated that Aph-1 and Pen-2 undergo proteolysis by the proteasome. We have examined the susceptibility of endogenous and overexpressed Aph-1a and Pen-2 to proteolysis by endogenous and purified proteasome as well as by recombinant caspases. We show that endogenous Aph-1a and Pen-2 resist proteolysis by caspases and by the proteasome. Furthermore, we show that unexpected interference of proteasome inhibitors with the cmv promoter region driving expression of Aph-1a and Pen-2 led to artifactual enhancement of overexpressed Aph-1a and Pen-2-like immunoreactivities but that these proteins also resist to in vitro degradation by endogenous and purified proteasome.
Differential Modulation of Neurite Growth by the S- and the L-Forms of bag1, a Co-Chaperone of Hsp70
Authors: Frebel Karin , Wiese Stefan , Funk Natalja , Pühringer Dirk , Sendtner Michael
Published: June 2007

Bag1 acts as a cochaperone for Hsp70. However, it also binds to members of the RAF family and to Akt. In addition, bag1 and Hsp70 are part of a complex with glucocorticoid receptors and thus modulate glucocorticoid receptor-mediated transcriptional activation. In the developing nervous system, bag1 is expressed in at least two isoforms. The L-form (bag1L) contains a nuclear localization signal and thus can translocate to the nucleus. In contrast, the S-form (bag1S) is localized exclusively in the cytoplasm. Former studies have shown that B-RAF is essential for neurotrophin-mediated survival signaling in motoneurons and sensory neurons, and that bag1 plays a role in coordinating B-RAF and Akt function in this context. In the absence of B-RAF, embryonic motoneurons and sensory neurons are not able to survive, indicating that bag1 and B-RAF are essential mediators for neuronal survival in response to neurotrophic factors during development. However, the role of the complex containing bag1, Hsp70 and B-RAF in mediating neurite growth in response to neurotrophic factors remained unclear. We have therefore studied the effect of bag1 overexpression in rat phaeochromocytoma (PC12) cells. Upon NGF treatment, proliferating PC12 become postmitotic and grow out neuronal processes. Bag1S overexpression interferes with neurite extension in PC12 cells. In contrast, bag1L does not disturb neurite outgrowth. Interaction of bag1S with Hsp70 appears necessary for this effect. These data indicate that the cytosolic form of bag1 participates in neurotrophin-mediated neurite growth, and that interaction with Hsp70 plays a crucial role in this context.
Pathway Proteomics and Chemical Proteomics Team Up in Drug Discovery
Authors: Hopf Carsten , Bantscheff Marcus , Drewes Gerard
Published: June 2007

Over the last 5 years, impressive technical advances in mass spectrometry-based analysis of proteins have enabled the parallel analysis of subproteomes and entire proteomes, thus triggering the departure from the traditional single gene-single protein – single target paradigm. Today, immunoaffinity chromatography as well as generic purification methods employing engineered composite affinity tags make streamlined identification of protein complexes as molecular machines possible. In addition, use of stable isotope techniques in protein mass spectrometry allows for the characterization of protein complex composition and posttranslational modifications in an increasingly quantitative fashion. Together, these methodologies allow the elucidation of medically relevant biological pathways, and the study of the interaction of their protein components with therapeutic agents, on a much larger scale. The present review discusses some of the current experimental strategies, with a focus on applications in neurobiology.
Nitric Oxide Synthase and NADPH Diaphorase Distribution in the Bullfrog (Rana catesbeiana) CNS: Pathways and Functional Implications
Authors: Huynh Phuong , Boyd Sunny K.
Published: June 2007

The gas nitric oxide (NO) is emerging as an important regulator of normal physiology and pathophysiology in the central nervous system (CNS). The distribution of cells releasing NO is poorly understood in non-mammalian vertebrates. Nitric oxide synthase immunocytochemistry (NOS ICC) was thus used to identify neuronal cells that contain the enzyme required for NO production in the amphibian brain and spinal cord. NADPH-diaphorase (NADPHd) histochemistry was also used because the presence of NADPHd serves as a reliable indicator of nitrergic cells. Both techniques revealed stained cells in all major structures and pathways in the bullfrog brain. Staining was identified in the olfactory glomeruli, pallium and subpallium of the telencephalon; epithalamus, thalamus, preoptic area, and hypothalamus of the diencephalon; pretectal area, optic tectum, torus semicircularis, and tegmentum of the mesencephalon; all layers of the cerebellum; reticular formation; nucleus of the solitary tract, octaval nuclei, and dorsal column nuclei of the medulla; and dorsal and motor fields of the spinal cord. In general, NADPHd histochemistry provided better staining quality, especially in subpallial regions, although NOS ICC tended to detect more cells in the olfactory bulb, pallium, ventromedial thalamus, and cerebellar Purkinje cell layer. NOS ICC was also more sensitive for motor neurons and consistently labeled them in the vagus nucleus and along the length of the rostral spinal cord. Thus, nitrergic cells were ubiquitously distributed throughout the bullfrog brain and likely serve an essential regulatory function.
Differences in Neurogenesis Differentiate between Core and Shell Regions of Auditory Nuclei in the Turtle (Pelodiscus sinensis): Evolutionary Implications
Authors: Zeng Shao-Ju , Xi Chao , Zhang Xin-Wen , Zuo Ming-Xue
Published: June 2007

There is a clear core-versus-shell distinction in cytoarchitecture, electrophysiological properties and neural connections in the mesencephalic and diencephalic auditory nuclei of amniotes. Determining whether the embryogenesis of auditory nuclei shows a similar organization is helpful for further understanding the constituent organization and evolution of auditory nuclei. Therefore in the present study, we injected [3H]-thymidine into turtle embryos (Pelodiscus sinensis) at various stages of development. Upon hatching, [3H]-thymidine labeling was examined in both the core and shell auditory regions in the midbrain, diencephalon and dorsal ventricular ridge. Met-enkephalin and substance P immunohistochemistry was used to distinguish the core and shell regions. In the mesencephalic auditory nucleus, the occurrence of heavily labeled neurons in the nucleus centralis of the torus semicircularis reached its peak at embryonic day 9, one day later than the surrounding shell. In the diencephalic auditory nucleus, the production of heavily labeled neurons in the central region of the reuniens (Re) was highest at embryonic day (E) 8, one day later than that in the shell region of reuniens. In the region of the dorsal ventricular ridge that received inputs from the central region of Re, the appearance of heavily labeled neurons also reached a peak one day later than that in the area receiving inputs from the shell region of reuniens. Thus, there is a core-versus-shell organization of neuronal generation in reptilian auditory areas.
Acute Renal Failure, Translocational Hyponatremia and Hyperkalemia following Intravenous Immunoglobulin Therapy
Authors: Daphnis Eugene , Stylianou Kostas , Alexandrakis Michael , Xylouri Irene , Vardaki Eleftheria , Stratigis Spyros , Kyriazis John
Published: June 2007

Background/Aims: Intravenous immunoglobulin (IVIG) therapy has been associated with renal adverse effects and electrolyte disturbances. Methods: We retrospectively evaluated a cohort of 66 unselected patients with idiopathic thrombocytopenic purpura, who received 140 courses of IVIG therapy. Acute renal failure (ARF), hyponatremia and hyperkalemia, as potential complications of IVIG therapy, were assessed from 100 IVIG courses with sufficient data for analysis. Results: Thirteen out of 100 (13%) IVIG courses in 10 (15%) patients were complicated with ARF. Risk factors included advanced age, pre-existing renal impairment, use of diuretics and the presence of diabetes mellitus. All patients recovered renal function 1–2 weeks after IVIG infusion. Serum sodium (sNa) fell by 5.7 and 2.7 mmol/l (p < 0.01) in patients with and without ARF, respectively. Correspondingly, serum potassium increased by 0.7 and 0.23 mmol/l (p < 0.01). There was a strong inverse correlation (r = –0.308; p < 0.01) between changes in sNa and creatinine. Changes in serum potassium could be independently predicted by changes in both sNa and creatinine (R2 = 0.11; p < 0.01). These data suggested that both hyponatremia and hyperkalemia were (a) due to the translocational effect of the osmotic load of sucrose, and (b) largely depended on the extent of IVIG nephropathy. Conclusion: In our series, ARF attributable to IVIG therapy, although not rare, was usually mild and fully reversible. High-risk patients were more susceptible to IVIG-related renal complications. Translocational hyponatremia and hyperkalemia following IVIG therapy, although unimportant in patients with normal renal function, may be of clinical significance in patients with severely compromised renal function, resulting in impaired sucrose excretion.
Messenger RNA Expression of Podocyte-Associated Molecules in the Urinary Sediment of Patients with Diabetic Nephropathy
Authors: Wang Gang , Lai Fernand Mac-Moune , Lai Ka-Bik , Chow Kai-Ming , Li Kam-Tao Philip , Szeto Cheuk-Chun
Published: June 2007

Background: Podocyte loss plays an important role in the pathogenesis of diabetic nephropathy. We hypothesize that messenger RNA expression of podocyte-associated molecules in urinary sediment may provide important clinical information in patients with diabetic nephropathy. Method: We studied 21 patients with biopsy-proven diabetic nephropathy and 9 healthy controls. The mRNA expression of nephrin, podocin, synaptopodin, Wilms’ tumor-1 (WT-1) and α-actinin-4 in urinary sediment were measured by real-time quantitative polymerase chain reaction. The degree of histological damage was quantified by morphometric analysis. Patients were then followed for an average of 25.63 ± 10.76 months. The rate of glomerular filtration rate (GFR) decline was calculated by the least-square regression. Results: There were significant differences in nephrin, podocin, synaptopodin, α-actinin-4 (p < 0.01 for all comparisons) and WT-1 (p = 0.028) expression between patients and normal controls. Urinary nephrin expression was significantly correlated with proteinuria (r = 0.502, p = 0.020); urinary synaptopodin was significantly correlated with proteinuria (r = 0.585, p = 0.005), serum creatinine (r = 0.516, p = 0.017) and estimated GFR (r = –0.560, p = 0.008), and urinary WT-1 expression was significantly correlated with the degree of tubulointerstitial fibrosis (r = 0.558, p = 0.009). There was no significant correlation between GFR decline and urinary expression of target genes. Conclusion: Urinary mRNA expressions of nephrin, podocin, synaptopodin, WT-1 and α-actinin-4 are higher in patients with diabetic nephropathy than in normal controls. Urinary nephrin and synaptopodin expressions are correlated with baseline clinical parameters such as proteinuria or renal function, while WT-1 expression is related to the degree of histological damage. Our results suggest that urinary mRNA expression of podocyte-associated molecules may be used for risk stratification of diabetic nephropathy.
Improvement in Central Arterial Pressure Waveform during Hemodialysis Is Related to a Reduction in Asymmetric Dimethylarginine (ADMA) Levels
Authors: Soveri Inga , Lind Lars , Wikström Björn , Zilmer Mihkel , Zilmer Kersti , Fellström Bengt
Published: June 2007

Background: Cardiovascular mortality is high in hemodialysis (HD) patients. Early arterial pressure wave reflections, reflecting arterial stiffness and the endogenous nitric oxide synthesis inhibitor asymmetric dimethylarginine (ADMA) levels predict mortality in HD patients. Therefore, we aimed to study changes in ADMA levels and central arterial pressure waveform during HD. Methods: Thirty-two chronic HD patients were studied before and after a HD session. In a subset of 22 patients without arrhythmias, pulse wave analysis was performed on radial artery (SphygmoCor). Augmentation index (AIx), defined as difference between the second and first systolic peak divided by central pulse pressure, was used as a measure of arterial stiffness. ADMA was measured in plasma with the ELISA technique. Homocysteine was measured in plasma using the EIA technique. Results: HD reduced both AIx (19%; p = 0.003) and ADMA levels (17%; p < 0.001). The magnitudes of changes in AIx and ADMA during HD were correlated (r = 0.44; p = 0.045). Mean arterial pressure change was not significant. HD reduced homocysteine levels, but homocysteine was not related to ADMA or AIx. Conclusion: The reduction in ADMA level seen after HD was associated with improvement in the central arterial pressure waveform, suggesting involvement of nitric oxide in the regulation of arterial stiffness in HD patients.
Costs Associated with Erythropoiesis-Stimulating Agent Administration to Hemodialysis Patients
Authors: Churchill David N. , Macarios David , Attard Cheryl , Kallich Joel , Goeree Ron
Published: June 2007

Background: Treatment of anemia in hemodialysis patients usually requires the use of expensive erythropoietic proteins. Cost analyses usually focus on drug acquisition costs. Other costs associated with anemia therapy include resources for anemia monitoring as well as preparation and administration of an erythropoiesis-stimulating agent. Methods: The nonacquisition costs associated with subcutaneous administration of epoetin alfa were determined in a Canadian hemodialysis unit. A time-and-motion technique was used to determine the nursing time for preparation and administration. Fixed anemia costs were inventory control, monitoring, blood sampling, and laboratory analysis. Variable costs were those which varied with dosing frequency. The costs are expressed in Canadian dollars (2005). Results: The mean time associated with preparation and administration was 3.2 min/injection. The annual nonacquisition per patient cost was CAD 2,290.04. Fixed costs were CAD 1,946.01, while the variable costs were CAD 344.03/year. Sensitivity analysis showed a decrease in cost to CAD 1,611.34, if iron monitoring were decreased from monthly to 3 monthly, and to CAD 2,090.66, if patients were converted to less frequent dosing using darbepoetin alfa. Conclusions: The nonacquisition costs associated with anemia therapy in hemodialysis patients are considerable. Less frequent monitoring of iron therapy and less frequent dosing could decrease costs by CAD 678.40 and CAD 199.38/patient/year, respectively.
Anatomical and Functional Results of Endotamponade with Heavy Silicone Oil – Densiron® 68 – in Complicated Retinal Detachment
Authors: Herbrig Erdmuth , Sandner Dirk , Engelmann Katrin
Published: June 2007

Background: High-density silicone oils are newly developed long-term tamponade agents for the treatment of complicated retinal detachment in the inferior retina. Previous studies describe satisfying anatomical and functional results. In this study we examined the largest cohort so far for a 9-month follow-up and performed a comparison to conventional silicone oil. Methods: Our study documents results and adverse effects after vitreoretinal surgery and endotamponade with Densiron® 68 in 99 cases of complicated retinal detachment. A 9-month follow-up was performed. Data of 21 patients with intraocular conventional silicone oil tamponade in complicated retinal detachment were retrospectively analyzed and served as control. Results: Anatomical success was achieved in 78 of 89 eyes (87.6%) with completed follow-up; visual acuity did not change significantly (from mean preoperative logMAR 1.88 to postoperative logMAR 1.96 (p = 0.9). Compared to control a higher anatomical success but a similar number of adverse effects were observed with heavy silicone oil in vitreous. Nevertheless, patients who received Densiron 68 twice due to redetachment showed a significantly higher rate of intraocular inflammation with the tamponade agent in situ. Conclusion: Our results support the hypothesis of Densiron 68 as potent tamponade agent for complicated retinal detachment in the inferior retinal segments especially in eyes where a previous operation failed.
Comparative Study on Efficacy of a Combination Therapy of Triamcinolone Acetonide Administration with and without Vitrectomy for Macular Edema Associated with Branch Retinal Vein Occlusion
Authors: Hirano Yoshio , Sakurai Eiji , Yoshida Munenori , Ogura Yuichiro
Published: June 2007

Aims: To compare the efficacy ofa combination therapy of triamcinolone acetonide (TA) administration with and without vitrectomy in eyes with macular edema associated with branch retinal vein occlusion over a 1-year period. Methods: A retrospective, case-control study was conducted in 15 eyes of 15 patients with macular edema associated with branch retinal vein occlusion. Eight eyes underwent simultaneous intravitreal and posterior sub-Tenon capsule injections of TA (TA-injected group). Seven eyes underwent vitrectomy with intravitreal or simultaneous posterior sub-Tenon capsule injection of TA (vitrectomy with TA group). Macular thickness and visual acuity were measured before and at 1, 3, 6 and 12 months after the therapy. Results: Twelve months after the therapy, mean visual acuity improved significantly from baseline in both the TA-injected (p = 0.0069) and vitrectomy with TA groups (p = 0.0145). Macular thickness also improved significantly in both the TA-injected (p = 0.0065) and vitrectomy with TA groups (p = 0.0058). At 12 months after the therapy, there was no significant difference in visual acuity and macular thickness between the two groups (p = 0.3308 and 0.3711, respectively). At the early postoperative stage (1 and 3 months after the therapy), the central macular thickness in the TA-injected group was significantly less than that in the vitrectomy with TA group (p = 0.0140 and 0.0275, respectively); there was no significant difference in visual acuity between the two groups (p = 0.0796 and 0.3753, respectively). Conclusion: TA injection without vitrectomy was as effective as a combination therapy of TA injection with vitrectomy.
Dysplasia and Cancer in Inflammatory Bowel Disease 10 Years after Diagnosis: Results of a Population-Based European Collaborative Follow-Up Study
Authors: Katsanos K.H. , Vermeire S. , Christodoulou D.K. , Riis L. , Wolters F. , Odes S. , Freitas J. , Hoie Ole , Beltrami Marina , Fornaciari G. , Clofent J. , Bodini P. , Vatn M. , Nunes Paula Borralho , Moum B. , Munkholm P. , Limonard C. , Stockbrugger R. , Rutgeerts P. , Tsianos E.V.
Published: June 2007

Objective: To determine dysplasia and cancer in the 1991–2004 European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort. Patients and Methods: A patient questionnaire and a physician per patient form were completed for each of the 1,141 inflammatory bowel disease patients (776 ulcerative colitis/365 Crohn’s disease) from 9 centers (7 countries) derived from the EC-IBD cohort. Rates of detection of intestinal cancer and dysplasia as well as extra-intestinal neoplasms were computed. Results: Patient follow-up time was 10.3 ± 0.8 (range 9.4–11) years. The mean age of the whole group of IBD patients was 37.8 ± 11.3 (range 16–76) years. Thirty-eight patients (3.3%; 26 with ulcerative colitis/12 with Crohn’s disease, 21 males/17 females, aged 61.3 ± 13.4, range 33–77 years), were diagnosed with 42 cancers. Cancers occurred 5.4 ± 3.3 (range 0–11) years after inflammatory bowel disease diagnosis. Colorectal cancer was diagnosed in 8 (1 Crohn’s disease and 7 ulcerative colitis patients – 0.3 and 0.9% of the Crohn’s disease and ulcerative colitis cohort, respectively) of 38 patients and 30 cancers were extra-intestinal. Four of 38 patients (10.5%) were diagnosed as having 2 cancers and they were younger compared to patients with one cancer (p = 0.0008). There was a trend for a higher prevalence of intestinal cancer in the northern centers (0.9%) compared to southern centers (0.3%, p = NS). Southern centers had more cases of extra-intestinal cancer compared to northern centers (2 vs. 3.8%, p = 0.08). Ten patients (0.9%; 8 with ulcerative colitis/2 with Crohn’s disease, 8 males, aged 62.3 ± 14.1 years) had colorectal dysplasia. Conclusions: In the first decade of the EC-IBD Study Group cohort follow-up study, the prevalence of cancer was as expected with most patients having a single neoplasm and an extra-intestinal neoplasm. In northern centers there was a trend for more intestinal cancers, while in southern centers there was a trend for more extra-intestinal cancers compared to northern centers.
Caspase-7, Fas and FasL in Long-Term Renal Ischaemia/Reperfusion and Immunosuppressive Injuries in Rats
Authors: Yang Bin , Harris Kevin P.G. , Jain Sunjay , Nicholson Michael L.
Published: June 2007

Background/Aims: Ischaemia/reperfusion (I/R) injury is important in kidney transplantation. We have previously demonstrated that long-term I/R injury and immunosuppression affect apoptosis and inflammation, but the underlying mechanisms are far from clear. In this study, the involvement of caspase-7, Fas and FasL was further investigated. Methods: The right renal pedicle was clamped for 45 min followed by left nephrectomy in 40 rats. Cyclosporine (CsA), tacrolimus (Tac), rapamycin (Rap) or mycophenolate mofetil (MMF) were administered daily for 16 weeks. Caspase-7, Fas and FasL expression, and their correlations with caspase-3, apoptosis, inflammation, renal structure and function were evaluated. Results: Active caspase-7 was significantly increased in I/R and CsA-treated kidneys and decreased by Tac, Rap and MMF, while the caspase-7 precursor was enhanced by Rap. Active caspase-7-stained cells were scattered throughout the tubulointerstitium and often had apoptotic features. Fas, but not FasL, was increased in I/R and CsA-treated kidneys and decreased by Rap and MMF. Fas and FasL proteins were mainly located in dilated tubules. There were close correlations among caspase-7, Fas, caspase-3, apoptosis, inflammation, renal structure and function. Conclusion: Caspase-7, associated with caspase-3, apoptosis and inflammation, might be involved in long-term I/R and immunosuppressive injury, at least in part through the Fas-signalling pathway.
Studies of Otic Capsule Morphology and Gene Expression in the Mov13 Mouse – An Animal Model of Type I Osteogenesis Imperfecta
Authors: Stankovic Konstantina M. , Kristiansen Arthur G. , Bizaki Argyro , Lister Matthew , Adams Joe C. , McKenna Michael J.
Published: June 2007

Type I osteogenesis imperfecta (OI) is a disorder of skeletal bones characterized by bone fragility and blue sclera, which can result from mutations in genes encoding for type I collagen – the COL1A1 and COL1A2 genes. Fifty percent of patients with type I OI develop hearing loss and associated histopathological changes in the otic capsule that are indistinguishable from otosclerosis, a major cause of acquired hearing loss. In an attempt to elucidate molecular and cellular mechanisms of hearing loss in type I OI, we have studied the Mov13 mouse, which has served as an animal model of type I OI by virtue of exhibiting variable transcriptional block of the COL1A1 gene. We studied the morphometry of the Mov13 otic capsule and compared expression levels of 60 genes in the otic capsule with those in the tibia and parietal bone of the Mov13 and wild-type mice. The degree of transcriptional block of the COL1A1 gene and its downstream effects differed significantly between the bones examined. We found that expression levels of bone morphogenetic protein 3 and nuclear factor ĸ-B1 best distinguished Mov13 otic capsule from wild-type otic capsule, and that osteoprotegerin, caspase recruitment domain containing protein 1, and partitioning defective protein 3 best distinguished Mov13 otic capsule from Mov13 tibia and parietal bone. Although the Mov13 mouse did not demonstrate evidence of active abnormal otic capsule remodeling as seen in type I OI and otosclerosis, studying gene expression in the Mov13 mouse has provided evidence that osteocytes of the otic capsule differ from osteocytes in other bones.
Regional Parameter Estimation of the VIC Land Surface Model: Methodology and Application to River Basins in China
Authors: Xie Zhenghui , Yuan Fei , Duan Qingyun , Zheng Jing , Liang Miaoling , Chen Feng
Published: June 2007

This paper presents a methodology for regional parameter estimation of the three-layer Variable Infiltration Capacity (VIC-3L) land surface model with the goal of improving the streamflow simulation for river basins in China. This methodology is designed to obtain model parameter estimates from a limited number of calibrated basins and then regionalize them to uncalibrated basins based on climate characteristics and large river basin domains, and ultimately to continental China. Fourteen basins from different climatic zones and large river basins were chosen for model calibration. For each of these basins, seven runoff-related model parameters were calibrated using a systematic manual calibration approach. These calibrated parameters were then transferred within the climate and large river basin zones or climatic zones to the uncalibrated basins. To test the efficiency of the parameter regionalization method, a verification study was conducted on 19 independent river basins in China. Overall, the regionalized parameters, when evaluated against the a priori parameter estimates, were able to reduce the model bias by 0.4%–249.8% and relative root-mean-squared error by 0.2%–119.1% and increase the Nash–Sutcliffe efficiency of the streamflow simulation by 1.9%–31.7% for most of the tested basins. The transferred parameters were then used to perform a hydrological simulation over all of China so as to test the applicability of the regionalized parameters on a continental scale. The continental simulation results agree well with the observations at regional scales, indicating that the tested regionalization method is a promising scheme for parameter estimation for ungauged basins in China.
Spatial Interpolation of Daily Potential Evapotranspiration for New Zealand Using a Spline Model
Authors: Tait Andrew , Woods Ross
Published: June 2007

Potential evapotranspiration (PET) is an important component of water balance calculations, and these calculations form an equally important role in applications such as irrigation scheduling, pasture productivity forecasts, and groundwater recharge and streamflow modeling. This paper describes a method of interpolating daily PET data calculated at climate stations throughout New Zealand onto a regular 0.05° latitude–longitude grid using a thin-plate smoothing spline model. Maximum use is made of observational data by combining both Penman and Priestley–Taylor PET calculations and raised pan evaporation measurements. An analysis of the interpolation error using 20 validation sites shows that the average root-mean-square error varies between about 1 mm in the summer months to about 0.4 mm in winter. It is advised that interpolated data for areas above 500-m elevation should be used with caution, however, due to the paucity of input data from high-elevation sites.
Evaluation of PERSIANN-CCS Rainfall Measurement Using the NAME Event Rain Gauge Network
Authors: Hong Yang , Gochis David , Cheng Jiang-tao , Hsu Kuo-lin , Sorooshian Soroosh
Published: June 2007

Robust validation of the space–time structure of remotely sensed precipitation estimates is critical to improving their quality and confident application in water cycle–related research. In this work, the performance of the Precipitation Estimation from Remotely Sensed Information using Artificial Neural Networks-Cloud Classification System (PERSIANN-CCS) precipitation product is evaluated against warm season precipitation observations from the North American Monsoon Experiment (NAME) Event Rain Gauge Network (NERN) in the complex terrain region of northwestern Mexico. Analyses of hourly and daily precipitation estimates show that the PERSIANN-CCS captures well active and break periods in the early and mature phases of the monsoon season. While the PERSIANN-CCS generally captures the spatial distribution and timing of diurnal convective rainfall, elevation-dependent biases exist, which are characterized by an underestimate in the occurrence of light precipitation at high elevations and an overestimate in the occurrence of precipitation at low elevations. The elevation-dependent biases contribute to a 1–2-h phase shift of the diurnal cycle of precipitation at various elevation bands. For reasons yet to be determined, the PERSIANN-CCS significantly underestimated a few active periods of precipitation during the late or “senescent” phase of the monsoon. Despite these shortcomings, the continuous domain and relatively high spatial resolution of PERSIANN-CCS quantitative precipitation estimates (QPEs) provide useful characterization of precipitation space–time structures in the North American monsoon region of northwestern Mexico, which should prove useful for hydrological applications.
Simulation and Projection of Arctic Freshwater Budget Components by the IPCC AR4 Global Climate Models
Authors: Kattsov Vladimir M. , Walsh John E. , Chapman William L. , Govorkova Veronika A. , Pavlova Tatyana V. , Zhang Xiangdong
Published: June 2007

The state-of-the-art AOGCM simulations have recently (late 2004–early 2005) been completed for the Intergovernmental Panel on Climate Change (IPCC) in order to provide input to the IPCC’s Fourth Assessment Report (AR4). The present paper synthesizes the new simulations of both the twentieth- and twenty-first-century arctic freshwater budget components for use in the IPCC AR4, and attempts to determine whether demonstrable progress has been achieved since the late 1990s. Precipitation and its difference with evapotranspiration are addressed over the Arctic Ocean and its terrestrial watersheds, including the basins of the four major rivers draining into the Arctic Ocean: the Ob, the Yenisey, the Lena, and the Mackenzie. Compared to the previous [IPCC Third Assessment Report (TAR)] generation of AOGCMs, there are some indications that the models as a class have improved in simulations of the Arctic precipitation. In spite of observational uncertainties, the models still appear to oversimulate area-averaged precipitation over the major river basins. The model-mean precipitation biases in the Arctic and sub-Arctic have retained their major geographical patterns, which are at least partly attributable to the insufficiently resolved local orography, as well as to biases in large-scale atmospheric circulation and sea ice distribution. The river discharge into the Arctic Ocean is also slightly oversimulated. The simulated annual cycle of precipitation over the Arctic Ocean is in qualitative agreement between the models as well as with observational and reanalysis data. This is also generally the case for the seasonality of precipitation over the Arctic Ocean’s terrestrial watersheds, with a few exceptions. Some agreement is demonstrated by the models in reproducing positive twentieth-century trends of precipitation in the Arctic, as well as positive area-averaged P–E late-twentieth-century trends over the entire terrestrial watershed of the Arctic Ocean.

For the twenty-first century, three scenarios are considered: A2, A1B, and B1. Precipitation over the Arctic Ocean and its watersheds increases through the twenty-first century, showing much faster percentage increases than the global mean precipitation. The arctic precipitation changes have a pronounced seasonality, with the strongest relative increase in winter and fall, and the weakest in summer. The river discharge into the Arctic Ocean increases for all scenarios from all major river basins considered, and is generally about twice as large as the increase of freshwater from precipitation over the Arctic Ocean (70°–90°N) itself. The across-model scatter of the precipitation increase for each scenario is significant, but smaller than the scatter between the climates of the different models in the baseline period.
A Gauge-Based Analysis of Daily Precipitation over East Asia
Authors: Xie Pingping , Chen Mingyue , Yang Song , Yatagai Akiyo , Hayasaka Tadahiro , Fukushima Yoshihiro , Liu Changming
Published: June 2007

A new gauge-based analysis of daily precipitation has been constructed on a 0.5° latitude–longitude grid over East Asia (5°–60°N, 65°–155°E) for a 26-yr period from 1978 to 2003 using gauge observations at over 2200 stations collected from several individual sources. First, analyzed fields of daily climatology are computed by interpolating station climatology defined as the summation of the first six harmonics of the 365-calendar-day time series of the mean daily values averaged over a 20-yr period from 1978 to 1997. These fields of daily climatology are then adjusted by the Parameter-Elevation Regressions on Independent Slopes Model (PRISM) monthly precipitation climatology to correct the bias caused by orographic effects. Gridded fields of the ratio of daily precipitation to the daily climatology are created by interpolating the corresponding station values using the optimal interpolation method. Analyses of total daily precipitation are finally calculated by multiplying the daily climatology by the daily ratio.

Cross-validation tests indicated that this gauge-based analysis has high quantitative quality with a negligible bias and a correlation coefficient of ∼0.6 for comparisons between withdrawn station data and the analysis at a 0.05° latitude–longitude grid box. The quality of the analysis increases with the gauge network density. The mean distribution and annual cycle of this new gauge analysis present similar patterns but with more detailed structures and slightly larger magnitude compared to other published monthly gauge analyses over the region.

The East Asia gauge analysis is applied to verify the performance of five satellite-based precipitation estimates. This examination reveals the regionally and seasonally dependent performance of the satellite products with the best statistics observed for relatively wet regions. Further improvements of the daily gauge analysis are underway to increase the gauge network density and to refine the algorithm to better deal with the orographic effects especially over South and Southeast Asia.
Kinship and Social Networks: A Regional Analysis of Sibling Relations in Twentieth-Century Netherlands
Authors: Bras Hilde , Theo van Tilburg
Published: June 2007

Given the paucity of information on historical kin relations, this study uses survey data in order to investigate how different family forms influenced the size and composition of social networks and the relationships among elderly siblings born in farming families between 1903 and 1937 in three regions of the Netherlands. In the area with stem families, impartible inheritance, and a custom of neighbor help, social networks are largest and contain the most siblings. Multilevel analyses show that even when controlling for other factors, this particular family form positively affects contact frequency in sibling relationships. Our results not only show the persistence of differential kinship values, but since respondents' networks were linked back to their families of socialization in the early twentieth century, findings also reflect regional disparities in kin relations in the past.
Relationship of Abuse History to Functional Gastrointestinal Disorders and Symptoms
Authors: Leserman Jane , Drossman Douglas A.
Published: June 2007

The primary goals of this article are to review the evidence that links sexual and physical abuse and intimate partner violence (IPV) with functional gastrointestinal (GI) symptoms and disorders and to explore physiological mechanisms that might mediate these health effects. The literature cited in this review has shown strong and consistent relationships of sexual and physical abuse history and IPV with functional GI symptoms and disorders. Among patients with these disorders, abuse history is associated with worse health-related quality of life, more health care utilization, and more pain. Although research has not determined what mechanisms might account for these associations, alterations in psychophysiological and cortico-limbic pain modulatory systems have been suggested. Given the high prevalence of abuse and long-lasting health consequences, referral for psychiatric and psychological treatment makes sense for many patients with abuse history seen within medical settings.
Overlooked But Critical
Authors: Banks Martha E.
Published: June 2007

Despite evidence that more than 80% of female victims of intimate partner violence, seen for medical treatment of violence-related injuries, have sustained facial injuries, traumatic brain injury is often overlooked as a consequence of those injuries. This article reviews the scant literature available and examines research on equivalent injuries sustained by athletes. Practical domains of symptoms are described, as is a review of literature pertinent to culturally relevant rehabilitation for victims sustaining traumatic brain injuries.
Acute Injury Patterns of Intimate Partner Violence Victims
Authors: Sheridan Daniel J. , Nash Katherine R.
Published: June 2007

Although millions of women receive injuries from intimate partner violence (IPV) each year in the United States alone, there has been only limited research of acute injury patterns and the types, locations, and mechanisms of IPV injuries. The mechanism of being punched to the face with a fist resulting in blunt trauma—related injuries is most commonly reported. Strangulation, especially manual strangulation, is a frequently cited mechanism of injury; however, less is known about the types of injuries that result from strangulation. In general, clinicians should assess all patients who present for treatment of head, neck, and face injuries for IPV. There is little consistency between and much inaccuracy with medical terms used to describe types of injuries. To increase the accuracy and generalizability of findings from studies of acute IPV injuries, researchers need to use more standardized medical forensic terminology.
Violence Against Women and the Perinatal Period
Authors: Kendall-Tackett Kathleen A.
Published: June 2007

Violence against women affects millions of women, including women who are pregnant or have recently given birth. During pregnancy, a woman's history of past abuse increases her risk of depression and posttraumatic stress disorder. And these increase the risk of pregnancy and neonatal complications. Women who have experienced past or current abuse are also at high risk for postpartum depression, which can affect their relationships with other adults and their babies. Violence against women can also affect women's ability to breastfeed, although abuse survivors often express an intention to breastfeed and are more likely to initiate breastfeeding than their nonabused counterparts. Current abuse, depression, posttraumatic stress disorder, social isolation, lack of social support, and cessation of breastfeeding all have negative health effects for mothers and babies.
The tyrosine kinase FES is an essential effector of KITD816V proliferation signal
Authors: Voisset Edwige , Lopez Sophie , Dubreuil Patrice , De Sepulveda Paulo
Published: June 2007

KIT is a tyrosine kinase receptor that is aberrantly activated in several neoplasms. In human pathologies, the most frequent mutation of KIT occurs at codon 816. The resulting KIT mutant protein is activated in the absence of ligand and is resistant to the clinically available inhibitors of KIT. In this report, we provide evidence for an essential function of the cytoplasmic tyrosine kinase FES downstream of KITD816V. FES is phosphorylated on tyrosine residues in cells that carry KITD816V mutation, and this phosphorylation is KIT dependent. Reduction of FES expression using RNA interference results in decreased cell proliferation in human or murine cells harboring KITD816V or the homologous mouse mutation KITD814Y. The reduced cell growth can be rescued using another cytokine (granulocyte-macrophage colony-stimulating factor [GM-CSF]) and is not observed when the closely related fer gene is targeted. Finally, signaling downstream of KITD816V is altered in cells lacking FES expression. This study shows a major function of FES downstream of activated KIT receptor and thereby points to FES as a novel target in KIT-related pathologies.
Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning
Authors: Kahl Christoph , Storer Barry E. , Sandmaier Brenda M. , Mielcarek Marco , Maris Michael B. , Blume Karl G. , Niederwieser Dietger , Chauncey Thomas R. , Forman Stephen J. , Agura Edward , Leis Jose F. , Bruno Benedetto , Langston Amelia , Pulsipher Michael A. , McSweeney Peter A. , Wade James C. , Epner Elliot , Bo Petersen Finn , Bethge Wolfgang A. , Maloney David G. , Storb Rainer
Published: June 2007

Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies depends on graft-versus-tumor effects for eradication of cancer. Here, we estimated relapse risks according to disease characteristics. Between 1997 and 2006, 834 consecutive patients (median age, 55 years; range, 5-74 years) received related (n = 498) or unrelated (n = 336) HCT after 2 Gy total body irradiation alone (n = 171) or combined with fludarabine (90 mg/m2; n = 663). Relapse rates per patient year (PY) at risk, corrected for follow-up and competing nonrelapse mortality, were calculated for 29 different diseases and stages. The overall relapse rate per PY was 0.36. Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) in remission (CR), low-grade or mantle cell non-Hodgkin lymphoma (NHL) (CR + partial remission [PR]), and high-grade NHL-CR had the lowest rates (0.00-0.24; low risk). In contrast, patients with advanced myeloid and lymphoid malignancies had rates of more than 0.52 (high risk). Patients with lymphoproliferative diseases not in CR (except Hodgkin lymphoma and high-grade NHL) and myeloid malignancies in CR had rates of 0.26-0.37 (standard risk). In conclusion, patients with low-grade lymphoproliferative disorders experienced the lowest relapse rates, whereas patients with advanced myeloid and lymphoid malignancies had high relapse rates after nonmyeloablative HCT. The latter might benefit from cytoreductive treatment before HCT.